Synthesis of the C1-C12 fragment of fostriecin

Article abstract of DOI:10.1021/ol016116x

(Matrix presented) The synthesis of the C₁-C₁₂ fragment of fostriecin was achieved from (S)-glycidol in 15 steps by using an enantioselective allytitanation reaction and a ring-closure metathesis as the key steps.

Full text of DOI:10.1021/ol016116x

ORGANIC
LETTERS
2001
Vol. 3, No. 14
2233-2235
Synthesis of the C1−C12 Fragment of
Fostriecin
Janine Cossy,* Fabienne Pradaux, and Samir BouzBouz
Laboratoire de Chimie Organique associe´ au CNRS, ESPCI, 10 rue Vauquelin,
75231 - Paris Cedex 05, France
janine.cossy@espci.fr
Received May 14, 2001
ABSTRACT
The synthesis of the C −C fragment of fostriecin was achieved from (S)-glycidol in 15 steps by using an enantioselective allytitanation
1
12
reaction and a ring-closure metathesis as the key steps.
In 1984, several articles1,2 were published describing CI-
920, a structurally novel antibiotic isolated from a fermenta-
tion broth of a new actinomycetes (Streptomyces pulVera-
ceus). This compound is active in vitro against leukemia
(L1210, IC50 0.46 µM), lung, breast, and ovarian cancer and
displays efficacious in vivo antitumor activity against L1210
and P338 leukemia.3,1c Currently, fostriecin is under evalu-
ation as an antitumor drug in clinical trials. (+)-Fostriecin
inhibits DNA, RNA, and protein synthesis4 and was shown
to block cells in the G2 phase of the cell cycle and to have
inhibition effects on partially purified type II topoisomerase
from Ehrlich ascites carcinoma.5 However, fostriecin is
distinctly different from previously described inhibitors of
topoisomerase II in that it does not cause protein-associated
DNA strand breaks.5
through inhibition of protein phosphatases 1 and 2A (IC50 4
µM and 40 nM respectively).7-9 Inhibition of the mitotic
entry checkpoint and protein phosphatase are novel properties
for a potential clinical antitumor agent. Despite its intriguing
biological properties, the complete relative and absolute
stereochemistry of fostriecin was only determined in 199710
(Figure 1).
Recently, the first total synthesis of fostriecin has been
reported.11 Here, we report the synthesis of the C1-C12
fragment of fostriecin from (S)-glycidol (the C2 of which
corresponds to the C11 of fostriecin) by using an enantio-
selective allyltitanation applied to 11 to control the C5 center,
an enantioselective osmylation of unsaturated ester 6 to
control the C9 and C8 centers, and a ring-closing metathesis
(RCM) reaction applied to the unsaturated ester 13 to build
up the lactone moiety (Scheme 1).
Instead, it inhibits the mitotic entry checkpoint,6 potentially
(1) (a) Tunac, J. B.; Graham, B. D.; Dobson, W. E. J. Antibiot. 1983,
36, 1595. (b) Stampwala, S. S.; Bunge, R. H.; Hurley, T. R.; Willmer, N.
E.; Brankiewicz, A. J.; Steinman, C. E.; Smitka, T. A.; French, J. C. J.
Antibiot. 1983, 36, 1601. (c) Leopold, W. R.; Shillis, J. L.; Mertus, A. E.;
Nelson, J. M.; Roberts, B. J.; Jackson, R. C. Cancer Res. 1984, 44, 1928.
(2) Hokanson, G. C.; French, J. C. J. Org. Chem. 1985, 50, 462.
(3) Scheithauer, W.; Von Hoff, D. D.; Clark, G. M.; Shillis, J. L.;
Elslager, E. F. Eur. J. Cancer Clin. Oncol. 1986, 22, 921.
(4) Fry, D. W.; Boritzki, T. J.; Jackson, R. C. Cancer Chemother.
Pharmacol. 1984, 13, 171.
(5) Boritzki, T. J.; Wolfard, T. S.; Besserer, J. A.; Jackson, R. C.; Fry,
D. W. Biochem. Pharmacol. 1988, 37, 4063.
(6) For a review, see: Murray, A. W. Nature 1992, 359, 599.
Figure 1.
10.1021/ol016116x CCC: $20.00 © 2001 American Chemical Society
Published on Web 06/12/2001

Scheme 1
(S)-Glycidol was transformed to the corresponding p-
methoxyphenol ether by using a Mitsunobu reaction (p-
methoxyphenol, DEAD, PPh3, THF, 0 °C, 15 h, yield 82%)
and then treated with vinylmagnesium cuprate in THF at
-40 °C to afford the corresponding homoallylic alcohol 2
in 95% yield. Transformation of 2 to the corresponding
Scheme 2a
i
a (a) p-CH3OC6H4OH, PPh3, DEAD, THF, 0 °C; (b) vinylMgCl, CuI, THF, -40 °C; (c) MOMCl, Pr2NEt, CH2Cl2, 0 °C; (d) OsO4,
NMO, acetone/H2O, NaIO4, 25 °C; (e) Ph3PC(CH3)CO2C2H5 15, benzene, 80 °C; (f) BF3‚Et2O, Me2S, 0 °C; (g) AD-mixâ, t-BuOH/H2O/
i
toluene, 0 °C; (h) MOMCl, Pr2NEt, CH2Cl2, 0 °C; (i) LiAlH4, THF, 25 °C; (j) (COCl)2, DMSO, CH2Cl2, -78 °C, Et3N, 25 °C; (k)
PPh3CHCO2C2H5 16, toluene, 80 °C; (l) DIBAL-H, toluene, -78 °C; (m) (S,S)-I, ether, -78 °C, 4 h; (n) acryloyl chloride, CH2Cl2, Et3N
-78 °C; (p) Grubbs’ catalyst II, CH2Cl2, 55 °C.
2234
Org. Lett., Vol. 3, No. 14, 2001

