Stereodivergence

Scheme 2.19 A highly stereodivergent synthesis of cis- and tram-2-alkenylaziridines.

Scheme 2.32 Stereodivergent synthesis of threo- and erythro-sphingosines 124.

Scheme 2.35 Stereodivergent synthesis of syn- and anti-amino alcohols.

Stereodivergent aldol addition is also possible when (.S,)-5,5-dimethyl-4-trimethylsiloxy-3-hexanonc (16) is chosen as the enolate precursor. Thus, the lithium enolate generated from 16 by treatment with lithium diisopropylamide and tetramethylethylenediamine leads predomi-... 

The antiviral agent virantmycin is an unusual chlorinated tetrahydroquinoline isolated from a strain of Streptomyces (Figure 6.10). Hydrolysis of a prochiral 2,2-disubstituted dimethyl malonate with PLE in DMSO-pH 8 phosphate buffer (1 4) was a key step in a stereodivergent synthesis of this natural product [57]. 

Catalytic C—C coupling is particularly valuable in asymmetric synthesis because of its potential for stereodivergent product generation [13], by which multiple stereoisomeric products can be derived from common synthetic building blocks (Eigure 10.1). Obviously, such a synthetic strategy depends on the prevalence of related stereocomplementary enzymes that must have a similarly broad substrate tolerance. 

A more general access to biologically important and structurally more diverse aldose isomers makes use of ketol isomerases for the enzymatic interconversion of ketoses to aldoses. For a full realization of the concept of enzymatic stereodivergent carbohydrate synthesis, the stereochemically complementary i-rhamnose (Rhal EC 5.3.1.14) and i-fucose isomerases (Fuel EC 5.3.1.3) from E. coli have been shown to display a relaxed substrate tolerance [16,99,113,131]. Both enzymes convert sugars and their derivatives that have a common (3 J )-OH configuration, but may deviate in... 

A new stereodivergent synthesis of optically pure 4-alkylisoxazolidin-4-ols starting from enantiopure 2-(alkyloxiran-2-yl)methanols has been reported. In particular, the (2/ )-glycidyl... 

A stereodivergent synthesis of derivatives of 1,2-diols with an Se 2-retention pathway can be performed via a-alkoxyorganolead compounds. 

An enantioselective intramolecular Pauson-Khand reaction based on chiral auxiliary-directed 7t-face discrimination in acetylenic 0-alkyl enol ether-dicobalt hexacarbonyl complexes, which proceeds with good yields and high facial diastereoselectivity, has recently been developed by M.A. Pericas, A. Moyano, A.E. Greene and their associates. The method has been applied to an enantioselective formal synthesis of hirsutene. Moreover, the process is stereodivergent and the chiral auxiliary -rran5-2-phenylcyclohexanol- is recovered in a yield as high as 92% [18]. 

Density functional theory calculations (B3LYP/6-31G level) have provided an explanation for the stereodivergent outcome of the Staudinger reaction between acyl chlorides and imines to form 2-azetidinones (/3-lactams). When ketene is formed prior to cycloaddition, preferential or exclusive formation of ct5-j6-lactam (50) is predicted. If, however, the imine reacts directly with the acid chloride, the step that determines the stereochemical outcome is an intramolecular 5n2 displacement, and preferential or exclusive formation of trans isomer (51) is predicted. These predictions agree well with the experimental evidence regarding the stereochemical outcome for various reactants and reaction conditions. 

Very recently, Lattanzi and coworkers reported on the use of enantiomericaUy pure camphor derived hydroperoxide 61 for the Ti(OPr-/)4 catalyzed chemoselective asymmetric oxidation of aryl methyl sulfides (equation 59) . The corresponding sulfoxides could be obtained in moderate yields (39-68%) and ee values up to 51%. The sulfoxidation to the sulfoxides is accompanied by further oxidation of the sulfone (kinetic resolution, yields of sulfone up to 9%). This process is stereodivergent with respect to the sulfoxidation step, which was found for the first time. Although the obtained enantioselectivities for the sulfoxides were only moderate, they proved to be among the best reported at that time with the use of enantiopure hydroperoxides as the only asymmetric inductor. The... 

