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.

Key words

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

References

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• Diallyl and dibenzyl acetals have been prepared according to reported procedures:
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• Acetal 4 was prepared from commercially available methyl (S)-3-hydroxy-2-methyl propionate following reported procedures:
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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.

10

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

12

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.