Substrate-based stereocontrol

The chiral center on the piperidine ring retained stereochemical integrity to this point in the synthesis, and provided the basis for a relatively modest level (72 28 threo erythro) of substrate-based stereocontrol in the BH3-THF/H202 hydroboration/oxidation of the... 

Whereas the thermodynamic route described above relied on reagent control to establish the spongistatin C19 and C21 stereocentres, the discovery of highly stereoselective 1,5-anti aldol reactions of methyl ketones enabled us to examine an alternative,16 substrate-based stereocontrol route to 5. Regioselective enolisation of enantiomerically pure ketone 37, derived from a readily available biopolymer, gave end... 

Stereocomplementary bioreduction of a,p-unsaturated dicarboxylic acids and dimethyl esters using enoate reductases enzyme- and substrate-based stereocontrol. Org. Lett., 9,... 

Figure 13.23 Substrate-based stereocontrol in the bioreduction of a,p-dehydroamino acid derivatives.

Paterson, L, Delgado, O., Florence, G.J., Lyothier, L, O Brien, M Scott, J.P., and Sereinig, N. (2005) A second-generation total synthesis of (+)-discodermolide The development of a practical route using solely substrate-based stereocontrol. J. Org. Chem., 70, 150-160. 

Still s synthesis of monensin (1) is based on the assembly and union of three advanced, optically active intermediates 2, 7, and 8. It was anticipated that substrate-stereocontrolled processes could secure vicinal stereochemical relationships and that the coupling of the above intermediates would establish remote stereorelationships. Scheme 3 describes Still s synthesis of the left wing of monensin, intermediate 2. This construction commences with an aldol reaction between the (Z) magnesium bromide enolate derived from 2-methyl-2-trimethylsilyloxy-3-pentanone (21) and benzyloxymethyl-protected (/ )-/ -hydroxyisobutyraldehyde (10).2° The use of intermediate 21 in aldol reactions was first reported by Heathcock21 and, in this particular application, a 5 1 mixture of syn aldol diastereoisomers is formed in favor of the desired aldol adduct 22 (85% yield). The action of lithium diisopropylamide (LDA) and magnesium(n) bromide on 21 affords a (Z) magnesium enolate that... 

Metal-catalyzed hydrophosphination has been explored with only a few metals and with a limited array of substrates. Although these reactions usually proceed more quickly and with improved selectivity than their uncatalyzed counterparts, their potential for organic synthesis has not yet been exploited fully because of some drawbacks to the known reactions. The selectivity of Pt-catalyzed reactions is not sufficiently high in many cases, and only activated substrates can be used. Lanthanide-catalyzed reactions have been reported only for intramolecular cases and also sulfer from the formation of by-products. Recent studies of the mechanisms of these reactions may lead to improved selectivity and rate profiles. Further work on asymmetric hydrophosphination can be expected, since it is unlikely that good stereocontrol can be obtained in radical or acid/base-catalyzed processes. 

Okamura and Nakatani [65] revealed that the cycloaddition of 3-hydroxy-2-py-rone 107 with electron deficient dienophiles such as simple a,p-unsaturated aldehydes form the endo adduct under base catalysis. The reaction proceeds under NEtj, but demonstrates superior selectivity with Cinchona alkaloids. More recently, Deng et al. [66], through use of modified Cinchona alkaloids, expanded the dienophile pool in the Diels-Alder reaction of 3-hydroxy-2-pyrone 107 with a,p-unsaturated ketones. The mechanistic insight reveals that the bifunctional Cinchona alkaloid catalyst, via multiple hydrogen bonding, raises the HOMO of the 2-pyrone while lowering the LUMO of the dienophile with simultaneous stereocontrol over the substrates (Scheme 22). 

From the literature only a few examples of an enzyme-catalyzed kinetic racemic resolution via C-C bond-cleavage are known [64]. The broad substrate range of BAL in combination with the high extent of stereoselectivity observed for BAL-catalyzed resolutions impressively demonstrates the high potential of this strategy. Very recently, it has become possible to determine the three-dimensional structure of BAL via X-ray crystal structure analysis, which will enable a structure-based discussion of the observed stereocontrol [65]. 

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