Download PDF
Synlett 2002(6): 0962-0966
DOI: 10.1055/s-2002-31905
LETTER
© Georg Thieme Verlag Stuttgart · New York

Chiral Dihydroxyacetone Equivalents in Synthesis: Rapid Assembly of Styryl 1,2-Polyols as an Entry to the Styryllactone Family of Natural Products

Dieter Enders*, Stuart J. Ince, Melanie Bonnekessel, Jan Runsink, Gerhard Raabe
Institut für Organische Chemie, Rheinisch-Westfälische Technische Hochschule, Professor-Pirlet-Straße 1, 52074 Aachen, Germany
Fax: +49(241)8092127; e-Mail: Enders@RWTH-Aachen.de;
Further Information

Publication History

Received 22 February 2002
Publication Date:
07 February 2007 (online)

    Permissions and Reprints All articles of this category

Abstract

A rapid entry to the polyol framework of the styryllactone family of natural products is reported. The key steps are two highly diastereoselective boron-mediated aldol reactions of a chiral dihydroxyacetone equivalent followed by a 1,3-anti or 1,3-syn-selective reduction. In addition, Evans-Tishchenko reduction of the cyclic aldol products effected an equilibration to the 1,2-syn aldol product before 1,3-anti selective reduction.

Key words

α-silyldioxanone - aldol reactions - cyclic ketone reduction - Evans-Tishchenko - styryllactones - asymmetric synthesis

8

All new compounds gave consistent analytical data including correct elemental analysis and/or HRMS.

10

CCDC 179448 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/conts/retrieving.html (or from the CCDC, 12 Union Road, Cambridge CB2 1EZ, UK; fax:+44(1223)336033; e-mail: deposit@ccdc.cam.ac.uk).

12

In contrast, the reaction of α-silyl ketone 1 with SmI2 and PhCHO, according to the conditions described for cyclohexanone in ref. [11] , was very sluggish and poorly diastereoselective.

13

NMR analysis of ketone 4 confirms it to be in a twist-boat conformation. In this respect a discussion of the reduction selectivity is complicated, as true axial or equatorial attack is no longer applicable in a twist-boat system. Pseudoaxial attack seems possible for both the syn- and anti-aldol products, the latter case may be disfavoured due to the proximity of the electron rich aryl ring and the coordinating Sm species.

14

A range of protic and Lewis acidic hydrolyses, transketalisations and thioketalisation were unsuccessful giving starting material or inseparable mixtures of TBS/acetal deprotection. It is possible that the C-5 alcohol is acting as a general acid.

15

(S,S)-10: See ref. [9]

17

Prepared in two steps from propane-1,3-diol (silylation, Dess-Martin oxidation). Purified by chromatography on silica gel before use.

18

Analytical HPLC (chiral stationary phase) showed that the ee of 1 was carried through to the reduction products with no depreciation. 1 was prepared in up to 96% ee as judged by GC (chiral stationary phase).

27

In this case the much smaller ligands on boron may make chelate formation much easier. The observed colour change of the reaction, from red to yellow, is consistent with H2 transfer to the Rh(I) catalyst. On closer examination of a model there would appear to be more steric crowding on the lower face of the chelated complex, consistent with the observed outcome.

