Synthesis of the C14-C29 Segment of Amphidinolide U Utilizing a Tandem Dihydroxylation-S_N2 Cyclization Protocol

Abstract

The synthesis of the C14-C29 subunit of amphidinolide U is described. The key steps include the trans-2,5-disubstituted tetrahydrofurans via a highly diastereoselective and high yielding tandem dihydroxylation-S_N2 cyclization, Wittig reaction, and Nozaki-Hiyama-Kishi coupling reaction.

amphidinolide U - cytotoxic - tandem dihydroxylation-S_N2 cyclization - Wittig reaction - Nozaki-Hiyama-Kishi coupling

References and Notes

1a Kobayashi J. Tsuda M. Nat. Prod. Rep.  2004,  21:  77 

1b Ishibashi M. Kobayashi J. Heterocycles  1997,  44:  543 

1c Chakraborty T. Das S. Curr. Med. Chem.: Anti-Cancer Agents  2001,  1:  131 

1d Kobayashi J. Ishibashi M. In Comprehensive Natural Products Chemistry   Vol. 8:  Mori K. Elsevier; Amsterdam: 1999.  p.415 

2

The IC₅₀ values as low as 0.00014 µg/mL were reported; hence, amphidinolides exhibit potencies similar to that of spongistatins, cf. ref. 1.

3 Tsuda M. Endo T. Kobayashi J. Tetrahedron  1999,  55:  14565 

4a Mohapatra DK. Nayak S. Mohapatra S. Chorghade MS. Gurjar MK. Tetrahedron Lett.  2007,  48:  5197 

4b Mohapatra DK. Rahman H. Chorghade MS. Gurjar MK. Synlett  2007,  567 

4c Mohapatra DK. Mohapatra S. Gurjar MK. Tetrahedron Lett.  2006,  47:  5943 

5 Marshal JA. Sabatini JJ. Org. Lett.  2005,  7:  4819 

6a Takano S. Kurotaki A. Takahashi M. Ogasawara K. Synthesis  1986,  403 

6b Vigneron JP. Meric R. Larcheveque M. Debal A. Lallemand J.-Y. Junesh G. Tagatti P. Gallois M. Tetrahedron  1984,  40:  3521 ; and references therein

6c Taniguchi M. Koga K. Yamada S. Tetrahedron  1970,  30:  3547 

7

Analytical and Spectral Data of 10
[α]_D ²⁵ -8.97 (c 1.8, CHCl₃). IR (neat): 3337, 3113, 3080, 3056, 2929, 2857, 1736, 1672, 1607, 1530, 1464, 1439, 1346, 1207, 1119, 837 cm^-1. ¹H NMR (200 MHz, CDCl₃):
δ = 0.03 (s, 6 H), 0.88 (s, 9 H), 1.31 (t, J = 7.2 Hz, 3 H), 3.57 (d, J = 4.5 Hz, 2 H), 3.99-4.14 (m, 2 H), 4.18-4.35 (m, 3 H). ¹³C NMR (50 MHz, CDCl₃-CCl₄): δ = -5.5, 14.0, 18.1, 25.7, 27.6, 27.8, 61.3, 65.4, 72.3, 79.8, 80.8, 172.8. Anal. Calcd (%) for C₁₅H₃₀O₅Si: C, 56.57; H, 9.49. Found: C, 56.38; H, 9.41.

8 Mitsunobu O. Synthesis  1981,  1 

9

Analytical and Spectral Data of 12
[α]_D ²⁵ -4.63 (c 1.4, CHCl₃). IR (neat): 3413, 3019, 2956, 2930, 2858, 1729, 1600, 1518, 1471, 1419, 1255, 1215, 1130, 838, 758 cm^-1. ¹H NMR (200 MHz, CDCl₃): δ = 0.04 (s, 6 H), 0.88 (s, 9 H), 1.29 (t, J = 7.2 Hz, 3 H), 1.72-2.06 (m, 4 H), 2.93 (br d, 1 H), 3.59 (d, J = 4.6 Hz, 1 H), 4.11 (m, 1 H), 4.19-4.37 (m, 4 H). ¹³C NMR (50 MHz, CDCl₃-CCl₄): δ = -5.4, -5.4, 14.2, 18.3, 25.7, 25.9, 27.9, 61.6, 65.7, 72.4, 80.4, 80.5, 172.4. Anal. Calcd (%) for C₁₅H₃₀O₅Si: C, 56.57; H, 9.49. Found: C, 56.42; H, 9.38.

