Applications of oxazolidinones as chiral auxiliaries in the asymmetric alkylation reaction applied to total synthesis

Abstract

Various chiral oxazolidinones (Evans’ oxazolidinones) have been employed as effective chiral auxiliaries in the asymmetric alkylation of different enolates. This strategy has been found promising and successful when used as the key step (steps) in the total synthesis of several biologically active natural products. In this report, we try to underscore the applications of oxazolidinones as chiral auxiliaries in asymmetric alkylation, and particularly in the crucial chiral inducing steps in the total synthesis of natural products that show biological activities. Chiral auxiliaries are generally considered reliable compounds with well-known configurations, enabling and controlling the synthesis of a large number of enantiomerically pure compounds in a time-efficient manner. Consequently, the use of chiral auxiliaries are frequently considered a method of choice in the early phases of drug discovery.

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Majid M. Heravi

Majid M Heravi was born in 1952 in Mashhad, Iran. He received his B. Sc. degree from the National University of Iran in 1975 and his M. Sc. and Ph. D. degrees from Salford University, England in 1977 and 1980, respectively. He completed his doctoral thesis under the supervision of the late Jim Clarck in Salford University, England. He started his career as a research fellow in Daroupakhsh (a pharmaceutical company) in 1981 Tehran, Iran and joined as an assistant professor to Ferdowsi University of Mashhad, Iran in 1983 and was promoted to associate professor in 1993 and full professor in 1997 in the aforementioned university. In 1999 he moved to Alzahra University of Tehran, Iran as professor of chemistry where he still works. He has previously been a visiting professor at UC Riverside, California, USA and Hamburg University, Hamburg, Germany. His research interests focus on heterocyclic chemistry, catalysis, organic methodology and green synthetic organic chemistry.

Vahideh Zadsirjan

Vahideh Zadsirjan was born in Shiraz, Iran in 1979. She received her B. Sc. in Pure Chemistry from Tarbiat Moalem University in 2002. Then, she obtained her M. Sc degree in organic chemistry under the supervision of Professor Majid M. Heravi at Alzahra University, Tehran, Iran in 2007. She is currently working towards her Ph. D in organic chemistry at Alzahra University under the supervision of Professor Majid M. Heravi. Her research interest is focused on heterocyclic chemistry, catalysis and organic methodology.

Behnaz Farajpour

Behnaz Farajpour was born in 1990 in Guilan, Iran. She received her B. Sc. degree from Guilan University, Iran in 2012 and her M. Sc. degree from Alzahra University, Tehran, Iran in 2015 under the direction of Dr Morteza Shiri. Her research interests focused on synthesis of novel heterocycles via multicomponent reactions.

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1. Introduction

A significant goal in organic synthesis is to achieve a valuable enantiopure compound, starting from commercially and readily available starting materials. Nowadays, it has been realized that asymmetric synthesis is the best approach for the enantioselective synthesis of desired targets, especially those showing biological activities.¹ To achieve asymmetric synthesis, various protocols have been developed to induce stereoselectivity in a reaction. Among them, a certain kind of compound, the so-called chiral auxiliary, chiral reagent, chiral media and above all, a chiral catalyst is commonly used. The chiral auxiliary is actually an enantiopure chiral molecule which temporarily attaches to the substrate to induce chirality to the resulting compound. The employment of chiral auxiliaries in the asymmetric reactions is as necessary and important as protection and deprotection in multi-step organic synthesis. In a similar way, the chiral auxiliary is attached to an appropriate substrate to play its role, which is inducing chirality to the product, and is then removed, usually in the final step of the reaction pathway. Nevertheless, dissimilar to protecting groups, which are often passive partners in a reaction, a chiral auxiliary is an effective and powerful way to induce chirality with a high stereoselectivity as desired in the target molecule. A good chiral auxiliary should be readily removable under mild conditions. This permits for elusive functionality elsewhere in the molecule without protection. Besides, the selected removal procedure must be all-purpose and wide-ranging, proceed smoothly and cleanly, and give the products in satisfactory yields. The chiral auxiliary also should not destroy the newly generated chiral center as well as other stereogenic centers already fixed in the precursor. The chiral auxiliary, especially those that are synthetic or modified are not usually readily available or if they are commercially available, they are expensive. Thus, the recyclability and reusability of the chiral auxiliary is very important and should be considered when the synthetic strategy for a total synthesis is designed.

In fact, the introduction of effective chiral auxiliaries has had a great effect on the progress and growth of asymmetric synthesis. Most chiral auxiliaries have been derived from natural sources such as amino acids, carbohydrates, terpenes, etc. They can be used as they were when isolated or after some structural modifications. However, to induce high levels of chirality and give satisfactory yields, they should be used in stoichiometric quantities. A very common chiral auxiliary employed in several, highly effective asymmetric reactions are amino alcohols, these are derived from the corresponding naturally occurring α-amino acids. A literature survey shows that many new chiral auxiliaries have been developed in the early 1990s, most of them being involved in enolate chemistry. They are mostly new derivatives of oxazolidinone, imidazolidinone, oxazoline, ephedrine, camphor, sugar derivatives, etc.

In general, chiral auxiliaries are regarded as reliable compounds with well-determined configurations, inducing chirality and controlling the synthesis of a large number of enantiomerically pure compounds in a time-efficient fashion. Consequently, in spite of not being a method of choice nowadays, the use of chiral auxiliaries were frequently considered in the early periods of drug development.

Asymmetric synthesis using chiral auxiliaries has attracted much attention and experienced outstanding progress over the past few decades. It has been found that in spite of the stoichiometric requirements, auxiliary-controlled reactions are still powerful tools in the construction of complex molecules, especially in their chiral inducing stage.^2,3 The market availability and ready accessibility of the starting materials along with the facile and versatile cleavage⁴ as well as their applicability and consistency in a wide range of stereoselective transformations results in the superiority of chiral auxiliaries as outstanding and distinct intermediates in asymmetric synthesis.

Only a few chiral auxiliaries fulfil these imperative requirements. Probably, the most suitable and common chiral auxiliaries, which meet nearly all these required criteria, are oxazolidin-2-ones, the so called Evans’ 2-oxazolidinones. Initially, it was discovered and presented by Evans and coworkers in 1981 (ref. 5) and since then, a large number of structural modifications of these auxiliaries have been accomplished and reported.^6–14 These readily available, powerful and easily removable auxiliaries have been employed in various asymmetric syntheses and have been shown to be effective in the highly stereoselective formation of a wide range of carbon–carbon and carbon–heteroatom bonds leading to the synthesis of complex molecules. Numerous highly diastereoselective reactions including asymmetric aldol reactions, alkylations, cycloadditions, Michael additions, aminations, azidations, brominations, hydroxylations, Diels–Alder reactions, and 1,4-conjugate additions have been successfully accomplished, using diverse Evans chiral oxazolidinones as chiral auxiliaries.^15–19 They are derived from the corresponding α-amino acids. They are the most popular auxiliaries for the conduction of efficient asymmetric syntheses, being frequently used for stereoselective C–C and C–X (X = O, N, Br, F, etc.) bond formation. Many reviews and reports have attractively collected and summarized the scope of Evans’ oxazolidinone systems for the stereoselective formation of carbon–carbon bonds.^20–22 To extend the chemistry of oxazolidinones, originally introduced by Evans and coworkers, several modified derivatives have been presented during the years and employed in various asymmetric synthesis. Useful and invaluable reviews on the applications of oxazolidin-2-ones as chiral auxiliaries in asymmetric synthesis have been published over the years.^22–26 Among these reports, the review article published in 1997 by Cowden and Paterson presents an outstanding collection of fruitfully applied oxazolidinone based chiral auxiliaries.²⁰ In spite of the introduction of a plethora of oxazolidinone derivatives, the basic principles that govern the induction of chirality and stereocontrol of the reaction with these derivatives used as chiral auxiliary are basically the same as with the original Evans’ auxiliary. However, they have their own merits and drawbacks in inducing and controlling chirality in specific reactions. Most naturally, occurring compounds and pharmaceutical targets exist as one of two possible enantiomers in an optically pure form. As a result, the total synthesis of natural products and pharmaceutical agents should be designed in a way to obtain the desired target in an enantiomerically pure form.²⁷ The use of chiral auxiliaries is one of many approaches realized and understood by synthetic chemists for the synthesis of the desired enantiopure stereoisomer.¹

We are interested in the asymmetric synthesis^28–34 and total synthesis of natural products.^35–40 Recently, we have published a report concerning the applications of oxazolidinones as chiral auxiliaries in the total synthesis of natural products.⁴¹ However, due to the plentiful work done in several laboratories worldwide, resulting in numerous publications and limitations of space, we have restricted ourselves to cover only the applications of oxazolidinones in asymmetric aldol reactions.⁴¹ Due to this self-limitation, as a complement to our previous work,⁴¹ herein, we wish to report the applications of oxazolidinones in asymmetric alkylation leading to a highly stereoselective alkylation of enolates leading to the total synthesis of various natural products, preferably, those showing remarkable biological activities. In this report, we try to reveal the usefulness of oxazolidinones employed as a chiral auxiliary in an essential asymmetric alkylation, in one or more decisive steps for the total synthesis of some natural and complex targets. We feel obliged to mention that a review concerning the applications of oxazolidinones as chiral auxiliaries in the asymmetric 1,4-addition in the total synthesis of natural products will be published separately.

2. Applications of oxazolidinones as chiral auxiliaries in the asymmetric synthesis: an overview

Generally speaking, asymmetric synthesis is a selective synthesis of one enantiomer or diastereomer form of an optically active compound. It is an ever growing important strategy in modern synthetic organic chemistry particularly in the total synthesis of biologically active natural products.⁴² In general, there are two strategies for the synthesis of enantio- and diastereomeric pure organic compounds. The first approach is to employ a resolution step, a so-called racemic modification. A second strategy, the so-called asymmetric synthesis is simply to start from an enantiomerically pure substrate, reagent, solvent or catalyst. These starting materials are often chosen from commercially available or readily accessible natural products, or their modified derivatives, obtained from the so-called “chiral pool,” for instance amino acids, saccharides, small terpenes. Commercially available chiral amino alcohols reacted with phosgene^43,44 are also frequently used for this purpose.

Undoubtedly, the superior method from different points of view for the preparation of enantiomerically pure compounds is asymmetric catalysis. In this methodology, a catalytic quantity of an enantiomerically pure (or enriched) agent is employed to provide an asymmetric environment in the transition state of a reaction, which results in the selective formation of one enantiomer of the product. This catalytic asymmetry has a high effectiveness, leading to an overall augmentation of asymmetry in the reacting system. Furthermore, a protocol that leads to a successful asymmetric synthesis involves using an appropriate compound, the so-called chiral auxiliary. Chiral auxiliaries are generally reliable and versatile, enabling the synthesis of a large number of enantiomerically pure compounds in a time-efficient fashion. Therefore, chiral auxiliaries have been used in the early phases of drug development.²

In an asymmetric synthesis, a suitable chiral auxiliary with well-established absolute configuration is initially assembled, provisionally by covalently bonding onto a compound, which can be used as a precursor in a chiral inducing step. In this approach, an ideal asymmetric synthesis should proceed with high stereoselectivity and must have highly predictable diastereoselectivity. Significantly, through using this approach in this step; an undesired diastereomer can be removed by an appropriate conventional method. Ultimately, the temporary directing segment is cleaved to afford the desired enantiomerically pure compound. Ideally, the liberated chiral auxiliary, should be directly recycled. However, some chiral auxiliary should be chemically modified after recovery for efficient recyclability.

Contrary to catalyzed asymmetric synthesis, using chiral auxiliaries is a relatively mature science. Several chiral auxiliaries have been developed and introduced to different substrates that in general are highly predictable in terms of efficiency, level, logical in their asymmetric induction, and other practical considerations. A good chiral auxiliary must be (a) commercially available or readily accessible in both enantiomeric forms, (b) rapid and easy to prepare, (c) easy to install, (d) give high levels of asymmetric induction, (e) easy to remove and (f) recyclable. It should give a high level of diastereocontrol. The obtained diastereomers can be separated by conventional methods such as chromatography, crystallization and the logic of its asymmetric induction can be determined by X-ray crystallography.

It should be noted that use of chiral auxiliaries may experience some draw backs such as (a) both enantiomers of auxiliary neither being commercially available, nor readily accessible, thus needing to be synthesized via difficult reaction approaches (b) similar to protection and deprotection, extra steps should be added to the multi-step reactions leading to decreases yields of the desired products. Assemblage and removal are also required (c) a stoichiometric quantity of chirality is required.

Chiral auxiliaries were first discovered and introduced by E. J. Corey in 1975,⁴⁵ using chiral 8-phenylmenthol followed by the discovery of chiral mandelic acid by B. M. Trost.⁴⁶ As menthol is difficult to synthesize, trans-2-phenyl-1-cyclohexanol was introduced by J. K. Whitesell in 1985 as an alternative.⁴⁷ Undoubtedly, the most efficient and frequently used chiral auxiliaries with prevalent applications are the chiral oxazolidinones developed and reported by David Evans.¹ Oxazolidinones are a class of compounds containing 2-oxazolidone. In their structures, 2-oxazolidone is a heterocyclic compound containing both nitrogen and oxygen in a 5-membered ring. They are usually prepared from chiral natural amino acids.^{43,44,48–52} Evans’ chiral auxiliaries usually react with acid chloride to form an imide. Substituents at the 4 and 5 positions of the oxazolidinones direct any aldol reaction to the alpha position of the carbonyl of the substrate. They have been used in the asymmetric synthesis of a wide variety of enantiomerically pure derivatives.

2.1. In the alkylation of enolates

One of the best realized and most popular reactions of acylated Evans’ oxazolidinones is diastereoselective alkylation. In spite of the advantages realized for asymmetric catalysis, organic synthetic chemists frequently turn to Evans’ methodology, especially when optically pure carboxylic acid derivatives are required as final products or as intermediates. Although it is not as graceful as asymmetric catalysis, the applications of chiral auxiliaries remains a very significant and frequently used strategy for asymmetric synthesis. In this line, the total synthesis of cytovaricin by Evans and coworkers is considered as a classic application of oxazolidinones as chiral auxiliaries for one asymmetric alkylation and four asymmetric aldol reactions required to settle the absolute configuration of nine stereogenic centers present in the aforementioned natural products.⁵³ Since then, Evans’ oxazolidinones are the most well-known and frequently used chiral auxiliaries for the stoichiometric asymmetric approach in the total synthesis of natural products.⁵⁴ The most conventional applications of Evans’ oxazolidinones are α-alkylation and syn-aldol reactions, which can provide either enantiomers or diastereomers containing susceptible function groups for further functionalization. In addition, Evans’ oxazolidinones owe their popularity to their reliable and readily scalable reaction procedures. Furthermore Evans’ oxazolidinones are applicable in asymmetric anti-aldol reactions, Michael addition, the addition to C=O and C=N bonds and cycloaddition etc.^15,16 It is observed that the steric hindrance of substituents at 4 and 5 positions of oxazolidinones control the stereoselectivities of many alkylations of enolates.

As an extension to the original oxazolidinones, a plethora of modified derivatives have been developed over the years and find applications in asymmetric synthesis. A pool of fruitfully applicable oxazolidinones based on these modified chiral auxiliaries has been collected in an informative review presented by Cowden et al.²⁰ The first step reaction for oxazolidinone acting as a chiral auxiliary in an asymmetric synthesis is the attachment of an appropriate substrate to the selected oxazolidinone derivative, which is commonly accomplished via an N-acylation reaction using n-BuLi as a base and an acid chloride or anhydride (mixed or symmetrical) as the acetylating agents.⁵⁵ The utilization of chiral N-acyloxazolidinone auxiliaries to control configuration of the generated stereogenic centers has found extensive applications in several reactions (Scheme 1).^22,24

Scheme 1

An efficient and facile approach for the N-acylation without observation of epimerization was achieved and reported by David Ager et al.⁵⁶ In addition, the alkylation of lithium, sodium, and potassium enolates derived from N-acyloxazolidinones was successfully achieved for the preparation of many chiral frameworks. Noticeably, the reaction is in general limited to a very few reactive alkylating agents, for instance allyl and benzyl halides.⁵⁷

Over the years, remarkable progresses in enolate chemistry has been realized and it has been proven to be a powerful tool, mostly in asymmetric carbon–carbon and C–X (X = hetero atom) bond formations.

One of the most common and famous reactions is the aldol reaction in which the enolate chemistry plays a key role. Two useful reviews revealing different aspects and issues of the aldol reaction have been presented by Cowden and Paterson²⁰ and by Nelson.⁵⁸ Cowden and Paterson collected and described auxiliary-, substrate and ligand-mediated stereo- and enantioselective aldol reactions¹ whereas Nelson summarized the catalytic, enantioselective aldol reaction employing chiral Lewis acids and bases.⁵⁸

During the years, chemists have developed various protocols to create regioselective (kinetic vs. thermodynamic) as well as generate enolates stereoselectively. Parameters that govern these controls are presented in reviews.^20,59–61 Under kinetic conditions, two stereoisomers, known as Z-(5) or E-enolates 6 are obtained via the enol ether which was generated from the keto derivative 4. Each isomer then can react with the electrophile (Re -or Si-face attack) to provide two different products 7 and 8. There are several parameters and factors that control the stereoselective formation of the enol ether. Subsequently the stereoselective enol generated by the π-face attacks the electrophile selectively. Generally, enolate geometry plays the key role in determining the stereochemical result of the aldol reaction, which is believed to proceed via a cyclic transition state. Z-Enolate, 5 reacts with an aldehyde to produce 1,2-syn products 10 or 12, while 1,2-anti products 14 or 16 are obtained from an E-enolate. Now it is well realized that the reaction proceeds via a six-membered cyclic transition state, suggested by Zimmerman (only favored transition states are illustrated, see: 9, 11, 13 and 15) in which the alkyl group of the aldehyde derivative espouses a pseudo equatorial position. In cases of 1,2-syn 10 and 12, or 1,2-anti 14 and 16 aldol products, the enantioselectivity can be achieved via a chiral auxiliary or a chiral ligand based enolate (Schemes 2–4).

Scheme 2

Scheme 3

Scheme 4

Evans, the pioneer, described that Z-enolates were often generated with excellent selectivity and then the electrophiles have a tendency to attack from the opposite face to the chiral controlling group at C₄ position of oxazolidinone ring.⁵⁷ The high to excellent diastereoselectivity of oxazolidinone as a chiral auxiliary in alkylation reactions has been realized and well-established. The model shown in Scheme 5 consistently assigns an example and the configuration of the major product.

Scheme 5

In the presence of Evans’ oxazolidinones, the transition states for alkylation are not energetically equivalent, thus they are diastereomeric, leading to asymmetric alkylation (Scheme 6).

Scheme 6

Bulky isopropyl groups block the attack of the electrophile from the bottom face; therefore, the attack takes place from the top face (Scheme 7).

Scheme 7

Evans’ oxazolidinone approach to α-alkylation of carbonyl compounds was a keystone of modern asymmetric synthesis (Scheme 8).

