Download PDF
Synlett 2008(11): 1737-1741  
DOI: 10.1055/s-2008-1077885
LETTER
© Georg Thieme Verlag Stuttgart · New York

Total Synthesis of Amphidinolide X and Its 12Z-Isomer by Formation of the C12-C13 Trisubstituted Double Bond via Ring-Closing Metathesis

Wei-Min Dai*a,b, Yile Chena, Jian Jina, Jinlong Wu*a, Jianshu Louc, Qiaojun Hec
a Laboratory of Asymmetric Catalysis and Synthesis, Department of Chemistry, Zhejiang University, Hangzhou 310027, P. R. of China
Fax: +86(571)87953128; e-Mail: chdai@zju.edu.cn;
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
c Institute of Pharmacology & Toxicology and Biochemical Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Zi-Jin-Gang Campus, Hangzhou 310058, P. R. of China
Further Information

Publication History

Received 27 March 2008
Publication Date:
11 June 2008 (online)

    Permissions and Reprints All articles of this category

Abstract

Amphidinolide X, a 16-membered cytotoxic macro­diolide, and its 12Z-isomer have been synthesized via ring-closing metathesis (RCM) for assembling the C12-C13 trisubstituted double bond. A 29:71 E/Z mixture was obtained from the seco substrate appended with a bulky C8-ODPS group in 50-65% combined yields by using 20 mol% of the second-generation Grubbs initiator and the corresponding indenylidene ruthenium complex. Amphidinolide X and 12Z-isomer exhibit similar cytotoxicity (IC50: 7.6-13.9 µg/mL) against A549, KB, and HL60 cell lines.

Key words

anti-selective aldehyde crotylation - macrodiolide - ring-closing metathesis - microwave - trisubstituted olefin

13

We used noncrystallized form of the reagent. An 85:15 mixture of (S,S)-9 and its Z-isomer was prepared from an 85:15 mixture of E- and Z-crotyl chloride obtained from Aldrich according to the literature procedure (ref. 11). The Z-isomer of (S,S)-9 reacted with (R)-8 to produce a syn-homoallyl alcohol which is different from 3′. The diaste-
reomeric ratio of >99:1 was estimated according to the 1H NMR spectrum of the product mixture.

19

Procedure for Synthesis of (12 Z )-Amphidinolide X via Ring-Closing Metathesis of the seco Ketone 19 Using Second-Generation Grubbs Initiator 23 To a degassed, refluxing solution of the seco ketone 19 (30.0 mg, 6.3×10-2 mmol) in anhyd CH2Cl2 (100 mL) under a nitrogen atmosphere was added the second-generation Grubbs initiator 23 (2.7 mg, 0.3×10-2 mmol). The resulting clear, pale pink solution changed to a clear yellow color after refluxing for 24 h. Three additional portions of 23 (2.7 mg, 0.3×10-2 mmol; a total of 1.2×10-2 mmol) were added after 24, 48, and 72 h, respectively. After refluxing for a total of 4 d, the reaction mixture was concentrated to <1 mL on a rotary evaporator, and the remaining mixture was purified directly by flash column chromatography over SiO2 [eluting with 3% EtOAc in PE (bp 60-90 °C)] to give (12Z)-amphidinolide X [(12Z)-1, 24.0 mg, 85%]. (12Z)-Amphidinolide X [(12Z)-1]: colorless oil; [α]D 17 -16.0 (c 1.00, CHCl3). IR (film): 2964, 1731, 1655, 1454, 1377, 1315, 1269, 1215, 1167, 1049 cm-1. 1H NMR (400 MHz, CDCl3): δ = 6.92 (dd, J = 16.0, 6.4 Hz, 1 H), 5.81 (dd, J = 16.0, 1.6 Hz, 1 H), 5.18 (dt, J = 8.8, 4.0 Hz, 1 H), 4.88 (d, J = 10.4 Hz, 1 H), 4.82 (dt, J = 8.8, 7.2 Hz, 1 H), 3.74 (ddd, J = 10.0, 7.6, 2.8 Hz, 1 H), 2.96-2.89 (m, 1 H), 2.85-2.80 (m, 1 H), 2.66-2.58 (m, 2 H), 2.53 (dd, J = 14.8, 4.8 Hz, 1 H), 2.42-2.33 (m, 2 H), 2.26-2.19 (m, 1 H), 2.16 (s, 3 H), 1.89-1.82 (m, 2 H), 1.70 (s, 3 H), 1.64 (dd, J = 13.2, 7.2 Hz, 1 H), 1.49-1.47 (m, 2 H), 1.36-1.30 (m, 2 H), 1.26 (s, 3 H), 1.15 (d, J = 7.6 Hz, 3 H), 1.05 (d, J = 6.8 Hz, 3 H), 0.91 (t, J = 7.6 Hz, 3 H). 13C NMR (125 MHz, CDCl3): δ = 206.4, 171.3, 166.0, 151.7, 137.3, 126.3, 120.0, 81.9, 79.5, 78.0, 72.8, 44.8, 43.8, 43.1, 40.0, 35.9, 33.9, 31.4, 30.1, 27.3, 26.7, 23.5, 19.6, 17.8, 14.7, 14.6. MS (+ESI): m/z (rel. int.) = 471 (100) [M + Na+]. HRMS (+ESI): m/z calcd for C26H40O6Na+ [M + Na+], 471.2717; found: 471.2719.

