Enantioselective synthesis of (+)-cephalostatin 1

Article abstract of DOI:10.1021/ja906996c

This Article describes an enantioselective synthesis of cephalostatin 1. Key steps of this synthesis are a unique methyl group selective allylic oxidation, directed C-H hydroxylation of a sterol at C12, Au(I)-catalyzed 5-endo-dig cyclization, and a kinetic spiroketalization.

Full text of DOI:10.1021/ja906996c

Published on Web 12/07/2009
Enantioselective Synthesis of (+)-Cephalostatin 1
Kevin C. Fortner,| Darryl Kato,‡ Yoshiki Tanaka,§ and Matthew D. Shair*,†
Department of Chemistry and Chemical Biology, HarVard UniVersity, 12 Oxford Street,
Cambridge, Massachusetts 02138
Received August 25, 2009; E-mail: shair@chemistry.harvard.edu
Abstract: This Article describes an enantioselective synthesis of cephalostatin 1. Key steps of this synthesis
are a unique methyl group selective allylic oxidation, directed C-H hydroxylation of a sterol at C12, Au(I)-
catalyzed 5-endo-dig cyclization, and a kinetic spiroketalization.
Introduction
An important property of modern anticancer therapeutics is
the selective killing of cancer cells over normal cells. One
approach to achieve selectivity is “synthetic lethality,”1 involving
combination of a mutation, only present in cancer cells, and a
small molecule, resulting in selective cell killing of the cells
bearing the mutation. Because many genetic mutations have
been identified in tumor cells, a challenge is to discover small
molecules that selectively target cells harboring these mutations.
We have become interested in the therapeutic potential and
cellular target of cephalostatin 1 (1), a natural product that may
be synthetic lethal with the p16 tumor suppressor gene. In a
bioinformatics comparison of the cytotoxicity profiles of
∼43 000 small molecules with cell lines bearing altered p16, 1
emerged as the compound with the highest correlation, sug-
gesting that it may be selectively cytotoxic to cells with altered
p16.2 The p16 gene encodes cyclin-dependent kinase inhibitor
2A (CDKN2A or Ink4a), a tumor suppressor protein that blocks
cell proliferation by binding to and inhibiting the kinase activity
of cyclin-dependent kinase 4 (CDK4) and cyclin-dependent
kinase 6 (CDK6).2 In cells, both CDK4 and CDK6 each form
active complexes with cyclin D that phosphorylate Rb (the
retinoblastoma protein), allowing progression through the G1-S
phase of the cell cycle. If CDKN2A is inactive due to a mutation
or lack of expression, tumor cells can progress uncontrollably
through the G1-S phase of the cell cycle.3 Because p16 is among
the most frequently mutated genes in human tumor cells, 1 may
be a uniquely selective anticancer therapeutic, and elucidation
of its unknown cellular target may reveal new ways to achieve
synthetic lethality with small molecules.
Figure 1. Cephalostatin 1, ritterazine B, OSW-1, and schweinfurthin A.
Four antiproliferative natural products with similar cytotoxicity patterns.
Cephalostatin 1 was first reported in 1988 as a potent growth
inhibitory marine natural product.4 The average GI50 of 1 against
the NCI-60, a collection of 60 human cancer cell lines, is 1.8
nM.5 Three other molecules, ritterazine B (2),6 OSW-1 (3),7
and schweinfurthin A (4),8 have cytotoxicity patterns resembling
† Harvard University.
| Present address: Department of Chemistry, University of Michigan.
‡ Present address: Gilead Sciences, Inc., Foster City, CA 94404.
§ Present address: Taiho Pharmaceutical Co., Ltd., Saitama, Japan.
(1) Kaelin, W. G., Jr. Nat. ReV. Cancer 2005, 5, 689–698.
(2) Serrano, M. Exp. Cell Res. 1997, 237, 7–13.
(5) NCI-60 data are available on the web at http://dtp.nci.nih.gov.
Cephalostatin 1 is NSC-363979.
(6) Fukuzawa, S.; Matsunaga, S.; Fusetani, N. J. Org. Chem. 1995, 60,
608–614.
(3) Kubo, A.; Nakagawa, K.; Varma, R. K.; Conrad, N. K.; Cheng, J. Q.;
Lee, W. C.; Testa, J. R.; Johnson, B. E.; Kaye, F. J.; Kelley, M. J.
