Enantioselective total synthesis source

While most of the syntheses of hyacinthacines are based on the modification and elaboration of precursors from the chiral pool, less effort has been directed toward the construction of the pyrrolizidine skeleton using non-natural precursors. This chapter summarizes racemic as well as enantioselective total synthesis of hyacinthacines reported to date, which start from nonchiral pool sources. In this context, biocatalysis constitutes the most widely used alternative to the chiral pool approach. Enzymatic kinetic resolution using lipases but also aldolase-mediated reactions have been successfully employed to provide precursors that were later elaborated toward hyacinthacines. Synthetic chiral auxiliaries have also been used successfully in this context. 

Using a related strategy, Zhu and coworkers [65] recently described a formal enantioselective total synthesis of (—)-physostigmine (110) that featured a novel asymmetric Mizoroki-Heck cyclization/cyanation sequence. Oxindole 114, an intermediate in an earlier synthesis of physostigmine [66], was prepared from anilide 113 by carrying out the cyclization under cationic Mizoroki-Heck conditions with (,S)-DIFLUORPHOS as the hgand and potassium ferricyanide as the source of cyanide. Using these conditions, (5)-oxindole 114 was formed in 78% yield and 61% ee (Scheme 16.28). 

When chiral, drugs and other molecules obtained from natural sources or by semisynthesis usually contain one of the possible enantiomeric forms. However, those obtained by total synthesis often consist of mixtures of both enantiomers. In order to develop commercially the isolated enantiomers, two alternative approaches can be considered (i) enantioselective synthesis of the desired enantiomer or (ii) separation of both isomers from a racemic mixture. The separation can be performed on the target molecule or on one of its chemical precursors obtained from conventional synthetic procedures. Both strategies have their advantages and drawbacks. 

Enantioselective enzymatic transesterifications have been used as a complementary method to enantioselective enzymatic ester hydrolyses. The first example of this particular type of biotransformation is the synthesis of the optically active 2-acetoxy-l-silacyclohexane (5 )-78 (Scheme 19). This compound was obtained by an enantioselective transesterification of the racemic l-silacyclohexan-2-ol rac-43 with triacetin (acetate source) in isooctane, catalyzed by a crude lipase preparation from Candida cylindracea (CCL, E.C. 3.1.1.3)62. After terminating the reaction at 52% conversion (relative to total amount of substrate rac-43), the product (S)-78 was separated from the nonreacted substrate by column chromatography on silica gel and isolated in 92% yield (relative to total amount of converted rac-43) with an enantiomeric purity of 95% ee. The remaining l-silacyclohexan-2-ol (/ )-43 was obtained in 76% yield (relative to total amount of nonconverted rac-43) with an enantiomeric purity of 96% ee. Repeated recrystallization of (R)-43 led to an improvement of enantiomeric purity by up to >98% ee. Compound (R)-43 has already earlier been prepared by an enantioselective microbial reduction of the l-silacyclohexan-2-one 42 (see Scheme 8)53. The l-silacyclohexan-2-ol (R)-43 is the antipode of compound (.S j-43 which was obtained by a kinetic enzymatic resolution of the racemic 2-acetoxy-l-silacyclohexane rac-78 (see Scheme 15)62. For further enantioselective enzymatic transesterifications of racemic organosilicon substrates, with a carbon atom as the center of chirality, see References 64 and 70-72. 

Further studies with P. citrinum VKM FW-800 obtained from the permafrost region of Northern Russia, led to the isolation of the alkaloids (+)-quinocitrinine A and (—)-quinocitrinine B, which are diastereomers at the C-1 and C-9 stereocenters (186). These alkaloids were the first pyrrolo[3,4-lr]quinoline-type representatives isolated from microbial sources. Their structures are unique in that a quinolone skeleton is conjugated with a y-lactam ring. A biomimetic total S3mthesis of quinolactacin B was reported by Tatsuta s group (215). A new enantioselective synthesis of quinolactacins A2 and B, via the skeletal rearrangement of a p-carboline to the pyrrolo[3,4- ]quinolin-4(lf-D-one system by an... 

---