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  • Tropane alkaloids comprise a large group of bases occurring predominantly in the family ofthe Solanaceae . Structurally they are esters of carboxylic acids with tropine (3-hydroxy-8-aza-8-methyl-[3.2.1]-bicyclooctane) and are biosynthetically derived from amino acid and acetateprecursors. Despite the relative structural simplicity of the alkaloids, their biosynthesis is notwell understood from a mechanistic point of view. In this article the available information pertaining to this question is summarized and discussed in context with the information thatis available from the analogous pelletierine class of alkaloids. A new proposal for the mecha-nism of assembly of the acetate derived C3 fragment of these alkaloids is introduced.

    Keywords. Tropanes, Alkaloids, Biosynthesis, Mannich condensation

    1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 176

    2 The Amino Acid Derived Fragment . . . . . . . . . . . . . . . . . . . . 177

    3 The Acetate Derived Fragment . . . . . . . . . . . . . . . . . . . . . . 185

    3.1 The Role of Hygrine . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1853.2 The Biosynthesis of N-Methylpelletierine . . . . . . . . . . . . . . . . 1873.3 Incorporation of Acetate into Tropine . . . . . . . . . . . . . . . . . . 1893.4 Incorporation of Advanced Precursors . . . . . . . . . . . . . . . . . . 193

    4 The Biosynthesis of Lycopodine . . . . . . . . . . . . . . . . . . . . . 196

    5 A New Proposal for the Assembly of the Acetate Derived C3 Unit . . . 201

    6 The Reduction of Tropinone . . . . . . . . . . . . . . . . . . . . . . . 203

    7 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 205

    8 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 205

    Tropane and Related Alkaloids

    Thomas Hemscheidt

    Department of Chemistry, University of Hawaii at Manoa, Honolulu, HI 96822, USAE-mail: tomh@gold.chem.hawaii.edu

    Topics in Current Chemistry, Vol. 209 Springer-Verlag Berlin Heidelberg 2000

  • 1Introduction

    Some 80 years ago, Robert Robinson published his elegant synthesis of tropinonefrom succindialdehyde, methylamine and acetonedicarboxylate [1]. Promptedby his synthetic strategy he took up his speculations on the origin of natural pro-ducts in Nature, among them the tropanes, which were published shortly there-after [2]. A fascinating account of the history of these early ideas is presented byA.J. Birch [3]. Ever since, the biological origin of tropine has held an importantposition in our thinking about the biogenesis of alkaloids. Thus, when suitableexperimental tools, i.e. radiotracers, for the investigation of the biosynthesis ofnatural products became available in the late 1940s and early 1950s, among thealkaloids it was again the origin of the tropane nucleus that was one of the firsttargets of investigations [4].

    The current status of knowledge of the biosynthesis of the tropane alkaloidsis almost paradoxical: our understanding of the mechanisms by which plantsassemble the tropane nucleus (1) still leaves much to be desired whilst some ofthe late events in the formation of one particular tropane alkaloid, scopolamine(2), are understood in great detail.Applications of this knowledge in the sense ofmetabolic engineering of medicinal plants have even been described [5].

    176 T. Hemscheidt

    Apart from the sizable primary literature on the biosynthesis of the tropanes,a substantial number of reviews on this topic has been published. The two mostrecent of these describe the work from the laboratory of the late Eddie Leete [6]and the encouraging results that have been obtained on an enzymological level[7]. Experiments aimed at elucidating the biosynthesis of the tropic acid moietypresent in many tropane alkaloids have been reviewed recently by workers in thefield [8] and will not be covered here.

    The present review will focus on progress made in the elucidation of the bio-synthesis of tropane and related alkaloids from a more chemical perspective andwill attempt to outline what in our current understanding is deficient and toidentify the remaining problems. For this purpose, the discussion will be dividedinto two parts, dealing with the assembly of the amino acid derived C4N portion,C-1,C-5,C-6,C-7,N-8, of the five-membered ring and then with the assembly ofthe acetate derived C3 fragment, C-2,C-3,C-4, and the formation of the azabicy-clooctane system. A liberal definition of the term tropane will be used, so thatthe biosynthesis of cocaine and some biogenetically related pelletierine-typealkaloids may be included in the discussion. In the view of this author, results

  • obtained in the latter group may have a bearing on our thinking about the bio-synthesis of the tropanes in the customary narrow definition.

