Methyl mannoside 16 containing an allyldimethylsilyl ether at C(2) was synthesized in nine steps from D-mannose. Reaction with TMSOTf in MeCN at room-temperature effected C-glycosylation to provide the alpha-allyl-C-mannosyl product 18 with excellent stereoselectivity. Crossover experiments over a range of reaction concentrations proved that reaction was proceeding via an intermolecular pathway rather than the hoped-for intramolecular delivery route. The exceptionally high stereoselectivity of this allylation in the presence of an acid-scavenger, 2,6-DTBMP, can be attributed to the allylsilyl ether 16 behaving as the allylating agent. Geometrical constraints in the seven-membered ring transition state account for the lack of intramolecular allyl transfer. Attaching a modified allylsilane 29a-c to C(2)OH of methyl mannoside 15 improved matters. Reaction of the tethered mannosides 27a-c with TMSOTf in the presence of 2,6-DTBMP in MeCN at rt provided a range of products, which depended on the size of the alkyl substituents at the silyl ether tether. Diene products were the major compounds irrespective of the size of the alkyl substituents at the silyl ether tether. Their formation can be understood by intramolecular allylation of the allylsilane on to the activated anomeric center, followed by collapse of the intermediate carbocation by preferential attack of an external nucleophile at the silyl ether tether, rather than at the allylic silicon center. A cascade of further reactions rationalizes the formation of the 2-dienyl-substituted tetrahydrofuran 30 and dienes 39 and 40. The desired beta-allyl-C-mannosyl products 42 and 43 were obtained, albeit in low yield, when bulky ethyl and isopropyl groups were employed at the silyl ether tether. Stereospecific oxidative cleavage of the silyl tether in 42 and 43 provided the corresponding stereodefined diols 44 and 45, respectively. Attempts to improve the yield and diastereoselectivity of the desired beta-allyl-C-mannosyls by moving to a sulfoxide mannosyl donor, which could be activated at low temperature, proved unsuccessful.

Synthesis and preliminary biological evaluation of a 35-member library of bistramide A stereoisomers are reported. All eight stereoisomers of the C1-C13 tetrahydropyran fragment of the molecule were prepared utilizing crotylsilane reagents 9 and 10 in our [4+2]-annulation methodology. In addition, the four isomers of the C14-C18 γ-amino acid unit were accessed via a Lewis acid mediated crotylation reaction using both enantiomers of organosilane 11. The spiroketal subunit of bistramide A was modified at the C39-alcohol to give another point of stereochemical diversification. The fragments were coupled using standard peptide coupling protocol to provide 35 stereoisomers of the natural product. These stereochemical analogs were screened for their effects on cellular actin and cytotoxicity against cancer cell lines (UO-31 renal and SF-295 CNS). The results of these assays identified one analog, 1.21, with enhanced potency relative to the natural product, bistramide A.

[reaction: see text]. Treatment of aldehyde 6 with TMSOTf, in the presence of a Brønsted acid scavenger, effects an intramolecular allylation to provide the oxasilacycle 7 as the major diastereoisomer. Tamao oxidation of the C-Si bond in 7 affords the corresponding 1,2,4-triol 9.

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Three gamma-(amino)silyl-substituted allylsilanes 14a-c have been prepared in three steps from the corresponding dialkyldichlorosilane. The aminosilyl group has been used to link this allylsilane nucleophile to a series of beta-hydroxy aldehydes through a silyl ether temporary connection. The size of the alkyl substituents at the silyl ether tether governs the outcome of the reaction on exposure to acid. Thus, treatment of aldehyde (E)-9aa, which contains a dimethylsilyl ether connection between the aldehyde and allylsilane, with a range of Lewis and Brønsted acid activators provides an (E)-diene product. The mechanism of formation of this undesired product is discussed. Systems containing a sterically more bulky diethylsilyl ether connection react differently: thus in the presence of TMSOTf and a Brønsted acid scavenger, intramolecular allylation proceeds smoothly to provide two out of the possible four diastereoisomeric oxasilacycles, 23 (major) and 21 (minor). A diene product again accounts for the remaining mass balance in the reaction. This side product can be completely suppressed by using a sterically even more bulky diisopropylsilyl ether connection in the cyclization precursor, although this is now at the expense of a slight erosion in the 1,3-stereoinduction in the allylation products. The sense of 1,3-stereoinduction observed in these intramolecular allylations has been rationalized by using an electrostatic argument, which can also explain the stereochemical outcome of a number of related reactions. Levels of 1,4-stereoinduction in the intramolecular allylation are more modest but can be significantly improved in some cases by using a tethered (Z)-allylsilane in place of its (E)-stereoisomer. Oxidation of the major diastereoisomeric allylation product 23 under Tamao-Kumada conditions provides an entry into stereodefined 1,2-anti-2,4-syn triols 28.

Carbohydrates U 0500 Stereoselective Synthesis of Allyl-C-mannosyl Compounds: Use of a Temporary Silicon Connection in Intramolecular AllylationStrategies with Allylsilanes. -(BEIGNET, J.; TIERNAN, J.; WOO, C. H.; KARIUKI, B. M.; COX*, L. R.; J. Org.

Pages 6345 and 6353. Compound 24 has been previously reported: Cipolla, L.; Lay, L.; Nicotra, F.