Synthesis of O-Benzyl Protected anti Aldols through the Cross-Coupling Reaction of Dibenzyl Acetals with a Chiral Titanium Enolate

Abstract

Addition of the chiral titanium enolate arising from 1 to dibenzyl acetals gives access to anti-β-benzyloxy-α-methyl carboxylic adducts in good yields and with diastereomeric ratios up to 99:1. These adducts can be easily converted into a plethora of enantiopure protected derivatives.

acetals - aldol reactions - chiral auxiliaries - stereoselective reactions - titanium enolates

References

1a Cowden CJ. Paterson I. In Organic Reactions   Vol. 51:  Paquette LA. John Wiley & Sons; New York: 1997.  p.1 

1b Carreira EM. In Comprehensive Asymmetric Catalysis   Vol. 3:  Jacobsen EN. Pfaltz A. Yamamoto H. Springer; Heidelberg: 1999.  p.997 

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Diallyl and dibenzyl acetals have been prepared according to reported procedures:

5a Tsunoda T. Suzuki M. Noyori R. Tetrahedron Lett.  1980,  21:  1357 

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6a Greene TW. Wuts PGM. In Protective Groups in Organic Synthesis   3rd ed.:  John Wiley & Sons; New York: 1999. 

6b Kocienski PJ. In Protecting Groups   Thieme; Stuttgart: 1994. 

7

Yields lower than 50% were usually obtained under the reported conditions.

8

Di-(p-methoxybenzyloxy) acetal derived from isobutyr-aldehyde, i-PrCH(OPMB)₂, was also tested. In this case, complex reaction mixtures were obtained because of the unstability of the corresponding oxocarbenium intermediate.

9

Typical Experimental Procedure. Neat TiCl₄ (0.12 mL, 1.1 mmol) was added dropwise to a solution of 1 (217 mg, 1.0 mmol) in CH₂Cl₂ (8 mL), at 0 °C under N₂. The yellow suspension was stirred for 5 min at 0 °C, cooled at -78 °C, and a solution of i-Pr₂EtN (0.19 mL, 1.1 mmol) in CH₂Cl₂ (1 mL) was added. The dark red enolate solution was stirred for 2 h at -40 °C, and 1 M SnCl₄ in CH₂Cl₂ (1.1 mL, 1.1 mmol) followed by acetal g (314 mg, 1.1 mmol) in CH₂Cl₂ (1 mL) were successively added dropwise at -78 °C. The resulting mixture was stirred at -78 °C for 15 min and kept at -20 °C for 2 h. The reaction was cooled at -78 °C and quenched by the addition of saturated NH₄Cl (8 mL) with vigorous stirring. The layers were separated. The aqueous layer was re-extracted with CH₂Cl₂, and the combined organic extracts were dried (Na₂SO₄), filtered, concentrated, and analyzed by HPLC. Purification by flash column chromatography on deactivated (2.5% Et₃N) silica gel (from hexanes to hexanes/CH₂Cl₂ 1:1), afforded 278 mg (71%) of the major diastereomer 2g: Yellow oil. R_f = 0.6 (CH₂Cl₂). HPLC (hexanes/EtOAc 98:2) t _R = 17.2 min. [α]_D = +106.5 (c = 0.75, CHCl₃). IR (film) 2957, 2861, 1699, 1684, 1653, 1559, 1456, 1364, 1256, 1157, 1094 cm^-1. ¹H NMR (500 MHz, CDCl₃) δ 7.40-7.20 (5 H, m, ArH), 5.25 (1 H, ddd, J = 8.5 Hz, J = 5.3 Hz, J = 1.4 Hz, NCH), 5.13-5.07 (1 H, m, COCHCH₃), 4.61 (1 H, d, J = 11.4 Hz, OCH_xH_yPh), 4.55 (1 H, d, J = 11.4 Hz, OCH_xH_yPh), 4.06 (1 H, ddd, J = 9.4 Hz,
J = 6.5 Hz, J = 2.7 Hz, CHOBn), 3.43 (1 H, dd, J = 11.5 Hz, J = 8.5 Hz, SCH_xH_y), 2.94 (1 H, dd, J = 11.5 Hz, J = 1.4 Hz, SCH_xH_y), 2.19 [1 H, hepd, J = 6.9 Hz, J = 5.3 Hz, NCHCH(CH₃)₂], 1.87-1.79 [1 H, m, CH_xH_yCH(CH₃)₂], 1.57 [1 H, ddd, J = 10.2 Hz, J = 9.4 Hz, J = 4.1 Hz, CH_xH_yCH(CH₃)₂], 1.30-1.23 [1 H, m, CH₂CH(CH₃)₂], 1.16 (3 H, d, J = 6.8 Hz, COCHCH₃), 0.93 (3 H, d, J = 6.9 Hz, CH₃), 0.92 (3 H, d, J = 6.7 Hz, CH₃), 0.89 (3 H, d, J = 6.9 Hz, CH₃), 0.87 (3 H, d, J = 6.6 Hz, CH₃). ¹³C NMR (75.4 MHz, CDCl₃) δ 202.5 (C), 176.1 (C), 138.8 (C), 128.1 (CH), 127.6 (CH), 127.3 (CH), 78.0 (CH), 71.8 (CH), 71.7 (CH₂), 42.1 (CH), 39.5 (CH₂), 30.8 (CH), 29.1 (CH₂), 24.5 (CH), 24.1 (CH₃), 21.9 (CH₃), 19.0 (CH₃), 16.9 (CH₃), 12.5 (CH₃). HRMS(+FAB): calcd for [M + H]⁺ C₂₁H₃₂NO₂S₂ 394.1874, found 394.1891.

