Synthesis of a biotin-like phosphonate model compound for (+)-hydantocidin

Abstract

Approaches to the synthesis of a biotinlike phosphonate are described. It was hoped that this would be a simpler model compound for the * Correspondence to: Hans Tobler, Novartis Crop Protection AG, Business Unit Herbicides, R-1047.110, CH-4002 Basel, Switzerland E-mail: hans.tobler@cp.novartis.com (Received 1 July 1998; revised version 20 August 1998; accepted 16 February 1999) 668Pestic Sci 55:633±675 (1999)Extended Summaries: IUPAC Congress naturally occurring spironucleoside ()-hydantocidin, but it showed no activity as a herbicide nor as an inhibitor of AdSS.Keywords: ()-hydantocidin; model compound; phosphonate; biotin-like 1 INTRODUCTION ()-Hydantocydin (1a; Fig 1) is a naturally occurring spironucleoside with potent herbicidal activity and is produced by certain strains of the actinomycete Streptomyces hygroscopicus (Tu È 2474). 1 It is actually a pro-herbicide, in that the corresponding 5'-phosphate (1b) inhibits adenylosuccinate synthetase (AdSS) in de-novo purine biosynthesis. 1,2The presently known synthetic methods for the parent compound 1a are not economically feasible and its close analogues lack biological activity.1 Since X-ray data of the enzyme-inhibitor complex 1b became available, the search for AdSS inhibitors has focused upon the CAMM-supported design of simpler model compounds: as an example, the biotin-like phosphonate 2 ful®ls the steric requirements for an AdSS inhibitor.Racemic 2 was synthesised in seven steps from the phosphonium salt 3a (Fig 2), a close analogue of a recently identi®ed biotin process key intermediate, 3 by using Wittig methodology for the introduction of the side chain (5) followed by appropriate functional group transformations and deprotection. In view of the well-known vigorous N-debenzylation reactions in biotin chemistry, a parallel synthesis using paramethoxybenzyl as a more-easily cleaved N-protecting group was carried out using 3b as starting material. The choice of protecting group proved to be critical. The key intermediates 3 are readily produced in two steps from thiolactones 4. 3±7 SYNTHESES 2.1 Introduction of side chain (Fig 3)Wittig reaction of phosphoranes derived from rac-3 with TBDMS-protected 2-hydroxy acetaldehyde 8,9 competed with reductive formation of thiophanes 6 and 7. The choice of base was crucial. Best results on a preparative scale (20 mmol) were achieved in the benzyl series with solid KN(TMS) 2 in the presence of a catalytic amount of 18-crown-6, 10 thus affording the exocyclic allylic silyl ether 5a in 66% yield (E-con®guration predominant), accompanied by the thiophane 6a.11 On the other hand, an analogous Wittig reaction with 3b under similar conditions proceeded disappointingly, 6b and 7b becoming the major components due to migration of the neighbouring p-MeO-phenyl moiety into the 2a-position. Thus Pestic Sci 55:633±675 (1999) 669Extended Summaries: IUPAC Congress the p-Meo-benzyl series was abandoned. Treatment of 3a with base alone furnished 6a as the sole product. Side-chain transformations 1 (Fig 4)Catalytic...