Nonracemic

Chiral nitrones react with alkenes to produce 3,5-disubstituted isoxazolidines that are nonracemic diastereomeric mixtures and are oriented predominantly cis (equation 53) (77CC303, 79JOC1212). 

Development of chiral, nonracemic dioxiranes for the catalytic enantioselective epoxidation of alkenes 99SL847. 

Chiral and nonracemic A-cyanomethyloxazolidines in diastereoselective synthesis, particularly of pyrrolidine and piperidine derivatives 99CSR383. 

Diastereoselective synthesis, particularly of piperidine derivatives using chiral and nonracemic A-cyanomethyloxazolidines 99CSR383. 

Nonracemic Mixture from Approved Racemate or Single Enantiomer... 

For an excellent review of synthetic applications of nonracemic glycidol and related 2,3-epoxy alcohols, see Hanson, R. M. Chem. Rev. 1991, 91, 437. 

Syntheses of nonracemic vinylaziridines by reagent- or substrate-controlled... 

The chemistry of aziridine-2-carboxylates and phosphonates has been discussed in part in several reviews covering the literature through 1999 [1-3], This chapter is intended to give an overview of asymmetric syntheses using chiral nonracemic aziridine-2-carboxylates and -phosphonates with particular emphasis on their applications as chiral building blocks in asymmetric synthesis since 2000. Some overlap with earlier reviews is necessary for the sake of continuity. 

The earliest method developed for the preparation of nonracemic aziridine-2-car-boxylates was the cyclization of naturally occurring (3-hydroxy-a-amino acid derivatives (serine or threonine) [4]. The (3-hydroxy group is normally activated as a tosyl or mesyl group, which is ideal for an intramolecular SN2 displacement. The cyclization has been developed in both one-pot and stepwise fashion [4—9]. As an example, serine ester 3 (Scheme 3.2) was treated with tosyl chloride in the presence of triethylamine to afford aziridine-2-carboxylate 4 in 71% yield [9]. Cyclization of a-hydroxy- 3-amino esters to aziridine-2-carboxylates under similar conditions has also been described [10]. 

Reactions between imines and a-diazo carboxylates afford aziridine-2-carboxylates [55]. An asymmetric version of this reaction using chiral nonracemic catalysts has been described [53, 56-58]. As an example, catalytic aziridination of inline 44 (Scheme 3.14) with ethyl diazoacetate in the presence of 10% catalyst generated... 

Darzens reactions between the chiral imine 52 and a-halo enolates 53 for the preparation of nonracemic aziridine-2-carboxylic esters 54 (Scheme 3.17) were studied by Fujisawa and co-workers [61], It is interesting to note that the lithium enolate afforded (2K,3S)-aziridirie (2i ,3S)-54 as the sole product, whereas the zinc enolate give rise to the isomer (2S,3i )-54. The a-halogen did not seem to affect the stereoselectivity. 

Ishikawa and co-workers reported that treatment of chiral nonracemic guanidin-ium bromide 66 (Scheme 3.22) with aldehyde 67, in the presence of tetramethyl-... 

Aziridine-2-carboxylates are playing important roles in the synthesis of natural products and pharmaceutically useful molecules. In this section, applications of chiral nonracemic aziridine-2-carboxylates in the synthesis of natural products are discussed. 

Azirines (three-membered cyclic imines) are related to aziridines by a single redox step, and these reagents can therefore function as precursors to aziridines by way of addition reactions. The addition of carbon nucleophiles has been known for some time [52], but has recently undergone a renaissance, attracting the interest of several research groups. The cyclization of 2-(0-tosyl)oximino carbonyl compounds - the Neber reaction [53] - is the oldest known azirine synthesis, and asymmetric variants have been reported. Zwanenburg et ah, for example, prepared nonracemic chiral azirines from oximes of 3-ketoesters, using cinchona alkaloids as catalysts (Scheme 4.37) [54]. 

In recent years, enantioselective variants of the above transannular C-H insertions have been extensively stiidied. The enantiodetermining step involves discrimination between the enantiotopic protons of a meso-epoxide by a homochiral base, typically an organolithium in combination with a chiral diamine ligand, to generate a chiral nonracemic lithiated epoxide (e.g., 26 Scheme 5.8). Hodgson... 

Pitfalls are encountered when allowing chiral nonracemic aldehydes to react with chiral, but racemic, reagents having a stereogenic center at the metal-bearing carbon atom, since its chiral induction usually overrides that of the substrate leading to mixtures of two diastereomers in essentially equal amounts26,27 (Sections D.1.3.3.1.4.1., D.1.3.3.3.3.3.2. and D.1.3.3.3.8.2.3.1.). 

