Versatile enantiocontrolled synthesis of (+)-fostriecin.

Article abstract of DOI:10.1039/b209742g

Fostriecin, a potent protein phosphatase inhibitor and antitumor agent, has been enantioselectively synthesized in naturally occurring form via a versatile route, which also allows one to secure all possible stereoisomeres of the C1-C13 fragment including

Full text of DOI:10.1039/b209742g

Versatile enantiocontrolled synthesis of (+)-fostriecin†
Tomoyuki Esumi, Nanako Okamoto and Susumi Hatakeyama*
Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki 852-8521, Japan.
E-mail: susumi@net.nagasaki-u.ac.jp
Received (in Cambridge, UK) 7th October 2002, Accepted 29th October 2002
First published as an Advance Article on the web 15th November 2002
Fostriecin, a potent protein phosphatase inhibitor and
antitumor agent, has been enantioselectively synthesized in
naturally occurring form via a versatile route, which also
allows one to secure all possible stereoisomeres of the C1–
C13 fragment including the C11 stereocenter and the
geometry of the D12-double bond.
methoxybenzylation of 7, iodination of 8 followed by Heck
reaction10 of 9 with acrolein afforded aldehyde 10. Brown’s
asymmetric allylation11 of 10 gave alcohol 11 in good yield.
The optical purity of 11 was not determined at this stage because
of its instability under conditions of the HPLC analysis using a
chiral column or formation of the corresponding MTPA esters.
After acryloylation, ring-closing alkene metathesis of 12 was
examined under various conditions and it was found that
cyclization took place between the two terminal alkenic double
bonds with high site selectivity.12 Thus, upon treatment of 12
with 0.1 equivalents of Grubbs’ catalyst in CH2Cl2 at reflux for
22 h, lactone 13 was obtained in 75% yield together with the
corresponding dimer in 4% yield. In this particular case, the
dimer was the only side-product produced and the conjugated
diene moiety did not react at all. The optical purity of 13 was
determined to be 77% ee by HPLC using a chiral column,
indicating the enantioselectivity of the above-mentioned asym-
metric allylation. However, we were pleased to find that
Sharpless dihydroxylation of 13 using AD-mix-b produced
enantiomerically pure diol 14 in 80% yield. Obviously, the
dihydroxylation reaction was accompanied by kinetic resolu-
tion and occurred at the most electron-rich and sterically less
hindered olefin with perfect regio- and diastereoselectivity.5c,13
Fostriecin (1, CI-920) is a structurally unique phosphate ester
produced by Streptomyces pulveraceus.1,2 This compound
displays potent in vitro activity against various cancerous cell
lines (i.e. leukemia, lung cancer, breast cancer, ovarian cancer)
as well as in vivo antitumor activity.3 However, despite the high
potential of fostriecin as an antitumor drug, phase I clinical trails
carried out at NCI were halted relatively early due to concerns
over the stability and purity of the natural material.4 Therefore,
an efficient and flexible synthetic route to fostriecin is required
for the discovery of analogues that have more desirable physical
properties. This situation has spurred much research on the
synthesis of fostriecin5 and Boger et al.3 have achieved the first
synthesis in 2001. Just recently, three groups6 also reported
successful total synthesis. We now report a novel enantiocon-
trolled synthesis of fostriecin, which enables us to prepare
various analogues as well.
From a retrosynthetic perspective (Scheme 1) we focused on
a strategy wherein the phosphate ester and sensitive triene arise
from alkenyl iodide 2 late in the synthesis. In order to make our
approach flexible, we envisaged ynone 6 as a precursor of 2. We
expected that alkenyl iodide 2 as well as its stereoisomers 3, 4
and 5 would each be available from 6 by the combination of
stereoselective formation of the E- or Z-b-iodoenone and 9-OH
directed anti- or syn-selective reduction.
Scheme 2 illustrates the asymmetric synthesis of the key
ynone based on asymmetric allylation, ring-closing alkene
metathesis,7 and Sharpless asymmetric dihydroxylation.8
According to Aldisson’s procedure,9 dihydrofuran was
converted to stannane 7 with perfect E-selectivity. After p-
Scheme 2 Reagents and conditions: i, t-BuLi, THF, 260 to 0 °C, then
(Bu3Sn)2Cu(CN)Li2, 230 to 210 °C, then MeI, 240 °C to rt, 83%; ii, p-
(MeO)PhCH2Cl, NaH, Bu4NI, DMSO, 90%; iii, I2, CH2Cl2, 0 °C, 100%; iv,
CH2NCHCHO, Pd(OAc)2 (2 mol%), K2CO3, Bu4NCl, DMF, 73%; v,
(+)-Ipc2BOMe, H2CNCHCH2MgBr, Et2O–toluene, 278 °C, then 30%
H2O2, 3 M NaOH, THF, 81%; vi, H2CNCHC(O)Cl, Et3N, CH2Cl2, 0 °C,
80%; vii, (Cy3P)2Cl2RuNCHPh (10 mol%), CH2Cl2, reflux, 75%; viii, AD-
mix-b, MeSO2NH2, t-BuOH–H2O (1+1), 0 °C, 80%; ix, Et3SiOTf,
2,6-lutidine, CH2Cl2, 278 °C, 91%; x, DDQ, CH2Cl2–H2O (20+1), 0 °C,
99%; xi, Dess–Martin periodinane, CH2Cl2, 0 °C, 100%; xii, HCCMgBr,
CeCl3, THF, 250 °C, 98%; xiii, as in xi, 95%.
Scheme 1 Retrosynthetic analysis.
† Electronic supplementary information (ESI) available: experimental
section. See http://www.rsc.org/suppdata/cc/b2/b209742g/
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This journal is © The Royal Society of Chemistry 2002

