Recent applications of the hetero Diels–Alder reaction in the total synthesis of natural products

Abstract

The synthetic utility and potential power of the Diels–Alder (D–A) reaction in organic chemistry is evident. These significances have been extended to the synthesis of a plethora and wide variety of heterocyclic compounds via [4 + 2] cycloaddition reactions, the so called hetero Diels–Alder (HDA) reaction. In this work we try to focus on the scope and preparative synthetic applications of the HDA reaction as a key step in the total synthesis of natural products.

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Majid M. Heravi

Majid M. Heravi received his B.S. degree in chemistry from the National University of Iran in 1975 and his M.S. and Ph.D. degrees in organic chemistry from Salford University, England in 1977 and 1980. He is currently professor in the department of chemistry at Alzahra University, Tehran, Iran. 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, and organic methodology. He has published more than 660 ISI cited papers so far.

Tahereh Ahmadi

Tahereh Ahmadi was born in 1975 in Shiraz, Iran. She graduated from Alzahra University, Tehran, Iran in 2007 under the supervision of Dr Shirazi Beheshtiha and received her MS degree in organic chemistry. She is currently working towards her Ph.D. in organic chemistry at Alzahra University under the supervision of Dr Ghodsi Mohammadi Ziarani. Her research focuses on the application of modified materials in the synthesis of heterocyclic compounds in the presence of nanostructure silicas as catalysts.

Mahdieh Ghavidel

Mahdieh Ghavidel was born in Tehran, Iran, in 1983. She graduated in chemistry in 2006 and received her MS degree in organic chemistry, in 2010, from Shahid Beheshti University, Iran. She is currently pursuing her Ph.D. degree in organic chemistry at Alzahra University, Tehran, Iran. Her research focuses on the application of multi-component reactions in the synthesis of new heterocyclic compounds.

Bahareh Heidari

Bahareh Heidari was born in Qorveh/Kurdistan, Iran, in 1989. She received her B.Sc. in chemistry from Razi University, Kermanshah, Iran in 2011, and her M.Sc. in organic chemistry from Shahid Beheshti University, Tehran, Iran, under the supervision of Dr Mohammad Reza Nabid, in 2013. Her research interests include synthesis, characterization and application of polymeric nanocomposites in the preparation of optical sensors to detect trace levels of metallic mercury and lead ions in aqueous environments. She is currently working towards her Ph.D. in organic chemistry at Alzahra University under the supervision of Dr Majid M. Heravi.

Hoda Hamidi

Hoda Hamidi was born in 1984 in Ramsar, Mazandaran, Iran. She received her B.Sc. degree in applied chemistry from Mohaghegh Ardebili University, Ardebil, Iran, in 2006. Also, she received her M.Sc. degree in organic chemistry from Alzahra University, Tehran, Iran, in 2010 and her Ph.D. in organic chemistry from Alzahra University, Tehran, Iran, in 2015 under the supervision of Prof. Majid Momahed Heravi. The interested field of her researches involves the synthesis of organic compounds particularly heterocycles and synthetic methodology.

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1. Introduction

Since the discovery of the Diels–Alder reaction (DA) by Otto Diels and Kurt Alder in 1928,¹ increasingly appreciable attempts and endeavors have been made to developing this useful methodology in different features, aspects, and issues. Undoubtedly, one of the most alluring and significant developments was the discovery and establishment of hetero-Diels–Alder (HDA) cycloaddition. It happens when the underlying concept is applied to other π-systems, such as carbonyls and imines to provide the corresponding heterocyles. This reaction was first conducted between aldehydes and dienes in an asymmetric fashion.^2–5 Imines can also employed as dienophiles in hetero Diels–Alder reactions. Similar to the D–A reaction, these reactions also involve the lowest unoccupied molecular orbital (LUMO) of the imine. It means that imines bearing electron-withdrawing groups on nitrogen are the most reactive.⁶ This transformation is very interesting since two newly generated bonds have the potential of being stereochemically controlled. In 1982, Danishefsky and his group discovered new types of HDA reactions using unactivated aldehyde and a diene, catalyzed by Lewis acid.⁷ Since then, several research groups have been concentrating on this area since the dihydropyranone products can be obtained from the reaction of an aldehyde with appropriate dienes. Pyran derivatives as a moiety are present in several natural products. The pivotal role of HDA reactions in the construction of heterocyclic scaffold can be translated to the synthesis of wide variety of heterocycles even with moderately complex structures.⁸ Noticeably, the HDA reactions generally proceed with high regio- and diastereoselectivity (generating to 4 contiguous chiral centers in a single step) and moderate to excellent de and chemical yields.^9,10

In recent years, intramolecular hetero-Diels–Alder (IMHDA) reactions have been employed extensively in organic synthesis, as a matter of fact chiefly due to their and stereocontrolled nature.^11–14 These reactions allow the construction of two or more rings simultaneously in a single step, escaping sequential chemical conversions.¹⁵ HDA reaction is a pericyclic reaction. These reactions are of especial interest due to their broad preparative importance in the chemistry of pharmaceuticals and naturally occurring compounds.¹⁶ Intramolecular hetero Diels–Alder (IMHDA) reactions seemed to be a versatile protocol for the construction of new polycyclic systems, which were fruitfully used in the design of framework for some naturally occurring products and biologically active compounds.^17–19

Due to these features, HDA reaction expectedly has been the subject of numerous reviews^20,21 and books^10,22 and have been extensively employed as key steps in the synthesis of several complex organic molecules.^23–32

Perhaps the most important feature of HDA is its asymmetric versions. It gives chemists the power and ability to generate, up to four adjoining stereogenic centers in single step. This can be achieved via different strategies such using either optically active dienes or hetero dienophiles. Alternatively, either chiral catalysts,³³ or chiral auxiliaries.^34,35 Asymmetric HDA reactions provide accessibility to chiral heterocyclic compounds in a similar. These chiral heterocyclic compounds can be the desired synthetic targets themselves or being highly functionalized intermediates which can be used in the synthesis more complex molecules including natural products. In the kingdom of plants and their power to biosynthesize biologically interesting compounds, asymmetric synthesis is a rule. Very recently, the asymmetric HDA reactions have been extensively reviewed.²⁰ We are interested in heterocyclic chemistry.^36–44 In addition, we are also keen on asymmetric synthesis.^45–49 We recently have been engaged in reviewing the applications of name reactions in total synthesis of natural products.^50–59 Very recently, we have published on the applications intramolecular Diels–Alder (IMDA) reaction in total synthesis of natural products.⁶⁰ Armed with these experiences, herein, we try to underscore the applications of HDA reaction in total synthesis of naturally occurring compounds, exhibiting biological properties.

2. Applications hetero Diels–Alder reaction in total synthesis

2.1. Intramolecular hetero Diels–Alder (IMHDA) reaction

In 2007, Jullian and his coworkers isolated the structurally complex sesterterpenoid and bolivianine, from Hedyosmum angustifolium (Chloranthaceae), along with another product named isobolivianine.⁶¹ Bolivianine bears a conspicuous heptacyclic framework and nine chiral centers. The convolution of this molecule has made it a fascinating candidate for biosynthesis and chemical synthesis. Jullian's research group suggested a hypothesis for its biosynthesis. As depicted in Scheme 1, the enal 4 could be provided via allylic oxidation of onoseriolide, a lindenane-type sesquiterpenoid that takes place together with bolivianine in H. angustifolium.^62–64 Synchronized hydrolysis of 4 followed by nucleophilic attack on geranylpyrophosphate (GPP). Ultimately, intramolecular IMHDA reaction gives bolivianine.

Scheme 1

Encouraged by this proposition and considering its steps, the total synthesis of bolivianine in a 14-step reactions was designed. That involved the synthesis of onoseriolide 3. Market purchasable (+)-verbenone (2) was chosen as stating material molecule for the synthesis of onoseriolide 3. The total synthesis includes a Pd-catalyzed intramolecular cyclopropanation involving an allylic metal carbene followed by a DA/IMHDA tandem reaction, letting a one-step assemblage of a tricyclic system having appropriate configuration.

A different route has also been envisaged for the total synthesis of onoseriolide and bolivianine, based on the modification of aforementioned hypothesis (Scheme 1). β-E-Ocimene (5), a natural monoterpene created from GPP in vivo, 4 is present in H. angustifolium.⁶⁵ Initially, onoseriolide (3) was reacted with 5 to give compound 7, which also was oxidized in vivo to compound 6 and ultimately yield bolivianine (1) (path a). On the other hand, initial oxidation of onoseriolide (3) could furnish 4, which could couple with 5 to yield bolivianine (1), via either a sequential cascade DA/IMHDA, cycloaddition (path b) or a HDA/IMDA reaction pathway (path c).⁶⁶

Polycycles having citran or cyclol nuclei are wide spread in nature.^67,68 They show a wide range of biological and pharmacological activities.^69,70 As part of research program focused on isolation of bioactive compounds from plants in China, in 2008 a sesquiterpene-chalcone conjugated sumadains A (9)⁷¹ with citran and chalcone frameworks were isolated from Alpinia katsumadai. This plant has been used as an antiemetic agent for centuries in folk Chinese medicine for the treatment of stomach disorders and it was remarkably has been registered and also coded in the Chinese pharmacopeia. A concise and efficient approach was reported for the total synthesis of 9. This strategy using a sequential reaction including the domino aldol-type reaction/electrocyclization/H-migration/HDA reaction, which eventually resulted in the fruitful synthesis of sumadain A (9). Using this protocol, the first total synthesis of sumadain A (9) was achieved. Scheme 2 illustrates a brief synthetic strategy leading to sumadain A (9). Treatment of 2,4,6-trihydroxyacetophenone (10) with trans, trans-farnesal in 20 mol% ethylenediamine diacetate in DMF under thermal conditions gave adduct 12 in satisfactory yield. The transformation of 12 to sumadain A (9) was successfully achieved by aldol condensation.⁷²

Scheme 2

The isocyanopupukeananes are classified as a new family of marine sesquiterpenes. 9-Isocyanopupukeanane was isolated from Phyllidia varicosa acquired.⁷³ 2-9-Isocyanopupukeanane also possesses the same framework.⁷⁴ Shortly after these isolations 9-isocyanoneopupukeanane⁷⁵ and 2-isocyanoallopupukeanane (14)⁷⁶ isomers as biogenetically related to the isocyanopupukeananes were provided by rearrangement routes.

The total synthesis of 2-isocyanoallopupukeanane (14) has been successfully achieved. This approach gives 14 as a racemate, starting from methyl-2-exo-methylbicyclo-[2.2.1]hept-5-ene-2-endo-carboxylate 15 which is subjected to dibromocarbene addition with subsequent S_N2′ substitution followed by chain elongation, to provide the unsaturated ketone 16. The latter is subjected to an IMHDA reaction, as a key step to give, 17 which is comprising all the skeletal carbon atoms. The dihydropyran unit was then cleaved via ozonolysis to give the tricarbocyclic intermediate which in seven further steps to elaborate this sophisticated total synthesis resulting in the formation of desired target 14.¹³ The reaction pathway is illustrated in Scheme 3.

Scheme 3

Many related fungi within the Aspergillus genus gives several metabolites of opposite absolute configuration, such as (+) or (−)-versicolamide B. These alkaloids are proposed being produced via biosynthetic Diels–Alder reactions, entailing that each Aspergillus species possesses enantiomerically divergent Diels–Alder reaction product. Experimental endorsement and support of these biosynthetic proposals via employing of the IMHDA reaction as a crucial step in the asymmetric total syntheses of (+)- and (−)-versicolamide B has been investigated. Operational validation proof of the suggested biosynthetic HDA construction, combined with the secondary metabolite profile of the producing fungi, discloses that each Aspergillus species has grown enantiomerically discrete indole oxidases, as well as enantiomerically discrete Diels–Alderases.

In this line, the laboratory operation commenced with the already known protected amino acid 19, coupling reaction of 19 with (R)-cis-3-hydroxy-L-proline (20) afforded the amide 21, with simultaneous cyclization gave the easily separable dioxopiperazines 22 and 23 (Scheme 4). Having the compounds 22 and 23 in pure form in hand, the oxidation of the indole C2–C3 double bond and HDA cycloaddition to complete the synthesis was contemplated. The enamide 24 or 26 was simultaneously underwent HDA reaction to give a mixture of (+)-versicolamide B ((+)-18) and the diastereomer (+)-28. In the same way, the enamide 25 or 27, under similar reaction conditions, gave a mixture of (−)-versicolamide B ((−)-18) and (−)-28) (Scheme 5).⁷⁷

Scheme 4

Scheme 5

The thiazolyl peptide antibiotics was initially isolated from Planobispora rosea ATCC53773. They showed selective anti-bacterial activity via inhibition of the bacterial elongation factor Tu, and not the eukaryote elongation factor-1 alpha.⁷⁸ The full structural elucidation of GE2270A (29) has been revealed via the outstanding endeavors of Tavecchia et al.,⁷⁹ and of Heckmann and Bach research group.^80,81 Besides, synthetic investigation toward the GE2270 factors were also accomplished and reported by Bach^80–82 and Shin's coworkers.^83,84

An efficient and relatively concise total synthesis of GE2270A (29) and GE2270T (30) via a convergent protocol that utilizes a HDA/dimerization process^85,86 as a key step to construct the trithiazolyl pyridine core of the molecule, has been achieved and reported.

In this approach, the thiazole derivative 31, previously synthesized,⁸⁵ was transformed into its methyl ester 32 in 84% chemical yield via a facile ester exchange.^87,88 The species 33 found being quite transitory and provided under the reaction conditions. After hydrolysis, the latter was subjected to HDA cycloaddition/dimerization to give, the amino dehydropiperidine segment 34 in satisfactory yield, albeit as a 1 : 1 mixture of trans diastereoisomers.⁸⁵ The Boc group was then cleaved off from this intermediate in the presence of TFA in CH₂Cl₂. This permitted its elongation to the glycine derivative 35 and 36 in 90% overall yield finally cleavage of the newly introduced Boc group (TFA), which was further extended to the macrocycle 37 (Scheme 6). In fact, reaction of 39 with L-proline amide 40 mediated by HATU and iPr₂NEt gave GE2270A (29) in 60% overall yield staring from 38. The generated intermediate oxazoline 38 run into along the way to form 29 which was also transformed into GE2270T (30) as depicted in Scheme 7.⁸⁹

Scheme 6

Scheme 7

The total syntheses of the thiopeptide antibiotics GE2270A, GE2270T, GE2270C1 (41) have been successfully by Nicolaou group in Scrript research center in San Diego Cal USA. The innovative synthetic protocol used the HDA cycloaddition reaction for the construction of the pyridine core of the desired molecules and based on a macrolactamization process to build up the macrocycle.⁹⁰

Of especial interest it was the possibility of modifying the HDA reaction downstream in order to shorten the sequence for the total synthesis of the tetrathiazole pyridine core segment 48 by several steps. In particular, an approach involving introduction of the hydroxyl phenylalanine subunit into the HDA precursor resulted in a strategy with more diversity. In this way the [4 + 2] dimerization step could be conducted on such a particularized system. In fact, this idea was examined in the laboratory (Scheme 8). Therefore, conversion of phenylalanine derivative 42 into its amide 43 (DCC, HOSu, NHOH) with treatment of the latter with the Lawesson reagent resulted in thioamide 44 in excellent yield over the two steps. After several steps thiazolidine 45 in 78% was obtained from 44. Delightfully, precursor 45 underwent into the desired D–A/dimerization cascade under optimized conditions (Ag₂CO₃, DBU, BnNH, py), thus giving the desired dehydropiperidine system 47 via the intermediacy of heterodiene 46. Ultimately, sequential deamination/aromatization of dehydropiperidine 47 was promoted with DBU in refluxing ethyl acetate to complete the total synthesis of tetrathiazole pyridine 48 (33% yield). The total synthesis of GE2270C1 (41) by these modified protocols, are called, complex HDA dimerization (synthesis of compound 48; Scheme 8).⁹⁰

Scheme 8

In the 1990s, Blackman and his coworkers reported the isolation of a small family of structurally related tricyclic alkaloids from the ascidian Clavelina cylindrica, which was found and collected from the east coast of Tasmania.^91–93 The major components of the alkaloidal extracted and isolated were identified as cylindricines A and B (49). Their structures were unambiguously elucidated by spectral analysis, and secured by X-ray crystallography of the corresponding picrates. Accordingly, it was found that cylindricine B have a C-ring-extended pyrido-[2,1-j]quinoline system.