Scheme 8

Diastereoisomeric ratios have been measured by (i) HPLC, (ii) GC or (iii) ¹H NMR. Diastereomers are separated by common methods (chromatography or crystallization). This reaction affords a single diastereomer, upon the removal of the chiral auxiliary affording a single enantiomer, the acid 22 as the product in 88% ee (Scheme 9).

Scheme 9

The origin of the high diastereoselectivity, in which only one enolate geometry (cis) generated can be attributed to (I) chelation of Li to the carbonyl of the auxiliary and (II) minimization of steric interactions as H prefers to take the position eclipse to i-Pr group instead of Me eclipsing i-Pr group. In addition, the large i-Pr group safeguards only one face of the enolate (Scheme 10).

Scheme 10

Szpilman et al. in 2015 reported the first example of highly stereoselective umpolung alkylation of Evans’ β-ketoimides. Umpolung alkylation of Evans’ auxiliary substituted β-ketoimides provides the diastereomerically pure products in 40–80% yields.⁶² The reaction proceeds with diastereoselectivities between 3 : 1 and 18 : 1. Umpolung of the β-ketoimide enolate was observed when dialkylzinc used as the nucleophile, along with the action of Koser’s reagent. This reaction actually relies on the oxidative umpolung alkylation of β-ketoimides 37 under mild conditions. In fact, this achievement solved the long-standing challenge of stereoselective alkylation of Evans’ β-ketoimides and it is an invaluable alternative to the conventional acylation chemistry intellectually developed by Evans and his coworkers. Remarkably, these β-keto-imides, under neutral mild basic conditions have been found to be configurationally stable.⁶³ These compounds are very popular as scaffolds in the total synthesis of naturally occurring products,⁶³ pharmaceutical agents,⁶⁴ and also in the synthesis of chiral frameworks.⁶⁵ In practice, methylation of β-ketoimide 29 or 30 using dimethyl zinc in the presence of Koser’s reagent 31 proceeded smoothly, resulting in the corresponding methylated compounds 32 and 34, in satisfactory yields and good stereoselectivity (Scheme 11). Notably, no tosylation products were isolated from these experiments. The relative stereochemistry of 33, which was synthesized as above, determined by X-ray analysis of crystals of the chief diastereoisomer. Relying on the known S-configuration of the starting material 29 the configuration of the new chiral center was determined unambiguously to be (R). It is worthwhile to note that the stereo-induction accomplished is identical to that obtained from Evans’ pioneering work on acylation⁶⁶ in which a completely different bond is formed. This reaction takes place via acylation of an in situ created Z-lithium enolate 35 (Scheme 12).⁶⁷ The present umpolung alkylation gives a product with the same relative configuration. Based on this observation and earlier mechanistic investigations,⁶⁷ it can be suggested that the alkyl group is delivered to the Si face of an incipient Z-iodine(III)-enolate as illustrated in 37.⁶⁷ Noticeably, in compound 37, dipole–dipole interactions are minimized, resulted in an anti-periplanar relationship between the two imide carbonyl groups (Scheme 12), identical to that seen in the X-ray of 33. It means that the nucleophile alkyl zinc delivers the alkyl group to the less shielded face of the enolate. This assumption is in line with the previous mechanistic investigations.⁶⁷

Scheme 11

Scheme 12

In addition, the deprotonation of the α-carbon of an oxazolidinone imide with a strong base i.e., LDA takes place selectively, generating the (Z)-enolate, which can be subjected to stereoselective alkylation.⁶⁸ Upon the stereospecific reaction using an oxazolidinone, the chiral auxiliary was conveniently separated from the product and can be examined for re-use. Notably, two kinds of oxazolidinone cleavage can occur: exocyclic and endocyclic cleavages.¹⁰ Exocyclic cleavage is frequently observed but endocyclic cleavage takes place when the oxazolidinone derived carboximides 38 are carrying a bulky R₁ group (Scheme 13). A wide variety of conversions have been introduced to the facile removal of the oxazolidinone auxiliary. A plethora of reagents i.e., KOH, LiOH, LiBH₄, LiOR, N₂H₄/n-amyl-ONO/NH₄Cl, Cp₂TiCl₂, and Cp₂ZrCl₂ MeONHMe HCl/AlMe have been used for this purpose (Scheme 14).^4,10,19 Very recently, in 2016, a useful discovery concerning the application of sodium borohydride in the reductive removal of Evans’ and other chiral auxiliaries has appeared in the chemical literature.⁴ Remarkably, it has been found that the removal of oxazolidinone auxiliaries occurs with neither racemization nor epimerization and most remarkably the auxiliaries can be readily recovered and reused.

Scheme 13

Scheme 14

2.2. In the total synthesis of natural products

Evans’ oxazolidinones are among the most well established and extensively used chiral auxiliaries for stoichiometric asymmetric methods in total synthesis. The most common applications of oxazolidinones are actually α-alkylation, syn-aldol reactions, and 1,4-addition which construct either the corresponding enantiomers or diastereomers containing flexible function groups for further elaboration. Most importantly, in spite of the general superiority of the catalyzed asymmetric synthesis, Evans’ oxazolidinones are still broadly used as chiral auxiliaries for stoichiometric stereoselective methodology in the total synthesis of some natural products. Significantly, in the crucial and determining step (steps) for the desired induction of chirality to the product and the construction of a stereogenic center that needs to be controlled, this kind of chiral auxiliary is required. The chiral auxiliary in this point can completely preserve or totally invert the configuration in a way to have an identical configuration with that of desired natural product as a target.

Laulimalide 49 was initially isolated from a marine sponge.⁶⁹ In addition to its observed cytotoxicity against the KB cell line,⁷⁰ this macrolide 49 has been an interesting target from the synthetic point of view, for synthetic organic chemists. The synthesis of the C₁–C₁₆ fragment of laulimalide 49 has been accomplished by Nishiyama and coworkers. For providing this fragment in a key step, an asymmetric induction by a chiral oxazolidinone is required. As illustrated in Scheme 15, the C₁–C₁₆ fragment can be obtained by alkylation of the C₃–C₁₁ fragment 50 using allyl iodide 51. The configuration of a newly generated stereogenic center at the C₁₁ position is induced by the Evans’ oxazolidinone strategy. The allyl iodide 51 is coupled with the lithium enolate of 50 to afford the alkylated adduct 52 as the sole alkylated product in 60% yield. Conversion of a carboximide to a methyl group, together with removing of the oxazolidinone auxiliary was productively performed in three steps to obtain 53. After several more steps, this gives the desired target, 49.⁷¹

Scheme 15

An efficient method for the synthesis of Sch 56592 54 which showed improved therapeutic potency relative to Sch 51048 55 as an antifungal agent has been reported.^72,73 There are two strategies for the synthesis of the key (−)-(2R)-cis-tosylate 56 and its (+)-(2S)-enantiomer 65. Saksena et al. reported two approaches for the synthesis of 56 using chiral oxazolidinones provided from (S)-valinol and (R)-phenylalaninol respectively.⁷⁴ In the first route, the acid chloride 60 was provided from allyl alcohol 57 upon treatment with the lithium salt of the (4S)-(−)-4-isopropyl-2-oxazolidinone under standard conditions.⁵⁷ Compound 60 reacted smoothly with the oxazolidinone Li-salt to afford chiral imide 62 in high yields. The benzyloxymethyl functionality was reacted with the lithium enolate of 62 using benzyloxymethyl chloride as the alkylating agent. In spite of the excellent diastereoselectivity observed (98 : 2) for the desired benzyl ether 63, the chemical yields were inappropriately low (30%). Delightfully, when titanium enolates of N-acyloxazolidinones were used, appreciable improvements over Li-enolates regarding the practical simplicity and high diastereoselectivity were realized.^75,76 Therefore, alkylation of 62 with benzyloxymethyl chloride via the Evans’ titanium enolate strategy⁷⁷ afforded the benzyl ether 63 in high chemical yields (>98% de). Reduction of 63 using LAH in THF, afforded the desired (−)-(2S)-diol monobenzyl ether 64 in high yield while simultaneous 80% recovery of the chiral auxiliary was possible. After several steps, the desired (−)-(2R)-cis-tosylate 56 (ref. 77) was obtained in an overall 90% chemical yield and excellent optical purity (>99% ee). The enantiomeric (+)-(2S)-cis-tosylate 65 could be easily prepared via conducting the above sequence using an appropriate chiral auxiliary i.e., (4R)-(+)-4-isopropyl-2-oxazolidinone. Compound 64 was converted into 56 (ref. 78) in two steps. Compound 56 can be transformed to the desired natural product 54 via a multi-step synthesis (Scheme 16).⁷⁴

Scheme 16

An alternative route for the synthesis of 56 to avoid protection–deprotection processes for obtaining higher yields was also considered. The allyl alcohol 57 was provided in four-steps starting from 1,3-difluorobenzene.⁷⁷ On the other hand, through the other route, the olefinic acid 59 can be synthesized in two facile steps, involving Friedel–Crafts reaction of m-difluorobenzene with succinic anhydride to afford the crystalline keto acid 66 in high yield. The keto acid then undergoes a Wittig reaction using two equivalents of methylene triphenyl phosphorane in THF to obtain olefinic acid 59 in satisfactory (60%) yield over two steps. The (R)-phenylalaninol derived chiral imide 62 was provided via activation of 59 by pivaloyl chloride with subsequent in situ treatment of the resulting anhydride with the Li-salt of (4R)-(+)-4-benzyl-oxazolidinone.⁵⁷ High diastereoselectivity of hydroxymethylation of 62 was achieved with s-trioxane using titanium enolate chemistry,⁷⁶ obtaining the aldol product 67 in satisfactory yield. The direct iodocyclization of 67 at ambient temperature gave the desired cis-iodo compound 68 in high diastereoselectivity (cis : trans > 90 : 10, 90% chemical yield). Lithium borohydride reduction of 68 under controlled conditions followed by column chromatography of the obtained, provided the cis-iodoalcohol 69 and recovered (4R)-benzyl-2-oxazolidinone in about 90% and 71% yields respectively. Then direct substitution of iodine in 69 with sodium-triazole afforded the alcohol 70 in 75% yields. This can be converted to the (−)-(2R)-cis-tosylate 56 which in turn can be transformed to the desired natural product 54. Consequently, two steps in the total synthesis were skipped in this manner (Scheme 17).⁷⁴

Scheme 17

Amphidinolides A–Q were isolated from dinoflagellate, genus amphidinium. They exhibited high toxicity against cancer tumor cell lines.⁷⁸ The enantioselective synthesis of the C₁–C₂₈ fragment of this cytotoxic natural product, amphidinolide B1 71, has been accomplished in 13 steps giving the desired target in 3.6% overall yield. The reaction starts with propionyl oxazolidinone 72. The important features of this total synthesis are to make use of oxazolidinone to induce chirality at C₁₁, Sharpless asymmetric epoxidation⁷⁹ for the construction of C₈, C₉-epoxide moiety, the ortho ester along with Claisen rearrangement for the formation of C₆, C₇-trans double bond and an ester functionality at C₃ which is used in the final functional group conversions. Initially, oxazolidinone 72 was treated with 2,3-dibromopropane using the Evans’ strategy to provide the alkylated compound 73 in good chemical yield as a 96 : 4 mixture of diastereomers. Oxazolidinone 73 was then reduced to give the primary alcohol 74. This was converted into the mesylate 75 in two steps in 85% yield. Upon filtration, the chiral oxazolidinone can be recovered. After several steps, the natural product 71 was obtained via intermediate, conjugate ester 76 (Scheme 18).⁸⁰

Scheme 18

The total synthesis of altohyrtin C has been accomplished and reported.⁸¹ Altohyrtin C (spongistatin 2) 77, was initially isolated from marine sponges. This category of compounds often exhibits biological activities.⁸² The reported total synthesis of 77 also confirmed the ambiguous structure assigned to altohyrtin C, which was isolated from spongistatin 2.⁸² The synthesis of the C₈–C₁₅ segment starts with the chiral synthon 79, easily provided from the titanium enolate alkylation of 78 carrying oxazolidinone as a chiral auxiliary.⁷⁶ Subsequent ketal hydrolysis followed by silyl protection gave the C₈–C₁₅ methyl ketone segment 80 in a seven-step reaction in 53% overall yield (Scheme 19).⁸³

Scheme 19

The zoanthamine alkaloids are placed in a family of marine metabolites with an interesting arrangement of structural and stereochemical features.⁸⁴ Zoanthamine 81 has exhibited a potent inhibitory activity against phorbol myristate-induced inflammations. A brief enantioselective synthesis of the enamine–aminal heterocyclic core existing in the zoanthamine alkaloids was reported by Williams et al. in 1998.⁸⁵ The attempted total synthesis began with an enantioselective synthesis of the essential C₁–C₅ amino alcohol segment. As depicted in Scheme 20, Evans’ protocol was employed for asymmetric alkylation of 3 affording the known oxazolidinone 82 (98% de).⁸⁶ Upon iodolactonization, 82 was converted to the trans-disubstituted butyrolactone 83 with excellent diastereoselectivity (ratio > 35 : 1). Under buffered conditions, N-iodosuccinimide (NIS) was generated in situ in accordance with the protocol reported by the Merck Company researchers.⁸⁷ Apparently, the remarkable enhancement in the practical 1,3-asymmertic induction for this kinetic cyclization is caused by iodine to obtain 84.⁸⁸ Then, 84, which was a required intermediate for the total synthesis was transformed into the desired natural product 81 in several steps by manipulating functional group transformations (Scheme 20).⁸⁵

Scheme 20

Upon iodolactonization, 2-methyl-4-pentenoic acid gives the respective cis-butyrolactone isomer with moderate selectivity. Nevertheless, the chiral auxiliary of 82 provides the potential for a (1,3) strain in the transition state 86 (Fig. 1). In this way, nonbonded interactions occur at the iminium ion, which positions the C₄ methyl group in the pseudo-axial position. A decrease to the minimization of 1,3-diaxial interactions led to a pseudo-equatorial orientation for the iodomethyl moiety.⁸⁹

Fig. 1 The transition state 86.

Epothilones 87 (ref. 90 and 91) have interesting biological properties as powerful antifungal and antitumor agents, showing even better microtubule-stabilizing properties than their taxol-like counterpart. Thus, they universally attract tremendous attentions of the organic chemists. Its total synthesis has been achieved and reported.⁹² Chakraborty et al. used samarium(II) iodide for the diastereo- and regioselective ring opening of a trisubstituted epoxy ketone, which is opened from the more substituted carbon. In this way, they reported an alternative strategy to provide the C₅–C₇ aldol moiety with a β-hydroxyketo scaffold in the stereoselective synthesis of the C₁–C₁₂ fragment 90 of epothilones A and B.⁹³ The total synthesis commenced with oxazolidinone 88 to provide the desired target, the mono-benzyl-protected hexane-1,6-diol in three steps. Diastereoselective alkylation of the sodium enolate of 88 carrying oxazolidinone as a chiral auxiliary was achieved using MeI as a methylating agent.⁵⁷ A conventional reduction removed the chiral auxiliary⁹⁴ (80% in two steps) to gave the desired alcohol 89. Ultimately, after several steps, involving functional group transformations, the desired target compound 90 was obtained. The conversion of an intermediate quite similar to 90 has already been reported for the synthesis of epothilone A (Scheme 21).⁹²

Scheme 21

Red algae and marine organisms, which use the Laurencia species for nutrition, can produce a natural product carrying medium ring ethers.⁹⁵ A number of these marine metabolites, including (+)-laurencin 91 as a representative was first isolated from the extracts of Laurencia glandulifera by Irie in 1965.⁹⁶ The stereoselective total synthesis of (+)-laurencin 91 starting from (S)-(+)-4-benzyl-3-benzyloxyacetyl-2-oxazolidinone 92 was accomplished in 18 steps.⁹⁷ The key step in this approach is an asymmetric glycolate alkylation leading to acyl oxazolidinone 98. Another important step is the subsequent ring-closure of olefin metathesis to provide the oxocene core of 91. The synthesis of chiral alcohol 95 started with (S)-(+)-benzyl-3-benzyloxyacetyl-2-oxazolidinone 92.⁹⁸ Alkylation of the sodium enolate of 92 using allyl iodide as alkylating agent afforded acyl oxazolidinone 93 (>98 : 2 ds) (Scheme 22). A conventional reduction removed the chiral auxiliary using lithium borohydride as the reducing agent to afford chiral alcohol 94 in high chemical yields. Upon Swern oxidation⁹⁹, this gave the desired secondary alcohol 95 in 83% yields over two steps (>95 : 5 ds). Having 95 available, everything was ready to examine the key glycolate alkylation-metathesis sequence to obtain the oxocene core of (+)-laurencin. The sodium alkoxide of 95 was alkylated using the sodium salt of bromoacetic acid to afford the acid 96 in 88% yields along with the recovery of 5% of the starting alcohol. Upon treatment with lithiated (S)-(+)-4-benzyl-2-oxazolidinone, 96 gave acyl oxazolidinone 97 in good yield. Reaction of the sodium enolate of 97 with allyl iodide led to asymmetric alkylation to give diene 98 in a short reaction time and good yields (>95 : 5 dr). The usual reduction based removal of the chiral auxiliary from triisopropylsilyl ether 99 using lithium borohydride, provided 90% of the primary alcohol, which was subsequently oxidized under Swern oxidation conditions to furnish the aldehyde 100 in 97% yield. Having aldehyde 100 in hand, the total synthesis of (+)-laurencin only needed the introduction of the (E)-pentenyl side chain followed by the conversion of the protected alcohol at C₁₁ into the alkyl bromide, which should be attempted (Scheme 23).⁹⁷

Scheme 22

Scheme 23

Isolaurallene was isolated from laurencia nipponica yamada collected in Izumihama near Hiroo on the Pacific Coast of Hokkaido by Kurata and his research group. The structures were initially assigned based on spectral data and later approved by single crystal X-ray crystallography.¹⁰⁰ A total synthesis of (−)-isolaurallene used alcohol 108 as an intermediate (Scheme 24).^101,102 Synthesis of 108 started from the diastereoselective alkylation of glycolate oxazolidinones 102 with allyl iodide mediated by NaN(SiMe₃)₂ in THF and at −40 °C to furnish alkylated product 103 in satisfactory yield and excellent diastereoselectivity. The chiral auxiliary was conventionally removed by reduction using NaBH₄, THF–H₂O to give the alcohol 104 in 89% yields. The alcohol 104 was then transformed to highly functionalized glycolate oxazolidinones 105 in several steps, manipulating functional group transformations. The second diastereoselective alkylation involving glycolate oxazolidinones 105 and the allylic iodide 106 was conducted, mediated by NaN(SiMe₃)₂ in THF and toluene at −45 °C to furnish the alkylated product 107 in good yield with excellent diastereoselectivity (>98 : 2). Once again, the chiral oxazolidinone in 107 was conventionally removed using NaBH₄ as the reducing agent in THF–H₂O at 0 °C to furnish alcohol 108 in high yield.

