Tandem chain extension-Mannich reaction: an approach to ß-proline derivatives.

A zinc carbenoid-initiated chain extension reaction provides access to an organometallic intermediate, which can be used to capture activated imines. Deprotection of the nitrogen and reduction provides access to racemic derivatives of ß-proline. The relative stereochemistry of the ß-proline can be controlled through use of different activating groups on the imine nitrogen.

Enantioselective total synthesis of (-)-acetylaranotin, a dihydrooxepine epidithiodiketopiperazine.

The first total synthesis of the dihydrooxepine-containing epidithiodiketopiperazine (ETP) (-)-acetylaranotin (1) is reported. The key steps of the synthesis include an enantioselective azomethine ylide (1,3)-dipolar cycloaddition reaction to set the absolute and relative stereochemistry, a rhodium-catalyzed cycloisomerization/chloride elimination sequence to generate the dihydrooxepine moiety, and a stereoretentive diketopiperazine sulfenylation to install the epidisulfide. This synthesis provides access to (-)-1 in 18 steps from inexpensive, commercially available starting materials. We anticipate that the approach described herein will serve as a general strategy for the synthesis of additional members of the dihydrooxepine ETP family.

Disparate behavior of carbonyl and thiocarbonyl compounds: acyl chlorides vs thiocarbonyl chlorides and isocyanates vs isothiocyanates.

The reaction of benzoyl chloride with methanol catalyzed by pyridine is 9 times more rapid than is the same reaction with thiobenzoyl chloride. The difference in reactivity, as well as the dealkylation reactions that occur when the reaction of thiobenzoyl chloride is catalyzed by bases such as Et(3)N, can be understood in terms of the charge distributions in the intermediate acylammonium ions. The reaction of PhNCO with ethanol occurs at a much higher rate (4.8 x 10(4)) than that of PhNCS, corresponding to a difference in activation free energies for the additions of 6 kcal/mol. Transition states for each of these reactions were located, and each involves two alcohol molecules in a hydrogen bonded six-membered ring arrangement. Information concerning differences in reactivity was derived from analysis of Hirshfeld atomic charge distributions and calculated hydrogenolysis reaction energies.

Enantioselective sulfonylation reactions mediated by a tetrapeptide catalyst.

While Nature excels at performing selective modifications of complex polyfunctional molecules through the use of tailoring enzymes, synthetic chemistry has lagged behind in this regard. In prior work, we have applied a biomimetic approach to this problem, developing small peptides to achieve various group transfer reactions on polyol substrates with high enantio- or regioselectivity. The utility of sulfonates as synthetic building blocks and the scarcity of direct, selective methods for their preparation prompted our investigation into this area. In this article we report the development of a pi-methyl histidine-based tetrameric peptide that effects the desymmetrization of meso-1,3-diols through enantioselective (mono)sulfonylation. The catalyst exhibits structural similarities to another catalyst found to be effective in orthogonal group transfers, but results in modification of the enantiotopic alcohol. The practical and mechanistic implications of this discovery may extend beyond synthetic considerations and provide analogies to the diverse roles of histidine in enzyme active sites.

Site-selective catalysis of phenyl thionoformate transfer as a tool for regioselective deoxygenation of polyols.

We report the application of peptide-embedded imidazoles as catalysts for the site-selective delivery of the phenyl thionoformate unit as a prelude to deoxygenation reactions of polyols. Methodology was developed that allows for the synthesis of thiocarbonyl derivatives based on a combination of additives that include N-alkylimidazoles and FeCl3 as co-catalysts. The use of this reagent combination leads to increased reaction rates and efficient yields relative to those of simple base-mediated reactions. In terms of controlling regioselectivity during the course of polyol modification, we found that histidine-containing peptides, in combination with FeCl3, could lead to modulation of the product distribution. Through screening of peptides and control of reaction conditions, products could be observed that reflected both the inherent preference of substrates and also reversal of inherent selectivity.