OH
tyltin13 23 in the presence of Pd(PPh3)4 successfully provided
the coupling product, E-diene§ 24, in 72% yield. Removal of
the O-acetyl group gave diol 25 in 95% yield. The final
transformation, introduction of the second epoxide function-
ality, was stereoselectively achieved by vanadium-catalyzed
epoxidation14 to give FR65814 1 in 70% yield.¶ The spectro-
scopic (1H and 13C NMR) data for synthetic 1 were identical
with those of natural FR65814, and the physical properties of 1
i
17
PMBO
PMBO
18
CH2OH
ii, iii
O
21
{mp 39–40 °C (from Et2O–hexanes); [a]D 2 41 (c 0.25,
O
MeOH)} showed good accord with those of the natural product
{mp 39–40 °C (from Et2O–hexanes); mixed mp, 39–40 °C;
iv
PMBO
23
[a]D 2 38.41 (c 2.4, MeOH)}. This successful first total
PMBO
PMBO
synthesis of 1 confirmed the assigned structure of FR65814, and
provided a novel synthetic pathway from carbohydrates to
highly oxygenated terpenes possessing a cyclohexane unit.
We thank Fujisawa Pharmaceutical Co., Ltd., (Osaka, Japan)
for providing us with natural FR65814. Financial support in the
form of a Grant-in-Aid for Scientific Research on Priority Areas
from the Ministry of Education, Science, Sports and Culture, of
the Japanese Government is gratefully acknowledged.
PMBO
19
OTBDMS
O
OTBDMS
20
v,vi
O
H
7
6
8
H
5
R1
4
RO
AcO
H
RO
Notes and References
AcO
4% NOE
H
H
8%
9%
† E-mail: chida@applc.keio.ac.jp
R
21 R = OH
22 R = Cl
‡ Compound 11 was obtained as an inseparable diastereomeric mixture at
C-1 (1:1). Interestingly, epimerization at C-1 occurred during the
saponification step and compound 12 was obtained as the single product.
The stereochemistry at C-9 in 12 was confirmed by NOE experiments.
§ The NOE experiments clearly showed that the geometry of the double
bond in both 17 and 24 should be E. No isomerization of the double bond
was observed during the coupling reaction between 22 and 23.
¶ A small amount (less than 5%) of diastereomeric epoxide (1A,2A-diepi-
FR65814) was isolated. The chemical shifts and appearance of the hydrogen
attached to the carbon bearing epoxide ring (H-2A) of 1 and its diastereomer
in the 1H NMR spectra (CDCl3) are found to be characteristic: FR65814,
fumagillol, d 2.61 (dd, J 5.9, 7.1); 1A,2A-diepi-FR65814, d 3.14 (br m); cf. d
2.56 (dd, J 5.9, 7.1).
vii
R = PMB
R1 = CMe=CHCH2OTBDMS
viii
O
J4,5 = 11.0 Hz, J5,6 = 8.6 Hz
J6,7ax = 13.1 Hz, J7ax,8ax = 13.9 Hz
x
FR65814 1
RO
OR
SnBun
3
24 R = Ac
25 R = H
ix
23
1 H. Hatanaka, T. Kino, M. Hashimoto, Y. Tsurumi, A. Kuroda, H.
Tanaka, T. Goto and M. Okuhara, J. Antibiot., 1988, 41, 999.
2 J. A. DiPaolo, D. S. Tarbell and G. E. Moore, in Antibiotics Annual
1958–1959, ed. H. Welch and F. Marti-Ibanez, Medical Encyclopedia,
Inc., New York, 1959, p. 541.
3 D. E. Ingber, T. Fujita, S. Kishimoto, K. Sudo, T. Kanamaru, H. Brem
and J. Folkman, Nature, 1990, 348, 555; D. E. Ingber, Semin. Cancer
Biol., 1992, 3, 57; J. Folkman and D. E. Ingber, Semin. Cancer Biol.,
1992, 3, 89; N. Sin, L. Meng, M. Q. W. Wang, J. J. Wen, W. G.
