Monday, December 19, 2011

Deslongchamps' Partial Synthesis of Hippuristanol

Hippuristanol is an antiproliferative agent that selectively targets an RNA helicase initiation factor [(eIF)4A] to block the translation stage of eukaryotic protein biosynthesis. This binding interaction triggers potent cytotoxic activity against cultured tumor cells and establishes RNA helicases as novel anticancer targets. Structurally, hippuristanol is a polyoxygenated steroid with a C22 spiroketal unit in a thermodynamically unfavorable stereochemical configuration (vida infra). The steroid framework is also hydroxylated on the beta-face at C11 and C20, that latter being a quaternary stereogenic position. Hippuristanol shares certain topological structural features with the ‘eastern’ substructure of cephalostatin 1, a dimeric steroidal pyrazine with uniquely selective and exquisitely potent anticancer properties. Pursuit of the currently unknown cellular target and mechanism of action of cephalostatin 1 is the subject of extensive research efforts in a number of academic laboratories and institutions.
A concise partial synthesis of hippuristanol, disclosed in 2010 from the laboratory of Pierre Deslongchamps, starts from hecogenin acetate, a plant-derived bulk chemical with side chain spiroketal functionality that can be rearranged and elaborated as needed. However, in order to make use of this inexpensive sapogenin as a precursor to hippuristanol, hecogenin’s C12 oxo moiety must be transposed to the C11 position. With this objective in mind, Deslongchamps and co-workers first employ osmium tetroxide-catalyzed dihydroxylation of the silyl enol ether derived from hecogenin to accomplish net alpha-hydroxylation at C11. The ketol thus obtained is then subjected to treatment with alkali under thermodynamically forcing conditions and rearrangement to the more stable ketol ensues, presumably via the intermediacy of the bracketed enediol shown above. This methodology was developed in the 1990’s by industrial chemists at Pfizer for the production of a steroidal cholesterol absorption inhibitor. The 11-keto-12beta-acetoxy intermediate then undergoes reduction with calcium metal, which effectively shifts the C12 keto group of hecogenin to C11. This reduction probably involves an initial epimerization of the C12 position to place the acetate in an axial position which would mechanistically facilitate the requisite 1,2-elimination.
In order to secure the C20 tertiary alcohol stereocenter, hecogenin’s C22 spiroketal must be truncated to a 20-oxo-pregnane. Historically, this has been achieved by implementation of Russell Marker’s degradation protocol, a three-step route that efficiently provides 3-hydroxypregna-5,16-dien-20-ones from various plant-derived sterols. The classical Marker degradation involves a base-mediated elimination (step 3) to install a delta(16,17) double bond. This results in the loss of stereochemical information (two stereocenters are abolished) and oxygenation at C16. In order to retain the beta-configuration at carbons 16-17 and retain the C16 hydroxyl, Deslongchamps has modifed step 3 of the Marker degradation by treating the intermediate derived from the chromic acid oxidation with vinylmagnesium bromide. This delivers an allylic alcohol that can then be oxidatively cleaved to provide the requisite beta-hydroxy ketone needed for elaboration to the natural product. Deslongchamps’ modification of the Marker degradation may be a generally useful process for the preparation of complex oxygenated steroids. In the next step, addition of a lithiated alkyne to the C17 methyl ketone stereoselectively affords the product of chelation control, the C20beta-tertiary alcohol.
Without question, the most interesting transformation in the synthesis of hippuristanol is the mercury(II)-catalyzed spiroketalization that generates semiprotected 22-epi-hippuristanol in one step from a 3-alkyn-1,7-diol precursor. A proposed mechanism was advanced by the authors involving intramolecular 5-exo-dig oxymercuration of the 16-hydroxyl onto the triple bond. A subsequent ketalization event establishes the C22 spirocarbon center. This latter mechanistic aspect is of great interest, as the reaction stereoselectively produces only one of two possible diastereomeric products (22S/22R = 99.9:0.1). Evidence is provided to suggest that this is a thermodynamically controlled process: treatment of hippuristanol under the aqueous mercury(II) reaction conditions leads to complete isomerization of the natural product to 22-epi-hippuristanol. Indeed, upon inspection of the possible diastereomeric products (stereo structures shown above), one can see that the observed product is stabilized by two anomeric effects and that hippuristanol’s bicyclic spiroketal is in the non thermodymanically-favored configuration (due to one anomeric effect). Therefore, the stereochemical outcome of the reaction is probably due to equilibration rather than selective kinetic ketalization of the nucleophilic hydroxyl onto the intermediate oxonium species from the alpha-face. Debenzylation and spiroketal isomerization completed the expedient synthesis of hippuristanol. The observation that partial epimerization of C22 to the natural configuration can only be accomplished in an aprotic acidic system implies the existence of an intramolecular hydrogen bond between the hippuristanol’s C20 tertiary hydroxyl group and a spiroketal oxygen atom.

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