Research

A long-standing focus of attention in our research group has been the area of natural products chemistry. A synthetic target of current interest is asperlicin (I), a microbially-derived non-peptide antagonist of the neuropeptide, cholecystokinin (CCK). CCK acts as an hormonal regulator of pancreatic and gastric secretions, gall bladder contractions, and gut motility. CCK also is found in the brain, and there are indications that it may also function importantly as a central nervous system transmitter. CCK antagonists - such as I -are of potential therapeutic interest for gastrointestinal problems.

The structure of I suggests that it originates biogenetically from two units of anthranilic acid and one each of L-tryptophan and L-leucine. Our synthetic plan anticipates relatively straightforward condensations of the anthranilic acid and tryptophan units, followed by a novel oxidative addition of the leucine unit to the tryptophan for which initial exploratory studies on model systems will be required.

A second major concern of our research centers on the discovery and development of new and useful synthetic strategies and methodologies. Presently, we are investigating the utility of chlorine dioxide as a convenient and chemoselective reagent for the oxidation of amines to iminium ions. Surprisingly, although the oxidation of tertiary amines by ClO₂ has been established to occur via an electron abstraction route similar to that involved in the electrochemical oxidation of amines (eq.l), the synthetic utility of this reaction has hardly been explored.

Recently we have shown that the iminium ions generated by ClO₂ oxidation of amines may be trapped in situ with both internal and external nucleophiles, yielding a variety of -substituted amines and nitrogen heterocycles on a synthetic scale. For example, l-piperidinepropanol (1) reacts with ClO₂ to give a moderate yield of the bicyclic oxazolidine 2 (eq. 2).

Alternately, reaction of tertiary amines [ (RCH₂)₃N] with aqueous ClO₂ solutions in the presence of excess sodium cyanide as an external nucleophile affords -cyano-substituted tertiary amines [(RCH₂)₂NCH(CN)R] in good yields. The latter can provide masked carbonyl anion equivalents in basic media, or iminium salts through loss of cyanide ion in acidic media. This versatility makes these N,N-disubstituted -aminonitries, available directly from fully-formed tertiary amines by ClO₂-mediated cyanation, excellent intermediates for synthetic purposes.

In the case of oxidative -cyanation on N-methylpyrrolidine, high regioselectivity favoring ring cyanation over methyl cyanation (>8:1) was observed (eq. 3). A further examination of this advantageous regioselectivity in the pyrrolidine series has resulted in a biogenetically-patterned total synthesis of (±)-elaeocarpidine (6) as described below.

The Elaeocarpus alkaloids comprise a large family of indolizidine alkaloids for which the iminium ion 5 (or its biological equivalent) has been suggested as a common precursor. Treatment of 3 with ClO₂-NaCN afforded a 90% yield of two monocyanated products (9:1). The major product, alpha-aminonitrile 4, represents a synthetic equivalent of 5. Addition of a solution of 4 (1 mol-eq) and p-toluenesulfonic acid (2 mol-eq) in ethanol-water to a solution of AgOTs ( 1 mol-eq) in refluxing EtOH-H20 containing 1 mol-eq of tryptamine afforded chromatographically pure (±)-elaeocarpidine in 38% yield based on 4 (eq. 4).

The synthesis of 6 was additionally facilitated in a chemoselective sense by the ability to prepare acid-sensitive 4 from 3 under the non-acidic conditions which prevail in the ClO₂ mediated oxidative cyanations.

Our studies on applications of the ClO₂ oxidation of amines to the generation of iminium ions of interest in both traditional and biomimetic syntheses of alkaloids are continuing. We are also investigating the synthetic utility of ClO₂ oxidations of other organic functional groups.

Selected Publications

• Alfred G. Hortmann, Douglas S. Daniel and Jack E. Martinelli, Biogenetically Patterned Total Syntheses of (+)-Occidentalol and 7-Epi-(-)- occidentalol, J. Org. Chem., 38, 728 (1973).
• Maria G. Straatmann, Alfred G. Hortmann, and Michael J. Welch, Production of 1-¹¹C-Acetoacetic Acid, J. Labelled Cmpds., 10, 175 (1974).
• Ajit K. Bhattacharya and Alfred G. Hortmann, A General Synthesis of 1,3-Dithiol-2-ones, J. Org. Chem., 39, 95 (1974).
• Alfred G. Hortmann, Ronald L. Harris and James A. Miles, Thiabenzenes. IV. Synthesis and Ylidic Properties of 1-Methyl-3,5-diphenylthiabenzene and 1-Aryl-2-methyl-2-thia-naphthalenes, J. Am. Chem. Soc., 96, 6119 (1974).
• Alfred G. Hortmann and Ja-young Koo, A New Route to 2-Vinylaziridines and an Unusual Intramolecular Analog of the S_N2' Reaction Leading to Aziridine Ring Formation, J. Org. Chem., 39, 3781 (1974).
• Alfred G. Hortmann and Anup Bhattacharjya, Heterobicyclobutanylidines. A Unique Synthesis of Tetramethylallene Episulfide, J. Am. Chem. Soc., 98, 7081 (1976).
• Alfred G. Hortmann, Ja-young Koo, and Chen-Cheu Yu, The Utility of Hexachlorodisilane for the Deoxygenation of Nitrones, 2H-Imidazole 1-Oxides, 5H-Pyrazole 1-Oxides, and Related N-Hydroxy Compounds, J. Org. Chem., 43, 2289 (1978).
• Ajit K. Bhattacharya and Alfred G. Hortmann, Peroxy Acid Oxidation of Alkyl Phenyl Disulfides, J. Org. Chem., 43, 2728 (1978).
• Alfred G. Hortmann, Alan J. Aron and Ajit K. Bhattacharya, 3H-1,2- Benzodithiole Oxides: Studies Directed Toward the Generation of o-Thiobenzoquinone Methide and Benzo[b]thiete, J. Org. Chem., 43, 3374 (1978).
• Anup Bhattacharjya and Alfred G. Hortmann, Synthesis of the Macrocyclic Polythia Ether, [7.7](2,6)Dithia(2,5)thiophenophane, J. Heterocyclic Chem., 15, 1223 (1978).
• Chien-Kuang Chen, Alfred G. Hortmann and Mohammad R. Marzabadi, ClO₂ Oxidation of Amines: Synthetic Utility and a Biomimetic Synthesis of Elaeocarpidine, J. Am. Chem. Soc., 110, 4829 (1988).