Enantioselective enzymatic desymmetrization

Enantioselective enzymatic desymmetrization is the transformation of a substrate that results in the loss of a symmetry element that precludes chirality (plane of... 

Garcia-Urdiales, E., Alfonso, I. and Gotor, V., Enantioselective enzymatic desymmetrizations in organic synthesis. Chem. Rev., 2005, 105, 313-354. 

Podophyllotoxin, a plant lignan, is a potent antimitotic agent (Figure 6.61). An enantioselective synthesis of (—)-podophyllotoxin was achieved via the enzymatic desymmetrization of an advanced meso-diacetate, through PPL-mediated diester hydrolysis [157]. 

The purpose of this review is to cover catalytic enantioselective desymmetriza-tions that have appeared in the literamre from early 1999 to mid-2004. Stoichiometric desymmetrizations will not be considered. Enzymatic desymmetrizations will also not be considered, largely because this method is firmly engrained as a powerful technique and the bulk of the work in this area in recent years has centered on applications of the method to specific substrates rather than developmental advances. This review will also attempt to focus on method development rather than application to synthesis. This field has recently been reviewed, and the purpose of this manuscript is to complement the previous treatises of this subject. 

With the same protocol, a heterocyclic dibenzoate 86 derived from furan in one step has been efficiently desymmetrized to provide facile entry to either D or L nucleosides (see Scheme 8E.10). As depicted in Scheme 8E.10, the catalyst derived from ligand 71 gave rise to high enantioselectivities in the alkylation with both a purine 83 and a pyrimidine 87 [62], Subsequent allylic alkylations with an achiral ligand introduced the tartronate and aminomalonate moieties to furnish enantiomerically pure Ci s-2,5-disubstituted-2,5-dihydrofurans 89 and 91, respectively. Only six steps from furan were required to synthesize the alio and talo isomers of the nucleoside skeleton of the polyoxin-nikkomycin complexes. It should be noted that the corresponding enzymatic desymmetrization of substrate 86 is impossible because the product is labile. 

Chenevert, R. Desjardins, M. Enzymatic desymmetrization of meso-2,6-dimethyl-l,7-heptanediol. Enantioselective formal synthesis of the vitamin E side chain and the insect pheromone tribolure. /. Org. Chem. 1996, 62, 1219-1222. 

This collection begins with a series of three procedures illustrating important new methods for preparation of enantiomerically pure substances via asymmetric catalysis. The preparation of 3-[(1S)-1,2-DIHYDROXYETHYL]-1,5-DIHYDRO-3H-2.4-BENZODIOXEPINE describes, in detail, the use of dihydroquinidine 9-0-(9 -phenanthryl) ether as a chiral ligand in the asymmetric dihydroxylation reaction which is broadly applicable for the preparation of chiral dlols from monosubstituted olefins. The product, an acetal of (S)-glyceralcfehyde, is itself a potentially valuable synthetic intermediate. The assembly of a chiral rhodium catalyst from methyl 2-pyrrolidone 5(R)-carboxylate and its use in the intramolecular asymmetric cyclopropanation of an allyl diazoacetate is illustrated in the preparation of (1R.5S)-()-6,6-DIMETHYL-3-OXABICYCLO[3.1. OJHEXAN-2-ONE. Another important general method for asymmetric synthesis involves the desymmetrization of bifunctional meso compounds as is described for the enantioselective enzymatic hydrolysis of cis-3,5-diacetoxycyclopentene to (1R,4S)-(+)-4-HYDROXY-2-CYCLOPENTENYL ACETATE. This intermediate is especially valuable as a precursor of both antipodes (4R) (+)- and (4S)-(-)-tert-BUTYLDIMETHYLSILOXY-2-CYCLOPENTEN-1-ONE, important intermediates in the synthesis of enantiomerically pure prostanoid derivatives and other classes of natural substances, whose preparation is detailed in accompanying procedures. 

The de novo enantioselective synthesis of the hexoses stands as a challenge to asymmetric catalysis (5). Despite some germinal efforts toward the hexoses, notably by Masamune/Sharpless (epoxidation) (2), Danishefsky (Diels-Alder) (d), Johnson/Hudlicky (enzymatic desymmetrization) 4) and Wong/Sharpless (osmium/enzyme) (7), there still does not exist a practical, non-enzymatic route to all the hexoses. More recently this challenge has also been taken up by MacMillan (iterative aldol strategy) (5) and White (allylic oxidation) (P). 

Excellent enantioselectivities are observed in the alkylation of various gem-dicarboxylates with both carbon and heteroatom nucleophiles as summarized in Table 8E.2 [71]. Screening various chiral ligands from the DPPBA module revealed that 1,2-diaminocyclohexane derived ligand 5 gives the best results, and the mnemonic of Figure 8E.8 correctly predicts the enantiomer obtained in this reaction. Notably, the corresponding desymmetrization by enzymatic hydrolysis or acylation is not feasible with these 1,1-diol derivatives. 

Enantioselective Intramolecular Cyclization (Sn2 reaction). The desymmetric transformation of meso-structures has been recognized as a versatile synthetic method for optically active compounds in organic enzymatic processes. The enantioselective intramolecular cyclization of the bis-phenyllithium species, which is generated by addition of butyllithium to a solution of cis-3,5-di(bromophenoxy)cyclopentene, has been attained by addition of lithium salt (1.2 equiv) of (/ )-BINOL-Me to produce a cyclopenta[fc]benzofuran with 87% ee (eq 18). ... 

Scheme 9 Enzyme-mediated chemical transformations. (A) Enatioselective enzymatic oxidation and lactonization (B) enzyme reduction with baker s yeast and enantioselective rule and (C) enzymatic hydrolytic desymmetrization.

A dynamic kinetic resolution extends the high yield advantage of desymmeUiza-tions to racemic substrates. A dynamic kinetic resolution is a kinetic resolution combined with rapid in situ racemization of the substrate. The requirements for a dynamic kinetic resolution are (1) the substrate must racemize at least as fast as the subsequent enzymatic reaction, (2) the product must not racemize, and (3) as in any asymmetric synthesis, the enzymic reaction must be highly stereoselective. The equations relating product enantiomeric purity and enantioselectivity are the same as those for desymmetrizations. 

The (R,/J)-Ph-DBFOX/Zn(OAc)2 combination is an effective catalyst to give optically pure 2-fluorinated malonates in a process similar to desymmetrization (Scheme 44.21). Although the malonates are nearly symmetrical and less acidic, the enantioselectivities observed in the desymmetrization-like fluorination reaction are high and superior to the corresponding enzymatic methods. This synthetically useful method was applied to the synthesis of pharmaceutically attractive molecules that include a-ben-zyl- 3-alanine, fiuorinated -lactams, fiuoro-alacepril, and a HIV-1 protease inhibitor. ... 

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