    2The Amino Acid Derived Fragment

    One of the first experimental results on tropane biosynthesis with radiotracermethodology in Datura stramonium [9] provided evidence that the C4N frag-ment of the five membered ring of the tropane alkaloids is derived from orni-thine (4) as had been envisioned by Robinson. This initial finding was subse-quently confirmed by work from various groups in a variety of genera [reviewedin 10]. In more recent studies, employing inhibitors of ornithine and argininedecarboxylases, it has been suggested that arginine (5) rather than ornithine isthe preferred source of the C4N fragment C-1,C-5,C-6,C-7,N-8 [11, 12]. Becauseof the close biogenetic relationship between ornithine and arginine via the ureacycle this finding does not constitute a fundamental contradiction to the earlierresults but rather a refinement of the model.

    The next question addressed first by Leete [13, 14], concerned the occurenceof a symmetrical intermediate on the pathway between ornithine and the alka-loids. The feeding of [2 14C]ornithine to Datura stramonium led to specificincorporation of the label into only C-1, the stereocenter of (R) configuration inthe tropine moiety of hyoscyamine (3), which was excised in unambiguous fashion. Leete concluded that an intermediate with C2v symmetry could not besituated on the pathway between ornithine and the tropane alkaloids.

    Several mechanistic interpretations have been put forth to explain this result.The first one of these envisioned the intermediacy of 5-N-methylornithine onthe pathway from ornithine to the alkaloids. After decarboxylation of this non-proteinogenic amino acid N-methylputrescine (6) would be obtained in whichthe secondary amino group originates from N-5 of ornithine and the primaryone from N-2 of the amino acid. No convincing experimental evidence could beaccumulated to support this hypothesis and it was later abandoned in favor of ascheme adapted from one first proposed by Spenser to account for the nonsym-metrical incorporation of lysine into sedamine [15].As formulated by Leete [16],this hypothesis requires the removal of the carboxyl group of the amino acid andthe subsequent N-methylation to occur without a free, i.e. not enzyme-bound,intermediate with C2v symmetry. This proposal mandates that the N-methylgroup of the resulting N-methylputrescine (6) is attached to the nitrogen atomoriginating from N-5 of ornithine and that N-5 of the amino acid is incorporatedinto the alkaloids (Path A1 in Scheme 1). An attractive variant of this proposalmentioned in passing by Leete, postulates that it may not be the N-methylationsubsequent to decarboxylation that results in a nonsymmetrical intermediate.Instead, differentiation of the two ends of the bound putrescine on the putativedecarboxylase enzyme would be achieved by transamination of the nitrogenatom from C-2 (ornithine numbering) subsequent to decarboxylation to yieldD1-pyrroline (Path A2). The usual mechanism of a-amino acid decarboxylases[17] involves binding of the a-amino group of the amino acid to the pyridoxalphosphate prosthetic group of the enzyme and delocalization of the negative

    Tropane and Related Alkaloids 177

  • charge resulting from loss of C-1 into the aromatic ring of the cofactor (see theintermediate in Path A2). After tautomerization an enzyme-bound imine isobtained (see the intermediate in Path A1) which is then hydrolyzed to the bio-genic amine. However, the first of these two intermediates can also be viewed asan intermediate in a transaminase reaction. Hydrolysis at this stage would resultin formation of a carbonyl group at C-2 of the original amino acid and conco-mitant loss of the amine nitrogen. The amine nitrogen could subsequently betransferred via transamination to an a-keto acid to regenerate the aldehyde functionality of the cofactor. This variant is conceptually particularly attractiveas it uses the pyridoxal phosphate prosthetic group common to amino aciddecarboxylases and transaminases to achieve the generation of the nonsymmet-rical intermediate. In any case, either version of this elegant proposal rational-

    178 T. Hemscheidt

    Scheme 1. Possible pathways for the incorporation of ornithine 4 or arginine 5 into tropanealkaloids

  • izes the experimental observation concerning nonsymmetrical incorporation ofornithine into the tropane ring in Datura stramonium. It has remained experi-mentally unsubstantiated on an enzymological level to this day, however.

    A third proposal to rationalize the nonsymmetrical incorporation of theamino acid precursor can be based on more recent experiments [11, 12] usingmechanism-based enzyme inhibitors. The results suggest that L-arginine (5) rather than L-ornithine (4) is the central intermediate on the amino acid level in the formation of the alkaloids. Recognizing the fact that in (5) the two aminogroups are differentiated, the model envisages that L-arginine is metabolized viaits biogenic amine agmatine (7) in which the two nit

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