Scheme 3 Reagents and conditions: i, NaI (2 equiv.), AcOH (1 equiv.), acetone, 20 (63%) + 21 (6%); ii, NaI (1.1 equiv.), AcOH (4.4 equiv.), 81%; iii, 47%
HF–pyridine–H2O–MeCN (1+4+2+20), 0 °C, 81%; iv, Me4NB(OAc)3H, AcOH, MeCN, 230 °C, 99%; v, NaBH4, Et3B, MeOH–THF, 278 °C, then 30%
H2O2, NaHCO3, 90%; vi, t-BuMe2SiOTf, 2,6-lutidine, CH2Cl2, 278 °C, 88%; vii, 28, Pd(MeCN)2Cl2 (2.5 mol%), DMF, 0 °C, 88%; viii
(H2CNCHCH2O)2PN(i-Pr)2, tetrazole, CH2Cl2, 0 °C, then t-BuO2H, 0 °C, 89%; ix, Pd(PPh3)4 (10 mol%), HCO2NH2, PPh3, THF, then Dowex-50 (H+ form),
MeOH; x, 47% HF–pyridine–H2O–MeCN (1+4+2+20), then NaHCO3, 79% from 30.
Diol 14 was then converted to ynone 19 via addition of
acetylene to aldehyde 17 in 84% overall yield via a five-step
sequence.
Ministry of Education, Science, Sports and Culture of Japan is
gratefully acknowledged.
Notes and references
According to Kishi’s methodology,14 19 was exposed to 1.1
equivalents of NaI and 4.4 equivalents of acetic acid without
solvent at room temperature. In this case, even after 30 min, the
kinetically formed Z-isomer 20 isomerized to the thermody-
namically more stable E-isomer 21 to an appreciable extent
(Z+E = 76+24) and after 3 h pure 21 was obtained in 81% yield.
After experimentation under various conditions using solvent to
retard the isomerization, we eventually found that acetone was
the solvent of choice for the predominant production of Z-
isomer 20. Thus, treatment of 19 with 2 equivalents of NaI and
1 equivalent of acetic acid in acetone at room temperature gave
a chromatographically separable 91+9 mixture of 20 and 21 in
69% yield. From Z-isomer 20 either the 11R- or 11S-
stereocenter was established selectively via 22 by two methods.
After selective desilylation of 20, Evans’ anti-selective reduc-
tion15 of 22 using Me4NB(OAc)3H resulted in formation of
11R-diol 23 with 84% de in quantitative yield. On the other
hand, NaBH4 reduction using triethylborane16 converted 22 to
11S-diol 24 with perfect selectivity in good yield. Similarly,
from E-isomer 21 the corresponding 11R-diol 25 and 11S-diol
26 were obtained with perfect selectivity, respectively (Scheme
3)
‡ Prepared from propargyl alcohol in 67% overall yield: i, propargyl
alcohol, LiAlH4, THF, 0 °C then Bu3SnOTf, rt; ii, (COCl)2, DMSO,
CH2Cl2, –78 °C then Et3N, Ph3PNCHCO2Et, rt; iii, i-Bu2AlH, CH2Cl2, 278
°C; iv, t-BuPh2SiCl, DMAP-Et3N, CH2Cl2, 0 °C. For step i: E. J. Corey and
T. M. Eckrich, Tetrahedron Lett., 1984, 25, 2419.
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2 Complete stereochemical assignment: D. L. Boger, M. Hikota and B. M.
Lewis, J. Org. Chem., 1997, 62, 1748.
3 The first synthesis and biological backgrounds: D. L. Boger, S.
Ichikawa and W. Zhong, J. Am. Chem. Soc., 2001, 123, 4161 and
references therein.
4 R. S. De Jung, N. H. Mulder, D. R. A. Uges, D. Th. Sleijfer, F. J. P.
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Lett., 2001, 41, 6069; see also ref. 5(b) and 6(c).
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Having developed the methodology to attain 23 and all of its
isomers including the C11 stereocenter and the geometry of the
12
D -double bond, we then investigated the conversion of 23 to
fostriecin. Selective silylation of 23 afforded Jacobsen’s
intermediate 276a which was then subjected to palladium-
catalyzed Stille coupling17 with stannane 28,18‡ to produce 29
with perfect stereoselectivity. It should be highlighted that the
final phosphorylation-deprotection step employed in the pre-
vious syntheses3,6 was highly improved by use of a diallyl
phosphoryl group in place of a di-p-methoxybenzyl phosphoryl
group. Thus, reaction of 29 with diallyl diisopropylaminophos-
phine19 followed by treatment of the resulting phosphite with
tert-butyl hydroperoxide gave 30 in good yield. Finally,
palladium-catalyzed reductive deallylation20 of 30 followed by
desilylation of 31 using HF–pyridine cleanly furnished (+)-fos-
triecin (1). The synthetic substance was identical with natural
1
fostriecin ([a]D, H and 13C NMR, FAB–MS, IR, UV and
HPLC).
In conclusion, we have accomplished a total synthesis of
(+)-fostriecin from dihydrofuran in 21 steps in 4.5% overall
yield. This synthesis provides a flexible route to fostriecin
analogues required for biological testing.
We thank Dr R. Schultz of the Drug Synthesis and Chemistry
Branch, Developmental Therapeutics Program, Division of
Cancer Treatment and Diagnosis, National Cancer Institute for
a sample of natural fostriecin. Partial financial support from the
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