Epoxide Opening-Induced Tandem 8-Azabicyclo[3.2.1]octane to 6-Azabicyclo[3.2.1]octane Rearrangement−Iminium Allylation: Synthesis of (±)-Peduncularine

Abstract

An efficient Lewis acid induced nitrogen-driven rearrangement iminium-trapping cascade from an epoxytropinone 3 gives a 7-allylated 6-azabicyclo[3.2.1]octan-3-one 2, which is converted into the alkaloid (+/-)-peduncularine (1).

Enantioselective desymmetrisation of an epoxytropinone for peduncularine synthesis

“…The residue was purified by column chromatography (50% Et 2 O in petroleum ether) to give the Mosher esters as a colourless oil (33 mg, 46%, 4:1 mixture of diastereomers by 19 F NMR analysis). Rf 0.24 (50% Et 2 O in petroleum ether); [α]D 24 −16.2 (c = 1.0, CH2Cl2); IR (film, cm -1 ) 2958br, 1753s (C=O ester), 1703s (C=O ketone), 1641s (C=O carbamate), 1513m, 1379m, 1274w, 1171m, 1029w; 1…”

“…In 2010 we reported a synthesis of the Aristotelia alkaloid (±)-peduncularine (5) (Scheme 1). 1 The key transformation was an efficient Lewis acid-induced nitrogen-driven rearrangement iminium-trapping cascade (most straightforwardly envisaged via 2 and 3) from an easily accessible epoxytropinone 1, which gave the more unusual 6-azabicyclo[3.2.1]octane system 4 present in the natural product. The current work describes our studies on enabling the rearrangement to proceed in an enantioselective manner, thereby providing an asymmetric entry to peduncularine (5).…”

Pyrroles as Dienes in (4+3) Cycloadditions

“…Cycloadduct 41 thus obtained is reduc-tively debrominated to afford desired 8-azabicyclo[3.2.1]octenone 42, a valuable meso intermediate for the synthesis of tropinoids and other natural products. 35,36,39,[43][44][45][46][47][48][49][50] Starting from meso 42, Mann and de Almeida Barbosa reported a synthetic route to (±)-scopoline (Scheme 10). 39 The Noyori group converted 42 into (-)-hyoscyamine in 3-4 steps.…”

“…35 In 2008, the Perlmutter group enantioselectively desymmetrized 42 in an asymmetric synthesis of the cancer MDR reversal agent, (+)-pervilleine C, 45 and in 2010 Hodgson and co-workers reported a synthesis of (±)-peduncularine from 42. 43 Scheme 7 (4+3) Cycloadditions of N-(electron-rich group)-substituted pyrroles [29][30][31] Scheme 8 (4+3) Cycloadditions of N-(electron-deficient group)-substituted pyrroles 27,28,33,34,36,39,41,42 Br O Br 39 (68%) 33 F. Hu et al…”

Synthesis of Normorphans through an Efficient Intramolecular Carbamoylation of Ketones

“…As part of our continuing interest in synthesizing lactams from trichloroacetamides, we report here an efficient method to synthesize the azabicyclic normorphan ring, based on an intramolecular carbamoylation of ketones. The 6-azabicyclo [3.2.1]­octane (normorphan) nucleus is the backbone of peduncularine and actinobolamine, and appears as a structural subunit in several other alkaloids . Additionally, various normorphans are pharmacologically interesting (Figure ).…”