Stoichiometric asymmetric processes

Contents

• 1. Introduction

• 2. Chiral auxiliaries
  • 2.1 α-Alkylation
  • 2.2 Aldol reactions and related processes
  • 2.3 Michael additions
  • 2.4 Addition to CO and CN bonds
  • 2.5 Cycloadditions
  • 2.6 Oxidation
  • 2.7 Miscellaneous uses of chiral auxiliaries

• 3. Chiral reagents
  • 3.1 Chiral amine and lithium amide bases
  • 3.2 Sparteine-mediated reactions and related processes
  • 3.3 Addition to CO, CN and CC bonds
  • 3.4 Miscellaneous uses of chiral reagents

• References

---

Abstract

Covering: January 2000 to December 2000. Previous review: J. Chem. Soc., Perkin Trans. 1, 2001, 95.

---

1. Introduction

When reading and abstracting this ‘millennium’ edition of Stoichiometric Asymmetric Processes it was immediately apparent that oxazolidinone and chiral hydrazone auxiliaries are the most widely used in asymmetric synthesis and in many places their use has become so routine and commonplace that synthetic procedures are cited rather than given explicitly. However, aside from chiral borane reagents, there are significantly fewer chiral reagents used routinely, which may perhaps be attributed to the cost of such reagents. As advances in the preparation and uses of polymer supported reagents are made this may well change in the near future.

The topic Stoichiometric Asymmetric Processes covers a huge range of chemical transformations when one considers that all diastereoselective reactions of non-racemic substrates containing a stereogenic centre fall under this heading, including areas as diverse as rearrangements and glycosylation reactions. Thus, following the lead of Peter O'Brien's contribution last year, I have decided to concentrate on those transformations whereby the stereodirecting group is or has the potential to be removed at the end of the synthetic scheme. I have surveyed a majority of the primary chemical literature from 2000 but this review is far from comprehensive. I have decided to keep to a similar format to that introduced last year and have concentrated on the applications that auxiliaries have been used for in organic synthesis rather than the fine details regarding their reactivity and selectivity. However, some things have changed, and I have removed the section on the use of chiral reagents and auxiliaries in synthesis and incorporated this into the sections relating to transformations of that auxiliary. I have also added a few more subsections to help categorise the transformations.

2. Chiral auxiliaries

2.1 α-Alkylation

Asymmetric alkylation of lithium and sodium enolates of oxazolidinone and camphor sultam auxiliaries is one the most widely used transformations for the preparation of synthetic targets. Such reactions have been employed in many synthetic sequences including the synthesis of renin inhibitor BILA 2157 BS on a 0.6 kg scale,¹ both enantiomers of enterlactone,² isotopically ¹³C and D labeled L-leucine and other α-amino acids,^3,4 β-amino acids through a subsequent Curtius rearrangement,⁵ pitiamide A,⁶ (−)-eburnamonine and (+)-epi-eburnamonine,⁷ the sex pheromone of the sandfly Lutzomyia longipalpis,⁸ α,α′-cis and trans-disubstituted medium ring ethers,⁹ (R)-2-propyloctanoic acid,¹⁰ orthogonally protected tricarballylic acid esters,¹¹ the terminal acid portion of zooxanthellatoxins,¹² epothilone B,¹³ the C1–C25 domain of sanglifehrin A,¹⁴ β²-amino acids¹⁵ and (1S,3S,7R)-3-methyl-α-himachalene, the sex pheromone of the sandfly Lutzomyia longipalpis.¹⁶ A few other interesting examples of oxazolidinone enolate alkylation stand out; alkylation of the lithium enolate of an oxazolidinone with a triflate electrophile gave a 3 ∶ 1 mixture of C-alkyl and O-alkyl products, the former as a single diastereomer.¹⁷ This was reported as the first example of O-alkylation in oxazolidinone enolate alkylation. Oxidative self coupling of lithium enolates of N-acyloxazolidin-2-ones with reagents such as TiCl₄ have been shown to occur with good yields and levels of selectivity.¹⁸ Sibi and Rheault have investigated the stereoselectivity of the radical allylation of α-bromo-N-acyloxazolidinones 1 with allyltin reagents (Scheme 1).¹⁹ Quite surprisingly, higher selectivities were obtained at higher temperatures and a working model was proposed based upon the rotational barriers of the chelated and non-chelated radical intermediates.

Scheme 1

Although extensively used in synthesis, work is still carried out aimed at improving the efficiency and/or selectivity of oxazolidinone auxiliaries. Perhaps the most well known examples of these are the SuperQuat auxiliaries developed by Davies. Bull et al. have demonstrated that enhanced stereoselectivity in the alkylation of lithium enolates of the valine-derived SuperQuat chiral auxiliary is due to the geminal methyl groups controlling the conformation of the isopropyl stereodirecting group.²⁰ This in effect makes the isopropyl group behave like a tert-butyl group as far as controlling the diastereoselectivity of the alkylation step. Asymmetric alkylation of benzyl SuperQuat auxiliaries has been demonstrated for a number of substrates and electrophiles and the products were subsequently cleaved to the α-substituted aldehydes using DIBAL-H with no loss of stereochemical integrity.²¹ The first C₂ symmetric bis(oxazolidinone) auxiliary 2 has been prepared and undergoes asymmetric alkylations using methyl iodide with facial selectivities at each enolate of 95 ∶ 5 (Scheme 2).²² The auxiliary also has excellent water solubility making recycling through aqueous extraction a viable option.

Scheme 2

Other analogues of oxazolidinones have also been used but to a lesser extent. The diastereoselectivity of the alkylation of 2-imidazolidinone derivatives was found to be dependent upon the second nitrogen substituent,²³ while alkylation of the enolate of a glycinamide imidazolidinone 3 has been used in the diastereoselective synthesis of α-amino acids (Scheme 3).²⁴

Scheme 3

Asymmetric alkylation of a dienolate provides quick access to chiral α-substituted β-alkenes, although this methodology has not been used to as great an extent as enolate alkylation. Application of this methodology has been demonstrated in the synthesis of 1α-hydroxyvitamin D5²⁵ and in the synthesis of a fragment of madindolines²⁶ using oxazolidinones as the stereodirecting group.

Another preferred method for preparation of chiral α-substituted carbonyls is through the alkylation of aza-enolates of chiral hydrazone auxiliaries, which has been applied to the synthesis of (+)-maritimol,²⁷ stigmolone,²⁸ indolizidine alkaloids,²⁹ and components from crocodile exocrine secretion.³⁰ Ring opening reactions of p-tolylsulfonylaziridines with aza-enolates derived from the hydrazone 4 proceeded in excellent diastereoselectivity and have been used in the synthesis of γ-amino nitriles 5 and ketones 6 (Scheme 4).^31,32

Scheme 4

The use of axially chiral reagents and catalysts continues to expand. Fujita et al. have reported in depth studies of the reaction of enolates derived from axially chiral pyrrolidinones 7 with a series of electrophiles (Scheme 5).³³ The pyrrolidinones were prepared in excellent yield and with apparent complete chirality transfer and underwent reaction with electrophiles with excellent selectivity.

Scheme 5

Clayden et al. have demonstrated that amides possessing axial chirality may be deprotonated and quenched with a variety of electrophiles giving good yields and reasonable selectivities (69% ee).³⁴ These compounds could be converted to chiral atropisomers bearing no stereogenic centers in a short synthetic sequence.

Terpenes have been used as a framework for chiral auxiliaries. A novel pinene-based auxiliary has been prepared and applied to asymmetric alkylations with poor to moderate diastereoselectivities,³⁵ while the diastereoselective ring opening of a chiral epoxide with the enolate of a hydroxypinanone auxiliary has been investigated using a variety of bases and additives.³⁶ Diastereoselective alkylation of a terpene-derived aza-enolate has been shown to proceed in excellent stereoselectivity and has been applied to the synthesis of 4,5-dihydroxypipecolinic acid.³⁷ A conformationally restricted metabotropic glutamate receptor agonist bearing a cyclopropyl group has been prepared by dialkylation of a bis(menthyl ester)³⁸ and asymmetric cyclopropanation has also been carried out by a tandem alkylation–Darzens reaction of a pyridinium salt 8 bearing the 8-phenylmenthyl auxiliary (Scheme 6).³⁹

Scheme 6

The preparation of amino acid derivatives still continues to attract attention. One of the more widely used methods has been alkylation of Schöllkopf's bislactim ether template that has been used in the synthesis of 3-heteroaromatic substituted alanines,⁴⁰ tryptophan analogues,⁴¹ silaproline,⁴² (+)-deoxypyridinoline,⁴³ and α-methyl-α-substituted amino acids using mild phase transfer conditions.⁴⁴ Chiral nickel(II) complexes of Schiff bases 9 have been used for the preparation of amino acids by alkylation of alanine and glycine templates (Scheme 7), which was amenable to large scale synthesis.⁴⁵ This methodology was applied to the synthesis of ω-borono-α-amino acids as active site probes of arginine NO synthase⁴⁶ and in the synthesis of 2′,6′-dimethyltyrosine via complex 10.⁴⁷

Scheme 7

Stereoselective alkylation of aldimines using chiral ansa pyridoxyl derivatives proceeded in good enantiomeric excess, while introduction of a second stereogenic element allowed double asymmetric induction and greatly increased selectivities.⁴⁸ Other methods to prepare amino acids include the alkylation of Williams' glycine template to prepare (2R,5R)- and (2S,5R)-5-hydroxylysine,⁴⁹ alkylation of a chiral morpholinecarboxylate to prepare a non-proteinogenic fluorescent amino acid,⁵⁰ alkylation of a novel chiral oxazoline with a range of active electrophiles,⁵¹ alkylation of a chiral aza-enolate with 1,2-fluorobromides,⁵² and an alkylation–cyclisation procedure to prepare α,α′-diaminodicarboxylic acids.^53,54

Many other chiral auxiliaries have been investigated in alkylation reactions. Some in particular merit further details. Denmark and Kim have reported good to excellent diastereoselectivities in the alkylation of phosphonamide auxiliaries based on a C₂ symmetric diamine.⁵⁵ Hanessian and Cantin have demonstrated that γ-chlorodienolates of similar chiral phosphonamides undergo a highly diastereoselective Darzens-like reaction with glyoxylaldehyde-derived oximes.⁵⁶ Seebach's self-replication of chirality is a useful procedure that has been used to prepare substrates for RCM reactions,⁵⁷ in the synthesis of both enantiomers of a neuroexcitant⁵⁸ and both enantiomers of the pheromone of the tropical wandering spider Cupiennius salei11 (Scheme 8).⁵⁹

Scheme 8

Diastereoselective alkylation of chiral oxazolidines has been used in the synthesis of the ladybird defence alkaloid (+)-calvine and (+)-2-epicalvine,⁶⁰ a compound from the pheromone gland of the stinkbug,⁶¹ and 3-alkyl-3-arylpyrrolidines.⁶² Alkylation of sodium enolates of sulfonamides with α-bromocarboxylates appeared to give single diastereomers of addition products that were subsequently reduced to diols.⁶³ This is interesting since the bromocarboxylates used were racemic implying that racemisation of such reagents is fast under these reaction conditions.

The chemistry of arene chromium tricarbonyls has been further expanded and the first example of the addition of the enolate of tert-butyl acetate to a chromium arene tricarbonyl complex to give a cyclohexadiene product has been reported with excellent levels stereoselectivity.⁶⁴ Huang and Comins achieved the highly diastereoselective addition (de >95%) of a zinc enolate equivalent to a trans-2-(α-cumyl)cyclohexanol pyridinium derivative, the key step in the synthesis of (+)-streptazolin.⁶⁵ Chiral alanine dianions have been shown to give excellent levels of selectivity in some alkylation reactions⁶⁶ and when employed with ethyl bromoacetate, a built-in ‘auxiliary release’ was used to free the chiral auxiliary. Chiral aldehydes have been used to prepare non-racemic aminals with good diastereoselection (84 ∶ 16)⁶⁷ and N-acyl derivatives of these have subsequently been used in enolate alkylations giving diastereoselectivities of over 90%. The diastereoselectivity of the allylation of enolates of bicyclic oxazolidines was found to be dependent upon the nature of the protecting group of the amino alcohol.⁶⁸

Other auxiliaries that have been used in asymmetric alkylations include a thiazolo[2,3-a]isoindolin-1-one,⁶⁹ α-methylbenzylamine⁷⁰ and phenylglycinol⁷¹ in the synthesis of tetrahydroisoquinolines, an 8-phenylmenthyl ester in an intramolecular radical cyclisation,⁷² a BINOL ester in the synthesis of (+)- and (−)-ferruginol,⁷³ 2-phenylcyclohexanol in the synthesis of (+)-huperzine A,⁷⁴N-methylephedrine in the synthesis of the C14–C25 portion of amphidinolide B1,⁷⁵ and O-methyl phenylglycinol in the deprotonation–alkylation of oxazolidines⁷⁶ and aziridines.⁷⁷

2.2 Aldol reactions and related processes

As with asymmetric alkylation, highly diastereoselective syn-aldol condensations using chiral boron enolates of oxazolidinones generated using dibutylboron triflate and an amine base are now used as a matter of routine in synthetic schemes. Although a robust model for the selectivity observed in this reaction is well established, the first report of the structure of a stable boron enolate of an oxazolidinone has been reported using 600 MHz 2D NOESY NMR and molecular modeling techniques.⁷⁸ Since the substitution pattern of the aldol product obtained closely matches that of many natural products, application of this methodology to total syntheses has been extensive. Successful uses include the synthesis of (+)-rajadone,⁷⁹ the C29–C51,⁸⁰ C29–C45⁸¹ and C29–C44⁸² fragments of spongistatin 1, the dihydrobenzofuran segment of ephedradine C,⁸³ a pyrrolidine α-glycosidase inhibitor,⁸⁴ antillatoxin,⁸⁵ the C1–C9 fragment of rhizoxin,⁸⁶ hapalosin,⁸⁷ (+)-madindoline A and (−)-mandinoline B,⁸⁸ (−)-CP-263,114,⁸⁹ and (+)-discodermolide.⁹⁰ Boron enolates of oxazolidinones have also been used to prepare substrates for stereoselective phenylsulfanyl rearrangements to provide spiro[4.5]decanes.⁹¹ Reactions of boron dienolates are not as widespread as those of enolates. A boron dienolate of an oxazolidinone 12 has been shown to react with a chiral aldehyde 13 to give the desired aldol product 14 as a 1 ∶ 1 mixture of Z and E isomers that was used in the synthesis of the tris(oxazole) macrolide ulapualide A⁹² (Scheme 9) and similarly in the synthesis of polyene macrolides.⁹³

Scheme 9

One of the advantages of aldol reactions of oxazolidinones is that syn- and anti-aldol products may be selected by changing the reaction conditions and examples of this have been used in the synthesis of ribavirin⁹⁴ and phoboxazole B.⁹⁵

Although highly successful, aldol reactions are obviously not limited to boron enolates of oxazolidinones. Titanium(IV) enolates of N-acyloxazolidine-2-selones 15 give predominately ‘non-Evans’ syn-aldol products 16 with excellent diastereoselectivity,⁹⁶ and the selone was found to play a pivotal role in determining the stereoselectivity (Scheme 10).

Scheme 10

Titanium enolates have also been used with oxazolidinones and oxazolidinethiones that undergo syn-selective aldol reactions with the best selectivities observed for the oxazolidinethione⁹⁷ which was applied to the synthesis of (+)-prelaureatin and (+)-laurallene. Such enolates have also been shown to react in the presence of (−)-sparteine to give excellent diastereoselectivity in favour of the syn-aldol product and used in the synthesis of carbocyclic nucleosides.⁹⁸ Tin enolates have been used to mediate an aldol reaction of an α-hydroxyacyloxazolidinone giving the anti-aldol product in good diastereoselectivity when treated with a chiral aldehyde.⁹⁹

Use of acetyl enolates in asymmetric aldol reactions is notoriously problematic and various methods have been employed to overcome this. A study of the use of a number of boron triflates and α-thioacetyl derivatives attempted to address this problem and was applied to the C1–C6 segment of epothilones.¹⁰⁰ Other types of enolate other than boron have also been investigated. An acetyl tin enolate of a thiazolidine-2-thione has been shown to give aldol products with excellent diastereomeric excess in the synthesis of (−)-teubrevin G,¹⁰¹ while intermolecular SmI₂-promoted Reformatsky-type reactions of a number of acetyloxazolidin-2-one derivatives 17 has been investigated with good levels of diastereoselectivity (Scheme 11).¹⁰²

Scheme 11

Examples of transformations of new oxazolidinone auxiliaries continue to be developed. The asymmetric boron-mediated aldol reactions of a new glucose-derived oxazolidinone 18 have been described giving diastereomeric ratios from 3 ∶ 1 to 16 ∶ 1 in favor of the expected syn-product 19 depending upon the protecting groups of the carbohydrate and the aldehyde employed (Scheme 12).¹⁰³

Scheme 12

Asymmetric aldol reactions are not limited to employing oxazolidinones or thio-substituted analogues as chiral auxiliaries and many other examples exist that make use of the formation of an amide-type bond in the addition and cleavage steps. Boron enolates of imidazolidin-2-ones¹⁰⁴ and imidazolidinone glycine equivalents¹⁰⁵ undergo highly diastereoselective syn-selective aldol reactions with good to excellent diastereoselectivities. Sultams are often comparable in their chemistry to oxazolidinones and have been used in boron-mediated aldol reactions with chiral aldehydes and α-ketoesters.¹⁰⁶ Although the former proceeded with total diastereoselectivity in favour of the syn-product, the ketoester gave a 3 ∶ 1 mixture to two diastereomers. Titanium enolates of sultams have also been employed giving the anti-aldol product in excellent yield (95%).¹⁰⁷ Amides derived from pseudoephedrine 20 have been used in asymmetric aldol reactions in the presence of different metal cations, in particular zirconocene dichloride gave selectivities of over 99 ∶ 1 in favour of the syn-isomer 21 (Scheme 13),¹⁰⁸ and this auxiliary was used in the first asymmetric synthesis of isoflavanones.¹⁰⁹ The aldol reactions of N-propionylprolinol derivatives have also been investigated with and without the addition of Lewis acids.¹¹⁰

Scheme 13

A number of auxiliaries make use of the formation of esters and acetals to facilitate the attachment or cleavage steps. Paterson et al. have made use of the excellent diastereoselective control in the aldol reaction of boron enolates derived from chiral ketones in an auxiliary type fashion.¹¹¹ Thus, after the desired aldol reaction had taken place, oxidative cleavage of the stereodirecting group was achieved, although this destroyed the stereochemistry of the attached chiral auxiliary.

