Chiral -cyano alcohols synthesis

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]. 

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. 

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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