i
methoxymethyl ether 3 (MOMCl, Pr2NEt, CH2Cl2, 0 °C,
was produced in 53% yield (for the two steps). Ring-closing
metathesis (RCM) was then attempted on 13. Treatment of
13 with the Grubbs’ catalyst II (in refluxing CH2Cl2)14
provided after 5 h the desired lactone 14 in 86% yield
(Scheme 2).14
The C1-C12 fragment of fostriecin was prepared from
(S)-glycidol in 15 steps with an overall yield of 9.8% by
using three key steps: an enantioselective allyltitanation
applied to an aldehyde, an enantioselective dihydroxylation
of an unsaturated ester, and a ring-closure metathesis
reaction.
70% yield) followed by oxidative cleavage of the double
bond led to aldehyde 4 (OsO4, NMO, acetone/H2O; NaIO4;
98% yield). Aldehyde 4 was treated with the phosphonium
salt 15 to give the unsaturated ester 5 (refluxing benzene,
15 h, 87% yield).
After deprotection of 5 using BF3‚EtO2 in Me2S at 0 °C,
alcohol 6 was isolated in 93% yield and subjected to
asymmetric dihydroxylation (ADmix-â, NaHCO3, CH3SO2-
NH2, K2OsO2(H2O)2, t-BuOH/H2O: 1/1, toluene, 0 °C, 48
h) to provide triol 7 in 99% yield and with an excellent
diastereoselectivity of up to 95%.12 It is worth noting that,
when the unsaturated ester 5 was dihydroxylated under the
same conditions that were used previously, the monopro-
tected triol was obtained with a low diastereoselectivity (de
Acknowledgment. F.P. thanks the MRES for a grant. The
cost program D13/0010/00 is acknowledged for support and
Eli Lilly (Indianapolis, IN) is acknowledged for financial
support.
i
) 80:20). The protection of triol 7 using MOMCl in Pr2-
NEt as solvent (MOMCl, 6 equiv; 0 °C; 15 h) led to
compound 8 (70% yield) which was transformed to aldehyde
9 in two steps. After reduction of ester 8 by LAH (THF, rt),
the alcohol was directly oxidized to aldehyde 9 using a Swern
oxidation [(COCl)2, DMSO, CH2Cl2, -78 °C]. Aldehyde 9
was isolated with an overall yield of 92%, and its subsequent
treatment with phosphonium ester 16 (refluxing toluene, 15
h) cleanly provided the unsaturated ester 10 (E/Z > 30/1) in
92% yield.
Ester 10 was then reduced to aldehyde 11 (85% yield)
using Dibal-H in toluene at -78 °C for 30 min. When
aldehyde 11 was treated with the (S,S)-I allyltitanium
complex according to the reported procedure,13 homoallylic
alcohol 12 was produced and esterified with acryloyl chloride
in the presence of Et3N and a catalytic amount of 4-DMAP
(CH2Cl2, -78 °C to 0 °C, 2 h). The corresponding ester 13
OL016116X
(7) Roberge, M.; Tudan, C.; Hung, S. M. F.; Harder, K. W.; Jirik, F. R.;
Anderson, H. Cancer Res. 1994, 54, 6115.
(8) Ho, D. T.; Roberge, M. Carcinogenesis 1996, 17, 967.
(9) For a review of protein serine/threonine phosphatases, see: Ingeb-
ritsen, T. S.; Cohen, P. Eur. J. Biochem. 1983, 132, 255.
(10) (a) Just, G.; O’Connor, B.; Lewis, B. M. Tetrahedron Lett. 1988,
29, 753. (b) Boger, D. L.; Masataka, H.; Lewis, B. M. J. Org. Chem. 1997,
62, 1748.
(11) Boger, D. L.; Ichikawa, S.; Zhong, W. J. Am. Chem. Soc. 2001,
123, 4161.
(12) The diastereoselectivity was determined from the corresponding
compound 8 by GC/MS (electron impact ionization using a 5971 Hewlett-
Packard instrument at 70 eV), and the relative anti stereochemistry between
the hydroxy groups at C3 and C5 was determined from the corresponding
acetonide and was confirmed by analyzing the 13C NMR chemical shifts.
Rychnovsky, S. D.; Skalitzky, D. J. Tetrahedron Lett. 1990, 31, 945.
(13) Hafner, A.; Duthaler, R. O.; Marti, R.; Rihs, G.; Rothe-Streit, P.;
Schwarzenbach, F. J. Am. Chem. Soc. 1992, 114, 2321.
(14) Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413.
Org. Lett., Vol. 3, No. 14, 2001
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