Relatively few examples of aldol reactions with terpene-derived auxiliaries have been reported. Thus, menthol- and camphor-derived acetylenic esters 22 have been used in titanium-mediated additions giving Baylis–Hillman products 23 with good regioselectivities and varying diastereoselectivities (Scheme 14).¹¹² The best auxiliary was found to be the alcohol derived from D-camphor giving diastereoselectivities >97 ∶ 3 for a range of structurally diverse aldehydes.

Scheme 14

Camphor derivatives have also been used as the stereodirecting group in a Darzens reaction of α-bromoacetyl substrates giving epoxides of >97 ∶ 3 diastereoselectivity,¹¹³ while a novel pinene-based auxiliary has been prepared and used in asymmetric aldol reactions with poor to moderate diastereoselectivities.³⁵ Aldol reactions of aza-enolates derived from the hydroxypinanone derivative 24 have been carried out using a catalytic quantity of base giving good diastereocontrol at the α-carbon but essentially no control at the β-centre (Scheme 15).¹¹⁴

Scheme 15

Seebach's self-reproduction of chirality has been demonstrated on a 100 g scale in the synthesis of (S)-oxybutynin¹¹⁵ and in the synthesis of a chiral spiro aminochromane,¹¹⁶ the latter giving poor levels of stereocontrol at the newly formed stereogenic centre.

Boron and titanium enolates of chiral α-chloromethyleneoxazolines give oxazolinyl oxiranes when treated with ketones in excellent diastereoselectivity.¹¹⁷ Other asymmetric aldol processes include the reaction of dienolates derived from chiral oxazolidines with aldehydes,¹¹⁸ a diastereoselective Mukiyama aldol reaction of a chiral furyl sulfoxide,¹¹⁹ the synthesis of enantiomerically pure mono- and bis-epoxides of isoprene using Ley's dispoke protected lactate,¹²⁰ and addition of (E)-enolates to chiral dithiane ketone equivalents.¹²¹

2.3 Michael additions

Michael additions are particularly important transformations as they facilitate bond formation β to a carbonyl centre and often allow construction of quaternary carbon centres. Examples of this include the use of a chiral aza-enolate in the first steps of the synthesis of some polycyclic diterpenes¹²² and chiral enamines 25 derived from β-oxoesters that react under copper catalysis at ambient temperature and without an inert atmosphere (Scheme 16).¹²³

Scheme 16

Addition of cuprate and organocopper reagents to chiral acceptors is a well used method for performing conjugate additions. Lithium alkyl cyanocuprates undergo highly diastereoselective conjugate addition from the least hindered exo-face to chiral bicyclic lactams and this has been applied to the synthesis of trans-3,4-disubstituted piperidines.¹²⁴ The addition of various cuprate and organocopper reagents to unsaturated tert-leucine oxazolidinone acceptors has been investigated with and without an added Lewis acid with excellent levels of diastereoselectivity.¹²⁵ Similar acceptors have been used in the synthesis of kalkitoxin,¹²⁶ an α,β-substituted histidine analogue¹²⁷ and 3′O,4′O-dimethylfuniculosin (Scheme 17).¹²⁸

Scheme 17

Organocopper and organoaluminium reagents have also been used in domino Michael–aldol and Michael–Mannich reactions with chiral oxazolidinones to construct highly functionalised cyclohexane frameworks.¹²⁹ In an interesting switch, organolithium reagents based on chiral oxazolidinones 26 undergo copper-mediated Michael addition to an unsaturated aldehyde with excellent levels of diastereocontrol (Scheme 18).¹³⁰

Scheme 18

Addition of organocopper reagents to unsaturated chiral phosphonate derivatives gave good to poor levels of diastereoselectivity.¹³¹ Under appropriate circumstances, organolithium and magnesium reagents can also add to chiral acceptors without the aid of copper additives. Diastereoselective Michael addition of MeLi to a vinyl selenide bearing a cyclohexanol auxiliary followed by quenching with an alkyl halide gave >15 ∶ 1 diastereoselectivity.¹³² Highly diastereoselective Grignard addition–alkylation to chiral aryloxazolines and imines have been shown to occur in good yield via an unusual Michael addition of the nucleophile directly to an aromatic ring.¹³³

Carbon-based nucleophiles derived from enolates or enolate equivalents are generally more useful in Michael additions than alkyllithium and magnesium reagents since the conditions for their generation are invariably less harsh. Enolates themselves have been used in the synthesis of a key intermediate of a muscarinic M-3 receptor antagonist,¹³⁴ the novel H₃ agonist Sch 50971¹³⁵ and in the synthesis of pyroglutamates.¹³⁶ An interesting example of an asymmetric intramolecular tandem Michael–aldol reaction of an enolate with phenylmenthyl enoates 27 gave tricyclic structures 28 with excellent levels of diastereoselectivity (Scheme 19).¹³⁷

Scheme 19

Glycine-derived enolates have been used in the synthesis of pyroglutamates,¹³⁸ and nickel(II) Schiff base complexes of such enolates found to react with α,β-unsaturated oxazolidin-2-one acceptors in excellent yield and diastereoselectivity.¹³⁹ The origin of the selectivity of this reaction was investigated in some detail and the stereochemical outcome was found to be independent of the stereochemistry of the Schiff base.¹⁴⁰ Aza-enolates generated from chiral imines have been shown to undergo Michael additions with excellent levels of diastereoselectivity¹⁴¹ and used in the synthesis of (+)-α-vetivone.¹⁴² α-Substituted δ-lactams 30 have been prepared via Michael addition of the enolate of a chiral hydrazone 29 to nitro alkenes with good to excellent levels of stereocontrol (Scheme 20).¹⁴³

Scheme 20

A study of the conjugate addition of an aza-enolate of Schöllkopf's bislactim ether to (E)- and (Z)-prop-1-enylphosphonates was found to occur with complete diastereoselectivity at the α-centre and excellent selectivity at the β-centre in all cases except when HMPA, SnCl₂ or CuBr₂ were used.¹⁴⁴ In a related reaction, Michael addition of a nitro enolate to a chiral chromium tricarbonyl Michael acceptor proceeded with excellent diastereocontrol.¹⁴⁵ Enolate equivalents are often prepared and reacted under milder conditions than enolates themselves and in this context enamines are very useful reagents as they can be prepared using chiral amines. A phenyloxazolopiperidine derivative 31 has been prepared and used as a latent enamine equivalent in an asymmetric Michael addition with methyl vinyl ketone giving the addition adduct 32 as a single diastereomer in reasonable yield (Scheme 21).¹⁴⁶

Scheme 21

Enantioselective Michael additions of enamines to nitro olefins have been shown to occur with excellent yield and degrees of diastereoselectivity and the products from these reactions converted into non-racemic pyrrolidines.¹⁴⁷

Other miscellaneous enolate equivalents have been used to perform carbon–carbon bond formation using Michael additions. 2,6-Dimethylmorpholine has been used as a chiral auxiliary in the Michael addition of Fischer carbene complexes to unsaturated nitro compounds in 75% de and 90% isolated yield.¹⁴⁸ Highly stereoselective conjugate additions of α-carbanions of chiral sulfoxides 33 to unsaturated esters followed by quenching with alkyl halides and aldehydes has been reported (Scheme 22),¹⁴⁹ while C₂ symmetric sulfoxides have been shown to add to stabilised Michael acceptors giving a single diastereomer of addition product.¹⁵⁰

Scheme 22

A diastereoselective Michael–Darzens-type addition of a sulfur ylide to an unsaturated chiral sultam has been used to prepare the pheromone of the pine sawfly.¹⁵¹ Hanessian et al. have demonstrated phosphonamide dianions undergo highly diastereoselective Michael additions with ketones, lactones and lactams,¹⁵² while phosphonamide anions have been used in a tandem Michael addition–Darzens-type type reaction to prepare cyclopropanes.¹⁵³ The asymmetric Michael addition of alkyl radicals has not received as much attention as other carbon–carbon bond forming processes, although a few reports have been made of addition to unsaturated chiral sulfoxides,¹⁵⁴ a crotonyl group tethered to a carbohydrate in the presence of diethylaluminium chloride¹⁵⁵ and of photosensitized radical addition to chiral fumaric acid derivatives¹⁵⁶ with good diastereoselectivities.

Michael additions are not limited to the formation of carbon–carbon bonds alone and additions of nitrogen nucleophiles are quite commonplace. One of the best-known examples of such reactions is the addition of homochiral ammonia equivalents developed by Davies. This work has been extended through the development of a new route towards chiral Baylis–Hillman products 35 by the diastereoselective Michael addition of a chiral lithium amide 34, followed by subsequent stereoselective boron-mediated aldol reaction and finally Cope elimination (Scheme 23).¹⁵⁷

Scheme 23

Bull et al. have provided further examples of chiral lithium amide additions to Michael acceptors in the preparation of substrates to demonstrate the debenzylation reactions of amines.¹⁵⁸ Other applications of this methodology have been reported including the synthesis of β-haloaryl β-amino acids,¹⁵⁹ cyclic β-amino acids,¹⁶⁰ β-homolysine,¹⁶¹ plakoridine A,¹⁶² trisubstituted piperidines¹⁶³ and the dihydrobenzofuran segment of ephedradine C.⁸³ Chiral hydrazines have also been used as ammonia equivalents and employed in the asymmetric synthesis of α-substituted β-amino sulfones¹⁶⁴ and in a stepwise Michael addition–α-alkylation of unsaturated lactones.¹⁶⁵ Michael addition of a chiral oxazolidinone 36 to a nitro olefin gave a good ratio of anti ∶ syn-addition products 37 (85 ∶ 15) that were used in the synthesis of dethiobiotin (Scheme 24).¹⁶⁶

Scheme 24

Asymmetric Michael addition of amines has also been carried out using chiral acceptors. Addition of resin-bound amino acids to a chiral oxazolidinone acceptor proceeded in good to poor diastereoselectivity,¹⁶⁷ while the synthesis of enantiomerically pure aziridines 39 was accomplished by a fairly diastereoselective (80 ∶ 20) addition of a hydroxylamine to a chiral imidazolidinone acceptor 38, followed by separation and cyclisation (Scheme 25).¹⁶⁸

Scheme 25

Addition of amine and alcohol nucleophiles to chiral α,β-unsaturated sulfamines has been shown to occur with good levels of diastereoselectivity, although this is limited in scope as the nucleophile must be used as the solvent.¹⁶⁹

Oxygen-based nucleophiles have been used less often in such reactions. Two consecutive diastereoselective Michael additions of a propargylic (prop-2-ynyl) alcohol to a chiral unsaturated sulfoxide have been used in the synthesis of (+)-asteriscanolide.¹⁷⁰ Oxidative cyclisation of chiral phenolic oxazolines 40 in the presence of iodobenzene diacetate gave an intermediate alkoxyspirolactam 41 that underwent spontaneous intramolecular Michael addition to give a single diastereomer of a tricyclic compound 42 (Scheme 26).¹⁷¹

Scheme 26

As with oxygen nucleophiles, relatively few examples of sulfur nucleophiles in Michael additions have been reported. Of particular interest is a novel tandem Michael addition and Meerwein–Ponndorf–Verley reduction which has been carried out using the 10-mercaptoisoborneol auxiliary 43 giving alcohols 44 in high yields and excellent levels of stereoselectivity (Scheme 27).^172,173

Scheme 27

The diastereoselectivity of the addition of thiols to camphor-derived Michael acceptors has been investigated giving a wide range of selectivities and yields depending upon the reaction conditions.¹⁷⁴ Addition of a thiol to cyclic acceptors derived from 3-hydroxybutyric acid gave inseparable mixtures of diastereomers, the selectivity of which depended upon the exocyclic alkyl group.¹⁷⁵

Two other unusual Michael additions warrant attention; Enders et al. have developed new methods for the synthesis of α-substituted β-nitrophosphonic acids using a chiral phosphite complex derived from 1,1,4,4-tetraphenyl-2,3-O-isopropylidene-L-threitol (TADDOL).¹⁷⁶ Reaction of such diethylzinc-activated complexes with a series of nitro alkenes afforded the desired products in good yield and diastereomeric excess with cleavage of the TADDOL auxiliary giving the nitrophosphonic acids. Degnan and Meyers have reported the only example in this survey of the highly diastereoselective conjugate addition–alkylation of silyl anions to naphthyloxazolines 45 and their application to the synthesis of aminotetralin (Scheme 28).¹⁷⁷

Scheme 28

2.4 Addition to C=O and C=N bonds

Stereocontrolled addition to C=O and C=N bonds represents an easy route to the introduction of an additional stereogenic centre, and when using enolates or their equivalents as nucleophiles, the formation of a carbon–carbon bond. Oxazolidinone chiral auxiliaries have again been used extensively, primarily in the addition to C=N bonds. Various substitution of N-acyl groups has been investigated in some detail to study the addition of enolates of oxazolidinones to iminium ions generated from piperidines.¹⁷⁸ New methodology has also been reported for the synthesis of β-amino acids by the addition of enolates of N-acyloxazolidinones 46 to N-acyloxyiminium ions generated in situ (Scheme 29).¹⁷⁹ The reactions proceeded with moderate levels of selectivity and the main advantage of this methodology is that chiral pyrrolidine and piperidine derivatives are easily prepared.

Scheme 29

Other types of chiral auxiliary have also been used. Enantioselective reaction of lithium enolates of sultam chiral auxiliaries with diphenylphosphinyl imines gave excellent diastereo- and enantioselectivities.¹⁸⁰ A camphor-derived auxiliary has been used to demonstrate the versatility of an asymmetric Mannich-type reaction giving good to excellent yields and diastereoselectivity.¹⁸¹ One report described the addition of an enolate to a chiral sulfinyl imine auxiliary in the synthesis of all four stereoisomers of 4-hydroxypipecolic acid.¹⁸²

Enolate equivalents, in particular silyl enol ethers, have also been employed extensively. Addition of silyl enol ethers to chiral imines generated in situ gave good to excellent levels of diastereocontrol, the products of which could be transformed themselves into silyl enol ethers that underwent subsequent aldol reaction with excellent degrees of stereoselectivity.¹⁸³ Further applications of this methodology have also been reported (Scheme 30).¹⁸⁴

Scheme 30

Ytterbium triflate has been used to catalyse the addition of chiral silyl ketene aminals to imines and the diastereomeric ratio was found to be dependent upon the structure of the imine.¹⁸⁵ A similar reaction has also been carried out under Mannich-type conditions.¹⁸⁶ Glycosyl bromides have been used to activate Schiff bases to nucleophilic attack of silylketene acetals.¹⁸⁷ Good yields were obtained but with moderate levels of diastereoselectivity (dr generally 3 ∶ 1) which was shown to be due to E to Z isomerisation of the C=N bond after activation.

α-Carbanions of chiral sulfoxides have been used as chiral carbon nucleophiles. Thus, lithiation of the benzylic position of a chiral sulfoxide followed by quenching with a chloroformate, aldehyde or ketone gave the desired products in excellent diastereomeric excess.¹⁸⁸ In the case of prochiral ketones and aldehydes, good to poor ratios of epimeric alcohols were formed. Such carbanions have also been shown to add in a matched/mismatched fashion to chiral N-sulfimines 47 (Scheme 31).¹⁸⁹ In the matched case a diastereomeric excess of over 98% in 99% yield was observed.

Scheme 31

Although in general significantly more reactive, organometallic reagents undergo facile addition to C=O and C=N bonds, sometimes with the added benefit of chelation to improve stereochemical control. In particular, addition of Grignard reagents to chiral imines has been widely used, for example, in the synthesis of 4-hydroxypipecolic acid by addition to a chiral pyridinium salt,¹⁹⁰ in the preparation of chiral substituted piperidines,¹⁹¹ and in the three step synthesis of an HIV non-nucleoside reverse transcriptase inhibitor.¹⁹² An in depth study has been carried out using allylmagnesium and zinc reagents with bisimines 48 bearing the α-methylbenzylamine stereodirecting group (Scheme 32)¹⁹³ and independent studies have shown that dynamic kinetic resolution may be observed with Grignard additions to such species.¹⁹⁴

Scheme 32

Grignard addition to chiral aza-acetals proceeded with reasonable levels of stereoselectivity dependent upon the Grignard reagent,³⁵⁷ and reactions with related C₂ symmetric bisoxazolidines have also been investigated.¹⁹⁵ An in depth study of the enantioselectivity of the addition of Grignard reagents to chiral sulfinyl imines has also been carried out.¹⁹⁶ Nakamura et al. have investigated the diastereoselective addition of Grignard reagents to axially chiral aryl sulfoxide aldehydes 49,^197,198 the selectivity of which was dependent upon the structure of the sulfoxide and any additive (Scheme 33). Attempted addition of silyl enol ethers gave poorer diastereoselectivities.

Scheme 33

The only surveyed report of the asymmetric addition of a Grignard reagent to a ketone has been the addition of 2-naphthylmagnesium bromide to a menthyl pyruvate ester with poor levels of diastereocontrol.¹⁹⁹

Organolithium reagents have also been employed with good degrees of success. Studies of the addition of such reagents to chiral 1-ferrocenylalkanimines,²⁰⁰ bisimines bearing the α-methylbenzylamine stereodirecting group,²⁰¹ chiral oxazolidines,²⁰² and aldehydes with axial chirality²⁰³ have all been reported. Addition of organolithium reagents to chiral hydrazones provides excellent degrees of stereocontrol and has been used in the synthesis of a defence alkaloid of the Mexican bean beetle (Scheme 34)²⁰⁴ and (+)-2-epideoxoprosopinine.²⁰⁵

Scheme 34

The application of heterosubstituted organolithium species has led to some success, for example, in the addition of lithium carbanions of chiral thiazolidines to aldehydes²⁰⁶ and lithiated allyl sulfones to chiral N-sulfinylamines.²⁰⁷

Other organometallic species, primarily organozinc and titanium reagents have been used, presumably due to their availability. Alexakis et al. have prepared a new C₂ symmetric diamine in excellent enantiomeric excess by using a diastereoselective addition of allylzinc bromide to an α-methylbenzylamine-derived imine.²⁰⁸ Reaction of chiral imines with alkenyltitanium²⁰⁹ and allyltitanium alkoxides²¹⁰ have been shown to proceed with good levels of diastereoselectivity. Addition of an allylindium reagent generated in situ to an activated ketone bearing a chiral amine gave excellent levels of diastereoselectivity.²¹¹

Reduction of C=O and C=N bonds provides one of the easiest methods to install a new stereogenic centre. Reduction of chiral imines with zinc borohydride has been extensively studied,²¹² and other borane- and alane-derived reducing agents have been used in the synthesis of chiral ferrocenyl amines,²¹³ 1,2-amino alcohols,²¹⁴ tetrahydroisoquinolines,⁷¹ and piperidines.²¹⁵ Related hydrazones have been reduced with LiAlH₄ with varying levels of stereocontrol using 2-aminobutan-1-ol as an auxiliary.²¹⁶

Chiral keto sulfoxides have been used widely as substrates for asymmetric reductions. The reduction of such γ-keto sulfoxides with and without addition of Lewis acids has been investigated for a number of substrates giving excellent yields and levels of diastereoselectivity.²¹⁷ Reduction of a β-keto sulfoxide with DIBAL-H gave >95% diastereomeric excess that could be completely inverted by addition of ZnI₂ to the reaction.²¹⁸ Such reductions have been used in the synthesis of chiral 2-amino alcohols²¹⁹ and in the synthesis of colletol (Scheme 35).²²⁰

Scheme 35

Fewer reports exist for the stereoselective reduction of ketones, presumably as there are now very efficient catalytic methods available for this transformation. The conditions for the stereocontrolled reduction of a chiral aziridinyl ketone have been optimised and used in the synthesis of threo-β-hydroxy-L-glutamic acid²²¹ and in the preparation of both enantiomers of 4-hydroxycyclohex-2-enone, an important chiral building block, achieved by using a 1,2-reduction of the chiral cyclohexenone acetal.²²²

Some reports have been made on diastereoselective radical or radical-type addition to chiral carbonyls and imines. N-Acylhydrazones based on oxazolidinones have been prepared and have been shown to undergo highly diastereoselective radical addition to give N-acylhydrazines²²³ and sultam auxiliaries have been used to control the stereoselectivity of the carbon radical addition to oxime derivatives 50 (Scheme 36).²²⁴ These reactions generally proceeded in good yield and selectivity (86 ∶ 14 to 96 ∶ 4) and the products 51 were easily converted to α-amino acids.

