Syntheses and Biological Evaluation of (+)-Lactacystin and Analogs

Abstract

Since its isolation in 1991, (+)-lactacystin (1) has attracted considerable attention among leading synthesis laboratories due to its highly selective and potent inhibition of the 20S proteasome. The syntheses of this molecule described herein demonstrate several important strategies in the area of acyclic stereocontrol including the use of chiral metal enolate and chiral allylmetal-based bond construction methods. Figure 1) is a secondary metabolite derived from a streptomyces bacterial strain (OM-6519) [a] with the area of organic synthesis. His research group is engaged in the development of new reaction methodology concerned with acyclic stereocontrol as well as the application of these methods to the asymmetric synthesis of natural products and complex organic molecules. Biological Activity of Lactacystin Adam J. Morgan was born in 1978 in Phoenix, AZ. He is currently a senior at Boston University working toward a B. A. degree in chemistrywhere he is engaged in undergraduate research in the laboratories of Professor James S. Panek. For the past two summers, he has been the recipient of a Pfizer PREPARE fellowship. His research efforts include the asymmetric syntheses of natural products containing α-amino-β-hydroxyacid functionalities. Upon graduation, he plans on pursuing a career in the pharmaceutical industry.MICROREVIEWS: This feature introduces the readers to the authors' research through a concise overview of the selected topic. Reference to important work from others in the field is included.

The Sharpless asymmetric aminohydroxylation

“…22 Hydroxyleucine derivatives such as 127 have been used as key synthetic intermediates in a number of syntheses of (ϩ)-lactacystin (128) with the result that a number of synthetic strategies have been developed to provide access to this building block. 22, 88 The AA based strategy remains among the shortest and most efficient approaches to this structural unit. 88,89 A related approach has been reported for the enantioselective synthesis of the hexahydroazepine core of (Ϫ)-balanol (129).…”

Metals in anticancer therapy: Copper(II) complexes as inhibitors of the 20S proteasome

“…It has been shown that human cancer cells are more sensitive to proteasome inhibition than normal cells, indicating that proteasome inhibitors could be used as novel anticancer drugs. [7] Therefore, inhibition of the 20S core particle in the 26S proteasome by substrate modifications such as alkylations, and ring formations has been demonstrated by a number of organic species such as lactacystin,[8] macrocyclic esters,[9] epoxyketones,[10] and several peptide derivatives,[11] including recently FDA-approved boronates. [12,13] The premise that stoichiometric mixtures of copper ions with organic chelators can form a new class of proteasome inhibitors has been investigated by the Dou group in recent years.…”

Natural product synthesis as a challenging test of newly developed methodology

“…10 (+)-Lactacystin was shown to inhibit the 20 S proteasome and subsequent investigations have shown that it acts as a prodrug for its b-lactone, known as clasto-lactacystin b-lactone or omuralide (22), which is responsible for acylating the proteasome. 11 Structure activity relationships have demonstrated that the only replaceable group in the molecule that retains the biological activity is the C4 methyl group. Accordingly we designed our approach to (+)-22 in order to provide a flexible route amenable to analogue synthesis at this position (Scheme 5).…”

“…11 Osmium-catalyzed oxidative cyclization for the diastereoselective synthesis of cis-THFs and pyrrolidines.Scheme 12 Preparation of diol 49 via selective asymmetric dihydroxylation of tetradecatetraene(47).Scheme 13 Double oxidative cyclization of 50 for the synthesis of cis-sylvaticin: (i) NaIO 4 , CH 2 Cl 2 , 89%; (ii) C 11 H 23 PPh 3 + Br À , KHMDS, PhMe, À78 1C-rt, 91%. Downloaded by State University of New York at Albany on 20 October 2012 Published on 19 October 2012 on http://pubs.rsc.org | doi:10.1039/C2CC36040C View Online This journal is c The Royal Society of Chemistry 2012 Chem.…”