A practical synthesis of cephalostatin 1

Article abstract of DOI:10.1002/asia.201000882

Let's get practical: A new practical synthetic strategy for natural sterols starting from pregnan-(16S,20S)-diols and steroid-(16S),22-lactones is presented. A tandem double oxymercuration-demercuration and a substitution-ketalization cascade are consider

Full text of DOI:10.1002/asia.201000882

COMMUNICATION
DOI: 10.1002/asia.201000882
A Practical Synthesis of Cephalostatin 1
Yong Shi, Lanqi Jia, Qing Xiao, Quan Lan, Xiaohu Tang, Dahai Wang, Min Li, Yu Ji,
Tao Zhou, and Weisheng Tian*[a]
Cephalostatin 1 is among the most powerful anticancer
agents ever tested by the National Cancer Institute. It is not
only the first discovered but it is also the most potent one
out of the 45 structurally related natural pyrazine bis-
(steroids) comprised with cephalostatins and ritterazines
logues are still highly demanded. Herein, we report a practi-
cal synthesis of cephalostatin 1.
As retrosynthetic analysis is shown in Scheme 1, cephalos-
tatin 1 could be synthesized by the connection of two sub-
structures, left hemisphere 2 and right hemisphere 3. The E/
(isolated by Pettit et al. and Fusetani et al. from the Indian
Ocean marine worm Cephalodiscus gilchrst and the tunicate
Ritterella tokio, respectively).[1] The structure of cephalosta-
tin 1 is characterized by an asymmetric union of two highly
oxygenated steroidal spiroketal subunits with a central pyra-
zine ring. Its unique structure, extremely powerful cytotoxic-
ity (with an IC50 value in the low nanomolar range), and nat-
ural scarcity have stimulated several synthetic endeavours.[2]
Although the research groups of both Fuchs[3] and Shair[4]
have completed the synthesis of cephalostatin 1 (1), more ef-
ficient/practical syntheses of cephalostatin 1 and its ana-
Scheme 1. Retrosynthetic analysis for cephalostatin 1 (1).
[a] Dr. Y. Shi, Dr. L. Jia, Dr. Q. Xiao, Dr. Q. Lan, Dr. X. Tang,
Dr. D. Wang, Dr. M. Li, Dr. Y. Ji, T. Zhou, Prof. Dr. W. Tian
Key Laboratory of Synthetic Chemistry of Natural Substances
Shanghai Institute of Organic Chemistry
Chinese Academy of Sciences
F spiroketal ring of 2 would be constructed by a tandem
oxymercuration–ketalization of the alkenyl enol ether in 4.
We also believed that a cascade ketalization of 5 could
result in the formation of the E/F spiroketal ring of 3. We
envisaged that intermediates 4 and 5 could be prepared
345 Lingling Road, Shanghai 200032 (China)
Fax : (+86)21-54925176
E-mail: wstian@mail.sioc.ac.cn
from pregnan-(3S,12R,16S,20S)-tetraol
6
and steroidal
(3S,12R,16S)-triol-22-lactone 7. Tetraol 6 and lactone 7 were
conveniently prepared from hecogenin, a plant-derived ster-
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.201000882.
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Chem. Asian J. 2011, 6, 786 – 790

oidal sapogenin, which is available in large quantities at
rather low cost (ca. $100–150/kg) in China, following two
methods we have developed to degradate the steroidal sapo-
genins.[5]
Tetraol 6 and lactone 7 were prepared as illustrated in
Scheme 2. Hecogenin was converted into rockogenin acetate
(8) by reduction (NaBH4, THF/MeOH, 12b/12a: 7.2–8.4/1)
and acetylation (recrystallization from ethanol removed the
worked well on other steroidal sapogenins (diosgenin and ti-
gogenin).
With adequate amounts of 6 and 7 in hand, we turned our
attention to their reactions and applications for the synthe-
ses of 2 and 3. The synthesis of the left hemisphere 2 in-
volved three challenging transformations: (1) functionaliza-
tion of the C18 angular methyl group, (2) introduction of
À
the C14 C15 double bond, and (3) construction of the E/F-
ring spiroketal. Our synthetic route for the left hemisphere
is shown in Scheme 3.
