Saturday, February 4, 2012
The First Semisynthesis of Hippuristanol by the Laboratory of Biao Yu
We have recently examined an elegant partial synthesis of the antiproliferative steroid natural product hippuristanol that was disclosed by the laboratory of Pierre Deslongchamps in 2010. An alternate synthetic synthetic route, starting from hydrocortisone, was described by Biao Yu (Shanghai Institute of Organic Chemistry) and co-workers in 2009. Hydrocortisone is a very judicious precursor to the target compound as it is relatively inexpensive and contains pre-installed oxygenated functionality at postitions C3, C11, and C20. Yu’s basic strategy is to elaborate the steroidal core structure and then to introduce the eastern bicyclic spiroketal appendage at a later stage via a stereocontrolled nucleophilic addition of an organometallic species to the methyl ketone at C17.
Hydrocortisone is first converted in several steps to a doubly benzoyl-protected 20-oxo-21-hydroxy derivative. In this preliminatry sequence, the A/B trans-fused ring junction stereochemistry is established with a dissolving metal reduction of the hydrocortisone enone system and the requisite axial 3alpha-ol is secured by a subsequent reduction of the corresponding C3 ketone with a sterically bulky hydride source (K-selectride). Next, deoxygenation of C21 is accomplished in three steps, followed by a semicarbazide-promoted elimination of water that installs a unit of unsaturation within the steroidal D-ring. Regio- and stereoselective hydration of the delta16,17 olefin is then achieved via the intermediacy of a bromohydrin that undergoes reductive dehalogenation under free-radical conditions to afford the 16beta-hydroxy pregnane advanced intermediate.
In the endgame, the lithiated dihydrofuran nucleophile adds to the beta-hydroxy C20-ketone to generate an initial adduct (shown in brackets) that is immediately subjected to Bronsted acid-mediated spiroketalization followed by deprotection of the benzoyl group with lithium aluminum hydride (LAH). Because the dihydrofuran is racemic, the maximum overall yield of this sequence is 50%. In light of this, a quite acceptable level of efficiency (43%) is observed. This is largely due to complete chelation control of the newly formed stereogenic position at C20 (For a discussion of this Cram chelate-controlled stereochemical outcome in a related system, see this post). Unfortunately, due to anomeric stability (For a discussion of the relevant anomeric effects pertaining to this transformation, see this post), C22-epi-hippuristanol is thermodynamically favored compared to the spiroketal configuration of the natural product. Happily, exposure of C22-epi-hippuristanol to a catalytic amount of a sulfonic acid in an aprotic medium effects epimerization of the spiroketal to provide synthetic hippuristanol. A very similar stereochemical phenomenon was observed by Deslongchamps et al. in the course of their partial synthesis of this structurally captivating steroidal natural product.
The semisynthetic preparation of hippuristanol by Biao Yu’s group is notable for its relative ease of synthesis and expediency. The lack of stereocontrol in the construction of the eastern bicyclic spiroketal appendage can be viewed as a shortcoming from the perspective of synthetic efficiency. However, from a medicinal chemistry viewpoint, the route provides access to stereochemical variation in the eastern hemispheric structural domain of hippuristanol. In vitro characterization of a series of analogues, produced in the course of the synthetic campaign, has revealed some very interesting structure-activity relationships (SARs) regarding bioactivity. For example, it was shown that the spiro configuration of the C22 position and the presence of the geminal dialkyl substitution on the steroidal F-ring are critical to the antiproliferative activity of hippuristanol. Notably, the configuration and presence of the C24 methyl group (adjacent to the geminal di-methyl) does not contribute significantly to the biological activity of hippuristanol and may represent a useful ‘point of diversity’ that could be modulated in a medchem optimization effort to improve the potency and/or physical properties of a potential anticancer drug candidate.