Scheme 24

Epothilone B 109 (ref. 103) exhibits unique microtubule binding affinities and cytotoxity towards tumor cells and multiple drug resistant tumor cell lines.¹⁰⁴ Epothilone B 109, as an active paclitaxel descendant, and the new trans-12,13-acetonide analogue 110 are interesting targets for organic synthetic chemists. An approach towards the total synthesis of this target makes use of two key steps involving the generation of intermediate 120 via the Sharpless asymmetric dihydroxylation reaction and stereoselective Davis’–Evans’-hydroxylation. Mulzer and coworkers accomplished and reported an asymmetric synthesis of the novel trans-12,13-acetonide analogue 110 of epothilone B as well as a highly stereoselective synthesis of epothilone B 109. In a total synthesis of both the aforementioned compounds, an appropriate aldehyde 120 is employed as the starting material.¹⁰⁵ The key segments for the synthesis of 120 are the phosphonium salt 114 (containing C₇–C₁₀) and the aldehyde 115 (containing C₁₁–C₁₆). The already known and provided oxazolidinone 112 (obtained from 111)¹⁰⁶ was first protected as TBS-ether 113, which was transformed into the phosphonium salt 114. After a multi-step synthesis, aldehyde 115 was provided (Scheme 25). The synthesis of the key aldehydes 120 and 121 commenced with a Wittig reaction between 114 and 115 to give the olefin 116, as expected. This was then transformed into the oxazolidinone 117 which was subjected to hydroxylation using the sodium enolate of 117, Davis’ oxaziridine,¹⁰⁷ to furnish 118 with the induction of 92% de at C₁₅. The oxazolidinone moiety in 118 was substituted by the Weinreb’s amide, followed by protection of the 15-hydroxy group as a TBS ether and then the addition of MeLi afforded methyl ketone 119. A sequential reaction, involving an E selective Wittig reaction (E : Z 30 : 1)/selective monodesilylation of the 7-TBS ether/Dess–Martin-oxidation, provided the key intermediate 120. Then, the aldehyde 121 was obtained via multi-step reactions (Scheme 26).¹⁰⁵

Scheme 25

Scheme 26

Notably, aldehyde 120 was converted into 110 after several steps using functional group transformations. In a similar way, aldehyde 121 afforded compound 109 following the procedure reported previously.¹⁰⁸ At last, compounds 109 (ref. 109) and 110 were obtained. Significantly, a highly stereoselective synthesis of 109 and 110 created chiral centers at C₃, C₆, C₁₂, C₁₃, and C₁₅ independently by utilizing external sources of chirality. Notably, centers C₆ and C₇ were determined during the aldol addition via an internal stereo induction. In the asymmetric synthesis of 110, the ratio of induction is 6 : 1, and in the case of 118, is >95 : 5 (Scheme 27).¹⁰⁵

Scheme 27

Leucascandrolide A 122 was initially isolated from the sponge Leucascandra caveolata in 1996 by Pietra and his group.¹¹⁰ This naturally occurring compound shows strong in vitro cytotoxicity against KB and P388 cancer cell lines and is also found to be a potent antifungal, inhibiting the growth of Candida albicans. The total synthesis of the C₁–C₁₃ segment of Leucascandrolide A uses the alcohol 125 as a key intermediate.¹¹¹ 125 was synthesized by alkylation of the titanium enolate of propionyl oxazolidinone 123 with chloromethyl benzyl ether with subsequent conventional reductive removal of the auxiliary in 124 using NaBH₄ as reductive agent and THF–H₂O as the solvent at room temperature in 95% overall yield (Scheme 28).

Scheme 28

Several natural products, such as alkaloids and terpenes, have quaternary carbon centers in their scaffolds. Thus, the synthesis of these kinds of natural products requires the enantioselective generation of the quaternary carbon centers. In this light, the total synthesis of (−)-eburnamonine and (+)-epi-eburnamonine was fruitfully accomplished.¹¹² For the total synthesis, a key chiral compound, i.e. the optically pure 4,4-disubstituted-lactone 131 was used for the stereoselective synthesis of the pentacyclic indole alkaloids¹¹³ (−)-eburnamonine 127 and (+)-epi-eburnamonine 128. To achieve this total synthesis, the diazomalonate 130 was easily synthesized starting from the already known N-butanoyloxazolidinone 128.¹¹⁴ Alkylation of 128 using allyl bromide with subsequent hydrolysis¹¹⁵ followed by reduction afforded the low boiling point, primary alcohol (S)-129. The absolute configuration of 129 was determined via its transformation to the p-methoxybenzyl ether 129. The optical rotation of 129 had the same magnitude but of the opposite sign for the optical rotation of the already structurally elucidated enantiomer.¹¹⁶ Then (R)-129 was converted to 130 as an intermediate for the synthesis of γ-lactone carboxylic acid 131 in two steps. This was used for achieving the total synthesis of (−)-eburnamonine and (+)-epi-eburnamonine (Scheme 29).¹¹²

Scheme 29

PNP405 132, is a known purine nucleoside phosphorylase inhibitor. Due to its pharmaceutical importance, it is produced in the large scale. It can be synthesized via asymmetric alkylation of 133 with bromoaceto nitrile in the presence of LiHMDS in THF at 20 °C to obtain the desired product 134 in high yield and excellent diastereosectivity (>99% de).¹¹⁷ Reductive removal of the Evans’ chiral auxiliary from 134 by NaBH₄ in THF–H₂O at ambient temperature furnished the desired alcohol 135 in excellent yield and >99% ee without observed racemization or any effects of the cyano group. On the contrary, removal of the Evans’ auxiliary via reduction using LiBH₄ or LiAlH₄ resulted in racemization or generation of a complex mixture due to the presence of the cyano group. Alcohol 135 was then transformed to PNP405 132 in a couple of steps (Scheme 30).

Scheme 30

Among the wide variety of amino acids, all of the amino acids found and extracted from any kind of living organisms are α-amino acids. In addition to the 20 essential ones, there are many other α-amino acids, which can be obtained from nature.¹¹⁸ A novel approach for the highly stereoselective synthesis of chiral α-amino acids has been achieved and reported by Chakraborty and coworkers.¹¹⁹ In this approach, the acid functionality was created via oxidation of a hydroxymethyl group introduced by Evans’ protocol in the α-position of the substrate. Then, the amino group can be installed by the amide of the original carboxyl group with the subsequent occurrence of a modified Hofmann rearrangement. The total synthesis began with the chiral oxazolidinone 137. Treatment of 137 with TiCl₄, mediated by diisopropylethylamine (DIPEA) afforded the enolate which reacted with benzyloxymethyl chloride under Evans’ conditions⁷⁶ to give the Bn-protected-hydroxymethyl-substituted intermediate 138 with excellent diastereoselectivity (>98%). The chiral auxiliary¹¹⁵ was then removed using LiOH–H₂O₂ resulting in the generation of an acid 139.¹²⁰ Finally, the desired D-amino acid 136 was obtained as its HCl salt. Remarkably, while L-phenylalanine-based oxazolidinone 137 affords D-amino acids, as claimed, its D-isomer could be similarly employed to obtain the corresponding L-amino acids (Scheme 31).¹¹⁹

Scheme 31

Laulimalide 140 is known as a novel structural lead for cancer therapeutics. It has been recently isolated in trace quantities from Pacific marine sponges.⁷⁰ Interestingly laulimalide also promotes abnormal tubulin polymerization and apoptosis in vitro, with a mode of action very similar to the famous Taxol® but with potentially less susceptibility to multidrug resistance.¹²¹ Due to these impressive biological potencies, it has attracted much attention of the community of synthetic organic chemists. Recently an outstanding strategy for the synthesis of C₂₂ from the groups of Ghosh, Paterson, and Mulzer has been achieved and reported.^122–124 C₂₂–C₂₇ subunit aldehyde 145 is an important intermediate in a total synthesis of (−)-laulimalide 140. It was synthesized via the Swern oxidation of alcohol 144,^125,126 which in turn was provided by the reductive removal of the oxazolidinone auxiliary in 143 using NaBH₄, THF–H₂O, 0 °C in 88% yield. 143 was provided by alkylation of O-allylglycolyl oxazolidinone 141 using methylallyl iodide in mediated by NaN(TMS)₂ in THF to furnish 142 in 85% yield and in 92% de with subsequent ring-closing metathesis of the diene 142 using the Grubbs catalyst in CH₂Cl₂ at 40 °C in satisfactory yield (Scheme 32).¹²⁵

Scheme 32

Cyclic depsipeptides have manifested themselves as a very important and remarkable class of biologically active compounds. They are generally isolated from marine natural products.¹²⁷ The isolation of callipeltin A as a cyclic depsipeptide showing antiviral and antifungal properties isolated from a shallow water sponge of the genus Callipelta was reported by Zampella et al. in 1996.¹²⁸ Callipeltin A has been screened and approved to be a selective and powerful inhibitor of the cardiac sodium/calcium exchanger.¹²⁹ An asymmetric synthesis of the silyl ether of (2R,3R,4S)-3-hydroxy-2,4,6-trimethylheptanoic acid 146 has been achieved and reported.¹³⁰ This synthesis involves the use of oxazolidinone as a chiral auxiliary for both stereoselective alkylation and aldol condensation reactions, which are required in this particular total synthesis.¹³¹ A silyl derivative of (2R,3R,4S)-3-hydroxy-2,4,6-trimethylheptanoic acid 146, a group existing in the cyclic depsipeptide callipeltin A was synthesized starting from L-valine 147 in nine steps. The chiral auxiliary required for the synthesis of ((4S)-4-isopropyl-3-[(2′S)-2′,4′-dimethylvaleryl)]-2-oxazolidinone 151 was actually the corresponding oxazolidinone 149. It was Evans and coworkers who reported the asymmetric alkylation reactions of chiral imide enolates as an operational strategy to the enantioselective synthesis of α-substituted carboxylic acids. Oxazolidinone 149 was synthesized from L-valine 147 in two steps in good overall yields.^132,133 N-Acylation using n-BuLi and 4-methylvaleric acid activated with pivaloyl chloride gave carboximide 150 in high yields. The 2′-position was methylated upon treatment with LDA followed by reaction with iodomethane to give 151 in a satisfactory yield. The absolute configuration of 151 was determined by X-ray crystallographic analysis. Transformation of the carboximide moiety to the desired aldehyde was accomplished via reduction using LiAlH₄ with a subsequent Swern oxidation.^134,135 The unstable aldehyde without further purification underwent the aldol reaction. (2S,3R,4S)-Trimethyl-3-tert-butyldimethylsiloxyheptanoic acid 146 can be transformed in to callipeltin A after several steps (Scheme 33).¹³⁰

Scheme 33

Bongkrekic acid 155 (ref. 136) is produced by the microorganism Pseudomonas cocovenenans. It is a natural toxic antibiotic. Bongkrekic acid 155, a polyene-tricarboxylic fatty acid, has in its structure three pairs of conjugated dienes and two allylic chiral centers. In its total synthesis, the stereocontrolled assembly of this characteristic polyene skeleton, in particular the C₂–C₃ and C₁₈–C₁₉ trisubstituted (Z)-alkenes, is crucial. The oxidation to obtain terminal carboxylic acids is also delicate since the polyene unit might be unstable under harsh conditions.¹³⁷ In this route, the synthesis of the (E)-vinyl borane starts with stereoselective an alkylation of Evans’ oxazolidinone 156 (ref. 57) using (E)-1-tert-butyldiphenylsiloxy-4-iodo-2-butene 157 (ref. 138) as an alkylating agent to afford 158 with excellent diastereoselectivity and in good chemical yield. Upon reductive removing of the chiral auxiliary, the desired alcohol 160 was provided. Ultimately, the alcohol 160 gave the unstable 161 as an intermediate, which directly underwent the next coupling reaction (Scheme 34).¹³⁷

Scheme 34

Macrolide antibiotics antascomicins are the products of fermentation broth of a strain of Micromonospora isolated from a soil sample collected in China.¹³⁹ Antascomicin A shows potent binding affinity to FKBP12 and antagonizes the immunosuppressive effect of FK506. An asymmetric synthesis of the C₁₈–C₃₄ segment of antascomicin A, which is an important key intermediate toward the total synthesis, has been accomplished and reported by Natsugari and coworkers.¹⁴⁰ Installation of the C₂₇–C₃₄ carbocycle moiety was accomplished by catalytic Ferrier carbocyclization and Johnson–Claisen rearrangement, which was transformed to iodide 169 through the Evans’ asymmetric alkylation and Sharpless epoxidation as key transformations. For the elaboration of the C₂₆ and C₂₇ stereogenic centers asymmetric Evans’ alkylation and Sharpless epoxidation were employed. This approach commences with ester 163 and after several steps carboxylic acid 164 is provided. Coupling¹⁴¹ of 164 with (R)-(+)-4-benzyl-2-oxazolidinone 165 gave oxazolidinone 166 in high chemical yield. The C₂₇ methyl group was fruitfully attached via the Evans’ stereoselective alkylation⁵⁷ of 166 under the conventional conditions (NaHMDS, MeI, THF) giving 167 in high chemical yield as a single isomer, proved by the ¹H NMR spectra analysis. Reductive removal of a chiral auxiliary using LiAlH₄ as the reductive agent afforded alcohol 168 which was converted to iodide 169 after several steps (Scheme 35).¹⁴⁰

Scheme 35

Marine cyanobacteria contain a wide range of natural products with different arrays of structures and functional groups.^142,143 They have been an abundant source for new biologically active molecules. The total synthesis of dragonamide has been accomplished and reported.¹⁴⁴ The synthesis of moya 176, which is an intermediate for the total synthesis of dragonamide 170 was commenced from the monoprotection of 1,5-pentanediol 171 and then transformed to ester 172, after several steps. 172 was hydrolyzed using LiOH in THF/H₂O and transformed into the acyl chloride using oxalyl chloride and DMF in CH₂Cl₂, followed by treatment with (R)-4-benzyl-2-oxazolidinone, DMAP and triethylamine, affording imide 173.¹⁴⁵ The α-methylation cleanly and smoothly proceeded following the Evans’ protocol¹⁴⁶ to generate the R-configuration at the newly-formed chiral center in 174. The chiral auxiliary was removed upon treatment of 174 with hydrogen peroxide in aqueous THF, with subsequent acidification to afford the corresponding acid, in excellent yields, which in turn gave ester 175 upon esterification with freshly prepared diazomethane. 175 was then transformed to the free acid 176 after several steps. Acid 176 was then converted to the desired natural product 170 via a sequential multi-step synthesis (Scheme 36).¹⁴⁴

Scheme 36

Male-produced pheromone components of the flea beetle Aphthona flava were initially isolated in 2001.¹⁴⁷ It was identified as (R)-ar-himachalene 177 and synthesized (97.7% ee) from (4-methylphenyl) acetic acid using Evans’ stereoselective alkylation as the key step. Mori et al. reported the synthesis of (R)-ar-turmerone.^148,149 (S)-(+)-ar-Turmerone 182 is recognized as a spice flavor of turmeric.¹⁵⁰ Although, several synthetic approaches have been reported for (±)-182,¹⁴⁸ only a few enantioselective synthesis of (S)-(+)-182 can be found in literature,^{148,151–154} including the approach.¹⁵⁵ Since component 177 has the (R)-configuration, the synthesis of the unnatural (−)-ar-turmerone (R)-182 is required. As shown in Scheme 37, asymmetric synthesis of (R)-182 is achieved via the Evans’ asymmetric alkylation of (S)-4-benzyl-3-(4-methylphenylacetyl)-2-oxazolidinone 179 as an important step to introduce the stereogenic center of (R)-182. Acyl chloride 178, (S)-4-benzyl-2-oxazolidinone is converted to 179, which upon methylation with methyl iodide and treatment with sodium hexamethyldisilazanide (NaHMDS) in THF gives gummy (S)-180.¹⁵⁶ The analysis of the ¹H NMR signals determines the diastereomeric ratio of the products as about 95 : 5. The major isomer was assigned as (S)-180 via the well-known stereochemical outcome of the Evans’ alkylation. Upon reduction with lithium aluminum hydride, (S)-180 afforded oily alcohol (S)-181 in 53% yield over four steps. The enantiomeric purity of (S)-181 showed ee 88%. After several steps, (R)-182 was obtained. Then (R)-ar-turmerone 182 was transformed to (R)-ar-himachalene 177 which was interestingly, dextrorotary in hexane whereas levorotary in chloroform. Impure (75% ee) (R)-3-(4-methylphenyl)butanoic acid crystallized easier than the enantiomerically pure stereoisomer (Scheme 37).¹⁵⁶

Scheme 37

Asymmetric synthesis of ¹⁴C-labeled LY450108 183, a 2-amino-3-(5-methyl-3-hydroxyisoxazol-4-yl)propanoic acid (AMPA) potentiator was accomplished by stereoselective alkylation of 184 with methyl-¹⁴C iodide in the presence of NaHMDS to give the alkylated product 185 in modest yield.¹⁵⁷ The auxiliary in 185 was removed conventionally using NaBH₄ in THF–H₂O at room temperature to provide the desired alcohol 186 in 87% yield. Noticeably, the reduction was found to be chemoselective as the nitro group was untouched under the above conditions. The alcohol 186 was then converted to the target LY450108-[¹⁴C] 183 after several steps (Scheme 38).