There have been many reports about the remote intramo-
lecular free radical functionalizations of (20R)-pregnanols.
However, few examples for the (20S)-pregnanols, particular-
ly for those with a substituted group in the D ring, are
known.[6] To avoid the side reactions during the functionali-
À
zation of the C18 CH3 in 6, selective protection of its hy-
droxy groups at C3, C12, and C16 was necessary. Tetraol 6
was subjected to acetonization (in acetone), acetylation (in
acetic anhydride/pyridine), and deacetonization (in aqueous
acetic acid) to afford diol 9. Regioselective oxidation of the
Scheme 2. Preparation of tetraol 6 and lactone 7: a) NaBH4, MeOH,
THF, 08C, 2 h; b) Ac2O, pyridine, 808C, 3 h, recrystallization from EtOH,
76% over two steps; c) HCOOH, 30% H2O2, 508C, 3 h; KOH, EtOH,
reflux, 2 h, 93%; d) AcOOH, I2 (10 mol%), cat. H2SO4, 5 h; KOH,
EtOH, reflux, 5 h, 84%.
À
C16 OH in 9 was achieved under Dess–Martin conditions
À
to afford 10. Proximal funtionalization of the C18 CH3
group in 10 was accomplished by using Meystreꢁs hypoiodite
method[7] (lead tetraacetate (LTA)/I2, hv), which convenient-
ly provided lactone 11 in 73% yield after Jones oxidation.
Further investigation of this reaction demonstrated that
undesired 12a isomer) on large scale. Baeyer–Villiger oxida-
tion of 8 with performic acid (generated in situ from com-
mercially available 30% H2O2 and formic acid) followed by
saponification provided tetraol 6 in 93% yield. In contrast,
8 reacted with peracetic acid in the presence of a catalytic
amount of iodine to afford the abnormal Baeyer–Villiger
oxidation product, steroidal lactone 7 in 84% yield. Both
tetraol 6 and lactone 7 could be prepared on large scale (>
200 g in our laboratory), and the degradation methods
À
À
C20(S) OH is more suitable for C18 CH3 functionalization
À
than its C20(R) OH isomer, owing to the faster reaction
rate and higher yield, and in addition to the facile prepara-
tion of the substrate.
Preparation of compound 14 from 10 by the Shapiro reac-
tion was not feasible because of the difficulty in gaining
Scheme 3. Synthesis of left hemisphere 2: a) acetone, TsOH, RT; b) Ac2O, pyridine, DMAP, 808C, 2 h, 98% over 2 steps; c) 80% AcOH, 608C, 3.5 h,
86% (98% brsm); d) Dess–Martin periodinane, CH2Cl2, RT, 3 h, 82% (96% brsm); e) Pb(OAc)4, I2, cyclohexane, hv, reflux, 4 h; then Jones oxidation,
AHCTUNGTRENNUNG
73%; f) NaBH4, THF/MeOH (4:1), 08C, 20 min; g) MsCl, pyridine, DMAP, CH2Cl2, RT, 18 h; h) NaI, HMPA, 1208C, 92% over three steps; i) K2CO3,
MeOH, RT, 4.5 h, 99%; j) RhCl3·3H2O, EtOH, 708C, 24 h, 82%; k) MOMCl, iPr2NEt, KI, CH2Cl2, reflux, 87%; l) LiAlH4, THF, 408C, 96%; m) Rh2
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
CH2Cl2, RT, 99%; w) LiBF4, CH3CN/H2O, reflux, 4 h, 93%, 23: 22-epi-23=3:1; x) Jones oxidation, 90% (65% for 2, 25% for 22-epi-2). DMAP=4-dime-
thylaminopyridine. brsm=based on recovered starting material.
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W. Tian et al.
COMMUNICATION
access to the C16 of the tosylhydrazone of 10. Stereoselec-
tive reduction of 11 with NaBH4 afforded the C16(S)-hy-
droxy lactone 12, which after subsequent conversion into
mesylate 13 underwent iodination (or bromination)-elimina-
tion to provide the D15 compound 14 in 92% yield over
three steps.
