Enantioconvergent synthesis

Paedragosa-Moreau, S., Morisseau, C., Baratti, J., Zylber, J., Archelas, A., and Furstoss, R. 1997. Microbiological transformations. 37. An enantioconvergent synthesis of the (l-blocker (R)-Nifenalol using a combined chemoenzymic approach. Tetrahedron, 53(28), 9707-9714. 

Kellogg, R. M. Enantioconvergent synthesis by sequential asymmetric Horner-Wadsworth-Emmons and palladium-catalyzed allylic substitution reactions. Chemtracts 2002, 15, 69-73. 

The Windaus Grundman Cjy ketone (21), a key intermediate in the synthesis of vitamin D2, has been prepared by an enantioconvergent synthesis via propyny] Grignard addition to aldehyde 18, separation of the isomers, hydrogenation and ortho ester rearrangement390. 

The concept of enantioconvergent synthesis has heretofore been virtually restricted to cases in which the chiral center is directly epimerizable such as in a-amino acids. In an alternative view, the separate transformation of two enantiomers via stereochemical 1y complementary pathways into a single enantiomeric series represents a case of enantioconvergence.(D For example, conversion of the enantiomeric alcohols la and lb to Ic via the Z and olefins respectively converge to the same enantiomer of the product derived via a Claisen ortho ester rearrangement (equation 1). (, 3)... 

An alternative conceptual approach to enantioconvergent synthesis involves intermediates whose enantiomers may be readily interconverted by simple chemical reactions. Compound 2 potentially represents such a species since it can be reasoned that a... 

Synthesis from a-mannitol An enantioconvergent synthesis of (-)-anisomycin... 

An enantioconvergent synthesis [64] of (-)-anisomycin (1) has been established starting from both (lt)-(126) and (S)-(134) enantiomers of epichloro-hydrin [65] that could be obtained from o-mannitol (Schemes 15 and 16). The (K)-epichlorohydrin (126) was first transformed to (K)-O-benzylglycidol (128) in 60% overall yield by treatment with benzyl alcohol in the presence... 

The ploy of ring expanding a stereospecifically formed cyclobutane to a cyclopentanone has been put to good use in a preparation of ( )-bakkenolide-A,in an enantioconvergent synthesis of... 

Enantioconvergent synthesis of the p-blocker (/ )-nifenalol using a combined chemoenzymatic approach. 

Mai DN, Rosen B-R, Wolfe JR Enantioconvergent synthesis of (-f)-aphanorphine via asymmetric Pd-catalyzed alkene carho-amination. Org. Lett. 2011 13(11) 2932-2935. 

The enantioconvergent biohydrolysis of sterically demanding trisubstituted oxiranes has also been reported [189,190]. For instance, the enantioconvergent hydrolysis of a trisubstituted rac-epoxide (Figure 6.70) was a key step in the chemoenzymatic synthesis of a volatile constituent of the beer aroma [190]. 

Sordaricin 2 is the aglycone of sordarin 3, the parent of a family of clinically-effective antifungal agents. Lewis N. Manderof the Australian National University has published (./. Org. Chern. 2005, 70, 1654) a full account of their enantioconvergent (see below) synthesis of 2, based on the intramolecular Diels-Alder cyclization of the triene 1. For a complementary total synthesis by Narasaka of sordaricin 2, see Org. Chem. Highlights 2005, April 4. 

Chiral synthesis of a prostanoid.Trost etal. have devised an enantioconvergent prostanoid synthesis from 1, in which a 1,3-hydroxy shift interconverts the two enantiomers. The interconversion was possible by equilibration of the urethane of 1 with (S)-l-o -naphthylethylamine catalyzed with mercury(II) trifluoroacetate (7, 382). At equilibrium the ratio of 2a/2b is about 1 3. By separation and repeated... 

In the steroid series, an enantioconvergent reaction sequence has been used for the synthesis of model steroids 7 and 8 in order to elucidate the absolute C-24 configuration of naturally occurring ooginols 14391. 

Despite e fascination of asymmetric synthesis, separation methods for enantiomers even today compete, often successfully, with direct synthetic routes. Thus it is appropriate that the topic of separation was included in the seminar. Chapter 18 is concerned with this topic, as was a paper presented by D. J. Cram on host-guest complexation [J. Am. Chem. Soc., 103, 3929 (1981) J. Org. Chem., 46, 393 (1981) and J. Chem. Soc., Chem. Comm., 625 (1981)]. Substantial parts of Chapters 1 and 10 also deal with the role of resolution and separation methods in the synthesis of chiral compounds, including enantioconvergent syntheses. 

Use ofenamine or iminium electrophiles. In their synthesis of spirotryprostatin B (133), Fuji and co-workers started from rac-3-prenyl-2-oxindole (149) with an interesting enantioconvergent nitroolefination affording the C3-quatemised product 151 ee 78%, Scheme 30). The proline-derived nitroenamine 150 was used with the pyrrolidine section functioning as auxiliary [135, 136]. 

Scheme 30 Enantioconvergent step of Fuji s synthesis of spirotryprostatin B (133) [135]...

There is the possibility to combine several KR reactions and to approach the theoretical maximum values of 50% recovery and 100% ee for one of the enantiomers. This can be achieved after isolation of the components of a first KR [30]. Consecutive KRs will also enhance the enantiomeric excess [31]. The amount of recovered material will decrease. KR has been used to increase the enantiomeric excess of an aheady enantioenriched material (obtained by KR or asymmetric synthesis). The conversion extent needed for going from 90% to 95% ee, for example, for a given s value, has been calculated for pseudo-first-order reactions [23]. Enantioconvergent reactions (see below. Section 2.5) is a rare but convenient way to optimize a KR from a racemic mixture where the enantiomers are susceptible to interconversion. 

Both procedures have their special merits in the total synthesis of natural products or of chiral biologically active compounds. A very simple and straightforward example of enantioconvergency was reported from the cyclopentenone field. 

Another example of an enantioconvergent transformation of racemic epoxides was reported by Faber and coworkers who employed a chemoenzymatic approach for the synthesis of optically enriched diols. They used an (S)-selective epoxide hydrolase from Nocardia sp. in connection with an add catalyzed hydrolytic step to convergently prepare (S)-diols 41 in good to excellent yields (71-98%) with enantiomeric excess values up to 99% (Scheme 9.13) [75]. 

Enantioconvergent biohydrolytic transformation of paraoxide using a bienzymatic process. The sequential use of Solanum tuberosum and Aspergillus niger EHs as biocatalysts led to the formation of enantiopure (/ )-para-chlorophenyl-1,2-diol, a chiral building block for the synthesis of (/ )-eliprodil. 

Preparative-scale resolution of rac-4-isobutyl- -methylstyrene oxide using an enzymatic extract of Aspergillus niger LCP 521. A four-step enantioconvergent procedure enabled the synthesis of (S)-ibuprofen. 

Chemoenzymatic asymmetric total synthesis of (S)-7,7-dimethyl -6,8-dioxabicyclo [3.2.1]octane, which is a volatile contributor to the aroma of beer, was also accomplished using lyophilized cells of R. ruber DSM 44540 in an enantioconvergent enz5miatic step. Inversion at the stereogenic center of (R)-2-methyl-7-octene-2,3-diol,... 

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