Sunday, February 8, 2015

Steroid Total Synthesis: New Transition Metal-Catalyzed Methods for Closure of the Steroid B-Ring

            Phil Baran’s group has recently disclosed a de novo synthetic approach for construction of the tetracyclic carbogenic steroid framework. Their methodology features (arguably underutilized) quinone diazide functionality as a latent cyclohexadienone carbene that readily undergoes intramolecular olefin cyclopropanation to close the steroid B-ring. The authors note that this unique carbene renders a phenol electrophilic at its normally nucleophilic para position. The quinone diazide cyclopropanation reaction exhibits quite broad substrate scope in an intermolecular sense as well.
            The advanced triazene intermediate (5) was designed by the Scripps team to serve as the masked quinone diazide that would, in the key synthetic operation (conversion of 6 à 7), undergo B-ring annulation. The synthesis of intermediate 5 involves a standard Sonogashira coupling to introduce the two carbon atoms of the requisite tether, followed by reduction of the nitro group. The resultant aniline 2 is then diazotized and trapped with diisopropylamine to generate the triazene functionality. The two-carbon tether is next elaborated to a vinyl cuprate species which engages the bicyclic enone 4 in a conjugate addition reaction. Preparation of the racemic steroidal C/D substructure 4 required six non-trivial synthetic operations starting from 2-methylcyclopentenone. Installation of an exocyclic olefin onto 5 is then required for the critical steroid annulation step. This is achieved by treatment of the silyl enol ether 5 with the well-known one-carbon electrophile, Eschenmoser’s salt. The critical rhodium-catalyzed cyclopropanation operation proceeds through the intermediacy of the transiently generated carbenoid shown above in the bracketed [TS-I]. The polycyclic steroid derivative 7 is used in crude form in a subsequent carbon-carbon bond fragmentation step (vida infra).
            As one would expect, cyclopropane ring-opening by nucleophilic chloride ion leads to cleavage of the C10-C19 bond, furnishing the dione 8 in acceptable yield over the previous five steps. The authors noted that much time and effort was invested in unsuccessful attempts to break the C9-C19 bond. A fragmentation of this nature would provide access to a synthetically useful prednisone-type carbocyclic connectivity. Unfortunately, in the case of substrate 7, the A-ring dienone acts as an efficient electron-sink and concomitant A-ring aromatization provides a strong thermodynamic driving force for cleavage of C10-C19. Alternate reductive conditions were developed to break the C9-C10 bond, expanding ring B to a seven-membered system reminiscent of the cortistatins. The Baran route to prepare the dione 8 should be considered the successful execution of a conceptually interesting retrosynthetic hypothesis for steroid synthesis. However, in terms of practicality, their protocol falls a bit short. The route requires a total of 18 synthetic operations (longest linear sequence of 13), beginning from a relatively costly trisubstituted nitrophenol (1). Moreover, the chemistry produces a racemic 11-oxo-estrone variant bearing a chloromethyl substituent at C9. This specific molecular architecture is non-naturally occurring and possesses (to my knowledge) no known pharmacologic or therapeutic medicinal value.
            On the contrary, novel methods for direct halogenation of the steroid C9 position offer tremendous value due to the demonstrated anti-inflammatory bioactivity of the 9-halo-corticosteroid series (e.g. fludrocortisone). Assuming that a 9-hydroxymethyl derivative of Baran’s advanced intermediate 8 could be accessed via cyclopropane cleavage with an O-nucleophile, a subsequent base-mediated retro-aldol process would afford an enolate (Int-I shown above) that could be trapped at C9 with an electrophilic source of fluorine. A proton quench of the same enolate, followed by equilibration to the thermodynamically favored natural estrone configuration would also be of interest.
            A related methodology for steroid total synthesis was recently reported by Wenjun Tang’s group. They have developed a new P-chiral biaryl monophosphine ligand (L*) that, in combination with a palladium catalyst, mediates the enantioselective dearomative cyclization of phenols that are tethered to enol triflates or aryl halides. For example, cyclization of the enol triflate 13, following initial oxidative addition, proceeds through the intermediacy of TS-I, depicted above in brackets. Nucleophilic substitution at the 4-position of the phenol moiety, followed by reductive elimination, then closes the steroid B-ring and furnishes 14 in a highly stereocontrolled fashion. Tang’s asymmetric synthesis of 14 (or 15, using the opposite antipode of the phosphine) proceeds in only four steps (!!!) starting from the readily available and optically active Hajos-Parrish ketone. This level of efficiency and practicality could potentially become competitive with analogous microbial biofermentation processes, particularly if the unique P-chiral catalyst were to become commercially available.

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