Chiral alcohols utility scheme

Nickel boride prepared from Nil2 and two equivalents of LiBH4 [42] was utilized as an oxazaborolidine catalyst support (Scheme 4) [43]. Reaction of nickel boride with 0.1 equivalents of chiral amino alcohol in THF at room temperature gave the anchored catalyst 6, which produced chiral alcohols in optical yields of up to 95%, and which furthermore showed higher activity as regards the reduction of acetophenone derivatives than that of the corresponding homogene-... 

In addition to synthesizing optically pure alkenes, this mediod can be utilized to produce chiral ketones and alcohols as shown in Scheme 10. The intermediate sulfoximine (45) can either be reduced with Raney nickel to the chiral alcohol (46) or, because it is not stable to thermolysis, heated to revert back to the ketone (47). 

Transmetalations of allenylstannanes represent an important conceptual development, which substantially increases the potential utility of these reagents. i 4 Corey established an early example via the transmetalation of 3-triphenylstannyl-l-propyne with (/ ,f )-B-bromo-4,5-diphenyl-l,3-diaza-2-borolidine (R,R-22S) yielding the intermediate formation of allenylborane 334. Low temperature condensations of 334 with aldehydes occurred via closed transition states in which the chirality of the Stein auxiliary determined the stereogenicity of the enantioenriched -alcohol 335 (Scheme 5.2.70). ... 

The asymmetric reduction of raeso-epoxides with hydrogen or hydrides has been scarcely explored, despite the synthetic utility of the chiral secondary alcohol products. The lone example has been provided by Chan, who treated the disodium salt of epoxysuccinic acid with H2 or MeOH as the reducing agent in the presence of a chiral rhodium catalyst (Scheme 13) [27]. Deuterium labeling experiments established that the reduction proceeded through direct cleavage of the epoxide C-O bond, rather than isomerization to the ketone followed by carbonyl reduction. 

Aggarwal and Fang utilized the chiral sulfur ylide 212 to impart chirality on the allylborane 214 that underwent smooth allylboration with aldehydes to provide the corresponding homoallylic alcohol 215 (Scheme 25.33). ... 

Asymmetric hydrogenolysis of epoxides has received relatively little attention despite the utility such processes might hold for the preparation of chiral secondary alcohol products. Chan et al. showed that epoxysuccinate disodium salt was reduced by use of a rhodium norbornadiene catalyst in methanol/water at room temperature to give the corresponding secondary alcohol in 62% ee (Scheme 7.31) [58]. Reduction with D2 afforded a labeled product consistent with direct epoxide C-O bond cleavage and no isomerization to the ketone or enol before reduction. 

A reiterative application of a two-carbon elongation reaction of a chiral carbonyl compound (Homer-Emmonds reaction), reduction (DIBAL) of the obtained trans unsaturated ester, asymmetric epoxidation (SAE or MCPBA) of the resulting allylic alcohol, and then C-2 regioselective addition of a cuprate (Me2CuLi) to the corresponding chiral epoxy alcohol has been utilized for the construction of the polypropionate-derived chain ]R-CH(Me)CH(OH)CH(Me)-R ], present as a partial structure in important natural products such as polyether, ansamycin, or macro-lide antibiotics [52]. A seminal application of this procedure is offered by Kishi s synthesis of the C19-C26 polyketide-type aliphatic segment of rifamycin S, starting from aldehyde 105 (Scheme 8.29) [53]. 

In case of primary alcohol substrates, biooxidation can also proceed to the carboxylic acid, enabling a facile separation of the chiral products by simple extraction. Whole-cells of Gluconobacter oxydans were utilized to produce S-2-phenylpro-panoic acid and R-2-phenylpropionic alcohol in excellent yields and optical purities (Scheme 9.4) [46]. 

Various chiral derivatizing agents have been reported for the determination of enantiomer compositions. One example is determining the enantiomeric purity of alcohols using 31P NMR.28 As shown in Scheme 1-8, reagent 20 can be readily prepared and conveniently stored in tetrahydrofuran (THF) for long periods. This compound shows excellent activity toward primary, secondary, and tertiary alcohols. To evaluate the utility of compound 20 for determining enantiomer composition, some racemic alcohols were chosen and allowed to react with 20. The diastereomeric pairs of derivative 21 exhibit clear differences in their 31P NMR spectra, and the enantiomer composition of a compound can then be easily measured (Scheme 1-8). 

In a related report, ruthenium-catalyzed enantioselective hydrogenation of 3-keto esters was utilized to prepare the crucial alcohol intermediate 36 (Scheme 14.16). The required (3-keto ester 49 was readily prepared from commercial thiophene carboxylic acid 40. Hydrogenation of 49 then led to the desired (S)-alcohol 50 in quantitative yield and 90% enantiomeric excess, catalyzed by a chiral diphosphine-ruthenium complex generated in situ. Catalyst-substrate ratios used were as low as 1/20,000, rendering this approach amenable to industrial application. Alcohol 50 was then converted to known intermediate 36 in three steps and 60% overall yield. 

In this context, a chiral hydride reagent, BINAL-H, prepared by modification of lithium aluminum hydride with equimolar amounts of optically pure binaphthol and a simple alcohol, is extremely useful (9b, 18a, 35) Scheme 15 shows the utility of the three-component coupling synthesis. The < > side-chain unit and the hydroxycyclopentenone can be prepared with very high enantioselectivity by reduction of the corresponding enone precursors (35-38). 

Analogous to the use of chiral acetals one can employ chiral N,O-acetals, accessible from a, -unsatu-rated aldehydes and certain chiral amino alcohols, to prepare optically active -substituted aldehydes via subsequent Sn2 addition and hydrolysis. However, the situation is more complicated in this case, since the N,0-acetal center constitutes a new stereogenic center which has to be selectively established. The addition of organocopper compounds to a, -ethylenic oxazolidine derivatives prepared from unsaturated aldehydes and ephedrine was studied.70-78 The (diastereo) selectivities were rather low (<50% ee after hydrolysis) in most cases, the highest value being 80% ee in a single case.73 There is a strong solvent effect in these reactions, e.g. in the addition of lithium dimethylcuprate to the ( )-cinnamaldehyde-derived oxazolidine (70 Scheme 28) 73 the (fl)-aldehyde (71) is formed preferentially in polar solvents, while the (S)-enantiomer [ent-71) is the major product in nonpolar solvents like hexane. This approach was utilized in the preparation of citronellal (80% ee) from crotonaldehyde (40% overall yield).78... 

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