Aldol reaction chiral

Ghosh also took advantage of the C—2 hydroxyl moiety of aminoindanols as a handle in the aldol reaction. Chiral sulfonamide 41 was O-acylated to give ester 42. The titanium enolate of ester 42 was formed as a single isomer and added to a solution of aldehyde, precomplexed with titanium tetrachloride, to yield the anft -aldol product 43 in excellent diastereoselectivities.63 One additional advantage of the ester-derived chiral auxiliaries was their ease of removal under mild conditions. Thus, hydrolysis of 43 afforded a ft -a-methyl- 3-hydroxy acid 44 as a pure enantiomer and cis-1-/ -1 o I y I s u I f on a m i do- 2 - i n da n ol was recovered without loss of optical purity (Scheme 24.7).63... 

In contrast with the above Lewis acid-catalyzed asymmetric aldol reactions, chiral Pd and Pt cationic complexes have been found to catalyze the asymmetric process by a transmetalation mechanism involving a metal enolate intermediate (Section 10.2.1.3). 

In recent years, catalytic asymmetric Mukaiyama aldol reactions have emerged as one of the most important C—C bond-forming reactions [35]. Among the various types of chiral Lewis acid catalysts used for the Mukaiyama aldol reactions, chirally modified boron derived from N-sulfonyl-fS)-tryptophan was effective for the reaction between aldehyde and silyl enol ether [36, 37]. By using polymer-supported N-sulfonyl-fS)-tryptophan synthesized by polymerization of the chiral monomer, the polymeric version of Yamamoto s oxazaborohdinone catalyst was prepared by treatment with 3,5-bis(trifluoromethyl)phenyl boron dichloride ]38]. The polymeric chiral Lewis acid catalyst 55 worked well in the asymmetric aldol reaction of benzaldehyde with silyl enol ether derived from acetophenone to give [i-hydroxyketone with up to 95% ee, as shown in Scheme 3.16. In addition to the Mukaiyama aldol reaction, a Mannich-type reaction and an allylation reaction of imine 58 were also asymmetrically catalyzed by the same polymeric catalyst ]38]. 

Parmee ER, Tempkin O, Masamune S, Abiko A. New catalysts for the asymmetric aldol reaction chiral boranes prepared from a, a-disubstituted glycine arenesulfonamides. J.Am. Chem. Soc. 1991 113 9365-9366. 

Asymmetric aldol reaction promoted by chiral oxazaborolidinone 97YGK313. 

Chiral salen chromium and cobalt complexes have been shown by Jacobsen et al. to catalyze an enantioselective cycloaddition reaction of carbonyl compounds with dienes [22]. The cycloaddition reaction of different aldehydes 1 containing aromatic, aliphatic, and conjugated substituents with Danishefsky s diene 2a catalyzed by the chiral salen-chromium(III) complexes 14a,b proceeds in up to 98% yield and with moderate to high ee (Scheme 4.14). It was found that the presence of oven-dried powdered 4 A molecular sieves led to increased yield and enantioselectivity. The lowest ee (62% ee, catalyst 14b) was obtained for hexanal and the highest (93% ee, catalyst 14a) was obtained for cyclohexyl aldehyde. The mechanism of the cycloaddition reaction was investigated in terms of a traditional cycloaddition, or formation of the cycloaddition product via a Mukaiyama aldol-reaction path. In the presence of the chiral salen-chromium(III) catalyst system NMR spectroscopy of the crude reaction mixture of the reaction of benzaldehyde with Danishefsky s diene revealed the exclusive presence of the cycloaddition-pathway product. The Mukaiyama aldol condensation product was prepared independently and subjected to the conditions of the chiral salen-chromium(III)-catalyzed reactions. No detectable cycloaddition product could be observed. These results point towards a [2-i-4]-cydoaddition mechanism. 

An enantioselective aldol reaction may also be achieved with non-chiral starting materials by employing an asymmetric Lewis acid as catalyst ... 

