Desymmetrization of Diols

DKR of racemic alcohols using the different ruthenium complex in combination with lipases or subtilisin. 

TABLE 9.3 Desymmetrization of A/-Protected Serinols Using PPL and Vinyl Acetate 

Desymmetrization of 2-substi-tuted propane-1,3-diols through acetylation reactions using vinyl acetate and a lipase. 

Finally, it is worthy mentioning other families of diols that are less known but have also been selectively desymmetrized using lipase acylation protocols. Hammel and Deska reported the acetylation of prochiral tetrasubstituted allenic diols, )deld-ing highly enantioenriched axially chiral allenyl monoesters (68-99% ee) with good yields (59-90%), after their reaction with five equivalents of vinyl butanoate in 1,4-diox-ane at 40 °C using PPL as biocatalyst [158]. Other prochiral diols bearing a heteroatom such as boron [159] or sulfur [160], have also been studied, leading usually to modest yields or selectivities. 

4 Selected Examples of Acylation Reaction with Interest for the Pharmaceutical Industry 

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Oiganocatalyzed enantioselective desymmetrization of diols in the preparation of chiral building blocks 12CEJ13920. 

Kinetic resolution of secondary alcohols and desymmetrization of diols were reported by asymmetric oxidation using chiral (nitrosyl)Ru(salen) chloride (31) (Eq. (7.42)) [97] in addition to the aerobic oxidation reaction [97d]. 

Cycloadduct 47 was readily transformed into diol 48 by standard chemistry. Enzymatic desymmetrization of diol 48 with crude Amano PS-30 gave monoacetate 49 in 76% yield and 85% ee (Scheme 19.19). Silylation of 49 followed by... 

Subsequent to the development of the (salen)Cr-catalyzed desymmetrization of meso-epoxides with azide (Scheme 7.3), Jacobsen discovered that the analogous (salen)Co(n) complex 6 promoted the enantioselective addition of benzoic acids to meso-epoxides to afford valuable monoprotected C2-symmetric diols (Scheme 7.15) [26], Under the reaction conditions, complex 6 served as a precatalyst for the (salen) Co(iii)-OBz complex, which was fonned in situ by aerobic oxidation. While the enantioselectivity was moderate for certain substrates, the high crystallinity of the products allowed access to enantiopure materials by simple recrystallization. 

Enzymatic desymmetrization of prochiral or meso-alcohols to yield enantiopure building blocks is a powerful tool in the synthesis of natural products. For example, a synthesis ofconagenin, an immunomodulator isolated from a Streptomyces, involved two enzymatic desymmetrizations [149]. The syn-syn triad of the add moiety was prepared via a stereoselective acylation of a meso-diol, whereas the amine fragment was obtained by the PLE-catalyzed hydrolysis of a prochiral malonate (Figure 6.56). 

Various biocatalytic options have been presented for the desymmetrization of meso-diols to chiral hydroxyl-ketones. A particularly facile system is represented by... 

Also, desymmetrization of prochiral hydroxyalkylphosphine P-boranes was successfully performed using similar reagents and conditions. In the case of bis(hydroxymethyl)phenylphosphine P-borane 87, both its acetylation and hydrolysis of the diacetyl derivative 89 gave good results, although in addition to the expected monoacetate 88, the diol 87 and diacetate 89 were always present in the reaction mixture (Equation 42). °°... 

The catalytic enantioselective desymmetrization of meso compounds is a powerful tool for the construction of enantiomerically enriched functionalized products." Meso cyclic allylic diol derivatives are challenging substrates for the asymmetric allylic substitution reaction owing to the potential competition of several reaction pathways. In particular, S 2 and 5n2 substitutions can occur, and both with either retention or inversion of the stereochemistry. In the... 

Trost and co-workers have explored asymmetric transition metal-catalyzed allylic alkylations. Details on this subject have been well reviewed by Trost and others.90 With the use of asymmetric palladium-catalyzed desymmetrization of meso-2-ene-l,4-diols, cw-l,4-dibenzoy-loxy-2-cyclopentene can be converted to the enantiometrically pure cA-4-tert-butoxycar-bamoyl-l-methoxycarbonyl-2-cyclopentene.91 The product is a useful and general building block for synthesis of carbocyclic analogs of nucleosides as presented in Scheme 5.12. 

The new heterocyclic derivative 130 has been shown to be an efficient chiral auxilliary for asymmetric desymmetrization of cyclic meso-l,2-diols via diastereoselective acetal cleavage . 

The 6,8-dioxabicyclo[3.2.1]octane skeleton has been a common structural subunit in natural products. A conceptually new strategy affording these structures is described by Burk et al. [Eqs. (6.67) and (6.68)]. For the syntheses of (+)-exo-brevicomin, they used desymmetrization of triene 97, derived from diol 96 with C2 symmetry, via ring-closing metathesis. Enantiomerically enriched (- -)-ent/o-brevicomm... 

In addition, new some epoxide hydrolases have also shown a great utility for the desymmetrization of meso-epoxides. An interesting example is the synthesis of nelfinavir-the active pharmaceutical ingredient (API) of the anti-human immunodeficiency virus drug Viracept-where the (R,R)-diol obtained by opening the meso-epoxide is a suitable starting material. Scheme 10.6 shows a synthetic route to nehinavir [14]. 

The ligand, (5)-6,6 -[oxybis(ethylene)dioxy]biphenyl-2,2 -diol (1), is prepared in three steps from readily available 2,2, 6,6 -tetrahydroxybiphenyl (4). The steps involved are firstly asymmetric desymmetrization of secondly bridging of the 6,6 -position by diethylene ether, and finally selective deprotection of the propane diol to afford 1 (Figure 6.12). 

Desymmetrization of some phosphorus derivatives has been achieved (Scheme 4.15). Thus, the monoacetate 21 can be obtained from the corresponding diol by PFL-catalyzed acylation with vinyl acetate in chloroform [60]. The monoacetate 22 can be obtained from the corresponding bis(hydroxymethyl)phenylphosphine borane by acylation of the latter in vinyl acetate mediated by CALB [61]. 

Hydrolase-catalyzed desymmetrizations of meso-diols have also been exploited (Scheme 4.16). Thus, the monoacetate 23 is produced in excellent yield and by acylation with vinyl acetate of the corresponding meso-diol catalyzed by CRL in hexane [62]. In a similar way the monoacetate 24 is produced from the meso-tetrol by acylation in vinyl acetate catalyzed by PPL [63]. The meso-piperidine derivative... 

Scheme 4.33 Some examples of products obtained by hydrolase-catalyzed desymmetrizations of meso-diols (products shown).

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