Aldehydes chiral oxazolidine

Chiral oxazolidines 6, or mixtures with their corresponding imines 7, are obtained in quantitative yield from acid-catalyzed condensation of methyl ketones and ( + )- or ( )-2-amino-l-phcnylpropanol (norephedrine, 5) with azeotropic removal of water. Metalation of these chiral oxazolidines (or their imine mixtures) using lithium diisopropylamide generates lithioazaeno-lates which, upon treatment with tin(II) chloride, are converted to cyclic tin(II) azaenolates. After enantioselective reaction with a variety of aldehydes at 0°C and hydrolysis, ft-hydroxy ketones 8 are obtained in 58-86% op4. 

Among chiral auxiliaries, l,3-oxazolidine-2-thiones (OZTs) have attracted much interest for their various applications in different synthetic transformations.2 Such simple structures, directly related to far better known chiral oxazolidinones,11,12,57 have been explored in asymmetric Diels-Alder reactions and asymmetric alkylations, but mainly in condensation of their /V-acyl derivatives with aldehydes. Chiral OZTs have shown interesting characteristics in anti-selective aldol reactions58 or combined asymmetric addition. 

Aldol reactions.1 The chiral oxazolidine (1), formed from 3-pentanone and (-)-norephedrine, after conversion to the tin azaenolate reacts with aldehydes to give predominantly anti-aldols (2) in >90% ee. Reduction of the carbonyl group of the anti-aldol 2 provides (3S,4R)-4-methyl-3-heptanol (3) in 95% ee. 

A polymer-supported synthesis of an array of a chirally pure (3-lactams in high purity has been demonstrated [129] from a resin-bound chiral oxazolidine aldehyde. Application of resin-bound chiral oxazolidine aldehyde equivalent was explored... 

Scheme 24 Application of chiral oxazolidine aldehyde in the synthesis of P-lactam library...

Diastereoselective addition in Et20/HMPT (1 1) leads to the (5)-aldehyde with an enantiomeric excess of 40%, whereas in -hexane the (2 )-aldehyde is formed with 80% ( ) enantiomeric excess. The (2 )-configured aldehyde is also obtained in benzene and in dichloromethane, but with lower ee values of 50% and 25%, respectively. Inverse results were obtained with a chiral oxazolidine prepared from ( )-cinnamaldehyde and (+)-ephedrine. Here, the (5)-aldehyde with ee = 79% is formed in -hexane, and the (7 )-aldehyde in Et20/HMPT (1 1) with ee = 50% [703], This result may be due to different structures of the organocopper reagent, and hence of the diastereomorphic activated complexes, in nonpolar solvents ( -hexane, benzene, dichloromethane) and in EPD solvents (Et20/HMPT) [703]. 

A chiral oxazolidine prepared from a,j6-unsaturated aldehydes and ( —)- or (-l-)-ephedrine efficiently induced asymmetric cyclopropanation with excess of diazomethane in the presence of palladium acetate, e.g. formation of 24 from ( —)-ephedrine and ( )-cinnamaldehyde 24 was cyclopropanated to give 25 and the auxiliary removed giving... 

A polymer-supported version of the Garner aldehyde (Scheme 12.25) was applied in the synthesis of a P-lactam [36], Owing to its strong electrophilicity the chiral, oxazolidine based Garner aldehyde is a versatile intermediate and often provides excellent asymmetric induction [37]. 

Preparation of the chiral oxazolidine-aldehyde 64 from D-serine 59 required various steps, including conversion into the silyl ether 60, reaction with ketone 61 to provide oxazolidine silyl ether 62 and subsequent desilylation of the tert-butyldiphenylsiloxy group. Oxidation of the hydroxy functionality and hydrogeno-lytic cleavage of the benzyl ester then gave the corresponding aldehyde 63. The acid functionality of 63 was then coupled to aminomethylated Merrifield resin (Scheme 12.26). 

Scheme 12.26 Preparation of a chiral oxazolidine aldehyde (64) on solid support.

An access to optically active P-hydroxy acids uses the bromoacetyl derivatives of chiral oxazolidin-2-ones to react with aldehydes. " 1,3-Diketones are obtained from reaction of a-haloketones with acyl cyanides. ... 