Clin. Cancer Res. 1999, 5, 4279–4286.
(7) (a) Kubo, S.; Mimaki, Y.; Terao, M.; Sashida, Y.; Nikaido, T.; Ohmoto,
T. Phytochemistry 1992, 31, 3969–3973. (b) Mimaki, Y.; Kuroda, M.;
Kameyama, A.; Sashida, Y.; Hirano, T.; Oka, K.; Maekawa, R.; Wada,
T.; Sugita, K.; Beutler, J. A. Bioorg. Med. Chem. Lett. 1997, 7, 633–
636.
(4) Pettit, G. R.; Inoue, M.; Kamano, Y.; Herald, D. L.; Arm, C.; Dufresne,
C.; Christie, N. D.; Schmidt, J. M.; Doubek, D. L.; Krupa, T. S. J. Am.
Chem. Soc. 1988, 110, 2006–2007.
9
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J. AM. CHEM. SOC. 2010, 132, 275–280 275

A R T I C L E S
Fortner et al.
Scheme 1. Synthesis Plan for 5 Requiring a C18 Methyl
Group-Selective Allylic Oxidation of 7
Scheme 2. Selective C18 Methyl Group-Selective Allylic Oxidation
Involving Ene Reaction, [2,3]-Sigmatropic Rearrangement, and
Oxidationa
1, suggesting that all four compounds share similar mecha-
nisms.9 The cellular target and mechanism of 1 (or 2-4) have
not been elucidated, although an increasing amount of research
is being focused on these issues.10
a Conditions: (a) hν, 1,4-dioxane, 25 °C; (b) 4-phenyl-1,2,4-triazoline-
3,5-dione, dichloroethane, 25 °C, 61% two steps; (c) NaOAc, DMF, 100
°C, 69%; (d) CH(OMe)3, TsOH ·H2O, MeOH, 25 °C; (e) PhI(OAc)2, MeCN/
H2O, 0 °C, 64% two steps; (f) NaBH4, MeOH, 0 °C, 88%; (g) NaH, DMF,
0 °C; allyl bromide, 25 °C, 93%; (h) PPTS, acetone, 25 °C; (i) BF3 ·OEt2,
PhMe, 0 °C, 61% two steps; (j) Ac2O, pyr., DMAP, 25 °C.
The unusually large and complex structure of 1 has been the
target of many synthesis studies, with one synthesis reported
by Fuchs.11 Because of the small quantities of 1 available from
natural sources, only through synthesis will sufficient amounts
of 1 (and analogues) be available to address questions sur-
rounding its potential synthetic lethality with p16, elucidate its
cellular target and mechanism, and determine its efficacy in vivo
for the treatment of cancer. This Article reports our synthesis
of 1 (Figure 1), enabling us to answer the questions posed above
surrounding its biological activity.
formation following the reactions developed by Heathcock12
and Fuchs.11a,13 The C22 spiroketal of 5 (Scheme 1) is in a
thermodynamically favorable configuration, meaning that its
stereochemistry can be established by acid-catalyzed equilibra-
tion.14 Hecogenin acetate (6), an inexpensive plant-derived
steroid that is available in kilogram quantities,15 is used as the
starting material for our synthesis of the western half because
it has handles for most of the functionality of 5, especially
oxygenation at C12. Compound 6 was also used by others for
their synthesis studies on 1. With 6 as a starting point for
synthesis of 5, we needed to rearrange the spiroketal, oxidize
C23, deoxygenate C16, install a C14-C15 olefin, and, most
challenging, oxidize the unactivated C18 angular methyl group
(see Scheme 1). Our plan was to generate lumihecogenin acetate
(7) by photolysis of 6, a reaction first described by Bladon.16
Selective oxidation of C18 of 7 to generate 8 followed by Prins
cyclization would deliver 9. Compound 9 would then be
converted to 5. We recognized that 7 is the only intermediate
in our synthesis in which C18 is activated (allylic), and therefore
we focused on methods to selectively oxidize the allylic methyl
Synthesis of the Western Half of Cephalostatin 1 (5)
Our synthesis plan involved construction of the eastern and
western portions of 1, followed by unsymmetrical pyrazine
(8) Beutler, J. A.; Shoemaker, R. H.; Johnson, T.; Boyd, M. R. J. Nat.