Scheme 36

Triethylborane and diethylzinc-mediated radical additions to chiral glyoxylate and cyclic imines gave good selectivities with cyclic compounds and poorer selectivities with open chain substrates.²²⁵ 2-Methoxymethylindolinone has been used as a chiral auxiliary in SmI₂-mediated pinacol couplings to give substituted tartrate derivatives of high enantiomeric purity,²²⁶ while 8-phenylmenthol has been used as an auxiliary in normal and crossed pinacol couplings with reasonable levels of diastereoselectivity.²²⁷

The asymmetric Strecker reaction is a useful method to prepare chiral amino acids and several methods have been reported that employ this methodology, including the synthesis of the Corey precursor of lactacystin.²²⁸ Use of chiral sulfimines as substrates for this reaction has been disclosed^229,230 and employed in the synthesis of diaminopimelic acids.²³¹ A number of carbohydrate derivatives have been examined in asymmetric Strecker reactions using α-methylbenzylamine as the stereodirecting group.²³² Diastereomeric ratios from 1 ∶ 1 to 7 ∶ 1 were obtained depending upon the substrate. An asymmetric Strecker reaction has been investigated in some detail with a series of chiral imines based on a racemic cyclopentane framework with varied levels of diastereoselection.²³³

Other miscellaneous additions to C=O and C=N bonds include the use of 1-phenylethylamine in the discrimination of enantiotopic symmetric bisketenes,²³⁴ stereoselective acetal formation in the desymmetrisation of glycerol using camphor sulfamides²³⁵ and in the synthesis of muricatetrocin C,²³⁶ the stereoselective synthesis of trans-aryl vinyl epoxides using a chiral sulfur ylide,²³⁷ an asymmetric Friedel–Crafts reaction of a menthyl pyruvate ester²³⁸ and the first example of a highly diastereoselective hydrophosphorylation of a C=N bond.²³⁹

2.5 Cycloadditions

Asymmetric cycloadditions provide an excellent method for the generation of cyclic structures with a number of stereogenic centres. The classical [4 + 2] cycloaddition of a diene with a dienophile may be conducted in an asymmetric manner by installing a stereodirecting group in either of these components. However, the most used approach is to incorporate the chiral auxiliary into the dienophile and the diastereoselectivity of such substrates with classically used auxiliaries such as sultams and hydrazides has been investigated as a function of solvent polarity.²⁴⁰ Applications of such reagents to synthesis include the use of chiral oxazolidinones in the preparation of the alkaloid (+)-gelsemine²⁴¹ and in the synthesis of ceralure B.²⁴² Extensive investigations of the asymmetric Diels–Alder additions of chiral sulfinyl benzoquinones with dienes have been carried out with and without added Lewis acid.^243–245 Chiral sulfoxides based on naphthoquinones,²⁴⁶ sulfinyl and menthylsulfonyl furanones²⁴⁷ have also been employed. Brimble et al. have shown that pantolactone or phenylmenthyl auxiliaries exert poor stereocontrol (1.4 ∶ 1) on the cycloaddition of a naphthoquinone derivative and a diene.²⁴⁸ These auxiliaries also required destructive removal after the reaction was complete. Carbohydrate-derived acrylates based on isomannide²⁴⁹ and fructose²⁵⁰ have been employed with good levels of diastereoselectivity, and the origins of the selectivity investigated with the former. Formation of each diastereomer from the Diels–Alder addition of a chiral oxazoline dienophile with cyclopentadiene can be achieved by using either Et₂AlCl or EtAlCl₂.²⁵¹ A chiral spirocyclic auxiliary 52 has been prepared via a lengthy procedure and used in asymmetric Diels–Alder reactions with excellent endo ∶ exo ratios and enantiomeric excess (Scheme 37).²⁵²

Scheme 37

Diels–Alder additions of exocyclic methylenemorpholinones have been described including cyclopropanation and reduction, both with excellent levels of selectivity.²⁵³ A new chiral glycine anion equivalent has been disclosed derived from α-aminoisovalerophenone and been used in the preparation of cyclopropyl and norbornane α-amino acids with excellent enantioselectivity.²⁵⁴

In contrast to employing a stereodirecting group in the dienophile, surprisingly few reports have been made that use a stereodirecting group in the diene. Those that have been used include a chiral sulfoxide butadiene derivative 53²⁵⁵ and oxazolidinyl 54²⁵⁶ and glycosyl 55^257,258 dienes (Scheme 38).

Scheme 38

A few examples also exist that use a tethered diene and dienophile or have used the auxiliary in both such components in the synthesis and include (−)-aminomenthol in the synthesis of tetrahydroepoxyisolindolines,²⁵⁹ (R)-2-phenylglycinol in the synthesis of solanoeclepin A,²⁶⁰ and menthol in the synthesis of kuehneromycin A.²⁶¹

Hetero-Diels–Alder reactions provide the added advantage of the introduction of a heteroatom into the reaction product and can often result in excellent stereoselectivities. Use of a chiral amine as the auxiliary in the imine component of an aza-Diels–Alder reaction is a strategy that has been employed successfully. Bailey et al. reported such an addition of cyclopentadiene 57 with an imine derived from ethyl glyoxylate 56 with 90% asymmetric induction (Scheme 39).²⁶² The [3.3.0] bicyclic systems 58 formed were subsequently converted to the N-oxides that spontaneously underwent a Meisenheimer-type rearrangement.

Scheme 39

A similar reaction has been performed with heterocyclic imines bearing the α-methylbenzylamine stereodirecting group in the presence of a Brønsted acid to give good yields and diastereoselectivity of the cycloadducts.²⁶³ A Lewis acid-catalysed Diels–Alder addition of a chiral imine and a diene has been reported with varying degrees of diastereoselectivity.²⁶⁴

Hetero-Diels–Alder reactions have also been performed using highly reactive chiral nitroso species. Stereodirecting groups such as chiral P-nitrosophosphates,²⁶⁵ carbohydrates,^266,267 and pyroglutamates²⁶⁸ have been successfully used in this manner and, in the case of a nitroso sultam, employed in a formal synthesis of (−)-epibatidine.^269,270

Several examples of an asymmetric Staudinger reaction have been reported that allow access to β-lactams, and auxiliaries that have been used in this reaction (with varying levels of stereocontrol) include chiral pyrrolidines,²⁷¹ a new class of D-xylose-derived oxazolidinones,²⁷² (+)-carene,²⁷³ and 2-phenylcyclohexanol.²⁷⁴ A double asymmetric [2 + 2] cycloaddition has also been carried out providing a single diastereomer in excellent yield.²⁷⁵ Asymmetric nitrile oxide cycloadditions have attracted considerable attention and the stereoselectivities of such intramolecular cyclisations have been investigated with a range of chiral auxiliaries.²⁷⁶ Only one report in this survey provided an example of chiral nitrile oxides from mannitol that reacted with 2-methylfuran with poor selectivity (3 ∶ 2).²⁷⁷ However, a number of examples where the chiral auxiliary has been installed in the acceptor have been reported. Magnesium ions were found to be essential for high diastereoselectivity in the nitrile oxide addition to chiral N-acryloyloxazolidinones²⁷⁸ and reactions with polymer-bound acceptors of this type have been investigated both in solution and with Merrifield and Wang grafted auxiliary.²⁷⁹ In general, the regio- and enantioselectivities were comparable but the solution yields were higher. Addition of nitrile oxides to camphor-derived auxiliaries 59 has been shown to occur with excellent diastereoselectivity in dichloromethane which dropped when THF was used as a solvent (Scheme 40).²⁸⁰

Scheme 40

Moving down one oxidation state from nitrile oxides, a number of examples of asymmetric addition of olefins to nitrones have been reported including using camphor derivatives in a formal synthesis of a carbapenem,²⁸¹ the preparation of aza-2′,3′-dideoxynucleosides employing diastereoselective addition of a Vasella-type nitrone to vinyl acetate,²⁸² using new morpholinone nitrones in the synthesis of carbocyclic polyoxin C,²⁸³ and in additions of furfural nitrones to an N-acryloyl chiral sultam.²⁸⁴ A chiral nitrone 60, itself prepared as a single diastereomer, has been used in intramolecular 1,3-dipolar cycloadditions with poor regioselectivity but excellent diastereoselectivity²⁸⁵ and this methodology applied to the synthesis of cylindricine-type alkaloids (Scheme 41).²⁸⁶

Scheme 41

Asymmetric nitrone cycloadditions have also been used in the synthesis of indolizidines using chiral nitrone²⁸⁷ and olefin acceptors.²⁸⁸ Denmark and co-workers described alternative routes to similar targets by making use of elegant tandem asymmetric [4 + 2]/[3 + 2] cyclisations giving products with good to excellent levels of diastereoselectivity that were used in the synthesis of (+)-casuarine, (−)-7-epiaustraline and (−)-1-epicastanospermine.^289,290

Azomethine ylides have previously been used extensively in the facile preparation of polycyclic ring systems and novel amino acids. Intramolecular 1,3-dipolar cycloaddition of chiral morpholinone azomethine ylides with alkenes and alkynes has been investigated with semi-empirical calculations and the results agree with experimental observations.²⁹¹ Intermolecular variants of this methodology have been used in the synthesis of syn- and anti-β -substituted α-amino acids²⁹² and in the syntheses of (+)- and (−)-spirotryprostatin B.²⁹³ Diastereoselective cycloadditions of novel chiral azomethine ylide templates bearing two electronically different nitrogen substituents have also been reported.²⁹⁴ Finally, Carreira and co-workers have reported the asymmetric [3 + 2] cycloadditions of Me₃SiCHN₂ to unsaturated sultams in the synthesis of stelleamide A,²⁹⁵ and in the preparation of pyrazolines and aspartic acid derivatives.²⁹⁶

A number of other miscellaneous types of asymmetric cycloadditions deserve mentioning. Photolysis of the chromium carbene complexes 61 with the chiral ene carbamate 62 gave a good yield of the cyclobutanone 63 as a single diastereomer which was used in the preparation of (+)-aristeromycin and (+)-carbovir (Scheme 42).²⁹⁷

Scheme 42

In a similar manner, asymmetric [2 + 2] cycloaddition of a chiral chromium tricarbonyl imine with a ketene gave a β-lactam with excellent control of diastereoselectivity.²⁹⁸ Highly diastereoselective [2 + 2] cycloadditions have been performed using a chiral carbinol enol ether and dichloroketene with total regioselectivity and used in the synthesis of (−)-slaframine.²⁹⁹ β-Lactams have been prepared with complete diastereoselectivity by asymmetric [2 + 2] cycloaddition of a chiral oxazolidinone tethered ketene and subsequent asymmetric alkylation studies of the β-lactam investigated.³⁰⁰ Finally, the cycloaddition of a chiral cyclopropyl vinyl sulfoxide with acrylonitrile has been studied giving cyclopentyl derivatives with moderate levels of diastereoselectivity.³⁰¹

2.6 Oxidation

In contrast to many of the other types of stoichiometric asymmetric processes that have been reported, examples of asymmetric oxidation processes are surprisingly scarce. As with asymmetric reduction, this is undoubtedly due to the highly successful catalytic asymmetric processes that now exist developed in particular by Jacobsen and Sharpless. Asymmetric epoxidation of proline-derived cinnamides 64 unexpectedly gave pyrrolidinooxazinones 65 and piperazinediones as the major products in good yield with an excellent ratio of diastereomers (Scheme 43).³⁰²

Scheme 43

Dihydroxylation of unsaturated sultams has been shown to proceed with excellent diastereoselectivity for α,β substrates but poor selectivity for the β,γ analogues,³⁰³ while dihydroxylation of a chiral iron tricarbonyl compound has been used in the asymmetric synthesis of halicholactone.³⁰⁴ Finally, high levels of regio- and diastereoselectivity have been observed in the photooxygenation of chiral vinyl oxazolidines.³⁰⁵

2.7 Miscellaneous uses of chiral auxiliaries

Many natural products contain a cyclopropyl functionality and several methods have been explored for the introduction of such a group in a stereoselective manner, as exemplified in the synthesis of the glycolipids plakoside A and B,³⁰⁶ (−)-β-cuparenone and (−)-cuparane.³⁰⁷ Several other methods for asymmetric cyclopropanation deserve attention. Unsaturated chiral oxazolidinones have been converted to cyclopropanes using sulfur ylides in the presence of a Lewis acid with good to poor diastereoselectivities observed.³⁰⁸ The synthesis of enantiomerically pure cis configured cyclopropyl boronic esters has been achieved for the first time³⁰⁹ and similar methodology used to investigate the asymmetric cyclopropanation of alkenes bearing a borate ester auxiliary and a chiral substrate. In this case, the diastereoselectivity of those reactions using diazomethane were found to be auxiliary-controlled while the selectivity of Simmons–Smith cyclopropanation was controlled by the substrate.³¹⁰ Bimetallic iron carbene–chromium tricarbonyl complexes have been used as substrates in the enantioselective synthesis of cyclopropanes giving enantioselectivities of >95% in some cases, the stereochemistry of which was controlled by the chromium moiety.³¹¹ Asymmetric cyclopropanation controlled by a chiral acetal 66 has been carried out using stable haloalkylzinc bipyridine derivatives 67 with excellent diastereomeric ratios obtained (Scheme 44).³¹²

Scheme 44

Asymmetric deprotonation, the stereochemistry of which is controlled by an adjacent stereodirecting group, is an excellent method for the selective remote introduction of functional groups. Asymmetric lithiation of an allyl carbamate induced by a complexing remote chiral group gave excellent diastereoselectivity after quenching with an electrophile, such as MeI.³¹³ Directed metallation of arene transition metal complexes has been used successfully in many applications. Ortholithiation of an arene chromium tricarbonyl complex bearing a tartrate ligand followed by quenching with DMF proceeded in excellent diastereoselectivity (de >94%).³¹⁴ Subsequent additions of organolithium and magnesium species to the aldehyde products of this reaction were investigated in some detail with diastereomeric excesses ranging from 82 to 94%. Directed metallation of a chromium tricarbonyl complex 68 and subsequent bromination controlled by an acetal stereodirecting group allowed the preparation of a key intermediate 69 in the synthesis of (−)-steganone (Scheme 45).³¹⁵ Similiar methodology was used in the synthesis of korupensamine A³¹⁶ and in an independent synthesis of (−)-steganone.³¹⁷

Scheme 45

The synthesis of planar chiral ortho-functionalised ferrocenyl ketones has been achieved in good enantioselectivity (71–96%) using asymmetric deprotonation mediated by chiral hydrazones³¹⁸ and O-methylephedrine.³¹⁹ Similar methodology was used to prepare ferrocenes with planar and central chirality.³²⁰ Kagan has prepared enantiomerically pure ferrocene-based phosphines with only elements of planar chirality using asymmetric deprotonation mediated by chiral sulfoxides that can later be removed.³²¹

Chiral enolates have not just been used in asymmetric alkylation and aldol reactions. Asymmetric amination α to a carbonyl has generated significant interest for use in amino acid synthesis. Potassium enolates of chiral oxazolidinones have been used successfully when reacted with trisyl azide (trisyl = 2,4,6-triisopropylbenzenesulfonyl) in the synthesis of an α-azidophosphotyrosyl mimic³²² and in the synthesis of glycopeptide antibiotics related to teicoplanin.³²³ Such enolates bearing a β-stereogenic centre undergo highly diastereoselective aziridination with complete control of stereochemistry from the oxazolidinone stereogenic centre only.³²⁴ An interesting practical observation has been made in the quenching of such enolates with trisyl azide.^325,326 Reproducible yields (75–95%) of the desired azides were obtained by addition of the solid trisyl azide in one portion at −78 °C. Electrophilic amination of enolates of chiral dithianes has been achieved with dibutyl azodicarboxylate giving relatively good levels of stereoselectivity, but with some loss of stereochemical integrity of the products that may have resulted during derivatisation procedures.³²⁷

Halogenation of chiral enolates is also of considerable synthetic importance. α-Fluoroalkylphosphonates have been prepared by quenching of the enolate of a chiral phosphonamide with N-fluorobenzenesulfonimide with poor selectivities.³²⁸ Davis et al. have used a highly diastereoselective fluorination of a dienolate of a chiral oxazolidinone in the synthesis of fluorinated carbohydrates.³²⁹ Other asymmetric halogenation reactions include stereoselective bromohydrin formation using glucose-derived auxiliaries to control the addition to a Michael acceptor,³³⁰ asymmetric bromination of acetals derived from tartrate derivatives,³³¹ and an intramolecular bromoetherification of a chiral aldehyde to effect the kinetic resolution of norbornene-type substrates.^332,333 Radical bromination and subsequent alcoholysis have also been investigated using a glucose-derived stereodirecting group giving good to poor levels of regio- and stereocontrol.³³⁴