For total synthesis, the required precursor for the crucial HDA step, tert-butyl acetoacetate, was chosen which was transformed to the Weiler dianion with subsequent alkylation with bromoethyl methyl ether to give 53 in satisfactory yield.⁹⁴ The latter was then converted intermediate 54, in two steps using following the previously procedure.⁹⁵ In the following was treated enamide 54 with TFA in dichloroethane at ambient temperature for relatively long period of time, with subsequent heating mediated by BF₃/Et₂O and anisole, resulting in the expected 3,5-dihydrooxazine cycloaddition product 55 as a single diastereoisomer in satisfactory chemical yield. In 2003, a strategy for the construction of the tricyclic pyridoquinoline framework of cylindricines B (49) and J (50) has been established based on use of HDA⁹⁵ and vinyl chloride RCM protocols.⁹⁶ Now determination of the C(2) stereochemistry of the key bicyclic intermediates 56a and 56b was intended. Ultimately, this diene was exposed into the second generation Grubbs ruthenium catalyst resulted in RCM product 57 in 36% yield over unoptimized conditions (Scheme 9). When the configuration was found correct for the cylindricines, the conversion of these compounds into the natural products via appropriate functional group manipulations was contemplated, designed and successfully achieved.⁹⁷

Scheme 9

Azimine (58)⁹⁸ and carpaine (59),^99,100 were initially isolated from Azima tetracantha L. and Carica papaya L., respectively and being the new family of macrocyclic dilactones comprising a 2,3,6-trisubstituted piperidine scaffold, and carpaine is reported to show a wide scope of biological activities as well as antitumor activity at even low concentrations.¹⁰¹ Synthetic potency in this field has led into the preparation of azimic acid^102,103 and carpamic acid^104,105 both as racemate and enantiomeric forms. However, there has been only a single report concerning with the synthesis of the macrocyclic dilactone family of alkaloid, carpaine (59), developed, and present jointly by Corey and Nicolaou.^106,107 In connection with studies on natural product, synthesis on the acylnitroso-DA protocol,^108–110 the enantioselective total syntheses of (+)-azimine and (+)-carpaine have been developed and reported. The synthesis started with (S)-1,2,4-butanetriol (60) as a single source of chirality (Scheme 10). Oxidation of 61 using NaIO₄ in aqueous medium¹¹¹ at 0 °C, the in situ created acylnitroso compound 62 which underwent IMHDA reaction afforded a 6.4 : 1 mixture of the trans and cis adducts (with respect to H4a and H5) 63 and 64 in 69% overall yield. The trans stereochemistry given to the major isomer 63 was relied on the ¹H NMR coupling constant of 8.8 Hz for two vicinal protons at C4a and C5 in an axial–axial organization. The final reactions resulted in the target azimine (58) and (+)-carpaine (59).¹¹²

Scheme 10

Lepadin A (65) was initially isolated by Steffan¹¹³ and his coworkers in 1991 from the tunicate Clavelina lepadiformis collected in the North Sea. As a matter of fact, this is the first species of a decahydroquinoline alkaloid from a marine natural source. Later, similar related compounds, lepadins B (66) and C (67), along with lepadin A have been observed in the predatory flatworm Prostheceraeus villatus and its tunicate prey C. lepadiformis.¹¹⁴ Lepadins A (65) and B (66) have demonstrated remarkable in vitro cytotoxicity toward human cancer cell lines.¹¹⁴ Literature survey showed no reports regarding the total synthesis of lepadins A and C. However, in 1999 Toyooka and Takahata research group¹¹⁵ has successfully accomplished and reported the total synthesis of the natural enantiomer of lepadin B, which resulted in approval of the suggested relative configuration and confirmed the absolute stereochemistry of this aforementioned alkaloid.

As depicted in the Scheme 11, the synthesis commenced from Horner–Emmons reaction of 69. Oxidation of 70 using tetrapropylammonium periodate (Pr₄NIO₄) under common nonaqueous conditions led to, in situ creation of acylnitroso compound 71. The latter was subjected to IMHDA cycloaddition reaction to afford the trans-oxazino lactam 72 as a chief isomer, albeit in very low diastereoselectivity of 1.7 : 1. The obtained (E)-alkenyl iodide 74, after several steps imposed on 72, played a key role as intermediate in the synthesis of the lepadin alkaloids. (−)Lepadin C (67) can undergo coupling reaction whereas (−)-lepadins A (65) and B (66) can be subjected into the Suzuki cross-coupling reaction.¹¹⁶

Scheme 11

Strychnine (75), which is found in abundantly in the Indian poison nut (Strychnos nux vomica) and Saint Ignatius' bean (Strychnos ignatii), is one the most notorious indole alkaloids.^117–119 The well-known toxicity of strychnine is consequences of its interaction with the strychnine sensitive glycine receptor in the lower brain stem and the spinal cord, hence disorderly normal nerve cell signaling and leading to overexcitation. Socrates, the renowned philosopher was forced to commit suicide by syrup of Strychnos nux vomica. In 1818, strychnine was initially isolated in pure form by Pelletier and his coworkers.¹²⁰ Robinson, in 1946 initially suggested the actual structure of strychnine via an extensive degradative analysis.^121,122 A year Woodward also independently proposed the same structure and announced strychnine as the most complex compound known for its molecular size.^123,124

IMHDA reaction of 79 gave 80 which was transformed into 81 in four steps,^125,126 The synthetic 81 thus can be converted into 75, which its spectral data (¹H NMR, ¹³C NMR, IR) was compared to those of identical an authentic sample and found being identical (Scheme 12).

Scheme 12

The related alkaloid akuammicine (82) was initially isolated from the seeds of Picralima klaineana,¹²⁷ and its structure shortly was elucidated.^128,129

The total synthesis of 82 has been accomplished and reported. The strategy involves the vinylogous Mannich reaction of 76 with 1-trimethylsilyloxybutadiene to afford 84 which subjected into the IMHDA reaction of 84 provide 85. In this way, thereby assembling the pentacyclic heteroyohimboid framework was assembled in just four steps starting from tryptamine (Scheme 13).¹³⁰ Before, to test of the feasibility of mimicking biosynthetic routes in accordance to Scheme 1, it was initially essential to convert 85 into 86 and 87. In fact, deformylgeissoschizine (87) is a key intermediate in several syntheses of the Corynanthe alkaloids. Accordingly, the feasibility of converting 87 directly into 82 was evaluated.¹³¹

Scheme 13

A tricyclic alkaloids, fasicularin (88) has been isolated in 1997 by Patil and his coworkers⁶⁵ from the Micronesian ascidian Nephtheis fascicularis, it has been found in being selective toward a DNA repair-deficient organism. Weinreb et al.¹³² attempted the synthesis of the presumed structure 95 for lepadiformine. Unexpectedly, they obtained a synthetic material, which was found being vividly and clearly, different from natural lepadiformine and it exists in a nonzwitterionic form as 95. In this line, Pearson et al.¹³³ have reported synthesis of the three other possible diastereomers of 95 at C(3) and C(5) and have declared that none of these three stereoisomers is actually, lepadiformine.¹³⁴

Shortly after (in 2000), the total synthesis of tricyclic marine alkaloids (±)-fasicularin (88) and (±)-lepadiformine (89) were claimed by Hideki Abe, and coworkers¹⁰⁹ In this approach, the decisive strategic element actually is the stereocontrolled IMHDA cycloaddition reaction of an N-acylnitroso moiety to an exocyclic diene, both with or without bromine substituent to control the syn-facial or anti-facial selectivity, resulting in formation of the trans- or cis-fused decahydroquinoline ring systems 93 or 94 respectively. This is a key and crucial step in the multi-step total synthesis provides a golden opportunity for the simultaneous introduction of the nitrogenated quaternary center in a single step. For further expansion of the six-membered or five-membered ring A, the trans-fused adduct 93 afforded either (±)-fasicularin (88) or (±)-lepadiformine (89). The comparison of physical and spectroscopic data revealed that the hydrochloride salt of synthetic compound is identical to (±)-89, isolated from natural source, and identified as lepadiformine. In this strategy initially, the synthesis of hydroxamic acid 91 required for the IMHDA cycloaddition to study the facial selectivity, was contemplated and designed. As illustrated in Scheme 14, the Horner–Emmons reaction of ketone readily obtainable 90 (ref. 135) was conducted to afford the desired precursor 91, after several steps. The latter was oxidized using Pr₄NIO₄ under the common nonaqueous conditions to create the corresponding acylnitroso compound 92 which was in situ underwent IMHDA cycloaddition reaction to afford the B/C trans-fused and cis-fused tricyclic lactams, 93 and 94, albeit in low diastereoselection of 2.1 : 1 and in 58% total yield.

Scheme 14

However, the tricyclic amino alcohol 95 having the suggested structure of lepadiformine in a nonzwitterionic form, obtained from the cis fused adduct 101, was established being totally dissimilar from lepadiformine via physical and spectral comparison. Thus the ketone 96 (ref. 135) was submitted to Horner–Emmons olefination to afford 97 after several steps. Subsequently, 97 was oxidized to give acylnitroso-diene 98 which in situ underwent to IMHDA cycloaddition reaction. This IMHDA reaction in the presence of 9,10-dimethylanthracene, proceeded smoothly to afford the corresponding adduct 100 in 84% yield (Scheme 15).¹⁰⁹

Scheme 15

The asymmetric synthesis of (−)-pumiliotoxin C (decahydroquinoline cis-195A) has been achieved and reported (102),^136–141 The latter was initially was isolated from skin extracts of the Panamanian poison-frog Dendrobates pumilio^142,143 as the first member of dendrobatid alkaloids.¹⁴⁴

This approach started from Wittig reaction of (2S,4S)-4-formyl-2-phenyl-1,3-dioxane (103) which afforded a mixture of (E)- and (Z)-dienes 104. Subsequently, 105 was oxidized using periodinane under nonaqueous conditions led to in situ formation of the intermediate acylnitroso diene 106 which simultaneously underwent IMHDA cycloaddition reaction to provide poor diastereoselectivity (1.4 : 1) of the trans (regarding to 4a-H and 5-H) vs. cis adducts (107 and 108). Compound 107 affords N-benzoyl-cis-decahydroquinolone 109 after several steps reaction. Ultimately, 110 with the precise oriented side chains at C-2 and C–S was subjected to desulfurization with RANEY® Ni with subsequent hydrogenolytic removal of the benzyl protecting group to afford (−)-pumiliotoxin C (102) (Scheme 16).¹⁴⁵

Scheme 16

3′-Prenylrubranine (111) bearing prenyl groups on citran rings were isolated from Mallotus philippinensis.^146,147 The extract obtained from Mallotus philippensis showed anti-bacterial potency.¹⁴⁷

Polycycles having citrans are wide spread in nature^67,148,149 and show a broad range of biological and pharmacological potencies.^69,70 In this approach compound 113 was provided in satisfactory yield via treatment of 2,4,6-trihydroxyacetophenone with prenyl bromide reaction of 113 with 1.2 equiv. citral at 100 °C for relatively long time in DMF gave tetracyclic adduct 115 in high yield. This protocol was also employed in one-step synthesis of natural 3′-prenylrubraine (111) from prepared adduct. Treatment of 115 with benzaldehyde afforded 3′-prenylrubraine (111) in excellent yield. This strategy is actually based on domino aldol-type reaction/electrocyclization/H-migration/HDA cycloaddition reaction.

This protocol was also employed in the first synthesis of unnatural petiolin D regioisomer (112) (Scheme 17).¹⁵⁰ Treatment of 116 with geranyl bromide mediated by N,N-diisopropylethylamine in DMF at ambient temperature for long period of time afforded 117 in satisfactory yield. Reaction of 117 with citral in the presence of 20 mol% ethylenediamine diacetate at 100 °C in DMF for relatively long reaction time gave adduct 112 in high yield. The structure and stereochemistry of 112 were suggested and approved via comparison of its spectral and physical data with those of previously reported for petiolin D which found being identical.¹⁵¹ A new synthetic approach for biologically interesting polycycles carrying prenylated, geranylated, and farnesylated citrans has been developed and reported. This strategy commences from substituted trihydroxybenzenes with prenyl, geranyl, and farnesyl groups on the benzene ring. This methodology based on cascade type sequential reaction including aldol-type reaction/electrocyclization/H-migration/HDA cycloaddition reaction. This approach was also employed in the synthesis of biologically important 3′-prenylrubranine (111) and petiolin D regioisomer (112).¹⁵⁰

Scheme 17

In 2002 Hemscheidt and his research group accomplished the discovery of a structurally important polycyclic natural product from an endophytic fungus utilizing a bioassay designed to perceive antimicrotubule/antimicrofilament agents.¹⁵² The unknown fungus was isolated from the bark of Ficus microcarpa L. which subsequently has been lost. Consequently, this natural product was called nomofungin (Fig. 1). Inquiringly, it was found that a structurally very similar natural product, communesin B 118 (Scheme 18), which has an NH instead of the suggested pyran oxygen for nomofungin,¹⁵³ HDA already been disclosed and remained relatively disregarded by the synthetic organic chemists. In addition, communesin B affords ¹H and ¹³C spectra closely similar to those revealed for nomofungin. In 2003 this divergence was disclosed by Stoltz et al. who suggested a biosynthetic pathway to communesin B via the oxidative coupling of tryptamine with the ergot alkaloid aurantioclavine.¹⁵⁴ Initially, experimental work validated this speculation and pressed the denial of the nomofungin structure.¹⁵⁵

Fig. 1 Ficus microcarpa L., nomofungin and communesin B.

Scheme 18

Delightfully, this general synthetic design illustrated in Scheme 18, was easily adapted which now required the creation of an aza-ortho-xylylene as a desired intermediate.¹⁵⁶ Expectedly, this reactive intermediate underwent the intramolecular cycloaddition with the indole heterodienophile and in this way introduce the “southern” aminal substructure of communesin B.¹⁵⁷ Pursuant to the purpose, ring opening of the already known epoxide 122 (ref. 158) with the benzazepine 121 afforded a mixture of regioisomer of amino alcohols that could be easily separated via conversion to the corresponding phenyl carbonates. The major carbonate 123 (ref. 159) was found to be an appropriate precursor to N-acyl-aza-ortho-xylylene 124 under thermolysis condition in dichlrobenzene which afford a single cycloadduct, aminal endo-125 as sole product. The stereochemical assignment was tenable upon hydrolysis of the carbamate motif of endo-125 to the aminal 120. More significantly, the chemical shift of the resonances for the aminal proton and aminal carbon of aminal 120 were identical to those reported for communesin B, previously.

