Carbonyl reduction diastereoselective

Johnson in 1993 described an approach to racemic p-amyrin involving application of a biomimctic polyene cyclization.7 In the same year Corey accomplished the enantioseleetive synthesis of compound 4. a key intermediate that opened the way to stereoselective preparation of compounds I, 2. and 3 8 A key step in the synthesis of P-amyrin (1) was the introduction of chiral oxazaboroli-dines for enantioseleetive carbonyl reduction. Ba ed on these methods, generation of an enantiomerically pure epoxide and its stereoselective cationic cyclization led to the pentacyclic system of structure 1 Diastereoselective cyclopropanation and an intramolecular protonation of a carbanion represent other interesting steps in this total synthesis. 

In addition to accelerating the rate of carbonyl reduction, chelation can be used to control the diastereoselectivity of reductions and carbon-carbon bondforming reactions through highly organised transition states. Keck showed that appropriately subsituted p-hydroxy ketones are stereoselectively reduced by... 

Further refinement of the model by calculated trajectory analysis enabled the steric influence of the group (R) attached directly to the carbonyl to be assessed. Increasing the size of R was known to enhance the reduction diastereoselectivity. This may be understood by the perturbation of the trajectory of the... 

Diastereoselectivities of up to 98.5 1.5 for carbonyl reductions by using catalytic amounts of racemic (ebthi)TiCl2 compound in situ reduction with zinc have been obtained. A disadvantage of this methodology is the fact that only aromatic and ct,/ -unsaturated aldehydes can be coupled while aliphatic aldehydes do not react under these conditions.1989,1990... 

One of the more important characteristics of carbonyl reduction with LiAlH4 is the diastereoselectivity of the reaction when reduction introduces a second stereogenic center. As a general rule, hydride is delivered to... 

Stereoselective Carbonyl Reductions. L-selectride reduction of U-acyl-Y-lactones has been shown to furnish the syn-reduction products in good yield and high diastereoselection which may be hydrolysed to threo-diols. The stereochemistry appears to be largely independent of the size of the acyl group and is in accord with reduction following the Felkin-Ahn transition-state model (Scheme 2). ... 

Industrial Synthetic Improvements. One significant modification of the Stembach process is the result of work by Sumitomo chemists in 1975, in which the optical resolution—reduction sequence is replaced with a more efficient asymmetric conversion of the meso-cyc. 02Lcid (13) to the optically pure i7-lactone (17) (Fig. 3) (25). The cycloacid is reacted with the optically active dihydroxyamine [2964-48-9] (23) to quantitatively yield the chiral imide [85317-83-5] (24). Diastereoselective reduction of the pro-R-carbonyl using sodium borohydride affords the optically pure hydroxyamide [85317-84-6] (25) after recrystaUization. Acid hydrolysis of the amide then yields the desired i7-lactone (17). A similar approach uses chiral alcohols to form diastereomic half-esters stereoselectivity. These are reduced and direedy converted to i7-lactone (26). In both approaches, the desired diastereomeric half-amide or half-ester is formed in excess, thus avoiding the cosdy resolution step required in the Stembach synthesis. 

There has been recent interest in naphtho-fused dithiepines as chiral acyl anion equivalents, particularly since the starting dithiol 128 can be obtained in enan-tiomerically pure form (89TL2575). This is transformed using standard methods into the dithiepine 129, but showed only moderate diastereoselectivity in its addition to carbonyl compounds. On the other hand, as we have seen previously for other systems, formation of the 2-acyl compound 130 and reduction or addition of a Grignard reagent gave the products 131 with much better stereoselectivity (91JOC4467). 