Prod. 1998, 61, 1509–1512.
(9) Zhou, Y.; Garcia-Prieto, C.; Carney, D. A.; Xu, R. H.; Pelicano, H.;
Kang, Y.; Yu, W.; Lou, C.; Kondo, S.; Liu, J.; Harris, D. M.; Estrov,
Z.; Keating, M. J.; Jin, Z.; Huang, P. J. Natl. Cancer Inst. 2005, 97,
1781–1785.
(10) (a) Dirsch, V. M.; Muller, I. M.; Eichhorst, S. T.; Pettit, G. R.; Kamano,
Y.; Inoue, M.; Xu, J. P.; Ichihara, Y.; Wanner, G.; Vollmar, A. M.
Cancer Res. 2003, 63, 8869–8876. (b) Muller, I. M.; Dirsch, V. M.;
Rudy, A.; Lopez-Anton, N.; Pettit, G. R.; Vollmar, A. M. Mol.
Pharmacol. 2005, 67, 1684–1689. (c) Lopez-Anton, N.; Rudy, A.;
Barth, N.; Schmitz, M. L.; Pettit, G. R.; Schulze-Osthoff, K.; Dirsch,
V. M.; Vollmar, A. M. J. Biol. Chem. 2006, 281, 33078–33086.
(11) (a) Jeong, J. U.; Sutton, S. C.; Kim, S.; Fuchs, P. L. J. Am. Chem.
Soc. 1995, 117, 10157–10158. (b) LaCour, T. G.; Guo, C.; Bhandaru,
S.; Fuchs, P. L.; Boyd, M. R. J. Am. Chem. Soc. 1998, 120, 692–707.
(c) Jeong, J. U.; Guo, C.; Fuchs, P. L. J. Am. Chem. Soc. 1999, 121,
2071–2084. (d) Kim, S.; Sutton, S. C.; Guo, C.; LaCour, T. G.; Fuchs,
P. L. J. Am. Chem. Soc. 1999, 121, 2056–2070. (e) Lee, S.; Fuchs,
P. L. Org. Lett. 2002, 4, 317–318.
(12) (a) Smith, S. C.; Heathcock, C. H. J. Org. Chem. 1992, 57, 6379–
6380. (b) Smith, S. C.; Heathcock, C. H. J. Org. Chem. 1994, 59,
6828–6839.
(13) Guo, C.; Bhandaru, S.; Fuchs, P. L. J. Am. Chem. Soc. 1996, 118,
10672–10673.
(14) Bhandaru, S.; Fuchs, P. L. Tetrahedron Lett. 1995, 36, 8351–8354.
(15) $5.50/g from Natland International Corp.
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Enantioselective Synthesis of (+)-Cephalostatin 1
A R T I C L E S
Scheme 3. Proposed Mechanism of the Selective Aza-Prins Reaction, [2,3]-Sigmatropic Rearrangement, and Urazole Oxidative Hydrolysis
group. This is a significant challenge because the olefin of 7 is
tetrasubstituted and there are four other allylic hydrogens (see
blue H’s), two methines, and one methylene. We required an
oxidation that was selective for the C18 methyl group and
tolerant of highly hindered double bonds, boundary conditions
that exclude many of the known allylic oxidation reactions.
The synthesis of 5 begins with the known conversion of 6 to
7 (Scheme 2).16 Attempts to perform allylic oxidation of C18
on either aldehyde 7 or the protected alcohol at C18 were
unsuccessful. As expected, SeO2 led to hydroxylation of the
C15 methylene. Radical halogenations were poorly regioselec-
tive, and the hindered double bond was inert to transition metal-
catalyzed allylic oxidation reactions.
to 11 achieving selective functionalization of the C18 methyl
group via an apparent ene reaction, combined with formation
of a seven-membered aminal. This transformation may in fact
be directed by the C12 aldehyde because the corresponding C12
dimethyl acetal reacted to form a PTAD adduct with abstraction
of a C15 proton. One explanation for the selective activation
of C18 in this reaction involves initial formation of a zwitterionic
adduct (18) between PTAD (10) and aldehyde 7 (Scheme 3).