A brief total synthesis of luotonin A, isolated from Peganum nigellastrum has been achieved and reported by Nomura and his coworkers in 1997.¹⁶⁰ Initially, the cyanide 130 was prepared via condensation of the amine 127 and 2-methoxybenzoic acid (128) mediated by BOP. Introduction of a nitrile group into 129 afforded the amide 130 in high yield. With the compound 130 available in hand, it was submitted into the vital IMHDA cycloaddition reaction. Treatment of 130 with TMSCl and Et₃N at 150 °C in toluene under pressure, mediated by ZnCl₂ gave luotonin A (126) in 46% yield (Scheme 19).¹⁶¹ The synthetic 126 was found identical with that reported, by comparison of its physical and spectroscopic data.¹⁶²

Scheme 19

Mappicine is an analog of camptothecin which was initially isolated from Mappia foetida.¹⁶³ Since the transformation of the ester 136 into mappicine (131) has been achieved by Kametani et al.¹⁶⁴ the synthesis of 136 completes the task. A novel synthetic route to mappicine (131) applying the IMHDA reaction as a key step has designed and being practiced.¹⁶⁵

The appropriate 2-chloroquinoline 132, was used as starting material being converted to the corresponding azide 133 via a two steps processes. However the formal synthesis of mappicine (131) began with compound 133 which was transformed to the unsaturated amide 134. IMHDA reaction of the latter resulted in the cycloadduct 135 (76%). At last, compound 135 was transformed into methyl ester 136 after several steps. The latter was then converted to mappicine (131) (Scheme 20).¹⁶⁵ This successful total synthesis was achieved and reported by Kametani et al. in 1975.¹⁶⁴

Scheme 20

Gloer and his coworkers in 1996 isolated the antiinsectan leporin A (137), which has been isolated from the sclerotia of Aspergillus leporis (NRRL 3126) by Gloer and his research group and its structure has been assigned, chiefly, based on 1D- and 2D-NMR experiments and studies.¹⁶⁶

The total synthesis of (±)-leporin A (137) has been achieved successfully and reported. This efficient approach involves a domino Knoevenagel condensation-inverse electron demand along with IMHDA cycloaddition reaction for construction of the key tricyclic 139 from pyridone 140 and dienal 141 via generation of intermediate 142 in one pot fashion to afford in overall 35% yield. The condensation of 140 and 141 in EtOH in the presence of piperidine and pyridine^167,168 gave variable quantities of the desired cis fused tricyclic inverse electron demand IMHDA adduct 139, along with the trans fused diastereomer 143, and two spiro fused DA adducts 144 and 145. Upon hydroxylation with subsequent methylation of 139 hydroxypyridone, 138 was obtained to complete the first total synthesis of (±)-leporin A (137) (Scheme 21).¹⁶⁹

Scheme 21

2.2. Hetero Diels–Alder (HDA) reaction

Aphadilactones A–D (146–149), a new family of diterpenoid dimers, were initially isolated from the leaves of Aphanamixis grandifolia, an arbor tree that grows chiefly in the tropical and subtropical areas of Asia, by Liu and his colleagues.¹⁷⁰ The total synthesis involves a catalytic asymmetric HDA cycloaddition reaction to construct the dihydropyran ring, along with simultaneous assemblage of the lactone and furan moieties via a cascade acid-catalyzed acetal cleavage/oxidation/cyclization process, and an IMHDA cycloaddition reaction to obtain the desired target products.

The reaction of alkoxybutadiene derivatives 150 with 2-butynal 151, was studied, revealing that 151 was actually an efficient partner in the stereoselective HDA reaction, giving cycloadducts 153 in high yield and excellent enantioselectivity (98% ee). Intermediate 154 was obtained in gram quantities. With key precursor 154 available in hand, the synthesis of 155 was then attempted which achieved in a three-step cascade sequence. Now, having monomer 155, available in hand, the stage was set to perform the bioinspired [4 + 2] dimerization/1,3 σ-hydrogen migration sequence to obtain the desired target. Aphadilactones A–D were produced in an approximate 1 : 1 : 1 : 1 mixture in satisfactory yield (Scheme 22). The synthetic samples obtained, had the identical ¹H and ¹³C NMR spectra with those of natural aphadilactones A–D.¹⁷¹

Scheme 22

Zhang et al. in 2008 isolated and elucidated the structure of a new sesquiterpene lactone dimer, (+)-ainsliadimer A (157), with an exceptional carbon skeleton from Ainsliaea macrocephala. It has been used in folk Chinese medicine for the treatment of different diseases, including angina and rheumatoid arthritis.¹⁷²

A protecting group free and biomimetic total synthesis of (+)-ainsliadimer A has been achieved in 14 steps starting from α-santonin. This synthetic approach based on a hydrogen bonding promoted HDA dimerization to provide the key homodimer intermediate, which shows the feasibility of employing nonenzymatic conditions to accomplish the suggested biosynthesis. The synthesis of dehydrozaluzanin C (162) started from α-santonin 158, a market purchasable material. Photolysis of 158 with a high-pressure Hg lamp (500 W), provided alkene 159 in satisfactory yield over two steps. Reaction of 160 with aluminum isopropoxide in toluene under microwave irradiation gave the R-allylic alcohol 3-epizaluzanin C (161), which upon oxidation by Dess–Martin procedure gave dehydrozaluzanin C (162). While this monomer 162 was available HDA dimerization could be examined to confirm the suggested biosynthetic process (Scheme 23). Worthy to mention here that hydrogen bonding catalysis that can mimic the effectiveness of enzymes or antibodies has recently attracted much attention as a significant progress in organic synthesis.¹⁷³ Encouraged by the sophisticated work of Rawal and his coworkers in hydrogen bond-promoted HDA cycloaddition reactions,^174–177 an extensive studies have started and going on.¹⁷⁸

Scheme 23

Synthesis of the dopamine derived alkaloids exiguamine A and B based on a biomimetic pericyclic reaction and oxidation cascade has been recently published (Scheme 24).¹⁷⁹ Exceptionally, the exiguamines generated in nature as racemic mixture and feature a spirobicyclic N,O-acetal as an important structural moiety. Thus the variecolortides (165a–b), a newly revealed family of racemate N,O-acetals, has stirred up, much interest.¹⁸⁰ These rarely occurring fungal natural products were isolated from a halotolerant strain of the fungus Aspergillus versicolor and exhibited moderate cytotoxic effects.¹⁸⁰

Scheme 24

A brief total synthesis of 165a and 165b has been successfully achieved. This strategy presents a remarkably facile approach resulted in linkage of the anthraquinone and diketopiperazine components by employing new type HDA reaction.¹⁸¹ This approach could be mimic of biosynthesis. The total synthesis of the variecolortides commenced with the providing of hydroxyviocristin (168; Scheme 24). Upon deprotonation the already known orsellinic acid was converted into anhydride 166,¹⁸² with subsequent addition of the resultant benzylic anion to chloro para-benzoquinone 167 which was transformed to hydroxyviocristin (168). For the incorporation of amino acid segment, carbobenzoxy-protected glycine 169 was condensed with serine methyl ester (170) to provide isoechinulin B (171a) as a sole single isomer via four steps.¹⁸³ A similar sequence beginning from indole 172 afforded neoechinulin B (171b; Scheme 24). Delightfully, HDA reaction of hydroxyviocristin (168) and isoechinulin B (171a) in ortho-dichlorobenzene under thermal conditions furnished variecolortide A in 48% yield. Analogously, variecolortide B was provided from building blocks 171b and 168.¹⁸⁴

Alantrypinone^185–187 (+)-173, is a polycyclic alkaloid. It has been found that is most probably biosynthetically derived from anthranilic acid and tryptophan. It was initially isolated from Penicillium thymicola in 1998. Its biological activities were evaluated at the isolation stage. In 2004, it was found that (+)-173 and (+)-serantrypinone,^188,189 which were isolated during binding assay based screening of fungal culture extracts, were insecticides. It was shown that this alkaloids are highly selective for insect (vs. mammalian) c-aminobutyric acid (GABA) receptors.¹⁹⁰ The design, synthesis, and biological properties of (±)-173 and these types of analogues were reported. For the total synthesis an approach for the synthesis of (±)-173 developed by Kende and coworkers was used.^186,187 Their strategy the synthesis of (±)-173 includes a HDA reaction between azadiene 176 and dienophile 178 as key step.

Kende's protocol includes the transformation of, 175 to 176. Primarily dienophile 178 was provided via the Peterson olefination of isatin (177). In a key step, HDA reaction of 176 with 178 took place regioselectively, to give desired (±)-exo-179 and undesired (±)-endo-179 in 52% and 18% respectively. By decreasing the amount of 176 in the reaction down to 1.5 equiv., (±)-endo-179 was provided in 43% yield together with 34% of (±)-exo-179. The same reactions under gave (±)-endo-179 with higher stereoselectivity under thermal conditions. These results reveal that (±)-endo-179 is a thermodynamically stable product. As a result (±)-exo-179 and (±)-endo-179 were converted to (±)-173 and (±)-174, respectively, using Kende protocol, reported hitherto. The synthetic pathway and results are illustrated in Scheme 25.¹⁹¹

Scheme 25

Brevetoxins secreted by the dinoflagellate Ptychodiscus brevis may cause wide-ranging natural catastrophe.¹⁹² Nakanishi et al. in 1981 reported the elucidation structure of brevetoxin B, as a first member of a new family of structurally unique marine toxins.¹⁹³ Brevetoxin has 11 adjoining trans-fused cyclic ether rings, fabulously arranged in a “ladder-like” rigid background.¹⁹³ Nakanishi et al. suggested an interesting biogenetic scheme showing that brevetoxins may be biosynthesized via a polyepoxide tandem cyclization.¹⁹⁴ An extensive investigation for ladder-frame polyethers resulted in the elucidation structure of brevenal (180) isolated from Karenia brevis (Fig. 2).^195,196 Delightfully, this smaller polyether was found to be an antagonist of brevetoxins. Recently, Wright et al. reported the isolation of a new marine alkaloid, brevisamide (181), from K. brevis (Fig. 2). Apparently it is the biogenetic template for the polyepoxide tandem reaction resulted in brevenal.¹⁹⁷ Satake and co-workers achieved and reported the first total synthesis relied on a multi-step build of the substituted tetrahydropyran ring as well as Suzuki–Miyaura coupling of the segments.¹⁹⁸ Lindsley et al. has recently reported their achievement to discover another approach to brevisamide.¹⁹⁹

Fig. 2 Brevenal and Brevisamide from K. brevis.

An asymmetric total synthesis of brevisamide relied upon a strategic easy installation of the highly substituted tetrahydropyran ring employing Jacobsen's asymmetric HDA reaction.^200,201 The protocol reduces high junction and flexibility to structural modulation. Initially aldehyde 182 (ref. 202) is transformed to enone 183 through addition of ethylmagnesium bromide with subsequent Swern oxidation to give 183 in high yield over two steps. The latter was reacted with TESOTf mediated by Et₃N to provide triethylsilyl diene 184 in high yield. Upon Jacobsen's asymmetric catalytic HDA cycloaddition reaction of diene 184 and aldehyde 185 in the presence of 152 mol% Jacobsen's chromium catalyst 152,²⁰⁰ and in the presence of molecular sieves the desired cycloadduct 186 in satisfactory yield was obtained. Scheme 26 shows the synthesis of brevisamide via installation of tetrahydropyran 187 and vinyl iodide 188 employing a Suzuki–Miyaura coupling reaction as the crucial step as used by Dossetter and Liu et al.^200,201 The cross-coupling of the resultant alkylborane and iodide 188 employing a catalytic quantity of PdCl₂-(dppf) in dichloromethane afforded a TBS–ether as an intermediate. This intermediate was then desilylated to afford 189 in moderate yield over two steps. Upon selective oxidation of the allylic alcohol in 189 gave synthetic brevisamide 181 in pure form and 87% chemical yield.²⁰³

Scheme 26

The ipecacuanha alkaloid emetine (190) and the Alangium alkaloid tubulosine (191) are placed in the group of tetrahydroisoquinoline alkaloids. It is suggested that they are created in nature from dopamine and the monoterpene secologanin. Emetine (190) was initially isolated from Radix ipecacuanha and the roots of Psychotria ipecacuanha and Cephalis acuminata^204,205 and possesses multifold remarkable biological and biological potency. It exhibits antiprotozoic properties²⁰⁶ and is used in the treatment of lymphatic leukaemia.²⁰⁷ At the present time, emetine (190) is a banned drug due to its substantial toxicity. Tubulosine (191) was initially isolated from the dried fruits of Alangium lamarckii²⁰⁸ and the sap of Pogonopus speciosus.²⁰⁹ It is significantly active towards several cancer cell lines²⁰⁹ and has been investigated for different biological properties, acting as inhibitor in protein biosynthesis²¹⁰ and inhibition of HIV reverse transcriptase.²¹¹

Protection of the secondary amino group along with CbzCl, deprotection of the TIPS group combined with oxidation of the generated primary hydroxy group resulted in the aldehyde (1S)-192. The domino reaction of (1S)-192, Meldrum's acid 193 and enol ether 194 was conducted under catalysis of ethylene diammonium diacetate. Initially, the 1-oxa-1,3-butadiene 195 is generated, which is converted 196 in a HDA reaction with inverse electron demand; under the reaction conditions 196 CO₂ is lost and acetone to give 197 as the desired product. The latter was then gave the benzoquinolizidine 198. Further conversion of 198 afforded enantiopure emetine (190) and tubulosine (191), respectively (Scheme 27). Besides, commencing from 197 the new benzoquinolizidine alkaloid 199 was prepared.²¹²

Scheme 27

Luotonin A is a structurally related cytotoxic alkaloid. It was initially isolated in 1997 from the aerial parts of Peganum nigellastrum Bunge.¹⁶² This plant has been used for a centuries in Chinese folk medicine for the treatment of various conditions, including rheumatism and inflammation. Luotonin A has attracted the attentions of several research group.^213–216 Particularly worthy to mention is an intermolecular Povarov approach to the synthesis of luotonin A, which has been reported by Stevenson et al.²¹⁴

Pyrrolo[3,4-b]quinolines could be provided via the coupling of anilines with N-propargylic substituted heterocyclic aldehydes mediated by mild Lewis acid catalysts such as (Ln(OTf)₃). The coupling proceeds via sequential reaction involving imine generation/a proper intramolecular aza-DA (Povarov) reaction. This strategy was employed in a total synthesis of luotonin A. The synthesis of luotonin A employing similar strategy requires the use of a quinazolinone aldehyde 201 as precursor. Ring-opening of market purchasable isatoic anhydride using propargylamine provided 2-amino benzamide 202 in satisfactory yield.²¹⁷ The latter was transformed to 203 in several step. Removal of the acetate group from 203 afforded the aldehyde precursor 204. HDA (Povarov) reaction between 204 and aniline took place in the presence of 10 mol% Dy(OTf)₃ in CH₃CN only in relatively long reaction time to afford luotonin A (Scheme 28). Apparently further oxidation of the initially generated 1,2-dihydroquinoline occurs in situ, resulted in isolation of impure luotonin A which after purification by flash column chromatography gave the pure desired natural product in 51% yield.²¹⁸

Scheme 28

Pyrido[4,3,2-mn]acridine alkaloids is a representative in a group of naturally occurring compounds, isolated from marine source. It have shown several remarkable biological potencies, such as tumor toxicity and are acting as fungal growth inhibitors. The isolation and structural elucidation of arnoamines A and B, as the first members of the pyridoacridine family that bears pyrrole fused to the pyridoacridine ring system, has been reported by Plubrukarn and Davidson²¹⁹ in 1998. Their total synthesis has been successfully achieved and reported.²²⁰ In 2002, the total synthesis of pyridoacridine alkaloid, sebastianine A (206) were accomplished and reported by Torres et al., from the ascidian Cystodytes delle chiaijei.²²¹

