William L. Scott

Enantioselective solution- and solid-phase synthesis of glutamic acid derivatives via Michael addition reactions

Abstract The enantioselective conjugate addition of Schiff base ester derivatives to Michael acceptors either in solution (56–89% e.e.) or on solid-phase (34–82% e.e.) gave optically active unnatural α-amino acid derivatives. The reaction was conducted in the presence of chiral, non-racemic quaternary salts derived from the cinchona alkaloids using neutral, non-ionic phosphazene bases.

The solid phase synthesis of α,α-disubstituted unnatural amino acids and peptides (di-UPS)

Abstract This paper reports a new, mild procedure (“di-UPS”) for the solid phase synthesis of racemic α,α-disubstituted amino acids ( 1 ) and epimeric α,α-disubstituted terminal amino acid residues ( 2 , R 3 =H) in a resin bound peptide. The synthetic route is compatible with most protected amino acid side chains and can be used in a continuing solid phase synthesis. Di-UPS should find wide applicability in the design and solid phase synthesis of hybrid amino acids and peptides, and the construction of basis units for combinatorial chemistry.

Distributed Drug Discovery, Part 1: Linking Academia and Combinatorial Chemistry to Find Drug Leads for Developing World Diseases

There continues to be a need for innovative and inexpensive drugs to treat diseases of the developing world.1,2 It is also important to link academic training and research to critical societal needs. Indiana University−Purdue University Indianapolis (IUPUI) is addressing both these concerns by developing a concept called “Distributed Drug Discovery” (D3).(3) This Perspective describes how D3 can harness combinatorial chemistry, distributed over multiple academic and industrial locations, to educate students while they perform a key role in the early stages of drug lead discovery for developing world and otherwise neglected diseases. Two other articles in this issue of the Journal of Combinatorial Chemistry present case histories implementing the chemistry component of D3. One involves replicated D3 syntheses in the United States, Poland, Russia, and Spain.(4) The second is an application in which students at IUPUI make analogs of a potential anticancer agent.(5) In this Perspective, D3 is discussed in three parts: (I) The Concept of D3, (II) The Role of Combinatorial Chemistry in D3, and (III) Implementation of D3.

Distributed Drug Discovery, Part 2: Global Rehearsal of Alkylating Agents for the Synthesis of Resin-Bound Unnatural Amino Acids and Virtual D 3 Catalog Construction

Distributed Drug Discovery (D3) proposes solving large drug discovery problems by breaking them into smaller units for processing at multiple sites. A key component of the synthetic and computational stages of D3 is the global rehearsal of prospective reagents and their subsequent use in the creation of virtual catalogs of molecules accessible by simple, inexpensive combinatorial chemistry. The first section of this article documents the feasibility of the synthetic component of Distributed Drug Discovery. Twenty-four alkylating agents were rehearsed in the United States, Poland, Russia, and Spain, for their utility in the synthesis of resin-bound unnatural amino acids 1, key intermediates in many combinatorial chemistry procedures. This global reagent rehearsal, coupled to virtual library generation, increases the likelihood that any member of that virtual library can be made. It facilitates the realistic integration of worldwide virtual D3 catalog computational analysis with synthesis. The second part of this article describes the creation of the first virtual D3 catalog. It reports the enumeration of 24 416 acylated unnatural amino acids 5, assembled from lists of either rehearsed or well-precedented alkylating and acylating reagents, and describes how the resulting catalog can be freely accessed, searched, and downloaded by the scientific community.

Solid-phase synthesis of substituted glutamic acid derivatives via Michael addition reactions

Abstract The conjugate addition of Michael acceptors to the resin-bound benzophenone imine of glycine leads to a variety of racemic unnatural glutamic acid derivatives. This new approach expands the scope of unnatural amino acid and peptide synthesis (UPS).

Unexpected Hydrolytic Instability of N-Acylated Amino Acid Amides and Peptides

Remote amide bonds in simple N-acyl amino acid amide or peptide derivatives 1 can be surprisingly unstable hydrolytically, affording, in solution, variable amounts of 3 under mild acidic conditions, such as trifluoroacetic acid/water mixtures at room temperature. This observation has important implications for the synthesis of this class of compounds, which includes N-terminal-acylated peptides. We describe the factors contributing to this instability and how to predict and control it. The instability is a function of the remote acyl group, R2CO, four bonds away from the site of hydrolysis. Electron-rich acyl R2 groups accelerate this reaction. In the case of acyl groups derived from substituted aromatic carboxylic acids, the acceleration is predictable from the substituent’s Hammett σ value. N-Acyl dipeptides are also hydrolyzed under typical cleavage conditions. This suggests that unwanted peptide truncation may occur during synthesis or prolonged standing in solution when dipeptides or longer peptides are acylated on the N-terminus with electron-rich aromatic groups. When amide hydrolysis is an undesired secondary reaction, as can be the case in the trifluoroacetic acid-catalyzed cleavage of amino acid amide or peptide derivatives 1 from solid-phase resins, conditions are provided to minimize that hydrolysis.

Distributed Drug Discovery, Part 3: Using D3 Methodology to Synthesize Analogs of an Anti-Melanoma Compound

For the successful implementation of Distributed Drug Discovery (D3) (outlined in the accompanying Perspective), students, in the course of their educational laboratories, must be able to reproducibly make new, high quality, molecules with potential for biological activity. This article reports the successful achievement of this goal. Using previously rehearsed alkylating agents, students in a second semester organic chemistry laboratory performed a solid-phase combinatorial chemistry experiment in which they made 38 new analogs of the most potent member of a class of antimelanoma compounds. All compounds were made in duplicate, purified by silica gel chromatography, and characterized by NMR and LC/MS. As a continuing part of the Distributed Drug Discovery program, a virtual D3 catalog based on this work was then enumerated and is made freely available to the global scientific community.

Solid-phase synthesis of amino amides and peptide amides with unnatural side chains

Abstract Unnatural amino amides and peptide amides can be synthesized, using solid-phase chemistry, from glycine attached directly (or through an intervening peptide sequence) to a Rink resin. The glycine is converted to an activated benzophenone imine derivative, followed by C -alkylation and hydrolysis. This sequence provides a mild, high yielding route to Rink resin-bound racemic, unnatural, amino amides and di- and tripeptide amides. Cleavage with trifluoroacetic acid provides the final amide products in good yield and purity.

Solid-Phase Synthesis of Amino- and Carboxyl-Functionalized Unnatural α-Amino Acid Amides

A new solid-phase synthesis efficiently incorporates three different substituents (from R(1)-X, R(2)-CO(2)H, and R(3)-NH(2)) into a glycine-based peptidomimetic scaffold. The synthetic sequence is general and is typically accomplished in >50% overall isolated yield. Alkylating agents with a range of reactivities and normal and branched primary amines give good results. Utility was demonstrated by the synthesis of a series of protected phosphotyrosine mimetics.

Solid-phase synthesis of unnatural α-amino acid derivatives using a resin-bound glycine cation equivalent

Abstract Unnatural amino acids were synthesized on solid-phase by reaction of a resin-bound Schiff base with organo-boranes. This novel use of a resin-bound glycine cation equivalent allows for the preparation of a variety of amino acid structural types not readily available by the complementary anionic equivalent.