Tuesday, February 28, 2012

Building Blocks for Steroid Total Synthesis

          The Wieland-Miescher ketone (3) is a bicyclic enedione that contains the A/B ring substructure of the steroidal carbon skeleton. As such, this well-known building block has been utilized in the total synthesis of numerous terpenoids and steroids, most notably in the pursuit of an industrial process for the preparation of contraceptives and other medicinally important steroids. The versatile steroid synthon is named for Karl Miescher and Peter Wieland, industrial chemists from Ciba Geigy who first prepared the bicyclic diketone in racemic form. A historically significant enantioselective synthesis of the Wieland-Miescher ketone and the so-called Hajos-Parrish ketone (4) proceeds via the intermediacy of an enamine derived from L-proline. This process is often referred to as the Hajos-Parrish-Eder-Sauer-Wiechert (H-P-E-S-W) reaction, named after its principal investigators from Hoffmann-La Roche and Schering AG. In 2004, Houk and Clemente invoked a cyclic transition state (depicted below) to account for the observed stereoselectivity, in which an intramolecular hydrogen bond facilitates proton transfer from proline’s carboxylic acid to the developing alkoxide. The critical role of hydrogen bonding in the stereocontrol of the transformation is reinforced by early reports of reduced enantioselectivity (27-83% enantiomeric excess or ee) when the reaction is run in alcoholic (protic) solvents.
          The proline-catalyzed synthesis of the Hajos-Parrish ketone proceeds with excellent enantioselectivity. However, the Wieland-Miescher ketone, under identical conditions, is obtained in only 70% enantiomeric excess (ee) and requires multiple recrystallizations at low temperature before acceptable levels of optical purity are achieved. With this shortcoming in mind, Luo and co-workers have very recently developed a structurally simple organocatalyst for the enantioselective synthesis of 3 (and analogues thereof) under solvent-free conditions and on gram scale. A significant preparative advantage of this method is its relatively short reaction time: It was found that addition of a second weak acid (meta-nitrobenzoic acid) to the reaction leads to rate enhancement with full conversion observed in twelve hours. Based on analogy to previous reports by the same authors, a plausible transition structure for the H-P-E-S-W transformation mediated by a chiral diamine catalyst is shown below in brackets (right side). The new protocol is very practical and should prove generally useful for organic chemists.
          The stereocontrolled synthesis of an interesting series of 17-b-aryl hydrindanes (e.g. 7 & 8) was also disclosed this year in JACS by the laboratory of Glenn Micalizio. The key step is a titanium-mediated cross-coupling of an internal alkyne (5) with a 4-hydroxy-1,6-enyne (6) to fashion a highly substituted and stereodefined dihydroindane (7). This complex carbocycle, similar to the Hajos-Parrish ketone, represents a valuable chiral building block, orthogonally protected and potentially suitable for elaboration into an oxygenated steroidal natural product such as ouabain or batrachotoxin.
          Mechanistically, the authors provide evidence to suggest that the overall metal-centered [2 + 2 + 2] annulation occurs by initial formation of a metallocyclopentadiene, followed by a [4 + 2] cycloaddition with the tethered olefin and finally cycloreversion to the substituted cyclohexadiene product. In addition, the diastereoselective conversion of intermediate 7 into the 11a-hydroxy derivative 8 by means of a 3-step protodesilylation/hydroboration sequence is also demonstrated. The metallacycle-mediated hydroindane synthetic methodology of Micalizio rapidly assembles a densely functionalized steroidal C/D ring substructure and may be of broad utility in the context of future total synthesis studies. For example, many interesting limonoid natural products substituted with a (hetero)aryl system appended at C17 and oxygenated functionality at C16 have been described, yet relatively few have been synthesized by organic chemists to date. These and other terpenoids, including cortistatin A, may become more accessible by implementation of the technologies described above.

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