Total synthesis of (±)-Wortmannin

Article abstract of DOI:10.1002/anie.200290014

A potent and specific phosphoinositide 3-kinase inhibitor (±)-wortmannin has been achieved through an intramolecular Heck reaction for the construction of an allylic quaternary carbon center and a diosphenol-Claisen rearrangement (see scheme). SEM = 2-(Tr

Full text of DOI:10.1002/anie.200290014

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hydrocortisone.[5] Following this primary achievement, we
planned to develop a direct total synthesis of 1, which would
hopefully lead to many more derivatives. Here, we report the
first direct total synthesis of (ꢀ )-1 using an intramolecular
Heck reaction for stereoselective construction of an allylic
quaternary carbon center (Scheme 1)[6] and a diosphenol -
Claisen rearrangement (Scheme 3)[7] as key steps.
[6] J. M. Thomas, Angew. Chem. 1999, 111, 3800; Angew. Chem. Int. Ed.
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Orlando, C. M. Zicovich-Wilson, K. Doll, B. Civalleri, CRYSTAL
User©s Manual, Univ. of Torino, Torino, 1998 and 2001.
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[13] F. Cor‡, C. R. A. Catlow, J. Phys. Chem. B 2001, 105, 10278.
[14] F. Cor‡, C. R. A. Catlow, A. D©Ercole, J. Mol. Catal. A 2001, 166, 87.
[15] J. Chen, J. M. Thomas, G. Sankar, J. Chem. Soc. Faraday Trans. 1994,
90, 3455.
[16] P. A. Barrett, G. Sankar, R. H. Jones, C. R. A. Catlow, J. M. Thomas,J.
Phys. Chem. B 1997, 101, 9555.
[17] J. J‰nchen, M. P. J. Peeters, J. H. M. C. van Wolput, J. P. Wolthulzen,
J. H. C. van Hooff, J. Chem. Soc. Faraday Trans. 1994, 90, 1033.
Scheme 1. Retrosynthesis of (ꢀ )-wortmannin. SEM ¼ 2-(trimethylsilyl)-
ethoxymethyl; TBS ¼ tert-butyldimethylsilyl; Tf ¼ trifluoromethanesulfon-
yl; Bn ¼ benzyl.
Total Synthesis of (ꢀ )-Wortmannin**
Takashi Mizutani, Shinobu Honzawa, Shin-ya Tosaki,
and Masakatsu Shibasaki*
Our synthesis began with alkenyl triflate 6, which was
synthesized from compound 5, and obtained as a racemate[8]
in eight steps and in 27% overall yield (Scheme 2).[6c] After
conversion of 6 into the SEM-protected ether 7 (87%), it was
chemoselectively coupled with 8 by the Suzuki method to give
4 (64%).[9] An intramolecular Heck reaction of 4 afforded
Wortmannin (1) is a potent and specific phosphoinositide 3-
kinase (PI3K) inhibitor with a low nanomolar IC50 value[1]
that was originally isolated from Penicillium Wortmannii as an
anti-inflammatory and antibiotic agent.[2] Wortmannin (1)
acts by covalently binding Lys802 in the ATPbinding pocket
of PI3K through nucleophilic attack of the Lys amino group at
the C21 position of 1.[3] PI3K is an important enzyme that
functions in signal transduction pathways, and is a potential
target for preventing proliferation of cancer cells.[4] Unfortu-
nately, 1 has not yet been applied to medical use because of its
high toxicity. Thus, wortmannin derivatives, which possess
more potent inhibitory activity against PI3K and have less
general toxicity, are necessary for the development of new
antitumor drugs. In addition to the medicinal aspect, the
challenging structural features of 1, namely an allylic quater-
nary carbon center and a furanocyclohexadienone lactone
unit, are very attractive from a synthetic point of view. In
1996, we reported the first chemical synthesis of 1 from
Scheme 2. Synthesis of enol ether 3. a) SEMCl, 2,6-lutidine, nBu4NI,
CH2Cl2, 408C; b) 9-BBN, THF, RT then 8, [PdCl2(dppf)], K3PO4, THF/
DMF, 608C; c) 10 mol% of Pd(OAc)2, 22 mol% of 1,3-bis(diphenylphos-
phanyl)propane, 1.0 equiv of nBu4NBr, 2.5 mol equiv of K2CO3, toluene,
1008C, 17 h. SEMCl ¼ 2-(trimethylsilyl)ethoxymethyl chloride, 9-BBN ¼ 9-
borabicyclo[3.3.1]nonane, dppf ¼ 1,1’-bis(diphenylphosphanyl)ferrocene.
enol ether 3 in 65% yield and in excellent diastereoselectivity
(b-Me:a-Me ¼ 18:1). It is noteworthy that the stereochemis-
try of the b-SEM ether in 4 plays a crucial role in the excellent
stereoselectivity achieved by the Heck reaction.[6] Unfortu-
nately, the use of the epimer, the a-SEM ether, afforded the
undesired (a-Me) isomer as the major product.
