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

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.

Key words

α,α-disubstituted α-oxyaldehyde - chiral synthesis - α-chloroepoxide - ring opening - methoxide anion

References

• 1a Fuji K. Chem. Rev.  1993,  93:  2037 
• 1b Corey EJ. Guzman-Perez A. Angew. Chem. Int. Ed.  1998,  37:  388 
• 1c Christoffers J. Mann A. Angew. Chem. Int. Ed.  2001,  40:  4591 
• 2a Katsuki T. Martin VS. Org. React.  1996,  48:  1 
• 2b Johnson RA. Sharpless KB. Catalytic Asymmetric Synthesis   Ojima I. VCH; New York: 1993.  Chap. 4.4.
• 2c Brandes BD. Jacobsen EN. J. Org. Chem.  1994,  59:  4378 
• 2d Fukuda T. Irie R. Katsuki T. Synlett  1995,  17 
• 2e Frohn M. Shi Y. Synthesis  2000,  1979 ; and references cited therein
• 2f Kolb HC. van Niewenhze MS. Sharpless KB. Chem. Rev.  1994,  94:  2483 
• 2g Evans DA. Burgey CS. Kozlowski MC. Tregay SW. J. Am. Chem. Soc.  1999,  121:  686 
• 2h Trost BM. J. Am. Chem. Soc.  1998,  120:  12702 
• 3a Besse P. Veschambre H. Tetrahedron  1994,  50:  8885 
• 3b Stecher H. Faber K. Synthesis  1997,  1 
• 3c Wills M. Tye H. J. Chem. Soc., Perkin Trans. 1  1999,  1109 
• 4 Masaki Y. Arasaki H. Shiro M. Chem. Lett.  2000,  1180 
• 5 Masaki Y. Arasaki H. Iwata M. Chem. Lett.  2003,  32:  4 
• 8a

  The reagent ΑD-Mix-β was purchased from Aldrich Com. Τhe glycol 9 proved to be obtained in 72% ee from chiral HPLC of the derived 7 using CHIRALCEL OJ (hexane/i-PrOH = 500/1).

• 8b Krief A. Castillo-Colaux C. Synlett  2001,  501 
• 8c Kolb HC. van Nieuwenhze MS. Sharpless KB. Chem. Rev.  1994,  94:  2483 
• 9a Kaczmarczyk G. Jonczyk A. Synlett  1997,  921 
• 9b Griesbaum K. Lie GO. Keul H. J. Org. Chem.  1984,  49:  679 
• 9c Kirrmann A. Duhamel P. Nouri-Bimorghi R. Liebigs Ann. Chem.  1966,  691:  33 
• 9d Stevens CL. Farkas E. Gillis B. J. Am. Chem. Soc.  1954,  76:  2695 
• 10a Aoyama Y. Urabe H. Sato F. Tetrahedron Lett.  1991,  32:  6731 
• 10b Paulmier C. Duturquin F. Plaquevent J.-C. Tetrahedron Lett.  1988,  29:  5889 
• 10c Eliel EL. Koskimies JK. Lohri B. J. Am. Chem. Soc.  1978,  100:  1614 

6

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).

7

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.