A variety of 1,3-oxazolidines have been used as chiral formyl anion equivalents for addition to aldehydes. Thus, for example, reaction of N-protected norephedrine with Bu3Sn-CH(OEt)2 gives 48, and transmetallation with BuLi followed by addition of benzaldehyde affords the expected adduct 49. The selectivity at the newly formed alcohol center is poor, but the situation can be salvaged by oxidation and re-reduction, which affords the product 50 with >95% d.e. It is then a simple matter to hydrolyze off the oxazolidine, although the resulting hydroxyaldehydes... 

Among the many chiral Lewis acid catalysts described so far, not many practical catalysts meet these criteria. For a,/ -unsaturated aldehydes, Corey s tryptophan-derived borane catalyst 4, and Yamamoto s CBA and BLA catalysts 3, 7, and 8 are excellent. Narasaka s chiral titanium catalyst 31 and Evans s chiral copper catalyst 24 are outstanding chiral Lewis acid catalysts of the reaction of 3-alkenoyl-l,2-oxazolidin-2-one as dienophile. These chiral Lewis acid catalysts have wide scope and generality compared with the others, as shown in their application to natural product syntheses. They are, however, still not perfect catalysts. We need to continue the endeavor to seek better catalysts which are more reactive, more selective, and have wider applicability. 

Reaction of the chiral (45,5R)-oxazolidine 9. obtained from 3-pentanone and (-)-2-amino-l-phenylpropanol, with aldehydes gives predominantly a H -aldol adducts of high enantiomeric purity. The corresponding spn-adducts, formed in low enantiomeric excess, are isolated from the diaslereomeric mixture by chromatography 5. 

In 2001, Braga et al. reported the synthesis of new chiral C2-symmetric oxazolidine disulfide ligands from (R)-cysteine and successfully applied them as catalysts in the asymmetric addition of ZnEt2 to various aldehydes (Scheme 3.23). In the presence of 2mol% of ligand, excellent enantioselectivities of up to >99% ee were obtained even with aliphatic aldehydes such as n-decanal or n-hexanal. These authors proposed that the active catalyst did not maintain its C2-symmetry during the reaction. The disulfide bond was probably cleaved in situ by ZnEt2. 

In addition, other chiral sulfide ligands containing oxazolidines have been tested for the enantioselective addition of ZnEt2 to aldehydes, providing moderate enantioselectivities, as shown in Scheme 3.25. ... 

In 2002, Braga el al. employed a chiral C2-symmetric oxazolidine disulfide as a ligand for the enantioselective synthesis of propargylic alcohols by direct addition of alkynes to aldehydes (Scheme 3.64). Good yields but moderate enantioselectivities (<58% ee) were obtained for the enantioselective alkyny-lation of aldehydes in the presence of ZnEt2. 

Prasad and Joshi121 presented a conceptually different catalyst system—zinc amides of oxazolidine. Because the addition of dialkylzinc to aldehyde is known to involve a chiral zinc alkoxide with a coordinately unsaturated tricoordinated center, they anticipated that a zinc amide with dicoordinate zinc should be a better Lewis acid. Examining three different zinc species 128-130, zinc amide derived from the corresponding oxazolidine 130 was found to lead to a very fast reaction (4 hours, 0°C) and 100% ee (Scheme 2-50). The reaction proceeds even faster at room temperature (completed within 1 hour) without significant loss of stereoselectivity. This reaction can provide excellent ee for aromatic aldehydes,... 

The types of dienophiles which have been studied most are acrylic aldehydes, acrylates and 3-acryloyl-l,3-oxazolidines. The latter have been used predominantly in copper, magnesium, zinc and lanthanide catalyzed reactions in which the chiral Lewis acid binds in an rj2 fashion to the dienophile (complexation to both carbonyls). 

Substituted chiral aldehydes can be derivatized with naturally occurring (1/ ,2S)-ephedrine to give oxazolidines, UC- and H-NMR analysis allows determination of the enantiomeric excess and in simple cases the absolute configuration of the analyzed aldehyde6. Very mild reaction conditions are required. 

Unlike the 13C-NMR method, H-NMR spectra are not applicable to 3-alkylaldehydes. For 3-arylaldehydes, the chemical shifts of 2-H, 3 -H, and 5-H appear deshielded in oxazolidines derived from chiral aldehydes with configuration A, where Rz is the aryl group. 

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