Synthesis of (5R,8S,10R)‐6‐(Allyloxy)‐ and (5R,8S,10R)‐6‐(Propyloxy)ergolines from the 6‐Methyl Precursors

Abstract

Ally1 bromide, K,CO,, DMF, 96 h, r.t. a) m-Chloroperbenzoic acid, CH,CI,, 1 h, ~ b) CH,CN, 45 min, reflux H,, 10% Pd/C, 16 h, r.t. CF,COOH, 30 min, r.t Et,NSO,CI, CHCI,, 16 h, 50°C -10°C; 91 % 85 % 65 % 64 % 53 % I1 % 59 % 53 % 29 % 25 Yo 31% 33 % Et,NCOCI, CHCI,, 16 h, 50°C HELVETICA CHIMICA ACTA -Vol. 69 (1986) Scheme 241 R' R' 3 CH, H 4 CH, Boc 5 CN Boc 6 H Boc 7 Ally1 Boc 7aWe report here the successful application of a Meisenheimer [2,3]-sigmatropic rearrangement [2] on a (5R,8S, lOR)-6-allyl-ergoline N6-oxide, which has ultimately led to analogues of 1 and 2 where N 6 has become part of a substituted hydroxylamine function. The Scheme illustrates our synthesis, whereas reaction conditions and chemical yields are summarized in the Table. 2. Synthesis. -To generate the substrate for the Meisenheimer rearrangement, 8aaminoergoline 3 [3] was first protected with (Boc),O to give 4, which was converted to ergoline 6 via 5 by an earlier developed modification of the uon Braun degradation [4].Alkylation to 6-allylergoline 7 (crystallized as hydrochloride) completed the first part of our synthesis. Oxidation of the free base 7 with m-chloroperbenzoic acid gave a polar product, presumably the "' -oxide 7a, which was not isolated but rearranged to 6-(allyloxy)ergoline 8a. Catalytic hydrogenation of 8a was surprisingly specific: the terminal double bond was hydrogenated without major cleavage of the N-0 bond to yield 6-propyloxyergoline 9a. The protecting group on the 8a -amino function was cleaved from both compounds 8a and 9a to give 8b and 9b, respectively, which were in turn converted to the derivatives 8c and 9c as well as 8d and 9d bearing the C(8) substituents of 1 and 2, respectively.The analytical data of all novel compounds are summarized in the Table, Section 1.3. Pharmacological Evaluation. -Compounds 8c, 8d, 9c, and 9d were evaluated for their pharmacological activity. None of them inhibited ovum implantation in rats [5] at doses of 3 mg/kg S.C. (cf. 1 (CQ 32-084): ID,, = 0.028 mg/kg S.C. [6]). We conclude that the