Removal of the SEM group, followed by oxidation and
reduction, produced a-allylic alcohol 9 (3 steps) together with
the b alcohol (Scheme 3). The b-alcohol can be recycled by
conventional methods. After protection of 9 as the TBS ether
to give 10, oxidation of the enol ether with 2.5 mol% of OsO4
and 1.5 equivalents of NMO gave the hydroxyaldehyde, which
was then reduced with LiAlH4 to give the desired diol 11
[*] Prof. Dr. M. Shibasaki
Graduate School of Pharmaceutical Sciences
The University of Tokyo
Hongo, Bunkyo-ku, Tokyo 113-0033 (Japan)
Fax : (þ 81)3-5684-5206
E-mail: mshibasa@mol.f.u-tokyo.ac.jp
T. Mizutani, S. Honzawa, S.-y. Tosaki
Graduate School of Pharmaceutical Sciences
The University of Tokyo (Japan)
[**] We thank Dr. Yuzuru Matsuda (Kyowa Hakko Co., Ltd) for kindly
supplying
a sample of wortmannin. This work was financially
supported by CREST, JST, and RFTF. T.M. thanks the Japan Society
for the Promotion of Science (JSPS) for a research fellowship.
Supporting information for this article is available on the WWW under
http://www.angewandte.org or from the author.
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Scheme 3. Total synthesis of 1. a) CsF, DMF, 1308C; b) PDC, NaOAc, CH2Cl2, RT; c) DIBAL-H, toluene, ꢁ788C; d) TBSCl, imidazole, DMF, RT; e) OsO4,
NMO, acetone/H2O, RT; f) LiAlH4, THF, ꢁ408C; g) MeI, Ag2O, RT; h) Ac2O, DMAP, pyridine, CH Cl2, RT; i) CrO3, 3,5-dimethylpyrazole, CH2Cl2, ꢁ208C;
2
j) 1. TMSOTf, H¸nig base, CH2Cl2, ꢁ788C; 2. dimethyldioxirane, acetone, RT; 3. PPTS, MeOH, RT; k) (COCl)2, DMSO, CH2Cl2, ꢁ408C; Et3N, ꢁ408C;
l) allyl bromide, K2CO3, acetone, 408C; m) xylene, 2008C, 50 min; n) NaBH4, CeCl3¥7H2O, MeOH, 08C; o) HC(OMe)3, PPTS, RT; p) OsO4, NMO, CH3CN/
H2O, RT; q) nBu4NIO4, CHCl3, 408C; r) K2CO3, MeOH, RT; s) TPAP, NMO, 4ä MS, CHCl2, RT; t) HC(NMe2)3, DMF, 1008C; u) phosphate buffer (pH 4
2
5), THF, RT; v) Me2SO4, K2CO3, acetone, RT; w) 1n NaOH, THF, RT; x) PDC, NaOAc, CH2Cl2, RT; y) (COCl)2, DMSO, CH2Cl2, ꢁ208C; Et3N, ꢁ208C;
z) Et2NH, CH2Cl2, RT; aa) 1n HCl, THF, RT; bb) 3HF¥Et3N, THF, 408C; cc) Ac2O, pyridine, RT. PDC ¼ pyridinium dichromate; DIBAL-H ¼ diisobutyl-
aluminum hydride; TBSCl ¼ tert-butyldimethylsilyl chloride; DMAP ¼ 4-(dimethylamino)pyridine; TMSOTf ¼ trimethylsilyl trifluoromethanesulfonate;
PPTS ¼ pyridinium p-toluenesulfonate; NMO ¼ 4-methylmorpholine N-oxide; TPAP¼ tetrapropylammonium perruthenate.
(2 steps, 42%) together with the undesired diol (50%).[10,11]
Selective methylation of the primary alcohol of diol 11 and
successive protection of the remaining secondary alcohol as
an acetyl group gave 12 (2 steps, 90%). Allylic oxidation of 12
proceeded well with 15 equivalents of CrO3 and 3,5-dime-
thylpyrazole at ꢁ208C to give enone 13. In the next trans-
formation, we faced a difficult task, that is, introduction of a
carbon unit at the sterically crowded neopentyl position for
lactone formation. After numerous attempts, a diosphenol
Claisen rearrangement[7] of 14 was found to be effective for
group of 16 led to the formation of hemiacetal, which was
oxidized by tetrapropylammonium perruthenate (TPAP) to
give lactone 2 (2 steps).