In this strategy, the two dienophiles 208 and 210 were prepared commencing, from 4,7-dimethoxyindole 207. The HDA cycloaddition reactions with both aforementioned dienophiles 208 and 210 in toluene under reflux conditions gave 212a/212b and 213a/213b in low yield upon oxidative aromatization using MnO₂ (8 and 6%, respectively) as a mixture of the two regioisomers 212a/212b and 213a/213b (Scheme 29). The HDA adducts 213a were then cyclized in the presence of aqueous sodium hydroxide to afford the corresponding pentacyclic compounds 206 in high yield.²²²

Scheme 29

Native people in Amazonian lowland, used to treat different types of eye ailments, such as inflammation and conjunctivitis with the extract obtained from root of the Martinella iquitosensis.²²³ It has been realized, that, two new guanidine alkaloids, martinellic acid 214a and martinelline 214b, present in extract are probably responsible for such medicinal usefulness. 214a and 214b have been screened, showing moderate antibiotics activity and also they micromolar binders of several G-protein coupled receptors.²²⁴

The total synthesis of 215 has been accomplished and reported. The total synthesis starts from methyl 4-aminobenzoate 215 which upon reaction with N-Cbz-2-pyrroline 216 gives the hexahydropyrrolo[3,2-c]quinoline core 217 of martinelline as a diastereomeric mixture with the ratio of 85 : 15 unfortunately in favor of the undesired endo substance (Scheme 30). A brief total synthesis of the guanidine alkaloids, (±)-martinelline and (±)-martinellic acid have been designed, operated and successfully achieved. In a key step a protic acid catalyzed HDA cycloaddition/coupling reaction between N-Cbz-2-pyrroline 216 and methyl-4-aminobenzoate 215, 2 : 1 was employed. Interestingly it was the use of protic acid catalysis, instead of Lewis acid catalysis, was compulsory to obtain the desired mode of diastereocontrol in the coupling reaction. This strategy caused the fast synthesis of (±)-martinellic acid and the biologically more important (±)-martinelline in 10% overall yield over nine steps via the longest linear sequence. 217 were then transformed into 218 in several steps using different functional group conversions. Deprotection of the two Boc groups which still remained in the molecule using TFA/CH₂Cl₂ with subsequent HPLC purification gave (±)-martinellic acid 214a in 14% overall yield in eight steps. On the other hand, after 2 steps martinelline 214b was obtained via deprotection of the Boc groups using TFA in dichloromethane, with subsequent reversed-phase preparative HPLC.²²⁵ This product showed identical spectroscopic data with those of the original natural products.²²⁴

Scheme 30

Several plants of the Euphorbiaceae family, especially those of the Securinega and Phyllanthus genera, provide a group of tetracyclic compounds classified as the Securinega alkaloids.²²⁶ Securinine, the main alkaloid which was isolated from the leaves of Securinega suffruticosa. Its structure elucidated in the 1960s.²²⁷ Subsequently, several other Securinega alkaloids were isolated. They contain the A-ring methoxylated compound phyllanthine (219).^228,229

The A-ring of phyllanthine (219) was successfully, synthesized from hydroxyketone 220 via a stereoselective Yb(OTf)₃-catalyzed HDA reaction of the imine 221 with Danishefsky's diene employing various common Lewis acid catalysts such as SnCl₄, TiCl₄, providing adduct 222. Conjugate reduction combined with asymmetric equatorial ketone reduction of vinylogous amide 222 gave tricyclic intermediate 223, which could be subsequently transformed in a few to stable hydroxyenone 225 in few steps, via the generation of R-selenophenylenone intermediate 223 (Scheme 31). Then D-ring was constructed, again employing an intramolecular Wadsworth–Horner–Emmons olefination reaction to afford phyllanthine (219).²³⁰

Scheme 31

The indole alkaloids^231,232 hirsutine 225 (ref. 233–235) and dihydrocorynantheine both are classified in the corynanthe family. They were isolated from the plant Uncaria rhynchophylla MIQ. This plant has been used in the preparation traditional Chinese medicine “Kampo.” for centuries.

In 2002, hirsutine 226 has tremendous attention in medicine, since it has been found showing to inhibit the growth of the influenza A virus. The total synthesis of hirsutine 226 has been accomplished successfully and reported. In this approach the enantiopure tetrahydro-β-carboline (3R)-aldehyde 227 was reacted with a mixture of Meldrum's acid 194 and the enol ether 228 (E/Z: 1 : 1) promoted by a catalytic amount of EDDA (ethylenediammonium diacetate) to afford 231 in high yield. It is proposed that this transformation occurs via a domino Knoevenegl–HDA. A 1,3 induction of >20 : 1, generates the Knoevenegl product 229 as an intermediate. This followed by transformation of 230, via HDA reaction which upon loss of CO₂ and acetone by reaction with water gives 231 (Scheme 32). The latter was transformed to the desired natural product (−)-hirsutine 226 via formation of 232 in several steps.²³⁶

Scheme 32

Agelastatin was initially isolated in 1993 from the deep water marine sponge Agelas dendromorpha by Pietra and his research group. The sample for isolation had been collected from deep water from the Coral Sea near New Caledonia.^237–239

A relatively concise total synthesis of agelastatin A (233), a cytotoxic marine metabolite, has been accomplished and reported. This approach interestingly starts from cyclopentadiene which upon HDA cycloaddition reaction with N-sulfinyl methyl carbamate (235) gave cycloadduct 236. The latter in several steps was transformed to silylpyrrole 237, which could be transformed to bromopyrrole 238. At last, the D-ring could be annulated onto an R-amino ketone derived from 238 employing methyl isocycanate, to afford racemic agelastatin A (233) (Scheme 33). This total synthesis has been completed in 14 steps, conducted in 12 operations giving the desired natural product in about 0.7% overall yield.²⁴⁰

Scheme 33

In the mid-1970s a new class of amphibian alkaloid epibatidine was initially isolated only in a trace quantity from the skin of the Ecuadorian poison frog, Epipedobates tricolor, of the family Dendrobatidae by Daly and his research group.²⁴¹ It took long time when in 1992 its structure 239 was elucidated.²⁴² This structure elucidation disclosed the relative stereochemistry and exceptional feature having a strained nitrogen-bridged six-membered carbon ring system (7-azabicyclo[2.2.1]heptane) carrying an exooriented 3-(6-chloropyridyl) substituent. Due to obtaining the very tiny amounts of the natural product (less than 1 mg can be isolated and collected from about 750 frogs), the assignment of absolute stereochemistry was difficult. However in 1994 Fletcher et al.^243,244 disclosed the absolute configuration, establishing it as 1R, 2R and 4S as illustrated in Scheme 34. Because of the shown unprecedented biological properties, interesting structure, and insufficiency in nature, epibatidine has attracted enormous attention of synthetic organic chemists worldwide,²⁴⁵ and shortly a plethora of synthetic strategy has been practiced and some of the successfully were accomplished.^246–251 Among these synthetic strategies, nevertheless, only two stereoselective total syntheses of (−)-epibatidine (239), a naturally occurring enantiomer, have been reported: (a) via Pd-catalyzed desymmetrization reported by Trost and co-workers²⁴⁹ and (b) via stereoselective protonation revealed by Kosugi et al.²⁴⁸ A stereoselective total synthesis of (−)-epibatidine (239) has been accomplished via development of stereoselective HDA cycloaddition with an N-acylnitroso dienophile carrying the optically active 8-arylmenthol as a chiral element. Therefore, upon in situ oxidation of the hydroxamic acid ent-241 incorporating the (1S,2R,5S)-8-(2-naphthyl)menthyl auxiliary was conducted applying the Swern conditions to produce the acylnitroso dienophile, which reacted rapidly with 2-chloro-5-(1,5-cyclohexadienyl)pyridine (242) to afford the (1S,4R)-meta-aza cycloadduct 243 as a major diastereoisomer. The resulted facial diastereoselectivity is consistent with a transitional state model with the naphthyl group in “stacked” position along with the acylnitroso group standing in the s-cis conformation, whereas π attractive interaction between the naphthyl and nitrosocarbonyl groups could control the facial stereoselectivity. In the following, compound 244 upon hydrogenation with subsequent of removing of the chiral auxiliary using LiH₂NBH₃ followed by reductive cleavage of the N–O bond using Mo(CO)₆ afforded the amino alcohol derivative 246. The latter was then transformed to (−)-epibatidine 239 through bromination with subsequent cyclization.²⁵²

Scheme 34

In 1993 polycavernoside A (247) was isolated by Yasumoto research group, along with a small amount of analogue polycavernoside B, as relevant toxins for the lethal human poisoning which happened in Guam in 1991 and in the Philippines in 2002–2003. The fatal cause was recognized being to the ingestion of the comestible red alga Gracilaria edulis (Polycavernosa tsudai).^253,254

In a total synthesis achieved by Sasaki group initially (−)-polycavernoside A converted to the THP (tetrahydropyran) ring via catalyzed asymmetric HDA cycloaddition, occurred between silyloxy diene 249 and aldehyde 250, in the presence of 152 to give the desired product 251. The latter was converted to desired tetrahydropyran 252 excellent yield in two steps including reduction (Scheme 35).²⁵⁵

Scheme 35

At last, glycosylation of 253 with thioglycoside 254 (ref. 256 and 257) in the presence of NBS²⁵⁸ (41%), was subjected into oxidative cleavage of the benzyl ether using DDQ (68%), followed by Stille coupling with the already known dienylstannane 255 (ref. 259 and 260) (45%) to achieve the synthesis of (−)-polycavernoside A (247).^52,261,262

Pederin (256) historical among bioactive natural products.²⁶³ Its presence in the haemolymph of rove beetles of the genus Paederus, has been recognized.²⁶⁴ Initially it was isolated in 1919 as a crystalline compound by Netolitzky. It was screened and found to be an active vesicant.²⁶⁵ Interestingly, Pavan and Bo collected massive Paederus fuscipes beetles, to be certain to isolate an appreciable amount of pure pederin, for further elucidation of its structure. In 1965 its structure was determined and reported by to allow its chemical formula and provisional structure to be determined by Quilico et al.²⁶⁶ Remarkably, Matsumoto et al. independently suggested a marginally modified structure for pederin,²⁶⁷ This modified structure latter was confirmed and validated by single crystal X-ray analysis.^267,268

The total synthesis of pederin was also claimed by Rawal group which also employed a HDA cycloaddition reaction as a vital step. Pyranone 259 initially was prepared reaction between 257 and 258 mediated by Al(2,6-diphenylphenol)₂Me and TMSOTf. In the last step of reaction again HDA reaction was performed affording THP ring 260 in excellent yield (Scheme 36).^262,269 The addition of this acid chloride in toluene gave to the lithium anion 260 which was converted to protected pederin 262 in satisfactory yield over two steps. Upon deprotection via initial treatment with TBAF with subsequent hydrolytic quench afforded pederin (256) in 88% yield.

Scheme 36

Azaspiracid poisoning is a recent toxic syndrome initially discovered and revealed in 1995. In one instance, at least 8 people became dizzy in Netherlands after overwhelming blue mussels (Mytilus edulis) harvested.²⁷⁰ The intoxications due to azaspiracid poisoning were also observed in several other countries. Due to these observations and incidents, natural product chemists were motivated for isolation of this compound. In 1998 Satake group proposed²⁷¹ marine dinoflagellate,²⁷² as the origin and their occurrence has assumed in multiple shellfish species involving mussels, oysters, scallops, clams, and cockles.²⁷² The interesting structure of this toxin has stimulate several research group worldwide and particularly motivated Nicolaou,²⁷³ Carter,²⁷⁴ Forsyth,²⁷⁵ research groups as well as some others.²⁷⁶ Eventually in 2003 it was Nicolaou group accomplished a fruitful synthesis of the suggested structure 263, and confirmed clearly the structure suggested for isolated natural product.^277–279

During the total synthesis, this group prepared THP rings in (+)-azaspiracid via HDA cycloaddition reaction. The THP E-ring 268 was constructed from dihydropyran 267. The latter in turn synthesized via a HDA reaction between 264 and 265 in the presence of copper box-complex 266. However this reaction afforded a mixture of cis and trans diastereomers in a total yield of 84% (Scheme 37).²⁷⁷

Scheme 37

The sulfone anion obtained from 269 was created using n-BuLi followed by addition to aldehyde 270 which subsequently quenched at −78 °C in pH 5 buffer. Delightfully, this approach gave a 50% overall yield. Noticeably, the lactol diastereomers 271 and 272 were easily separated in virtually equal amounts by flash column chromatography.²⁸⁰ This step actually successfully completed the total synthesis of (+)-azaspiracid-1 (ent-263).²⁷⁷

Illicium oligandrum has been for long time, as long as centuries, used as Chinese traditional medicine mostly for the treatment of rheumatoid arthritis. Yu et al. initially isolated a pair of spiro carbon epimers, spirooliganones A and B, from the roots of I. oligandrum and revealed their results in 2013.²⁸¹

A facile and efficient approach to achieve the stereoselective total syntheses of (−)-spirooliganones A and B in 8 steps has been disclosed. This strategy uses market purchasable 1,3-cyclohexanedione, formalin, (−)-sabinene, prenyl bromide, and allyl bromide. As shown in Scheme 38, the synthesis commenced with preparation the tetracyclic intermediate 278a and 278b. Upon Hoffmann conditions,^282–285 1,3-cyclohexanedione was reacted with formalin and (−)-sabinene in acetonitrile as solvent, along with HDA cycloaddition reaction which occurs monotonously in one pot to give a 1 : 1.2 mixture of epimeric tetracyclic adducts in high yield. Allyl ether 279 were also provided in several steps in high yield. Spirooliganone B (274) and (−)-spirooliganone A (273) was obtained in 15% overall yield.²⁸⁶

Scheme 38

In 2002 Yoshida and co-workers isolated GEX1Q1 280 as one of the six natural occurring compounds including GEX1A (herboxidiene) from a culture broth of Streptomyces sp.²⁸⁷ The stereoselective synthesis of tetrahydropyranone derivative 285 is illustrated in Scheme 39. Silyloxy diene 283 was provided using aldehyde 282 as precursor according to the procedure reported previously.²⁸⁸ A stereoselective HDA cycloaddition reaction of diene 283 with market purchasable aldehyde 151 under catalysis effect of Jacobsen's catalyst 152 (ref. 289 and 290) gave cycloadduct 284 in excellent yield, finally leading to synthetic GEX1Q1 (280) in high yield along with 5-epi-GEX1Q1 281.²⁹¹

Scheme 39

In 2013 Yu²⁹² and other co-workers isolated the two structurally novel antiviral spirooliganones A and B from the roots of Illicium oligandrum. They were found, showing a wide range of antiviral activities and has been extensively used for centuries in Chinese traditional medicine for treatment of rheumatoid arthritis.