Asymmetric ring opening reactions of chiral acetals and aza-acetals with nucleophiles has been performed with varying degrees of success. Allylsilanes have traditionally been used in nucleophilic additions to imines generated in situ and examples such as reaction with chiral bicyclic oxazolidines,³³⁵ chiral α-sulfonylalkylimidazolidones,³³⁶ and atropisomeric lactams³³⁷ have been reported. They have also been used in an intramolecular route to prepare piperidines,³³⁸ in the synthesis of (−)-coniceine³³⁹ and pipecolic acids.³⁴⁰ Lewis acid-mediated reaction of chiral silylketene and thioketene acetals with acetals and peroxyacetals has been studied with a number of auxiliaries, but poor selectivities have been observed.³⁴¹

Enantiomerically pure C₂ symmetric keto sulfoxides have been used to prepare symmetrical acetals 70 that undergo base-promoted asymmetric ring opening reactions giving the benzyl ether 71 in excellent yield and diastereomeric excess (Scheme 46).^342,343

Scheme 46

Chiral oxazolidines derived from (R)-phenylglycinol react with dialkylalkynylalane–triethylamine complexes giving alkynylamines in excellent diastereomeric excess³⁴⁴ while enantiopure substituted pyrrolidines may be prepared by the reduction of chiral bicyclic oxazolidines with LiBHEt₃.³⁴⁵

A number of miscellaneous reactions of organometallic reagents other than addition to carbonyl compounds have been reported. Cuprates have been shown to add to menthol derivatives in a highly diastereoselective S_N2′ reaction, giving alkenes that can be cleaved by ozonolysis to chiral aldehydes.^346,347 Alcohols from N-Boc oxazolidines have also been used in S_N2′ organocuprate displacements with good stereoselectivities.³⁴⁸ Chiral α-chloro alkyl borates have been shown to undergo efficient S_N2 displacement with Grignard reagents giving products of >99% ee.³⁴⁹ Chiral sulfoxides have been prepared by the sequential ring opening of chiral sulfites using organolithium and magnesium reagents.³⁵⁰ Stereocontrolled addition of Grignard reagents to chiral pyridinium salts facilitated access to tetrahydropyridines but with only modest levels of diastereoselectivity.³⁵¹ Miscellaneous organometallic-based asymmetric transformations include the preparation of D-α-amino acids using a morpholinone template to control the stereochemistry of the condensation of a borate ester and aldehydes,³⁵² the use of 8-phenylmenthol in samarium iodide-mediated radical formation–reprotonation,²²⁷ asymmetric Friedel–Crafts reaction,³⁵³ and a route to the synthesis of ¹¹C enriched α-amino acids³⁵⁴ using lithium oxazolidinyl-derived auxiliaries. Reactive intermediates such as radicals and carbenoids have been used to effect stereoselective cyclisations. Such reactions of the former include using a new cyclohexanol chiral auxiliary to prepare chiral cyclopentanes but with low diastereoselectivity,³⁵⁵ in the asymmetric synthesis of (S)-pipecoline using reductive photocyclisation of dienamides controlled by a chiral amine,³⁵⁶ photoinduced electron transfer in the diastereoselective cyclisation of a prolinol derivative³⁵⁷ and in the synthesis of pyrrolidines.^358,359 One example of a carbenoid-initiated cyclisation has been reported in the copper(II)-catalysed decomposition of a chiral diazomorpholinone that gave a 1 ∶ 2 mixture of diastereomeric bicyclic adducts.³⁶⁰

Stereoselective rearrangements provide an excellent method to introduce new stereogenic centres. Examples that have been reported include a highly diastereoselective thio-Claisen rearrangement using a C₂ symmetric pyrrolidine stereodirecting group,³⁶¹ desymmetrisation of a meso-N-hydroxyimide via a chiral Lossen rearrangement using a camphorsulfonyl auxiliary,³⁶² asymmetric Meisenheimer rearrangements,^363,364 an asymmetric Johnson ortho ester rearrangement of a chiral oxazolidine³⁶⁵ and a diastereoselective aza-Claisen rearrangement used in the synthesis of (−)-antimycin A_3b.³⁶⁶

Stereoselective reductions of functional groups other than carbonyl groups have been carried out. Reduction of α,β-unsaturated sultams has been shown to give the highest levels of diastereoselectivity using hydrogenation conditions³⁶⁷ while the diastereoselective hydrogenation of ortho-substituted benzoic acid derivatives has been shown to be most effective using a pyroglutamic acid derivative.³⁶⁸ Asymmetric Birch reduction followed by quenching with methyl iodide has been optimised using proline-based auxiliaries 72 capable of controlling the intermediate enolate geometry by hindered rotation (Scheme 47).³⁶⁹ Products 73 with diastereomeric ratios of 93 ∶ 7 have been obtained in this way.

Scheme 47

A number of axially chiral biaryls have been prepared using a chiral template based upon L-threitol.³⁷⁰ BINOL has also been used as chiral tether for TiCl₄-mediated oxidative coupling reactions giving chiral 2,3-diarylbutane-1,4-diols as single diastereomers.³⁷¹ Axially chiral biaryls have also been prepared using diastereoselective cross coupling reactions and a series of such reactions have been carried out using chiral oxazolines.³⁷² The selectivity was found to be dependent upon the structure of the substrate and selectivities of up to 8.5 ∶ 1 were obtained.

A number of other asymmetric transformations have been reported that cannot easily be grouped together. An asymmetric variant of a four component coupling of a silyl enol ether, chiral 1-alkoxy-1,3-diene, SO₂ and an alkyl halide has been shown to occur with good to excellent diastereomeric excess, making use of a (S)-1-(2,4,6-triisopropylphenyl)ethyl stereodirecting group.³⁷³ A new chiral sulfenylating agent has been prepared and used in the sulfenylation of keto esters with good levels of enantioselectivity dependent upon the substrate structure³⁷⁴ and chiral diselenides have been used in the methoxy and hydroxyselenenylation of styrene giving good to excellent levels of diastereoselectivity.³⁷⁵ Chiral nucleophiles have been used in the asymmetric synthesis of β²-homoglycines by reaction of aryl ketenes with chiral alcohols, giving selectivities of greater than 90 ∶ 10³⁷⁶ and a similar transformation used in the first stages of a formal synthesis of roseophilin using menthol as the nucleophile, giving selectivities of 5 ∶ 1.³⁷⁷ Highly enantioselective propenoylation of lithium enolates of oxazolidinones has been carried out in the synthesis of the C13–C19 fragment of sanglifehrin A.³⁷⁸ Finally, diastereoselective ring opening reactions of gem-dibromocyclopropanes controlled by cyclohexyl and menthol derived auxiliaries have been used to prepare the core structures of epibatidine and anatoxin A.³⁷⁹

3. Chiral reagents

3.1 Chiral amine and lithium amide bases

Desymmetrisation of meso-ketones using chiral amines or lithium amide bases is now growing more widespread in use in organic synthesis. For example, the first step in the synthesis of the C38–C44 segment of altohyrtin A was asymmetric deprotonation with a chiral lithium amide, followed by silyl enol ether formation that proceeded in 95% enantiomeric excess.³⁸⁰ This methodology has been further extended by the use of new chiral lithium amides,³⁸¹ chiral magnesium amides,³⁸² in the synthesis of the pseudoguaiane framework,³⁸³ and chiral amine–silyl triflate complexes to generate chiral silyl enol ethers for a subsequent asymmetric tandem Michael–aldol reaction.³⁸⁴ Asymmetric deprotonation using chiral lithium amides 74 has provided substrates for subsequent asymmetric aldol reactions with good levels of diastereoselectivity (Scheme 48).^385,386

Scheme 48

Asymmetric deprotonation of epoxides can lead to unexpected rearrangement products and Kee et al. have disclosed preliminary observations of such reactions with cyclohexene epoxides.³⁸⁷ Attempted kinetic resolution of racemic epoxides with a chiral lithium amide base gave the product allylic alcohol (32% yield, 63% ee) and recovered starting material (51% yield, 44% ee). This method forms an excellent route for the preparation of highly functionalised cyclohexyl ring systems. Enantioselective deprotonation–rearrangement of meso-amino epoxides 75 gave good levels of stereoselectivity with a number of diamine-derived lithium amides 76 (Scheme 49).³⁸⁸

Scheme 49

The asymmetric deprotonation and subsequent quenching of substituted arene chromium tricarbonyl derivatives has been extensively studied with a variety of lithium amide bases and aryl directing groups.³⁸⁹ Axially chiral anilides have also been prepared with varying degrees of enantioselectivity by employing this methodology.³⁹⁰

3.2 Sparteine-mediated reactions and related processes

Interest in using sparteine and other chiral amines in mediating asymmetric deprotonation has been gaining momentum and this methodology appears to deliver excellent levels of stereoselectivity in many of the reactions studied. Beak et al. have reviewed similar chemistry to this, in particular, the use of dynamic thermodynamic resolution in achieving high levels of stereocontrol with particular emphasis on the use of chiral amines and organolithium species.³⁹¹ Several interesting observations have been made in the area of (−)-sparteine-mediated deprotonation–alkylation, including those made by Deiters et al.³⁹² Intramolecular trapping of an allylic anion in the presence of (−)-sparteine with an allylic chloride gave cyclonona-1,5-dienes in excellent enantiomeric excess. Introduction of an additional stereogenic centre in the substrate was found to only affect the diastereoselectivity of the reaction, not the enantioselectivity. A highly enantioselective anionic oxy-Cope rearrangement of the products was also shown to occur. A carbamate protecting group was used in this chemistry to direct metallation and a similar directed asymmetric deprotonation of a carbamate 77 in the presence of (−)-sparteine was followed by quenching with a variety of aldehydes 78. Excellent enantioselectivities were observed and the products used to make 5- to 8-membered ring unsaturated oxacycles (Scheme 50).³⁹³

Scheme 50

Wiberg and Bailey have used molecular modeling to propose a transition state for the related enantioselective deprotonation of N-Boc pyrrolidine with isopropyllithium–(−)-sparteine.³⁹⁴ Carbamate groups are not essential for the directed metallation step and other methods have been used to generate the alkyllithium species. Addition of (−)-sparteine to aryllithiums prepared by lithium–halogen exchange facilitated the carbocyclic ring closure with a pendant allyl group giving selectivities of >86 ∶ 14 except when using THF as solvent.³⁹⁵ Identical work has also been reported with the additional feature that the resultant alkyllithium species 79 was trapped with a number of electrophiles (Scheme 51).³⁹⁶

Scheme 51

Nakamura et al. have demonstrated that α-thiobenzyllithium reagents react with aldehydes and ketones in the presence of chiral diamine ligands giving good yields and excellent levels of enantioselectivity.³⁹⁷ Of the diamines studied, bisoxazolines proved to be the most successful, while (−)-sparteine gave the worst results. Optically active phosphine–borane complexes have been prepared using (−)-sparteine–s-BuLi deprotonation followed by oxidation.³⁹⁸ The enantiomeric excess varied with the choice of alkyl group and with 1-adamantyl 93% was obtained. Sparteine-mediated deprotonation of medium ring epoxides has been investigated and gives different products with moderate to good levels of stereoselectivity depending upon the substrate structure and whether BF₃·Et₂O is added or not.³⁹⁹

Other chiral amines have also been used in similar reactions; chiral bisoxazolines have been used to induce chirality in the reaction of benzylic lithium reagents with benzophenone with good to excellent enantioselectivities.⁴⁰⁰ Similar studies have also been reported for methylation reactions.⁴⁰¹ In a study of the catalytic use of a chiral amine in the asymmetric alkylation of achiral lithium enolates, stoichiometric use of these additives gave excellent yields and enantioselectivities using DME as solvent.⁴⁰²

Amine and amino alcohol additives have also been used successfully to control the stereochemistry of addition to carbonyl compounds. Diastereoselective additions of monosubstituted acetylenes to aldehydes have been shown to proceed in excellent enantioselectivity using N-methylephedrine and zinc triflate.⁴⁰³ These reactions have the advantage over similar dialkylzinc additions in that the reactions can be conducted in air. The asymmetric synthesis of (+)-salsolidine has been accomplished using the enantioselective addition of an alkyllithium to an imine in the presence of a chiral amino alcohol⁴⁰⁴ and a chiral C₂ symmetric methyl ether 81 used to control the stereoselectivity of the addition of organolithium reagents to imines 80 with good to excellent enantioselectivities (Scheme 52).⁴⁰⁵

Scheme 52

Similar reactions have also been shown to occur in the presence of stoichiometric quantities of bisoxazoline ligands with different bite angles.⁴⁰⁶ Slight variations in enantioselectivities were observed with each of these ligands. The mechanism and structure of the intermediates used in the highly successful addition of lithium acetylides to an aryl trifluoromethyl ketone used in the asymmetric synthesis of efavirnez have been reported.⁴⁰⁷

3.3 Addition to C=O, C=N and C=C bonds

Perhaps one of the most used chiral reagents for addition to C=O bonds are the terpene-derived borane reagents originally developed by Brown and the origins of the stereoselectivity of B-chlorodiisopinocamphenylborane [(Ipc)₂BCl] reagents have been investigated using molecular modeling.⁴⁰⁸ These reagents have been used to introduce the allyl functionality in a stereoselective manner and have been used in the total synthesis of many natural products including the macrocyclic core of apoptolidin,⁴⁰⁹ salicylihalamide A,¹⁰⁷ epothilone analogues,⁴¹⁰ lankacyclinol,⁴¹¹ lamoxirene,⁴¹² cryptophycin-24,⁴¹³ the C29–C45 fragment of spongistatin 1,⁸¹ sanglifehrin A,⁴¹⁴ δ-lactones,⁴¹⁵ polyenes based upon (−)-stipiamide,⁴¹⁶ nicotine analogues,⁴¹⁷ and glycosphingolipids.⁴¹⁸ Development of new methodology and applicability is still carried out in this field and Brown himself has reported application of this chemistry in the synthesis of both enantiomeric forms of perfluoroalkyl and aryl homoallylic alcohols.⁴¹⁹ A new method for the preparation of chiral allylsilanes has also been reported using modified chiral allylborane reagents.⁴²⁰ Barrett et al. have described the synthesis of asymmetric bidirectional allylboration reagents 82 and their use in the preparation of C₂ symmetric 1,5-diols 83 in excellent enantiomeric excess (Scheme 53).⁴²¹ These diols were used to prepare enantiomerically pure spiroketals.

Scheme 53

Only one example of an asymmetric alkyl transfer reagent that uses a non-terpene stereodirecting group has been reported using the addition of an alkynyl BINOL borate to an unsaturated ketone with high regio- and stereoselectivities.⁴²²

Use of stoichiometric reducing agents is limited, undoubtedly for similar reasons as covered in Section 2.4. Binaphthol aluminium hydride complex (BINAL) has been used successfully to perform enantioselective reductions in the synthesis of (S)-coriolic acid⁴²³ and in the desymmetrisation of thioanhydrides used in the synthesis of d-biotin.⁴²⁴ Biomimetic NADH reagents have attracted some attention and macrocyclic analogues have been evaluated in the reduction of carbonyl compounds⁴²⁵ while chiral-bridged models have been used in the reduction of pyruvate analogues both with excellent enantioselectivities.⁴²⁶ Use of chiral dihydropyridine sulfoxides 84 in this sense has facilitated the asymmetric reduction–cyclisation of the ethylidenemalononitrile 85 with low levels of enantioselectivity (Scheme 54).⁴²⁷ Only one example in this survey of asymmetric hydroboration has been reported in the reduction of (E)- and (Z)-2-methoxybut-2-enes.⁴²⁸

Scheme 54

Chiral organometallic-based reagents have not been widely used, probably due to the difficulty in their preparation and/or expense. Of those described, chiral organotitanium reagents have been studied the most. The total synthesis of (+)-sedamine has been carried out using the key step of the enantioselective allylation of an aldehyde using a chiral titanium complex,⁴²⁹ methodology that has also been used in the synthesis of the lactone units of compactin and mevinolin.⁴³⁰ Allylation of acetylenic aldehydes with excellent enantiomeric excess has also been reported with this reagent.⁴³¹ Chiral cyclopentadienyltitanium complexes based upon carbohydrates have been used in asymmetric aldol reactions giving the desired aldol products in good yield and enantiomeric excess (>90%).⁴³² In the only example of a chiral allyltin reagent in this survey, addition of these reagents to N-acyliminium ions generated in situ proceeded with excellent levels of enantio- and diastereoselectivity.⁴³³ The matched/mismatching characteristics of this reaction were also evaluated.