10a Ohtani I. Kusumi J. Kashman Y. Kakisawa H. J. Am. Chem. Soc.  1991,  113:  4092 

10b Yoshida WY. Bryan PJ. Baker BJ. McClintock JB. J. Org. Chem.  1995,  60:  780 

11

Analytical and Spectral Data of 14
[α]_D ²⁵ +37.42 (c 0.9, CHCl₃). IR (neat): 3063, 3030, 2927, 1745, 1496, 1454, 1368, 1262, 1199, 1087, 1028, 736, 697 cm^-1. ¹H NMR (200 MHz, CDCl₃): δ = 1.21 (t, J = 7.2 Hz, 3 H), 1.67 (m, 1 H), 1.81-2.04 (m, 3 H), 3.37 (d, J = 5.0 Hz, 2 H), 4.01 (d, J = 4.4 Hz, 1 H), 4.06-4.23 (m, 3 H), 4.28 (m, 1 H), 4.42 (d, J = 11.8 Hz, 1 H), 4.48 (s, 2 H), 4.64 (d, J = 11.8 Hz, 1 H), 7.16-7.30 (m, 10 H). ¹³C NMR (50 MHz, CDCl₃-CCl₄): δ = 14.3, 26.5, 28.4, 60.8, 72.7, 72.8, 73.3, 79.0, 79.7, 80.7, 127.5, 127.6, 127.7, 127.9, 128.3, 137.6, 138.4, 170.7. Anal. Calcd (%) for C₂₁H₂₆O₄: C, 73.66; H, 7.65. Found: C, 73.26; H, 7.61.

12 Song F. Fidanze S. Benowitz AB. Kishi Y. Org. Lett.  2002,  4:  647 

13

Analytical and Spectral Data of 16
[α]_D ²⁵ +51.43 (c 1.45, CHCl₃). IR (neat): 3425, 3019, 2928, 1709, 1602, 1453, 1269, 1216, 1097, 1027, 757, 698, 668 cm^-1. ¹H NMR (200 MHz, CDCl₃): δ = 1.32 (t, J = 7.2 Hz, 3 H), 1.64-1.85 (m, 2 H), 1.91-2.07 (m, 5 H), 3.40-3.53 (m, 2 H), 3.98 (dd, J = 4.7, 6.9 Hz, 1 H), 4.09 (m, 1 H), 4.16-4.27 (m, 3 H), 4.46 (d, J = 12.1 Hz, 1 H), 4.56-4.57 (m, 2 H), 4.64 (d, J = 12.1 Hz, 1 H), 6.02 (dd, J = 7.0, 15.3 Hz, 1 H), 6.56 (ddd, J = 1.1, 11.4, 15.3 Hz, 1 H), 7.21 (d, J = 11.4 Hz, 1 H), 7.28-7.34 (m, 10 H). ¹³C NMR (50 MHz, CDCl₃-CCl₄): δ = 12.7, 14.3, 12.0, 28.4, 60.5, 71.1, 72.6, 73.2, 78.7, 81.4, 127.4, 127.5, 127.5, 127.6, 127.7, 128.2, 128.2, 128.3, 137.0, 138.3, 168.1. Anal. Calcd (%) for C₂₈H₃₅O₅: C, 74.64; H, 7.61. Found: C, 74.82; H, 7.45.

14 Jin H. Uenishi J. Chirst WJ. Kishi Y. J. Am. Chem. Soc.  1986,  108:  5644 

15

Analytical and Spectral Data of 2
[α]_D ²⁵ +22.34 (c 0.9, CHCl₃). IR (neat): 3445, 3018, 2959, 2931, 2872, 2400, 1717, 1636, 1496, 1454, 1382, 1216, 1087,1028, 927, 757, 698, 668, 625 cm^-1. ¹H NMR (200 MHz, CDCl₃): δ = 0.90 (t, J = 7.1 Hz, 3 H), 1.29-1.50 (m, 4 H), 1.67 (s, 3 H), 1.62-1.72 (m, 2 H), 1.82-2.05 (m, 4 H), 3.41-3.54 (m, 2 H), 3.88-3.94 (m, 2 H), 4.12 (m, 1 H), 4.25 (m, 1 H), 4.41-4.67 (m, 5 H), 4.97 (s, 1 H), 5.15 (s, 1 H), 5.66 (dd, J = 7.7, 15.2 Hz, 1 H), 6.18 (d, J = 10.9 Hz, 1 H), 6.47 (dd, J = 10.9, 15.2 Hz, 1 H), 7.28-7.38 (m, 10 H). ¹³C NMR (100 MHz, CDCl₃): δ = 12.4, 12.4, 14.0, 22.5, 27.0, 28.5, 30.1, 31.6, 70.6, 70.7, 72.8, 73.3, 78.7, 79.9, 81.7, 81.8, 81.9, 109.9, 110.0, 125.8, 125.9, 127.0, 127.4, 127.5, 127.7, 128.2, 128.3, 128.6, 129.5, 129.6, 138.2, 138.3, 138.4, 138.8, 140.9, 149.4, 149.4. Anal. Calcd for C₃₂H₄₂O₄: C, 78.33; H, 8.63. Found: C, 78.12; H, 8.49.