Biomimetic total syntheses of potent antiviral spirooliganones A and B were accomplished and reported in 3% and 2% yield, respectively, in 12 steps starting from market purchasable materials. This relatively concise total synthesis (Scheme 40) commenced with the synthesis of acetonide 287 from market purchasable or readily available 2,6-dihydroxybenzoic 286 in which the spiro-fused AB rings of spirooliganones can be provided via the phenol oxidative dearomatization.^293–297 The assemblage of the key tetracyclic scaffold (BCDE rings, 289) could be obtained in a biomimetic manner after several steps including a HDA reaction of (−)-sabinene (277) and o-quinone methide 288. The desired spirooliganones A and B can be obtained in several steps.²⁹⁷

Scheme 40

Verbist and co-workers in 1988 disclosed the isolation of a novel marine metabolite of Lissoclinum bistratum named bistramide A.^298,299 Initially it showed prompt active cytotoxicity, and then bistramide A (290) to have a deep effect on cell cycle regulation, resulted in growth arrest, diversity, and apoptosis in some cell lines.^300,301 A concise impressive sequential involving asymmetric HDA cycloaddition reaction and oxidative carbon–hydrogen bond functionalization to access spiroacetals achieved.

Initially, 4-choloro-1-butanol 291 was transformed into the silyloxy diene 292. In turn the spiroacetal was provided via HDA coupling/cycloaddition of 292 with the aldehyde 293, which can be accessed in one step from (+)-b-citronellene,^302,303 in the presence of ent-294. With subsequent DDQ treatment combined with acid-catalyzed ring closure provided the spirocycle 295 in 58% yield as a sole stereoisomer with a contracted sequential reaction. Finally, bistramide A (290) was obtained in 69% overall yield after several steps. Noticeably, the longest linear sequence in this approach is 14 steps commencing from market purchasable 4-chloro-1-butanol as starting material to the aforementioned naturally occurring compound 292 (Scheme 41).³⁰⁴

Scheme 41

An enantioselective synthesis of the anti-proliferatory agent (+)-neopeltolide has been achieved in 2.1% overall yield for 21 steps by the longest linear sequence. Remarkably, this synthetic approach was convergent and operationally scalable, using, market purchasable starting materials.

Neopeltolide (296) is a complex macrolide which was isolated by Wright and co-workers in 2007. It was initially collected from a deep-water sponge of the family neopeltidae from the northwest coast of Jamaica.³⁰⁵ Although, this species was not identified but was categorized as a member of the genus Daedalopelta and a close relative of Callipelta. Compound 296 have been proven being a rich source of biologically potent marine metabolites.^306,307

The enantioselective total synthesis of (+)-neopeltolide 296 has been achieved and reported. The total synthesis of the macrolactone ring of (+)-neopeltolide (296) started with market purchasable 3-methylglutaric anhydride 297, which gives the desired silyloxy diene 298 in virtually quantitative yield (Scheme 42). Upon the synthesis of silyloxy diene 298 it was reacted with, several aldehydes following HDA reaction to obtain product 300. The latter exhibited excellent diastereoselectivity upon purification using flash chromatography. Ultimately after several steps, the anti-proliferatory agent (+)-neopeltolide 296 was produced from 300.³⁰⁸

Scheme 42

In light of extension of the usefulness of this protocol for the synthesis of 4-deoxy-D-hexopyranose-containing natural products, the synthesis of neosidomycin 302 was developed. This natural product initially was isolated in 1979 from Streptomyces hygroscopicus by the Furuta group.³⁰⁹ These molecules exhibit antibacterial or antiviral potencies. For neosidomycin 302 only one approach has been previously reported. In this procedure 302 has been synthesized as an inseparable anomeric mixture. The syntheses were started with the highly enantio- and diastereoselective HDA reaction of 1-methoxybutadiene 303 and (tert-butyldimethylsilyloxy)-acetaldehyde 250 under the 1.5 mol% of Jacobsen chiral tridentate chromium(III) catalysis conditions 152 (ref. 289 and 310) to afford 304 (Scheme 43). Dihydropyran 304 (89% yield, ee > 99%, de > 99%) has two stereogenic center, thus setting C-1 with a β configuration and C-5 creating the D series of the newly generated carbohydrate core.

Scheme 43

Compound 305 was prepared utilizing a de novo protocol as follows. The second-generation and the first-generation preparation of glycosyl donor 305 progressed through an identical protocol.

The HDA cycloaddition of 1-methoxybutadiene 303 and ethyl glyoxylate 306 using a 2 : 1 molar ratio of (−)-(S)-1,1′-binaphthol (20 mol%) and Ti(O-i-Pr)₄ (10 mol%) as catalyst system gave dihydropyran 307 in good yield but in high de and ee.³¹¹ The already made compound 305 found available upon hydroxyl group protection employing PivCl in pyridine in high yield, with subsequent acetolysis to give the corresponding product in 70% yield. The compound 305 gave neosidomycin 302 after 3 reaction steps.³¹²

The first total synthesis of (+)-keto-deoxyoctulosonate (308, (+)-KDO) is relied on the HDA reaction of α-selenoaldehyde 309 to the α-furylsubstituted diene 310.³¹³ The reaction provides an adduct mixture which upon treatment with CF₃COOH gives a 5 : 1 mixture of cis/trans dihydropyrones 311 and 312. Compound 311 was separated and used as pure form to afford the target KDO (Scheme 44).³¹⁴

Scheme 44

Evans^315,316 and Jørgensen³¹⁷ have independently demonstrated that β,γ-unsaturated α-keto ester 314 reacts stereoselectively with ethyl vinyl ether 315 catalyzed by optically pure bisoxazoline copper(II) complex 316 as a chiral catalyst. From this reaction, enantiomerically pure dihydropyran 317 was provided via HDA cycloaddition reaction. The latter was transformed into ethyl β-D-manno-pyranoside tetraacetate 313 in several steps (Scheme 45).^314,318

Scheme 45

Enigmazole A (318) is a member of class of cytotoxic macrolides which were isolated from the sponge Cinachyrella enigmatica which includes compounds that selectively target aberrant c-Kit.^319,320 The total synthesis of 318 was the completed in 22 steps. It is actually the longest linear sequence. Combination of “Eastern” and “Western” hemispheres of enigmazole A commenced with HDA cycloaddition between aldehyde 319 and diene 320 (Scheme 46). Optimization of the reaction resulted in a mixture of three of the four possible diastereomers which can be separated via flash column chromatography to give pure (321a–c).

Scheme 46

Upon hydrogenolysis of 321b, with subsequent Swern oxidation of product 322, afforded aldehyde 323. Compound 326 were found surprisingly unaffected to desilylation. The best conditions afforded the desired alcohol in satisfactory average yield. The phosphate was introduced to the C5 hydroxy group of 327 as a protected phosphoramidite (i-Pr₂NP(OFm)₂) to provide the entirely protected natural product 328 in satisfactory yield.^321–323 Dissolving of 328 dissolved K₂CO₃ in MeOH/H₂O smoothly and cleanly slashed the C15 acetate and both 9-fluorenylmethyl groups of the phosphate ester, giving raise to enigmazole A (318) (Scheme 47).³²⁴

Scheme 47

Lycogarubin C (329) and lycogalic acid (330) as natural products were initially isolated in 1994 from Lycogala epidendrum, a slime mold and shortly after, identified independently by Steglich³²⁵ and Akazawa and co-workers.³²⁶ The total synthesis of 329 or 330 has been achieved and reported,^{325,327–329} In another approach, 329 and 330 were readily synthesized via use of a 1,2,4,5-tetrazine → 1,2-diazine → pyrrole, HDA cycloaddition reaction protocol, which apparently perfectly suited for their synthesis.^330,331 The reaction of 1,2-bis(tributylstannyl)acetylene (332)^332–334 with dimethyl-1,2,4,5-tetrazine-3,6-dicarboxylate (331) progressed cleanly in dioxane under mild thermal conditions, providing the HDA adduct 333 in excellent conversions (97%). The indole N-methoxylcarbonyl groups of 334 under mild conditions, were selectively, removed to afford lycogarubin C (329) in good to excellent conversion (65–89%), while exhaustive hydrolysis of 334 or hydrolysis of 329 provided lycogalic acid (330) in exceptional conversion (95%) (Scheme 48).³³⁵

Scheme 48

Several highly cytotoxic polyketides, including the anguinomycins,³³⁶ have initially been isolated from Streptomyces strains.³³⁷ The total synthesis of anguinomycins C (335) and D (336) commenced with the providing dihydropyran 338 via a HDA cycloaddition reaction of already known aldehyde 337 (ref. 338) and market purchasable 1-methoxy-1,3-butadiene (305) catalyzed by the Cr(III) catalyst (152) developed by Jacobsen et al.²⁹⁰ Interestingly this HDA reaction was performed under solventless system and in the presence of 4 Å molecular sieves.³³⁹ The dihydropyran 338 was obtained in high chemical yield (86%), and excellent enantioselectivity (96% ee), however as a 5 : 1 diastereomeric mixture due to unavoidable epimerization at the anomeric center under the reaction conditions. In this case delightfully, the trans isomer 339 was obtained, and by an inversion of the configuration gave the cis product it is required in the anguinomycin structure. The reaction made progress smoothly, and the coupled product 340 featured the complete scaffold of anguinomycin C was isolated in 80% yield (Scheme 49).³⁴⁰ Notably both anguinomycins C (335) and D (336) were isolated as colorless oils.³⁴¹

Scheme 49

(−)-Centrolobine is a naturally occurring compound, which initially isolated from the heartwood of Centrolobium robustum^342–344 and from the stem of Brosimum potabile³⁴⁵ in the Amazon forest in Brazil. It shows potency towards Leishmania amazonensis promastigotes, a bug accompanying with leishmaniasis, which is one of chief health problem in Brazil.^344,346 Its structure, was elucidated by the synthesis of racemic 347 which showed it contains 2,6-syn-tetrahydropyran 347.^342,343 Its absolute configuration was revealed by the first enantioselective total synthesis of (−)-1 in 2002.^347,348 Stimulated with structural assignment, several research groups have attempted, successfully achieved and reported the total synthesis of 347 in both racemic^349–351 and optically active forms.^352–355

Among them an efficient protocol employed for the total synthesis of (−)-centrolobine 342 is outlined in Scheme 50 is worthy being mentioned. The paramount this approach is the utilization of the readily available sterically modified salen complex 344 which acts as catalyst in HDA cycloaddition reaction of Danishefsky's diene 345 to various aldehydes in high yields and enantioselctivities to yield the pyranones of type 346 and after that the corresponding dihydropyran.³⁵⁶ In a key step of this total synthesis, dihydropyran 347, which was obtained from HDA reaction of anisaldehyde in 67% chemical yield and 93% ee, was hydrogenated and followed by conducting other chemical reaction to be converted into 348 in high overall yield. Upon acidic workup of the reaction mixture deprotection of the phenolic hydroxy function occurred, affording the alcohol 349 in 91% yield. The hydroxy group at the benzylic position was removed via utilization of combination of NaBH₄ and TFA in THF,³⁵⁷ to give (−)-centrolobine 342 in 73% yield.³⁵⁸

Scheme 50

Kusumi and co-workers initially in 2008, isolated the secondary metabolites, aspergillides C, from a marine-derived fungus, Aspergillus ostianus strain 01F313. They collected the samples from the coast of Pohnpei.³⁵⁹ Significantly, aspergillides A–C exhibited cytotoxicity against mouse lymphocyticleukemia cells. An enantioselective approach to the total synthesis of (+)-aspergillide C (350) has been accomplished. Noticeably that overlaps at a late stage with recently reported Kuwahara's synthesis.³⁶⁰ It was envisioned that aspergillide C could be synthesized staring from lactone (+)-355 upon sequential saponification/protecting group adjustment/macrolactonization. This approach for the total synthesis started with a zinc-mediated HDA cycloaddition reaction of (S)-(−)-glyceraldehyde acetonide (351), provided from L-(+)-arabinose,^361,362 and the Danishefsky–Kitahara diene^363,364 (345) to give dihydropyrone (−)-352 (Scheme 51). According to prior accounts, dihydropyrone (−)-352 was isolated as a single diastereomer as expectedly by Felkin's model, thus securing the required configuration at C(7).³⁶⁵ Upon treatment with acid, (+)-353 to the cyclized via a procedure reported by Larock³⁶⁶ to give lactone (+)-354 in 78% yield. The final stage of the synthesis involved the hydrolysis of the lactone in (+)-355, protecting group adjustment, along with macrolactonization. In fact, during the course of this approach, an alternative route to (+)-355 and its fruitful expansion to (+)-aspergillide C via such a sequence was achieved and published by Kuwahara et al.^360,367

Scheme 51

Azadirachtin (356) is a complex natural product which was initially isolated from the Indian neem tree in 1968.³⁶⁸ It is known as an active insect antifeedant and growth inhibitor,^369,370 the stimulating architecture, created a great interest and challenge in its total synthesis.^371–378 Recently a first total synthesis of azadirachtin by using a strategy which evolved over many repetitions was successfully accomplished and reported.³⁷⁹

Initially the appropriate aldehyde 357 was synthesized from readily available 2-propyn-1,4-diol via HDA reaction (Scheme 52).³⁸⁰ Noticeably, there are only few examples of alkynal derivatives employed as substrates in the HDA reaction,^381–384 and in addition the aldehyde 357 was found being extremely unstable. Consequently, many known suitable catalysts used in HDA reactions were inappropriate for this transformation and gave raise either to low yield or poor enantioselectivity. After several practical attempts, Hashimoto's dirhodium carboximidate catalyst 358 (ref. 382 and 383) was found effective. Therefore it was specifically optimized for the HDA reaction of propargylic aldehydes. Under catalysis of 358 the desired cycloaddition, was promoted affording the target molecule in 90% ee and 77% chemical yield over the two steps. With adequate amounts of the dihydropyranone 359 in hand it was converted to the enol ether 360 after two steps reaction.

Scheme 52

Nevertheless, the enol ether 360 presented several alternatives for the assemblage of the remaining moiety in the mesylate 361. Consequently, this pathway offers a greatly efficient synthesis of the azadirachtin 356 coupling partner 361 after several steps reaction (Scheme 52), and progressed being completed in only 17 steps which is more concise in comparison to 26 steps reported previously for the original approach.³⁸⁵

Generally, the aryl-substituted tetrahydropyran core is present in several biologically important natural products having small molecules in many of.^386–388 Natural products bearing tetrahydropyran scaffold, are somehow privileged since this moiety dedicates several biological properties including potency of inhibitory activity to the molecules. One of the most important is, the interesting C-aryl glycoside natural products diospongins A (363) and B (362). They were isolated from the rhizomes of Diocorea spongiosa via a bioassay-guided fractionation exhibit suspicious antiosteoporotic activity. Thus compounds bearing pyran moiety, are considered being a model and a lead for the discovery and design of active new antiosteoporotic agents.

Jennings et al.³⁸⁹ initially accomplished unambiguous total syntheses of both (−)-diospongins A (363) and B (362). These total synthesis was not only a great achievement but also confirmed the structures suggested for the structures 362 and 363 by Kadota et al.³⁹⁰ Consequently, a plethora of synthetic approaches and routes has appeared in the chemical literature for the total synthesis of this family of compounds.^{389,391–393}

The catalytic asymmetric HDA reaction between Danishefsky's diene 345 and furfuraldehyde 364 in the presence of 10 mol% of the (S)-BINOL/Ti(OiPr)₄ as a derived catalyst generated gave dihydropyranone 367 in 96% ee. Furthermore, single re-crystallization of 364 led to 99.9% ee with 60% chemical yield. The reaction made progress giving a mixture of alcohol 366 or ent-366. The (R)-BINOL/Ti(OiPr)₄ derived catalyst created ent-365, then, ent-365 was transformed to ent-366 using the same reagents and similar sequence. At last, 367 was subjected to DDQ in DCM/H₂O (9 : 1) for 1 h to provide the desired compound 362 in excellent isolated yield (Scheme 53). The 2,6-trans enantiomer ent-362 was obtained in moderate yield overall yield (over 6 steps) from ent-366 pursuing the aforementioned conditions (Scheme 54). The C-5 hydroxyl group of diospongin B (362) gave product 363 in 86% yield over two reaction steps. Under similar conditions ent-368 also led to ent-363.