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The stereochemistry of the adducts has been assigned by analogy. The absolute stereochemistry of 2i has been confirmed by chemical correlation.

Acetal 4 was prepared from commercially available methyl (S)-3-hydroxy-2-methyl propionate following reported procedures:

11a Ley SV. Anthony NJ. Armstrong A. Brasca MG. Clarke T. Culshaw D. Greck C. Grice P. Jones AB. Lygo B. Madin A. Sheppard RN. Slawin AMZ. Williams DJ. Tetrahedron  1989,  45:  7161 

11b Roush WR. Palkowitz AD. Ando K. J. Am. Chem. Soc.  1990,  112:  6348 

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Selected data for 5. [α]_D = +75.5 (c = 0.75, CHCl₃). ¹H NMR (300 MHz, CDCl₃) δ 7.70-7.60 (4 H, m, ArH), 7.46-7.14 (11 H, m, ArH), 5.31 (1 H, ddd, J = 8.5 Hz, J = 5.5 Hz, J = 1.2 Hz, NCH), 5.07 (1 H, dq, J = 9.9 Hz, J = 6.9 Hz, COCHCH₃), 4.67 (1 H, d, J = 11.7 Hz, OCH_xH_yPh), 4.61 (1 H, d, J = 11.7 Hz, OCH_xH_yPh), 4.30 (1 H, dd, J = 9.9 Hz, J = 1.7 Hz, CHOBn), 3.67 (1 H, dd, J = 10.1 Hz, J = 9.3 Hz, CH_xH_yOSi), 3.56 (1 H, dd, J = 10.1 Hz, J = 6.2 Hz, CH_xH_yOSi), 3.35 (1 H, dd, J = 11.4 Hz, J = 8.5 Hz, SCH_xH_y), 2.88 (1 H, dd, J = 11.4 Hz, J = 1.2 Hz, SCH_xH_y), 2.10-2.03 [1 H, m, CH(CH₃)₂], 1.98-1.85 (1 H, m, CHCH₂OSi), 1.08 [9 H, s, SiC(CH₃)₃], 1.07 (3 H, d, J = 6.9 Hz, COCHCH₃), 0.82 (6 H, d, J = 6.9 Hz, 2 × CH₃), 0.81 (3 H, J = 6.9 Hz, CH₃). ¹³C NMR (75.4 MHz, CDCl₃) δ 202.6 (C), 177.0 (C), 139.4 (C), 135.6 (CH), 135.5 (CH), 133.8 (C), 133.7 (C), 129.7 (CH), 129.6 (CH), 128.0 (CH), 127.6 (CH), 126.9 (CH), 126.8 (CH), 80.3 (CH), 74.3 (CH₂), 71.8 (CH), 64.1 (CH₂), 41.4 (CH), 37.3 (CH), 30.9 (CH), 28.7 (CH₂), 26.9 (CH₃), 19.2 (C), 19.0 (CH₃), 16.8 (CH₃), 15.1 (CH₃), 9.8 (CH₃). HRMS(+FAB): calcd for [M + H]⁺ C₃₆H₄₈NO₃SiS₂ 634.2845, found 634.2823.

13 Masamune S. Choy W. Petersen JS. Sita LR. Angew. Chem., Int. Ed. Engl.  1985,  24:  1