Scheme 2.2.5.5 Stereodivergent isomerization of (3R)-configured aldolase products as an access route to aldoses.

M. C. McIntosh and S. M. Weinreb, A strategy for synthesis of conduritols and related cyclitols via stereodivergent vinylsilane-aldehyde cyclizations, J. Org. Chem. 56 5010 (1991). 

Stereodivergent synthesis of almost enantiomerically pure and stereospecifically deuterium-labeled 2,2-dimethylcyclopropanols has been achieved by treating 2,2-dimethylpropane-l,3-diol dicarbamate with alkyllithium in the presence of (-)-sparteine (equation 17)29. 

On the other hand, most of the lyases allow a reasonably broad variation of the electrophilic acceptor component, which usually is an aldehyde. This feature, which nicely complements the emerging trend of combinatorial synthesis [38-40], makes possible a stereodivergent strategy for the synthesis of groups of stereoisomeric compounds by employing separate enzymatic catalysts to selectively produce individual diastereomers at will from the same starting material (Sect. 7). 

Being restricted to DHAP as the nucleophile, aldol additions will only generate ketoses and derivatives from which aldose isomers may be obtained by biocatalytic ketol isomerization (cf. Sect. 7.1) [306]. For a more direct entry to aldoses the inversion strategy may be followed (Scheme 19) [290] which utilizes monoprotected dialdehydes. After aldolization and stereoselective chemical or enzymatic ketone reduction, the remaining masked aldehyde function is deprotected to provide the free aldose. Further examples of the directed, stereodivergent synthesis of sugars and related compounds such as aza- or thiosugars are collected in Sect. 7. 

The availability and the rather similar substrate tolerances exhibited by most members within the families of related lyases fulfills the demand for a complete set of catalysts for a directed stereodivergent synthesis of a set of diastereomeric products from common synthetic building blocks [189]. The verification of this concept ( combinatorial synthesis ) has indeed been pursued in a different respect, and will be highlighted by pertinent examples for the synthesis of simple sugars and for the synthesis of azasugars , an emerging class of glycosidase inhibitors. 

Scheme 23. Stereodivergent synthesis of all eight possible hexokctoses from glyceraldehyde by DHAP aldolases...

Scheme 24. Stereodivergent isomerizations of hexoketoses by rhamnose and fucose isomerases. Possible enzymatic pathways for the differentiation of fructose...

The stereodivergent action of DHAP aldolases is also preparatively useful under conditions of thermodynamic control [202,230, 294]. Starting from racemic 3-hydroxybutanal 84 the enantiocomplementary nature of the FruA RhuA enzyme couple will extend to the selection of the dependent stereocenter at C-6 to yield the corresponding mirror imaged products 78 with high selectivity [189], Conversely, the FucA will contribute a different major diastereomer 173, albeit only at a low de because of more balanced energetic relations [362],... 

Scheme 25. Stereodivergent synthesis of 1-dcoxy azasugars of the nojirimycin type by enzymatic aldolization followed by catalytic reductive amination. a) 1. Aldolase, DHAP 2. phosphatase 3. H2/Pd-C...

Scheme 17 Stereodivergent synthesis of spiro- [S-lactams using ester enolates and chiral imines...

Fujisawa et al. [89] have reported the stereodivergent synthesis of spiro-[S-1 act a ms 64, 65 (Scheme 17) by reaction of lithium or titanium ester enolates 62 with single chiral imines 63 by taking advantage of different coordination states of the enolate metals. Almost complete reversal of the diastereofacial-discrimination with respect to the C-4 of the (3-lactam skeleton has been attained in this reaction coupled with flexibility in the selection of the enolates and ready removal of the chiral auxiliary. 

Carstens, A. Hoppe, D. Generation of a configurationally stable, enantioenriched a-oxy-a-methylbenzyllithium stereodivergence of its... 

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