Enantioselective aldol reactions have been carried out with chiral reagents, the most used of which appear to be chiral oxazaborolidine-mediated condensations with silyl ketene acetals and aldehydes^434,435 and applied in the synthesis of amamistatin A⁴³⁶ and of a filipin III polyacetate unit.⁴³⁷ In the specific case of the addition of the silyl ketene acetal 86 to chiral aldehyde 87 in the presence of oxazaborolidine 88, excellent stereoselectivity was observed for the matched case and inverted stereoselection for the mismatched one (Scheme 55).⁴³⁸

Scheme 55

Corey and Choi have examined the use of chiral diazaborolidines in asymmetric aldol reactions and applied them to the synthesis of chloramphenicol.^439,440 Chiral boron enolates have been prepared using (+)-(Ipc)₂BCl and used to override the stereocontrolling elements of existing stereogenic centres in the synthesis of (+)-discodermolide.⁴⁴¹

Several other transformations have been carried out on C=O and C=N bonds. Preparation of a cyclopropylstannane as a key intermediate in the synthesis of dictyopterene A was achieved in excellent enantioselectivity using the Charette asymmetric cycloprotonation methodology.⁴⁴² Five molar equivalents of Zn(CH₂I)₂ were essential for high enantioselectivities. Chiral nucleophiles can be useful in deracemisation and desymmetrisation reactions. Thus, pantolactone has been used as a chiral nucleophile in the diastereoselective synthesis of α-phenyl δ-amino valeric acid with excellent diastereoselectivity by deracemisation of a ketene intermediate,⁴⁴³ while ring opening of meso-anhydrides with chiral carbinols gave good levels of diastereoselectivity but took 5 days for reaction to occur.⁴⁴⁴ Finally, chiral zirconium alkoxides have been used to effect the enantioselective Meerwein–Ponndorf–Verley cyanation of aldehydes giving enantioselectivities of 61–91%.⁴⁴⁵

3.4 Miscellaneous uses of chiral reagents

A number of stoichiometric chiral agents have been used to promote cycloaddition reactions. Diels–Alder addition of butadiene to N-acryloyloxazolidinones proceeded in 85% yield and >92% ee in the presence of stoichiometric quantities of TADDOL ligands, products of which were used to prepare δ-peptide analogues of pyranosyl RNA.⁴⁴⁶ Significant improvements have been made in the selectivity of such reactions by addition of 4 Å molecular sieves.⁴⁴⁷ Chiral titanium(IV) complexes have also been used to promote Diels–Alder reactions of cyclohexa-1,3-diene and N-sulfinylbenzoyl carbamate with poor to good enantioselectivities.⁴⁴⁸ Other cycloadditions that have been carried out include a photochemical [2 + 2] cyclisation in the presence of a ‘chiral host’, the purpose of which was to participate in hydrogen bonding and transmit stereochemical information during the reaction, ⁴⁴⁹ and the use of chiral dioxazaborocines in nitrile oxide and nitrone cycloadditions.⁴⁵⁰

The asymmetric Pauson–Khand reaction has attracted much attention and excellent selectivities have been obtained by preparing and using chiral dicobalt carbonyl reagents based on chiral propargylic alcohols.⁴⁵¹ Chiral dicobalt carbonyl complexes bearing chiral ligands such as phosphines,^452,453 and bidentate (P,S) ligands⁴⁵⁴ have also been employed generally with good selectivities. Optically pure heterobimetallic alkyne–cobalt complexes have also been used with excellent levels of enantioselectivity⁴⁵⁵ and brucine N-oxide has been employed as an ‘external’ source of chirality with encouraging enantioselectivities (Scheme 56).⁴⁵⁶

Scheme 56

A number of reactions involving organometallic species deserve attention; Coldham and Vennall have shown that the rate of cyclisation of chiral organolithium species is considerably slower for the formation of six-membered rings than for five-membered analogues.⁴⁵⁷ In the former case, this led to predominant racemisation giving products of low enantiomeric excess. Using a more reactive alkene acceptor increased the rate of the cyclisation giving improved enantiomeric excesses. The synthesis of a chiral secondary Grignard reagent has been achieved by making use of a carbenoid homologation procedure.⁴⁵⁸ Once prepared the reagent was found to be configurationally stable at −78 °C, racemising at higher temperatures. Addition of this reagent to phenyl isothiocyanate gave the addition product in excellent enantioselectivity, while oxidation gave secondary alcohols with varying degrees of selectivity. Copper-catalysed Grignard addition to alkene acceptors has been carried out using chiral dioxazaborocines as acceptors.⁴⁵⁹

Chiral organoaluminium reagents have been used to effect the stereoselective displacement of α-bromo amino acids using stoichiometric quantities of BINOL and trialkylaluminiums giving N-sulfonyl amino acids with moderate levels of enantioselectivity,⁴⁶⁰ while chiral aluminium trinaphthoxide derivatives have been used to effect a regio- and enantioselective siloxybutylation at the more hindered α-site of unsymmetrical ketones.⁴⁶¹ Miscellaneous uses of organometallic reagents include addition of a Reformatsky-type reagent to a nitrone using a tartrate-derived additive ⁴⁶² and one example of a titanium-mediated dihydrodimerisation of dihydrotetrahydrofurans in good enantiomeric excess using titanium TADDOLates.⁴⁶³

Asymmetric protonation of prochiral enolates has attracted much attention and the use of a wide range of chiral auxiliaries in enantioselective protonation has been studied.⁴⁶⁴ Lewis acid-assisted chiral Brønsted acids, such as those derived from BINOL and SnCl₄, have been used successfully in enantioselective protonations of silyl enol ether and silyl ketene acetals both stoichiometrically and catalytically.⁴⁶⁵ Seebach and co-workers have reported the highly enantioselective protonation (>99% ee) of lithium enolates using TADDOL derivatives⁴⁶⁶ and a fluorous chiral proton source gave higher enantioselectivies than a non-fluorous analogue in the asymmetric protonation of a samarium enolate.⁴⁶⁷ Enantioselective protonation of an organolithium species was carried out using chiral amines with good degrees of selectivity (83–86% ee) and applied to the synthesis of salsolidine.⁴⁶⁸ Chiral bisphosphonates have been shown to adopt linear or cyclic macrocyclic structures when treated with HBF₄.⁴⁶⁹ The former gave good levels of enantioselectivity when used in asymmetric protonation, while the latter demonstrated essentially no selectivity. Reasonable levels of enantioselectivity have also been observed by using chiral diamines.⁴⁷⁰ Enolates or their equivalents have also been shown to undergo asymmetric fluorination using chiral spirocyclic N-fluorosulfonamides⁴⁷¹ and alkylation using a chiral alkylating agent used in the synthesis of (+)-chimonanthine.⁴⁷² Several examples of asymmetric oxidants have been reported. Dichlorocamphorsulfonyloxaziridine has been shown to give significantly increased levels of diastereoselectivity (80 ∶ 20) compared to the parent oxaziridine in the asymmetric oxidation of an aromatic sulfide.⁴⁷³ Chiral hypervalent iodine oxidants 90 have been used in the oxidation of sulfides 91 with poor levels of enantioselectivity (Scheme 57).⁴⁷⁴

Scheme 57

Very few examples of cyclisation reactions that proceed under the influence of a chiral additive have been reported. Lewis acid-assisted chiral Brønsted acids, such as those derived from BINOL and SnCl₄, have been used and have also been employed in enantioselective biomimetic cyclisations of isoprenoids with good to moderate levels of selectivity.⁴⁷⁵

Finally in this survey are a group of miscellaneous transformations that cannot easily be categorised elsewhere. A few examples of chiral organophosphorus chemistry have been reported. α-Methylbenzyl- and naphthylamines have been used in lanthanide three component couplings to prepare amino phosphonic acids with moderate diastereoselectivity.⁴⁷⁶ Enantioselective ring opening of meso-disulfides has been carried out using chiral phosphinamides with low levels of enantioselectivity.⁴⁷⁷ Phosphorothiolates containing a stereogenic phosphorus atom have been prepared with good selectivities (20 ∶ 1) using phosphorylating reagents derived from indole.⁴⁷⁸ Another asymmetric heteroatom involves the asymmetric amidoselenenylation of alkenes using a camphor-derived selenenylation reagent.⁴⁷⁹ Several radical or radical-type reactions have been performed. Inter- and intramolecular asymmetric radical carbon–carbon bond formation of sulfonamides has been studied using chiral diamine or TADDOL ligands with allyltributyltin reagents,⁴⁸⁰ while asymmetric pinacol coupling of aromatic aldehydes has been carried out in the presence of chiral amines and hydrazines giving diols with varying degrees of enantioselectivities.⁴⁸¹ Chiral nucleophiles have been used in several applications. Use of either the sodium 91 or lithium alkoxide 92 of a chiral alcohol in the alcoholysis of a bis(vinyl sulfoxide) 93 leads to formation of either enantiomer of product 94 (Scheme 58).⁴⁸²

Scheme 58

Desymmetisation of meso-norbornadiene diesters with chiral alcohols and thiols gave poor to moderate degrees of diastereoselectivity,⁴⁸³ while an intramolecular oxy-Michael addition mediated by a carbohydrate derivative gave good levels of stereocontrol.⁴⁸⁴

Finally, an enantioselective Prins reaction has been developed using chiral tin BINOL derivatives that gives reasonable levels of enantioselectivity,⁴⁸⁵ and enantioselective acylating agents for amines have been described that perform excellently in kinetic resolutions of racemic piperidines.⁴⁸⁶

