A bidirectional S(E)' strategy for 1,5-syn and 1,5-anti stereocontrol toward the synthesis of complex polyols.

Studies report a bidirectional S(E)' strategy applicable for the stereocontrolled synthesis of nonracemic 1,5-syn and 1,5-anti diols and their derivatives. Nonracemic 1,3,2-diazaborolidine auxiliaries are incorporated by chemoselective tin-boron exchange to provide reactive allylic boranes. The convergent pathway utilizes sequential reactions with two aldehydes producing stereochemical outcomes from cyclic, closed, and open transition state preferences, respectively.

Studies for the synthesis of marine natural products.

The process of allylic transposition in S(E)' reactions is a significant construct for synthesis. The flexibility of a variety of allylation strategies provides for the rational design of pathways to a diverse array of complex targets. Our recent studies of S(E)' reactions will examine issues of stereoselectivity and efficiency in the context of applications toward the synthesis of marine natural products such as the xenicane diterpenes, which feature the strained E-cyclononene ring system, and peloruside A, a 16-membered macrocyclic lactone.

Mechanistic plasticity of DNA topoisomerase IB: phosphate electrostatics dictate the need for a catalytic arginine.

Four conserved amino acids of type IB topoisomerases (Arg130, Lys167, Arg223, and His265 in vaccinia topoisomerase) catalyze the attack by tyrosine on the scissile phosphodiester to form a DNA-(3'-phosphotyrosyl)-enzyme intermediate. The mechanism entails general acid catalysis (by Lys167 and Arg130) and transition-state stabilization (via contact of His265 with the pro-Sp oxygen). Here we query the function of Arg223, which accelerates transesterification by a factor of 10(5).

Identification of specific nonbridging phosphate oxygens important for DNA cleavage by human topoisomerase I.

Methylphosphonate-bearing oligonucleotides are characterized by the replacement of one of the nonbridging oxygen atoms with a methyl group. While neutralizing the negative charge associated with the phosphodiester at the point of substitution, the methyl group also imparts chirality to the phosphorus atom. Herein we report the synthesis of a number of oligonucleotides containing isomerically pure S(p) and R(p) methylphosphonates at single positions for the purpose of investigating the hydrogen-bonding contacts necessary for human topoisomerase I function.

Remote phosphate contacts trigger assembly of the active site of DNA topoisomerase IB.

Vaccinia topoisomerase IB forms a covalent DNA-(3'-phosphotyrosyl)-enzyme intermediate at its target site 5'-CCCTTp downward arrow in duplex DNA. The contributions of backbone electrostatics and individual phosphate oxygens to the transesterification reaction were probed by introducing 22 single Rp and Sp methylphosphonate diastereomers at 11 positions flanking the cleavage site. Methyl groups at eight positions (four on the scissile strand and four on the nonscissile strand) inhibited the rate of single-turnover cleavage by factors of 50-50,000.

3'-modified oligonucleotides by reverse DNA synthesis.

Reverse DNA oligonucleotide synthesis (i.e. from 5'-->3') is a strategy that has yet to be exploited fully.

Guarding the genome: electrostatic repulsion of water by DNA suppresses a potent nuclease activity of topoisomerase IB.

Type IB topoisomerases cleave and rejoin DNA strands through a stable covalent DNA-(3'-phosphotyrosyl)-enzyme intermediate. The stability of the intermediate is a two-edged sword; it preserves genome integrity during supercoil relaxation, but it also reinforces the toxicity of drugs and lesions that interfere with the DNA rejoining step. Here, we identify a key determinant of the stability of the complex by showing that introduction of an Sp or Rp methylphosphonate linkage at the cleavage site transforms topoisomerase IB into a potent endonuclease.

Use of Electrochemical Methods as an Alternative to Tin Reagents for the Reduction of Vinyl Halides in Inositol Synthons.

Several vinyl halides previously used in inositol syntheses were subjected to electrochemical reduction. The unreactivity of allylic alcohols or allylic ethers at the applied potentials allowed the selective reduction of vinyl halides to olefins. Electrochemical methods provide for selective reduction of vinyl iodides over vinyl bromides, with better yields than analogous tin methodology.