Sunday, April 6, 2014

An Organocatalytic One-Step Approach to Synthetic Steroids

            The laboratory of Karl Anker Jørgensen at Aarhus University (Denmark) has developed a family of silylated diarylprolinol derivatives that serve as broadly applicable organocatalysts for various enamine and iminium-type synthetic transformations including the asymmetric a-functionalization of aldehydes. Yujiro Hayashi’s group independently and concurrently discovered an identical organocatalyst system and has recently applied it to a masterful one-pot protocol for the synthesis of (-)-oseltamivir (Tamiflu). More recently, Jørgensen’s group has used their diarylprolinol 3 to rapidly assemble a range of optically active 14b-steroids with near perfect stereoselectivity.
            The reaction involves conjugate addition of the dienamine derived from the condensation of 1 and 3 to the highly electrophilic cyclopentanedione 2, which establishes the eventual C14 (b) stereocenter. The electron-rich aminocatalyst 3 renders the enal 1 sufficiently nucleophilic to engage 2 in the reaction and provides a stereoinducing molecular handle. Subsequent stereocontrolled aldol type C-ring closure then forges the steroidal carbocyclic framework of 4. Importantly, the condensation products are all oxygenated at the C12 position. The 12-hydroxy steroid motif is found in cardenolides such as digoxin and drug candidates such as INT-777. They are also precursors to C-nor-D-homosteroids such as cyclopamine and nakiterpiosin. Jørgensen’s steroid synthesis exhibits broad substrate compatibility, providing access to A-ring substituted derivatives as well as steroids  containing heteroatoms in the B ring. Moreover, the 14b-steroid organocatalysis product 4 can be converted in four steps into Torgov’s diene, a key intermediate in historic syntheses of (+)-estrone.
            Jørgensen’s concept borrows from classic approaches toward synthetic steroids that rely on formation of the C-ring by a Diels-Alder reaction. In the 1930’s, the chemist Dane pioneered this strategy, which was based on a cycloaddition between the electron-rich ‘Dane’s diene’ and a dienophile. E. J. Corey has recently rendered this process catalytic and enantioselective by activating the dienophilic partner (5) with the cationic proline derivative 6. The chiral oxazaborolidine Lewis acid 6 catalyzes the enantioselective [4+2]-cycloaddition between Dane’s diene and 5 to furnish the Diels-Alder adduct 7 with outstanding efficiency and good enantioselectivity. Optically pure (99% ee) 7 can be obtained from a single recrystallization and this versatile steroidal building block can be elaborated into Torgov’s diene in only three additional steps. The powerful synthetic methodologies described above are among the most expedient technologies developed to date for the de novo assembly of fully synthetic steroid derivatives.
We will conclude with a particularly apropos quote from Jørgensen: "Steroids are among the most privileged structures, and the impact of steroid-based research on modern society can hardly be overestimated. Being one of the most competitive research fields in the last century, steroids have a vital role in the development of organic synthesis, but also in medicine and biology."

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