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Synlett 2012(5): 783-787  
DOI: 10.1055/s-0031-1290339
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Total Synthesis and Stereochemical Revision of Burkholdac A

Junyang Liua, Xiao Maa, Yuqing Liub, Zhuo Wangb, Shuqin Kwongb, Qi Rena, Shoubin Tanga, Yi Menga, Zhengshuang Xu*a,b, Tao Ye*a,b
a Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, University Town of Shenzhen, Xili, Nanshan District, Shenzhen, 5180505, P. R. of China
b Department of Applied Biology & Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong, P. R. of China
Fax: +85222641912; e-Mail: bctaoye@inet.polyu.edu.hk; e-Mail: xuzs@szpku.edu.cn;
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Publication History

Received 13 December 2011
Publication Date:
08 February 2012 (online)

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Abstract

A stereocontrolled total synthesis of burkholdac A was completed, leading to a revision of the reported stereochemistry.

Key words

burkholdac A - total synthesis - antitumor - stereochemical assignment

13

Synthesis of the Proposed Burkholdac A (1)
Compound 2 (46 mg, 0.04 mmol) was dissolved in MeOH-CH2Cl2 (50 mL, 1:9) and added to a vigorously stirred solution of I2 (126 mg, 0.50 mmol) in MeOH-CH2Cl2 (200 mL, 1:9) at r.t. over 0.5 h. After 10 min, the reaction was quenched by addition of sat. aq solution of Na2S2O3 (20 mL) and concentrated in vacuo. The residue was extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with sat. aq solution of Na2S2O3 (20 mL) and brine (30 mL), dried over anhyd Na2SO4 and concentrated in vacuo. The residue was dissolved in pyridine (1 mL), after HF˙py (0.8 mL) was added at 0 ˚C, the reaction mixture was stirred at r.t. for 12 h. All volatiles were removed in vacuo; the residue was diluted with EtOAc (100 mL) and washed with HCl (20 mL, 1.0 M in H2O) and brine (20 mL), dried over anhyd Na2SO4 and concentrated in vacuo. The residue was purified by flash chromatography (eluted with EtOAc-hexanes-MeOH = 3:1:0.3) to provide the desired compound 1 (13.4 mg, 63% yield over 2 steps) as a white amorphous solid: [α]D ²0 -166.5 (c 0.35, MeOH). ¹H NMR (400 MHz, CD3CN): δ = 7.71 (d, J = 5.4 Hz, 1 H), 7.09 (d, J = 9.8 Hz, 1 H), 7.02 (br s, 1 H), 5.90 (br s, 1 H), 5.77 (d, J = 15.5 Hz, 1 H), 5.58 (dd, J = 6.1, 2.3 Hz, 1 H), 4.74 (br s, 1 H), 3.97-3.92 (m, 1 H), 3.83 (ddd, J = 10.2, 6.5, 4.0 Hz, 1 H), 3.68 (td, J = 10.3, 3.0 Hz, 1 H), 3.40-3.22 (m, 2 H), 2.73-2.67 (m, 2 H), 2.64-2.56 (m, 3 H), 2.51-2.43 (m, 3 H), 2.40-2.26 (m, 3 H), 2.18-2.08 (m, 2 H), 2.06 (s, 3 H), 0.83 (d, J = 0.8 Hz, 3 H), 0.81 (d, J = 1.0 Hz, 3 H) ppm. ¹³C NMR (100 MHz, CD3CN): δ = 172.4, 171.4, 171.2, 170.8, 131.9, 131.0, 70.0, 69.6, 60.1, 54.9, 54.8, 43.7, 41.2, 41.2, 41.1, 31.4, 29.1, 28.3, 20.8, 15.6, 15.0 ppm. ESI-HRMS m/z calcd for C22H36N3O6S3 + [M + H]+: 534.1761; found: 534.1757.

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The Analytical Data of the Revised Burkholdac A ( epi- 1)
[α]D ²0 -54.0 (c 0.23, MeOH). ¹H NMR (500 MHz, CD3CN): δ = 7.51 (s, 1 H), 7.41 (d, J = 6.9 Hz, 1 H), 6.90 (d, J = 8.9 Hz, 1 H), 6.12-6.06 (m, 1 H), 5.90 (d, J = 15.5 Hz, 1 H), 5.56-5.54 (m, 1 H), 4.70 (td, J = 9.2, 3.6 Hz, 1 H), 4.47-4.43 (m, 1 H), 4.18-4.13 (m, 1 H), 3.33-3.30 (m, 1 H), 3.21 (d, J = 10.5 Hz, 1 H), 3.13 (d, J = 14.0 Hz, 1 H), 2.96 (dd, J = 13.1, 7.2 Hz, 1 H), 2.86-2.57 (m, 8 H), 2.25 (dq, J = 13.6, 6.8 Hz, 1 H), 2.10 (s, 3 H), 2.08-2.01 (m, 2 H), 0.96 (d, J = 6.8 Hz, 3 H), 0.87 (d, J = 6.8 Hz, 3 H) ppm. ¹³C NMR (125 MHz, CD3CN): δ = 173.0, 172.2, 171.7, 170.1, 132.4, 131.5, 71.7, 69.0, 63.2, 56.8, 56.4, 41.8, 41.1, 40.8, 33.3, 31.2, 30.6, 30.5, 21.1, 19.8, 15.2 ppm. ESI-HRMS: m/z calcd for C22H36N3O6S3 + [M + H]+: 534.1761; found: 534.1760.