20

Procedure for the Synthesis of Amphidinolide X via Ring-Closing Metathesis of 17 Using Second-Generation Grubbs Initiator 23 as the Key Step To a degassed, refluxing solution of 17 (150.0 mg, 0.21 mmol) in anhyd CH2Cl2 (150 mL) under a nitrogen atmosphere was added the second-generation Grubbs initiator 23 (8.9 mg, 1.1×10-2 mmol). The resulting clear, pale pink solution changed to a clear yellow color after refluxing for 24 h. Three additional portions of 23 (8.9 mg, 1.1×10-2 mmol; a total of 4.4×10-2 mmol) were added after 24, 48, and 72 h, respectively. After refluxing for a total of 6 d, the reaction mixture was concentrated to <1 mL on a rotary evaporator and the remaining mixture was purified directly by flash column chromatography over SiO2 [eluting with 3% EtOAc in PE (bp 60-90 °C)] to give a 71:29 mixture of the Z and E RCM products 20 and 21 (70.0 mg, 50%) as a colorless oil. The Z/E ratio was determined by the integration of the corresponding signals in the 1H NMR spectrum. An pure sample of isomer 20 was obtained by flash column chromatography [eluting with 3% EtOAc in PE (bp 60-90 °C)] of the product mixture.
Compound 20: colorless oil; [α]D 17 -35.9 (c 2.0, CHCl3).
IR (film): 2929, 1733, 1653, 1456, 1428, 1379, 1268, 1167, 1112, 1086 cm-1. 1H NMR (400 MHz, CDCl3): δ = 7.68-7.65 (m, 4 H), 7.42-7.32 (m, 6 H), 6.93 (dd, J = 16.0, 6.0 Hz, 1 H), 5.75 (dd, J = 16.0, 1.6 Hz, 1 H), 5.02-5.00 (m, 1 H), 4.86 (d, J = 10.8 Hz, 1 H), 4.78 (dt, J = 8.4, 7.2 Hz, 1 H), 3.82-3.78 (m, 1 H), 3.74-3.70 (m, 1 H), 2.97-2.89 (m, 1 H), 2.74-2.67 (m, 1 H), 2.43-2.36 (m, 2 H), 2.30-2.22 (m, 2 H), 1.91-1.71 (m, 4 H), 1.67 (s, 3 H), 1.64-1.61 (m, 2 H), 1.48-1.44 (m, 2 H), 1.36-1.30 (m, 2 H), 1.25 (s, 3 H), 1.14 (d, J = 6.8 Hz, 3 H), 1.02 (d, J = 6.0 Hz, 3 H), 1.00 (s, 9 H), 0.96 (d, J = 7.2 Hz, 3 H), 0.91 (t, J = 7.2 Hz, 3 H). 13C NMR (125 MHz, CDCl3): δ = 171.3, 166.2, 151.8, 136.3 (2), 136.1 (2), 135.7, 135.3, 134.2, 129.7, 129.6, 127.7 (2), 127.6 (2), 127.4, 119.9, 81.7, 79.8, 77.8, 74.3, 67.6, 44.8, 44.0, 40.1, 38.5, 36.1, 33.4, 31.3, 27.2 (3), 27.1, 26.8, 24.2, 23.3, 19.5, 19.3, 17.9, 14.8, 14.4. MS (+ESI): m/z (rel. int.) = 711 (100) [M + Na+]. HRMS (+ESI): m/z calcd for C42H60O6SiNa+ [M + Na+], 711.4051; found: 711.4054.
