Synlett 2004(3): 546-548  
DOI: 10.1055/s-2004-815406
LETTER
© Georg Thieme Verlag Stuttgart · New York

Stereospecific Construction of Chiral Quaternary α-Oxygenated Aldehydes from Chiral Secondary Alcohol Derivatives

Hideki Arasaki, Masashi Iwata, Daisuke Nishimura, Akichika Itoh, Yukio Masaki*
Gifu Pharmaceutical University, 5-6-1 Mitahora-Higashi, Gifu 502-8585, Japan
Fax: +81(58)2375979; e-Mail: masaki@gifu-pu.ac.jp;
Further Information

Publication History

Received 18 November 2003
Publication Date:
12 January 2004 (online)

Abstract

Chiral tertiary dichloromethylcarbinol derivatives 2, prepared from protected chiral secondary alcohols 1, were converted stereospecifically into chiral quaternary α-oxygenated aldehyde ­derivatives 4 and 11 via intermediary α-chloroepoxides 3 under weakly basic conditions (K2CO3/MeOH/r.t.). The fashion generating the quaternary centers was proved to be quite different depending on the substrates: inversion of configuration of non-benzylic substrate 2a and apparent retention with benzylic one 2b.

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Typical Experimental Procedures: Dichlorocarbene insertion reaction of TMS-ether of 1 under ultrasonic conditions: A mixture of NaOH (4.0 g) and Ca(OH)2 (1.0 g) was heated at 400 °C for 1.5 h, and the melted mixture was cooled to r.t. and ground to give a powdered alkali. Crude TMS-ether (155 mg) was obtained by stirring a mixture of 1a (100 mg, 0.77 mmol), TMSCl (125 mg, 1.15 mmol), and Et3N (150 mg, 1.5 mmol) in THF (2.0 mL) at r.t. for 3 h, followed by concentration. A mixture of the crude
TMS-ether 1a, the alkali powder (300 mg), and n-C16H33N+(Me)3Cl- (40 µL of 1 mg/mL CHCl3 stock solution) in CHCl3 (0.5 mL) was irradiated by ultrasound at 20-50 °C for 1 h. The mixture was filtered and the filtrate was washed with brine followed by concentration in vacuo to give a crude oil, which was submitted to the above conditions for the dichlorocarbene insertion reaction one more time. The crude product obtained was dissolved in MeOH (1.0 mL) and stirred with 3% HCl (0.1 mL) at r.t. for 2 h. The whole was concentrated, taken up with Et2O, washed with brine, dried over Na2SO4, and evaporated to give an oil. Purification of the crude product by chromatography on silica gel to give 2a (88 mg, 54%) as an oil with a recovery of 1a (31 mg, 31%). The same treatment of 1b (100 mg, 0.82 mmol) gave 2b (135 mg, 81%) with a recovery of 1b (10 mg, 10%). Compound 2a: [α]D 20 +1.5 (c 1.05, CHCl3). IR (neat): 3460, 2941, 2922, 2914, 2861, 1457 cm-1. 1H NMR (270 MHz, CDCl3): δ = 0.99 (s, 3 H), 1.40-1.87 (m, 13 H), 2.15 (br, 1 H), 5.78 (s, 1 H). Compound 2b: [α]D 20 -21.2 (c 1.0, CHCl3). IR (neat): 3558, 3479, 2990, 2918, 1495, 1448
cm-1. 1H NMR (270 MHz, CDCl3): δ = 1.92 (s, 3 H), 2.99 (br, 1 H), 6.05 (s, 1 H), 7.42-7.66 (m, 5 H).
Reaction of dichloromethylcarbinol 2 with K2CO3 in MeOH: A mixture of 2a (100 mg, 0.47 mmol) and K2CO3 (345 mg, 2.5 mmol) in MeOH (2.0 mL) was stirred for 10 h at r.t., and filtered through a short column of silica gel to give a crude product as an oil. The oil was purified by chromatography on silica gel to give 4 (64 mg, 79%) as an oil. The same treatment of 2b (100 mg, 0.49 mmole) gave 11 (88 mg, 92%) as an oil. Compound 4: [α]D 20 -43.3 (c 1.15, CHCl3). IR(neat): 2934, 2861, 2847, 1737, 1461 cm-1. 1H NMR (270 MHz, CDCl3): δ = 0.88 (br t, J = 6.8 Hz, 3 H), 1.22 (s, 3 H), 1.20-1.45 (br, 8 H), 1.45-1.68 (br, 2 H), 9.57 (s, 1 H). Compound 11: [α]D 20 -28.6 (c 1.10, CHCl3). IR (neat): 3479, 2923, 2913, 2847, 1448 cm-1. 1H NMR (270 MHz, CDCl3): δ = 1.55 (s, 3 H), 2.78 (bs, 1 H), 3.34 (s, 3 H), 3.44 (s, 3 H), 4.21 (s, 1 H), 7.26-7.55 (m, 5 H).

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Chiral HPLC was performed on CHIRALCEL OJ for 7 and 11 using a solvent system of hexane/i-PrOH (500/1 or 200/1). These compounds analyzed were determined to be >98% ee, which stands for no detection of the other enantiomer.