References

1. B. Simoneau, P. Lavallée, M. Bailey, J.-S. Duceppe, C. Grand-Maître, L. Grenier, W. W. Ogilvie, M. A. Poupart and B. Thavonekham, Can. J. Chem., 2000, 78, 739.
2. M. P. Sibi, P. Liu and M. D. Johnson, Can. J. Chem., 2000, 78, 133.
3. M. D. Fletcher, J. R. Harding, R. A. Hughes, N. M. Kelly, H. Schmalz, A. Sutherland and C. L. Willis, J. Chem. Soc., Perkin Trans. 1, 2000, 43.
4. J. R. Harding, R. A. Hughes, N. M. Kelly, A. Sutherland and C. L. Willis, J. Chem. Soc., Perkin Trans. 1, 2000, 3406.
5. M. P. Sibi and P. K. Deshpande, J. Chem. Soc., Perkin Trans. 1, 2000, 1461.
6. S. Ribe, R. K. Kondru, D. N. Beratan and P. Wipf, J. Am. Chem. Soc., 2000, 122, 4608.
7. A. G. H. Wee and Q. Yu, Tetrahedron Lett., 2000, 41, 587.
8. T. Tashiro, M. Bando and K. Mori, Synthesis, 2000, 1852.
9. M. T. Crimmins and K. A. Emmitte, Synthesis, 2000, 899.
10. T. Hasegawa and H. Yamamoto, Bull. Chem. Soc. Jpn., 2000, 73, 423.
11. N. J. S. Harmat, S. Mangani, E. Perrotta, D. Giannotti, R. Nannicini and M. Altamura, Tetrahedron Lett., 2000, 41, 1261.
12. H. Nakamura, K. Maruyama, K. Fujimaki and A. Murai, Tetrahedron Lett., 2000, 41, 1927.
13. J. Mulzer, G. Karig and P. Pojarliev, Tetrahedron Lett., 2000, 41, 7635.
14. M. Duan and L. A. Paquette, Tetrahedron Lett., 2000, 41, 3789.
15. R. Ponsinet, G. Chassaing, J. Vaissermann and S. Laville, Eur. J. Org. Chem., 2000, 83.
16. K. Mori, T. Tashiro and S. Sano, Tetrahedron Lett., 2000, 41, 5243.
17. D. C. Braddock and J. M. Brown, Tetrahedron: Asymmetry, 2000, 11, 3591.
18. N. Kise, T. Ueda, K. Kumada, Y. Terao and N. Ueda, J. Org. Chem., 2000, 65, 464.
19. M. P. Sibi and T. R. Rheault, J. Am. Chem. Soc., 2000, 122, 8873.
20. S. D. Bull, S. G. Davies, M.-S. Key, R. L. Nicholson and E. D. Savory, Chem. Commun., 2000, 1721.
21. S. D. Bull, S. G. Davies, R. L. Nicholson, H. J. Sanganee and A. D. Smith, Tetrahedron: Asymmetry, 2000, 11, 3475.
22. S.-G. Lee, C. W. Lim, D. C. Kim and J. K. Lee, Tetrahedron: Asymmetry, 2000, 11, 1455.
23. A. A.-M. Abdel-Aziz, J. Okuno, S. Tanaka, T. Ishizuka, H. Matsunaga and T. Kunieda, Tetrahedron Lett., 2000, 41, 8533.
24. G. Guillena and C. Nájera, J. Org. Chem., 2000, 65, 7310.
25. L.-J. Gao, X.-Y. Zhao, M. Vandewalle and P. de Clercq, Eur. J. Org. Chem., 2000, 2755.
26. S. Hosokawa, K. Sekiguchi, M. Enemoto and S. Kobayashi, Tetrahedron Lett., 2000, 41, 6429.
27. A. Toró, P. Nowak and P. Deslongchamps, J. Am. Chem. Soc., 2000, 122, 4526.
28. D. Enders and A. Ridder, Synthesis, 2000, 1848.
29. D. Enders and C. Thiebes, Synlett, 2000, 1745.
30. Z. Yang, A. B. Attygalle and J. Meinwald, Synthesis, 2000, 1936.
31. D. Enders, C. F. Janeck and G. Raabe, Eur. J. Org. Chem., 2000, 3337.
32. D. Enders, C. F. Janeck and J. Runsink, Synlett, 2000, 641.
33. M. Fujita, O. Kitagawa, Y. Yamada, H. Izawa, H. Hasegawa and T. Taguchi, J. Org. Chem., 2000, 65, 1108.
34. J. Clayden, P. Johnson, J. H. Pink and M. Helliwell, J. Org. Chem., 2000, 65, 7033.
35. S. Pinheiro, C. B. S. S. Gonçalves, M. B. de Lima and F. M. C. de Farias, Tetrahedron: Asymmetry, 2000, 11, 3495.
36. Y. Matsukawa, J. S. D. Kumar, Y. Yoneyama, T. Katagiri and K. Uneyama, Tetrahedron: Asymmetry, 2000, 11, 4521.
37. M. Thieme, E. Vieira and J. Liebscher, Synthesis, 2000, 2051.
38. H. Pajouhesh, J. Chen and S. H. Pajouhesh, Tetrahedron: Asymmetry, 2000, 11, 4537.
39. S. Kojima, K. Fujitomo, Y. Shinohara, M. Shimizu and K. Ohkata, Tetrahedron Lett., 2000, 41, 9847.
40. P. D. Croce, C. L. Rosa and E. Pizzatti, Tetrahedron: Asymmetry, 2000, 11, 2635.
41. C. Ma, S. Yu, X. He, X. Liu and J. M. Cook, Tetrahedron Lett., 2000, 41, 2781.
42. B. Vivet, F. Cavelier and J. Martinez, Eur. J. Org. Chem., 2000, 807.
43. M. Adamczyk, S. R. Akireddy and R. E. Reddy, Tetrahedron, 2000, 56, 2379.
44. C. Nájera, T. Abellán and J. M. Sansano, Eur. J. Org. Chem., 2000, 2809.
45. W. Qiu, V. A. Soloshonok, C. Cai, X. Tang and V. J. Hruby, Tetrahedron, 2000, 56, 2577.
46. S. Collet, F. Carreaux, J.-L. Boucher, S. Pethe, M. Lepoivre, R. Danion-Bougot and D. Danion, J. Chem. Soc., Perkin Trans. 1, 2000, 177.
47. X. Tang, V. A. Soloshonok and V. J. Hruby, Tetrahedron: Asymmetry, 2000, 11, 2917.
48. K. Miyashita, H. Miyabe, K. Tai, H. Iwaki and T. Imanishi, Tetrahedron, 2000, 56, 4691.
49. A. M. C. H. van den Nieuwendijk, N. M. A. J. Kriek, J. Brusse, J. H. van Boom and A. van der Gen, Eur. J. Org. Chem., 2000, 3683.
50. P. Kele, G. Sui, Q. Huo and R. M. Leblanc, Tetrahedron: Asymmetry, 2000, 11, 4959.
51. S. Chandrasekhar and A. Kausar, Tetrahedron: Asymmetry, 2000, 11, 2249.
52. K. W. Laue, S. Kröger, E. Wegelius and G. Haufe, Eur. J. Org. Chem., 2000, 3737.
53. F. Paradisi, G. Porzi, S. Rinaldi and S. Sandri, Tetrahedron: Asymmetry, 2000, 11, 4617.
54. F. Paradisi, G. Porzi, S. Rinaldi and S. Sandri, Tetrahedron: Asymmetry, 2000, 11, 1259.
55. S. E. Denmark and J.-H. Kim, Can. J. Chem., 2000, 78, 673.
56. S. Hanessian and L.-D. Cantin, Tetrahedron Lett., 2000, 41, 787.
57. L. P. Rapado, V. Bulugahapitiya and P. Renaud, Helv. Chim. Acta, 2000, 83, 1625.
58. H. Pajouhesh, M. Hosseini-Meresht, S. H. Pajouhesh and K. Curry, Tetrahedron: Asymmetry, 2000, 11, 4955.
59. M. Papke, S. Schulz, H. Tichy, E. Gingl and R. Ehn, Angew. Chem., Int. Ed., 2000, 39, 4339.
60. P. Laurent, J.-C. Braekman and D. Daloze, Eur. J. Org. Chem., 2000, 2057.
61. S. Kuwahara, J. Ishikawa, W. S. Leal, S. Hamade and O. Kodama, Synthesis, 2000, 1930.
62. K. Oda and A. I. Meyers, Tetrahedron Lett., 2000, 41, 8193.
63. J. Lin, W. H. Chan, A. W. M. Lee, W. Y. Wong and P. Q. Huang, Tetrahedron Lett., 2000, 41, 2949.
64. J. D. Dudones and A. J. Pearson, Tetrahedron Lett., 2000, 41, 8037.
65. S. Huang and D. L. Comins, Chem. Commun., 2000, 569.
66. D. B. Berkowitz, J. M. McFadden and M. K. Sloss, J. Org. Chem., 2000, 65, 2907.
67. J. Mulzer, O. Langer, M. Hiersemann, J. W. Bats, J. Buschmann and P. Luger, J. Org. Chem., 2000, 65, 6540.
68. J. H. Bailey, A. T. J. Byfield, P. J. Davis, A. C. Foster, M. Leech, M. G. Moloney, M. Müller and C. K. Prout, J. Chem. Soc., Perkin Trans. 1, 2000, 1977.
69. S. M. Allin, D. G. Vaidya, M. I. Page, A. M. Z. Slawin and T. Smith, Tetrahedron Lett., 2000, 41, 2219.
70. J. L. Vicario, D. Badía, E. Domínguez and L. Carrillo, Tetrahedron: Asymmetry, 2000, 11, 3779.
71. V. Jullian, J.-C. Quirion and H.-P. Husson, Eur. J. Org. Chem., 2000, 1319.
72. D. Yang, X.-Y. Ye and M. Xu, J. Org. Chem., 2000, 65, 2208.
73. M. Tada, S. Nishiiri, Y. Zhixiang, Y. Imai, S. Tajima, N. Okazaki, Y. Kitano and K. Chiba, J. Chem. Soc., Perkin Trans. 1, 2000, 2657.
74. A. Haudrechy, C. Chassaing, C. Riche and Y. Langlois, Tetrahedron, 2000, 56, 3181.
75. D.-H. Lee and M.-D. Rho, Tetrahedron Lett., 2000, 41, 2573.
76. V. Alezra, M. Bonin, A. Chiaroni, L. Micouin, C. Riche and H.-P. Husson, Tetrahedron Lett., 2000, 41, 1737.
77. V. Alezra, M. Bonin, L. Micouin and H.-P. Husson, Tetrahedron Lett., 2000, 41, 651.
78. K.-H. Baringhaus, H. Matter and M. Kurz, J. Org. Chem., 2000, 65, 5031.
79. M. Christmann, U. Bhatt, M. Quitschalle, E. Claus and M. Kalesse, Angew. Chem., Int. Ed., 2000, 39, 4364.
80. S. Lemaire-Audoire and P. Vogel, J. Org. Chem., 2000, 65, 3346.
81. G. C. Micalizio, A. N. Pinchuk and W. R. Roush, J. Org. Chem., 2000, 65, 8730.
82. G. A. Wallace, R. W. Scott and C. H. Heathcock, J. Org. Chem., 2000, 65, 4145.
83. M. G. N. Russell, R. Baker, R. G. Ball, S. R. Thomas, N. N. Tsou and J. L. Castro, J. Chem. Soc., Perkin Trans. 1, 2000, 893.
84. A. N. Hulme, C. H. Montgomery and D. K. Henderson, J. Chem. Soc., Perkin Trans. 1, 2000, 1837.
85. F. Yokokawa, H. Fujiwara and T. Shioiri, Tetrahedron, 2000, 56, 1759.
86. R. J. Davenport and A. C. Regan, Tetrahedron Lett., 2000, 41, 7619.
87. C. Hermann, G. C. G. Pais, A. Geyer, S. M. Kühnert and M. E. Maier, Tetrahedron, 2000, 56, 8461.
88. T. Sunazuka, T. Hirose, T. Shirahata, Y. Harigaya, M. Hayashi, K. Komiyama, S. Omura and A. B. Smith, J. Am. Chem. Soc., 2000, 122, 2122.
89. N. Waizumi, T. Itoh and T. Fukuyama, J. Am. Chem. Soc., 2000, 122, 7825.
90. A. B. Smith, T. J. Beauchamp, M. J. LaMarche, M. D. Kaufman, Y. P. Qiu, H. Arimoto, D. R. Jones and K. Kobayashi, J. Am. Chem. Soc., 2000, 122, 8654.
91. J. Eames, D. J. Fox, M. A. de las Heras and S. Warren, J. Chem. Soc., Perkin Trans. 1, 2000, 1903.
92. S. K. Chattopadhyay and G. Pattenden, J. Chem. Soc., Perkin Trans. 1, 2000, 2429.
93. G. J. McGarvey, J. A. Mathys and K. J. Wilson, Tetrahedron Lett., 2000, 41, 6011.
94. R. Kuang, A. K. Ganguly, T.-M. Chan, B. N. Pramanik, D. J. Blythin, A. T. McPhail and A. K. Saksena, Tetrahedron Lett., 2000, 41, 9575.
95. D. A. Evans, V. J. Cee, T. E. Smith, D. M. Fitch and P. S. Cho, Angew. Chem., Int. Ed., 2000, 39, 2533.
96. Z. Li, R. Wu, R. Michalczyk, R. B. Dunlap, J. D. Odom and L. A. Silks, J. Am. Chem. Soc., 2000, 122, 386.
97. M. T. Crimmins and E. A. Tabet, J. Am. Chem. Soc., 2000, 122, 5473.
98. M. T. Crimmins, B. W. King, W. J. Zuercher and A. L. Choy, J. Org. Chem., 2000, 65, 8499.
99. M. A. Brimble, M. R. Nairn and J. S. O. Park, J. Chem. Soc., Perkin Trans. 1, 2000, 697.
100. B. Panicker, J. M. Karle and M. A. Avery, Tetrahedron, 2000, 56, 7859.
101. I. Efremov and L. A. Paquette, J. Am. Chem. Soc., 2000, 122, 9324.
102. S. Fukuzawa, H. Matsuzawa and S. Yoshimitsu, J. Org. Chem., 2000, 65, 1702.
103. M. Stöver, A. Lützen and P. Köll, Tetrahedron: Asymmetry, 2000, 11, 371.
104. T. H. Kim and G. J. Lee, Tetrahedron Lett., 2000, 41, 1505.
105. S. Caddick, N. J. Parr and M. C. Pritchard, Tetrahedron Lett., 2000, 41, 5963.
106. P. Perlmutter and W. Selajarern, Aust. J. Chem., 2000, 53, 349.
107. Y. Wu, L. Esser and J. K. De Brabander, Angew. Chem., Int. Ed., 2000, 39, 4308.
108. J. L. Vicario, D. Badía, E. Domínguez, M. Rodríguez and L. Carrillo, J. Org. Chem., 2000, 65, 3754.
109. J. L. Vicario, D. Badiá, E. Domínguez, M. Rodríguez and L. Carrillo, Tetrahedron Lett., 2000, 41, 8297.
110. E. Hedenström, F. Andersson and M. Hjalmarsson, J. Chem. Soc., Perkin Trans. 1, 2000, 1513.
111. I. Paterson, V. A. Doughty, M. D. McLeod and T. Trieselmann, Angew. Chem., Int. Ed., 2000, 39, 1308.
112. D. Suzuki, H. Urabe and F. Sato, Angew. Chem., Int. Ed., 2000, 39, 3290.
113. C. Palomo, M. Oiarbide, A. K. Sharma, M. C. González-Rego, A. Linden, J. M. Garćia and A. González, J. Org. Chem., 2000, 65, 9007.
114. A. Solladié-Cavallo and B. Crescenzi, Synlett, 2000, 327.
115. P. T. Grover, N. N. Bhongle, S. A. Wald and C. H. Senanayake, J. Org. Chem., 2000, 65, 6283.
116. S. Usse, G. Guillaumet and M.-C Viaud, J. Org. Chem., 2000, 65, 914.
117. S. Florio, V. Capriati and R. Luisi, Tetrahedron Lett., 2000, 41, 5295.
118. A. G. Waterson and A. I. Meyers, J. Org. Chem., 2000, 65, 7240.
119. Y. Arai, T. Masuda, S. Yoneda, Y. Masaki and M. Shiro, J. Org. Chem., 2000, 65, 258.
120. D. Zhang, C. Bleasdale, B. T. Golding and W. P. Watson, Chem. Commun., 2000, 1141.
121. J. L. G. Ruano, D. Barros, M. C. Maestro, A. M. Z. Slawin and P. C. B. Page, J. Org. Chem., 2000, 65, 6027.
122. M. Toyota, T. Wada and M. Ihara, J. Org. Chem., 2000, 65, 4565.
123. J. Christoffers and A. Mann, Angew. Chem., Int. Ed., 2000, 39, 2752.
124. M. Amat, J. Bosch, J. Hidalgo, M. Cantó, M. Pérez, N. Llor, E. Molins, C. Miravitlles, M. Orozco and J. Luque, J. Org. Chem., 2000, 65, 3074.
125. C. Schneider and O. Reese, Synthesis, 2000, 1689.
126. M. Wu, T. Okino, L. M. Nogle, B. L. Marquez, R. T. Williamson, N. Sitachitta, F. W. Berman, T. F. Murray, K. McGough, R. Jacobs, K. Colsen, T. Asano, F. Yokokawa, T. Shioiri and W. H. Gerwick, J. Am. Chem. Soc., 2000, 122, 12041.
127. S. Wang, X. Tang and V. J. Hruby, Tetrahedron Lett., 2000, 41, 1307.
128. D. R. Williams, P. D. Lowder and Y.-G. Gu, Tetrahedron Lett., 2000, 41, 9397.
129. C. Scheider and O. Reese, Angew. Chem., Int. Ed., 2000, 39, 2948.
130. T. Tomoyasu, K. Tomooka and T. Nakai, Tetrahedron Lett., 2000, 41, 345.
131. K. Afarinkia, H. M. Binch and I. Forristal, Synlett, 2000, 1771.
132. M. Bella, R. Margarita, C. Orlando, M. Orsini, L. Parlanti and G. Piancatelli, Tetrahedron Lett., 2000, 41, 561.
133. S. V. Kolotuchin and A. I. Meyers, J. Org. Chem., 2000, 65, 3018.
134. M. Mitsuya, Y. Ogino, N. Ohtake and T. Mase, Tetrahedron, 2000, 56, 9901.
135. R. Aslanian, G. Lee, R. V. Iyer, N. Y. Shih, J. J. Piwinski, R. W. Draper and A. T. McPhail, Tetrahedron: Asymmetry, 2000, 11, 3867.
136. J. H. Bailey, D. T. Cherry, J. Dyer, M. G. Moloney, M. J. Bamford, S. Keeling and R. B. Lamont, J. Chem. Soc., Perkin Trans. 1, 2000, 2783.
137. K. Takasu, M. Ueno and M. Ihara, Tetrahedron Lett., 2000, 41, 2145.
138. A. Ali, V. U. Ahmad, B. Ziemer and J. Liebscher, Tetrahedron: Asymmetry, 2000, 11, 4365.
139. V. A. Soloshonok, C. Cai and V. J. Hruby, Angew. Chem., Int. Ed., 2000, 39, 2172.
140. V. A. Soloshonok, C. Cai and V. J. Hruby, Tetrahedron Lett., 2000, 41, 9645.
141. M. Nour, K. Tan, C. Cavé, D. Villeneuve, D. Desmaële, J. d'Angelo and C. Riche, Tetrahedron: Asymmetry, 2000, 11, 995.
142. G. Revial, I. Jabin and M. Pfau, Tetrahedron: Asymmetry, 2000, 11, 4975.
143. D. Enders, P. Teschner and G. Raabe, Synlett, 200, 637.
144. V. Ojea, M. Ruiz, G. Shapiro and E. Pombo-Villar, J. Org. Chem., 2000, 65, 1984.
145. C. Baldoli, S. Maiorana, E. Licandro, D. Perdicchia and B. Vandoni, Tetrahedron: Asymmetry, 2000, 11, 2007.
146. D. François, E. Poupon, M.-C. Lallemand, N. Kunesch and H.-P. Husson, J. Org. Chem., 2000, 65, 3209.
147. G. Revial, S. Lim, B. Viossat, P. Lemoine, A. Tomas, A. F. Duprat and M. Pfau, J. Org. Chem., 2000, 65, 4593.
148. E. Licandro, S. Maiorana, C. Baldoli, L. Capella and D. Perdicchia, Tetrahedron: Asymmetry, 2000, 11, 975.
149. S. Nakamura, Y. Watanabe and T. Toru, J. Org. Chem., 2000, 65, 1758.
150. I. Fernńdez, C. S. Araújo, M. J. Romero, F. Alcudia and N. Khiar, Tetrahedron, 2000, 56, 3749.
151. S. Karlsson and H.-E. Högberg, Synthesis, 2000, 1863.
152. S. Hanessian, A. Gomtsyan and N. Malek, J. Org. Chem., 2000, 65, 5623.
153. M. Marinozzi and R. Pellicciari, Tetrahedron Lett., 2000, 41, 9125.
154. N. Mase, Y. Watanabe, T. Toru, T. Kakumoto and T. Hagiwara, J. Org. Chem., 2000, 65, 7083.
155. R. Munakata, K. Totani, K. Takao and K. Tadano, Synlett, 2000, 979.
156. G. Campari, M. Fagnoni, M. Mella and A. Albini, Tetrahedron: Asymmetry, 2000, 11, 1891.
157. S. G. Davies, C. A. P. Smethurst, A. D. Smith and G. D. Smyth, Tetrahedron: Asymmetry, 2000, 11, 2437.
158. S. D. Bull, S. G. Davies, G. Fenton, A. W. Mulvaney, R. S. Prasad and A. D. Smith, J. Chem. Soc., Perkin Trans. 1, 2000, 3765.
159. S. D. Bull, S. G. Davies, S. Delgado-Ballester, G. Fenton, P. M. Kelly and A. D. Smith, Synlett, 2000, 1257.
160. P. O'Brien, D. W. Porter and N. M. Smith, Synlett, 2000, 1336.
161. M. Baenziger, L. Gobbi, B. P. Riss, F. Schaefer and A. Vaupel, Tetrahedron: Asymmetry, 2000, 11, 2231.
162. D. Ma and H. Sun, Tetrahedron Lett., 2000, 41, 1947.
163. D. Ma and H. Sun, J. Org. Chem., 2000, 65, 6009.
