Friday, May 25, 2012

Tian's Partial Synthesis of the Eastern Side of Cephalostatin 1

          The synthesis of the eastern hemisphere of the bis-steroidal pyrazine cephalostatin 1 by Tian and co-workers is notable for its efficiency on relatively large scale. The authors report that >2.5 grams of the oxygenated steroid structure shown above (right side) have been prepared as of the date of publication (2011) of their manuscript in Chemistry - An Asian Journal. The major challenges associated with the synthesis of this molecule are regio- and stereoselective oxidative manipulations of the D-ring along with ketalization to establish rings E and F. The latter task is accomplished by the Tian laboratory in an elegant way with a cascade reaction that will be discussed below.
          Intermediate 1 is obtained in eight steps from the inexpensive steroidal saponin hecogenin. The hindered thioketal of 1 is then metallated with n-butyl lithium and the lithiated anion quenched at low temperature with the aldehyde 2. This provides a 68% yield of a mixture of products favoring (5-6:1) the diastereomer predicted by the Cram-Reetz model for asymmetric induction. Two additional protecting group manipulations then secured the advanced intermediate 3. The diene 3 undergoes smooth cycloaddition with singlet oxygen and reduction of the crude endoperoxide product with zinc afforded 4 with good overall stereoselectivity (d.r. 10:1).
          The following step is remarkable and proceeds efficiently on gram-scale. In a cascade spiroketalization/SN2' E-ring-closure one-pot sequence, the intermediate 4 is exposed to aqueous hydrochloric acid with mild heating. This results in the removal of four acid-labile protecting groups (C3, C12, C23, C25) with concomitant assembly of the E/F ring system. The stereoselectivity of the transformation is quite good considering complexity of the system, providing 68% of the desired C22(S), C23(R) product along with about 20% of separable stereoisomers. Selective oxidation of the C3 hydroxyl of 5 with Fetizon's reagent (Ag2CO3/Celite) and acetylation of the C23 hydroxyl completes the synthesis of the eastern side of cephalostatin 1, with ~700 mg of 6 harvested from a single run. In the next post at Modern Steroid Science, we will discuss the mechanism of the Fuchs-Guo unsymmetrical pyrazine synthesis that is utilized in the endgame of all of the completed total syntheses (Tian, Shair, and Fuchs) of cephalostatin 1.

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