Scheme 38

Cyclomarin A 187 is a novel cyclic peptide that was initially isolated from estuarine actinomycete.¹⁵⁸ The total synthesis of (2S,4R)-δ-hydroxyleucine methyl ester, which is the N-dimethyl analogue of an amino acid contained within the macrocycle of cyclomarin A, has been successfully accomplished and reported in 2005.¹⁵⁹ In this total synthesis a combination of Evans’ asymmetric alkylation and Davis’ asymmetric Strecker reaction has been employed. Among a number of asymmetric alkylation conditions examined, Evans’ oxazolidinone strategy was chosen and performed. This method was complementary to the pathway chosen by Wen et al. who used two Evans’ alkylations to fix the stereochemistry of both stereogenic centers.¹⁶⁰ The appropriate propionyl oxazolidinone 3 was provided from (S)-phenylalanine.^55,161 Enolization with the subsequent addition of allyl iodide afforded oxazolidinone 188 as the main diastereomer in 96% de. Under reduction conditions, the chiral auxiliary was removed to afford alcohol 189 and converted to the methyl ester of (2S,4R)-δ-hydroxyleucine after several steps (Scheme 39).¹⁵⁹

Scheme 39

Debromoaplysiatoxin 191 is a bicyclic diolide isolated from the sea hare Stylocheilus longicauda.¹⁶² During the isolation of 191, several other structurally related bioactive metabolites such as oscillatoxin A 192, oscillatoxin D 193 and 30-methyloscillatoxin D 194.^163,164 Debromoaplysiatoxin and oscillatoxin A are mainly recognized as tumor promoters that operate on protein kinase C and have been studied for better understanding of the carcinogenic processes.¹⁶⁵ On the other hand, oscillatoxin D and 30-methyloscillatoxin D are nontoxic metabolites showing an antileukemic activity.¹⁶⁴ An asymmetric synthesis of the C₉–C₂₁ segment of debromoaplysiatoxin and oscillatoxins A and D was designed in 2006. This new strategy involves the cross coupling of titanium enolates from N-acyl-1,3-thiazolidine-2-thiones and dialkyl acetals followed by the selective hydrogenolysis of O-benzyl protective groups. Attention has mainly been paid to the installation of the C₁₂ stereogenic-center. To obtain crystalline products, a stereoselective alkylation of a well-established intermediate employing Evans’ methodology was envisaged and conducted. Hence, the reaction of lithium enolate derived from tert-butyl acetate with iodide 195 afforded ester 196 virtually quantitatively, which was readily converted into the respective carboxylic acid 197. The acylation of (S)-4-benzyl-1,3-oxazolidinone with 197 followed by a stereoselective alkylation using methyl iodide were performed in accordance with routine procedures. The ¹H NMR spectra analysis of the reaction mixture disclosed the presence of a single diastereomer 199 (dr > 97 : 3), which was isolated in 78% chemical yield upon purification by flash column chromatography. The removal of the chiral auxiliary gave alcohol 201 in excellent yield. Thus, the enantiomerically pure alcohol 201 was provided in good yield after five steps. Then, after several steps, the adduct 202 as a benzyl protected derivative of the corresponding anti-aldol intermediate was obtained and used as an intermediate for the synthesis 203, C₉–C₂₁ segment. ¹H NMR spectrum analysis of lactone 203 confirmed the configuration of the C₉–C₂₁ segment (Scheme 40 and 41).¹⁶⁶

Scheme 40

Scheme 41

Antascomicins are produced via the fermentation strain of the genus Micromonospora which was initially isolated from a soil sample collected in China.¹³⁹ Initial screening and evaluations of 204 showed that it could be promising for the treatment of different neuro-degenerative disorders like Alzheimer’s and Parkinson’s diseases.¹⁶⁷ An asymmetric synthesis of the C₁–C₂₁ segment of this natural product, 204 was accomplished, employing a highly stereoselective aldol reaction that constructs the C₁–C₁₇ segment along with a Nozaki–Hiyama–Kishi reaction to couple the obtained segment with the residual C₁₈–C₂₁ fragment. Significantly, the asymmetric synthesis of the C₁–C₁₆ segment 208 can be accomplished using Evans’ oxazolidinone as one of the key steps.¹⁶⁸ In this approach, acid 205 was used for N-acylation of the chiral oxazolidinone 165, followed by the mixed anhydride method¹⁴¹ to give 206 in high yield. Diastereoselective alkylation of the Na-enolate of 206 using MeI as s methylating agent with subsequent reductive removal of the chiral auxiliary under standard conditions afforded the alcohol 207 as the sole isomer in moderate overall yields. Aldehyde 208, as an intermediate for the synthesis of dienone 209 was provided from 207 in several steps. The target, antascomicin A 204 was obtained via a multi-step synthesis using various functional group transformations in a satisfactory overall yield (Scheme 42).¹⁶⁸

Scheme 42

Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear receptor group, including steroids, thyroid, retinoid, vitamin D and other receptors.¹⁶⁹ PPARα regulates the appearance of genes encoding for proteins mixed up in lipid and lipoprotein homeostasis.¹⁷⁰ Enantiometrically, pure (S)-2-ethylphenylpropanoic acid derivatives are dual agonists for human (PPAR) α and δ. Miyachi et al. reported an effective and operational synthetic approach to the enantioriched 2-ethylphenylpropanoic acid derivatives 210a and 210b. They employed the Evan’s stereoselective alkylation and reductive N-alkylation as vital steps.¹⁷¹ In this route, 210 and 210b were synthesized by the route outlined in Scheme 43.¹⁷² This approach suffers from too many reaction steps (seven steps), requiring chromatographic purification of intermediates, and giving low total yield (3% overall yield), as well as being inappropriate for scale-up and pilot plants.¹⁷¹

Scheme 43

Thus, the same authors envisaged an alternative route for the synthesis of 210a, 210b. The N-alkylation of 2-fluoro-4-trifluoromethylbenzamide (or 3-fluoro-4-trifluoromethylbenzamide) using the bromomethyl derivative 215 was performed. Compound 215 was provided by the facile reduction of 211 using the BH₃–THF complex followed by bromination with PPh₃–CBr₄ in 67% yield over two steps. 3-Fluoro-4-trifluoromethylbenzamide was treated with NaH (or LiHMDS, or t-BuOK) and then reacted with 215 to give a mixture containing several compounds, including 216. After direct subjection of the crude to silica gel column chromatography, pure 216 was isolated, albeit in only 15% yield, and an appreciable amount of the starting 3-fluoro-4-trifluoromethylbenzamide was also recovered. Thus, the route starting with a direct N-alkylation was considered insignificant. Recently, an efficient reductive N-alkylation of amides using TFA/Et₃SiH with an aldehyde was reported by Dube et al.¹⁷³ This methodology was examined in the synthesis of 210a, 210b (Scheme 44). Accordingly, a mixture of 2-fluoro-4-trifluoromethylbenzamide, aldehyde 217, triethylsilane and trifluoroacetic acid was refluxed in toluene. Upon completion of this reaction, the desired N-alkylation product 216 was successfully prepared and isolated in 66% yield. The oxazolidinone moiety was removed using LiOH/30% H₂O₂ system⁵⁷ giving desired 210a in high yield. Notably, 210a was provided from 211 in a total yield of about 50% over only three steps. In a similar way, 210b was obtained from 211 in overall yield of around 50% (Scheme 44).¹⁷¹

Scheme 44

Taranabant (MK-0364), 218, is recognized as a cannabinoid-1 receptor inverse agonist and also as an anti-obesity agent. In 2007, Lee et al. reported a relatively convenient total synthesis of 218.¹⁷⁴ An alternative stereoselective synthesis of 218 employing the Evans’ chiral auxiliary protocol has been reported. As depicted in Scheme 45, the total synthesis of taranabant (MK-0364) was achieved using a classical Evans’ asymmetric reaction route.¹⁷⁵ The total synthesis starts from the commercially available 3-bromophenyl acetic acid 219 which is coupled with lithiated (S)-4-benzyloxazolidin-2-one via pivaloyl mixed anhydride provided from pivaloyl chloride in the presence of a base i.e. Et₃N to afford N-acyloxazolidinone 220 in relatively high yields. Then, 220 was alkylated in the presence of NaHMDS using 1-(bromomethyl)-4-chlorobenzene to provide the alkylated product 221 in good yields. The ¹H NMR spectrum of 221 confirms the formation of the product has a very high de value. As usual, the chiral auxiliary of acyloxazolidinone 221 was removed by standard conditions (LiOOH) to give the corresponding acid 222 uneventfully. Ultimately, bromo alcohol 223 was obtained as an intermediate for the total synthesis of taranabant 218 (Scheme 45).¹⁷⁴

Scheme 45

Pinnatoxins are ‘fast-acting’ marine toxins generally found in the bivalve Pinna pectinata (muricata).¹⁷⁶ Pinnatoxin A was initially isolated in 1995 by Uemura and coworkers. Interestingly, they characterized its structure in the same year.¹⁷⁷ The outstanding chemical structure of pinnatoxins having an unusual spiroimine gave a persuasive challenge to the organic chemists working in the field of total synthesis.¹⁷⁸ The first strategy for installation of the spiroimine segment relied on a tandem Claisen–Mislow–Evans rearrangement. That induced the quaternary stereogenic center at the core of the ring system.¹⁷⁹ An enantioselective strategy to the spiroimine segment of pinnatoxins was designed, performed and reported by Zakarian and coworkers in 2007.¹⁸⁰ The synthesis of carboxylic acid 232 was commenced with the condensation of (S)-citronellic acid¹⁸¹ with 4R-methyl-5S-phenyl-2-oxazolidinone 226 to provide the appropriate Evans’ imide. Upon methylation of sodium enolate created from the imide using methyl iodide, 227 was obtained in 83% yield. Sequential standard reduction/benzylation/oxidative cleavage of the double bond gave acid 229. Interestingly, at this juncture, the chiral oxazolidinone 226 recovered in the sodium borohydride reduction stage was reunited, followed by allylation with bromide 230 providing imide 231 in good yield. Next, peroxide-assisted hydrolytic removal of the chiral auxiliary was practically conducted. The chemoselective hydrogenation of the double bond afforded acid 232 in ten steps starting from (S)-citronellic acid. Finally, after several steps, acid 232 gave ester 233 which is an intermediate for the for the total synthesis of the spiroimine of pinnatoxins 224 in several steps (Scheme 46).¹⁸⁰

Scheme 46

C₁–C₁₂ fragment 241 is a key intermediate in the synthesis of bitungolides A–E.¹⁸² The formation of 241 commences with the asymmetric alkylation of oxazolidinone 235 with chloromethylbenzyl ether mediated by TiCl₄ in CH₂Cl₂ at 0 °C to give the target alkylated product in 90% yield, which upon treatment with NaBH₄ in THF–H₂O after removal of the chiral auxiliary to provide alcohol 236 in 90% yields. This alcohol 236 was further reacted to give aldehyde 237. Evans’ aldol reaction between the enolate of oxazolidinone 238 and aldehyde 237 in the mediated by TiCl₄ and sparteine in CH₂Cl₂ at 0 °C gave the syn adduct in 90% yield as a single diastereomer where its secondary hydroxyl group was selectively protected with MOMCl in the mediated by i-Pr₂NEt in CH₂Cl₂ to give 239 in high yields. The chiral auxiliary in 239 was removed through reduction using NaBH₄ in THF–H₂O to provide alcohol 240 in 90% yield (Scheme 47).

Scheme 47

Monitoring of the fermentation broth of the mycobacteria Chondromyces crocatus resulted in the isolation of four compounds, i.e. the chondramides A–D 242 showing antifungal and cytostatic depsipeptides activities.^183,184 A brief protocol to stereoisomers of the 7-hydroxy acid of the chondramides were presented.¹⁸⁵ Following this pathway, allyliodide 243 acts as an alkylating agent in the Evans’ alkylation protocol in one of the key steps, ultimately leading to hydroxy acid 246 which should help elucidate the correct stereogenic center of the chondramide depsipeptides. The double bond of 243 is susceptible to isomerization during flash chromatography. Thus, crude iodide 243 was used for the subsequent alkylation of propionyl oxazolidinone 156.¹⁸⁶ Deprotonation of 156 with NaN(SiMe₃)₂ in THF followed by the addition of iodide 243 afforded compound 244 in 71% yield. Upon hydrolysis of the carboxylic acid derivative 244 the OH-protected acid 245 was obtained. At last, the hydroxy ester 246 was obtained which was appropriate for esterification with the tripeptide segment of the chondramides (Scheme 48).¹⁸⁵

Scheme 48

Similar to the synthesis of 6,7-syn-hydroxy ester 250, asymmetric alkylation of 156 afforded 248 (77%, over two steps), then saponification (84%) provided the acid 249 (90%) (Scheme 49).

Scheme 49

A practical and efficient stereoselective synthesis of biologically active hydroxyl thiophene sulfonamide 251 has been described.¹⁸⁷ The paramount of the total synthesis of this compound is the generation of two stereogenic centers. The biologically potent hydroxyl thiophene sulfonamide 251 is recognized as a novel γ-secretase inhibitor, which is used for the treatment of Alzheimer’s disease. In this strategy, the total synthesis was started from commercially purchasable 4,4,4-trifluorobutyric acid 252 which was transformed into a mixed anhydride, and then treated with lithiated oxazolidinone to provide carboximide 253. The stereoselective methylation was performed by the formation of an anion with sodium bis(trimethylsilyl)amide in THF at −40 °C. Subsequent addition of methyl iodide under thermal conditions gave 254 as single diastereomer in 64% yield. Treatment of 254 with LiBH₄ afforded the chiral alcohol 255 in high yield. Compound 255 was transformed to target 251 via a multi-step synthesis (Scheme 50).¹⁸⁷

Scheme 50

Amphidinolides, macrolides isolated from marine Amphiscolops sp.,¹⁸⁸ show a strong biological potency, chiefly with antitumor activity and scarce abundance. This group of macrolides has thus attracted the attention of synthetic organic chemists.¹⁸⁹ Amphidinolide W 256 is a 12-membered macrolide initially isolated by Kobayashi¹⁹⁰ in 2002. It exhibited high cytotoxicity against murine lymphoma L1210 cells in vitro. It is structurally different from other members in the family, as it has no exo-methylene unit in its structure.¹⁹⁰ Ghosh and coworkers accomplished the total synthesis of amphidinolide W.¹⁹¹ This research group developed a highly efficient approach to the macrolactone core of amphidinolide W.¹⁹² The synthesis started with the already provided oxazolidinone 257,¹⁹³ which upon asymmetric methylation using methyl iodide afforded 258 with high diastereoselectivity (17 : 1). The stereochemical outcome was confirmed by hydrolysis of 258 to the corresponding acid and comparison of resulting data with the previously reported values.¹⁹⁴ Reductive cleavage of the auxiliary¹⁹⁵ with the sequence of benzylation/hydroboration/Dess–Martin oxidation¹⁹⁶ gave the aldehyde 260 which was entered into the next Evans’ aldol reaction and after several other reactions, the desired isomer of the macrolactone derivative 261, the macrolactone core of amphidinolide W was fruitfully obtained in 42% overall yield (Scheme 51).¹⁹³

Scheme 51

(+)-Neopeltolide 262 was initially isolated in 2007 from the north coast of Jamaica by Wright and his research group, from a deep-water sponge.¹⁹⁷ (+)-Neopeltolide was found to be a potent in vitro anti-proliferative agent towards the growth of several cancer cell lines. 2,4,6-Trisubstituted tetrahydrofuran subunit 266 acts as a key intermediate in the synthesis of the correct structure of (+)-neopeltolide 262.¹⁹⁸ Its total synthesis makes use of 265 with correct chiral centers as the precursor for 266. Alcohol 265 was synthesized by diastereoselective alkylation of 263 with methyl iodide mediated by NaHMDS in THF at −78 °C to provide methylated product 264 as a single diastereomer in high yield. The chiral auxiliary in 264 was conventionally removed by NaBH₄ in THF–H₂O to provide alcohol 265 in virtually quantitative yields (Scheme 52).

Scheme 52

Bongkrekic acid (BKA) 267 is a natural toxic antibiotic generated by the bacterium Burkholderia cocovenenans.¹³⁶ An efficient total synthesis of (+)-BKA, has been reported by Shindo et al. the apoptosis inhibitor bongkrekic acid, using a torquoselective olefination and Kocienski-Julia olefination followed by the Suzuki–Miyaura coupling as the segment-binding steps. It is noteworthy that after combining the three segments, it took only two steps to complete the synthesis, indicating the high efficiency of this synthesis to provide BKA and its analogues. Furthermore, the torquoselective olefination also contributes to the shortening of the synthesis. The longest linear sequence is only 18 steps and completed in 6.4% overall yield, which is an improvement over previous process (32 steps and 0.6% overall yield). Noticeably, the total synthesis of BKA had already been reported by the Corey group¹⁹⁹ in 1984 and by the Shindo group in 2004.¹³⁷ Corey et al. did not claim the isolation of BKA in its pure form, due to its instability. Likewise, another semi-convergent synthetic approach¹³⁷ was too long (32 steps in the longest linear sequence). In an approach for the second-generation synthesis of BKA, in 2009, Shindo and coworkers reported a three-component convergent strategy employing a doubly terminally functionalized fragment B.²⁰⁰ The synthesis of segment B began with the stereoselective alkylation of the Evans’ oxazolidinone 156 using 269 readily prepared from 4-pentyn-1-ol 271 in five steps to obtain 270 with excellent diastereoselectivity and in good chemical yield. Removal of the chiral auxiliary was conducted with a conventional reduction, followed by protection of the alcohol with a TBDPS protective group to provide 271. The doubly terminally functionalized middle fragment 272 was synthesized after several steps (Scheme 53).²⁰⁰

Scheme 53

Borrelidin 273, is an 18-membered macrolide antibiotic showing anti-Borrelia activity. It was initially isolated from Streptomyces rochei by Berger et al. in 1949.²⁰¹ Its structure was suggested by Keller-Schierlein in 1967,²⁰² and its absolute configuration was confirmed via X-ray crystallographic analysis and finalized by Anderson et al.²⁰³ An asymmetric total synthesis of borrelidin was reported in 2009 by Yadav and coworkers. In the preparation of the C₁–C₁₁ segment of borrelidin, all the chiral centers were induced via desymmetrization protocols, including Sharpless asymmetric epoxidation, regioselective opening of chiral epoxide and our subject, asymmetric alkylation using the Evans’ chiral oxazolidinones.²⁰⁴ As depicted in Scheme 54, synthesis of the intermediate 278 was commenced from compound 274. The acid group in compound 275 was activated via preparation of the mixed anhydride coupled with the Evan’s chiral auxiliary followed by methylation using methyl iodide to provide compound 276. This was then reduced to the corresponding alcohol, which was protected using DHP, as THP ether to obtain 277. Deprotection of the benzyl group in the presence of Li-naphthalene gave benzyl the group, free alcohol, which, upon smooth and clean oxidation, using TEMPO, BAIB,²⁰⁵ afforded the desired compound 278 (Scheme 54).²⁰⁴

Scheme 54

Emericellamides A and B are components of the marine family. They were isolated from marine-derived fungus Emericella sp.²⁰⁶ From a structural point of view, they hold two main portions: a pentapeptide and an adjoining di- or trimethyl hydroxy acid. Emericellamides A and B exhibited antibacterial potencies toward methicillin-resistant Staphylococcus aureus. A diverse and flexible protocol considering peptide chemistry, employing stereoselective alkylations and decisive macrolactamization was accomplished and reported by Xu, Yea and coworkers.²⁰⁷ The overall yield of this total synthesis for emericellamide A 279 was reported to be 22% over eight steps, whereas the total synthesis of emericellamide B 280 was achieved in only 14% overall yield. The synthesis started with generation of both enantiomers of N-octanoyl-4-benzyloxazolidinone using conventional procedures. (S)-4-Benzyloxazolidinone 1 gave 281a in good yields. Upon treatment with NaHMDS and reaction with methyl iodide in THF, 281a provided the alkylated product 282a in satisfactory yield as a sole diastereoisomer. Reductive removal of the Evans’ auxiliary upon treatment with LiBH₄ afforded the substituted alcohol 283a virtually in quantitative yield.²⁰⁸ This was employed as a precursor to synthesize substituted acid portion of both emericellamides A and B. Alcohol 283b was provided from (R)-4-benzyloxazolidinone in a similar sequential reaction for the synthesis of the C₂₅ epimer of emericellamide B (Scheme 55).²⁰⁷

Scheme 55

For the total synthesis of emericellamide B, alcohols 283a and 283b were independently reacted with triflic anhydride and the provided alcohol was used to alkylate (R)-(−)-4-benzyl-3-propionyl-2-oxazolidinone 156, again following the Evans’ strategy, thus adding the extra methyl substituent on the side chain. Then, the reductive removal of chiral auxiliary provided 285a and 285b. Finally, after several steps including functional group conversions, compound 286 was provided. Unfortunately, the analysis data for 286 were very inconsistent and different with those of the natural products 280. A comparison of the δ values for the C₁₃ spectra shows that there are more differences between 286 and the natural product than those recorded for 280. As a result, 280 was implied to have the correct stereochemistry in accordance with emericellamide B (Scheme 56).²⁰⁷