This species could participate in an intramolecular aza-Prins
reaction via intermediate 19. Close proximity between the C12
alkoxide and the C18 methyl group in 19 could explain the
selective proton abstraction at C18. Alternatively, PTAD could
add to the C12 aldehyde via its carbonyl and engage in an ene
reaction, although inspection of molecular models appears to
preclude this mechanism due to lack of required orbital overlap.
Ultimately, an unusual allylic oxidation of C18 was achieved.
It was discovered that treatment of 7 with 4-phenyl-1,2,4-
triazoline-3,5-dione (PTAD, 10), a potent eneophile, led directly
Scheme 4. Conversion of 17 to Cephalostatin 1 Western Half (5)a
a Conditions: (a) OsO4, NaIO4, 2,6-lutidine, 1,4-dioxane/H2O, 25 °C; (b) NaBH(OAc)3, PhH/AcOH, 0 °C; (c) TBDPSCl, Im., DMAP, CH2Cl2, 25 °C,
74% four steps; (d) trifluoroacetyl trifluoromethanesulfonate, 2,6-tert-butyl-4-methyl-pyridine, CH2Cl2, -78 °C, then PPTS, CH2Cl2, 40 °C; (e) PCC, CH2Cl2,
25 °C; (f) DBU, CH2Cl2, 43%three3 steps; (g) (HMe2Si)2O, H2PtCl6, PhMe, 25 °C; (h) TBAF, AcOH, THF, 25 °C, 51% two steps; (i) DMSO, i-Pr2NEt,
SO3 ·pyr, CH2Cl2, 25 °C; (j) piperidine, AcOH, 25 °C, 75% two steps; (k) 1-methoxy-1-tert-butyldimethylsilyloxyethene, LiClO4, CH2Cl2, 27ꢀ, 51%, 27r,
18%; (l) TBAF, THF, 25 °C, 100%; (m) Ph3P, DIAD, chloroacetic acid, THF, 25 °C, 69%; (n) HDTC, 2,6-lutidine, AcOH, 25 °C, 80%; (o) TBDPSCl, Im.,
DMAP, CH2Cl2, 25 °C, 93%; (p) MeMgBr, Et2O, 25 °C; (q) TPAP, NMO, CH2Cl2, 25 °C, 69% two steps; (r) PhSeBr, pyridine, CH2Cl2, -78 to 0 °C, 92%;
(s) AIBN, Bu3SnH, toluene, 100 °C, 100%; (t) CSA, DCE, 83 °C, 78%.
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Fortner et al.
Finally, an ene reaction may occur between 10 and 7 followed
by hemiaminal formation.
28 with phenylselenyl bromide afforded 29. Reductive deha-
logenation of 29 delivered 30 as a single diastereomer with
hydrogen atom addition occurring from the convex face. To
complete the preparation of the cephalostatin western half 5,
C22 was epimerized by treatment of 30 with camphorsulfonic
acid in refluxing dichloroethane.
Treatment of 11 with sodium acetate induced opening of the
hemiaminal followed by apparent [2,3]-sigmatropic rearrange-
ment, affording allylic N-Ph urazole 12 (Scheme 3). Protection
of the C12 aldehyde as its dimethyl acetal was followed by
oxygenation of C18 by treatment of 13 with PhI(OAc)2,
affording aldehyde 14. In this reaction, the N-N bond is
oxidized to NdN. Tautomerization, addition of water, and
release of the urazole afforded 14. Allylation of the primary
hydroxyl group, followed by acid-catalyzed acetal hydrolysis,
set the stage for C-ring closure, which was accomplished by
treatment with BF3 ·OEt2 (Scheme 2). Finally, acetylation of
the secondary alcohol provided 17.