After production of 2, the introduction of a C1 unit at the
a position of the lactone and formation of the furan ring
remained. Similar to previous reports on synthetic studies[17]
and chemical synthesis of 1,[5] aminomethylenation was
effective for the introduction of the C1 unit. As expected,
treatment of lactone 2 with HC(NMe2)3 at 1008C gave the
desired compound in good yield, and the rather unstable
product was successively treated with aqueous acid to furnish
enol 17 (2 steps). Protection of the enol and conversion of the
cyclic orthoester into a formate group occurred simultane-
ously following treatment of 17 with Me2SO4 and K2CO3 in
acetone, and further treatment with aquous NaOH gave diol
18 (2 steps, ca. 3:1 mixture of diastereomers). Oxidation of the
major diastereomer of diol 18 with PDC gave 19,[14] and then
Swern oxidation of 19 afforded diosphenol 20.[18] Direct
construction of the furan ring from 20 was first investigated
under acidic conditions. Unexpectedly, however, only decom-
position occurred. Several subsequent trials revealed that
diosphenol 20 was very reactive toward nucleophiles. Thus,
there was clean consumption of 20 to give 21 when it was
treated with Et2NH, and successive treatment of 21 with 1n
HCl promoted the desired cyclization and simultaneous
deprotection of acetal to afford furan 22 (2 steps). Finally,
introducing a C C bond at the neopentyl position.[12,13] Thus,
ꢁ
enone 13 was converted into 14, by five successive trans-
formations: enol silyl ether formation, oxidation of enol ether
with dimethyldioxirane, removal of the TMS group, oxidation
of a-hydroxyketone to a mixture of diosphenol and a-
diketone, and allylation with allyl bromide. The Claisen
rearrangement of 14 proceeded very well under thermal
conditions to give the a-diketone as a single diastereom-
er.[14,15] The obtained a-diketone was subsequently reduced to
the diol, followed by protection to give cyclic orthoester 15
(3 steps) as an inseparable mixture of several diastereomers.
The formation of several diastereomers is not a serious
problem, because in principle all the isomers can be trans-
formed into 1. The terminal olefin of cyclic orthoester 15 was
oxidatively cleaved (cat. OsO4 then nBu4NIO4[16] in CHCl3 at
408C) to give aldehyde 16 (2 steps). Removal of the acetyl
Angew. Chem. Int. Ed. 2002, 41, No. 24
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[10] At this stage, the undesired diastereomer of 11 was recrystallized from
acetone and an X-ray crystallographic analysis succeeded in confirm-
ing the stereochemistry. CCDC-191844 contains the supplementary
crystallographic data for this paper. These data can be obtained free of
charge via www.ccdc.cam.ac.uk/conts/retrieving.html (or from the
Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge
CB21EZ, UK; fax: (þ 44)1223-336-033; or deposit@ccdc.cam.ac.uk).
[11] The undesired diastereomer could be readily recycled to the desired
diastereomer in several ways.
[12] Intermolecular Michael addition of various reagents to the corre-
sponding enone failed.
[13] We tried other several strategies for the construction of wortmannin
skeleton from 3 (Scheme 5). These strategies, however, were unsuc-
cessful.
removal of the TBS group proceeded smoothly with excess
3HF¥Et3N, and subsequent acetylation of the generated
alcohol gave (ꢀ )-1 (2 steps).
In conclusion, we have achieved the first total synthesis of 1.
Although several issues remain to be addressed, such as the
low stereoselectivities in several steps, much useful informa-
tion about the synthesis of wortmannin derivatives has been
accumulated. Further optimization of the current scheme and
continuing efforts to realize an efficient catalytic asymmetric
synthesis are now under intense investigation and the results
will be reported in due course.
Received: August 21, 2002 [Z50016]
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[6] This synthetic route would lead to an asymmetric total synthesis of 1
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pp. 457 487; we actually succeeded in an efficient kinetic resolution
with an asymmetric Heck reaction as shown in Scheme 4. Further
conversions toward 1, however, have not been achieved so far,
Scheme 5. TES ¼ triethylsilyl.
[14] The stereochemistry of Ha was clearly determined by NOE measure-
ments on 19, and that of Hb was also determined by the same method.
[15] Longer reaction times (e.g. 3 h) produced the corresponding diosphe-
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[18] When a minor diastereomer was used as a substrate for
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(ca. 10%).
Scheme 4. MOM ¼ methoxymethyl; TBDPS ¼ tert-butyldiphenylsilyl; binap ¼ 2,2’-
bis(diphenylphosphanyl)-1,1’-binaphthyl.
because of the problem of deprotection. Optimization using 4 is
currently under investigation, see c) S. Honzawa, T. Mizutani, M.
Shibasaki, Tetrahedron Lett. 1999, 40, 311 314.
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