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DOI: 10.1055/s-2004-829092
An Enantioselective Formal Total Synthesis of (-)-TAN1251A
Publication History
Publication Date:
22 June 2004 (online)
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Abstract
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.
Key words
total synthesis - alkaloid - carbene insertion - asymmetric synthesis - spiro compounds
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References
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%.
10Flash column chromatography over AgNO3-impregnated SiO2 allowed small amounts of the (E)-vinylbromide-10 to be isolated as a single geometric isomer.
11Coincidentally, 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).
12We 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.