Diols, desymmetrization prochiral

In contrast to the resolution of secondary alcohols, where the more simple Upase technology is recommended instead of redox reactions, desymmetrization of primary diols of prochiral or meso-structure has been shown to be a valuable method for the synthesis of chiral lactones (Scheme 2.143) [1034]. 

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). 

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). °°... 

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.

This chapter covers the kinetic resolution of racemic alcohols by formation of esters and the kinetic resolution of racemic amines by formation of amides [1]. The desymmetrization of meso diols is discussed in Section 13.3. The acyl donors employed are usually either acid chlorides or acid anhydrides. In principle, acylation reactions of this type are equally suitable for resolving or desymmetrizing the acyl donor (e.g. a meso-anhydride or a prochiral ketene). Transformations of the latter type are discussed in Section 13.1, Desymmetrization and Kinetic Resolution of Cyclic Anhydrides, and Section 13.2, Additions to Prochiral Ketenes. 

Additions to prochiral ketenes [13.2] Desymmetrization of meso-diols [13.3] Desymmetrization of meso-epoxides [13.4]... 

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...

The proper stereochemistry was achieved by enzyme catalyzed desymmetrization of the prochiral 1,3-diol 30. Candida antarctica lipase (CAL)-catalyzed transesterification yielded the monoacetate 31, which gave rise to the methyl with the proper stereochemistry 32. The generation of the desired chiral epoxide 35 was achieved by asymmetric dihydroxylation employing AD-mix-a,42 followed by epoxide formation. Base-catalyzed etherification yielded the mixture of the enantiopure (+)-heliannuol A and (-)-heliannuol D. Unfortunately these compounds correspond to the opposite d/l series and correspond to the enantiomers of the natural products (-)-heliannuol A and (+)-heliannuol D (Fig. 5.6.A). 

Enzymatic resolution has been successfully applied to the preparation of optically active gem-difluorocyclopropanes (see Scheme 12.4). We succeeded in the first optical resolution of racemic gm-difluorocyclopropane diacetate, trans-43, through lipase-catalyzed enantiomer-specific hydrolysis to give (R,R)-(-)-44 with >99% ee (see equation 9, Scheme 12.4) [4a], We also applied lipase-catalyzed optical resolution to an efficient preparation of monoacetate cw-46 from prochiral diacetate m-45 (see equation 10, Scheme 12.4) [4a], Kirihara et al. reported the successful desymmetrization of diacetate 47 by lipase-catalyzed enantiomer-selective hydrolysis to afford monoacetate (R)-48, which was further transformed to enantiopure amino acid 15 (see equation 11, Scheme 12.4) [19]. We demonstrated that the lipase-catalyzed enantiomer-specific hydrolysis was useful for bis-gem-difluorocyclopropane 49. Thus, optically pure diacetate (R,S,S,R)-49 and (S,R,R,S)-diol 50, were obtained in good yields, while meso-49 was converted to the single monoacetate enantiomer (R,S,R,S)-51 via efficient desymmetrization (see equation 12, Scheme 12.4) [4b, 4e], Since these mono- and bis-gm-difluorocyclopropanes have two hydroxymethyl groups to modify, a variety of compounds can be prepared using them as building blocks [4, 22],... 

In this chapter, we attempt to review the current state of the art in the applications of cinchona alkaloids and their derivatives as chiral organocatalysts in these research fields. In the first section, the results obtained using the cinchona-catalyzed desymmetrization of different types of weso-compounds, such as weso-cyclic anhydrides, meso-diols, meso-endoperoxides, weso-phospholene derivatives, and prochiral ketones, as depicted in Scheme 11.1, are reviewed. Then, the cinchona-catalyzed (dynamic) kinetic resolution of racemic anhydrides, azlactones and sulfinyl chlorides affording enantioenriched a-hydroxy esters, and N-protected a-amino esters and sulftnates, respectively, is discussed (Schemes 11.2 and 11.3). 

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... 

Chiral ligand 651 is obtained from the appropriate natural amino-acid phenylalanine, whereas the corresponding derivatives of valine or leucine proved to be slightly less effective [46], Axially prochiral, enantiotopic, biaryl-2,6-diols have been converted to the respective chiral compounds via enzymatic desymmetrization. Thus Pseudomonas cepacia lipase (PCL) catalysed the atropisomerically-selective hydrolysis of diacetate 654 to give monoacetate 655 in 67% yield and 96% e. e. [47], Scheme 24. 

