Prochiral diols

Mono cylDiols. Enzymatic synthesis of chiral monoacyl diols can be carried out either by direct enzymatic acylation of prochiral diols or by hydrolysis of chemically synthesized dicarboxylates. 

In contrast to the hydrolysis of prochiral esters performed in aqueous solutions, the enzymatic acylation of prochiral diols is usually carried out in an inert organic solvent such as hexane, ether, toluene, or ethyl acetate. In order to increase the reaction rate and the degree of conversion, activated esters such as vinyl carboxylates are often used as acylating agents. The vinyl alcohol formed as a result of transesterification tautomerizes to acetaldehyde, making the reaction practically irreversible. The presence of a bulky substituent in the 2-position helps the enzyme to discriminate between enantiotopic faces as a result the enzymatic acylation of prochiral 2-benzoxy-l,3-propanediol (34) proceeds with excellent selectivity (ee > 96%) (49). In the case of the 2-methyl substituted diol (33) the selectivity is only moderate (50). 

Chiral Alcohols and Lactones. HLAT) has been widely used for stereoselective oxidations of a variety of prochiral diols to lactones on a preparative scale. In most cases pro-(3) hydroxyl is oxidized irrespective of the substituents. The method is apphcable among others to tit-1,2-bis(hydroxymethyl) derivatives of cyclopropane, cyclobutane, cyclohexane, and cyclohexene. Resulting y-lactones are isolated in 68—90% yields and of 100% (164,165). 

The synthetic problem has now been substantially simplified. Retrosynthetic cleavage of the indicated carbon-carbon bond in 24 provides aldehyde 25 as a potential precursor. A simple carbonyl addition reaction could bring about the conversion of the latter substance to the former. Compound 25 could, in turn, be fashioned in a few straightforward steps from prochiral diol 26. 

The synthesis of the right-wing sector, compound 4, commences with the prochiral diol 26 (see Scheme 4). The latter substance is known and can be conveniently prepared in two steps from diethyl malonate via C-allylation, followed by reduction of the two ethoxy-carbonyl functions. Exposure of 26 to benzaldehyde and a catalytic amount of camphorsulfonic acid (CSA) under dehydrating conditions accomplishes the simultaneous protection of both hydroxyl groups in the form of a benzylidene acetal (see intermediate 32, Scheme 4). Interestingly, when benzylidene acetal 32 is treated with lithium aluminum hydride and aluminum trichloride (1 4) in ether at 25 °C, a Lewis acid induced reduction takes place to give... 

By performing the desymmetrization on a prochiral diol, a far more efficient asymmetric biocatalytic route was subsequently developed. Enzyme screening found that... 

Scheme 4.14 Hydrolase-catalyzed desymmetrization products obtained from the corresponding prochiral diols.

Scheme 4.15 Desymmetrization products of some phosphorus containing prochiral diols.

Prochiral diols -enzymatic acylation [ENZYMES IN ORGANIC SYNTHESIS] (Vol 9)... 

An efficient synthesis of (R)- and (S)-1 -amino-2,2-difluorocycloropanecarboxylic acid (DFACC) 91 via lipase-catalyzed desymmetrization of prochiral diols 89 and prochiral diacetates 92 was recently reported.28 Thus, the lipase-catalyzed transesterification of 89 using vinyl acetate as acyl donor in benzene di-z-propyl ether (20 1) as organic solvent... 

Figure 46 Lipase-catalyzed desymmetrization of prochiral diols 89 and diacetates 92.28...

Dodds and colleagues at Schering-Plough described the acylation of a prochiral diol 38 on the synthetic route to a potential antifungal drug, SCH 51048 (39) (Scheme 19.22). Numerous commercial... 

Asymmetrization of Prochiral Diol Double-Step Process... 

A prochiral diol can be converted into enantiomeric compounds as shown by the example in Scheme 7.5. Catalyzed by a hydrolytic enzyme like a lipase, it can be enantioselectively acetylated by vinyl acetate in organic solvent to yield a mixture of monoacetates. The chiral monoacetates will be formed at unequal rates and also react further at unequal rates. It is usually anticipated that if kj > k2, then k4 > ky and, moreover, that the ratio ki/ki is constant throughout the reaction [4c],... 

Asymmetrization of prochiral diols by esterification also shows anomalous behavior. More experiments have to be carried out before final conclusions can be drawn. 

