Synlett 2008(7): 1013-1016  
DOI: 10.1055/s-2008-1072504
LETTER
© Georg Thieme Verlag Stuttgart · New York

Synthesis of C3-C12 Fragment of 24-Demethylbafilomycin C1 via anti-Selective Aldol Condensation as the Key Stereocontrol Step

Wei-Min Dai*a,b, Gaofeng Fenga,b, Jinlong Wua, Liang Suna,b
a Laboratory of Asymmetric Catalysis and Synthesis, Department of Chemistry, Zhejiang University, Hangzhou 310027, P. R. of China
Fax: +86(571)87953128; e-Mail: [email protected];
b Center for Cancer Research and Department of Chemistry, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong SAR, P. R. of China
Fax: +85223581594; e-Mail: [email protected];
Further Information

Publication History

Received 2 January 2008
Publication Date:
17 March 2008 (online)

Abstract

An efficient synthesis of the C3-C12 aldehyde fragment of 24-demethylbafilomycin C1 was accomplished for assembling the 16-membered plecomacrolide skeleton according to a 1,3-diene-ene ring-closing metathesis (RCM) strategy. A boron-mediated anti-selective aldol condensation of Abiko’s chiral propionate was used to secure the C6 and C7 stereogenic centers while the C8 chirality was introduced from a chiral building block. The dithiane alkylation and the methyl ketone Horner-Wittig olefination using allyldiphenylphosphine oxide were employed for construction of the requisite (E)-1,3-diene subunit.

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23

Procedure for Oxidation of the Alcohol 9 with Stabilized IBX to Form Aldehyde 10
To a solution of the alcohol 9 (1.990 g, 9.66 mmol) in DMSO (40 mL; without drying) was added stabilized IBX in six portions (45 wt%, 1.002 × 6 g, 9.66 mmol). After each addition of stabilized IBX, the resultant mixture was stirred for 2 h at r.t. The reaction was quenched by aq Na2S2O3 followed by addition of sat. aq NaHCO3. The aqueous mixture was extracted with EtOAc (100 × 2 mL) and the combined organic layer was dried over anhyd Na2SO4, filtrated, and concentrated under reduced pressure. The residue was purified by flash column chromatography (SiO2, 14% EtOAc in hexane) to provide the aldehyde 10 (1.399 g, 71% yield).
Compound 10: yellow oil; [α]D 20 -2.2 (c 1.35, CHCl3). 1H NMR (300 MHz, CDCl3): δ = 9.71 (d, J = 1.8 Hz, 1 H), 2.94-2.60 (m, 6 H), 2.10-1.80 (m, 2 H), 1.70 (dd, J = 14.7, 3.0 Hz, 1 H), 1.56 (s, 3 H), 1.15 (d, J = 7.2 Hz, 3 H). 13C NMR (75 MHz, CDCl3): δ = 203.4, 48.3, 43.2, 42.5, 28.3, 26.5 (¥2), 24.6, 16.2. HRMS (ESI+): m/z calcd for C9H17OS2 [M + H+]: 205.0721; found: 205.0729.

27

We checked the diastereomeric ratio of the isolated aldol products prepared in several runs by 1H NMR spectroscopy and found that the ratio is about 95:5 in all cases. We did not obtain any separable minor diastereomers on the 3-gram-scale reaction, implying that the minor diastereomer is not separable from the major isomer.

28

Epimerization of the aldehyde 20 obtained from both the DMP (aq NaHCO3, CH2Cl2, r.t.) and SIBX (DMSO, r.t.) oxidation was observed. The diastereomeric ratios are about 95:5. We are not sure whether the epimerization occurred during the oxidation or over silica gel during column chromatographic separation.

29

Physical and Spectroscopic Data of 3
Colorless oil; [α]D 20 31.9 (c 0.73, CHCl3). 1H NMR (300 MHz, CDCl3): δ = 9.40 (s, 1 H), 6.72 (dd, J = 9.9, 1.2 Hz, 1 H), 6.61-6.48 (m, 1 H), 5.81 (d, J = 11.4 Hz, 1 H), 5.09 (dd, J = 16.8, 1.8 Hz, 1 H), 4.99 (d, J = 10.2 Hz, 1 H), 3.54 (dd, J = 4.5, 3.0 Hz, 1 H), 2.95-2.85 (m, 1 H), 2.19 (d, J = 8.4 Hz, 1 H), 1.85-1.64 (m, 2 H), 1.76 (s, 3 H), 1.71 (s, 3 H), 1.04 (d, J = 7.5 Hz, 3 H), 0.92 (s, 9 H), 0.74 (d, J = 6.3 Hz, 3 H), 0.07 (s, 3 H), 0.06 (s, 3 H). 13C NMR (75 MHz, CDCl3): δ = 195.6, 157.6, 137.3, 137.2, 133.0, 127.4, 115.0, 79.4, 43.7, 36.9, 35.9, 26.0 (¥3), 18.6, 18.3, 16.3, 15.3, 9.3, -3.9, -4.0. HRMS (ESI+): m/z calcd for C21H39O2Si [M + H+]: 351.2719; found: 351.2729.