Bornmann and C. M. Crews, Proc. Natl. Acad. Sci. USA, 1997, 94,
6099; E. C. Griffith, Z. Su, B. E. Turk, S. Chen, Y.-H. Chang, Z. Wu,
K. Biemann and J.O. Liu, Chem. Biol., 1997, 4, 461.
4 (a) E. J. Corey and B. B. Snider, J. Am. Chem. Soc., 1972, 94, 2549; (b)
D. Kim, S. K. Ahn, H. Bae, W. J. Choi and H. S. Kim, Tetrahedron Lett.,
1997, 38, 4437.
5 R. J. Ferrier and S. Middleton, Chem. Rev., 1993, 93, 2779.
6 (a) N. Chida, M. Ohtsuka, K. Nakazawa and S. Ogawa, J. Org. Chem.,
1991, 56, 2976; (b) N. Chida, M. Ohtsuka and S. Ogawa, J. Org. Chem.,
1993, 58, 4441; N. Chida, M. Jitsuoka, Y. Yamamoto, M. Ohtsuka and
S. Ogawa, Heterocycles, 1996, 43, 1385; N. Chida, K. Sugihara and S.
Ogawa, J. Chem. Soc., Perkin Trans. 1, 1997, 275.
7 N. Chida, M. Ohtsuka, K. Ogura and S. Ogawa, Bull. Chem. Soc. Jpn.,
1991, 64, 2118.
8 F. C. Chang and N. F. Wood, Tetrahedron Lett., 1964, 2969.
9 S. V. Ley, J. Norman, W. P. Griffith and S. P. Marsden, Synthesis, 1994,
639.
10 Y. Ito, T. Hirao and T. Saegusa, J. Org. Chem., 1978, 43, 1011.
11 E. J. Corey and M. Chaykovsky, J. Am. Chem. Soc., 1965, 87, 1353.
12 F. K. Sheffy, J. P. Godschalx and J. K. Stille, J. Am. Chem. Soc., 1984,
106, 4833; J. K. Stille, Angew. Chem., Int. Ed. Engl., 1986, 25, 508.
13 M. L. Saihi and M. Pereyre, Bull. Soc. Chim. Fr., 1977, 1251.
14 K. B. Sharpless and R. C. Michaelson, J. Am. Chem. Soc., 1973, 95,
6136.
Scheme 2 Reagents and conditions: i, DIBAL-H, toluene, 278 °C, then
Bun4NF, THF; ii, TBDMSCl, imidazole, DMF; iii, DMSO, Ac2O; iv,
Me3S(O)I, NaH, DMSO, room temp.; v, DDQ, CH2Cl2–H2O; vi, Ac2O,
pyridine, then Bun4NF, THF; vii, LiCl, MeSO2Cl, collidine, DMF; viii, 23,
Pd(PPh3)4 (10 mol%), THF, 50 °C; ix, MeONa, MeOH; x, vanadyl
acetylacetonate (5 mol%), ButOOH, CH2Cl2, 218 °C
hydroboration-oxidation to provide 15 (85% yield). Perruthe-
nate oxidation9 of 15 gave aldehyde 16 in 81% yield, which was
converted into a,b-unsaturated aldehyde with E-geometry§ 17
in 45% yield by silyl enol ether formation followed by treatment
with stoichiometric amount of Pd(OAc)2.10 The Z-isomer of 17
was isolated as the minor product (4% yield).
Having finished the preparation of highly oxygenated
cyclohexane ring with carbon side-chain, elongation of the
carbon chain and introduction of the bis-epoxide functionality
were explored. DIBAL-H reduction of 17 and subsequent
deprotection of the O-silyl group afforded diol 18 (Scheme 2).
Protection of the primary alcohol function followed by
oxidation of the secondary alcohol with Ac2O–DMSO gen-
erated ketone 19 in 82% yield from 17. Reaction of 19 with
stabilized sulfur ylide11 proceeded stereoselectively and af-
forded spiro epoxide 20 as the sole product in 57% yield. The
observed coupling constants and NOE of 20 supported the
assigned structure. Treatment of 20 with DDQ followed by
conventional acetylation afforded diacetate, whose O-silyl
protecting group was removed to provide 21 in 90% yield. The
allyl alcohol 21 was transformed into allylic chloride 22
quantitatively. Stille coupling12 of 22 with isobutenyltribu-
Received in Cambridge, UK, 19th March 1998; 8/02169D
1264
Chem. Commun., 1998