Wednesday, April 16, 2014

Consider the Cyclopentane.


            The cyclopentane carbocyclic ring system, while ubiquitous in Nature, is not usually considered a privileged core structure for the development of a drug candidate due, in part, to a perceived synthetic intractability of stereochemically complex target molecules. But, to the contrary, a recent miniperspective in the Journal of Medicinal Chemistry by R. D. Taylor and co-workers, focusing on key scaffold components found in drugs listed in the FDA Orange Book, highlights the cyclopentane as a frequently encountered ring system (see Figure below, box 18/50). Another very recent J. Med. Chem. manuscript describes the discovery and development of simeprevir, a cyclopentane-based NS3/4A protease inhibitor, recently approved for the treatment of chronic HCV infection in combination with pegylated interferon-alpha and ribavirin.

from: Taylor, R. D.; MacCoss, M.; Lawson, A. D. G. J. Med. Chem. 2014, Articles ASAP.
            In this month’s issue of Current Organic Chemistry, we advance the argument that the cyclopentane motif has been utilized as an effective core scaffold for several highly successful medicinal chemistry programs and, thus, has provided an underappreciated yet significant value for biomedical research. Moreover, we have compiled an assortment of modern synthetic methods that offer a wealth of attractive and accessible technologies for the stereocontrolled construction of exceedingly complex cyclopentanoid chemotypes of natural and unnatural origin.
            In this Review article, we contend that cyclopentanes should be regarded as privileged scaffolds for drug discovery research and that expanded screening campaigns of novel cyclopentane-based small molecule libraries for therapeutically relevant biological properties will have a favorable impact on the development of the active pharmaceutical ingredients (APIs) of tomorrow. The Review should be of great interest to scientists who apply state of the art synthetic technologies to drug discovery research.

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."