Scheme 56

Licochalcone E was initially isolated from the roots of Glycyrrhiza inflate since cytotoxicity was observed against the HT1080 cell line.²⁰⁹ Further biological properties were observed from the extract of this natural product.^210,211 The absolute configuration of (−)-licochalcone E 287 was determined and being revealed as (S) via the first asymmetric total synthesis of this natural product. Interestingly, the chirality in (S)-(−)-licochalcone E 287 can be induced via stereoselective methylation of an appropriate Evans’ oxazolidinone derivative. This method not only is applicably flexible enough to synthesize (S)-(−)-licochalcone E 287 but is also quite versatile and flexible for the synthesis of its analogs for biological evaluations. The synthesis of the key intermediate 291 from 2, 4-dihydroxybenzaldehyde 288 is depicted in Scheme 57.²¹² 2-Arylacetic acid 289 was provided via a multi-step synthesis, upon reaction with pivaloyl chloride mediated with Et₃N to provide mixed anhydride, upon which treatment with the lithium anion of (4R,5S)-(+)-4-methyl-5-phenyl-2-oxazolidinone 290 gave the imide 291 in high yields over two steps. (4R,5S)-(+)-4-Methyl-5-phenyl-2-oxazolidinone 290 was selected as the Evans’ auxiliary since it was found to disclose a well-defined absolute stereochemistry unambiguously with high ee via a stereoselective reaction.²¹³ Delightfully, the imide 291 happened to give the same enantiomer as the natural licochalcone E after several additional other reactions required reactions. Having the key intermediate 291, the required chirality was induced to the molecule as illustrated in Scheme 57. Upon treatment with NaHMDS and reaction with methyl iodide, the Evans’ oxazolidinone auxiliary 291 gave methylated imide 292 in satisfactory yields. It was also found to be formed as a single isomer proven by ¹H NMR spectra analysis. Upon hydrolysis with LiOH and H₂O₂ the Evans’ oxazolidinone was converted to acid 293 also in satisfactory yield (Scheme 57).²¹⁴

Scheme 57

Peptaibiotics are well-recognized as an outstanding, persistently growing family of polypeptides with more than 850 known members during the past 50 years. Non-proteinogenic amino acids for instance 4-hydroxyproline (Hyp), 2-amino-6-hydroxy-4-methyl-8-oxo-decanoic acid (AHMOD), β-alanine (β-Ala) and some others are widespread in their structures. Among them, C^α-dialkylamino acids and most importantly α-aminoisobutyric acid (Aib) and, L-or D-isovaline (Iva) if present, play a pivotal role in determining the biological activities of peptaibiotics.^215–218 An efficient synthesis of (2S,4S)- and (2S,4R)-2-amino-4-methyldecanoic acids was achieved using a glutamate derivative as starting material. Notably an appropriate Evans’ oxazolidinone is involved in a decisive asymmetric alkylation step. The two synthesized diastereomers NMR data were compared with those of the natural product, already reported. Consequently, the configuration of this novel amino acid unit in culicinins was unambiguously assigned as (2S,4R). As depicted in Scheme 58, the commercially available reagent N-Boc-γ-benzyl L-glutamate 296 was initially converted into the N, O-protected carboxylic acid 297 readily in accordance to the already reported procedure.²¹⁹ Next the acid was linked to the chiral auxiliary, (R)-4-benzyl-2-oxazolidinone under the mild reaction conditions developed and reported by Ho et al.⁸⁶ The resultant important intermediate 298 was then submitted to Evans’ asymmetric alkylation at low temperature. In this step, initially, 1-iodohexane was used as an electrophilic reagent. Nevertheless, the desired product was not obtained, probably due to the poor electrophilic intensity of the iodoalkane used. Thus, an ‘auxiliary line’ was required. Therefore, 1-iodohex-2-ene, with more electrophilic intensity was used instead of 1-iodohexane. Compound 298 can be enolized at low temperature. Addition of 1-iodohex-2-ene afforded the alkylated R-adduct 299 as the major diastereomer, which could be readily separated from its diastereomer by column chromatography. The chiral auxiliary was removed under reductive conditions to afford the alcohol 300. After several steps, the desired amino acid 302 was obtained. The NMR data of 302 was compared with that of obtained from natural product and found being identical. Acid 297 was reacted with the (S)-4-benzyl-2-oxazolidinone instead of its enantiomer affording compound 298a, which was transformed into free amino acid 302a in eight steps. Then, the NMR data of 302, 302a and those of the natural product were cautiously compared. Significantly, no difference was found between the ¹H NMR data of the two diastereomers and those of the natural product.²²⁰ Delightfully, their ¹³C NMR shifts were found being pretty different. It was then concluded that, the configuration of this amino acid residue in the natural products should be (2S,4R).^221​

Scheme 58

Malyngic acid 303 is placed in the oxylipin family of natural products. It was initially isolated by Cardellina and coworkers from the marine blue-green algae Lyngbya majuscula. On the basis of chemical degradation, combined with analysis of spectroscopic data, compound 303 was characterized as a trihydroxy unsaturated fatty acid.²²² Fulgidic acid 304, was initially isolated from the terrestrial higher plant Rudbeckia fulgida, by Herz and coworkers. It was characterized by comparison of its NMR spectra with those of malyngic acid 303 as the C₁₂-epimer of 303.²²³ An asymmetric total synthesis of malyngic acid 303 was accomplished from the known oxazolidinone derivative 305 in 26% yield over eight steps.²²⁴ The total synthesis was started from 305 (ref. 225) which undergoes Evans’ asymmetric alkylation with (Z)-1-iodo-2-pentene 306 (ref. 226) to afford 307 in high yield.²²⁷ Removal of the oxazolidinone moiety of 307 using alkaline hydrogen peroxide under standard conditions provided the carboxylic acid 308. After two steps, this was transformed into keto phosphonate 309 in excellent yields. Fulgidic acid 304, the C₁₂-epimer of malyngic acid 303, was also prepared from 305 in 25% yield over eight steps (Scheme 59).²²⁴

Scheme 59

Apratoxins A 310 is a marine secondary metabolite. It was first isolated from the remarkably prolific Lyngbya majuscula collected in Guam and Palau. It exhibits activity in vitro toward LoVo cell lines and the KB.^228,229 A stereoselective strategy to the key intermediate 316 in which the Evans’ alkylation is employed has been reported. In this approach, as depicted in Scheme 60, commercially purchasable lactone 311, is converted into free acid part 312 in 81% overall yield after two steps. It was then activated with ethyl chlorocarbonate and the resulting mixture was subsequently reacted in situ with the lithium salt of oxazolidinone to provide amide 313 in satisfactory yields. This was then subjected to methylation with MeI to furnish product 314 with high diastereoselectivity (dr > 98 : 2) and satisfactory chemical yield. The auxiliary was removed under standard conditions (LiBH₄, H₂O) affording the primary alcohol 315 in excellent yield. After several steps, the key intermediate 316 was obtained from 315. Compound 316 in turn could be transformed to the desired natural product, (E)-dehydroapratoxin A 310 (Scheme 60).²³⁰

Scheme 60

In 2002, Molinski and coworkers isolated caylobolide A 317 via bioassay-guided purification from the marine cyanobacteria Lyngbya majuscule collected at Cay Lobos, Bahamas.²³¹ Caylobolide A contained eight undetermined stereogenic centers. Thus, there are 256 diastereomeric structural possibilities. It has another significant feature. It is the repeating 1,5-diol moieties existed along the 36-membered lactone core. Besides, it has a fascinating macrocyclic structure. Caylobolide A has exhibited cytotoxic potencies towards the human colon tumorcell line HCT 116. In 2011, a convergent and flexible synthesis of two possible diastereomers of the C₂₅–C₄₀ segment in (−)-caylobolide A, has been achieved and reported by Jennings et al.²³² According to this approach, for the synthesis of the C₂₅–C₄₀ sub-unit of 317, the synthesis of chiral aldehyde 321 is required as depicted in Scheme 61. Thus, a stereoselective alkylation of the known chiral oxazolidinone 318 using NaHMDS and MeI afforded 319 in high yield with excellent diastereoselectivity (>15 : 1 dr). As usual, the oxazolidinone moiety was removed upon smooth reduction with LiBH₄ giving the chiral primary alcohol 320 in excellent yield. Upon oxidation of the hydroxyl group of 320, using TEMPO and PhI(OAc)₂ as oxidants, the desired aldehyde 321 was obtained in high yield. Chiral aldehyde 321 is recognized as the key intermediate for the synthesis of C₂₅–C₄₀ fragment in (−)-caylobolide A (Scheme 61).²³³

Scheme 61

Compound 326 is a key intermediate for the synthesis of (+)-vittatalactone and (+)-norvittatalactone.²³⁴ It has been isolated from the striped cucumber beetle Acalymma vittatum and synthesized via stereoselective alkylation of 323 with methyl iodide mediated by NaHMDS in THF at −78 °C to give 324 in high yield and excellent diastereoselectivity (>98 : 2). The chiral auxiliary in 324 was next conventionally removed (NaBH₄, THF–H₂O, 0 °C) to give the alcohol 325 in high yield, chemoselectively, since benzoate group was not reduced and un-affected (Scheme 62).²³⁴

Scheme 62

A Streptomyces-derived lipidated peptide metabolite 327 has recently attracted enormous attention of the organic chemists. Among them, Lear and coworkers focused on elucidation of the structure of dipeptide 327, which was successfully established. In 2004, the application of the dipeptide 327 was patented by the Yamanouchi Pharmaceutical Co. It was found that 327 can inhibit the growth of Plasmodium falciparum.²³⁵ The absolute configuration of 327 was determined via degradation and Marfey’s derivatization investigations. The total synthesis of a potent antimalarial lipid–peptide 327 was revealed in 2012.⁹⁰ In this approach Lear and coworkers used stereocontrolled routes along with a catalytic Mannich reaction, Sharpless epoxidation, Evans’ alkylation, and Kocienski-Julia olefination to obtain nonproteinogenic amino acids. In this pathway, the preparation of Evans’ oxazolidinones 328a/b were required²³⁶ for the synthesis of chiral trans fatty acids 330a and 330b. Then 328 was converted to the thiotetrazoles 329 upon reduction under standard conditions and Mitsunobu reaction. Next, via a multi-step reaction, and Jones oxidation, the fatty acids 330a (5S) and 330b (5R) were obtained. At last, after several additional steps, involving functional group transformations, the trimethyl ester derivative (+)-331 obtained from 330a could be converted to 327 (Scheme 63).⁹⁰

Scheme 63

A cyclic depsipeptide tumescenamide C 332, is a novel member related of tumescenamides. It has been isolated from a culture broth of an actinomycete Streptomyces sp. Its structure was fully characterized. Tumescenamide C was a relative of tumescenamides A and B, containing a sixteen-membered ring system, which bears two proteinogenic and three non-proteinogenic amino acids. In its structure, it has a methyl-branched fatty acid. The planar structure was established by spectra analysis, whereas its absolute configuration was defined by chemical degradation and most importantly by an asymmetric synthesis. It has been found that tumescenamide C shows an antimicrobial activity with a high level of selectivity towards Streptomyces species.^237,238 For the definite determination of the absolute configuration of C₃₂, the total synthesis of (2S,4R)-336 and (2S,4S)-337 was envisaged.²³⁹ If the stereoselective alkylation using Evans’ protocol is performed, it was expected to obtain the 2S configuration.¹⁰⁶ Initially, Kakeya and coworkers synthesized (R)-2-methypentyl trifluoromethanesulfonate 334 from (S)-methyl-3-hydroxy-2-methypropanoate 333 in six steps in 23% overall yield²³⁹ in accordance with a procedure reported, previously.²⁴⁰ Next, diastereoselective alkylation of (4R)-propionyloxazolidinone 156 using the chiral triflate 334 was performed to provide (2S,4R)-2,4-dimethylsubstituted oxazolidinone 335a and its C₂ diastereomer 335b in 8 : 1 ratio. The mixture was separable by column chromatography to obtain 335a in 24% yield. Removal of the chiral auxiliary from 335a was conducted under standard conditions (treatment with alkaline hydrogen peroxide) to give 336 (Scheme 64). On the other hand, 338, a C₄ diastereomer of 336, was synthesized starting from commercially purchasable racemic alcohol 337 and transformed to a triflate through a subsequent reaction with oxazolidinone 156 to give a 2S mixture of 335a and 335c in 32% yield and a 2R mixture of 335b and 335d in 4% yield respectively. The major mixture was readily separated from the minor mixture by column chromatography on silica gel. While 335a and 335c showed similar elution qualities on a reversed-phase HPLC column, they were sufficiently separated on a small scale pure enough for the next two steps. Purified 335c was subjected to oxidative hydrolysis with alkaline hydrogen peroxide to afford 338 (Scheme 65).²³⁹

Scheme 64

Scheme 65

A syn/syn-deoxypropionate segment is widespread in many natural products such as (2R,4R,6R,8R)-2,4,6,8-tetramethylundecanoic acid 339. A brief total synthesis of (2R,4R,6R,8R)-2,4,6,8-tetramethylundecanoic 339 acid has been accomplished via a lipase catalyzed desymmetrization protocol to generate two methyl stereogenic centers. Asymmetric alkylation reactions were employed in the total synthesis of 339.²⁴¹ In this approach, the total synthesis of (2R,4R,6R,8R)-2,4,6,8-tetramethyl undecanoic acid 339 was accomplished starting from the readily available, allylic alcohol intermediate 340. After two steps, acid 341 was obtained and coupled with Evans’ (R)-oxazolidinone using pivaloyl chloride mediated by Et₃N and LiCl to give the compound 342 in excellent yield. Upon methylation, the Na-enolate of compound 342 using methyl iodide furnished the compound 343 in excellent yield. Finally, compound 343 was treated with LiOH/H₂O₂ in THF/H₂O (4 : 1) to give the desired (2R,4R,6R,8R)-2,4,6,8-tetramethylundecanoic acid 339 (ref. 242 and 243) in excellent chemical yield and >99% dr and ee (Scheme 66).²⁴¹

Scheme 66

In 2002, amphidinolide W 344, a 12-membered macrolide was isolated by Kobayashi and coworkers. It exhibits potent cytotoxicity against murine lymphoma L1210 cells in vitro.¹⁹⁰ A versatile strategy for the total synthesis of a 12-membered macrolactone core and a 6-epi analogue of amphidinolide W has been designed, performed and reported.²⁴⁴ The total synthesis was started from the commercially available 4-pentenoic acid 346. The strategy was designed based on of a highly stereo and regioselective introduction of the chiral centers employing Evans’ asymmetric alkylation followed by aldol reactions. Other important reactions employed in this synthesis are Julia-Kocienski olefination, Kita’s macrolactonization, ring closing metathesis (RCM) reaction and Yamaguchi’s esterification. These reactions were remarkable for the buildup of the macrolactone cores. However, the prominent feature of this synthesis is highly stereocontrolled Evans’ and syn-aldol reaction mediated by dibutyl boron triflate, employing an oxazolidinone-based chiral auxiliary. These reactions are inducing chirality to the C₅ and C₆ centers. The C₂ center was designed in a way to be created from the Evans’ chiral auxiliary via alkylation. The remaining C₁₁ center could be fixed using D-mannitol.^245,246 In this approach, the synthesis of fragment 350 was examined as the initial target. Thus the required N-pentenoyl oxazolidinone 347 for the implementation of stereoselective alkylation was provided through N-acylation of the readily available (4S)-4-benzyloxazolidin-2-one using a mixed anhydride. It was provided from the reaction of 4-pentenoic acid 346 and pivaloyl chloride mediated by lithium chloride and triethylamine in THF.¹⁹² Then, methylation of oxazolidinone 347 using CH₃I in the presence of NaHMDS resulted in 348 in high yields and high diastereoselectivity (17 : 1). The diastereomeric purity was determined by the analysis of ¹H and ¹³C NMR spectra. The stereochemical result could be reconfirmed by hydrolysis of 348 into the corresponding already known acid by comparing its analytical data with the previously reported values. The oxazolidinone derivative 348 was removed under standard conditions using lithium aluminium hydride¹⁹⁵ in Et₂O to afford alcohol 349 which was difficult to purify due to its volatile nature. The desired aldehyde 350 was a required precursor for the synthesis of the 12-membered macrolactone core 351 and its 6-epi analogue 352 of amphidinolide W which were obtained in two steps (Scheme 67).²⁴⁴

Scheme 67

(−)-Spongidepsin 354 is a cyclodepsipeptide initially isolated from the Vanuatu marine sponge Spongia sp. This compound shows cytotoxic and antiproliferative potencies towards J774.A1, WEHI-164, and HEK-293 cancer cell lines.²⁴⁷ Notably, (−)-spongidepsin is a 13-membered macrolactam containing five chiral centers. In its total synthesis, acid 358 acts as a key intermediate.²⁴⁸ Preparation of 358 involved stereoselective alkylation of 355 with methyl iodide mediated by NaHMDS in THF at −78 °C to afford the methylated product 356 in 80% yield as an 8 : 2 diastereomeric mixture. It is followed by the conventional reductive removal of the chiral auxiliary in 356 by NaBH₄ in THF–H₂O to give alcohol 357 in satisfactory yield. This was then oxidized to acid 358 using Jones reagent (Scheme 68).