Starting with compound 17, allyl group-selective oxidative
olefin cleavage, aldehyde reduction, and protection of the
resulting primary hydroxyl afforded 20 (Scheme 4). Next, the
atoms comprising the spiroketal were removed starting with
application of a modified Marker degradation.17 Treatment of
20 with trifluoroacetyl trifluoromethanesulfonate (TFAT) opened
the F-ring, giving E-ring dihydrofuran 21. Oxidative cleavage
of the cyclic enol ether provided the corresponding ketoester,
which was subjected to DBU-promoted elimination. The
product, dienone 22, underwent 1,4-reduction under platinum-
catalyzed hydrosilylation conditions, affording the saturated
methyl ketone 23 as a 4:1 mixture of ꢀ/R-methyl ketone
stereoisomers. After removal of the TBDPS ether, and separation
of the diastereomers, the undesired C17 R-methyl ketone was
equilibrated in favor of the ꢀ-diastereomer. Oxidation of the
C23 primary hydroxyl preceded an intramolecular aldol reaction
to afford enal 26.
Synthesis of the Cephalostatin 1 Eastern Half (31)
The E and F rings of the eastern half of cephalostatin 1 consist
of a 5,5-spiroketal in a thermodynamically unfavorable config-
uration at C22, which require a kinetically controlled spiroket-
alization reaction (Scheme 5, 31). The spiroketal in the natural
C22-(S) configuration exhibits a single anomeric effect, while
the unnatural C22-(R) configuration permits additional stabiliza-
tion from a second anomeric effect. To form the 5,5-spiroketal,
we planned to induce cyclopropane opening on 32 followed by
irreversible attack by the C25 hydroxyl group on the less
hindered ꢀ-face of the incipient oxonium ion, which would
simultaneously give rise to the desired configurations of both
the C22 spiroketal and the C21 methyl group. Rather than
starting with hecogenin acetate (6) to make use of its C12
oxygenation as was done for the western half of 1, we thought
it would be more expedient to hydroxylate the C12 position of
the steroid trans-androsterone (34) by a remote C-H oxidation
process (see Scheme 5, 34). To increase convergency of the
synthesis of 32, the remote oxidation of 34 would be followed
by incorporation of alkyne 33, which comprises seven of the
eight carbons of the E,F-rings spiroketal.
Our synthesis of alkyne 33 began with the known diol 35
(two steps from 3-methyl-3-buten-1-ol, 89% yield, 96% ee).18
Installation of the C24-C25 fragment of the incipient F-ring
was accomplished by way of a Mukaiyama aldol reaction. Thus,
treatment of aldehyde 26 with the enolsilane of methyl acetate
in the presence of lithium perchlorate delivered a 3:1 mixture
of diastereomers favoring the undesired 23-(S)-stereoisomer
(27ꢀ). Unfortunately, extensive efforts to override the substrate’s
inherent facial selectivity for aldol addition were met with
failure. Attempts at Mukaiyama aldol addition with other
catalysts, including chiral catalysts, afforded product mixtures
favoring 23-(S)-configured products. Likewise, chiral auxiliary-
based acetate equivalents reacted to give predominantly adducts
with the undesired 23-(S) stereochemistry. Removal of the TBS
group from 27ꢀ, Mitsunobu reaction with chloroacetic acid,
hydrolysis of the chloroacetate, silylation of the C23 secondary
carbinol, and addition of excess MeMgBr afforded 28 after
oxidation with TPAP/NMO.
Scheme 5. Synthesis Plan for 31 Requiring a Remote Oxidation of
34 and Sonogashira Coupling with 33
Because the spiroketal of 5 is known to be under thermody-
namic control, we expected mild acid treatment of 28 would
furnish the F-ring while establishing the desired (S)-stereo-
chemistry at C20. However, in the presence of camphorsulfonic
acid, 28 cyclized to give a spiroketal with the undesired 20-(R)
stereochemistry. Surprisingly, the observed product results from
protonation of the more hindered concave face of the dihydro-
pyran E-ring. This result is in contrast to a similar reaction
reported by Fuchs in which protonation of a compound closely
related to 28 (except that the C14-C15 double bond was
saturated) afforded the desired C20-(S) stereochemistry.14
This outcome was corrected by a two-step bromoetherifica-
tion/reductive debromination sequence. Bromoetherification of
Scheme 6. Synthesis of Alkyne 33 from Known Diol 35a
a Conditions: (a) TBDPSCl, imidazole, DMF; (b) CAN, CH3CN, H2O,
0 °C; (c) TMSCl, imidazole, DMF, 80% three steps; (d) oxalyl chloride,
DMSO, Et3N, CH2Cl2, -78 °C; (e) Zn(OTf)2, (+)-N-methylephedrine,
Et3N, ethynyltrimethylsilane, toluene, 40 °C, 57% two steps; (f) TBSCl,
imidazole, DMAP, CH2Cl2; (g) AgNO3, THF, H2O, EtOH, 2,6-lutidine,
93% two steps.