164. D. Enders, S. F. Müller, G. Raabe and J. Runsink, Eur. J. Org. Chem., 2000, 879.
165. D. Enders, J. Vázquez and G. Raabe, Eur. J. Org. Chem., 2000, 893.
166. D. Lucet, P. Heyse, A. Gissot, T. Le Gall and C. Mioskowski, Eur. J. Org. Chem., 2000, 3575.
167. A. Volonterio, P. Bravo, N. Moussier and M. Zanda, Tetrahedron Lett., 2000, 41, 6517.
168. G. Cardillo, L. Gentilucci, M. Gianotti and A. Tolomelli, Eur. J. Org. Chem., 2000, 2489.
169. C. P. Rayner (née Baird), A. J. Clark, S. M. Rooke, T. J. Sparey and P. C. Taylor, J. Chem. Soc., Perkin Trans. 1, 2000, 79.
170. L. A. Paquette, J. Tae, M. P. Arrington and A. H. Sadoun, J. Am. Chem. Soc., 2000, 122, 2742.
171. N. A. Braun, M. Ousmer, J. D. Bray, D. Bouchu, K. Peters, E.-M. Peters and M. A. Ciufolini, J. Org. Chem., 2000, 65, 4397.
172. M. Node, K. Nishide, Y. Shigeta, H. Shiraki and K. Obata, J. Am. Chem. Soc., 2000, 122, 1927.
173. H. Shiraki, K. Nishide and M. Node, Tetrahedron Lett., 2000, 41, 3437.
174. C.-H. Lin, K.-S. Yang, J.-F. Pan and K. Chen, Tetrahedron Lett., 2000, 41, 6815.
175. A. Ali, V. U. Ahmad, J. Leistner and J. Liebscher, J. Chem. Soc., Perkin. Trans. 1, 2000, 1897.
176. D. Enders, L. Tedeschi and J. W. Bats, Angew. Chem., Int. Ed., 2000, 39, 4605.
177. A. P. Degnan and A. I. Meyers, J. Org. Chem., 2000, 65, 3503.
178. Y. Matsumura, Y. Kanda, K. Shirai, O. Onomura and T. Maki, Tetrahedron, 2000, 56, 7411.
179. T. Kawakami, H. Ohtake, H. Arakawa, T. Okachi, Y. Imada and S.-I. Murahashi, Bull. Chem. Soc. Jpn., 2000, 73, 2423.
180. A. B. McLaren and J. B. Sweeney, Synlett, 2000, 1625.
181. C. Palomo, M. Oiarbide, M. C. González-Rego, A. K. Sharma, J. M. García, A. González, C. Landa and A. Linden, Angew. Chem., Int. Ed., 2000, 39, 1063.
182. F. A. Davis, T. Fang, B. Chao and D. M. Burns, Synthesis, 2000, 2106.
183. F. Steif, B. Wibbeling, O. Meyer and D. Hoppe, Synthesis, 2000, 743.
184. A. Kreier, R. Fröhlich, E. Wegelius and D. Hoppe, Synthesis, 2000, 1391.
185. B. Dudot, J. Royer, M. Sevrin and P. George, Tetrahedron Lett., 2000, 41, 4367.
186. B. Dudot, A. Chiaroni and J. Royer, Tetrahedron Lett., 2000, 41, 6355.
187. P. Allef and H. Kunz, Tetrahedron: Asymmetry, 2000, 11, 375.
188. J. L. G. Ruano, M. C. Carreño, M. A. Toledo, J. M. Aguirre, M. T. Aranda and J. Fischer, Angew. Chem., Int. Ed., 2000, 39, 2736.
189. J. L. G. Ruano, A. Alcudia, M. del Prado, D. Barros, M. C. Maestro and I. Fernández, J. Org. Chem., 2000, 65, 2856.
190. C. A. Brooks and D. L. Comins, Tetrahedron Lett., 2000, 41, 3551.
191. C. Agami, F. Couty and G. Evano, Tetrahedron: Asymmetry, 2000, 11, 4639.
192. N. A. Magnus, P. N. Confalone and L. Storace, Tetrahedron Lett., 2000, 41, 3015.
193. A. Giuseppe, G. Alvaro, F. Grepioni, S. Grilli, L. Maini, G. Martelli and D. Savoia, Synthesis, 2000, 581.
194. S. Roland and P. Mangeney, Eur. J. Org. Chem., 2000, 611.
195. T. Yamauchi, K. Higashiyama, H. Kubo and S. Ohmiya, Tetrahedron: Asymmetry, 2000, 11, 3003.
196. W. H. Chan, A. W. M. Lee, P. F. Xia and W. Y. Wong, Tetrahedron Lett., 2000, 41, 5725.
197. S. Nakamura, H. Yasuda, Y. Watanabe and T. Toru, Tetrahedron Lett., 2000, 41, 4157.
198. S. Nakamura, H. Yasuda, Y. Watanabe and T. Toru, J. Org. Chem., 2000, 65, 8640.
199. A. Ichikawa, S. Hiradate, A. Sugio, S. Kuwahara, M. Watanabe and N. Harada, Tetrahedron: Asymmetry, 2000, 11, 2669.
200. T. Fukuda, A. Takehara, N. Haniu and M. Iwao, Tetrahedron: Asymmetry, 2000, 11, 4083.
201. G. Martelli, S. Morri and D. Savoia, Tetrahedron, 2000, 56, 8367.
202. C. Agami, S. Comesse and C. Kadouri-Puchot, Tetrahedron Lett., 2000, 41, 6059.
203. J. Clayden, C. McCarthy and J. G. Cumming, Tetrahedron Lett., 2000, 41, 3279.
204. D. Enders and C. Thiebes, Synthesis, 2000, 510.
205. D. Enders and J. H. Kirchhoff, Synthesis, 2000, 2099.
206. R. E. Gawley, Q. Zhang and A. T. McPhail, Tetrahedron: Asymmetry, 2000, 11, 2093.
207. R. Kumareswaran and T. Balasubramanian, Tetrahedron Lett., 2000, 41, 8157.
208. A. Alexakis, A. Tomassini, C. Chouillet, S. Roland, P. Mangeney and G. Bernardinelli, Angew. Chem., Int. Ed., 2000, 39, 4093.
209. T. Hamada, R. Mizojiri, H. Urabe and F. Sato, J. Am. Chem. Soc., 2000, 122, 7138.
210. S. Okamoto, K. Fukuhara and F. Sato, Tetrahedron Lett., 2000, 41, 5561.
211. T.-P. Loh, J.-M. Huang, K.-C. Xu, S.-H. Goh and J. J. Vittal, Tetrahedron Lett., 2000, 41, 6511.
212. C. Cimarelli and G. Palmieri, Tetrahedron: Asymmetry, 2000, 11, 2555.
213. E. M. Cayuela, L. Xiao, T. Sturm, B. R. Manzano, F. A. Jalon and W. Weissensteiner, Tetrahedron: Asymmetry, 2000, 11, 861.
214. F. Segat-Dioury, O. Lingibé, B. Graffe, M.-C. Sacquet and G. Lhommet, Tetrahedron, 2000, 56, 233.
215. S. Cutri, M. Bonin, L. Micouin, O. Froelich, J.-C. Quirion and H.-P. Husson, Tetrahedron Lett., 2000, 41, 1179.
216. P. Bataille, M. Paterne and E. Brown, Tetrahedron: Asymmetry, 2000, 11, 1165.
217. S. Nakamura, M. Kuroyanagi, Y. Watanabe and T. Toru, J. Chem. Soc., Perkin Trans. 1, 2000, 3143.
218. G. Solladié, X. J. Salom-Roig and G. Hanquet, Tetrahedron Lett., 2000, 41, 551.
219. F. Yuste, B. Ortiz, A. Carrasco, M. Peralta, L. Qunitero, R. Sánchez-Obregón, F. Walls and J. L. G. Ruano, Tetrahedron: Asymmetry, 2000, 11, 3079.
220. G. Solladié, L. Gressot and F. Colobert, Eur. J. Org. Chem., 2000, 357.
221. C. S. Park, H. G. Choi, H. Lee, W. K. Lee and H.-J. Ha, Tetrahedron: Asymmetry, 2000, 11, 3283.
222. P. de March, M. Escoda, M. Figueredo, J. Font, E. García-García and S. Rodríguez, Tetrahedron: Asymmetry, 2000, 11, 4473.
223. G. K. Friestad and J. Qin, J. Am. Chem. Soc., 2000, 122, 8329.
224. H. Miyabe, C. Ushiro, M. Ueda, K. Yamakawa and T. Naito, J. Org. Chem., 2000, 65, 176.
225. M. P. Bertrand, S. Coantic, L. Feray, R. Nouguier and P. Perfetti, Tetrahedron, 2000, 56, 3951.
226. S. M. Kim, I. S. Byun and Y. H. Kim, Angew. Chem., Int. Ed., 2000, 39, 728.
227. J.-M. Fang, M.-Y. Chen, J.-S. Shiue, L. Lu and J.-L. Hsu, Tetrahedron Lett., 2000, 41, 4633.
228. S. Iwama, W.-G. Gao, T. Shinada and Y. Ohfune, Synlett, 2000, 1631.
229. F. A. Davis, V. Srirajan, D. L. Fanelli and P. Portonovo, J. Org. Chem., 2000, 65, 7663.
230. F. A Davis, S. Lee, H. Zhang and D. L. Fanelli, J. Org. Chem., 2000, 65, 8704.
231. F. A. Davis and V. Srirajan, J. Org. Chem., 2000, 65, 3248.
232. S. P. Vincent, A. Schleyer and C.-H. Wong, J. Org. Chem., 2000, 65, 4440.
233. J. Wede, F.-J. Volk and A. W. Frahm, Tetrahedron: Asymmetry, 2000, 11, 3231.
234. W.-W. Huang, P. A. Moore, A. R. Far and T. T. Tidwell, J. Org. Chem., 2000, 65, 3877.
235. M. Marzi, P. Minetti, G. Moretti, M. O. Tinti and F. De Angelis, J. Org. Chem., 2000, 65, 6766.
236. D. J. Dixon, S. V. Ley and D. J. Reynolds, Angew. Chem., Int. Ed., 2000, 39, 3622.
237. A. Solladié-Cavallo, L. Bouérat and M. Roje, Tetrahedron Lett., 2000, 41, 7309.
238. F. M. Hauser and D. Ganguly, J. Org. Chem., 2000, 65, 1842.
239. I. Schlemminger, A. Lützen, A. Willecke, W. Maison, R. Koch, W. Saak and J. Martens, Tetrahedron Lett., 2000, 41, 7285.
240. C. Chapuis, A. Kucharska and J. Jurczak, Tetrahedron: Asymmetry, 2000, 11, 4581.
241. S. Yokoshima, H. Tokuyama and T. Fukuyama, Angew. Chem., Int. Ed., 2000, 39, 4073.
242. A. S. Raw and E. B. Jang, Tetrahedron, 2000, 56, 3285.
243. M. C. Carreño, J. L. G. Ruano, C. Z. Remor and A. Urbano, Tetrahedron: Asymmetry, 2000, 11, 4279.
244. M. C. Carreño, J. L. G. Ruano, A. Urbano, C. Z. Remor and Y. Arroyo, J. Org. Chem., 2000, 65, 453.
245. J. L. G. Ruano, C. Alemparte, A. M. M. Castro, H. Adams and J. H. R. Ramos, J. Org. Chem., 2000, 65, 7938.
246. M. C. Carreño, S. García-Cerrada, A. Urbano and C. D. Vitta, J. Org. Chem., 2000, 65, 4355.
247. J. L. G. Ruano, F. Bercial, A. Fraile, A. M. M. Castro and M. R. Martín, Tetrahedron: Asymmetry, 2000, 11, 4737.
248. M. A. Brimble, R. J. Elliott and J. F. McEwan, Aust. J. Chem., 2000, 53, 571.
249. G. B. Jones and M. Guzel, Tetrahedron Lett., 2000, 41, 4695.
250. E. J. Enholm and S. Jiang, J. Org. Chem., 2000, 65, 4756.
251. Y. Huang, P. E. Sonnet, P. J. Carroll and D. R. Dalton, Tetrahedron Lett., 2000, 41, 2519.
252. M. J. Burke, M. M. Allan, M. Parvez and B. A. Keay, Tetrahedron: Asymmetry, 2000, 11, 2733.
253. R. Chinchilla, L. R. Falvello, N. Galindo and C. Nájera, J. Org. Chem., 2000, 65, 3034.
254. T. Abellán, C. Nájera and J. M. Sansano, Tetrahedron: Asymmetry, 2000, 11, 1051.
255. M. T. Aranda, M. C. Aversa, A. Barattucci, P. Bonaccorsi, M. C. Carreño, M. B. Cid and J. L. G. Ruano, Tetrahedron: Asymmetry, 2000, 11, 1217.
256. J. M. Janey, T. Iwama, S. A. Kozmin and V. H. Rawal, J. Org. Chem., 2000, 65, 9059.
257. S. Pornpakakul, R. G. Pritchard and R. J. Stoodley, Tetrahedron Lett., 2000, 41, 2691.
258. N. S. Trotter, D. S. Larsen, R. J. Stoodley and S. Brooker, Tetrahedron Lett., 2000, 41, 8957.
259. R. Pedrosa, C. Andrés and J. Nieto, J. Org. Chem., 2000, 65, 831.
260. J. C. J. Benningshof, R. H. Blaauw, A. E. van Ginkel, F. P. J. T. Rutjes, J. Fraanje, K. Goubitz, H. Schenk and H. Hiemstra, Chem. Commun., 2000, 1465.
261. J. Jauch, Angew. Chem., Int. Ed., 2000, 39, 2764.
262. P. D. Bailey, I. M. McDonald, G. M. Rosair and D. Taylor, Chem. Commun., 2000, 2451.
263. C. Hedberg, P. Pinho, P. Roth and P. G. Andersson, J. Org. Chem., 2000, 65, 2810.
264. R. Paugam, E. Valenciennes, L. L. Coz-Bardol, J.-C. Garde, L. Wartski, M. Lance and M. Nierlich, Tetrahedron: Asymmetry, 2000, 11, 2509.
265. R. W. Ware Jr. and S. B. King, J. Org. Chem., 2000, 65, 8725.
266. A. Hall, P. D. Bailey, D. C. Rees, G. M. Rosair and R. H. Wightman, J. Chem. Soc., Perkin Trans. 1, 2000, 329.
267. A. Defoin, M. Joubert, J.-M. Heuchel, C. Strehler and J. Streith, Synthesis, 2000, 1719.
268. M. Joubert, A. Defoin, C. Tarnus and J. Streith, Synlett, 2000, 1366.
269. I. Cabanal-Duvillard, J.-F. Berrien, L. Ghosez, H.-P. Husson and J. Royer, Tetrahedron, 2000, 56, 3763.
270. I. Cabanal-Duvillard, J.-F. Berrien and J. Royer, Tetrahedron: Asymmetry, 2000, 11, 2525.
271. R. Fernández, A. Ferrete, J. M. Lassaletta, J. M. Llera and A. Monge, Angew. Chem., Int. Ed., 2000, 39, 2893.
272. R. Saul, J. Kopf and P. Köll, Tetrahedron: Asymmetry, 2000, 11, 423.
273. S. N. Joshi, A. R. A. S. Deshmukh and B. M. Bhawal, Tetrahedron: Asymmetry, 2000, 11, 1477.
274. I. Ojima, S. Lin, T. Inoue, M. L. Miller, C. P. Borella, X. Geng and J. J. Walsh, J. Am. Chem. Soc., 2000, 122, 5343.
275. K. Karupaiyan, V. G. Puranik, A. R. A. S. Desmukh and B. M. Bhawal, Tetrahedron, 2000, 56, 8555.
276. E. Falb, A. Nudelman, H. E. Gottlieb and A. Hassner, Eur. J. Org. Chem., 2000, 645.
277. P. J. Zimmermann, I. Blanarikova and V. Jäger, Angew. Chem., Int Ed., 2000, 39, 910.
278. H. Yamamoto, S. Watanabe, K. Kadotani, M. Hasegawa, M. Noguchi and S. Kanemasa, Tetrahedron Lett., 2000, 41, 3131.
279. G. Faita, A. Paio, P. Quadrelli, F. Rancati and P. Seneci, Tetrahedron Lett., 2000, 41, 1265.
280. K.-S. Yang, J.-C. Lain, C.-H. Lin and K. Chen, Tetrahedron Lett., 2000, 41, 1453.
281. M. Mauduit, C. Kouklovsky and Y. Langlois, Eur. J. Org. Chem., 2000, 1595.
282. U. Chiacchio, A. Rescifina, A. Corsaro, V. Pistarà, G. Romeo and R. Romeo, Tetrahedron: Asymmetry, 2000, 11, 2045.
283. O. Tamura, K. Gotanda, J. Yoshino, Y. Morita, R. Terashima, M. Kikuchi, T. Miyawaki, N. Mita, M. Yamashita, H. Ishibashi and M. Sakamoto, J. Org. Chem., 2000, 65, 8544.
284. P. Merino, S. Anoro, S. Franco, F. L. Merchan, T. Tejero and V. Tuñon, J. Org. Chem., 2000, 65, 1590.
285. M. C. Bagley and W. Oppolzer, Tetrahedron: Asymmetry, 2000, 11, 2625.
286. W. Oppolzer and C. G. Bochet, Tetrahedron: Asymmetry, 2000, 11, 4761.
287. S. Cicchi, P. Ponzuoli, A. Goti and A. Brandi, Tetrahedron Lett., 2000, 41, 1583.
288. F. M. Cordero, C. Faggi, F. De Sarlo and A. Brandi, Eur. J. Org. Chem., 2000, 3595.
289. S. E. Denmark and A. R. Hurd, J. Org. Chem., 2000, 65, 2875.
290. S. E. Denmark and B. Herbert, J. Org. Chem., 2000, 65, 2887.
291. M. G. B. Drew, L. M. Harwood, D. W. Price, M.-S. Choi and G. Park, Tetrahedron Lett., 2000, 41, 5077.
292. O. Tamura, S. Yoshida, H. Sugita, N. Mita, Y. Uyama, N. Morita, M. Ishiguro, T. Kawasaki, H. Ishibashi and M. Sakamoto, Synlett, 2000, 1553.
293. P. R. Sebahar and R. M. Williams, J. Am. Chem. Soc., 2000, 122, 5666.
294. F. Roussi, A. Chauveau, M. Bonin, L. Micouin and H.-P. Husson, Synthesis, 2000, 1170.
295. G. A. Whitlock and E. M. Carreira, Helv. Chim. Acta, 2000, 83, 2007.
296. H. Sasaki and E. M. Carreira, Synthesis, 2000, 135.
297. B. Brown and L. S. Hegedus, J. Org. Chem., 2000, 65, 1865.
298. P. Del Buttero, C. Baldoli, G. Molteni and T. Pilati, Tetrahedron: Asymmetry, 2000, 11, 1927.
299. M. Pourashraf, P. Delair, M. O. Rasmussen and A. E. Greene, J. Org. Chem., 2000, 65, 6966.
300. C. Palomo, J. M. Aizpurua, R. Galarza, A. Benito, U. K. Khamrai, U. Eikeseth and A. Linden, Tetrahedron, 2000, 56, 5563.
301. K. Hiroi and A. Yamada, Tetrahedron: Asymmetry, 2000, 11, 1835.
302. O. Meth-Cohn, D. J. Williams and Y. Chen, Chem. Commun., 2000, 495.
303. J. Raczko, M. Achmatowicz, P. Kwiatkowski, C. Chapuis, Z. Urbańczyk-Lipkowska and J. Jurczak, Tetrahedron: Asymmetry, 2000, 11, 1027.
304. Y. Takemoto, Y. Baba, G. Saha, S. Nakao, C. Iwata, T. Tanaka and T. Ibuka, Tetrahedron Lett., 2000, 41, 3653.
305. W. Adam, K. Peters, E.-M. Peters and S. B Schambony, J. Am. Chem. Soc., 2000, 122, 7610.
306. K. C. Nicolaou, J. Li and G. Zenke, Helv. Chim. Acta, 2000, 83, 1977.
307. B. R. Aavula, Q. Cui and E. A. Mash, Tetrahedron: Asymmetry, 2000, 11, 4681.
308. A. Mamai and J. S. Madalengoitia, Tetrahedron Lett., 2000, 41, 9009.
309. J. E. A. Luithle and J. Pietruszka, Eur. J. Org. Chem., 2000, 2557.
310. J. Pietruszka and A. Witt, J. Chem. Soc., Perkin Trans. 1, 2000, 4293.
311. Q. Wang, M. F. Mayer, C. Brennan, F. Yang, M. M. Hossain, D. S. Grubisha and D. Bennett, Tetrahedron, 2000, 56, 4881.
312. A. B. Charette, J.-F. Marcoux, C. Molinaro, A. Beauchemin, C. Brochu and E. Isabel, J. Am. Chem. Soc., 2000, 122, 4508.
313. D. K. Heimbach, R. Fröhlich, B. Wibbeling and D. Hoppe, Synlett, 2000, 950.
314. M. K. McKay and J. R. Green, Can. J. Chem., 2000, 78, 1629.
315. K. Kamikawa, T. Wantanabe, A. Daimon and M. Uemura, Tetrahedron, 2000, 56, 2325.
316. T. Watanabe, M. Shakadou and M. Uemura, Synlett, 2000, 1141.
317. L. G. Monovich, Y. Le Huérou, M. Rönn and G. A. Molander, J. Am. Chem. Soc., 2000, 122, 52.
318. D. Enders, R. Peters, R. Lochtman and J. Runsink, Eur. J. Org. Chem., 2000, 2839.
319. R. Kitzler, L. Xiao and W. Weissensteiner, Tetrahedron: Asymmetry, 2000, 11, 3459.
320. D. Enders, R. Peters, R. Lochtman, G. Raabe, J. Runsink and J. W. Bats, Eur. J. Org. Chem., 2000, 3399.
321. G. Argouarch, O. Samuel, O. Riant, J.-C. Daran and H. B. Kagan, Eur. J. Org. Chem., 2000, 2893.
322. T. R. Burke Jr., D.-G. Liu and Y. Gao, J. Org. Chem., 2000, 65, 6288.
323. A. J. Pearson and P. O. Belmont, Tetrahedron Lett., 2000, 41, 1671.
324. M. C. Evans and R. L Johnson, Tetrahedron, 2000, 56, 9801.