Scheme 68

In 2006, Kobayashi and coworkers²⁴⁹ accomplished the isolation of amphidinin B 359 from the dinoflagellate Amphidinium sp. (strain number Y-56). The same authors reported the structural characterization of amphidinin B 359 as a linear polyketide. It exhibited potency toward MCF-7 (breast cancer cell line).²⁵⁰ From the structural point of view, amphidinin B 359 contains a core tri-substituted tetrahydrofuran scaffold with a chiral side-chain at C₁₆. In the side chain, an exo methylene, two branched methyl groups, a propyl and two carboxyl groups are attached whereas another methyl group is attached at C₁₇ on the tetrahydrofuran framework. C₁₉ is also substituted with an ethanoic acid moiety. In 2013, an efficient, flexible, highly stereoselective synthesis of amphidinin B 359 was accomplished by Krishna and coworkers.²⁵¹ Their approach for the total synthesis of amphidinin B involved some important named reactions such as Sharpless asymmetric epoxidation, Evans’ aldol, Julia olefination, oxa-Michael, Keck allylation, Mannich reaction, Evans’ asymmetric alkylation, and Yamaguchi esterification. The C₁–C₉ 365 segment in amphidinin B was provided in nine steps, starting from mono-PMB ether of 1,4-butane diol 360. On the other hand, the synthesis of segment 365 was started with compound 361, synthesized as reported previously.²⁵² Reaction of alcohol 362 (provided in three steps from 361), with triphenylphosphine in the presence of iodine and imidazole in THF gave the corresponding allyl iodide, which upon Evans’ alkylation²⁵³ with N-propionyl oxazolidinone gave 363 in good yield as a single isomer as confirmed by analysis of the ¹H or ¹³C NMR spectra of the crude reaction mixture. Reductive removal of the chiral auxiliary under standard conditions (LiBH₄ in MeOH) gave the corresponding alcohol 364 in 82% yields. Compound 365 (ref. 250) was obtained in 71% yield over two steps. After several steps, the desired natural product 359 was obtained (Scheme 69).²⁵¹

Scheme 69

Bakuchiol and Δ³-2-hydroxybakuchiol 366 is a member of one family of monoterpene phenols occurring in the medicinal plant Psoralea corylifolia L. Its crude extract has been used for a long time as a Chinese traditional medicine.²⁵⁴ For its total synthesis, 370 acts as a key intermediate reported by Xu et al.²⁵⁵ For the synthesis of 370 they used Evans’ asymmetric alkylation of 367 with 369 giving the desired intermediate 369 in 66–68% yield with excellent diastereoselectivity (>20 : 1). Conventional reductive removal of the Evans’ auxiliary in 369 using NaBH₄ in THF–H₂O at room temperature did not afford alcohol 370 in satisfactory yields. However, reductive removal with LiBH₄ from ethyl and t-butyl esters gave the desired alcohol 370 in <30% and 70% yield respectively (Scheme 70).²⁵⁵

Scheme 70

Marine cyanobacteria is a rich source of new biopotential secondary metabolites with unique structural frameworks. A class of macrolides with a rare N-methyl enamide, 1,3-methyl and tertiary butyl containing a branch linked through a lactone such as laingolide, laingolide A or madangolide were first isolated from Lyngbya bouillonii.²⁵⁶ Structurally related is a neuroactive 15-membered macrolide palmyrolide. They contain a rare N-methyl enamide and 1,3-methyl and tertiary butyl containing branch linked through lactone. An asymmetric synthesis of palmyrolide A, the 15-membered neuroactive macrolide and its epimer has been accomplished and reported.²⁵⁷ The route was planned in a way that configurations of the required stereoisomers were similar to the absolute configuration of palmyrolide A. In this line, for the preparation of all stereoisomers of palmyrolide A, an efficient synthesis was designed for the fragment 375 starting from commercially purchasable 1,6-hexanediol 372. Selective benzyl group protection on 1,6-hexanediol afforded a monobenzyl ether, which upon sequential oxidation gave the acid 373. The reaction of 373 with pivaloyl chloride followed by treatment with lithiated (R)-4-benzyl-2-oxazolidinone gave 374. This was methylated using methyl iodide and subsequently subjected to basic hydrolysis to give 375 in 60% yields from 373 (dr 97.4 : 2.6 upon methylating stage) (Scheme 71).²⁵⁷

Scheme 71

Xanthanolide sesquiterpenoids were initially isolated from the plants of the genus Xanthium from the family Compositae, where more than 100 compounds have been isolated so far.²⁵⁸ These compounds exhibit imperative biological activities, such as allelopathic, antitumor, antimicrobial, anti-MRSA, anti-ulcerogenic, and anti-inflammatory activities. Among them xanthatin 376 has attracted much attention. It has been revealed that they have a seven-membered carbocycle containing a cis- or trans-fused γ-butyrolactone at their C₈ position. In 2013, the total synthesis of xanthatin 376 and 11,13-dihydroxanthatin 377 was fruitfully accomplished via the stereocontrolled conjugate allylation to an optically pure γ-butenolide. Shindo and coworkers reported a straight and highly effective synthetic approach for xanthanolides via a stereocontrolled conjugate allylation to a γ-butenolide to provide xanthatin 376 and 11,13-dihydroxanthatin 377 in 14 and 13 steps, respectively.²⁵⁹ This synthetic approach provides a powerful tool for the synthesis of congener xanthanolides and other natural products bearing the trans-fused γ-butyrolactone.²⁶⁰ This strategy was started with the stereoselective alkylation of the Evans’ oxazolidinone 156 using allyl bromide to afford 378 in high yield with a high degree of diastereoselectivity. 378was reduced under standard conditions using lithium aluminum hydride. Upon the protection of the resulting alcohol, using TBDPSCl, 379 was obtained in excellent yield over two steps. Finally, the desired natural products 376 and 377 can be obtained from the intermediate 379 (Scheme 72).²⁵⁹

Scheme 72

Several natural phenylpropanoids were isolated from plants.²⁶¹ Although, their structures are not very complex, their absolute configurations were not determined and reported for unstipulated reasons. Both (S)- and (R)-enantiomers 383 and 380, have been isolated from Xanthoxylum nitidum, but both were totally synthesized²⁶² in high enantiomeric purity using an Evans’ chiral auxiliary in their stereoselective alkylation with subsequent reductive removal of the auxiliary employing the Prashad method. Asymmetric alkylation of 381 with a methyl iodide mediated by NaN(SiMe₃)₂ in THF furnished 382 in moderate yields but high 87.7% de. Reductive removal of the chiral auxiliary in 382 by NaBH₄ in THF–H₂O at room temperature furnished (S)-383 in a 90% yield. This reductive removal of the Evans’ auxiliary in 382 was found be chemoselective since the methyl ester moiety in the molecule was not reduced and remained unaffected. Since the optical rotation of the synthetic (S)-383 was opposite to that of natural product 380, the configuration of the latter was designated as (R). This confirmed the alkylation of 384 was successfully achieved to give 385 in 84% yield with 90.2% de. Upon conventional reductive removal of the chiral auxiliary in 385 using NaBH₄, THF–H₂O, (R)-380 in 96% yield was obtained. The obtained spectral data and the amount of optical rotation of the product synthesized via total synthesis were in agreement with those reported already for the natural product 380. This also confirmed the (R)-configuration for naturally occurring 380 (Scheme 73).²⁶²

Scheme 73

Aliskiren 386 is a well-known non-peptidic renin inhibitor.²⁶³ It has been prescribed and is market purchasable as an oral drug for the treatment of hypertension.²⁶⁴ This molecule involves four chiral centers in an aliphatic carbon chain, which naturally makes its synthesis extremely stimulating and challenging. Thus, the structural complexity as well as the interesting biological activity of aliskiren has attracted much attention and stirred the interest of synthetic and medicinal chemists since its innovation.²⁶⁵ The synthesis of aliskiren 386, as a marketed drug has been successfully achieved and reported. (2S,7R,E)-2-Iso-propyl-7-(4-methoxy-3-(3-methoxypropoxy)benzyl)-N,N,8-trimethylnon-4-enamide 391a, is an advanced intermediate toward aliskiren. To approach towards 391a, three different protocols were designed for the construction of the E-olefin functionality in 391a using olefin cross-metathesis. These strategies employ Horner–Wadsworth–Emmons (HWE), and Julia-type olefinations. The most recent one for the synthesis of 391a is a substantially improved protocol in terms of the yield (ca. 33%), and diastereo- and E/Z-selectivity. In this protocol, the Evans’ chiral auxiliary-assisted asymmetric allylation for the synthesis of the suitable enantiopure (higher than 97% ee) intermediates and a modified Julia-Kocienski olefination for the highly selective synthesis of E-391a with up to 13.6 : 1 E/Z ratio from the chiral intermediates are considered key steps. Consequently, the results obtained are in fact an appealing option for the total synthesis of aliskiren.²⁶⁶ As depicted in Scheme 74, the reaction of market purchasable 387 with allyl bromide or 3,3-dimethylallyl bromide proceeded cleanly and smoothly to afford 388a and 388c, respectively, in excellent yields. On other hand, 388b was readily prepared via a two-step procedure involving the allylation of 387 with trans-1,4-dibromo-2-butene. It was followed by reductive elimination of the bromo group in the presence of NaBH₃CN.²⁶⁷ Hydrolytic cleavage of Evans’ chiral auxiliary in 388a–c gave the corresponding carboxylic acids 389a–c. Interestingly, 389a–c could be synthesized at bench scale (dozens of grams) with continual efficiency and can be used as versatile intermediates for the synthesis of various chiral precursors for other designed protocols.

Scheme 74

Bicyclic ester intermediate 396 is a key intermediate in the synthesis of (−)-calyciphylline.^268,269 In this route, the synthesis of (−)-calyciphylline was started with the alcohol 395 by asymmetric alkylation of 393 with methyl iodide in the presence of LDA to afford the alkylated product 394 in 56% yield with >99% diastereoselectivity. Compound 393 has the oxazolidinone moiety as a chiral auxiliary. Conventional removal of the chiral auxiliary in 394 via reductive cleavage using NaBH₄ in THF–H₂O at room temperature provided alcohol 395 in 95% yield (Scheme 75).

Scheme 75

11β-HSD1. 11β-HSD1 has been found to be a promising biological target for the treatment of Met S. However, the development of selective compounds is needed to promote its therapeutic value in biological systems. In part of its total synthesis, the Evans’ chiral auxiliary was employed for the construction of the acyclic precursor 401 to provide the acorane core 403 in excellent yield using a modified Heck reaction. The colletoic acid core derivatives exhibited modest activity against 11β-HSD1 and are used for further biological evaluation. A protocol for the total synthesis of the core of colletoic acid has been improved and reported in 2016. In this protocol the Evans’ chiral auxiliary,⁵⁷ is used and removed under mild conditions (Scheme 76). The synthesis of compound 398 had previously been reported.²⁷⁰ Reaction of (R)-4-benzyl-2-oxazolidinone with pivaloyl chloride gives the mixed-anhydride,⁵⁷ followed by the addition of 398, provided 399 in multigram scale. The generation of the enolate of compound 399 was achieved in the presence of NaHMDS and quenched with electrophile 400a–e to give the required precursor 401 in excellent enantioselectivity (ee ≥ 98%) and excellent diastereoselectivity (dr > 20 : 1) as well as excellent chemical yields. Removal of benzyl-2-oxazolidinone using NaBH₄ in methanol provided the corresponding hydroxyl group which upon protection with TESCl in the presence of imidazole provided the Heck reaction precursor. The intramolecular Heck reaction catalyzed by palladium(0) in CH₃CN/THF at 60 °C and gave the α,β-unsaturated spirocycle 403 as a single diastereoisomer upon protecting group removal using aqueous HCl.²⁷⁰ The conducted Heck reaction was observed to proceed in high regio and stereo control in the tested substrates. It is proposed that the exo-transition state is favored to avoid conflicting interactions between the palladium complex and the R group in the transition state. Having intermediate 403 available in hand, different colletoic acid-like compounds as well as colletoic acid in multi-milligram scale for further mechanistic investigation were synthesized.²⁷¹

Scheme 76

3. Conclusion

In this report, we tried to reveal the importance of the applications of several chiral oxazolidinones in asymmetric synthesis and in particular, the total synthesis of several naturally occurring compounds exhibiting diverse biological activities. In this approach, a chiral center is generated. Notably, the configuration of this newly generated chiral center must be controlled and either completely preserved or totally inverted during the required steps. This ultimately depends on whether it is identical to the configuration of the same stereogenic center which was already defined in the target natural product in the crucial step (steps) in the total synthesis of some biologically active natural products. In spite of the known superiority of catalyzed asymmetric reactions over all other established approaches, the use of chiral auxiliaries in certain asymmetric syntheses and its application in the total synthesis of some natural products is inevitable. Among them, the asymmetric α-alkylation of an appropriate enolate as the determining chiral inducing step has been found promising with the use of an appropriate chiral auxiliary. When the strategy of using a chiral auxiliary is contemplated and justified, in most cases an appropriate Evans’ oxazolidinone is the chiral auxiliary of choice, particularly for the asymmetric alkylation of an enolate. Apart from requiring stoichiometric amounts, which applies to all known chiral auxiliaries, Evans’ oxazolidinones have several merits, making them a superior chiral auxiliary. Nowadays some of them are commercially available or can be readily prepared from market purchasable chiral amino alcohols. They are perfect intermediates and owe their importance chiefly to their ability to induce stereogenic centers during C–C bond formations via asymmetric alkylations, aldol reactions and 1,4-asymmetric addition. For these important reasons, the chemistry of chiral oxazilidinones as commercially available or easily accessible compounds is still a vivacious area of research and the study of their applications stands out, especially in the strategic asymmetric C–C bond forming key step in the total synthesis of natural products. Sophisticated and necessary C–C bond stereoselective formations in one or more steps of the total synthesis of natural products are frequently provided by the application of oxazolidinones as chiral auxiliaries. In this report, the applications of oxazolidinone as a chiral auxiliary for alkylations via an alpha substitution to generate stereoselective C–C bonds in one or more steps of the total synthesis of a natural product was comprehensively showcased. This report discloses the unprecedented role of Evans’ oxazolidinones in the efficient and highly stereoselective formation of C–C bonds. We hope that it stimulates those organic synthetic chemists who are already engaged to continue using them and to motivate beginners to consider Evans’ oxazolidinones and chiral auxiliaries in general, particularly for stereoselective alkylations in their route for total synthesis and in their future attempts and endeavors.

Acknowledgements

MMH is thankful to Iran National Science Foundation for partial financial support.