(16) Bladon, P.; McMeekin, W.; Williams, I. A. J. Chem. Soc. 1963, 5727–
5737.
(17) Lee, J. S.; Fuchs, P. L. Org. Lett. 2003, 5, 3619–3622.
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Enantioselective Synthesis of (+)-Cephalostatin 1
A R T I C L E S
Scheme 7. Synthesis of Vinyl Triflate 43 from Commercially
Available trans-Androsterone 34 by Remote Oxidation at C12a
reomer in 25% yield. Acetylation with Ac2O/pyridine and treatment
with PhN(Tf)2/KHMDS led to vinyl triflate 43 in 88% yield.
Pd-catalyzed Sonogashira coupling of vinyl triflate 43 and
alkyne 33 provided enyne 44 in 94% yield (Scheme 8).
Sharpless dihydroxylation of the enyne proceeded with complete
stereocontrol to install the R-hydroxyl at C17. Further oxidation
with benzeneseleninic anhydride22 converted the cis-diol into
unstable R-hydroxy cyclopentenone 45 in fairly low yield despite
extensive efforts toward optimization.
Treatment of the enone 45 with NaBH(OAc)3 resulted in C17
hydroxyl-directed reduction to trans-diol 46. Diol 46 underwent
Au(I)-catalyzed 5-endo-dig cyclization23 to provide dihydrofuran
47 in 88% yield. It is worth noting the ease with which the
Au(I)-catalyzed cyclization takes place on what is a highly
hindered internal alkyne. Again, using the C17 hydroxyl as a
directing group, Simmons-Smith conditions stereoselectively
converted the dihydrofuran 47 to cyclopropane 48. Deprotection
of the C25 hydroxyl with PPTS delivered spiroketalization
substrate 32 as a single diastereomer in 73% yield from 47.
Treatment of 32 with Zeise’s dimer [{(η2-C2H4)PtCl2}2] resulted
in quantitative spiroketalization;24 however, the undesired C22-
(R) spiroketal stereoisomer was favored by a 13:1 ratio. This
may be due to HCl generated during the reaction, and attempts
to buffer the reaction with nitrogenous bases inhibited spiroket-
alization. We later discovered that oxidative spiroketalization
using NBS in THF furnished a separable mixture of bromom-
ethylene spiroketals favoring the desired C22-(S) isomer 49 by
a 5:1 ratio. Lack of equilibration in this reaction is due to the
neutral reaction conditions. Debromination of 49 by Bu3SnH/
AIBN followed by silylation of the extremely hindered C17
hydroxyl using neat pyridine/TMSOTf delivered 50 in 65% yield
from 49. Selective hydrolysis of the C3 acetate (the C12 acetate
is shielded by the C17 OTMS group) followed by Brown-
modified Jones oxidation25 provided 31, the eastern half of
cephalostatin 1, in 88% yield over two steps.
a Conditions: (a) 2-aminomethylpyridine, TsOH, toluene, 110 °C, 89%;
(b) Cu(OTf)2; benzoin, Et3N, acetone, O2, HCl, NH4OH, 25%; (c) Ac2O,
pyridine, 97%; (d) PhN(Tf)2, KHMDS, THF, -78 to 25 °C, 91%.
We protected the primary hydroxyl as a TBDPS ether, removed
the PMP group by CAN oxidation, and protected both hydroxyl
groups of the resulting 1,3-diol as TMS ethers to afford 37 in
80% yield over three steps (Scheme 6). The Swern reagent
chemoselectively converted the TMS ether of the primary
carbinol directly into aldehyde 38. Carreira alkynylation19 with
ethynyltrimethylsilane favored the desired (4R)-propargyl al-
cohol by 32:1 and provided it in 57% yield from 37. The
secondary carbinol was protected as a TBS ether to deliver 39,
and the alkynyl TMS was removed with AgNO3 and 2,6-
lutidine,20 affording alkyne 33.