Scheme 53

Scheme 54

(±)-Machaeriols A, B, C, and D, having the cannabinoid structure, in 2009 were isolated from the bark of the Machaerium multiflorum spruce found in Loreto and Peru.^394,395 They exhibited potential in vitro antimicrobial potency.

The first total syntheses of machaeriol B (369) were accomplished and presented by Avery et al. Their strategy stated from phloroglucinol (¼benzene-1,3,5-triol) proceeding via a HDA cycloaddition and Suzuki coupling reaction as the crucial steps giving the targets in high overall yields in 7 steps for both compound 369.³⁹⁶

Scheme 55 illustrates a brief synthetic route to natural (+)-machaeriol B (369) and its unnatural enantiomer 370. (+)-Machaeriol B (369) can be synthesized stating from stemofuran A (374) and (−)-(3S)-citronellal (375a) via a HDA cycloaddition reaction.³⁹⁷ The precursor 376 for this total synthesis of 369 and 370 was provided by a previously reported method.^398,399 Thus, the condensation of O-phenylhydroxylamine (371) with 3,5-bis(dibenzoyloxy)acetophenone (372) catalyzed by conc. HCl in EtOH gave the oxime ether 373 in excellent yield.

Scheme 55

In the registered plants used in folk medicine in Asia, the Goniothalamus species (Annonaceae) are well documented. The phytochemical investigations of the genus Goniothalamus was strengthened when, in 1972, Geran and his coworkers reported the observed toxicity of that the ethanolic extract of stem bark of Goniothalamus giganteus to mice during a P-388 in vivo antileukemic screening.⁴⁰⁰ Further studies of this extract by McLaughlin research group, resulted in isolation and extraction and structural elucidation of two major families of compounds showing biologically remarkable activities and properties including annonaceous acetogenins⁴⁰¹ and styryllactones.^402–405 Nowadays, more than 30 bioactive molecules belonging to the styryllactone family from various Goniothalamus species can be found in a prepared list.^406,407

(+)-Goniodiol (376) was first initially isolated from the leaves and twigs of Goniothalamus sesquipedalis,⁴⁰⁸ (+)-goniotriol (377) a poly oxygenated styryllactone, has been, initially, isolated from the stem bark of Goniothalamus giganteus,⁴⁰⁵ and (−)-goniofupyrone (378), and (+)-altholactone (379). They have actually a common bicyclic framework. They were initially isolated from the stem bark of Goniothalamus giganteus⁴⁰⁹ and from the bark of an unnamed Polyalthia (Annonaceae) samples, respectively.⁴¹⁰

A brief, stereoselective pathway to bioactive styryllactones, namely, (+)-goniodiol (376),⁴¹¹ (+)-goniotriol (377), (−)-goniofupyrone (378), and (+)-altholactone (379) by employing a cascade reaction appropriate for the synthesis of different stereoisomers along with the design of analogues has been reported.⁴¹²

In this total synthesis, the reaction sequence started by the formation of cyclic allylboronate 382 provided from ethyl vinyl ether and boroacrolein pinacolate by employing a catalyzed enantioselective inverse-electron-demand HDA reaction. The stereoselective total synthesis of few members of the styryllactone family was accomplished efficiently via an intermediate 384, provided by a catalyzed asymmetric inverse electron-demand sequential HDA/allylboration reaction. The conversion of 384 into α,β-unsaturated lactone resulted in the synthesis of (+)-goniodiol (376) in a compact number of steps. The epoxidation reaction was employed to create the remaining chiral centers on the lactone moiety of 384, and these intermediates were subsequently expanded into (+)-goniotriol (377), (−)-goniofupyrone (378), and (+)-altholactone (379) (Scheme 56) via either isomerization or cyclization step.⁴¹³

Scheme 56

Asian trees of the genus Goniothalamus have been found a rich source of plethora families of compounds showing significant biological activities including alkaloids,⁴¹⁴ styryllactones⁴¹⁵ and acetogenins.⁴¹⁶ In 2005, the isolation of new members of the natural styryllactones have been reported from Goniothalamus amuyon.^417,418 The structure and absolute stereochemistry of one of these compounds, 385a, have been found being very similar with those of (+)-goniodiol, except for the existence of a methoxy group at C-8. For this reason, the common name of 8-methoxygoniodiol was given to this compound. Despite of this structural similarity, 385a showed a very dissimilar cytotoxicity from (+)-goniodiol, depends on the kind of human cancer cell lines.^417,418

The asymmetric synthesis of cyclic allylboronate 388 was accomplished starting from ethyl vinyl ether and 380, with subsequent HDA cycloaddition reaction under catalysis of Jacobsen's chiral Cr(III) complex 152.⁴¹⁹ Compound 388 was converted to 389a in several steps. The desired natural product was obtained upon desilylation with TBAF in 28.9% overall yield from the generated intermediate 389a.⁴¹² The spectral and physical data of synthetic (+)-8-methoxygoniodiol 385a were compared with those of already reported and found being identical.⁴¹⁷

The synthesis of 8-deoxygoniodiol 385b commenced with the asymmetric catalyzed HDA/allylboration sequence using phenylacetaldehyde instead of O-methyl mandelic aldehyde. The cascade process was conducted in ‘one pot fashion’ and furnished the desired pyran 389b in high yield as single diastereoisomer in excellent ee (96%).⁴²⁰ The final steps, includes isomerization of the double bond and of the removal of silyl protective group, to give the desired product 385b (Scheme 57).⁴¹²

Scheme 57

In 1994, lasonolide A (390), a structurally exceptional 20-membered macrolide, was initially isolated from the Caribbean marine sponge Forcepia sp. by McConnell and his research group.⁴²¹ Lasonolide A shows a potent cytotoxic activity towards the proliferation of A549 human lung carcinoma and P388 murine leukemia cells.

In their total synthesis route to (−)-lasonolide A to Ghosh and Gong also employed a HDA cycloaddition reaction for the construction of THP ring. A convergent and enantioselective synthesis of (−)-lasonolide A HDA been previously reported.⁴²² The details of this synthetic achievement includes a Lewis acid catalyzed HDA cycloaddition reaction for the construction of the lower tetrahydropyran ring as the key step along with an intramolecular 1,3-dipolar cycloaddition reaction to install the upper tetrahydropyran ring.

The construction of the bottom tetrahydropyran ring commenced with the synthesis of nucleophilic diene 392 (Scheme 5). The alcohol 391 was protected with BnBr and NaH to provide the benzyl ether in virtually quantitative yield. The enone was prepared as an appropriate Diels–Alder precursor dienol silyl ether 392 via treatment with Et₃N and TESOTf. The chiral tridentate Schiff base chromium-(III) complex (1S,2R)-152 developed previously by Jacobsen et al.^289,310 was employed as the catalyst (10 mol%) in the stereoselective HDA cycloaddition reaction between diene 392 and (tert-butyldimethylsilyloxy)acetaldehyde (250). The resultant, dihydropyran silyl enol ether was then treated with TBAF/AcOH in the same reaction vessel for the removal the TES group resulting in the corresponding ketone 393 in satisfactory yield and excellent ee (94%). Tetrahydropyran 394 provided by the HDA cycloaddition reaction was now available in hand being used for the synthesis of 395 after several steps, manipulating functional group transformation (Scheme 58). Ultimately, conventional TBS removal using HF·Py in the presence of excess amount of pyridine completed the total synthesis of (−)-lasonolide A (390).⁴²³

Scheme 58

Marine natural products are important source for obtain structurally diverse molecules with interesting biological and physiological activities. Several such compounds exhibit antitumor activity; however, the insufficiency of natural richness frequently limits or even prevents their subsequent biological investigation.⁴²⁴ Lasonolide A (390), a 20-membered macrolide, was initially isolated from the Caribbean marine sponge, Forcepia sp., in 1994 by McConnell and his research group.⁴²¹ The primarily structural elucidation and stereochemical determination of lasonolide A was well established by NMR spectra analysis. However its structure and absolute configuration were later revised and modified via total synthesis⁴²⁵ and Lasonolide A's structural features combined with its active antitumor activities attracted substantial synthetic chemist interest as a target. So far, three total syntheses^425–427 and a number of synthetic investigations on both tetrahydropyran rings 6 have been accomplished and disclosed. An efficient and enantioselective has the total synthesis of (−)-lasonolide A (390). Has been successfully achieved and reported.

The synthesis of ring A commenced with the already known aldehyde 396 (ref. 428) as illustrated in Scheme 59. Initially alcohol 397 was protected using benzoyl peroxide and Me₂S furnishing MTM ether 398 in high yield.⁴²⁹ The synthesis of the lower tetrahydropyran ring B of lasonolide A is also depicted in Scheme 59. In a key step of this total synthesis, the chiral tridentate Schiff base chromium(III) complex (1S,2R)-152 developed and reported previously by Jacobsen⁴¹⁹ was employed as catalyst (10 mol%) in the asymmetric HDA reaction between diene 392 (ref. 430) and aldehyde 250.⁴³¹ The obtained dihydropyran silyl enol ether upon treatment with TBAF/AcOH in a one pot fashion caused the removal of the TES group to afford the corresponding ketone 393 in satisfactory chemical yield but excellent ee (94%) to provide aldehyde 395 in high chemical yield in several steps. Finally conventional TBS-deprotection with HF·Py in the presence of excess pyridine gave (−)-lasonolide A.⁴³² The spectra data of synthetic lasonolide A (390) were compared with those previously reported for natural product and found being identical.⁴²¹

Scheme 59

Marine macrolides showing potent cytotoxic activities is found to be promising anticancer agents, if the supply issue can be committed.⁴³³ Neopeltolide (296, Scheme 60) is a bioactive macrolide which was in 2007 initially two species of the sponge Daedalopelta were collected³⁰⁵ from a deep-water Caribbean sponge of the class Neopeltidae by Wright and co-workers.³⁰⁵ Initial investigations disclosed high antiproliferative potency towards several cancer cell lines, as well as the ability of inhibition of the growth of the fungal pathogen Candida albicans.

Scheme 60

A relatively brief but efficient total synthesis of the potent antiproliferative macrolide (+)-neopeltolide (296) has been accomplished in 18 steps as a longest linear sequence, and 5.8% overall yield. This approach involves a Jacobsen catalyzed HDA cycloaddition reaction as the crucial step. The synthesis of the needed aldehyde 400 started with a Noyori stereoselective hydrogenation⁴³⁴ of the β-keto ester 399 employing the (S)-BINAP–Ru(II) catalyst to afford the desired (13S)-alcohol.^435–437 While the aldehyde 400 was available in hand, the formation of the tetrahydropyran ring of neopeltolide initially was contemplated (Scheme 60). Therefore, conduction a Jacobsen catalyzed asymmetric HDA cycloaddition reaction of 400 and the easily accessible 2-siloxydiene 401,⁴³⁸ promoted by the chiral tridentate chromium as catalyst 152 (ref. 439) (10 mol%), was attempted which was successfully, upon mild acidic workup, afforded the desired cis-tetrahydropyranones 402. Interestingly the reaction proceeded with absolute control over the introduction of the C3 and C7 stereogenic centers. At this stage, the major isomer 402 (60%) was easily separated from its C9 epimer. All that continued for the final result was reduction of the ketone 403 to the equatorial alcohol 404 using NaBH₄ in MeOH, with subsequent Mitsunobu esterification reaction with the side chain acid,⁴³⁸ as used by other groups,^435,436,440 giving (+)-neopeltolide (296) in satisfactory yield.⁴⁴¹

In 1984, two new monocarboxylic acid ionophores, griseocholin and antibiotic M144255, were initially isolated from cultured strains of Streptomyces griseus.^442,443

Polyoxygenated ionophore-containing naturally occurring products show high potency as anti-infectious via proton-cation exchange courses across biological membranes. (+)-Zincophorin possesses show strong in vivo activity against Gram-positive bacteria and Clostridium coelchii. In addition its ammonium and sodium salts exhibit high anti-coccidal potency towards Eimeria tenella in chicken embryos. Moreover its methyl ester was reported in a patent as exhibiting high inhibitory potencies towards influenza WSN/virus with decreased toxicity for the host cells.⁴⁴⁴

Over the last two decades, (+)-zincophorin has attracted tremendous attentions and stirred up array of synthetic attempts including Danishefsky's first total synthesis together with two recent sophisticated total syntheses successfully achieved and reported by Komatsu and Miyashita.⁴⁴⁵ A part from those successful endeavors a formal total syntheses of (+)-zincophorin based on seizure of Miyashita's advanced intermediate (if 50 = 411) has been developed. The key feature in this approach based on previously reported asymmetric inverse electron demand HDA cycloaddition of chiral allenamides (Scheme 61).^446–452 In this line the synthesis of Cossy's C1–C9 subunit of (+)-zincophorin relied on the aforementioned approach was attempted. Notably, in this strategy was an unusual urea-directed Stork–Crabtree hydrogenation was observed.

Scheme 61

Total synthesis of chiral allenamide 407 started from (+)-ephedrine hydrochloride salt 406 and urea. Chiral enone 409 was provided from the market purchasable chiral hydroxy ester 408 as illustrated in Scheme 61. Having chiral allenamides 407 available in hand, the key inverse demand HDA reaction was performed. Having in mind with the fact that the stereochemical result could be controlled via either the suitable chiral auxiliary attached to the allenamide or the chiral enone, leading potentially to matched and/or mismatched consequences. It has been found that by conduction cycloaddition protocol in CH₃CN as the solvent under pressure in the sealed tube, upon heating at 85 °C, reactions of 407 with 409 proceeded easily and smoothly to afford pyrans 410 in satisfactory yield, as single isomers. For completion of the synthesis of the C1–C9 fragment as subunit, the crotylated pyran 411 was transformed to aldehyde 412 to afford (+)-zincophorin in reasonable yield over three steps.⁴⁵³

Diarylheptanoid natural products comprising a tetrahydropyran ring, such as centrolobine,^344,345 de-O-methylcentrolobine,^344,454 calyxins⁴⁵⁵ and diospongins,⁴⁵⁶ showed wide scope of biological potencies. For these features, thus, these compounds have attracted great attentions among the medicinal and synthetic organic chemistry chemists.^457–459

(−)-Centrolobine (413) is an antibiotic which initially isolated from the heartwood of Centrolobium robustum and from the stem of Brosimum potabile in the Amazon rain forest in Brazil.^344,345 (−)-De-omethylcentrolobine (414), isolated from the same heartwood of C. robustum, exhibits reasonable antileishmanial potency.³⁴⁴ In 2002 Solladie and his research group attempted the first asymmetric.