Since most often the selective formation of just one stereoisomer is desired, it is of great importance to develop highly selective methods. For example the second step, the aldol reaction, can be carried out in the presence of a chiral auxiliary—e.g. a chiral base—to yield a product with high enantiomeric excess. This has been demonstrated for example for the reaction of 2-methylcyclopenta-1,3-dione with methyl vinyl ketone in the presence of a chiral amine or a-amino acid. By using either enantiomer of the amino acid proline—i.e. (S)-(-)-proline or (/ )-(+)-proline—as chiral auxiliary, either enantiomer of the annulation product 7a-methyl-5,6,7,7a-tetrahydroindan-l,5-dione could be obtained with high enantiomeric excess. a-Substituted ketones, e.g. 2-methylcyclohexanone 9, usually add with the higher substituted a-carbon to the Michael acceptor ... 

Stork and Takahashi took -glyceraldehyde synthon from the chiral pool and condensed it with methyl oleate, using lithium diisopropyl amide as catalyst for the mixed aldol reaction, leading to The olefinic linkage is a latent form... 

We now tum our attention to the C21-C28 fragment 158. Our retrosynthetic analysis of 158 (see Scheme 42) identifies an expedient synthetic pathway that features the union of two chiral pool derived building blocks (161+162) through an Evans asymmetric aldol reaction. Aldehyde 162, the projected electrophile for the aldol reaction, can be crafted in enantiomerically pure form from commercially available 1,3,4,6-di-O-benzylidene-D-mannitol (183) (see Scheme 45). As anticipated, the two free hydroxyls in the latter substance are methylated smoothly upon exposure to several equivalents each of sodium hydride and methyl iodide. Tetraol 184 can then be revealed after hydrogenolysis of both benzylidene acetals. With four free hydroxyl groups, compound 184 could conceivably present differentiation problems nevertheless, it is possible to selectively protect the two primary hydroxyl groups in 184 in... 

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 ... 

Aldol reactions of a-substituted iron-acetyl enolates such as 1 generate a stcrcogenic center at the a-carbon, which engenders the possibility of two diastereomeric aldol adducts 2 and 3 on reaction with symmetrical ketones, and the possibility of four diastereomeric aldol adducts 4, 5, 6, and 7 on reaction with aldehydes or unsymmetrical ketones. The following sections describe the asymmetric aldol reactions of chiral enolate species such as 1. 

The achiral molybdenum enolate 2 reacts with benzophenone and benzaldehyde at —78 °C to yield the x,/i-unsaturated molybdenum-acyl complexes34, which presumably arise via elimination of hydroxide from unobserved aldolate intermediates such as 3. No examples of such aldol reactions with complexes that are chiral at molybdenum have been reported. 

In a chiral aldehyde or a chiral ketone, the carbonyl faces are diastereotopic. Thus, the addition of an enolate leads to the formation of at least one stereogenic center. An effective transfer of chirality from the stereogenic center to the diastereoface is highly desirable. In most cases of diastereoface selection of this type, the chiral aldehyde or ketone was used in the racemic form, especially in early investigations. However, from the point of view of an HPC synthesis, it is indispensable to use enantiomerically pure carbonyl compounds. Therefore, this section emphasizes those aldol reactions which are performed with enantiomerically pure aldehydes. 

Thus, the inherent selectivity of a chiral aldehyde is much stronger in Mukaiyama-type aldol reactions than in the additions of lithium or magnesium enolates17. 

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. 

J)-4-Hydroxy-6-phenyl-2-hexanone (8, R1 =CH, R2 = (CH2)2C6H5) Typical Procedure for Enantioselective Aldol Reaction via Chiral Oxazolidines4 ... 

Aldehydes, 43 a-Chiral, 112 a/MJnsaturated, 85,110 /3-Aldchydosi lanes, 22 Aldol reaction, directed, 139 Alkoxytrimethylsilanes, 122 Alkyl lithium. 67 Alkyl silyl ethers, 91-97,127 Alkylation, 33 of ethyl glycinate, 88-89 t-Alkylation, 111-135... 

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