Paul A. Bartlett

CAVEAT: a program to facilitate the design of organic molecules.

SummaryA frequently encountered problem in the design of enzyme inhibitors and other biologically active molecules is the identification of molecular frameworks to serve as templates or linking units that can position functional groups in specific relative orientations. The program CAVEAT was designed to address this problem by searching 3D databases for such molecular fragments. Key innovations introduced in CAVEAT are a focus on relationships between bonds and the provision of automated methods to identify and classify structural frameworks. Performance has been a particular concern in formulating CAVEAT, since it is intended to be used in an interactive manner. The focus in this report is the design and implementation of the principal algorthms and the performance achieved.

Electrophilic lactonization as a tool in acyclic stereocontrol. Synthesis of serricornin

Abstract Several electrophilic lactonization procedures have been explored as a means of functionalizing olefinic carboxylic acids with relative asymmetric induction, Iodolactonization of δ,ϵ -unsaturated acids under conditions of thermodynamic control exhibits good 1,2- and 1,3-, but not 1,4-induction in the formation of δ-lactones. Mercurilactonization proceeds with good stereocontrol in the formation of both γ- and δ-lactones (1,2-induction), but suffers from the difficulty of elimination during reductive demercuration; phenylselenolactonization with N-(phenylseleno)phthalimide is apparently kinetically controlled, affording high induction with 10 , a strongly sterically biased substrate leading to a δ-lactone, but not with 16 , which leads to a γ-lactone. In contrast, hydroxymethyllactonization proceeds with good stereocontrol in the case of 26 , the ester of 10 , but not with the analogous ester of 16 . The lactones resulting from cyclization of 10 and 13 were converted in stereospecific fashion into each of the stereoisomers of(±)-serricornin.

Inhibition of chymotrypsin by phosphonate and phosphonamidate peptide analogs

Abstract A series of mono-, di-, and tetrapeptide analogs incorporating an activated, tetrahedral phosphorus moiety in place of the scissile carbonyl group have been synthesized and evaluated as inactivators of porcine pancreatic elastase (EC 3.4.21.11) and bovine pancreatic chymotrypsin (EC 3.4.21.1). As previously reported (Lamden, L. A., and Bartlett, P. A. (1983) Biochem. Biophys. Res. Commun.112, 1085–1090), the simple phosphonofluoridate analogs of alanine (6a-F) and phenylalanine (6b-F) are the most rapid inactivators yet reported for these enzymes. More hydrolytically stable derivatives of 5b and 6b were explored for chymotrypsin, and the thiophenyl, thiomethyl, and phenyl esters were shown to be effective inactivators, with the latter being the most stable. This strategy was extended to the tetrapeptide level by the synthesis of the four diastereomers of analog 8. However, each isomer proved to be comparable in its behavior toward chymotrypsin. Potential reasons for this unexpected lack of stereoselectivity were investigated, and it was shown that the phosphorus amide substituent is capable of functioning as a leaving group. In a related dipeptide diester analog, l -15, a threefold difference in reactivity between phosphorus diastereomers was seen.

A disulfide-bridge bifunctional imidoester as a reversible cross-linking reagent.

Abstract A disulfide-bridged bifunctional imidoester, dimethyl 3, 3′ dithio-bispropionimidate (DTP) has been prepared and investigated as a reagent to introduce covalent cross-links in proteins that can subsequently be broken by mild reduction. Such reversible cross-links were shown to be introduced by DTP in the soluble subunit proteins aldolase and Concanavalin A. DTP was also used to modify human intact erythrocytes. Such modification rendered the erythrocytes resistant to hypotonic lysis; subsequent treatment with mercaptoethanol lysed the cells. After DTP-modification of the cells, the hemoglobin contained in them could still be reversibly oxygenated and deoxygenated.

Stereoselective synthesis of the dihydroxyisoleucine constituent of the amanita mushroom toxins

Abstract Ester-enolate Claisen rearrangement of cis -croytl N- t -Boc-glycinate and iodolactonization of the N-phthaloyl derivative of the resulting unsaturated acid are used as the stereocontrolling steps in a synthesis of the title compound.

A stereocontrolled synthesis of the methyl ester of (±)-nonactic acid

Abstract Iodine-induced cyclization of a homoallylic phosphate and hydrogenation of a 2,3-dehydrononactic acid derivative are used to introduce the chiral centers selectively in a highly efficient synthesis of methyl nonactate.

Sequence-specific crosslinking agents for nucleic acids: Use of 6-bromo-5,5-dimethoxyhexanohydrazide for crosslinking cytidine to guanosine and crosslinking RNA to complementary sequences of DNA☆

A class of compounds of the form: NH2NHCO(CH2)nC(OR)2CHR′X has been designed to allow selective blocking of specific genetic sequences of DNA and RNA (Summerton, unpublished data). This paper describes the synthesis and use of 6-bromo-5,5-dimethoxyhexanohydrazide for such site-specific inactivation. In model reactions it is shown that this compound can be attached to the C-4 position of cytidine and that, after activation, the cytidine-bound agent crosslinks to the N-7 position of guanosine. This reaction sequence has been applied to the crosslinking of bacteriophage T7 RNA to its complementary DNA in a highly specific fashion. The RNA is derivatized with the hydrazide reagent, activated, and incubated under annealing conditions with the complementary DNA, resulting in crosslinks between the two strands that are stable to denaturing conditions, dependent on the presence of the crosslinking agent, and specific for the complementary DNA sequence. These studies show that the title compound is a promising sequence-specific blocking agent for nucleic acids. The capability of introducing site-specific blocks in DNA and RNA in this way may have a wide variety of applications in the study of genetic processes. In particular, the combination of this compound with appropriate restriction fragments may enable systematic mapping and characterization of viral genomes.

Phosphorus-containing purines and pyrimidines: A new class of transition state analogs

Abstract Synthetic routes to the [1,5,2]-diazaphosphorine (“4-phosphapyrimidine”), imidazo[4,5-e][1,5,2]-diazaphosphorine (“6-phosphapurine”), and imidazo[4,5-d][1,3,2]-diazaphosphorine (“2-phosphapurine”) ring systems have been developed. Appropriately functionalized derivatives of these heterocycles are desired as possible transition state analogs of the nucleoside deaminases.

Virtual Hydrocarbon and Combinatorial Databases for Use with CAVEAT

Three new virtual databases have been developed for use with the bond-orientation-based database searching program CAVEAT. These consist of a database of trisubstituted monocyclic hydrocarbons having ethyl, vinyl, and phenyl substituents; a database of unsubstituted bicyclic hydrocarbons; and a database of core structures from established combinatorial synthetic methods having hydrogen, ethyl, vinyl, and phenyl substituents at the readily varied positions. Each collection of molecules was subjected to a batch conformational search, minimization, and conversion to a vector database for use with CAVEAT.

A highly stereoselective synthesis of davanone

Abstract Iodocyclization of the anti 4-bromobenzyl ether acetate 4f is a key step in the first stereocontrolled synthesis of the trisubstituted tetrahydrofuran davanone.