Natural product synthesis enantiopure intermediate

Enantiopure, bifunctional acyloins (a-hydroxy ketones) are versatile intermediates in natural product synthesis (also see Sect. 2.3, Fig. 11). In nature, the formation of a-hydroxy ketones is efficiently catalyzed by thiamine diphosphate-dependent enzymes transketolases, decarboxylases, and other lyases, such as BALs. A great portfolio of biotransformations, especially with benzaldehyde derivatives as starting materials, were realized [204]. 

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. 

One classic application of the Tsuji-Trost reaction in natural products synthesis is found in the synthesis of strychnine by Overman and co-workers in 1993. Reaction of acetoacetate derivative 138 with enantiopure allylic carbonate 137 in the presence of Pd2(dba)3, PPh3, and NaH in THF yielded the cw-adduct 139 in 91%. It is worth noting that the selective displacement of carbonate group occurs with retention of the configuration and proceeds via the reactive 7i-allyl intermediate (see. Scheme 13.38). Derivative 139 could then be elaborated in a number of steps, to complete the total synthesis of strychnine. 

In a recently published report by MacMillan s group [121] on the enantioselective synthesis of pyrroloindoline and furanoindoline natural products such as (-)-flustramine B 2-219 [122], enantiopure amines 2-215 were used as organocatalysts to promote a domino Michael addition/cyclization sequence (Scheme 2.51). As substrates, the substituted tryptamine 2-214 and a, 3-unsaturated aldehydes were used. Reaction of 2-214 and acrolein in the presence of 2-215 probably leads to the intermediate 2-216, which cyclizes to give the pyrroloindole moiety 2-217 with subsequent hydrolysis of the enamine moiety and reconstitution of the imidazolid-inone catalyst. After reduction of the aldehyde functionality in 2-217 with NaBH4 the flustramine precursor 2-218 was isolated in very good 90 % ee and 78 % yield. 

The rather complex furylvinylcarbinol derivative 76 shown in Scheme 4.28 was required in enantiopure form as a key intermediate in the synthesis of the natural product cneorin. The carbinol moiety is heavily substituted with sterically demanding groups. Therefore attempts to resolve the furylvinylcarbinol with CALB or lipase PS-II led to very slow reactions. However, the rarely used enzyme Candida antarctica lipase A (CALA), which is known to act on sterically hindered substrates offers an alternative. Thus acylation of the furylvinylcarbinol 76 with 2,2,2-trifluoroethyl butanoate catalyzed by CALA (immobilized on celite with sucrose at pH 7.9) furnished the enantiomerically enriched propanoate of S-76 and R-76 (Scheme 4.28) [90]. Small-scale experiments gave E > 300. 

Enantiomerically pure cyclopropanes are a frequent motif in the structure of natural products. Their synthesis is often demanding and many approaches have been made [50, 51]. Porcine pancreatic lipase (PPL) was used for the stereoselective desymmetrization of a cyclopropane dibutanoate (Fig. 2). The asymmetric hydrolysis of the meso compound yielded the corresponding enantiopure alcohol almost quantitatively. The intermediate obtained was successfully applied in the total synthesis of dictyopterenes A and C, sexual pheromones of brown algae [52], and constanolactones (see below) [53]. 

For example, the fermentation of (2-bromoethyl)-benzene with recombinant E. coli furnished excellent yields of the corresponding c/.v-diol. enantiopure 3-(2-bromoethyl)-benzene-l,2-diol. The latter was used as a building block in the total synthesis of (+)-codeine (Fig. 29). Besides a Mitsunobu inversion of one of the stereogenic centers, two successive Heck cyclizations led to the enantiomer of the natural product [173]. Slight modifications of the reaction sequence, generating an epoxide intermediate, also furnished access to the naturally occurring enantiomer (—)-codeine [28]. 

Enantiopure citronellal (7) which can be quantitatively derived by hydrolysis from citronellal enamine 6 can be used for the synthesis of a broad array of optically active natural products. A list of compounds produced commercially on a 7 to 1500 ton-scale annually, serving as fragrances, insect growth regulators, or intermediates in organic synthesis, is given in Table 1. 