4 differs from that of the alkene; the former afforded abnor-
mal cis-addition product, while the latter provided the trans-
addition product.
Although the S stereochemistry at C22 of 22 was unde-
sired, it can be easily transformed into its natural stereoiso-
mer under suitable reaction conditions. Acetylation of 22
gave its C23 acetate. Removal of the MOM protecting
groups with LiBF4 in refluxing aqueous acetonitrile[15] result-
ed in isomerization at C22, thereby leading to an insepara-
ble equilibrium mixture (3:1) of the C22(R) (23) and C22(S)
(22-epi-23) spiroketals, as expected. The resulting mixture
was then subjected to Jones oxidation to yield the known di-
ketone 2 and its 22-epimer in 65% and 24% yield, respec-
tively. The new strategy for the construction of the E/F spi-
roketal rings of 2 from 4 required only four reaction steps,
which is much shorter than 10 steps, as previously reported
for comparable transformations from similar synthetic pre-
cursors.
Surprisingly, the RhCl3-catalyzed double bond migration[8]
À
did not work when the C3 OH was protected as either an
acetate or as a tert-butyldiphenylsilyl (TBDPS) ether. How-
ever, the reaction was dramatically accelerated when a cata-
lytic amount of progesterone-3-ol was added. This result in-
dicated that the rhodium(I) (generated by oxidating the sub-
strate) might be the real active catalyst for this transforma-
tion. For this reason, compound 14 was hydrolyzed to afford
15 (without increasing the overall number of steps of the
synthesis because the C3,12-acetates needed to be converted
into methoxymethyl (MOM) ethers anyway). Gratifying, 15
was treated with 10 mol% RhCl3 (EtOH, 708C, 24 h) to
afford the desired 3,12-dihydoxy-D14-lactone 16 (X-ray
structure available)[9] in 82% yield, along with a small
amount of the 3-oxo byproduct (about 5%). Compound 16
was reprotected as MOM ethers and treated with LiAlH4 to
afford (18,20S)-diol 17 in high yield.
The right hemisphere 3 is not only the most common unit
in the cephalostatin family, but is also strongly associated
with the most potent antitumor activity based on the re-
search results of their structure–activity relationship.[2]
Therefore, a highly efficient synthesis is very important, not
only for cephalostatin 1 but also for all the pyrazine bis-
The direct introduction of the side chain to 17 by selective
À
oxidation (C20 OH) and an inter- or intramolecular
ACHTUNGTRENNUNG
Horner–Wadsworth–Emmons (HWE) reaction was unsuc-
cessful. Referring to Fuchsꢁ procedure,[10] diol 17 was con-
veniently transformed into pentacyclic ester 19 in 67% over-
all yield, although it has a different structure to that of the
Scheme 4 and 5. To minimize the unnnecessary redox ma-
nipulations, various conditions have been investigated to
open the lactone ring directly, however, all of which met
with failure. Therefore, lactone 7 was protected as C3,C12-
MOM ethers and reduced with LiAH4. The resulting diol
À
one reported by Fuchs, in which the C14 C15 double bond
was saturated. This highly efficient sequence involved regio-
À
À
selective rhodium-mediated C18 OH insertion reaction of
underwent selective acetylation of the primary C22 OH
À
a-diazophosphate ester 18 (Rh
N
and mesylation–elimination of C16 OH in one pot to afford
À
oxidation of the C20 OH, and an intramolecular HWE re-
action between the C18 phosphonate ester and the C20
ketone (tBuOK, tetrahydofuran (THF), 87%).
steroid-16-en-22-ol 24 in 60–76% overall yield. Treatment of
24 with N-bromosuccinimide (NBS) and azobisisobutyroni-
trile (AIBN) in refluxing tetrachloromethane for 10 hours
resulted in direct formation of the conjugated double bond
in the D ring by allylic bromination–elimination to give
diene-22-acetate in 87% yield. Solvolysis of acetate, fol-
lowed by oxidation with Dess–Martin reagent formed C22
aldehyde, which was further converted to the corresponding
thioketal 26 by treating it with propanedithiol and 10 mol%
of TsOH at 08C.