Prochiral Compounds. The enantiodifferentiation of prochi-ral compounds by lipase-catalyzed hydrolysis and transesterification reactions is fairly common, with prochiral 1,3-diols most frequently employed as substrates. Recent reports of asymmetric hydrolysis include diesters of 2-substituted 1,3-propanediols and 2-0-protected glycerol derivatives. The asymmetric transesterification of prochiral diols such as 2-0-benzylglycerol and various other 2-substituted 1,3-propanediol derivatives is also fairly common, most frequently with Vinyl Acetate as an irreversible acyl transfer agent. 

Asymmetric lactonization of prochiral diols has been performed vsdth chiral phosphine complex catalysts (Ru2Cl4((-)-DIOP)3 and [RuCl((S)-BINAP)(QH6)]Cl [17, 18]. Kinetic resolution of racemic secondary alcohol was also carried out with chiral ruthenium complexes 7 and 8 in the presence of a hydrogen acceptor, and optically active secondary alcohols were obtained with >99% e.e. (Eqs. 3.7 and 3.8) [19, 20]. 

Another advantageous use of hydrolytic enzymes consists in the enantioselec-tive hydrolysis of prochiral substrates, making use of the ability of these biocatalysts to discriminate between enantiotopic groups. An elegant way to obtain both enantiomers (/ )-7 and (5)-7 from the prochiral diol 6 is the combination of porcine pancreatic lipase (PPL)-mediated hydrolysis and esterification as shown in Scheme 3 [26]. 

A simpler approach gave even better results. The prochiral diol 213 was cleanly monoacetylated by the same enzyme (98% yield, 98% ee) and iodo-etherification gave the required diastereoselectivity 215 with suitable functionality for the introduction both of the triazole and of the other side chain.57... 

Chiral monoesters, obtained either from a prochiral diol or diester, may be converted by a suitable series of chemoselective transformation to either enantiomer of a given target compound (enantiodivergent synthesis) (Scheme 11.1-13)110 40l... 

Oxidation of Meso Diols. Asymmetric induction of meso and prochiral diols by lipases is very successful in the field of organic synthesis. Also it is well known that selective oxidation of prochiral or meso diols by HLADH provides oxidized products with a significant degree of enantioselectivity. However, it has not been reported that alcohol oxidases were applied to such types of oxidation. The microbial oxidation of meso diols by Candida boidinii SA051 was carried out and gave optically active hydroxy ketones (Figure 8). 

Oxidation of Prochiral Diol. The oxidation of prochiral diol 3-methyl-1,5-pentanediol did not give the corresponding -hydroxy aldehyde but gave the corresponding lactol at 22% yield. To determine stereochemistry of the lactol, this was chemically oxidized by Ag20 and afforded 3-(R)-methyl-pentan-l,5-olide at 38% optical purity. (Figure 9). This was determined by comparison of optical rotation with a reference (70). 

Alcohol dehydrogenases alcohols, including prochiral diols... 

Recently in 2005, we synthesized 10 g of (+)-endo-brevicomin, the minor component of the pheromone of the male southern pine beetle, Dmdroctonus frontalis [22-24]. We used lipase AK in this synthesis to desymmetrize the prochiral diol. Dr. B. T. Sullivan at the U.S. Forest Service is currently studying the practicality of the pheromone traps with a mixture of (+)-endo-brevicomin, frontaKn and a-pinene. 

Desymmetrization of the prochiral diol 283 was attained, using vinyl acetate as an acetylating agent and several lipases (CAL, AK, AH, PS, LPL, PFL), of which only Pseudomonas fluorescens lipase proved efficient. It was found that the use of various solvents led to opposite enantiomers of the product 284 and substantially influenced the stereoselectivity of the process. For example, the replacement of chloroform by isopropyl ether led to the formation of the optical antipode of 284 [175, 176]. Wiktelius [177] reported that the Candida antarctica lipase B (Novozym 435) afforded better results in the desymmetrization of prochiral... 

Isolated enzymes can also be used to catalyse selective oxidation reactions. For, example, galactose oxidase oxidizes xylitol into (L)-xylose (Scheme 4.15), while HLAD catalyses the stereoselective oxidation of prochiral diols of the type (12) to give, initially, a chiral hydroxyaldehyde... 

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