Despite the absence of stereochemical information in the reactive immunogen, the aldolase antibodies promote carbon-carbon bond formation with surprisingly high selectivity. For instance, the enamine formed from acetone adds to the si face of various aldehydes with ee s in excess of 95% [53], In other examples, Robinson annula-tions have been carried out with high enantioselectivity [55], tertiary aldols and other compounds have been successfully resolved [56], and enantiopure intermediates have been prepared for the synthesis of various natural products [57, 58]. 

Chiral alcohols are useful starting materials for the synthesis of various biologically active compounds. The need for enantiomerically pure drugs and agrochemicals has increased in recent years [13]. Derivatives of enantiopure 1-phenylethanol are important chiral building blocks, which can be used as synthetic intermediates for the production of pharmaceuticals, fine-chemicals agrochemicals, and natural products. In particular (R)-1-phenylethanol is in widespread use as an ophthalmic preservative, an inhibitor of cholesterol intestinal adsorption, a solvatochromic dye, a fragrance, and so on. 

Gamer s aldehyde (N-Boc-2,2-dimethyloxazolidine-4-carbaldehyde) as a versatile intermediate in the synthesis of enantiopure natural products 13BJ02641. 

Overman and Rosen [76] reported a total synthesis of spirotryprostatin B (137), a structurally novel diketopiperazine alkaloid, that featured a cascade Mizoroki-Heck cyclization/jj -allylpalladium capture process and the exploration of a related catalytic asymmetric sequence (Scheme 16.36). The plan was to relay the relative configurations of the quaternary stereocentre and the adjacent tertiary stereocentre in the natural product from the geometry of the trisubstimted alkene in the Mizoroki-Heck cyclization substrate. It was anticipated that the favoured 5-exo intramolecular Mizoroki-Heck cyclization of enantiopure triene precursor 135 would generate an -allylpalladium intermediate, with a chiral palladium catalyst controlling the absolute configuration of the initially formed quaternary carbon stereocentre. 

Asymmetric Induction on the Nucleophile The use of the tBu-PHOX ligand led to the first catalytic enantioselective Tsuji allylations of simple alkanone enol derivatives 62. These mild, operationally straightforward and stereoselective reactions described by Stoltz et al. [52] produce chiral cycloalkanones 63 with quaternary stereocenters at the a-position with high enantiopurities and in excellent chemical yields (Scheme 12.31). Mechanistic studies showed the incorporation of an O-bound enolate in the intermediate Pd-allyl complex [53]. Further investigations on the substrate scope led to several applications in the synthesis of natural products [54]. Recently, a similar approach was used to afford enantiopure quaternary lactams 65 that intercept synthetic intermediates previously used in the synthesis of the Aspidospcrma alkaloids quebrachamine and rhazinilam, but that were previously only available by chiral-auxiliary-assisted approaches or as racemic mixtures (Scheme 12.32) [55],... 

The scope of this chapter is to provide a comprehensive overview of the most interesting applications of EHs for the generation of enantiopure epoxides or diols, which are valuable chiral building blocks and key intermediates for the synthesis of various natural products or pharmacologically active compoimds. 

The total synthesis of pentacyclic alkaloid (-)-haliclonadiamine was accomplished by D.F. Taber and co-workers. The Noyori asymmetric hydrogenation was used to prepare a bicyclic 3-hydroxy ester intermediate in enantiopure form from a racemic bicyclic P-keto ester via kinetic resolution. It was found that the hydrogenation only took place in the presence of added HCI and by optimizing the amount of HCI added, the proportion of the total reduced ketone could be controlled. About 87% of the "matched" ketone was reduced, while the other P-keto ester enantiomer was not significantly converted to the reduced product. Interestingly, the diastereoselectivity of the hydrogenation depended on the nature of the added acid with HCI, the trans diastereomer was the major product, while with AcOH the cis diastereomer was dominant. 

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