M. Mark Midland

Asymmetric reductions of propargyl ketones : An effective approach to the synthesis of optically-active compounds

Abstract Propargyl ketones are readily reduced by the asymmetric reducing agent B -3-pinanyl-9- borabicyclo[3.3.1]-nonane (Alpine-borane). The reagent prepared from (+)-α-pinene and 9-BBN provides the R enantiomer while the S enantiomer can be obtained from (-)-α-pinene. Alternatively the S enantiomer can be prepared from the reagent derived from 9-BBN and the benzyl ether of nopol (6,6-dimethyl-bicyclo[3.11.]hept-2-ene-2-ethanol). The limiting factor in obtaining high enantiomeric induction is often the enantiomeric purity of the α-pinene. With 100% enantiomerically pure α-pinene, propargyl alcohols of essentially 100% ee can be obtained. A predictive rationalization of the transition state leading to this remarkable selection is presented. The acetylene unit of the propargyl alcohol provides a convenient handle for transformations to other useful, optically-active products. The use of propargyl alcohols for the synthesis of optically-active α- and β-substituted γ-lactones, and δ-lactones is illustrated

Chemistry and conformation of vitamin D molecules.

1 alpha,25-Dihydroxyvitamin D3 (1,25) is a structurally unique steroid hormone because it not only possesses the complete 25-hydroxycholesterol side chain, but most notably, it possesses a seco-B triene structure (it lacks a B-ring and is usually depicted in a non-steroidal, extended conformation). In contrast, the classical steroid hormones possess a truncated side chain (progesterone, cortisol, and aldosterone) or no side chain (estradiol and testosterone) and they all possess the fully intact ABCD steroid rings. These structural differences render the seco-B-steroid 1,25 considerably more conformationally flexible. Since 1,25 is now known to target a myriad of tissues where specific interactions occur to produce an array of biological responses, it is of interest to determine whether different topologies of 1,25 (resulting from different conformational orientations of 1,25) are necessary to interact effectively at the different target sites. The array of biological responses include both non-genomic and genomic effects and there is considerable promise for the efficacy of 1,25 analogs as chemotherapeutic agents in a variety of human disease states. For the non-genomic calcium transport response of transcaltachia, the finding that two 6-s-cis locked analogs, 1 alpha,25-dihydroxyprevitamin D3 (pre-1,25) and 1 alpha,25-dihydroxylumisterol3 (1,25-Lumi), are equipotent to 1,25, points strongly to the involvement of the 6-s-cis conformer of 1,25 as the biologically active conformer. Since there is a continuum of easily interconvertible 6,7-single bond conformers of the seco-B ring available to 1,25, conformational minima (either local or global) may have little to do with the manner in which 1,25 is bound to receptor. For the genomic calcium transport response, and for other genomic (or non-genomic) effects, there is no clear evidence whether the steroidal (s-cis) or non-steroidal (s-trans) conformer of 1,25 is involved. In order to address this matter further, efforts are underway to evaluate other conformationally locked analogs of 1,25 which might mimic either the planar 6-s-trans-1,25 or some intermediate conformer between it and the planar-6-s-cis form.

Stereochemistry of hydroboration of .alpha.-chiral olefins and reduction of .alpha.-chiral ketones. An unusual anti-Cram selectivity with dialkylboranes

An 4 Modellverbindungen, dem Steroid (I) (keine nahere Angabe), dem Pregnenolon (IV), dessen Wittig- Produkt (VII) unddem Butanon (IX) wird der Einflus von Reduktionsmitteln auf die Stereochemie der Reduktion untersucht.

Effect of C2O stereochemistry on the conformational profile of the side chains of vitamin D analogs.

The occupancy volumes have been explored using molecular mechanics based conformational analysis for the side chain of vitamin D analogs KH 1060, its C2O epimer, 1α,25-dihydroxyvitamin D3 and its C2O epimer. Dot maps reflect the sites most accessible by the hydroxyl group. The stereochemistry at C2O causes the hydroxyl group to preferentially populate different (but not exclusively different) regions of space.

The synthesis of naturally occurring 4-alkyl- and 4-alkenyl-γ-lactones using the asymmetric reducing agent B-3-pinanyl-9-borabicyclo[3.3.1]nonane

4-Hydroxy-2-alkynoates of high enantiomeric purity, available from the reduction of the corresponding ketones with B-3-pinanyl-9-BBN, are converted to 4-substituted-γ-lactones found in beetle and deer pheromones.

Diastereoselection in the Lewis acid catalyzed cycloaddition reaction of .alpha.-alkoxy imines

The Lewis acid catalyzed cycloaddition reactions of α-benzyloxy imines (RCH(OCH 2 C 6 H 5 6)CH=NCH 2 C 6 H 5 ) were investigated using 1,3-dimethoxy-1-[(trimethylsilyl)oxy]-1,3-butadiene. The observed diastereoselectivity was dependent on both the Lewis acid and substrate structure. Strong Lewis acids such as diethylaluminum chloride (DEAC) exhited moderate to good success in promoting the cycloaddition reaction. When DEAC was used as the Lewis acid, the diastereoselectivity was also dependent on the stoichiometry of the Lewis acid to the substrate

A rapid and efficient cycloaddition of simple imines with activated dienes leading to amino sugars; unusually high chelation-controlled diastereoselectivity in the addition to an α, β-dihydroxy imine protected as a ketal

Abstract The addition of a ketal-protected imine to an activated diene using diethylaluminum chloride as a catalyst leads to an unexpected “chelation-controlled” product.

The reaction of B-alkyl-9-borabicyclo[3.3.1]nonanes with aldehydes and ketones. A facile elimination of the alkyl group by aldehydes

Abstract Certain B-alkyl-9-borabicyclo[3.3.1]nonanes (9-BBN) reduce benzaldehyde to benzyl alcohol under exceptionally mild conditions. Factors which contribute to a high rate of reaction include: an increase in the degree of substitution at the position β to the boron (isobutyl > 1-butyl >> ethyl), the ability of the alkyl group to form a syn-planar B—C—C—H conformation (cyclopentyl ⋍ norbornyl > sec-butyl >> cyclohexyl), and the presence of an electron-withdrawing para-substituent on the benzaldehyde (p-Cl > p-H > p-CH3O). The B-alkyl group is transformed into an olefin as the benzaldehyde is reduced. Elimination takes place predominantly if not exclusively towards the more highly substituted β hydrogen. The reaction obeys second order kinetics. The observations are consistent with a cyclic mechanism rather than a dehydroboration-reduction pathway.

The isomerization of optically-active propargyl alcohols to terminal acetylenes.

Abstract The isomerization of optically-active secondary propargyl alcohols, RCHOHCC(CH2)nCH3, to terminal acetylenic alcohols, RCHOH(CH2)n+1 C=CH, by potassium 3-aminopropylamide (KAPA) proceeds without loss of configuration at the hydroxy center.

Studies on Chirality Transfer in the [2,3] Sigmatropic Rearrangement of Anions Derived from Trialkylstannylmethyl Allylic Ethers. Stereospecific Synthesis of (2R)-3-Benzyloxy-2-methylpropanol.

Abstract Virtually complete chirality transfer is observed in the [2,3] sigmatropic rearrangement of the anion derived from trialkylstanylmethyl ( E )- or ( Z )-allylic ethers.