Federation of Asian Chemical Societies (FACS)

  Last updated on 13 June, 2001      

Adventures in Enantioselective Synthesis 

Dr. E. J. Corey
the Professor of Harvard University　

Much of the recent research effort of Dr. Corey's group at Harvard has been devoted to the chemical synthesis of important biologically active molecules and to the development of new methods and strategies of synthesis which are crucial to the efficient and successful execution of such multistep processes. His lecture collects several related projects and illustrates the close relationship between synthetic strategy and design, on the one hand, and the development of powerful new tools for synthesis, on the other. These projects also exemplify the close relationship of synthetic chemistry to medicine and biology.

Ecteinascidin 743 (Et 743) is an exceedingly potent and rare marine-derived antitumor agent which is currently in Phase 2 clinical trials for a variety of cancers. The first part of this lecture deals with the development of efficient enantioselective syntheses of this complex structure, which are suitable for large scale commercial development. The same key intermediates have been applied to an effective enantiocontrolled total synthesis of saframycin A (Sf A).



Modeling studies of the Et 743 molecule, its possible mode of interaction with double-stranded DNA, and studies of the antitumor activity of a few selected derivatives of some of the pentacyclic intermediates on the pathway to Et 743, led to the design of a new series of antitumor agents of simpler structure than Et 743. The second of these to be synthesized, phthalascidin 650 (Pt 650) was found to be an exceedingly active antitumor agent against a wide range of cell types. The potency of Pt 650 is essentially identical to that of Et 743 and its mode of action and antitumor spectrum appear to be the same. Figure 1 shows in vitro antriproliferative activity for Et 743, Pt 650 and a number of commonly used antitumor agents against four tumor cell lines.

Phthalascidin and ecteinascidin 743 both complex with double-stranded DNA and induce DNA alkylation, probably at N(7) of guanine. In addition, they induce crosslinking of DNA with protein, and it probably this reaction is responsible for their extraordinary potency. The formation of a DNA-protein-Pt 650 complex has been demonstrated using 【14C】phthalascidin. The identity of the target protein is currently under investigation.



In the total syntheses of Et 743, Pt 650 and Sf A the chiral intermediates 1 and 2 shown below served as important early building blocks. Although the initially used synthetic routes to 1 and 2 (involving a Monsanto/Knowles-type reduction) were satisfactory for the synthesis of ca. 50 gram amounts, the development of a new synthetic route suitable for synthesis of much larger quantities would be highly desirable if Pt 650 or Et 743 were to be produced commercially on multikilogram scale. This fact and previous experiments on the origin of enantioselectivity in cinchona alkaloid-catalyzed enantioselective reactions led us to the rational design of a superior chiral phase transfer catalyst (3) for the synthesis of α-amino acids by enantioselective alkylation of tert-butyl glycinate derivatives. 



It was shown that a wide variety of α-amino acids could be synthesized in good yield and with extraordinary enantioselectivity (up to 400: 1, commonly 50:1) simply by stirring the benzophenone Schiff base of tert-butyl glycinate with an alkylating agent in CH₂Cl₂ in the presence of solid CsOH.H₂O. A detailed interpretation of the mechanistic basis of enantioselectivity has been presented. This lecture discussed the scope and theory of the various highly enantioselective phase transfer reactions catalyzed by 3 and the corresponding fluoride.

Another major application of the chiral quaternary ammonium ion 3 has been to charge-accelerated stereocontrolled 1,2-carbonyl and α,β-enone Michael addition reactions. An example of such a process is the application of the face-selective addition of nitromethane to an aldehyde formyl group in the synthesis of the second generation HIV protease inhibitor amprenavir (5 steps, 50% overall yield).



In the last section of the lecture studies on the enantioselective total synthesis of the alkaloids of Hyplophyton cimicidum was described, including aspidophytine and haplophytine. The ground leaves of this plant 〝La hierbe de la cucaracha〞were used at least since the Aztec era as an anticockroach / insecticidal powder. Despite remarkable advances in the synthesis of aspidosperma alkaloids in recent years, the syntheses of aspido- and haplophytine have remained as classic unsolved problems.

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