Total synthesis of (−)-centrolobine (413) and successfully achieved. They have also determined and confirmed the absolute configuration of 413.⁴⁶⁰ Since then, a plethora of research group have attempted to develop their strategy leading to the total synthesis of 413 in both racemic⁴⁶¹ and optically active forms.⁴⁶² Remarkably in neither of these attempts, the HDA reaction has not still been employed to the diarylheptanoid tetrahydropyran system.⁴⁶³ Dirhodium(II)-tetrakis-[(S)-3-(benzene-fused-phthalimido)-2-piperidinonate], Rh₂-(S-BPTPI)₄ 419 has been used as a highly effective Lewis acid catalyst in the endo- and enantioselective HDA cycloaddition reactions of a wide and different range of aldehydes with Danishefsky-type dienes as well as with monooxygenated dienes. By using this superior and efficient catalyst the expected corresponding products were obtained in up to 99% ee and turnover numbers as high as 48 000.^464,465

In a developed the total synthesis, the dienes 417 were initially provided by the reaction of easily accessible α,β-unsaturated ketones 415.^466,467 Then phenylpropargyl aldehydes 418, contain tert-butyldimethylsilyloxy and methanesulfonyloxy groups at the para-position on the benzene ring, were synthesized via the Sonogashira coupling⁴⁶⁸ of propargyl alcohol with two iodophenols 416.^469,470

Catalytic asymmetric syntheses of (−)-centrolobine and (−)-de-O-methylcentrolobine have been successfully accomplished, combining a HDA reaction of 4-aryl-2-silyloxy-1,3-butadienes 417 and phenylpropargyl aldehyde derivatives 418 as a decisive step (Scheme 62). This HDA reaction was catalyzed by dirhodium(II)tetrakis[(R)-3-(benzene-fused-phthalimido)-2-piperidinonate], Rh₂(R-BPTPI)₄ 419 as an efficient chiral Lewis acid catalyst to furnish entirely cis-2,6-disubstituted tetrahydropyran-4-ones 420 in excellent ee (93%).

Scheme 62

The asymmetric total synthesis of (−)-dactylolide has been achieved and reported. The absolute configuration of the tetrahydropyran was determined by catalyzed asymmetric Jacobsen HDA cycloaddition reaction. Initially in 2001, Riccio and his research group⁴⁷¹ isolated dactylolide 421 from a marine sponge belongs to the genus Dactylospongia found and collected the coast of Vanuatu. It showed cytotoxicity toward L1210 and SK-OV-3 tumor cell lines, with a range of 40–63% inhibition.⁴⁷¹ The absolute configuration was determined by Smith et al.⁴⁷² in the first total synthesis of (+)-dactylolide 421. Notably, after this first communication, four other approaches for total synthesis by research groups of Hoye, Jennings, Floreancig, and Keck till date have been reported for the total synthesis of dactylolide.^473–476

The synthesis of tetrahydropyran 423 with the combination of triethylsilyl enol ether 401 and aldehyde 250 catalyzed by Jacobsen's chiral tridentate chromium(III) catalyst 152 (Scheme 63).^438,439 Cautious workup of the resulting silyl enol ether gave the cis-tetrahydropyranone 422 in high chemical yield and excellent ee (99%) via an endo-selective HDA cycloaddition approach, providing of compound 422 on a multigram scale. The last step in the total synthesis of (−)-dactylolide involved the conventional oxidation of diols 424.⁴⁷⁷

Scheme 63

The thiopeptide (or thiostrepton) antibiotics are a class of sulfur containing greatly modified cyclic peptides with remarkable biological activities, including reported potency against methicillin-resistant Staphylococcus aureus (MRSA),⁴⁷⁸ and malaria. One reported total synthesis of the thiopeptide naturally occurring product amythiamicin D, is based on a biosynthesis-inspired HDA cycloaddition pathway leading to the pyridine core of the antibiotic as a vital step. The amythiamicins (A–D) are among the most outstanding thiopeptide antibiotics, and initially were isolated from a strain of Amycolatopsis sp. MI481-42F4. Notably, structures are determined by combination of degradative protocol and spectroscopic techniques,^478,479 which is worthy to mention. They are among the very few thiopeptides that do not have a dehydroalanine residue,⁴⁸⁰ the details of the first total synthesis of the thiopeptide antibiotic amythiamicin D 425 is described. Basically the pathway to synthesis 425 is similar to a route that, Nicolaou group synthesized thiostrepton, utilizing a biomimetic strategy to construct the 2,3,6-trisubstituted pyridine core of the naturally occurring product.⁴⁸¹

Dienophile 428 were synthesized via reduction of the corresponding oximes 426 employing iron and acetic anhydride–acetic acid in refluxing toluene.⁴⁸² Silyl derivative 427 was transformed into 429 after several steps manipulating functional group transformation. In this way 2-azadiene component 429 containing the remaining three thiazole rings was provided. Now the synthetic path way HDA grasped the important HDA reaction. Upon non-conventional heating of the azadiene 429 with enamide dienophile 428 under microwave irradiation in toluene at 120 °C afforded the required 2,3,6-tris(thiazolyl)pyridine 430, albeit in a moderate chemical yield. As a matter of fact obtained pyridine 430 is actually the core of the natural product since it is necessary to control and establish its stereochemical dignity, and this is again accomplished by generation of Mosher amides. This led in macrolactamization in a satisfactory yield stating from 431 to afford amythiamicin D 425 (Scheme 64).⁴⁸³

Scheme 64

The reveromycins A (432) is member of a class of compounds which were initially isolated from the soil actinomycete Steptomyces sp.^484,485 Reveromycin A (432) has been found to be active inhibitor of the mitogenic activity of epidermal growth factor in a mouse keratinocyte. Besides, compound 432 shows antiproliferative potency towards human tumor cell lines. Until now, only one total synthesis of 432 has been successfully achieved and reported,⁴⁸⁶ Besides several strategies to the 6,6-spiroketal core have been reported.^487–489 In 2000 the total synthesis of (−)-reveromycin A (432) employing a HDA protocol to build up the stimulating spiroketal motif of this molecule.⁴⁸⁹

The HDA reaction between 433 and 434 was treated with 15 mol% Eu(fod)₃ as catalyst, promoted by ZnCl₂ in THF at 0 °C. Although the reaction provided the desired spiroketal 435 as a single diastereoisomer in a higher yield than that obtained employing K₂CO₃,⁴⁸⁹ the by-product 436, obtained from an ene reaction, was also insulated as a mixture of diastereoisomers. Hydroboration of spiroketal 435 with subsequent oxidation completed in good yield to provide the tertiary alcohol 437 as the single isomer. The fully protected reveromycin A, precursor 438, was exposed to TBAF in DMF affording reveromycin A (432) in high yield (Scheme 65). The synthetic compound was purified via reverse-phase chromatography and its physical and spectroscopic data (NMR, IR, UV, HRMS) was found to be in agreement in full aspects with those to the natural product.⁴⁹⁰

Scheme 65

Spiroketals or spiroacetals are sub-structures that ensue in a wide variety of naturally occurring compounds from several and different sources such as, plants, fungi, marine organisms, insects and microbes⁴⁹¹ Reveromycins A, B (439), C, and D are specimens of natural products bearing 5,6- and 6,6-spiroketal moieties. They have been isolated from a soil actinomycete belonging to the Sreptomyces genus.^492–494 Reveromycin B (439) has been found to act as epidermal growth factor inhibitor. Its total synthesis has been accomplished and reported in 25 linear steps staring from chiral methylene pyran 434. The key step in this approach is an inverse electron demand HDA reaction between dienophile 434 and diene 440 for construction of the 6,6-spiroketal 441. The latter upon oxidation using dimethyldioxirane followed by acid catalyzed rearrangement provided the 5,6-spiroketal aldehyde 442. A sequential reaction including lithium acetylide addition/oxidation/reduction, using protective group manipulation afforded the reveromycin B spiroketal core 443. Other crucial steps in this strategy leading to the target molecule 439 are a Stille coupling, succinoylation, selective deprotection, oxidation, and Wittig condensation to form the final bond. Finally reveromycin B (439) is obtained in pure form and satisfactory overall yield (Scheme 66).⁴⁹⁵

Scheme 66

A highly stereoselective total synthesis of leucascandrolide A (444) has been achieved and reported. Leucascandrolide A is a cytotoxic 18-membered macrolide which was isolated in 1996 from the New Caledonian calcareous sponge Leucascandra caveolata by Pietra and his research group.⁴⁹⁶ The total synthesis begins with a Jacobsen asymmetric HDA reaction to construct the 2,6-cis-tetrahydropyran ring. Leucascandrolide A has drawn enormous attention and several research groups focused on its total synthesis,^27,497–500 The first total synthesis was accomplished and reported by Leighton et al.⁴⁹⁷ In 2003, a successful strategy to (+)-leucascandrolide A has also been achieved,²⁷ In this synthetic attempt Jacobsen HDA reaction⁴³⁹ plays a key role in constructing of the right-hand tetrahydropyran ring of 444 in a decisive step. The total synthesis starts from easily accessible 2-silyloxydiene 401. The latter could be provided by silyl enol ether generation from the corresponding enone.²⁷ Reaction of a neat mixture of diene 401 and aldehyde 250 catalyzed with the chiral tridentate chromium-(III) catalyst 152 followed by mild acidic work-up which hydrolyses the initially generated [4 + 2]-cycloadduct, afforded the required 2,6-cis-tetrahydropyran 445 in high yield. The latter could be subsequently converted to both alcohols 446 and 447 under different reaction conditions. Initially, isomer 446 was chosen to be used in the in the synthetic route in order to assess and evaluate the chemistry in ahead. It was delightfully observed that the reaction of the side-chain acid 449 and macrocycle 448, in the presence of excess DEAD and PPh₃, smoothly proceeded, leading to the formation of expected coupled product. At last, upon smooth double Lindlar hydrogenation of the two triple bonds, (+)-leucascandrolide A (Scheme 67), was obtained in 92% yield.⁴³⁸ The physical and spectroscopic data for this synthetic material were compared with those reported previously by Pietra⁴⁹⁶ and Leighton⁴⁹⁷ and found being identical in aspects.

Scheme 67

Phorboxazoles A (450, Scheme 68) and B (451) were initially isolated^501,502 from the sponge Phorbas sp. found in western coast of Australia and Indian Ocean. Due to the remarkable structural complexity of these marine macrolides, combined with their high biological potency and properties, the phorboxazoles have stirred up appreciable synthetic interest, resulted in sphosticated total syntheses reported by Forsyth,⁵⁰³ Evans⁵⁰⁴ and Smith,^505,506 along with of wide variety of structural fragments by professional chemists, worldwide.^507–509

Scheme 68

The tetrahydropyranone 452, containing a pentacyclic C4–C32 fragment of the phorboxazoles, was prepared by a complex HDA cycloaddition coupling taken place between the 2-siloxydiene 457 and the oxazole aldehyde 453, catalyzed by the chiral tridentate Cr(III) 294. In this way ketones 452 and 458 as diastereomers were obtained, in a ratio of 1.5 : 1. The chief product 452 attributes to the full pentacyclic C4–C32 fragment of the phorboxazoles. The C15–C32 subunit 455 were provided via aldol reaction between ketone 454 and aldehyde 453. On the other hand the diene 457 having an exo-methylene was provided in the several steps and 50% overall yield.⁵¹⁰

In 1996, muricatetrocin C (459) was isolated by McLaughlin et al. from the leaves of Rollinia mucosa, a tropical fruit tree grown in the West Indies and some part of Central America. It shows antitumor potency.⁵¹¹

The synthesis began with 1,4-butanediol, which was monoprotected to give the primary benzyl ether 460, then a tandem Swern–Wittig reaction afforded the α,β-unsaturated tert-butyl ester 463 in excellent yield (Scheme 69). With 463 now readily available, the key HDA reaction was investigated. It was found that overnight stirring of a methanol/dichloromethane (1 : 1) solution of 463 with nitrosobenzene at 0 °C afforded a mixture of regioisomers (464/465 7 : 3), favoring the desired adduct 464, in overall 89% yield. Pleasingly, inspection of the crude ¹H NMR showed that the major regioisomer 464 had been formed with a diastereoisomeric ratio of greater than 20 : 1 thus the observed diastereoselection appeared to be limited only by the original geometry of the external olefin in the diene precursor. According to this precedent, reduction of 466 with hydrogen in ethanol/benzene in the presence of Wilkinson's catalyst gave, after eleven hours, fully protected 459 in good (76%) yield with no reduction of the butenolide portion.^512,513

Scheme 69

The talaromycins A and B are toxic metabolites that were isolated from the fungus Talaromyces stipitatus^514,515 in 1982 by Lynn and co-workers. It has already been found that the chemotherapeutic potency of cytostatics toward estrone hormone-receptive tumors could be increased via the formation of linkage between them and estrone.^515–517 Thus, any attempt to combine estrone with mycotoxins for designing a new class of cytotoxic compounds are desirable. The asymmetric total synthesis of the established highly biologically active spirocyclic mycotoxin (−)-talaromycin B (467b) has been achieved and reported.⁵¹⁸ This approach was chiefly relied on an HDA cycloaddition reaction⁵¹⁹ of methyl-O-benzoyldiformylacetate (474)⁵²⁰ as a 1-oxa-1,3-butadiene derivative with the exocyclic enol ether 473. The latter in turn can be obtained from 472 by iodoetherification followed by elimination (Scheme 70).⁵²¹

Scheme 70

In this line the total synthesis of hybrid natural mycotoxin talaromycin 467b employing the same approach have been achieved and reported. This protocol this commenced from the D-secoestrones 476 and 477.⁵²² Upon HDA cycloaddition reaction, steroidal exocyclic enol ethers 478 to 479, the secoestrones 476 and 477 were obtained which by sequential reduction/iodoetherification/elimination, with ethyl O-benzoyldiformylacetate (480) resulted in the spiroacetals 481 and 482 as a mixture of four diastereomers respectively. Reduction of the chief diastereomers 481a and 482a using DIBAH followed by hydrogenation led to the novel natural product hybrids 468, 469, 470, and 471, which show the structural features similar to those of the mycotoxin talaromycin 467b.⁵²³

Curiosity in polyketide coumarins was flashed by the discovery of the strong anthelmintic⁵²⁴ and molluscicidal⁵²⁵ properties of ethuliacoumarin A (483). It is one of the constituent of the Egyptian medicinal plant Ethulia conyzoides L.⁵²⁶ The relative analogues 484–486 were also isolated,⁵²⁷ some exhibited biological properties similar to 483 (Fig. 3).⁵²⁵ Ethuliacoumarins (483–485) can be obtained in substantial amounts by isolation.⁵²⁸ However their source in plant kingdom is not readily accessible, nor is the natural analogues are numerous to withstand a remarkable natural products chemistry effort.

Fig. 3 Ethuliacoumarin A and its relative analogues.