Reduction of 19 with LiAlH4 followed by Dess–Martin
oxidation afforded the corresponding aldehyde at C23 in
97% overall yield. Aldehyde 21 was subjected to various
methylallylation conditions, among which treatment with
methylallylmagnesium chloride at 08C exhibited the best se-
lectivity, thus affording 4 and 4a as a 1.1:1 mixture in nearly
quantitative yield.[11] The minor 23(S) isomer 4a was further
converted into 4 by an oxidation–reduction protocol in 43%
yield (with 4a recovered in 56%).
With thioketal 26 and aldehyde 27[16] in hand, we were set
to achieve their union. The metalation of thioketal 26
proved to be quite difficult because of the bulkiness of the
steroid skeleton. After screening several anion-generating
conditions (nBuLi; tBuLi, hexamethyl phosphoramide
(HMPA)/THF; nBuLi/tBuOK; nBuLi/nBu2Mg,[17] etc), we
found that generation of the desired lithio derivative of 26
was short-lived and it was necessary to be quickly trapped.
After treatment of 26 with nBuLi at 08C for 10 minutes, the
resulting anion was immediately trapped with 27 at À788C
to afford an inseparable mixture of isomers (5–6:1), favoring
the desired 23(R)-stereoisomer 28 in 68% yield (91% based
on recovered starting material). The C23(R) stereochemistry
of 28 was proposed according to the transition state of the
With key intermediate 4 in hand, we next turned our at-
tention to the construction of the spiroketal moiety by utiliz-
ing the enol ether and alkene in 4.[12] Treatment of 4 with
2.2 equivalents of HgACHTUNTRGNEUNG(OAc)2 in a solution of deoxygened
THF followed by reduction with NaBH4 directly provided
22 with the E/F spiroketal moiety in 93% yield.[13] The ste-
reochemical outcome at C20 and C22 of this transformation
was similar to those previously reported (acid-mediated cyc-
lization by Fuchs,[14] and bromoetherification/reductive de-
bromination sequence by Shair).[4] This transformation was
considered as a tandem oxymercuration–ketalization proto-
col. It is noteworthy that the oxomecuration of enol ether in
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Chem. Asian J. 2011, 6, 786 – 790

Total Synthesis
Cram–Reetz model.[18] It was further confirmed in subse-
quent transformations.
It was desirable to convert 28 into 31 in one pot.[19] How-
ever, the attempt was unsuccessful because the reaction was
too complex. For this reason, we first transformed 28 into 29
through oxidative dethioketalization[20] and acetylation. The
cycloaddition reaction of 29 with singlet oxygen, which oc-
curred with moderate stereoselectivity (a/b: 2.5–4.5:1 mea-
sured by NMR spectroscopy on the crude product), fol-
lowed by reduction with Zn/HOAc in tetrahydrofuran af-
forded 5 in 62% yield (d.r.: 10:1). Using tetrahydrofuran as
a solvent for this reduction is crucial to obtain compound 5.
Treatment of 5 with 1m HCl in tetrahydrofuran at room
temperature for two hours led to 30 in 90% yield.[21] How-
ever, conducting this reaction at 458C for two days provided
the expected product 31 in 68% yield (C22(S),C23(R)/
C22(S),C23(S): 12–15:1), along with another inseparable
mixture of two isomers (C22(R),C23(R) and C22(R),C23(S):
4:5) in 15–21% yield. This highly efficient transformation
involved the removal of protecting groups at C3,C12,C23,
and C25 in 5 and the construction of the E/F-ring spiroketal
in one operation.