A plastic tube was charged with the 71:29 mixture of 20 and 21 (50.0 mg) in THF (2 mL) followed by adding 70% hydrogen fluoride pyridine (2 mL) at r.t. The resultant mixture was stirred for 24 h at r.t. and the reaction was quenched carefully with sat. aq Na2CO3. The reaction mixture was extracted with Et2O and the combined organic layer was dried over anhyd Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography over SiO2 [eluting with 20% EtOAc in PE (bp 60-90 °C)] to give a mixture of the alcohol (34.0 mg, 75%) as a colorless oil. The structure of the alcohol was confirmed by mass spectrometry data. MS (+ESI): m/z (rel. int.) = 473 (100) [M + Na+]. HRMS (+ESI): m/z calcd for C26H42O6Na+ [M + Na+]: 473.2874; found: 473.2880.
To a solution of the above mixture (34.0 mg, 7.5×10-2 mmol) in CH2Cl2 (1 mL) at r.t. was added NaHCO3 (19 mg, 0.225 mmol) followed by carefully adding a solution of Dess-Martin periodinane in CH2Cl2 (0.3 M, 0.5 mL, 0.15 mmol). The resultant mixture was stirred at r.t. for 4 h followed by treating with sat. aq Na2S2O3. The reaction mixture was extracted with CH2Cl2. The organic layer was washed with brine, dried over anhyd Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography over SiO2 [eluting with 15% EtOAc in PE (bp 60-90 °C)] to give amphidinolide X (1, 8.0 mg, 23%) and (12Z)-amphidinolide X [(12Z)-1, 21.0 mg, 62%].
Amphidinolide X (1): colorless oil; [α]D 17 -26.8 (c 1.00, CHCl3). IR (film): 2963, 1717, 1654, 1453, 1377, 1265, 1186, 1039 cm-1. 1H NMR (500 MHz, CDCl3): δ = 7.12 (dd, J = 15.8, 7.2 Hz, 1 H), 5.79 (dd, J = 15.8, 1.6 Hz, 1 H), 5.20 (m, 2 H), 4.95 (d, J = 10.3 Hz, 1 H), 3.96 (dt, J = 11.2, 3.6 Hz, 1 H), 2.78 (m, 1 H), 2.69 (dd, J = 16.6, 6.1 Hz, 1 H), 2.69 (m, 1 H), 2.58 (dd, J = 13.6, 3.9 Hz, 1 H), 2.58 (dd, J = 16.5, 7.5 Hz, 1 H), 2.41 (dd, J = 13.3, 6.3 Hz, 1 H), 2.18 (m, 1 H), 2.17 (m, 1 H), 2.14 (s, 3 H), 2.12 (m, 1 H), 1.94 (tt, J = 13.5, 3.3 Hz, 1 H), 1.75 (dd, J = 13.9, 2.4 Hz, 1 H), 1.55 (s, 3 H), 1.54 (m, 1 H), 1.50 (m, 2 H), 1.35 (m, 2 H), 1.30 (s, 3 H), 1.14 (d, J = 6.9 Hz, 3 H), 0.92 (t, J = 7.5 Hz, 3 H), 0.91 (d, J = 7.1 Hz, 3 H). 13C NMR (125 MHz, CDCl3): δ = 205.5, 170.7, 165.8, 153.2, 135.6, 126.1, 120.3, 83.0, 80.6, 78.5, 74.3, 47.2, 44.3, 43.6, 41.5, 35.6, 35.4, 33.1, 30.5, 30.5, 24.7, 18.2, 17.9, 17.6, 15.5, 14.7. MS (+ESI): m/z (rel. int.) = 471 (100) [M + Na+]. HRMS (+ESI): m/z calcd for C26H40O6Na+ [M + Na+]: 471.2717; found: 471.2699.