Synlett 2004(8): 1443-1445  
DOI: 10.1055/s-2004-829092
© Georg Thieme Verlag Stuttgart · New York

An Enantioselective Formal Total Synthesis of (-)-TAN1251A

James M. A. Autya, Ian Churcherb, Christopher J. Hayesa
a School of Chemistry, University of Nottingham, University Park, Nottingham, NG7 2RD, UK
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b The Neurosciences Research Centre, Merck Sharp & Dohme, Terlings Park, Harlow, Essex, CM20 2QR, UK
Further Information

Publication History

Received 19 April 2004
Publication Date:
22 June 2004 (online)


An enantioselective total synthesis of the muscarinic inhibitor (-)-TAN1251A has been achieved. An alkylidene 1,5-CH insertion reaction was used as a key step to produce a [5,5]-spirocyclic intermediate, which was transformed into the [6,5]-spirocyclic core of the natural product via an oxidative cleavage/aldol condensation sequence. The synthesis of the natural product was then completed using standard procedures.


Typical CH-Insertion Procedure: KHMDS (0.5 M in PhMe, 127 mL, 63.4 mmol) was added to a stirring solution of 11 (12.8 g, 31.7 mmol) in dry Et2O (200 mL) and the resulting mixture was stirred at r.t. for 1 h. The solvent was removed in vacuo and the residue was partitioned between brine (100 mL) and Et2O (100 mL). The separated organic layer was dried (MgSO4), concentrated in vacuo and purified by column chromatography [SiO2, petrol (40-60 °C):Et2O (10:1)] to give 5 as a colourless oil (10.7 g, 93%). [α]D -61.5 (c 1.07, CHCl3). 1H NMR (400 MHz, DMSO-d 6, 100 °C): δ = 5.30 (br s, 1 H), 4.30 (app. quin., J = 4.5 Hz, 1 H), 3.55 (ddd, J = 11.2, 5.6, 0.8 Hz, 1 H), 3.20 (ddd, J = 11.2, 4.5, 1.2 Hz, 1 H), 2.40-2.13 (m, 3 H), 2.05 (dd, J = 12.7, 4.5 Hz, 1 H), 1.87-1.79 (m, 2 H), 1.70 (s, 3 H), 1.36 (s, 9 H), 0.90 (s, 9 H), 0.10 (s, 3 H), 0.10 (s, 3 H). HRMS: 368.2638 [MH+] (C20H38NO3Si requires 368.2621). Anal. Calcd for C20H37NO3Si: C, 65.4%; H, 10.2%; N, 3.8%. Found: C, 65.1%; H, 9.9%; N, 3.8%.


Flash column chromatography over AgNO3-impregnated SiO2 allowed small amounts of the (E)-vinylbromide-10 to be isolated as a single geometric isomer.


Coincidentally, the spirocycle 14 was also a key intermediate on Kawahara’s second generation route, although it was synthesised in a different manner. Our 1H NMR, 13C NMR, HRMS and CHN analysis data were identical to that reported by Kawahara2f [α]D +9.1 (c 1.03, CHCl3) (lit2f [α]D +8.9 (c 0.99, CHCl3).


We found that the final reduction of 15 was capricious and that (-)-TAN1251A(1) was quite difficult to isolate in pure form. These difficulties have not previously been reported for this compound, but significant losses of material were incurred upon repeated chromatography.