LETTER
Synthesis of the C14–C29 Segment of Amphidinolide U
839
(4) (a) Mohapatra, D. K.; Nayak, S.; Mohapatra, S.; Chorghade,
M. S.; Gurjar, M. K. Tetrahedron Lett. 2007, 48, 5197.
(b) Mohapatra, D. K.; Rahman, H.; Chorghade, M. S.;
Gurjar, M. K. Synlett 2007, 567. (c) Mohapatra, D. K.;
Mohapatra, S.; Gurjar, M. K. Tetrahedron Lett. 2006, 47,
5943.
(5) Marshal, J. A.; Sabatini, J. J. Org. Lett. 2005, 7, 4819.
(6) (a) Takano, S.; Kurotaki, A.; Takahashi, M.; Ogasawara, K.
Synthesis 1986, 403. (b) Vigneron, J. P.; Meric, R.;
Larcheveque, M.; Debal, A.; Lallemand, J.-Y.; Junesh, G.;
Tagatti, P.; Gallois, M. Tetrahedron 1984, 40, 3521; and
references therein. (c) Taniguchi, M.; Koga, K.; Yamada, S.
Tetrahedron 1970, 30, 3547.
15.3 Hz, 1 H), 6.56 (ddd, J = 1.1, 11.4, 15.3 Hz, 1 H), and
7.21 (d, J = 11.4 Hz, 1 H) ppm which were characteristic
of the E,E-dienoic group. Subsequent reduction of 16 with
DIBAL-H at –78 °C gave the allylic alcohol 17, which
was converted into the aldehyde derivative 4 (Scheme 3).
The Nozaki–Hiyama–Kishi coupling14 reaction between 4
and 18 was effected in the presence of CrCl2 and catalytic
amount of NiCl2 to give a 1:1 diastereomeric mixture of
our targeted segment 2.15
OH
(7) Analytical and Spectral Data of 10
O
[a]D25 –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):
d = 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): d = –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.
H
H
OBn
OBn
2
OR
O
H
OBn
H
OBn
18
R = Ac, Bz, PNB, TBS, MOM, MEM
(8) Mitsunobu, O. Synthesis 1981, 1.
(9) Analytical and Spectral Data of 12
Scheme 4 Protection of 2 with different protecting groups
[a]D25 –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): d = 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):
d = –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.
We protected the secondary hydroxy group with different
protecting groups (Scheme 4) to generate variously pro-
tected diastereomers 19. Unfortunately, no separation of
diastereomers with different solvent systems was discern-
ible. The diastereomers could be separated by preparative
liquid chromatography and assigned the absolute stereo-
chemistry as reported for amphidinolide C.4b
(10) (a) Ohtani, I.; Kusumi, J.; Kashman, Y.; Kakisawa, H. J. Am.
Chem. Soc. 1991, 113, 4092. (b) Yoshida, W. Y.; Bryan, P.
J.; Baker, B. J.; McClintock, J. B. J. Org. Chem. 1995, 60,
780.
In conclusion, the efficient and convergent route present-
ed here led to the first synthesis of the entire top half of the
amphidinolide U in 15 steps and 18% overall yield, offer-
ing the promise of the total synthesis of this molecule but
also other structurally similar congeners. Further work is
in progress.
(11) Analytical and Spectral Data of 14
[a]D25 +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): d = 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): d = 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.
Acknowledgment
We are thankful to Dr. Mukund K. Gurjar for his constant support
and encouragement. H.R. thanks CSIR, New Delhi for financial as-
sistance in the form of a Senior Research Fellowship. We also thank
Dr. Ganesh Pandey, HOD, Organic Chemistry Division, for his va-
luable suggestions and support. Help from Dr. P. R. Rajmohanan
for NMR data is also well recorded.
(12) Song, F.; Fidanze, S.; Benowitz, A. B.; Kishi, Y. Org. Lett.
2002, 4, 647.
(13) Analytical and Spectral Data of 16
[a]D25 +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): d = 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): d =
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.
References and Notes
(1) (a) Kobayashi, J.; Tsuda, M. Nat. Prod. Rep. 2004, 21, 77.
(b) Ishibashi, M.; Kobayashi, J. Heterocycles 1997, 44, 543.
(c) Chakraborty, T.; Das, S. Curr. Med. Chem.: Anti-Cancer
Agents 2001, 1, 131. (d) Kobayashi, J.; Ishibashi, M. In
Comprehensive Natural Products Chemistry, Vol. 8; Mori,
K., Ed.; Elsevier: Amsterdam, 1999, 415.
(2) The IC50 values as low as 0.00014 mg/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.
Synlett 2008, No. 6, 837–840 © Thieme Stuttgart · New York