An Enantioselective Formal Total Synthesis of (-)-TAN1251A

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

References

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9

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%.

10

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

11

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 Kawahara^2f [α]_D +9.1 (c 1.03, CHCl₃) (lit^2f [α]_D +8.9 (c 0.99, CHCl₃).

12

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.