Stereoselective Cyanosilylation Reactions in Hindered Cyclic Ketones

Abstract

An efficient, mild and inexpensive protocol for the stereo­selective construction of cyanohydrins in hindered, and in some cases, multifunctional cyclic ketones has been established.

Key words

cyanohydrin - diastereoselectivity - ketones

References

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1

Moloney, M. G.; Trippier, P. C.; Yaqoob, M.; Wang, Z. Current Drug Discovery Technologies 2004, 1, submitted.

19

A typical experimental procedure is as follows: to the ketone (2-3 mmol) was added freshly distilled TMSCN (3 equiv, distilled over CaH₂) and ZnI₂ (3-5 mg, dried over P₂O₅) and the mixture was stirred at r.t. (or 90 °C for tetramic acid 2) for 24 h (6 h for compound 9). The crude product was immediately purified by flash chromatography using a petroleum ether-EtOAc eluant.

20

All new compounds gave satisfactory spectroscopic and high-resolution mass spectrometric or analytical data.

21

These diastereomers were readily distinguishable by ¹H NMR spectroscopy: for 6a at δ = 2.9 and 3.4 ppm (J = 13.6 Hz) and for 7a, the benzylic resonances appeared as a dd at δ = 2.5 and 3.6 ppm (J = 13.2 Hz).

22

The reaction of 5b differs from the earlier cases, since it exists exclusively as the enol tautomer, and product 6b/7b was not stable.

23

Additional support for the fact that lactam 10 was epimeric at C-7 came from a consideration of ¹³C NMR values: the ¹³C nitrile resonances for the two disatereomers of 4a were at δ = 120.16 and 118.99 ppm, for 4b were at δ = 122.32 and 119.32 ppm, and for 6a and 7a were at δ = 119.08 and 118.86 ppm. For cyanohydrin 10, the corresponding values were 114.8 and 114.9 ppm, and for the single diastereomers 11 and 13, the values were 115.0 and 116.2 ppm.