Synthesis of the steroid-derived Sonogashira coupling partner
began with the commercially available steroid trans-androsterone
34 (Scheme 7). Utilizing the procedure of Scho¨necker for the
hydroxylation of unactivated C-H bonds,21 we treated the steroid
with 2-(aminomethyl)pyridine and catalytic TsOH to form imine
40 in 89% yield. Treatment of 40 with Cu(OTf)2, benzoin, and
Et3N in acetone to generate Cu(I), followed by the addition of
molecular oxygen, resulted in hydroxylation at the unactivated C12
position. Hydrolytic workup provided diol 41 as a single diaste-
Completion of a Synthesis of Cephalostatin 1
To prepare the A rings of western half 5 and eastern half 31
for pyrazine coupling, we used a sequence of reactions
Scheme 8. Completion of the Synthesis of the Eastern Half of Cephalostatin 1a
a Conditions: (a) 33, (Ph3P)4Pd, CuI, i-Pr2NEt, DMF, 94%; (b) (DHQ)2PHAL, K2CO3, K3Fe(CN)6, MeSO2NH2, K2OsO4 ·2H2O, t-BuOH, H2O, 95%; (c)
(PhSeO)2O, K2CO3, toluene, 110 °C; (d) NaBH(OAc)3, THF, 65 °C, 36% two steps; (e) Ph3PAuCl, AgBF4, THF, 88%; (f) CH2I2, Et2Zn, toluene, 0 °C; (g)
PPTS, CH2Cl2, MeOH, 73% two steps; (h) NBS, THF, -10 °C; (i) Bu3SnH, AIBN, toluene, 110 °C; (j) TMSOTf, pyridine, 65% three steps; (k) KHCO3,
MeOH, H2O, 65 °C; (l) HCrO4, Et2O, CH2Cl2, 0 °C, 88% two steps.
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A R T I C L E S
Fortner et al.
Scheme 9. Pyrazine Coupling and Completion of the Synthesis of Cephalostatin 1a
a Conditions: (a) PhMe3NBr3, THF, 0 °C; (b) tetramethylguanidinium azide, EtNO2, 83% two steps; (c) PhMe3NBr3, THF, 0 °C; (d) tetramethylguanidinium
azide, EtNO2, 78% two steps; (e) NH2OMe ·HCl, pyridine/CH2Cl2; (f) PPh3, THF/H2O, 0 to 25 °C, 77% two steps; (g) polyvinylpyridine, Bu2SnCl2, benzene,
80 °C; (h) TBAF, THF, 47% two steps.
developed by Fuchs11b (Scheme 9). Bromination R to the C3
ketone and azidation with tetramethylguanidinium azide in
EtNO2 provided 52 from 5 and 54 from 31. The C3 ketone of
54 was converted to methoxime 55, and Staudinger reduction
of the azide to an amine gave pyrazine coupling partner 56. 52
and 56 were treated with polyvinylpyridine and Bu2SnCl2 in
refluxing benzene to provide protected cephalostatin 1 (57) along
with a trace of recovered 56. Global deprotection of the silyl
groups and the C12 acetate was affected by TBAF in refluxing
THF to afford cephalostatin 1 in 47% yield from 52.
western half, a unique methyl group-selective allylic oxidation
was developed. PTAD underwent selective functionalization of
the C18 methyl group, apparently directed by a proximal
aldehyde. Subsequent [2,3]-sigmatropic rearrangement and
oxidative hydrolysis of the resulting urazole led to a C18
aldehyde that could not be produced using other methods. This
allylic functionalization sequence may be useful in other systems
where conventional methods fail. Key steps in the eastern half
synthesis include a remote C-H hydroxylation of C12, Sono-
gashira coupling between a steroid-derived vinyl triflate and an
alkyne containing most of the atoms of the E and F rings, a
Au(I)-catalyzed 5-endo-dig cyclization, and a kinetic spiroket-
alization by cyclopropane ring-opening. Our goal is to uncover
the cellular target of cephalostatin 1 and explore its therapeutic
potential. This synthesis is a first step toward achieving these
goals.
Conclusion
In conclusion, an enantioselective synthesis of cephalostatin
1 has been achieved. In the course of our synthesis of the
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Acknowledgment. We thank Novartis and Taiho Pharmaceuti-
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Supporting Information Available: Experimental procedures
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