325. S. Derrer, J. E. Davies and A. B. Holmes, J. Chem. Soc., Perkin Trans. 1, 2000, 2957.
326. S. Derrer, J. E. Davies and A. B. Holmes, J. Chem. Soc., Perkin Trans. 1, 2000, 2943.
327. P. C. B. Page, M. J. McKenzie, S. M. Allin and D. R. Buckle, Tetrahedron, 2000, 56, 9683.
328. C. C. Kotoris, W. Wen, A. Lough and S. D. Taylor, J. Chem. Soc., Perkin Trans. 1, 2000, 1271.
329. F. A. Davis, H. Qi and G. Sundarababu, Tetrahedron, 2000, 56, 5303.
330. M. S. Idris, D. S. Larsen, R. G. Pritchard, A. Schofield, R. J. Stoodley and P. D. Tiffin, J. Chem. Soc., Perkin Trans. 1, 2000, 2195.
331. S. A. Boyes and A. T. Hewson, J. Chem. Soc., Perkin Trans. 1, 2000, 2759.
332. H. Fujioka, Y. Nagatomi, N. Kotoku, H. Kitagawa and Y. Kita, Tetrahedron, 2000, 56, 10141.
333. H. Fujioka, N. Kotoku, Y. Nagatomi and Y. Kita, Tetrahedron Lett., 2000, 41, 1829.
334. A. P. Esteves, A. M. Freitas, C. M. Raynor and R. J. Stoodley, J. Chem. Soc., Perkin Trans. 1, 2000, 1753.
335. S. M. Allin, C. J. Northfield, M. I. Page and A. M. Z. Slawin, J. Chem. Soc., Perkin Trans. 1, 2000, 1715.
336. A. Giardiná, T. Mecozzi and M. Petrini, J. Org. Chem., 2000, 65, 8277.
337. C. R. A. Godfrey, N. S. Simpkins and M. D. Walker, Synlett, 2000, 388.
338. M. Cellier, Y. Gelas-Mialhe, H.-P. Husson, B. Perrin and R. Remuson, Tetrahedron: Asymmetry, 2000, 11, 3913.
339. M. D. Groaning and A. I. Meyers, Chem. Commun., 2000, 1027.
340. C. Agami, S. Comesse and C. Kadouri-Puchot, J. Org. Chem., 2000, 65, 4435.
341. P. H. Dussault, T. K. Trullinger and S. Cho-Shultz, Tetrahedron, 56, 9213.
342. N. Maezaki, Y.-X. Li, K. Ohkubo, S. Goda, C. Iwata and T. Tanaka, Tetrahedron, 2000, 56, 4405.
343. N. Maezaki, A. Sakamoto, N. Nagahashi, M. Soejima, Y.-X. Li, T. Imamura, N. Kojima, H. Ohishi, K. Sakaguchi, C. Iwata and T. Tanaka, J. Org. Chem., 2000, 65, 3284.
344. J. Blanchet, M. Bonin, L. Micouin and H.-P. Husson, J. Org. Chem., 2000, 65, 6423.
345. J. M. Andrés, I. Herráiz-Sierra, R. Pedrosa and A. Pérez-Encabo, Eur. J. Org. Chem., 2000, 1719.
346. C. Spino, C. Beaulieu and J. Lafrenière, J. Org. Chem., 2000, 65, 7091.
347. C. Spino and C. Beaulieu, Angew. Chem., Int. Ed., 2000, 39, 1930.
348. C. Agami, F. Couty, G. Evano and H. Mathieu, Tetrahedron, 2000, 56, 367.
349. R. P. Singh, B. Twamley, L. Fabry-Asztalos, D. S. Matteson and J. M. Shreeve, J. Org. Chem., 2000, 65, 8123.
350. J. C. de la Rosa, N. Díaz and J. C. Carretero, Tetrahedron Lett., 2000, 41, 4107.
351. B. Guilloteau-Bertin, D. Compère, L. Gil, C. Marazano and B. C. Das, Eur. J. Org. Chem., 2000, 1391.
352. G. S. Currie, M. G. B. Drew, L. M. Harwood, D. J. Hughes, R. W. A. Luke and R. J. Vickers, J. Chem. Soc., Perkin Trans. 1, 2000, 2982.
353. S. Madan, A. K. Sharma and S. S. Bari, Tetrahedron: Asymmetry, 2000, 11, 2267.
354. F. Jeanjean, G. Fournet, D. Le Bas and J. Goré, Eur. J. Org. Chem., 2000, 1297.
355. A. Nishida, F. Shirato and M. Nakagawa, Tetrahedron: Asymmetry, 2000, 41, 3789.
356. F. Bois, D. Gardette and J.-C. Gramain, Tetrahedron Lett., 2000, 41, 8769.
357. G. Pandey, P. Das and P. Y. Reddy, Eur. J. Org. Chem., 2000, 657.
358. R. Pedrosa, C. Andrés, J. P. Duque-Soladana and C. D. Rosón, Tetrahedron: Asymmetry, 2000, 11, 2809.
359. R. Pedrosa, C. Andrés, J. P. Duque-Soladana and P. Mendiguchía, Eur. J. Org. Chem., 2000, 3727.
360. G. Chelucci, A. Saba, R. Valenti and A. Bacchi, Tetrahedron: Asymmetry, 2000, 11, 3449.
361. S. He, S. A. Kozmin and V. H. Rawal, J. Am. Chem. Soc., 2000, 122, 190.
362. S. Chandrasekhar and M. Sridhar, Tetrahedron: Asymmetry, 2000, 11, 3467.
363. J. Blanchet, M. Bonin, L. Micouin and H.-P. Husson, Tetrahedron Lett., 2000, 41, 8279.
364. A. Guarna, E. G. Occhiato, M. Pizzetti, D. Scarpi, S. Sisi and M. van Sterkenburg, Tetrahedron: Asymmetry, 2000, 11, 4227.
365. C. Agami, F. Couty and G. Evano, Tetrahedron Lett., 2000, 41, 8301.
366. T. Tsunoda, T. Nishii, M. Yoshizuka, C. Yamasaki, T. Suzuki and S. Itô, Tetrahedron Lett., 2000, 41, 7667.
367. A. Otaka, E. Mitsuyama, T. Kinoshita, H. Tamamura and N. Fujii, J. Org. Chem., 2000, 65, 4888.
368. M. Besson, P. Gallezot, S. Neto and C. Pinel, Tetrahedron: Asymmetry, 2000, 11, 1809.
369. T. J. Donohoe, A. A. Calabrese, C. A. Stevenson and T. Ladduwahetty, J. Chem. Soc., Perkin Trans. 1, 2000, 3724.
370. T. M. T. Tuyet, T. Harada, K. Hashimoto, M. Hatsuda and A. Oku, J. Org. Chem., 2000, 65, 1335.
371. V. D. Rao and M. Periasamy, Tetrahedron: Asymmetry, 2000, 11, 1151.
372. R. W. Baker, R. V. Kyasnoor, M. V. Sargent, B. W. Skelton and A. H. White, Aust. J. Chem., 2000, 53, 487.
373. V. Narkevitch, K. Schenk and P. Vogel, Angew. Chem., Int. Ed., 2000, 39, 1806.
374. T. Tanaka, T. Azuma, X. Fang, S. Uchida, C. Iwata, T. Ishida, Y. In and N. Maezaki, Synlett, 2000, 33.
375. M. Tiecco, L. Testaferri, C. Santi, C. Tomassini, F. Marini, L. Bagnoli and A. Temperini, Tetrahedron: Asymmetry, 2000, 11, 4645.
376. M. Calmès, F. Escale, C. Glot, M. Rolland and J. Martinez, Eur. J. Org. Chem., 2000, 2459.
377. B. M. Trost and G. A. Doherty, J. Am. Chem. Soc., 2000, 122, 3801.
378. P. Hall, J. Brun, D. Denni and R. Metternich, Synlett, 2000, 315.
379. M. Banwell, A. Edwards, J. Harvey, D. Hockless and A. Willis, J. Chem. Soc., Perkin Trans. 1, 2000, 2175.
380. H. Kim and H. M. R. Hoffmann, Eur. J. Org. Chem., 2000, 2195.
381. J. Busch-Petersen and E. J. Corey, Tetrahedron Lett., 2000, 41, 6941.
382. K. W. Henderson, W. J. Kerr and J. H. Moir, Chem. Commun., 2000, 479.
383. A. M. Montaña, D. Fernández, R. Pagès, A. C. Filippou and G. Kociok-Köhn, Tetrahedron, 2000, 56, 425.
384. K. Takasu, K. Misawa, M. Yamada, Y. Furuta, T. Taniguchi and M. Ihara, Chem. Commun., 2000, 1739.
385. M. Majewski and P. Nowak, J. Org. Chem., 2000, 65, 5152.
386. M. Majewski, M. DeCaire, P. Nowak and F. Wang, Synlett, 2000, 1321.
387. A. Kee, P. O'Brien, C. D. Pilgram and S. T. Watson, Chem. Commun., 2000, 1521.
388. S. Barrett, P. O'Brien, H. C. Steffens, T. D. Towers and M. Voith, Tetrahedron, 2000, 56, 9633.
389. S. Pache, C. Botuha, R. Franz, E. P. Kündig and J. Einhorn, Helv. Chim. Acta, 2000, 83, 2436.
390. T. Hata, H. Koide and M. Uemura, Synlett, 2000, 1145.
391. P. Beak, D. R. Anderson, M. D. Curtis, J. M. Laumer, D. J. Pippel and G. A. Weisenburger, Acc. Chem. Res., 2000, 33, 715.
392. A. Deiters, R. Fröhlich and D. Hoppe, Angew. Chem., Int. Ed., 2000, 39, 2105.
393. K. R. K. Prasad and D. Hoppe, Synlett, 2000, 1067.
394. K. B. Wiberg and W. F. Bailey, Angew. Chem., Int. Ed., 2000, 39, 2127.
395. W. F. Bailey and M. J. Mealy, J. Am. Chem. Soc., 2000, 122, 6787.
396. G. S. Gil and U. M. Groth, J. Am. Chem. Soc., 2000, 122, 6789.
397. S. Nakamura, R. Nakagawa, Y. Watanabe and T. Toru, Angew. Chem., Int. Ed., 2000, 39, 353.
398. K. Nagata, S. Matsukawa and T. Imamoto, J. Org. Chem., 2000, 65, 4185.
399. A. Alexakis, E. Vrancken and P. Mangeney, J. Chem. Soc., Perkin Trans. 1, 2000, 3354.
400. S. Nakamura, R. Nakagawa, Y. Watanabe and T. Toru, J. Am. Chem. Soc., 2000, 122, 11340.
401. K. Tomooka, L.-F. Wang, F. Okazaki and T. Nakai, Tetrahedron Lett., 2000, 41, 6121.
402. M. Imai, A. Hagihara, H. Kawasaki, K. Manabe and K. Koga, Tetrahedron, 2000, 56, 179.
403. D. A. Evans, J. S. Johnson and E. J. Olhava, J. Am. Chem. Soc., 2000, 122, 1635.
404. D. Taniyama, M. Hasegawa and K. Tomioka, Tetrahedron Lett., 2000, 41, 5533.
405. M. Hasegawa, D. Taniyama and K. Tomioka, Tetrahedron, 2000, 56, 10153.
406. S. E. Denmark and C. M. Stiff, J. Org. Chem., 2000, 65, 5875.
407. F. Xu, R. A. Reamer, R. Tillyer, J. M. Cummins, E. J. J. Grabowski, P. J. Reider, D. B. Collum and J. C. Huffman, J. Am. Chem. Soc., 2000, 122, 11212.
408. M. M. Rogic, J. Org. Chem., 2000, 65, 6868.
409. K. C. Nicolaou, Y. Li, B. Weyershausen and H. Wei, Chem. Commun., 2000, 307.
410. C. B. Lee, T.-C. Chou, X.-G. Zhang, Z.-G. Wang, S. D. Kuduk, M. D. Chappell, S. J. Stachel and S. J. Danishefsky, J. Org. Chem., 2000, 65, 6525.
411. D. R. Williams, G. S. Cortez, S. L. Bogen and C. M. Rojas, Angew. Chem., Int. Ed., 2000, 39, 4612.
412. C. Hertweck and W. Boland, J. Org. Chem., 2000, 65, 2458.
413. M. Eggen, C. J. Mossman, S. B. Buck, S. K. Nair, L. Bhat, S. M. Ali, E. A. Reiff, T. C. Boge and G. I. Georg, J. Org. Chem., 2000, 65, 7792.
414. K. C. Nicolaou, F. Murphy, S. Barluenga, T. Ohshima, H. Wei, J. Xu, D. L. F. Gray and O. Baudoin, J. Am. Chem. Soc., 2000, 122, 3830.
415. P. V. Ramachandran, M. V. R. Reddy and H. C. Brown, Tetrahedron Lett., 2000, 41, 583.
416. M. B. Andrus, T. M. Turner, Z. E. Sauna and S. V. Ambudkar, J. Org. Chem., 2000, 65, 4973.
417. S. Girard, R. J. Robins, J. Villiéras and J. Lebreton, Tetrahedron Lett., 2000, 41, 9245.
418. A. G. M. Barrett, J. C. Beall, D. C. Braddock, K. Flack, V. C. Gibson and M. M. Salter, J. Org. Chem., 2000, 65, 6508.
419. D. J. S. Kumar, S. Madhavan, P. V. Ramachandran and H. C. Brown, Tetrahedron: Asymmetry, 2000, 11, 4629.
420. W. R. Roush, A. N. Pinchuk and G. C. Micalizio, Tetrahedron Lett., 2000, 41, 9413.
421. A. G. M. Barrett, D. C. Braddock, P. D. de Koning, A. J. P. White and D. J. Williams, J. Org. Chem., 2000, 65, 375.
422. J. M. Chong, L. Shen and N. J. Taylor, J. Am. Chem. Soc., 2000, 122, 1822.
423. F. Baburi, V. Fiandanese, G. Marchese and A. Punzi, Tetrahedron, 2000, 56, 327.
424. F.-E. Chen, Y.-D. Huang, H. Fu, Y. Cheng, D.-M. Zhang, Y.-Y. Li and Z.-Z. Peng, Synthesis, 2000, 2004.
425. U. Gran, O. Wennerström and G. Westman, Tetrahedron: Asymmetry, 2000, 11, 3027.
426. N. Kanomata and T. Nakata, J. Am. Chem. Soc., 2000, 122, 4563.
427. J. Li, Y.-C. Liu, J.-G. Deng, X.-Z. Li, X. Cui and Z. Li, Tetrahedron: Asymmetry, 2000, 11, 2677.
428. D. Murali, B. Singaram and H. C. Brown, Tetrahedron: Asymmetry, 2000, 11, 4831.
429. J. Cossy, C. Willis, V. Bellosta and S. Bouzbouz, Synlett, 2000, 1461.
430. S. Bouzbouz and J. Cossy, Tetrahedron Lett., 2000, 41, 3363.
431. S. Bouzbouz, F. Pradaux, J. Cossy, C. Ferroud and A. Falguières, Tetrahedron Lett., 2000, 41, 8877.
432. Z. Wu, F. Zhang and S. J. Danishefsky, Angew. Chem., Int. Ed., 2000, 39, 4505.
433. J. A. Marshall, K. Gill and B. M. Seletsky, Angew. Chem., Int. Ed., 2000, 39, 953.
434. S. Kiyooka and K. A. Shahid, Tetrahedron Lett., 2000, 41, 2633.
435. P. Kocienski, R. Narquizian, P. Raubo, C. Smith, L. J. Farrugia, K. Muir and F. T. Boyle, J. Chem. Soc., Perkin Trans. 1, 2000, 2357.
436. F. Yokokawa, J. Izumi, J. Omata and T. Shioiri, Tetrahedron, 2000, 56, 3027.
437. S. Kiooka, M. A. Hena, T. Yabukami, K. Murai and F. Goto, Tetrahedron Lett., 2000, 41, 7511.
438. S. Kiyooka, K. Goh, Y. Nakamura, H. Takesue and M. A. Hena, Tetrahedron Lett., 2000, 41, 6599.
439. E. J. Corey and S. Choi, Tetrahedron Lett., 2000, 41, 2765.
440. E. J. Corey and S. Choi, Tetrahedron Lett., 2000, 41, 2769.
441. I. Paterson, G. F. Florence, K. Gerlach and J. P. Scott, Angew. Chem., Int. Ed., 2000, 39, 377.
442. T. Itoh, H. Inoue and S. Emoto, Bull. Chem. Soc. Jpn., 2000, 73, 409.
443. M. Calmes, F. Escale, E. Juan, M. Rolland and J. Martinez, Tetrahedron: Asymmetry, 2000, 11, 1263.
444. M. Müller, K. Lamottke, E. Löw, E. Magar-Veenstra and W. Steglich, J. Chem. Soc., Perkin Trans. 1, 2000, 2483.
445. T. Ooi, K. Takaya, T. Miura, H. Ichikawa and K. Maruoka, Synlett, 2000, 1133.
446. G. Karig, A. Fuchs, A. Busing, T. Brandsletter, S. Scherer, J. W. Bats, A. Eschenmoser and G. Quinkert, Helv. Chim. Acta, 2000, 83, 1049.
447. S. M. Moharram, G. Hirai, K. Koyama, H. Oguri and M. Hirama, Tetrahedron Lett., 2000, 41, 6669.
448. A. Bayer and O. R. Gautun, Tetrahedron Lett., 2000, 41, 3743.
449. T. Bach, H. Bergmann and K. Harms, Angew. Chem., Int. Ed., 2000, 39, 2302.
450. C. D. Davies, S. P. Marsden and E. S. E. Stokes, Tetrahedron Lett., 2000, 41, 4229.
451. A. R. Kennedy, W. J. Kerr, D. M. Lindsay, J. S. Scott and S. P. Watson, J. Chem. Soc., Perkin Trans. 1, 2000, 4366.
452. J. Castro, A. Moyano, M. A. Pericàs, A. Riera, A. Alvarez-Larena and J. F. Piniella, J. Am. Chem. Soc., 2000, 122, 7944.
453. D. R. Carbery, W. J. Kerr, D. M. Lindsay, J. S. Scott and S. P. Watson, Tetrahedron Lett., 2000, 41, 3235.
454. X. Verdaguer, A. Moyano, M. A. Pericàs, A. Piera, M. A. Maestro and J. Mahía, J. Am. Chem. Soc., 2000, 122, 10242.
455. A. J. Fletcher, D. T. Rutherford and S. D. R. Christie, Synlett, 2000, 1040.
456. W. J. Kerr, D. M. Lindsay, E. M. Rankin, J. S. Scott and S. P. Watson, Tetrahedron Lett., 2000, 41, 3229.
457. I. Coldham and G. P. Vennall, Chem. Commun., 2000, 1569.
458. R. W. Hoffmann, B. Hölzer, O. Knopff and K. Harms, Angew. Chem., Int. Ed., 2000, 39, 3072.
459. C. N. Farthing and S. P. Marsden, Tetrahedron Lett., 2000, 41, 4235.
460. P. E. Morgan and R. McCague and A Whiting, J. Chem. Soc., Perkin Trans. 1, 2000, 515.
461. S. Saito, M. Nakadai and H. Yamamoto, Synlett, 2000, 1107.
462. Y. Ukaji, Y. Yoshida and K. Inomata, Tetrahedron: Asymmetry, 2000, 11, 733.
463. A. de Meijere, B. Stecker, A. Kourdioukov and C. M. Williams, Synthesis, 2000, 929.
464. E. Vedejs, A. W. Kruger, N. Lee, S. T. Sakata, M. Stec and E. Suna, J. Am. Chem. Soc., 2000, 122, 4602.
465. S. Nakamura, M. Kaneeda, K. Ishihara and H. Yamamoto, J. Am. Chem. Soc., 2000, 122, 8120.
466. A. Cuenca, M. Medio-Simón, G. A. Aguilar, D. Weibel, A. K. Beck and D. Seebach, Helv. Chim. Acta, 2000, 83, 3153.
467. Y. Nakamura, S. Takeuchi, Y. Ohgo and D. P. Curran, Tetrahedron, 2000, 56, 351.
468. A. J. Burton, J. P. Graham and N. S. Simpkins, Synlett, 2000, 1640.
469. S. Matsukawa and T. Imamoto, J. Am. Chem. Soc., 2000, 122, 12659.
470. J. Eames and N. Weerasooriya, Tetrahedron Lett., 2000, 41, 521.
471. Z. Liu, N. Shibata and Y. Takeuchi, J. Org. Chem., 2000, 65, 7583.
472. L. E. Overman, J. F. Larrow, B. A. Stearns and J. M. Vance, Angew. Chem., Int. Ed., 2000, 39, 213.
473. C.-C. Wang, J. J. Li, H.-C. Huang, L. F. Lee and D. B. Reitz, J. Org. Chem., 2000, 65, 2711.
474. V. V. Zhdankin, J. T. Smart, P. Zhao and P. Kiprof, Tetrahedron Lett., 2000, 41, 5299.
475. S. Nakamura, K. Ishihara and H. Yamamoto, J. Am. Chem. Soc., 2000, 122, 8131.
476. K. Manabe and S. Kobayashi, Chem. Commun., 2000, 669.
477. Y. Miyake, H. Takada, K. Ohe and S. Uemura, J. Chem. Soc., Perkin Trans. 1, 2000, 1595.
478. Y. Lu and G. Just, Tetrahedron, 2000, 56, 4355.
479. M. Tiecco, L. Testaferri, C. Santi, C. Tomassini, F. Marini, L. Bagnoli and A. Temperini, Eur. J. Org. Chem., 2000, 3451.
480. K. Hiroi and M. Ishii, Tetrahedron Lett., 2000, 41, 7071.
481. D. Enders and E. C. Ullrich, Tetrahedron: Asymmetry, 2000, 11, 3861.
482. S. Cossu, O. De Lucchi, P. Peluso and R. Volpicelli, Tetrahedron Lett., 2000, 41, 7263.
483. I. Michieletto, F. Fabris and O. De Lucchi, Tetrahedron: Asymmetry, 2000, 11, 2835.
484. H. Watanabe, D. Itoh and T. Kitahara, Synthesis, 2000, 1925.
485. K. Ishihara, H. Nakamura and H. Yamamoto, Synlett, 2000, 1245.
486. A. G. Al-Sehemi, R. S. Atkinson, J. Fawcett and D. R. Russell, Tetrahedron Lett., 2000, 41, 2239.

---