Preparation of Enantiomerically-Pure Building Blocks

Convergent construction directed toward the preparation of enantiomerically-pure targets depends on the availability of enantomerically-pure starting materials. There are many ways that these can be prepared. One way is from carbohydrate precursors, but this approach has been limited, in that L-sugars are much more expensive than D-sugars. Tzenge-Lien Shih of Tamkang University in Taipei describes (Tetrahedron Lett. 45 1789, 2004) the facile conversion of the inexpensive D-ribonolactone derivative 1 to the much more valuable L-ribonolactone derivative 3, by careful hydrolysis of the intermediate mesylate. The epoxide 2 is presumed to be an intermediate in this transformation. 

While secondary alcohols are now relatively easy to prepare in enantiomerically-pure form, secondary amines have been more challenging. Larry Overman of UC Irvine reports (J. Am. Chem. Soc. 125 12412, 2003) the catalytic rearrangement of primary allylic alcohols such as 4 to the corresponding protected vinyl amine 5 with excellent ee. Hydrolysis of the amine 5 gives the GABA aminotransaminase inhibitor 6. Unnatural amino acids can be prepared by oxidative cleavage of the protected vinyl amines. 

Another approach to secondary amines has been reported (J. Am. Chem. Soc. 125 16178, 2003) by Masakatsu Shibasaki of the University of Tokyo. Addition of methoxyamine to a chalcone 7 (alkyl enones work in slightly lower ee) gives the amine 8. The amine 8 can be reduced with high stereocontrol to the amino alcohol 9. K-Selectride gives the complementary diastereomer. 

Professor Shibasaki has also investigated (J. Am. Chem. Soc. 125 15840, 2003) Michael addition to prepare alkylated secondary centers in high enantiomeric excess. Addition of substituted acetoacetates to cyclohexenone and to cycloheptenone proceeds with high ee. With 

It is apparent that enantiomerically-pure , written over and over again, can be cumbersome. We have suggested (C E News Aug. 19, 1991, p. 5 J. Org. Chem. 57 5990, 1992) symchiral as a pleasing alternative. 

---

Subsequently, a number of new epoxide pheromones were identified, and there was a need to develop a general synthetic method for epoxide pheromones. As shown in Figure 4.29, preparation of enantiomerically pure building block D facilitated the synthesis of (+)-disparlure 85 and other epoxide pheromones. We prepared D by employing lipases.57,58... 

F. W. Lichtenthaler, Enantiomerically pure building blocks from sugars Efficient preparation and utilization in natural product synthesis, in New Aspects of Organic Chemistry, I, Z, Yoshida,... 

E Santaneillo, P Ferraboschi, P Grisenti, A Manzocchi. The biocatalytic approach to the preparation of enantiomerically pure chiral building blocks. Chem Rev 92 1071-1140, 1992. 

A catalytic method for the preparation of enantiomerically pure oc,/i-epoxy ketones as building blocks for organic synthesis is highly desirable. Unfortunately, the Julia-Colonna... 

The Biocatalytic Approach to the Preparation of Enantiomerically Pure Chiral Building Blocks. Santaniello, E. Ferraboschi, P. Grisenti, P Manzochi, A. Chem. Rev. 1992, 92, 1071. 

Carbohydrates are an immensly important natural source of building blocks for the preparation of enantiomerically pure and highly oxygenated derivatives [78]. A... 

Finally, reaction E in Fig. 4 illustrates a stereoselective synthesis that proceeds by differentiation of two enantiotopically related groups of a meso compound. Here, one hydroxyl group of d.s-1,2-cyclohexanediol is preferentially benzoylated in the presence of one molar equivalent of an enantiomerically pure diamine [26]. These desymmetrization reactions (that have many biological versions) are also called meso-tricks , and are currently receiving a great deal of attention for the preparation of new chiral building blocks [27]. 

Both monocyclic building blocks were prepared in a multistep reaction sequence from L-glutamic acid. In another alternative reaction sequence the succinic imide 107 as a common intermediate for rings A an B was synthesized from R-malate. The enantiomerically pure buildings blocks could be transformed along different routes with appropriate D,C pyrroles into the dimers 108 and 109 which on treatment with acid formed the desired bilinimine 110. The outlined total synthesis of porphyrin di established the absolute configuration of natural heme di. 

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]. 

Kolbe electrolysis of trilfuoromethylated carboxylic acids has been shown to be a versatile method for providing useful building blocks having a CF3 group. Seebach and Renaud have prepared new types of trifluoromethylated chiral building blocks from enantiomerically pure 3-hydroxy-4,4,4-trifluorobutyric acid (Scheme 7.6) [76]. 

A number of enantiomerically pure chiral building-blocks, such as 292-294, have been prepared (270,271) by zinc-copper cleavage of 5-bromo-5-deoxy-2,3-0-isopropylidene-D-ribono-1,4-lactone, followed by reduction. Similarly, from the 5-iodo lactone analogue the enoic acid 295 was obtained by reaction with zinc/silver-graphite (272). 

---