References

1. D. A. Evans, G. Helmchen and M. Rüping, Chiral Auxiliaries in Asymmetric Synthesis, in Asymmetric Synthesis-The Essentials, ed. M. Christmann, Wiley-VCH Verlag GmbH & Co., 2007, pp. 3–9.
2. F. Glorius and Y. Gnas, Synthesis, 2006, 1899–1930.
3. H. Pellissier, Tetrahedron, 2006, 62, 1619–1665.
4. M. Prashad, W.-C. Shieh and Y. Liu, Tetrahedron, 2016, 72, 17–43.
5. D. A. Evans, J. Bartroli and T. L. Shih, J. Am. Chem. Soc., 1981, 103, 2127–2129.
6. T. Hintermann and D. Seebach, Helv. Chim. Acta, 1998, 81, 2093–2126.
7. C. Gaul, K. Scharer and D. Seebach, J. Org. Chem., 2001, 66, 3059–3073.
8. C. L. Gibson, K. Gillon and S. Cook, Tetrahedron Lett., 1998, 39, 6733–6736.
9. K. Alexander, S. Cook, C. L. Gibson and A. R. Kennedy, J. Chem. Soc., Perkin Trans. 1, 2001, 1538–1549.
10. S. G. Davies, G. J. M. Doisneau, J. C. Prodger and H. J. Sanganee, Tetrahedron Lett., 1994, 35, 2369–2372.
11. S. D. Bull, S. G. Davies, S. Jones, M. E. C. Polywka, R. S. Prasad and H. J. Sanganee, Synlett, 1998, 519–521.
12. S. D. Bull, S. G. Davies, M. S. Key, R. L. Nicholson and E. D. Savory, Chem. Commun., 2000, 1721–1722.
13. A. K. Ghosh, T. T. Duong and S. P. McKee, J. Chem. Soc., Chem. Commun., 1992, 1673–1676.
14. C. A. De Parrodi, A. Clara-Sosa, L. Perez, L. Quintero, V. Maranon, R. A. Toscano, J. A. Avina, S. Rojas-Lima and E. Juaristi, Tetrahedron: Asymmetry, 2001, 12, 69–79.
15. S. Jones, J. Chem. Soc., Perkin Trans. 1, 2002, 1–21.
16. A. C. Regan, J. Chem. Soc., Perkin Trans. 1, 1998, 1151–1166.
17. C. W. Y. Chung and P. H. Toy, Tetrahedron: Asymmetry, 2004, 15, 387–399.
18. D. A. Evans, K. T. Champman and J. Bisaha, J. Am. Chem. Soc., 1984, 106, 4261–4263.
19. D. Y. Ager, I. Prakash and D. R. Schaad, Chem. Rev., 1996, 96, 835–875.
20. C. J. Cowden and I. Paterson, in Organic Reactions, ed. L. A. Paquette, Wiley, 1997, vol. 51, ch. 1.
21. A. S. Franklin and I. Paterson, Contemp. Org. Synth., 1994, 1, 317–338.
22. D. J. Ager, I. Prakash and D. R. Schaad, Aldrichimica Acta, 1997, 30, 3–12.
23. D. A. Evans, J. M. Takacs, L. R. McGee, D. Ennis, D. Marthre and J. Bartroli, Pure Appl. Chem., 1981, 53, 1109–1127.
24. D. A. Evans, Aldrichimica Acta, 1982, 15, 23–32.
25. D. Swern and M. E. Dyen, Chem. Rev., 1967, 67, 197–246.
26. G. Zappia, E. Gacs-Baitz, G. Delle Monache, D. Misiti, L. Nevola and B. Botta, Curr. Org. Synth., 2007, 4, 81–135.
27. J. Fakhreddin, Stereochemically Pure Drugs: An Overview, in Drug Stereochemistry: Analytical Methods and Pharmacology, ed. Irving W. Wainer, Marcel Dekker, Inc., 1993, ch. 14, pp. 375–382.
28. M. M. Heravi and P. Hajiabbasi, Mol. Diversity, 2014, 18, 411–439.
29. M. M. Heravi, P. Hajiabbasi and H. Hamidi, Curr. Org. Chem., 2014, 18, 489–511.
30. M. M. Heravi and V. Zadsirjan, Tetrahedron: Asymmetry, 2014, 25, 1061–1090.
31. M. M. Heravi, S. Asadi and B. Malekzadeh Lashkariani, Mol. Diversity, 2013, 17, 389–407.
32. M. M. Heravi and S. Asadi, Tetrahedron: Asymmetry, 2012, 23, 1431–1465.
33. M. M. Heravi and V. Fathi Vavsari, Adv. Heterocycl. Chem., 2015, 114, 77–145.
34. M. M. Heravi, T. Ahmadi, M. Ghavidel, B. Heidari and H. Hamidi, RSC Adv., 2015, 5, 101999–102075.
35. M. M. Heravi, E. Hashemi and N. Nazari, Mol. Diversity, 2014, 18, 441–472.
36. M. M. Heravi, E. Hashemi and F. Azimian, Tetrahedron, 2014, 70, 7–21.
37. M. M. Heravi and E. Hashemi, Tetrahedron, 2012, 68, 9145–9178.
38. M. M. Heravi, V. Zadsirjan and Z. Savadjani Bozorgpour, Curr. Org. Chem., 2014, 18, 2857–2891.
39. M. M. Heravi, E. Hashemi and N. Ghobadi, Curr. Org. Chem., 2013, 17, 2192–2224.
40. M. M. Heravi and V. Vavsari Fathi, RSC Adv., 2015, 5, 50890–50912.
41. M. M. Heravi and V. Zadsirjan, Tetrahedron: Asymmetry, 2013, 24, 1149–1188.
42. J. Hassfeld, M. Kalesse, T. Stellfeld and M. Christmann, Adv. Biochem. Eng./Biotechnol., 2005, 97, 133–203.
43. M. S. Newman and A. J. Kutner, J. Am. Chem. Soc., 1951, 73, 4199–4204.
44. H. L. Crowther and H. McCombie, J. Chem. Soc., Trans., 1913, 103, 27–31.
45. E. J. Corey and H. E. Ensley, J. Am. Chem. Soc., 1975, 97, 6908–6909.
46. B. M. Trost, D. O’Krongly and J. L. Belletire, J. Am. Chem. Soc., 1980, 102, 7595–7596.
47. J. K. Whitesell, H. H. Chen and R. M. Lawrence, J. Org. Chem., 1985, 50, 4664–4665.
48. M. P. Sibi, D. Rutherford and R. Sharma, J. Chem. Soc., Perkin Trans. 1, 1994, 1675–1678.
49. M. P. Sibi, P. K. Deshpande, A. J. L. Loggia and J. W. Christensen, Tetrahedron Lett., 1995, 36, 8961–8964.
50. L. Liao, F. Zhang, O. Dmitrenko, R. D. Bach and J. M. Fox, J. Am. Chem. Soc., 2004, 126, 4490–4491.
51. N. Lewis, A. McKillop, R. J. K. Taylor and R. J. Watson, Synth. Commun., 1995, 25, 561–568.
52. P. G. M. Wuts and L. E. Pruitt, Synthesis, 1989, 622–623.
53. K. C. Nicolaou, Classics in Total Synthesis, Wiley-VCH, New York, New York, 5th edn, 2008, pp. 485–508.
54. A. C. Regan, J. Chem. Soc., Perkin Trans. 1, 1999, 357–373.
55. J. R. Gage and D. A. Evans, Org. Synth., 1990, 68, 83–91.
56. D. J. Ager, D. R. Allen and D. R. Schaad, Synthesis, 1996, 1283–1285.
57. D. A. Evans, M. D. Ennis and D. J. Mathre, J. Am. Chem. Soc., 1982, 104, 1737–1739.
58. S. G. Nelson, Tetrahedron: Asymmetry, 1998, 9, 357–389.
59. D. A. Evans, in Asymmetric Synthesis, ed. J. D. Morrison, Academic Press, New York, 1984, vol. 3.
60. C. H. Heathcock, Modern Enolate Chemistry: Regio- and stereoselective formation of enolates and the consequence of enolate configuration on Subsequent Reactions, VCH, Weinheim, 1992.
61. C. Gennari, Synthesis, 1990, 629–660.
62. T. A. Targel, J. N. Kumar, O. S. Shneider, S. Bar, N. Fridman, S. Maximenko and A. M. Szpilman, Org. Biomol. Chem., 2015, 13, 2546–2549.
63. (a) R. H. Currie and J. M. Goodman, Angew. Chem., Int. Ed., 2012, 51, 4695–4697; (b) D. A. Evans, D. H. B. Ripin, D. P. Halstead and K. R. Campos, J. Am. Chem. Soc., 1999, 121, 6816–6826; (c) T. Nakata, M. Fukui and T. Oishi, Tetrahedron Lett., 1988, 29, 2219–2222; (d) L. A. Paquette, M. Duan, I. Konetzki and C. Kempmann, J. Am. Chem. Soc., 2002, 124, 4257–4270; (e) G. Sirasani, T. Paul and R. B. Andrade, J. Org. Chem., 2008, 73, 6386–6388; (f) G. Sirasani, T. Paul and R. B. Andrade, Bioorg. Med. Chem., 2010, 18, 3648–3655; (g) A. B. Smith III and B. M. Brandt, Org. Lett., 2001, 3, 1685–1688; (h) E. M. Stang and M. C. White, Nat. Chem., 2009, 1, 547–551; (i) N. Waizumi, T. Itoh and T. Fukuyama, J. Am. Chem. Soc., 2000, 122, 7825–7826; (j) J. Willwacher, N. Kausch-Busies and A. Fuerstner, Angew. Chem., Int. Ed., 2012, 51, 12041–12046.
64. (a) J. Bartroli, E. Turmo, J. Belloc and J. Forn, J. Org. Chem., 1995, 60, 3000–3012; (b) M. G. Bock, R. M. DiPardo, B. E. Evans, K. E. Rittle, J. S. Boger, R. M. Freidinger and D. F. Veber, J. Chem. Soc., Chem. Commun., 1985, 109; (c) M. D. Burke, E. M. Berger and S. L. Schreiber, Science, 2003, 302, 613–618; (d) M. D. Burke, E. M. Berger and S. L. Schreiber, J. Am. Chem. Soc., 2004, 126, 14095–14104; (e) S. J. Davies, A. P. Ayscough, R. P. Beckett, R. A. Bragg, J. M. Clements, S. Doel, C. Grew, S. B. Launchbury, G. M. Perkins, L. M. Pratt, H. K. Smith, Z. M. Spavold, S. W. Thomas, R. S. Todd and M. Whittaker, Bioorg. Med. Chem. Lett., 2003, 13, 2709–2713; (f) T. M. Judge, G. Phillips, J. K. Morris, K. D. Lovasz, K. R. Romines, G. P. Luke, J. Tulinsky, J. M. Tustin, R. A. Chrusciel, L. A. Dolak, S. A. Mizsak, W. Watt, J. Morris, S. L. Vander Velde, J. W. Strohbach and R. B. Gammill, J. Am. Chem. Soc., 1997, 119, 3627–3628; (g) H.-S. Oh, J.-S. Yun, K.-H. Nah, H.-Y. Kang and D. H. Sherman, Eur. J. Org. Chem., 2007, 3369–3379; (h) K. K. Sharma and C. N. Boddy, Bioorg. Med. Chem. Lett., 2007, 17, 3034–3042.
65. (a) D. A. Evans, J. S. Clark, R. Metternich, V. J. Novack and G. S. Sheppard, J. Am. Chem. Soc., 1990, 112, 866–868; (b) V. Flores-Morales, M. Fernandez-Zertuche and M. Ordonez, Tetrahedron: Asymmetry, 2003, 14, 2693–2696; (c) T. Kimura, R. Shoda, N. Taniguchi, K. Kamikawa and M. Uemura, Inorg. Chim. Acta, 2004, 357, 1829–1835; (d) G. A. Molander and C. Kenny, J. Am. Chem. Soc., 1989, 111, 8236–8246; (e) K. R. Romines, K. D. Lovasz, S. A. Mizsak, J. K. Morris, E. P. Seest, F. Han, J. Tulinsky, T. M. Judge and R. B. Gammill, J. Org. Chem., 1999, 64, 1733–1737; (f) S. M. Sieburth and C.-A. Chen, Synlett, 1995, 928–930.
66. (a) R. M. DePardo and M. G. Bock, Tetrahedron Lett., 1983, 24, 4805–4808; (b) D. A. Evans, M. D. Ennis, T. Le, N. Mandel and G. Mandel, J. Am. Chem. Soc., 1984, 106, 1154–1156.
67. O. S. Shneider, E. Piseravsky, P. Fristrup and A. M. Szpilman, Org. Lett., 2015, 17, 282–285.
68. (a) J. Clayden, N. Geeves and S. Warren, Organic Chemistry, Oxford University Press, 2nd edn, 2012; (b) G. Procter, Asymmetric Synthesis, Oxford University Press, 1997; (c) G. Procter, Stereoselectivity in Organic Synthesis, Oxford primer, 1998.
69. D. G. Corely, R. Herb, R. E. Moore, P. J. Scheuer and V. J. Paul, J. Org. Chem., 1988, 53, 3644–3646.
70. E. Quinoa, Y. Kakou and P. Crews, J. Org. Chem., 1988, 53, 3642–3644.
71. S. Nishiyama, Tetrahedron Lett., 1997, 38, 6011–6014.
72. A. K. Saksena, V. M. Girijavallabhan, R. G. R. E. LoveyPike, J. A. Desai, A. Ganguly, K. R. S. Hare, D. Loebenberg, A. Cacciapuoti and R. M. Parmegiani, Bioorg. Med. Chem. Lett., 1995, 5, 2023–2028.
73. A. K. Saksena, V. M. Girijavallabhan, R. G. Lovey, R. E. Pike, H. Wang, A. K. Ganguly, B. Morgan, A. Zaks and M. S. Puar, Tetrahedron Lett., 1995, 36, 1787–1790.
74. A. K. Saksena, V. M. Girijavallabhan, H. Wang, Y. T. Liu, R. E. Pike and A. K. Ganguly, Tetrahedron Lett., 1996, 37, 5657–5660.
75. M. Nerz-Stormes and E. R. Thornton, Tetrahedron Lett., 1986, 27, 897–900.
76. D. A. Evans, F. Urpi, T. C. Somers, J. S. Clark and M. T. Bilodeau, J. Am. Chem. Soc., 1990, 112, 8215–8216.
77. A. K. Saksena, V. M. Girijavallabhan, R. G. Lovey, R. E. Pike, J. A. Desai, A. K. Ganguly, R. S. Hare, D. Loebenberg, A. Cacciapouti and R. M. Parmegiani, Bioorg. Med. Chem. Lett., 1994, 4, 2023–2028.
78. J. Kobayashi and M. Ishibashi, Chem. Rev., 1993, 93, 1753–1769.
79. M. M. Heravi, T. Baie Lashaki and N. Poorahmad, Tetrahedron: Asymmetry, 2015, 26, 405–495.
80. D. H. Lee and S. W. Lee, Tetrahedron Lett., 1997, 38, 7909–7910.
81. M. Kobayashi, S. Aoki, H. Sakai, N. Kihara, T. Sasaki and I. Kitagawa, Chem. Pharm. Bull., 1993, 41, 989–991.
82. G. R. Pettit, Z. A. Cichacz, F. Gao, C. L. Herald and M. R. Boyd, J. Am. Chem. Soc., 1993, 1166–1168.
83. D. A. Evans, P. J. Coleman and L. C. Dias, Angew. Chem., Int. Ed. Engl., 1997, 36, 2737–2741.
84. C. B. Rao, A. S. R. Anjaneyula, N. S. Sarma, Y. Venkataeswarlu, R. M. Rosser, D. J. Faulkner, M. H. M. Chen and J. Clardy, J. Am. Chem. Soc., 1984, 106, 7983–7984.
85. D. R. Williams and G. S. Cortez, Tetrahedron Lett., 1998, 39, 2675–2678.
86. G. J. Ho and D. J. Mathre, J. Org. Chem., 1995, 60, 2271–2273.
87. P. E. Maligres, V. Upadhyay, K. Rossen, S. J. Cianciosi, R. M. Purick, K. K. Eng, R. A. Reamer, D. Askin, R. P. Volante and P. J. Reider, Tetrahedron Lett., 1995, 36, 2195–2198.
88. H. S. Moon, S. W. E. Eisenberg, M. E. Wilson, N. E. Schore and M. J. Kurth, J. Org. Chem., 1994, 59, 6504–6505.
89. Y. Tamura, M. Mizutani, Y. Furukawa, S. Kawamura, Z. Yoshida, K. Yanagi and M. Minobe, J. Am. Chem. Soc., 1984, 106, 1079–1085.
90. K. Gerth, N. Bedrof, G. Hofle, H. Irschik and H. Reichenbach, J. Antibiot., 1996, 49, 560–563.
91. D. M. Bollag, P. A. McQueney, J. Zhu, O. Hensens, L. Koupal, J. Liesch, M. Goetz, E. Lazarides and C. M. Woods, Cancer Res., 1995, 55, 2325–2333.
92. Z. Yang, Y. He, D. Vourloumis, H. Vallberg and K. C. Nicolaou, Angew. Chem., Int. Ed. Engl., 1997, 36, 166–168.
93. T. K. Chakraborty and S. Dutta, Tetrahedron Lett., 1998, 39, 101–104.
94. T. P. Penning, S. W. Djuric, R. A. Haack, V. J. Kalish, J. M. Miyashiro, B. W. Rowell and S. S. Yu, Synth. Commun., 1990, 20, 307–312.
95. D. Faulkner, Nat. Prod. Rep., 1999, 16, 155–198.
96. T. Irie, M. Suzuki and T. Masamune, Tetrahedron Lett., 1965, 1091–1099.
97. M. T. Crimmins and K. A. Emmitte, Org. Lett., 1999, 1, 2029–2032.
98. D. A. Evans, J. R. Cage, J. L. Leighton and A. S. Kim, J. Org. Chem., 1992, 57, 1961–1963.
99. D. Swern, A. J. Mancuso and S. Huang, J. Org. Chem., 1978, 43, 2480–2482.
100. K. Kurata, A. Furusaki, K. Suehiro, C. Katayama and T. Suzuki, Chem. Lett., 1982, 1031–1034.
101. M. T. Crimmins, K. A. Emmitte and A. L. Choy, Tetrahedron, 2002, 58, 1817–1834.
102. M. T. Crimmins and K. A. Emmitte, J. Am. Chem. Soc., 2001, 123, 1533–1534.
103. G. Hofle, N. Bedrof, H. Steinmetz, D. Schomburg, K. Gerth and H. Reichenbach, Angew. Chem., Int. Ed., 1996, 108, 1671–1673.
104. K. C. Nicolaou, F. Roschangar and D. Vourloumis, Angew. Chem., Int. Ed., 1998, 110, 2120–2153.
105. J. Mulzer, G. Karig and P. Pojarliev, Tetrahedron Lett., 2000, 41, 7635–7638.
106. D. A. Evans, R. L. Dow, T. L. Shih, J. M. Takacs and R. Zahler, J. Am. Chem. Soc., 1990, 112, 5290–5313.
107. D. A. Evans, M. M. Morrissey and R. L. Dorow, J. Am. Chem. Soc., 1985, 107, 4346–4348.
108. H. J. Martin, M. Drescher and J. Mulzer, Angew. Chem., 2000, 112, 591–593.
109. J. Mulzer, A. Mantoulidis and E. Ohler, Tetrahedron Lett., 1998, 39, 8633–8636.
110. M. D’Ambrosio, A. Guerriero, C. Debitus and F. Pietra, Helv. Chim. Acta, 1996, 79, 51–60.
111. M. T. Crimmins, C. A. Carroll and B. W. King, Org. Lett., 2000, 2, 597–599.
112. G. H. Andrew and W. Q. Yu, Tetrahedron Lett., 2000, 41, 587–590.
113. A. G. Schultz and L. Pettus, J. Org. Chem., 1997, 62, 6855–6861.
114. D. A. Evans, R. P. Polniaszek, K. M. Devries, D. E. Guinn and D. J. Mathre, J. Am. Chem. Soc., 1991, 113, 7613–7630.
115. D. A. Evans, T. C. Britton and J. A. Ellman, Tetrahedron Lett., 1987, 28, 6141–6144.
116. D. A. Evans, D. L. Reiger, T. K. Jones and S. W. Kaldor, J. Org. Chem., 1990, 55, 6260–6268.
117. M. Prashad, D. Har, L. Chen, H. Y. Kim, O. Repic and T. J. Blacklock, J. Org. Chem., 2002, 67, 6612–6617.
118. A. M. Burja, B. Banaigs, E. Abou-Mansour, J. G. Burgess and P. C. Wright, Tetrahedron, 2001, 57, 9347–9377.
119. T. K. Chakraborty and A. Ghosh, Tetrahedron Lett., 2002, 43, 9691–9693.
120. I. Kawamoto, R. Endo, K. Ishikawa, K. Kojima, M. Miyauchi and E. Nakayama, Synlett, 1995, 575–577.
121. S. L. Mooberry, G. Tien, A. H. Hernandez, A. Plubrukarn and B. S. Davidson, Cancer Res., 1977, 37, 151–159.
122. A. K. Ghosh and Y. Wang, J. Am. Chem. Soc., 2000, 122, 11027–11028.
123. (a) A. K. Ghosh, Y. Wang and J. T. Kim, J. Org. Chem., 2001, 66, 8973–8982; (b) I. Paterson, C. De Savi and M. Tudge, Org. Lett., 2001, 3, 213–216.
124. (a) I. Paterson, C. De Savi and M. Tudge, Org. Lett., 2001, 3, 3149–3152; (b) J. Mulzer and E. Ohler, Angew. Chem., Int. Ed., 2001, 40, 3842–3846; (c) V. S. Evev, H. Kaehlig and J. Mulzer, J. Am. Chem. Soc., 2001, 123, 10764–10765.
125. M. T. Crimmins, M. G. Stanton and S. P. Allwein, J. Am. Chem. Soc., 2002, 124, 5958–5959.
126. J. Mulzer and E. Ohler, Chem. Rev., 2003, 103, 3753–3786.
127. C. M. Ireland, T. F. Molinski, D. M. Roll, T. M. Zabriskie, T. C. McKee, J. C. Swersey and M. P. Foster, Bioorg. Mar. Chem., 1989, 3, 1–46.
