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Synlett 2003(8): 1109-1112
DOI: 10.1055/s-2003-39891
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

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

Anabel Cosp, Igor Larrosa, Irina Vilasís, Pedro Romea*, Fèlix Urpí*, Jaume Vilarrasa
Departament de Química Orgànica, Universitat de Barcelona, Martí i Franqués 1-11, 08028 Barcelona, Catalonia, Spain
Fax: +34(93)3397878; e-Mail: promea@qo.ub.es; e-Mail: furpi@qo.ub.es;
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Publication History

Received 7 April 2003
Publication Date:
11 June 2003 (online)

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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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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. Rf = 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, OCHxHyPh), 4.55 (1 H, d, J = 11.4 Hz, OCHxHyPh), 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, SCHxHy), 2.94 (1 H, dd, J = 11.5 Hz, J = 1.4 Hz, SCHxHy), 2.19 [1 H, hepd, J = 6.9 Hz, J = 5.3 Hz, NCHCH(CH3)2], 1.87-1.79 [1 H, m, CHxHyCH(CH3)2], 1.57 [1 H, ddd, J = 10.2 Hz, J = 9.4 Hz, J = 4.1 Hz, CHxHyCH(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, OCHxHyPh), 4.61 (1 H, d, J = 11.7 Hz, OCHxHyPh), 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, CHxHyOSi), 3.56 (1 H, dd, J = 10.1 Hz, J = 6.2 Hz, CHxHyOSi), 3.35 (1 H, dd, J = 11.4 Hz, J = 8.5 Hz, SCHxHy), 2.88 (1 H, dd, J = 11.4 Hz, J = 1.2 Hz, SCHxHy), 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.