Short, Enantiospecific Syntheses of Indolizidines 209B and 209D, and Piclavine A from Diethyl‐L‐Glutamate

Abstract

The Iff-pyrrole derivative obtained from diethyl L-glutamate hydrochloride and tetrahydro-2,5-dimethoxyfuran was cyclized with BBr, to ethyl (5S)-5,6,7,8-tetrahydro-8-oxoindolizine-5-carboxylate (18). Catalytic hydrogenation of 18 over PdjC in AcOH gave ethyl (5S,8aR)-octahydroindolizine-5-carboxylate (21), whereas hydrogenation over Rh/AI,O, in EtOH/AcOH 99 : 1 afforded mainly ethyl (5S,8S,8aS)-octahydro-8-hydroxyindolizine-5-carboxylate (22). By functional-group interconversions, 21 was transformed into piclavine A (1) and indolizidine 209D (2). Similarly, (5R,8R,8aS)-octahydro-5-pentylindolizine-8-methanol (37), the final relay for indolizidine 209B (3), was obtained from 22.Introduction. -Indolizidine ( = octahydroindolizine) alkaloids attract attention because of their diverse biological properties and scarce occurrence in exotic organisms [ 13. Of particular relevance are the 5-alkyl-and 5,8-dialkylindolizidines which, despite their seemingly simple structures, are not easy to prepare in an enantiomerically pure state. A typical example is piclavine A (l), an antimicrobial constituent extracted from the tunicate Clavelina picta, which represents the first indolizidine occurring in the marine biosphere [2]. Equally typical are the highly toxic indolizidines 209D') (2) and 209B (3) which were isolated in infinitesimally small amounts from the skin of neotropical frogs of the Dendrobatidue family [4] [5]. Several approaches to 2 and 3 have been undertaken, whereas 1 has yet to be synthesized. The stereochemical problem centers on the construction of the bicyclic entity of the desired configuration at the C(5) and C(8a) positions and, in the case of 3, the creation of the trans-disposed Me group. A variety of solutions have been propounded. Most make use of chiral auxiliaries, whereas some exploit optically active starting materials of natural origin which were incorporated to various degrees in the final product [&lo]. However, they usually require many steps and, with few exceptions, are characterized by low yields.

Indolizidine (−)-235B′ and related structural analogs: Discovery of nicotinic receptor antagonists that inhibit nicotine-evoked [3H]dopamine release

“…1. Indolizidine (−)-235B′ ([5 R ,8 R ,8a S ]-(−)-5-(hept-6-enyl)-8-methyloctahydroindolizine), (−)-B-6 ([5 R ,8 R ,8a S ]-(−)-5-(hex-5-enyl)-8-methyloctahydroindolizine), (−)-B-8 ([5 R ,8 R ,8a S ]-(−)-8-methyl-5-(oct-7-enyl)octahydroindolizine), (−)-207A ([5 R ,8 R ,8a S ]-(−)-8-methyl-5-(pent-4-enyl)octahydroindolizine), (−)-205A ([5 R ,8 R ,8a S ]-(−)-8-methyl-5-(pent-4-ynyl)octahydroindolizine), (−)-237D ([5 R ,8 R ,8a S ]-(−)-5-heptyl-8-methyloctahydroindolizine) and ZZ-257 (methyl 8-oxo-5,6,7,8-tetrahydrohydroindolizine-5-carboxylate) were synthesized as previously reported (Jefford et al 1995; Toyooka et al, 2005). Indolizidine (−)-235B′ fragments, ZZ-261 (1,8- bis (2-methyl-6-piperidinyl)octane) and ZZ-262 (2-methyl-6-octylpiperidine), were prepared through catalytic hydrogenation of the corresponding ammonium precursors.…”

Total synthesis and study of myrmicarin alkaloids

“…16 Condensation between the D-glutamic acid diethyl ester and tetrahydro-2,5-dimethoxyfuran furnished the enantioenriched N -alkylpyrrole 29 . Lewis acid-induced intramolecular Friedel-Crafts cyclization of diester 29 yielded bicycle 30 17. Exhaustive reduction of the C7 ketone with sodium cyanoborohydride in the presence of zinc diiodide followed by ester reduction with lithium aluminum hydride generated alcohol 31 .…”

“…Reagents and conditions: i, BBr 3 , CH 2 Cl 2 , 5→23 °C;17 ii, NaBH 3 CN, ZnI 2 , CH 2 Cl 2 , 40 °C; iii, LiAlH 4 , THF, 0→23 °C (72% (2-steps)); iv, MsCl, pyridine, CH 2 Cl 2 , 0 °C; v, NaCN, DMF, 90 °C (90% (2-steps)); vi, NaOH, H 2 O, MeOH, 65 °C (90%); vii, EtOC(O)Cl, Et 3 N, THF, 0 °C; viii, BF 3 OEt 2 , CH 2 Cl 2 , 40 °C (57% (2-steps)); ix, MeC(O)Cl, AlCl 3 , CH 2 Cl 2 , 40 °C (93%); x, LiAlH 4 , THF, 65 °C (60%); xi, MeCH 2 C(O)NMe 2 , POCl 3 , toluene, 90 °C (68%); xii, LiAlH 4 , 1,4-dioxane, 100 °C (60%).…”

Indolizidine and quinolizidine alkaloids

“…153 With all four piclavines in hand, the biological activities could be individually assessed. That by Takahata and Okamoto 151 commenced with the (R)-2-(pent-4-enyl)pyrrolidine 247 (90% enantiomerically pure, according to a previous report by the authors 152 ), asymmetric dihydroxylation of which with AD-mix-β followed by acid-induced cyclisation yielded epoxide 248 and an inseparable diastereomer (Scheme 22).…”