Enantiomerically pure /J-keto sulfoxides are prepared easily via condensation of a-lithiosulfinyl carbanions with esters. Reduction of the carbonyl group in such /J-keto sulfoxides leads to diastereomeric /J-hydroxysulfoxides. The major recent advance in this area has been the discovery that non-chelating hydride donors (e.g., diisobutylaluminium hydride, DIBAL) tend to form one /J-hydroxysulfoxide while chelating hydride donors [e.g., lithium aluminium hydride (LAH), or DIBAL in the presence of divalent zinc ions] tend to produce the diastereomeric /J-hydroxysulfoxide. The level of diastereoselectivity is often very high. For example, enantiomerically pure /J-ketosulfoxide 32 is reduced by LAH in diethyl ether to give mainly the (RR)-diastereomer whereas DIBAL produces exclusively the (.S R)-diastereomer (equation 30)53-69. A second example is shown in... 

There are other stereochemical aspects to the reduction of aldehydes and ketones. If there is a chiral center to the carbonyl group, even an achiral reducing agent can give more of one diastereomer than of the other. Such diastereoselective reductions have been carried out with considerable success. In most such cases Cram s rule (p. 147) is followed, but exceptions are known. ... 

The Leuckart-Wallach reaction is the oldest method of reductive amination of carbonyl compounds. It makes use of formamide, formic acid or ammonium formate at high temperature. The final product is a formamide derivative, which can be converted to an amine by reduction or hydrolysis. The method has been applied to the preparation of 1,2-diamines with a norbornane framework, which are interesting rigid analogues of 1,2-diaminocyclohexanes. As a matter of fact, starting from N-acetyl-2-oxo-l-norbornylamine 222, the diamide 223 was obtained with excellent diastereoselectivity and then converted to the M-methyl-N -ethyl derivative 224 by reduction with borane [ 104] (Scheme 34). On the other hand, when the reac-... 

Diastereoselective intermolecular nitrile oxide—olefin cycloaddition has been used in an enantioselective synthesis of the C(7)-C(24) segment 433 of the 24-membered natural lactone, macrolactin A 434 (471, 472). Two (carbonyl)iron moieties are instrumental for the stereoselective preparation of the C(8)-C(ii) E,Z-diene and the C(i5) and C(24) sp3 stereocenters. Also it is important to note that the (carbonyl)iron complexation serves to protect the C(8)-C(ii) and C(i6)-C(i9) diene groups during the reductive hydrolysis of an isoxazoline ring. 

Although a cobalt-catalyzed intermolecular reductive aldol reaction (generation of cobalt enolates by hydrometal-lation of acrylic acid derivatives and subsequent reactions with carbonyl compounds) was first described in 1989, low diastereoselectivity has been problematic.3 6 However, the intramolecular version of this process was found to show high diastereoselectivity (Equation (37)).377,377a 378 A Co(i)-Co(m) catalytic cycle is suggested on the basis of deuterium-labeling studies and the chemistry of Co(ll) complexes (Scheme 81). Cobalt(m) hydride 182, which is... 

Diastereoselective reduction of p-keto esters.1 Reduction of p-keto esters (3) of the chiral a-naphthylborneol (2)2 is stereoselective because one face of the carbonyl group is blocked by the naphthyl group. Chelation of the keto ester with... 

The use of a chiral sulfoxide group as the stereoinducing element is at the center of Solladie s approach to the smaller fragment [44] and a C(8)-C(18) segment [44,45] of the larger fragment of lb (Scheme 27). jS-Ketosulfoxide 200 was obtained from S-ketoester 198 via carbonyl protection and condensation with chiral sulfoxide 199. Two completely diastereoselective reductions of 200... 

Racemic diquinane enone rac-6 was prepared by Piers and Orellana starting from cyclopentenone (Scheme 6) [11]. After the preparation of the heterocuprate from stannane 20, conjugate addition to cyclopentenone in the presence of BF3 Et20 provided carbonyl compound 21. It was expected that conversion of 21 by intramolecular alkylation and subsequent hydrogenation should provide the desired endo-substituted diquinane rac-13. While other hydrogenation methods proved to be rather unselective, reduction in the presence of Wilkinson s catalyst finally resulted in the formation of rac-13 with good facial diastereoselectivity [11]. 

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