Chiral -cyano alcohols

A direct enantioselective cross-aldol-type reaction of acetonitrile with an aldehyde (RCHO) has been reported, giving /3-cyano alcohol product, R-CH (OH)-CH2-CN, (7e) in up to 77% ee.148 CH3CN, acting as an acetate surrogate, is chemoselectively activated and deprotonated using a soft metal alkoxide (CuO-Bu1) in a strong donor solvent (HMPA), with a bulky chiral diphosphine as auxiliary. 

Enantiomerically pure lactonic pheromones 607-611, of the carpenter bee, blacktailed deer, Japanese beetle, rove beetle, and Oriental hornet, respectively, have been synthesized from racemic cyano alcohols of type 612. The key to the success of the overall approach is the facile separation of diastereomeric carbamates derived from cyano alcohols of type 612 by automated multigram LC. The chosen approach also facilitates the assignment of absolute configurations to the lactone enantiomers and their precursors. In the case of 607, direct determination of enantiomeric purity and absolute configuration is also possible using the chiral solvating agent 2,2,2-trifluoro-l-(9-anthryl)ethanol [439]. 

The mechanism of these reactions is usually Sn2 with inversion taking place at a chiral RX, though there is strong evidence that an SET mechanism is involved in certain cases, ° especially where the nucleophile is an a-nitro carbanion and/or the substrate contains a nitro or cyano group. Tertiary alkyl groups can be introduced by an SnI mechanism if the ZCH2Z compound (not the enolate ion) is treated with a tertiary carbocation generated in situ from an alcohol or alkyl halide and BF3 or AlCla, or with a tertiary alkyl perchlorate. ... 

The transformation of the cyano group could also introduce a new chiral center under diastereoselective control (Figure 5.13). Grignard-transimination-reduction sequences have been employed in a synthesis of heterocyclic analogues of ephedrine [81]. The preferential formation of erythro-/3-amino alcohols may be explained by preferential hydride attack on the less-hindered face of the intermediate imine [82], and hydrocyanation of the imine would also appear to proceed via the same type of transition state. In the case of a,/3-unsaturated systems, reduction- transimination-reduction may be followed by protection of the /3-amino alcohol to an oxazolidinone, ozonolysis with oxidative workup, and alkali hydrolysis to give a-hydroxy-/3-amino acids [83]. This method has been successfully employed in the synthesis L-threo-sphingosine [84]. 

Enantiomeric purity is often determined by derivatization with an optically pure chiral agent. For alcohols and amines, a-methoxy-a-trifluoromethylphenylacetic acid (MTPA) and a-cyano-a-fluoropheny lace tic acid (CFPA) [45] work well. 

The products can be converted into chiral cyanohydrins or a-hydroxy esters by oxidation and -elimination of the chiral side chain (equatjon 1). Alternatively, the cyano group can be reduced (BH,-THF) prior to oxidation and (i-elimination for a synthesis of ehiral 3-amino seeondary alcohols. 

Fenvalerate[(RS)-a-cyano-3-phenoxybenzyl (RS)-2-(4-chlorophenyl)iaovalerate] consists of four optical isomers due to the presence of two chiral carbons in the acid and alcohol moieties. Of the four isomers, one specific isomer ([2R,CXS]) was preferentially metabolized in mammals including rats and mice to a cholesterol ester which was formed by condensation of the acid moity with cholesterol. This conjugate does not seem to be produced via three known endogenous biosynthesis routes of cholesterol esters, but via transesterification mediated by microsomal... 

Thus reaction of the alcohol 2 with 1 leads to the two diastereomeric cyano-carbamates 3 formed as a 1 1 mixture. They are converted into the diastereomeric carbamates 4, which are separated by liquid chromatography on silica gel. The reaction of one carbamate (4a) with lithium di-n-octylcuprate affords the chiral allene 5. The final step to 6 involves introduction of the fronr-double bond. ... 

A. Chemical structure of fenvalerate denoting two asymmetric carbon atoms ( ) the 2C position of the acid moiety, and the aC position of the a-cyano-3-phenoxybenzyl alcohol moiety. These two chiral centers, at the 2C and aC positions, yield a mixture of four stereoisomers, in approximately equal amounts, but with greatly different biological properties. 

Compound 11 is, however, unexpectedly unreactive with Wittig-Horner reagents. Upon heating with the carbanion of ester phosphonates an addition across the allenic bond occurs [14]. In contrast, a slow normal 1,2-addition takes place [14] with the ylide from cyano-methylphosphonate but, unexpectedly, this proceeds with concomitant inversion at the chiral axis as shown in Scheme 3, to give a mixture of 6R or 6S, and (9E)- or (9Z)-isomers 12-15. However, a fast and very clean 1,2-addition occurs with the ethynyl ketone 18 to yield the esters 19 and 20 (Scheme 4). DIB AH reduction of the separated stereoisomers gives the allenic alcohols 21 and 22 in high yield. Mild oxidation to the aldehydes 23 and 24, followed by their condensation with the acetylenic Cio-bis-ylide 25, leads to the stereoisomeric 15,15 -didehydromimulaxanthins 26 and 28, respectively (Schemes 5 and 6). The optically active. 

A different conceptual approach to amino-alcohol preparation Involved use of chiral N,0-heterocycles as templates for enantiospecific syntheses of these compounds. Alkylations of the carbanion derived from 2-cyano-6-oxazolopiperidine (36) had been successfully applied to the synthesis of a number of alkaloids. 

Nevertheless, a more efficient approach is to attach an electron-accepting atom or radical directly to the chiral carbon atom. Chiral acids and alcohols containing chlorine at the chiral carbon atom can easily be produced from natural amino acids via the Sandmeyer reaction they are widely used in the synthesis of FLCPs [25,26,49,52-54]. A cyano group [55,56] or a perfluorinated alkyl chain [21,57] can also be attached to the chiral center. Lactic acid is a natural chiral product as well, and its derivatives are widely used as chiral terminal groups of FLCPs [27,58-61]. The search for new chiral structures with high transverse dipole moments for FLCPs has resulted in the successful application of heterocycles such as 1,3-dioxolanes [39,62] and oxiranes [63,64]. 

Ort/io-selectivity is generally observed in the reactions of 2,4-dichloro- and 2,4-difluoro-nitrobenzene with alkoxide and thiophenoxide ions [199]. Also in less activated systems, nucleophiles generated from phenols and thiophenols with potassium fluoride-alumina and 18-crown-6-polyether will react in DMSO with cyano- or nitro-substituted fluoro- or chloro-benzenes [200]. Interestingly, the reaction of difluorobenzenes with two diffoent alcohols can occur sequentially. Introduction of the first etho" function deactivates the ring, and use of more forcing conditions allows substitution of the second fluorine [201]. Consecutive displacements of fluorine and nitro groups have been observed in the reaction of ort/io-fluoronitrobenzene with chiral acyl bicyclic lactones in a highly enantioselective synthesis of spirooxindoles [202]. 

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