128. A. Zampella, M. V. D’Auria, L. G. Paloma, A. Casapullo, L. Minale, C. Debitus and Y. Henin, J. Am. Chem. Soc., 1996, 118, 6202–6209.
129. L. Trevisi, S. Bova, G. Cargnelli, D. Danieli-Betto, M. Floreani, E. Germinario, M. V. D’Auria and S. Luciani, Biochem. Biophys. Res. Commun., 2000, 279, 219–222.
130. V. Guerlavais, P. J. Carroll and M. M. Joullie, Tetrahedron: Asymmetry, 2002, 13, 675–680.
131. F. J. Walker and C. H. Heathcock, J. Org. Chem., 1991, 56, 5747–5750.
132. G. A. Smith and R. E. Gawley, Org. Synth., 1984, 63, 136–139.
133. D. A. Evans and D. Mathre, J. Org. Chem., 1985, 1830–1835.
134. A. J. Mancuso and D. Swern, Synthesis, 1981, 165–185.
135. T. T. Tidwell, Synthesis, 1990, 857–870.
136. J. Zyblir, F. Gaudemer and A. Gaudemer, Experientia, 1973, 29, 648–649.
137. M. Shindo, T. Sugioka, T. Umaba and K. Shishido, Tetrahedron Lett., 2004, 45, 8863–8866.
138. W. R. Roush, J. A. Straub and M. S. Nieuwenhze, J. Org. Chem., 1991, 56, 1636–1648.
139. T. Fehr, J. J. Sanglier, W. Schuler, L. Gschwind, M. Ponelle, W. Schilling and C. Wioland, J. Antibiot., 1996, 49, 230–233.
140. H. Fuwa, Y. Okamura and H. Natsugari, Tetrahedron, 2004, 60, 5341–5352.
141. T. K. Chakraborty and V. R. Suresh, Tetrahedron Lett., 1998, 39, 7775–7778.
142. W. H. Gerwick, L. T. Tan and N. Sitachitta, in Alkaloids, 2001, vol. 57, pp. 75–184.
143. H. Luesch, G. G. Harrigan, G. Goetz and F. D. Horgen, Curr. Med. Chem., 2002, 9, 1791–1806.
144. H. Chen, Y. Feng, Z. Xu and T. Ye, Tetrahedron, 2005, 61, 11132–11140.
145. P. Wipf, Y. Kim and P. C. Fritch, J. Org. Chem., 1993, 58, 7195–7203.
146. D. A. Evans, L. D. Wu and J. J. M. Wiener, J. Org. Chem., 1999, 64, 6411–6417.
147. R. J. Bartelt, A. A. Cosse, B. W. Zilkowski, D. Weisleder and F. A. Momany, J. Chem. Ecol., 2001, 27, 2397–2423.
148. M. C. Pirrung and A. T. Morehead Jr, A Sesquidecade of Sesquiterpenes: Total Synthesis, 1980–1994. Part A: A cyclic and Monocyclic Sesquiterpenes, in The Total Synthesis of Natural Products, ed. D. Goldsmith, John Wiley, New York, 1997, vol. 10, pp. 29–44.
149. J. R. Vyvyan, C. Loitz, R. E. Looper, C. S. Mattingly, E. A. Peterson and S. T. Staben, J. Org. Chem., 2004, 69, 2461–2468.
150. H. Rupe and A. Gassmann, Helv. Chim. Acta, 1936, 19, 569–581.
151. A. I. Meyers and R. K. Smith, Tetrahedron Lett., 1979, 2749–2752.
152. T. Sato, T. Kawara, A. Nishizawa and T. Fujisawa, Tetrahedron Lett., 1980, 21, 3377–3380.
153. C. Fuganti, S. Serra and A. Dulin, J. Chem. Soc., Perkin Trans. 1, 1999, 279–282.
154. A. Zhang and T. V. RajanBabu, Org. Lett., 2004, 6, 3159–3161.
155. T. Kitahara, Y. Furusho and K. Mori, Biosci., Biotechnol., Biochem., 1993, 57, 1137–1140.
156. K. Mori, Tetrahedron: Asymmetry, 2005, 16, 685–692.
157. B. A. Czeskis, D. D. O’Bannon, W. J. Wheeler and D. K. Clodfelter, J. Labelled Compd. Radiopharm., 2005, 48, 85–100.
158. M. K. Renner, Y. C. Shen, X. C. Cheng, P. R. Jensen, W. Frankmoelle, C. A. Kauffman, W. Fenical, E. Lobkovsky and J. Clardy, J. Am. Chem. Soc., 1999, 121, 11273–11276.
159. D. B. Hansen, M. L. Starr, N. Tolstoy and M. M. Joullie, Tetrahedron: Asymmetry, 2005, 16, 3623–3627.
160. S. J. Wen and Z. J. Yao, Org. Lett., 2004, 6, 2721–2724.
161. J. R. Gage and D. A. Evans, Org. Synth., 1990, 68, 77–82.
162. Y. Kato and P. J. Scheuer, J. Am. Chem. Soc., 1974, 96, 2245–2246.
163. S. S. Mitchell, D. J. Faulkner, K. Rubins and F. D. Bushman, J. Nat. Prod., 2000, 63, 279–282.
164. M. Entzeroth, A. J. Blackman, J. S. Mynderse and R. E. Moore, J. Org. Chem., 1985, 50, 1255–1259.
165. H. Knust and R. W. Hoffmann, Helv. Chim. Acta, 2003, 86, 1871–1892.
166. A. Cosp, E. Llacer, P. Romea and F. Urpi, Tetrahedron Lett., 2006, 47, 5819–5823.
167. S. H. Snyder, D. M. Sabatini, M. M. Lai, J. P. Steiner, G. S. Hamilton and P. D. Suzdak, Trends Pharmacol. Sci., 1998, 19, 21–26.
168. T. K. Chakraborty and B. K. Mohan, Tetrahedron Lett., 2006, 47, 4999–5002.
169. D. Porte Jr and M. W. Schwartz, Science, 1996, 272, 699–700.
170. R. Mukherjee, L. Jow, D. Noonan and D. P. McDonnell, J. Steroid Biochem. Mol. Biol., 1994, 51, 157–166.
171. J. I. Kasuga, Y. Hashimoto and H. Miyachi, Bioorg. Med. Chem. Lett., 2006, 16, 771–774.
172. M. Nomura, T. Tanase and H. Miyachi, Bioorg. Med. Chem. Lett., 2002, 12, 2101–2104.
173. D. Dube and A. A. Scholte, Tetrahedron Lett., 1999, 40, 2295–2298.
174. M. A. Kim, J. Y. Kim, K. S. Song, J. Kim and J. Lee, Tetrahedron, 2007, 63, 12845–12852.
175. R. Dharanipragada, K. Van Hulle, A. Bannister, S. Bear, L. Kennedy and V. J. Hruby, Tetrahedron, 1992, 48, 4733–4748.
176. M. Kita and D. Uemura, Chem. Lett., 2005, 34, 454–459.
177. D. Uemura, T. Chuo, T. Haino, A. Nagatsu, S. Fukuzawa, S. Zheng and H. Chen, J. Am. Chem. Soc., 1995, 117, 1155–1156.
178. S. Sakamoto, H. Sakazaki, K. Hagiwara, K. Kamada, K. Ishii, T. Noda, M. Inoue and M. Hirama, Angew. Chem., Int. Ed., 2004, 43, 6505–6510.
179. M. J. Pelc and A. Zakarian, Org. Lett., 2005, 7, 1629–1631.
180. C. E. Stivala and A. Zakarian, Tetrahedron Lett., 2007, 48, 6845–6848.
181. S. Muto, M. Bando and K. Mori, Eur. J. Org. Chem., 2004, 9, 1946–1952.
182. Y. Xu, X. Huo, X. Li, H. Zheng, X. She and X. Pan, Synlett, 2008, 1665–1668.
183. B. Kunze, R. Jansen, F. Sasse, G. Hofle and H. Reichenbach, J. Antibiot., 1995, 48, 1262–1266.
184. R. A. Hughes and C. J. Moody, Angew. Chem., Int. Ed., 2007, 119, 8076–8101.
185. A. Schmauder, S. Müller and M. E. Maier, Tetrahedron, 2008, 64, 6263–6269.
186. J. R. Gage and D. A. Evans, Org. Synth., 1989, 68, 77–82 (Org. Synth., 1993, 8, 528–531).
187. Z. Wang and L. Resnick, Tetrahedron, 2008, 64, 6440–6443.
188. J. Kobayashi and M. Tsuda, Nat. Prod. Rep., 2004, 21, 77–93.
189. J. Jin, Y. Chen, J. Wu and W. Dai, Org. Lett., 2007, 9, 2585–2588.
190. K. Shimbo, M. Tsuda, N. Izui and J. Kobayashi, J. Org. Chem., 2002, 67, 1020–1023.
191. A. K. Ghosh and G. Gong, J. Org. Chem., 2006, 71, 1085–1093.
192. N. A. Powell and W. R. Roush, Org. Lett., 2001, 3, 453–456.
193. D. K. Mohapatra, B. Chatterjee and M. K. Gurjar, Tetrahedron Lett., 2009, 50, 755–758.
194. A. V. Rama Rao, M. K. Gurjar, B. R. Nallaganchu and A. Bhandari, Tetrahedron Lett., 1993, 34, 7081–7084.
195. M. T. Crimmins and R. O. Mahony, J. Org. Chem., 1989, 54, 1157–1161.
196. D. B. Dess and J. C. Martin, J. Org. Chem., 1983, 48, 4155–4156.
197. A. E. Wright, J. C. Botelho, E. Guzman, D. Harmody, P. Linley, P. J. McCarthy, T. P. Pitts, S. A. Pomponi and J. K. Reed, J. Nat. Prod., 2007, 70, 412–416.
198. H. Fuwa, A. Saito, S. Naito, K. Konoki, M. Yotsu-Yamashita and M. Sasaki, Chem.–Eur. J., 2009, 15, 12807–12818.
199. E. J. Corey and A. Tramontano, J. Am. Chem. Soc., 1984, 106, 462–463.
200. Y. Sato, Y. Aso and M. Shindo, Tetrahedron Lett., 2009, 50, 4164–4166.
201. J. Berger, L. M. Jampolsky and M. W. Goldberg, Arch. Biochem. Biophys., 1949, 22, 476–478.
202. W. Keller-Schierlein, Helv. Chim. Acta, 1967, 50, 731–753.
203. B. F. Anderson, A. J. Herlt, R. W. Rickards and G. B. Robertson, Aust. J. Chem., 1989, 42, 717–730.
204. J. S. Yadav, P. Bezawada and V. Chenna, Tetrahedron Lett., 2009, 50, 3772–3775.
205. A. De Mico, R. Margarita, L. Parlanti, A. Vescovi and G. Piancatelli, J. Org. Chem., 1997, 62, 6974–6977.
206. D. C. Oh, C. A. Kauffman, P. R. Jensen and W. Fenical, J. Nat. Prod., 2007, 70, 515–520.
207. S. Li, S. Liang, W. Tan, Z. Xu and T. Yea, Tetrahedron, 2009, 65, 2695–2702.
208. D. Enders and S. Schüßeler, Tetrahedron Lett., 2002, 43, 3467–3470.
209. G. Yoon, Y. D. Jung and S. H. Cheon, Chem. Pharm. Bull., 2005, 53, 694–695.
210. H. J. Chang, G. Yoon, J. S. Park, M. H. Kim, M. K. Baek, N. H. Kim, B. A. Shin, B. W. Ahn, S. H. Cheon and Y. D. Jung, Biol. Pharm. Bull., 2007, 30, 2290–2293.
211. G. Yoon, W. Lee, S. Kim and S. H. Cheon, Bioorg. Med. Chem. Lett., 2009, 19, 5155–5157.
212. Z. Liu, G. Yoon and S. H. Cheon, Tetrahedron, 2010, 66, 3165–3172.
213. S. W. Goldstein, L. E. Overman and M. H. Rabinowitz, J. Org. Chem., 1992, 57, 1179–1190.
214. V. Mamane, A. B. Garcia, J. D. Umarye, T. Lessmann, S. Sommer and H. Waldmann, Tetrahedron, 2007, 63, 5754–5767.
215. T. Degenkolb and H. Bruckner, Chem. Biodiversity, 2008, 5, 1817–1843.
216. C. Toniolo, M. Crisma, F. Formaggio, C. Peggion, R. F. Epand and R. M. Epand, Cell. Mol. Life Sci., 2001, 58, 1179–1188.
217. T. Degenkolb, A. Berg, W. Gams, B. Schlegel and U. Gräfe, J. Pept. Sci., 2003, 9, 666–678.
218. L. Whimore and B. A. Wallace, Eur. Biophys. J., 2004, 33, 233–237.
219. S. Osada, T. Ishimaru, H. Kawasaki and H. Kodama, Heterocycles, 2006, 67, 421–431.
220. H. He, J. E. Janso, H. Y. Yang, V. S. Bernan, S. L. Lin and K. Yu, J. Nat. Prod., 2006, 69, 736–741.
221. W. Zhang, N. Ding and Y. Li, J. Pept. Sci., 2011, 17, 576–580.
222. J. H. Cardellina and R. E. Moore, Tetrahedron, 1980, 36, 993–996.
223. W. Herz and P. Kulanthaivel, Phytochemistry, 1985, 24, 89–91.
224. Y. Kurashina, A. Miura, M. Enomoto and S. Kuwahara, Tetrahedron, 2011, 67, 1649–1653.
225. D. Askin, R. A. Reamer, D. Joe, R. P. Volante and I. Shinkai, Tetrahedron Lett., 1989, 30, 6121–6124.
226. P. A. Grieco and N. Abood, J. Org. Chem., 1989, 54, 6008–6010.
227. B. Schmidt and H. Wildemann, J. Chem. Soc., Perkin Trans. 1, 2002, 1050–1060.
228. H. Luesch, W. Y. Yoshida, R. E. Moore, V. J. Paul and T. H. Corbett, J. Am. Chem. Soc., 2001, 123, 5418–5423.
229. S. Matthew, P. J. Schupp and H. Luesch, J. Nat. Prod., 2008, 71, 1113–1116.
230. J. Y. Ma, W. Huang and B. G. Wei, Tetrahedron Lett., 2011, 52, 4598–4601.
231. J. B. MacMillan and T. F. Molinski, Org. Lett., 2002, 4, 1535–1538.
232. D. D. Joarder and M. P. Jennings, Tetrahedron Lett., 2011, 52, 5124–5127.
233. C. P. Decicco and P. Grover, J. Org. Chem., 1996, 61, 3534–3541.
234. C. F. Weise, M. C. Pischl, A. Pfaltz and C. Schneider, J. Org. Chem., 2012, 77, 1477–1488; E. Walz, Final Results of the Third Biennial National Organic Farmers’ Survey, Organic Farming Research Foundation, Santa Cruz, CA, 1999.
235. A. Nakagawa, K. Tanaka, H. Yamaguchi, K. Nagai, K. Kamigiri, Y. Takeda, K. Suzumura and S. Takahashi, Application: WO, 2004/111076, Yamanouchi Pharmaceutical Co., Ltd., Japan.
236. V. Garcia-Ruiz and S. Woodward, Tetrahedron: Asymmetry, 2002, 13, 2177–2180.
237. R. H. Baltz, V. Miao and S. K. Wrigley, Nat. Prod. Rep., 2005, 22, 717–741.
238. K. M. VanderMolen, W. McCulloch, C. J. Pearce and N. H. Oberlies, J. Antibiot., 2011, 64, 525–531.
239. S. Kishimoto, Y. Tsunematsu, S. Nishimura, Y. Hayashi, A. Hattori and H. Kakeya, Tetrahedron, 2012, 68, 5572–5578.
240. M. G. Organ, Y. V. Bilokin and S. Bratovanov, J. Org. Chem., 2002, 67, 5176–5183.
241. J. S. Yadav, S. Sengupta, N. N. Yadav, D. N. Chary and A. A. Al Ghamdi, Tetrahedron Lett., 2012, 53, 5952–5954.
242. G. Odham, Ark. Kemi, 1963, 21, 379–393.
243. K. Mori and S. Kuwahara, Liebigs Ann. Chem., 1987, 555–556.
244. B. Chatterjee, D. Mondal and S. Bera, Tetrahedron: Asymmetry, 2012, 23, 1170–1185.
245. R. W. Kierstead, A. Faraone, F. Mennona, J. Mullin, R. W. Guthrie, H. Crowley, B. Simko and L. C. Blaber, J. Med. Chem., 1983, 26, 1561–1569.
246. G. J. Boons, G. H. Castle, J. A. Clase, P. Grice and S. V. Ley, Synlett, 1993, 913–914.
247. A. Grassia, I. Bruno, C. Debitus, S. Marzocco, A. Pinto, L. Gomez-aloma and R. Riccio, Tetrahedron, 2001, 57, 6257–6260.
248. G. V. Reddy, R. S. C. Kumar, G. Shankaraiah, K. S. Babu and J. M. Rao, Helv. Chim. Acta, 2013, 96, 1590–1600.
249. T. Kubota, T. Endo, Y. Takahashi, M. Tsuda and J. Kobayashi, J. Antibiot., 2006, 59, 512–516.
250. J. S. Yadav, A. S. Reddy, C. S. Reddy, B. V. S. Reddy, V. Saddanapu and A. Addalagatta, Eur. J. Org. Chem., 2011, 696–706.
251. P. R. Krishna, K. Anitha and G. Raju, Tetrahedron, 2013, 69, 1649–1657.
252. S. Takahashi, A. Kubota and T. Nakata, Angew. Chem., Int. Ed., 2002, 41, 4751–4754.
253. P. R. Krishna and K. Anitha, Tetrahedron Lett., 2011, 52, 4546–4549.
254. N. J. Sun, S. H. Woo, J. M. Cassady and R. M. Snapka, J. Nat. Prod., 1998, 61, 362–366.
255. Q. Q. Xu, Q. Zhao, G. S. Shan, X. C. Yang, Q. Y. Shi and X. Lei, Tetrahedron, 2013, 69, 10739–10746.
256. S. Matthew, L. A. Salvador, P. J. Schupp, V. J. Paul and H. Luesch, J. Nat. Prod., 2010, 73, 1544–1552.
257. G. Sudhakar, K. J. Reddy and J. B. Nanubolu, Tetrahedron, 2013, 69, 2419–2429.
258. A. Vasas and J. Hohmann, Nat. Prod. Rep., 2011, 28, 824–842.
259. K. Matsumoto, K. Koyachi and M. Shindo, Tetrahedron, 2013, 69, 1043–1049.
260. A. Schall and O. Reiser, Eur. J. Org. Chem., 2008, 2353–2364.
261. (a) J. L. Torres y Torres and J. P. N. Rosazza, J. Nat. Prod., 2001, 64, 1408–1414; (b) D. K. Tewary, A. Bhardwaj, A. Sharma, A. K. Sinha and A. Shanker, J. Pestic. Sci., 2006, 79, 1–12.
262. X. L. Liu, H. J. Chen, Y. Y. Yang, Y. Wu and J. You, Eur. J. Org. Chem., 2014, 3451–3459.
263. (a) R. Goeschke, V. Rasetti, N. C. Cohen, J. Rahuel, M. Grütter, S. Stutz, W. Fuhrer, J. M. Wood and J. Maibaum, 15th International Symposium on Medicinal Chemistry, Edinburgh, 1998; (b) J. Rahuel, V. Rasetti, J. Maibaum, H. Rüeger, R. Göschke, N. C. Cohen, S. Stutz, F. Cumin, W. Fuhrer, J. M. Wood and M. G. Grütter, Chem. Biol., 2000, 7, 493–504.
264. (a) J. Maibaum and D. L. Feldman, in Annual Reports in Medicinal Chemistry, ed. E. M. John, Academic Press, 2009, vol. 44, pp. 105–127; (b) C. Jensen, P. Herold and H. R. Brunner, Nat. Rev. Drug Discovery, 2008, 7, 399–410; (c) H. M. Siragy, S. Kar and P. Kirkpatrick, Nat. Rev. Drug Discovery, 2007, 6, 779–780.
265. (a) R. Lakerveld, B. Benyahia, P. L. Heider, H. Zhang, A. Wolfe, C. J. Testa, S. Ogden, D. R. Hersey, S. Mascia, J. M. B. Evans, R. D. Braatz and P. I. Barton, Org. Process Res. Dev., 2015, 19, 1088–1100; (b) P. L. Heider, S. C. Born, S. Basak, B. Benyahia, R. Lakerveld, H. Zhang, R. Hogan, L. Buchbinder, A. Wolfe, S. Mascia, J. M. B. Evans, T. F. Jamison and K. F. Jensen, Org. Process Res. Dev., 2014, 18, 402–409; (c) S. Mascia, P. L. Heider, H. Zhang, R. Lakerveld, B. Benyahia, P. I. Barton, R. D. Braatz, C. L. Cooney, J. M. B. Evans, T. F. Jamison, K. F. Jensen, A. S. Myerson and B. L. Trout, Angew. Chem., Int. Ed., 2013, 52, 12359–12363; (d) S. Hanessian and E. Chénard, Org. Lett., 2012, 14, 3222–3225; (e) Y. Nakamura, Y. Ogawa, C. Suzuki, T. Fujimoto, S. Miyazaki, K. Tamaki, T. Nishi and H. Suemune, Heterocycles, 2011, 83, 1587–1602.
266. L. Le-Le, D. Jin-Ying, G. Lian-Xun and H. Fu-She, Org. Biomol. Chem., 2015, 13, 1133–1140.
267. (a) F. Rolla, J. Org. Chem., 1981, 46, 3909–3911; (b) M. Sawamura, Y. Kawaguchi, K. Sato and E. Nakamura, Chem. Lett., 1997, 26, 705–706.
268. A. Shvartsbart and A. B. Smith, J. Am. Chem. Soc., 2015, 137, 3510–3519.
269. J. S. Yadav, A. K. Basak and P. Srihari, Tetrahedron Lett., 2007, 48, 2841–2843.
270. T. Ling, E. Griffith, K. Mitachi and F. Rivas, Org. Lett., 2013, 15, 5790–5793.
271. T. Ling, L. N. Gautam, E. Griffith, S. Das, W. Lang, W. R. Shadrick, A. Shelat, R. Lee and F. Rivas, Eur. J. Med. Chem., 2016, 110, 126–132.

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