In an attempt to total synthesis of natural product 485, initially an swift path way was designed to the acetal 490, involving its remodeling to the vinyl-substituted lactol 491 and the ultimate transformation of the later into (±)-preethulia coumarin (485),⁵²⁷ Compound 485 is the least oxygenated of ethulia coumarins member. The strategy to install the acetal 490 involved the development of a three-component sequential cascade Knoevenagel/HDA reaction^236,283 between 4-hydroxy-5-methylcoumarin (487), diacetyl (=2,3-butandione, 488) and a vinyl ether 489. As a model to have access to ethulia coumarins from the hemiacetal 492, its transformation into (±)-preethulia coumarin (485)⁵²⁷ was contemplated and successfully accomplished. Practically, norprenylation of the hemiacetal via reaction with 2-methyl-1-propenyllithium under sonication afforded a ca. 2 : 1 pair of diastereomeric alcohols 493, which subjected to Mitsunobu intramolecular etherification to afford 485 in 55% yield (Scheme 71). This compound showed identical spectroscopic properties identical data except the optical rotation to those of natural preethulia coumarin (485).⁵²⁹

Scheme 71

(R)-Dihydroactinidiolide (494) has been found as one of the three components of the pheromone involved in queen recognition of the workers of the red fire ant, namely Soleneopsis invicta.⁵³⁰ Due to importance of pheromones in controlling insects its, total synthesis has attracted much attentions. Thus a plethora of different syntheses of dihydroactinidiolide have been attempted, achieved and reported, all of them, resulted in isolation of racemate.^531,532 However a few asymmetric synthesis is also available.^533,534 The asymmetric total syntheses of (R)-dihydroactinidiolide (494) is relied on the use of chiral starting materials and multistep reactions, or compounds which, at a definite step of the reaction route, are separated as the pure enantiomers, frequently resulting in low overall yields of 494. A close structurally related compound to (R)-dihydroactinidiolide (494) is (R)-actinidiolide (495). Both 494 and 495 were initially isolated as cat attractants from leaves from Actinidia polygama.⁵³¹ Therefore since then they also been recognized as flavor components in many plant sources such as tobacco⁵³⁵ and tea.⁵³⁵

The total synthesis of (R)-dihydroactinidiolide (494) and (R)-actinidiolide (495) with excellent enantiomeric excess (ee) and in high overall chemical yield by asymmetric catalytic (HDA) has been achieved. In addition and delightfully, a common intermediate generated in this approach for the total synthesis of 494 and 495 were found being useful for the synthesis of a series of related compounds (Scheme 72). This strategy for the total synthesis of 494 and 495 is made possible by development to perform a highly selective and enantioselective HDA reactions of conjugated dienes with glyoxylates mediated by Cu(II)–bisoxazoline complexes 497.^536–538

Scheme 72

The pathway to total synthesis of (R)-dihydroactinidiolide (494) and (R)-actinidiolide (495) from 2,6,6-trimethyl-1,3-cyclohexadiene (496) and ethyl glyoxylate (306) is depicted in Scheme 72. (R)-Dihydroactinidiolide (494) and (R)-actinidiolide (495) can be synthesized from 499b. The bicyclic lactone 499b was provided from 498 upon treatment of base followed by acid.^536,537 Compound 498 was provided by an asymmetric catalytic HDA reaction of 2,6,6-trimethyl-1,3-cyclohexadiene (496) with ethyl glyoxylate (306). Therefore the key step in the total synthesis of 494 and 495 via this strategy is thus the HDA reaction, which is pleasantly proceeded with high regio- and endo-diastereoselectivity, and in excellent ee (Scheme 72). The catalytic effectiveness of several Cu(II)–bisoxazoline complexes in this HDA reaction was evaluated and 2,2′-isopropylidenebis[(4S)-4-tert-butyl-2-oxazoline] Cu(SbF₆)₂ ((S)-497) was found to be as the catalyst of choice. Compound 499b was converted to the desired natural product in several steps.⁵³⁹

Diazaquinomycin A (500) has been found to be a naturally occurring antibacterial agent. It was initially isolated by Ōmura and his coworkers⁵⁴⁰ from a Streptomyces strain. Further investigation by the same group⁵⁴¹ attributed its antibiotic potency to inhibition of thymidylate synthase. Till now, there is only one total synthesis reported for diazaquinomycin, (A) 500 involving a double Knorr cyclization as the key step.⁵⁴²

Due to the symmetry of the target ring system, in this approach, a double HDA cycloaddition reaction was envisaged. The first one involved the HDA cycloaddition of 1-dimethylamino-l-azadienes⁵⁴³ and a benzoquinone derivative which resulted in a short approach to a 1,8-diaza-anthraquinone system, which would then be expanded to provide the double lactam. Consequently, reaction of 2-metyl-2-hexenal dimethylhydrazones 501 (ref. 544) with 2,6-dibromobenzoquinone 502 promoted by triethylamine via trapping the liberated hydrobromic acid gave compound 503. Notably all attempts for aromatization of compound 503 with simultaneous double elimination of dimethylamine under previously reported conditions^545,546 failed. Ultimately, the doubly N-oxide 505 with perearbamide in trifluoroacetic acid followed by rearrangement to the double lactam via treatment with tosyl chloride in CH₃CN–H₂O gave diazaquinomycin A 500, which found being identical to the natural product in all points of view (Scheme 73).⁵⁴⁷

Scheme 73

The most plentiful calystegines, A₃, B₁, and B₂ (506), occur in C. sepium.⁵⁴⁸ Nitroso compounds are known to act as an ideal dienophiles especially in HDA cycloadditions to provide bicyclo-dihydroxazines.⁵⁴⁹ Calystegines are chiral polyhydroxylated nortropanic substances. The absolute configuration of natural calystegine B₂ has been determined as (1R,2S,3R,4S,5R).⁵⁵⁰ Generally, the chirality can be introduced in various ways. One of the most global way is to induce chirality during the HDA cycloaddition reaction, involving a chiral nitroso substrate.

This synthesis of natural calystegine B₂ has been remarkably improved, decreasing the steps and providing to obtain a satisfactory (13%) overall yield.⁵⁵¹

In this protocol for the total synthesis of natural calystegine B₂, the trisubstituted cycloheptadiene 508, is an appropriate precursor.⁵⁵² then, the produced free dihydroxazine 509 was protected as its benzylcarbamate derivative (510) and the subsequent steps according to the procedure as in the literature gave B₂ (Scheme 74).^550,552

Scheme 74

Canthin-6-one (511), was first isolated from Zanthoxylum chiloperone. It exhibited a wide scope of antifungal and leishmanicidal activities.⁵⁵³ To date, several approaches for the total synthesis of canthin-6-one (511) have been accomplished and reported.^554–558 Among them, perhaps the following pathway (Scheme 75) is exceptionally concise (six synthetic steps) and in addition gives a satisfactory overall yield (18%) because to the high yielding key step. In addition, it is one of the rare electron transfer induced total syntheses of a naturally occurring compounds.⁵⁵⁹ The acceptor, substituted 2-vinylindoles in the cycloaddition is provided from readily available harmalane 512,⁵⁶⁰ and acyl halides or anhydrides.⁵⁶¹ In present approach the trifyl substituted harmalanc derivative 513, was provided from harmalane 512. Interestingly, HDA cycloaddition reaction between 513 and methyl-E-3-(N,N-dimethylamino)-acrylate (514) as the dienophile was conducted electrochemically at a potential of 400 mV in CH₃CN/CH₂Cl₂ at ambient temperature in accordance with previously reported general procedure.⁵⁶² A ratio of 5 : 1 between the diene 513 and the dienophile 514 provided the best yield (87%) of the corresponding adduct 515. Noticeably, it is one of the highest yields ever reported for this kind of cycloaddition reaction. In addition, 84% of the residual diene 513 can be recovered upon chromatography. Compound 517 is also an intermediate for the synthesis of canthin-6-one 511 reported by Mitscher et al.⁵⁵⁵ The latter could be transformed into the natural product 511 in 50% yield during acidic ester hydrolysis and decarboxylation promoted by Cu/pyridine.⁵⁶³

Scheme 75

In 1989, the extracts of the soil microorganism Streptoverticillium verticillus were proved to have an unusual pentasubstituted cyclopentane namely, mannostatin A.^564,565 Manoalide has previously been prepared by Katsumura and Isoe,^566,567 Garst,⁵⁶⁸ Kocieński^569,570 and their respective colleagues. All these reported strategies have one thing in common. That is, the sensitive γ-hydroxybutenolide moiety was created in the last step, via HDA cycloaddition reaction of singlet oxygen to a 2-trialkylsilylfuran derivative. Accordingly, a new protocol employing, a 3-formylated butenolide, 520 has been reported. In this approach the latter was subjected to a Lewis acid-catalyzed HDA reaction. In this regard several silyloxydienes were employed in the key cycloaddition reaction.

Furfural provides the desired 4-formyl-5-[2-(trimethylsilyl)eth-1-oxy]furan-2(5H)-one 520 as key intermediate. The required 20 carbon western silyloxydiene 521 was synthesized in 5 steps, starting from commercially available β-ionone 519. Reaction of silyloxydiene 521 and aldehyde 522 under the optimized conditions concluded, from the model reaction (Scheme 76), gave raise into the HDA cycloadduct, which was desilylated in situ (silica gel, H₂O) at carbon C-24 affording monoprotected seco-manoalide (524). Deprotection, of the latter using trifluoroacetic acid gave manoalide (518b) (Scheme 4). As an alternative to the common photoisomerization of 518b into 518a, compound 524 was cyclized to monoprotected manoalide 525.⁵⁷¹

Scheme 76

In 1982 Lynn et al. isolated and identified the highly toxic mycotoxins talaromycin A (467a) and B (467b) as the first spiro-acetals of the fungus Talaromyces stipitatus.⁵¹⁵ This interesting structural feature takes place in several natural product, such as, polyether antibiotics, pheromones, milbemycins, and avermectins. They exhibit a wide range of biological potencies.⁵⁷²

Thus, the synthetic strategies to spiroacetals have been extensively studied.⁵⁷³ A concise and enantioselective synthesis of (−)-talaromycin B (467b) through nine steps has been achieved and afforded the desired natural product in an overall yield of 5%.⁵¹⁴ In this protocol the key step in the synthesis is a HDA reaction of exocyclic vinyl ether 473 and methyl-O-benzoyldiformylacetate (474). The oxa-1,3-butadiene 474, was readily prepared by formylation of methyl-3,3-dimethoxypropionate via benzoylation. It is a versatile substrate for HDA reactions. In addition analogous compounds, 474 was used in the synthesis of 3,4-dihydropyrans, as shown in Scheme 77.⁵⁷⁴

Scheme 77

Vinyl ether 473 should be instantly subjected to the HDA reaction, which cleanly and smoothly reacted with O in a ratio of 3 : 1.5 : 2 : 1 with the overall yield of 77% (Scheme 77). Delightfully, the major isomer 528 have the correct (4S,6R) configuration at the two newly generated chiral centers. Thus, flash chromatography of the cycloadducts provided a mixture of the trans adducts 528 and 529 along with a mixture of the cis adducts 526 and 527. At last, hydrogenation of the double bond in 530 and 531 gave (−)-talaromycin B (467b) along with a small amount of the diastereomer 531. This hydrogenation was highly stereo selective, taking place only from the bottom side of 530 and 531 to provide exclusively 467b from 530 and moreover, 532 were obtained from 531 (Fig. 4).

Fig. 4 Mycotoxins talaromycin B and mycotoxins talaromycin A from Talaromyces stipitatus.

Kawain 533, is α-pyrones among others isolated from the kava plant, Piper methysticum. Substances isolated from this plant have exhibited several biological properties.⁵⁷⁵

The HDA cycloaddition reaction between dienes, 1,3-dimethoxy-1-trimethylsilyloxybutadiene 534 and aldehydes, cinnamaldehyde 535 in dichloromethane under N₂, atmosphere catalyzed by Eu(fod)₃ or Yb(fod)₃ offers a facile and effective synthesis of (+) kawain 533 (ref. 576 and 577) in 75% and 84% yield respectively. When Ag(fod) is used as an effective catalyst a unique condensation reaction takes place in which two acyclic diastereomers were obtained in 72% yield (Scheme 78).⁵⁷⁸

Scheme 78

(−)-Pyrimidoblamic acid, 537, and its related peptide naturally occurring derivative, P-3A, 538, are known as key subunit for the classical synthesis of modified or simplified bleomycin analogs. The bleomycin (536, Fig. 5) is known as a group of basic glycopeptides that were initially isolated by Umezawa⁵⁷⁹ as copper complexes from cultures of Streptomyces verticillus.⁵⁸⁰ The total synthesis of (−)-pyrimidoblamic acid were and accomplished and reported by Umezawa,⁵⁸¹ Hecht,⁵⁸² and by other research groups.^583,584

Fig. 5

It is proposed that the pyrimidine core of (−)-pyrimidoblamic acid is constructed via an inverse electron demand D–A reaction between the highly functionalized amidine 544 and 1,2,3-triazine 541a (Scheme 79). Moreover, the same amidine 544 via cycloaddition with 1,2,3-triazine 541b can produce the pyrimidine core present in P-3A. The required N-aminopyrazole 540a for oxidative ring expansion to the 1,2,3-triazine 541a was provided from 539a. On the other hand, the required N-aminopyrazole 540b employed to obtain 1,2,3-triazine 541b was provided from pyrazole 539b. Amidine 544 was provided from market purchasable N-(triphenylmethyl)-L-asparagine (542) and aldehyde 543. [4 + 2] cycloaddition reaction of 1,2,3-triazine 541a with amidine 544 afforded the desired pyrimidine 545. Under the optimized conditions, the reaction of 544 and 541a, gives 545 as single diastereomer in 54% chemical yield. With this efficient pathway for the synthesis of 545 in hand, (−)-pyrimidoblamic acid 537 was prepared in virtually quantitative yield which was found identical by comparison of its physical and spectral data with those of authentic sample (Scheme 79). Accordingly, the cycloaddition reaction between 544 and 541b gave P-3A (538) in 89% yield after several steps reactions.⁵⁸⁵

Scheme 79

The ergot alkaloids initially isolated from the fungus Claviceps purpurea, containing a large group of biologically active indole alkaloids.⁵⁸⁶ Among this class of naturally occurring products, the notorious lysergic acid (LSD)⁵⁸⁷ is the most widely renowned member. However its several semi-synthetic derivatives are used as medicine in the treatment of wide range of neurological diseases.

An efficient total synthesis of dihydrolysergic acid (546) and dihydrolysergol (547) have been achieved and revealed. This strategy used an inverse electron demand D–A reaction of the tricyclic ketone 548 derived enamine 549 with 5-carbomethoxy-1,2,3-triazine (550) for the late-stage synthesis of the tetracyclic scaffold of the ergot alkaloid core structure (Scheme 80). As a matter of fact, in the synthesis of tricyclic ketone 548 a key step is intramolecular Pd(0)-catalyzed Larock indole annulation of a N-acetyl-2-bromoaniline derivative which is substituted with a pendant alkyne for the assemblage of the tricyclic fused indole, already known being present in ergot alkaloids. This approach consciously designed to permit the late-stage cycloaddition reaction of the electron-rich dienophile 549 with additional reactive heterocyclic azadienes for the divergent synthesis of several corresponding heterocyclic D-ring derivatives which were not easily accessible via conventional strategies, including alternatives such as substituted pyridines, pyrimidines, pyridazines and pyrroles.⁵⁸⁸

Scheme 80

3. Summary

In conclusion, six-membered aza- and oxa-heterocycles as frameworks are frequently present in naturally occurring products, including drugs endowed with a gathering of biologicalactivities. HDA and IMHDA reactions provide efficient and convenient access to these scaffolds. HDA reactions of aza- or oxa-substituted dienes or dienophiles are powerful approach to synthesize a wide variety of heterocyclic system, in a regio- and stereoselective fashions, especially to assemble them as a moiety in the structures of natural products. However, the strategic incorporation of a HDA reaction in the synthesis of complex molecules, for instance, natural products, sometimes may be complicated, on the one hand, often multistep and tedious synthesis of the required precursors, and selectivity problems may frequently be encountered. In general, the development of asymmetric, reactions remains highly challenging, and commonly stoichiometric amounts of chiral precursors are required to obtain appreciate levels of stereoselectivity.

Using of organo-catalysts or Lewis acid catalysts under mild reaction conditions, high atom economy, and tolerance of non-interacting functional groups makes the HAD or IMHDA, a reaction of choice for construction of complex molecules and natural products as key step (steps) in total synthesis of naturally occurring compounds. IMHDAs are particularly have been found useful for this purpose, due to their economical and stereocontrolled nature. These reactions permit the generation of two or more rings in a single operation, circumventing sequential chemical transformations.

Acknowledgements

The authors gratefully acknowledge the partial financial support from the Research Council of Alzahra University and from Iran National Science Foundation (INSF), allocated to the grant no. 93043105.

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