The introduction of a phosphate moiety into a polyhydroxy compound by classic chemical methods is tedious since it usually requires a number of protection and deprotection steps. Furthermore, oligophosphate esters as undesired byproducts arising from overphosphorylation are a common problem. Employing enzymes for the regioselective formation of phosphate esters can eliminate many of these disadvantages thus making these syntheses more efficient. Additionally, enantioselective transformations are also possible involving the desymmetrization of prochiral or weso-diols or the resolution of racemates. 

As a rule of thumb, oxidation of the (S)- or pro-(S ) hydroxyl group occurs selectively with HLADH (Scheme 2.143). In the case of 1,4- and 1,5-diols, the intermediate y- and 8-hydroxyaldehydes spontaneously cyclize to form the more stable five- and six-membered hemiacetals (lactols). The latter are further oxidized in a subsequent step by HLADH to form y- or 5-lactones following the same (S)-or pro-(5) specificity [1035]. Both steps - desymmetrization of the prochiral or meso-diol and kinetic resolution of the intermediate lactol - are often highly selective. By using this technique, enantiopure lactones were derived from... 

First hints on the stereoselectivity of halohydrin dehalogenases were obtained from studies on the desymmetrization of prochiral 1,3-dichloropropan-2-ol yielding epichlorohydrin using resting cells of Corynebacterium sp. (Scheme 2.235) [1836]. In two-step sequence, (/ )-3-chloropropane-l,2-diol was formed in 74% e.e. via epichlorohydrin through the sequential action of an (unspecified) halohydrin de-halogenase and an epoxide hydrolase [1837]. Further studies revealed that these activities are widespread among bacteria [1838-1842]. 

Desymmetrization of Prochiral and wieso-Diols. Chiral 1,3-propanediol derivatives are useful building blocks for the preparation of enantiomerically pure bioactive compounds such as phospholipids [176], platelet activating factor (PAF), PAF-antagonists [177], and renin inhibitors [178]. A simple access to these syn-thons starts from 2-substituted 1,3-propanediols (Scheme 3.8). Depending on the substituent R in position 2, (/ )- or (5)-monoesters were obtained in excellent optical purities using Pseudomonas sp. lipase (PSL) [179-182]. The last three entries demonstrate an enhancement in selectivity upon lowering the reaction temperature [183]. 

On the basis of their previous work utilizing oligopeptides containing alkylimidazoles in asymmetric acylation reactions. Miller has reported the successful desymmetrization of bisphenol 171. Treatment of diol 171 with peptide 172 (5 mol%) and acetic anhydride gave ester 173 in 80% yield and 95% ee. This unprecedented desymmetrization represents a particularly challenging and impressive case as the desired site of functionalization is >5.7 A from the prochiral stereogenic center of the substrate (Scheme 29). ... 

Hydrolases and mainly lipases have appeared as valuable biocatalysts for the development of asymmetric transformations. Several strategies have been carried out involving the classical KR and DKR of racemic alcohols and the desymmetrization of meso- and prochiral diols. Taking into account the reversibility of this type of process in complementary hydrolysis pathway and adequate conditions must be established to favor synthetic acylation reactions. 

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. 

Lipase-catalyzed desymmetrization of prochiral diol intermediates forthe synthesis of antifungal and antitumor antibiotics. 

This chapter illustrates the application of lipases and esterases as user-friendly biocatalysts in (i) desymmetrization of prochiral or meso-diols and diacetates, (ii) kinetic resolution of racemic alcohols, and (iii) preparation of enantiopure intermediate(s) from a mixture of stereoisomers by enzymatic differentiation. All the examples were taken from our own works in natural products synthesis. 

The most important technical applications of catalytic hydrolysis and acylation involve technical enzymes, as used in food processing, washing powders, or derace-misations. Especially the latter application has also found significant application in chemical synthesis. The kinetic resolution of chiral, racemic esters, anhydrides, or alcohols relies on the faster conversion of only one substrate enantiomer by the chiral catalyst, whereas the other enantiomer ideally remains unchanged. A special case within kinetic resolutions is the desymmetrization of prochiral mexo-compounds like mera-anhydrides (2) or meso-diols, (5) that requires a selective conversion of one of the two enantiotopic functional groups (carbonyl or OH-group, Scheme 7.1). 

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