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Synlett 2008(15): 2379-2383  
DOI: 10.1055/s-2008-1078270
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Total Synthesis of Largazole

Qi Rena, Lu Daia, Hui Zhanga, Wenfei Tana, 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 518055, P. R. of China
b Department of Applied Biology & Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong
Fax: +86(852)22641912; e-Mail: bctaoye@inet.polyu.edu.hk;
Further Information

Publication History

Received 16 May 2008
Publication Date:
21 August 2008 (online)

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Abstract

The stereocontrolled total synthesis of largazole was accomplished, unambiguously confirming its structure. Key steps included the use of the Nagao thiazolidinethione auxiliary for a diastereoselective acetate aldol reaction, thiazoline-thiazole formation, and macrolactamization by use of the Mukaiyama reagent.

Key words

largazole - cyclodepsipeptide - total synthesis - anti­tumor - macrolactamization

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14

Procedure for the Preparation of Intermediate 13
(R)-3-Acetyl-4-isopropyl-1,3-thiazolidine-2-thione (12, 821 mg, 4.0 mmol) was dissolved in CH2Cl2 (10 mL), TiCl4 (751 mg, 4.0 mol) was added at 0 ˚C. After 5 min, the reaction was brought to -78 ˚C, DIPEA (516 mg, 4.0 mmol) was added via a syringe over 10 min. The reaction was kept at -78 ˚C for 2 h before aldehyde 11 (428.3 mg, 2.0 mmol) in CH2Cl2 (3 mL) was added dropwise. Saturated NH4Cl (20 mL) was added to the reaction mixture and CH2Cl2 (3 × 30 mL) was used for extraction. The combined organic phases were dried over anhyd MgSO4 and concentrated in vacuo to give the crude product, which was purified by chromatogra-phy on SiO2, eluting with EtOAc-hexane (1:8), to afford the desired compound 13 (692.1 mg, 83%) along with the minor isomer (53.2 mg, 6%).

19

Cyclodepsipeptide 20
[α]D ²0 17.5 (c 0.2, MeOH). ¹H NMR (500 MHz, CDCl3): δ = 7.75 (s, 1 H), 7.18 (d, 1 H, J = 9.3 Hz), 6.50 (dd, 1 H, J = 2.7, 9.0 Hz), 5.88 (dd, 1 H, J = 6.9, 14.6 Hz), 5.65-5.71 (m, 1 H), 5.54 (dd, 1 H, J = 6.7, 15.5 Hz), 5.26 (dd, 1 H, J = 9.4, 17.6 Hz), 4.60 (dd, 1 H, J = 3.6, 9.4 Hz), 4.27 (dd, 1 H, J = 3.1, 17.6 Hz), 4.03 (d, 1 H, J = 11.3 Hz), 3.28 (t, 1 H, J = 10.5 Hz), 2.85 (dd, 1 H, J = 9.9, 16.3 Hz), 2.67-2.75 (m, 3 H), 2.37-2.46 (m, 2 H), 2.06-2.14 (m, 1 H), 1.86 (s, 3 H), 1.32 (s, 9 H), 0.68 (d, 3 H, J = 6.9 Hz), 0.53 (d, 3 H, J = 6.9 Hz). ¹³C NMR (125 MHz, CDCl3): δ = 173.5, 169.3, 168.8, 167.9, 164.5, 147.4, 132.8, 128.1, 124.1, 84.3, 71.9, 57.7, 47.8, 43.2, 41.0, 40.4, 39.4, 34.0, 31.8, 29.9, 24.1, 18.8, 16.6. ESI-MS: m/z (%) = 585.17 (100.0), 607.15 (88.8). ESI-HRMS: m/z calcd for C25H37N4O4S4 [M + H]+: 585.1698; found [M + H]+: 585.1689.

20

Procedure for the Synthesis of Largazole (1)
Compound 20 (9.9 mg, 0.02 mmol) was dissolved in degassed THF-H2O (v/v = 4:1, 2 mL) and treated with n-Bu3P (6.1 mg, 0.03 mmol) at r.t. for 6 h. The reaction solution was made up to 50 mL with EtOAc and dried over anhyd Na2SO4. The free thiol intermediate was obtained after removal of solvent in vacuo. The thiol intermediate was then dissolved in CH2Cl2 (5 mL), DIPEA (21.9 mg, 0.17 mmol), and octanoyl chloride (22 mg, 0.136 mmol) was added at 0 ˚C followed by a catalytic quantity of DMAP. The reaction mixture was stirred at r.t. for 10 min and then quenched by sat. NaHCO3 (5 mL). CH2Cl2 (3 × 30 mL) was used for extraction. The combined organic phases were dried over anhyd Na2SO4 and concentrated in vacuo to give the crude product. Purification with chromatography on SiO2, using EtOAc-hexane (2:1), provided the target molecule 1 (8.2 mg, 0.0132 mmol, 78%).
[α]D ²0 18.5 (c 0.2, MeOH). ¹H NMR (500 MHz, CDCl3): δ = 7.76 (s, 1 H), 7.15 (d, 1 H, J = 9.3 Hz), 6.46 (dd, 1 H, J = 2.6, 9.5 Hz), 5.80-5.84 (m, 1 H), 5.65-5.68 (m, 1 H), 5.51 (dd, 1 H, J = 7.1, 15.5 Hz), 5.29 (dd, 1 H, J = 9.4, 17.6 Hz), 4.61 (dd, 1 H, J = 3.3, 9.2 Hz), 4.27 (dd, 1 H, J = 2.8, 17.6 Hz), 4.05 (d, 1 H, J = 11.3Hz), 3.28 (d, 1 H, J = 11.3 Hz), 2.90 (t, 2 H, J = 7.2 Hz), 2.86 (dd, 1 H, J = 10.5, 16.5 Hz), 2.68 (dd, 1 H, J = 2.0, 16.3 Hz), 2.53 (t, 2 H, J = 7.4 Hz), 2.29-2.33 (m, 2 H), 2.07-2.13 (m, 1 H), 1.87 (s, 3 H), 1.62-1.66 (m, 2 H), 1.25-1.30 (m, 8 H), 0.87 (t, 3 H, J = 6.8 Hz), 0.69 (d, 3 H, J = 7.0 Hz), 0.51 (d, 3 H, J = 7.1 Hz). ¹³C NMR (75 MHz, CDCl3): δ = 199.4, 173.5, 169.4, 168.9, 167.9, 164.6, 147.4, 132.7, 128.4, 124.2, 84.4, 72.1, 57.7, 44.1, 43.3, 41.1, 40.4, 34.2, 32.2, 31.6, 29.0, 28.9, 27.9, 25.6, 24.2, 22.6, 18.9, 16.6, 14.0. ESI-MS: m/z (%) = 623.23 (44.5) [M + H]+, 645.21 (100.0) [M + Na]+. ESI-HRMS: m/z calcd for C29H43N4O5S3 [M + H]+: 623.2396; found: 623.2371 [M + H]+.