28

Preparation of 1,3-syn diol 14 (over 2 steps from ketone 11):
To a stirred solution of Cy2BCl [29] (2.0 mL, 9.0 mmol, 1.5 equiv) in anhyd Et2O (50 mL) at -78 ºC, under an Ar atmosphere, was sequentially added freshly distilled Et3N (1.42 mL, 10.2 mmol, 1.7 equiv) and a solution of ketone 11 (2.35 g, 6.0 mmol, 1.0 equiv, de = 73%) in anhyd Et2O (20 mL) dropwise via syringe. Stirring was continued at -78 ºC for a further 20 min before warming to 0 ºC for 1 h. The resulting bright yellow suspension was recooled to -78 ºC and a solution of freshly prepared 3-(tert-butyl-diphenyl-silanyloxy)-propionaldehyde (3.45 g, 11.0 mmol, 1.8 equiv) in anhyd Et2O (10 mL) was added dropwise via syringe. Stirring was continued at -78 ºC for a further 90 min before the flask was sealed and allowed to stand in a freezer (-24 ºC) for 10 h. The reaction was quenched with phosphate buffer (pH 7, 120 mL) and extracted. The aq layer was extracted with Et2O and the combined organic portions were concentrated in vacuo. The oily residue was resuspended in phosphate buffer (pH 7, 36 mL) and MeOH (36 mL) and cooled to 0 ºC. Aq H2O2 solution (30%, 18 mL) was added dropwise and the mixture stirred vigorously for a further 1 h. The mixture was poured into phosphate buffer (pH 7, 120 mL) and extracted with CH2Cl2 (4 × 100 mL). The combined organic portions were washed with H2O (50 mL), dried (Na2SO4), filtered and concentrated in vacuo to give a colourless oil. Purification by chromatography on silica gel (gradient elution: 19:1 → 8:1 pentane:Et2O) gave the title compound 13 (4.94 g, de = 74%) heavily contaminated with aldehyde. An analytical sample (de = 74%) was afforded by further chromatography; [α]25 D +58.9 (c 1.0 in CHCl3); IR (thin film): 3543, 3071, 3050, 3032, 2942, 2891, 2866, 1739, 1472, 1464, 1428, 1383, 1219, 1169, 1112, 1068, 1030 cm-1; 1H NMR (400 MHz, CDCl3): δ = 0.96-1.08 (m, 30 H, CH TIPS, CH3 TIPS and TBDPS), 1.33 (s, 3 H, CH3 acetal), 1.41 (s, 3 H, CH3 acetal), 1.66-1.74 (m, 1 H, CH aHb), 1.75-1.82 (m, 1 H, CHa H b), 3.15 (d, 1 H, J = 3.3 Hz, (CHOH), 3.72 (dd, 1 H, J = 5.9, 1.0 Hz, H-4), 3.74-3.88 (m, 1 H, CH2OTBDPS), 4.06-4.12 (m, 1 H, CHOH), 4.46 (dd, J = 2.8, 1.0 Hz, 1 H, H-6), 5.28 (d, J = 2.8 Hz, 1 H, (CH(OTIPS)), 7.20-7.67 (m, 15 H, Ar-H); 13C NMR (100 MHz, CDCl3): δ = 12.5 (SiCH(CH3)2), 18.1, 18.2 (SiCH(CH3)2), 19.4 (SiC(CH3)3), 24.0, 24.3 (CH3 acetal), 27.1 (SiC(CH3)3), 34.6 (CH2), 61.6 (CH2OTBDPS), 68.6 (CHOH), 74.4 (CH(OTIPS)), 76.1 (C-4); 80.0 (C-6), 101.5 (acetal C), 127.7, 127.8, 127.9, 128.0, 129.9, 130.0, (Ar-C), 133.7, 133.8 (Ar-C, ipso), 135.8 (Ar-C), 140.2 (Ar-C, ipso), 209.5 (C=O); MS (CI): m/z (%)= 350(4), 349(16), 313(56), 263(100), 235(62), 175(13); HRMS (EI): m/z calcd for C19H29O4Si [M+ - C22H31O2Si]: 349.1835. Found: 349.1835. Anal. Calcd for C40H60O6Si (705.08): C, 69.84; H, 8.85. Found: C, 69.29; H, 8.60.
To a stirred suspension of NaBH4 (2.70 g, 70 mmol, 2.0 equiv) in anhyd Et2O (210 mL) under an Ar atmosphere, at r.t., was added a solution of ZnCl2 in Et2O (Aldrich, 1.0 M, 35 mL, 35 mmol, 1.0 equiv) via syringe. The resulting white suspension was stirred for a further 2 d before allowing the precipitate to settle. The resulting clear supernatant solution of Zn(BH4)2 in Et2O (ca. 0.14 M) was cooled to -78 ºC.
To a stirred solution of the crude ketone 13 (4.21 g, ca 5.97 mmol, 1.0 equiv) at -78 ºC, under an Ar atmosphere, was added the chilled supernatant solution of Zn(BH4)2 in Et2O (ca 240 mL, ca 34 mmol, 5.6 equiv), via double-ended needle over 45 min. The reaction mixture was warmed very slowly to r.t. The reaction mixture was quenched after 24 h with H2O until effervescence ceased (ca 5 mL) and stirred vigorously for 1 h. The resulting white suspension was filtered through Celite® and the filter-cake washed thoroughly with Et2O (400 mL). The combined filtrates were washed with sat. aq NaHCO3 solution and the aq portion back-extracted with Et2O (200 mL). The combined organic portions were dried (Na2SO4), filtered and concentrated in vacuo to give a cloudy colourless oil. Purification by chromatography on silica gel (gradient elution: 6:1 → 1:1 pentane:Et2O gave the title compound 14 (3.67 g, 87%, 52% ds, 74% de for reduction). On smaller scales a reduction de of 85% could be achieved; IR (thin film): 3472, 3071, 3050, 3031, 2943, 2892, 2866, 1471, 1463, 1428, 1380, 1224, 1198, 1172, 1112, 1069, 1029 cm-1; 1H NMR (400 MHz, CDCl3): δ = 0.95-1.10 (m, 30 H, CH TIPS, CH3 TIPS and TBDPS), 1.21 (s, 3 H, CH3 acetal), 1.39 (s, 3 H, CH3 acetal), 1.70-1.81 (m, 2 H, CH2), 3.14 (d, 1 H, J = 2.5 Hz, CHOH), 3.59 (ap t, 1 H, J = 5.5 Hz, H-4), 3.70 (dd, J = 4.7, 3.0 Hz, 1 H, H-6), 3.78-3.90 (m, 2 H, CH2OTBDPS), 3.92-3.97 (m, 1 H, CHOH), 4.09-4.13 (m, 1 H, H-5), 4.45 (d, 1 H, J = 3.6 Hz, 5-OH), 5.16 (d, 1 H, J = 4.7 Hz, CH(OTIPS)), 7.24-7.46 (m, 10 H, Ar-H), 7.63-7.67 (m, 5 H, Ar-H); 13C NMR (100 MHz, CDCl3): δ = 12.7 (SiCH(CH3)2), 18.2 (× 2) (SiCH(CH3)2, 19.4 (SiC(CH3)3), 24.1, 25.5 (CH3 acetal), 27.2 (SiC(CH3)3), 34.5 (CH2), 63.2 (CH2OTBDPS), 69.7 (C-5), 72.4 (CHOH), 73.8 (C-6), 77.7 (CH(OTIPS)), 78.6 (C-4), 101.3 (acetal C), 127.1, 127.9 (× 2), 128.3 (× 2), 130.0 (Ar-C), 133.2, 133.3 (Ar-C, ipso), 135.7, 135.8 (Ar-C)], 141.3 (Ar-C, ipso); MS (CI): m/z (%) = 709(9) [MH+ + 1], 534(54), 476(41), 458(29), 235(10), 175(100), 163(15); HRMS (EI): m/z calcd for C38H55O6Si2 [M+ - C3H7]: 663.3537. Found: 663.3534.