Lewis acid catalyzed carbonyl addition reactions of nonracemic chiral allylsilanes34 were shown to proceed with anti-S E attack, thus also enabling 1,3-chirality transfer in an opposite direction (Section D.l. 3.3.3.5.2.3.). 

On the other hand, high levels of diastereoselectivity are relatively easy to achieve in matched double asymmetric reactions since the intrinsic diastereofacial preference of the chiral aldehyde reinforces that of the reagent, and in many cases it has been possible to achieve synthetically useful levels of matched diastereoselection by using only moderately enantioselective chiral allylboron reagents. Finally, it is worth reminding the reader that both components of double asymmetric reactions need to be both chiral and nonracemic for maximum diastereoselectivity to be realized. 

Chiral, nonracemic allylboron reagents 1-7 with stereocenters at Cl of the allyl or 2-butenyl unit have been described. Although these optically active a-substituted allylboron reagents are generally less convenient to synthesize than those with conventional auxiliaries (Section 1.3.3.3.3.1.4.), this disadvantage is compensated for by the fact that their reactions with aldehydes often occur with almost 100% asymmetric induction. Thus, the enantiomeric purity as well as the ease of preparation of these chiral a-substituted allylboron reagents are important variables that determine their utility in enantioselective allylboration reactions with achiral aldehydes, and in double asymmetric reactions with chiral aldehydes (Section 1.3.3.3.3.2.4.). 

A chiral nonracemic cyclic allyl iodide was shown to react with excess chromium(II) chloride and (4-methoxyphenylmethoxy)acetaldehyde to yield a single diastereomer, which was converted to la,25-dihydroxy vitamin D332. 

Within this section, the term aldol reaction includes additions of enols and enolates to carbonyl compounds. This section concentrates on aldol additions which deliver nonracemic, /i-hydroxycarbonyl compounds. The chiral information can be located ... 

Thermodynamically controlled aldol additions leading to the formation of nonracemic products are rare and will be discussed below. 

JVH-Aldols are also obtained from ( Jo-2-inethylbicyelo[2.2.1]hept-5-en-2-yl)ethyl ketone. Subsequently, the thennolabile norbonenyl group can be removed by retro-Diels Alder reaction531. For applications in syntheses of nonracemic aldols, see Section 1.3.4.4. 

The aldol reaction of 2,2-dimethyl-3-pentanone, which is mediated by chiral lithium amide bases, is another route for the formation of nonracemic aldols. Indeed, (lS,2S)-l-hydroxy-2,4,4-trimethyl-l-phenyl-3-pentanone (21) is obtained in 68% ee, if the chiral lithiated amide (/ )-A-isopropyl-n-lithio-2-methoxy-l-phenylethanamine is used in order to chelate the (Z)-lithium cnolate, and which thus promotes the addition to benzaldehyde in an enantioselective manner. No anti-adduct is formed25. 

High, simple diastereoselection was also observed on the reaction of the anion of racemic (Z)-1-(phenylsulfinyl)-2-butene (2 equiv) with a nonracemic bicyclic chiral enone (1 equiv) giving a 7-1,4-adduct in 82% eeI5b. 

The anion of nonracemic l,4-dimethyl-3-(phenylsulfinyl)-1-cyclohexene underwent conjugate addition to methyl 2-methyl-5-oxo-Tcyclopentenecarboxylate with high diastereoselectivity22. 

This method was extended to the diastereoselective synthesis of amino acid derivatives from the 1,4-addition of chiral nonracemic azaenolates derived from optically active imines to enones90. 

The asymmetric Michael addition of chiral nonracemic ketone enolates has most frequently been used as part of the Robinson annulation methodology in the synthesis of natural products171-172. The enolates are then derived from carbocyclic chiral ketones such as (+)-nopinone, (-)-dihydrocarvone, or (-)-3-methylsabinaketone. 

Several methods for asymmetric C —C bond formation have been developed based on the 1,4-addition of chiral nonracemic azaenolates derived from optically active imines or enamines. These methods are closely related to the Enders and Schollkopf procedures. A notable advantage of all these methods is the ready removal of the auxiliary group. Two types of auxiliaries were generally used to prepare the Michael donor chiral ketones, such as camphor or 2-hydroxy-3-pinanone chiral amines, in particular 1-phenylethanamine, and amino alcohol and amino acid derivatives. 

Addition of organolithiutn reagents in toluene to A-cyclohexyl enimines in the presence of chiral nonracemic diethers or diamines (1.2-2,4 equiv) gives, after hydrolysis, //-substituted aldehydes2. It is important to note that these reactions do not occur in the absence of the chiral additive which can be recovered quantitatively for reuse without loss of enantiomeric purity6. 

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