Scheme 4. Synthesis of dithiane 8 and aldehyde 7: a) MOMCl, iPr2NEt,
Bu4NI, CH2Cl2, reflux, 6 h, 95%; b) LiAlH4, THF, RT, 2 h, 99%; c) Ac2O,
DMAP, Et3N, CH2Cl2, 08C; MsCl, pyridine, 558C, 4 h, 60–76%; d) NBS,
AIBN, cyclohexene oxide, CCl4, reflux, 87%; e) K2CO3, MeOH, RT,
97%; f) Dess–Martin periodinane, NaHCO3, CH2Cl2, 91%; h) 1,3-pro-
panedithiol, cat. TsOH, CH2Cl2, 08C, 4 h, 87%; h) nBuLi, THF, 08C,
Efforts on selective hydrolysis of the C3 acetate in triace-
tate of 31 were met with failure due to the competition of
À
the C23 acetate. Selective oxidation of the C3 OH in 31
25 min; then À788C, 27, 2 h, 68% (91% brsm); i) PhI
ACHTUNGRTEN(NUNG OCOCF3)2,
with Ag2CO3/Celite (known as Fꢂtizonꢁs reagent)[22] fol-
lowed by acetylation provided the right hemisphere 3 in
92% yield. A significant amount of 3 has been prepared by
this route (>2.5 g in total, with largest run harvests 698 mg)
in our laboratory. The synthesis of 3 from steroidal lactone
7 was achieved in 13 steps in 18% overall yield.
CaCO3, CH3CN/water, 08C, 10 min; j) Ac2O, Et3N, DMAP, CH2Cl2, RT,
97%; k) O2, TPP, CH2Cl2, À788C, sunlamp, 2 h; then Zn, AcOH, THF,
4 h, 62% (68.4% brsm). TPP=5,10,15,20-tetraphenyl-21H,23H-porphine.
With the left hemisphere 2 and the right hemisphere 3 in
hand, the synthesis of cephalostatin 1 (1) was completed as
illustrated in Scheme 5. The coupling partners, azidoketone
33 and aminomethoxime 32, were obtained by known proto-
cols.[3a,23] Condensation of 33 (1.1 equiv) with 32 in benzene
delivered the protected cephalostatin 1 in 67% yield. The
global deprotection resulted in (+)-cephalostatin 1 (1) in
86% yield (ca. 250 mg of 1 prepared in this laboratory). The
spectroscopic properties of our compound 1 are consistent
with those reported in the literature.
In conclusion, a new synthetic strategy for natural sterols
is illustrated through the synthesis of (+)-cephalostatin 1,
which features: 1) using pregnan-(3S,12R,16S,20S)-tetraol
(6) and steroid-16(S),22-lactone (7) instead of the traditional
prognenolone or epiandrostenone as a starting point for
sterols synthesis for the first time; 2) the construction of
chiral centers of target molecules by using either substrate
control or chiral starting materials, with an emphasis on ex-
cluding expensive reagents and difficult operations; 3) the
successful application of cascade reactions (the construction
of spiroketals in 22 and 31) and one-pot reactions made our
synthesis convenient, simple, and practical. This practical
synthesis of (+)-cephalostatin 1 also represents an excellent
example for the rational utilization of readily available re-
source compounds (resource chemistry). Utilizing such syn-
Scheme 5. Synthesis of right hemisphere 3 and completion of the synthe-
sis of cephalostatin 1: a) 1m HCl/THF (1:10), RT, 2 h, 90% 30; or 1m
HCl/THF (1:10), 458C, 45 h, 59–68% 31; b) Ag2CO3 on Celite, toluene,
Dean–Stark Trap, reflux, 4 h; then Ac2O, DMAP, Et3N, CH2Cl2, 92%;
c) PhNMe3Br3, THF, 15 min, 91%; d) NaN3, DMF, 08C, 2 h;
MeONH2·HCl, pyridine, CH2Cl2, RT, 4 h; PPh3, THF/water, RT, 20 h, 50–
70%; e) PhNMe3Br3, THF, 08C, 10 min, 87%; f) TMGA, MeNO2, RT,
4 h, 86%; g) PVP, Bu2SnCl2, benzene, Dean–Stark trap, 6 h, 67%;
h) TBAF, THF, reflux, 2 h; then K2CO3, MeOH, 3 h, reflux, 86%.
TMGA=tetramethylguanidinium azide; PVP= polyvinylpyridine;
TBAF= tetrabutylammonium fluoride.
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W. Tian et al.
COMMUNICATION
[8] M. Ando, N. Kataoka, M. Yasunami, K. Takase, N. Hirata, Y.
Yanagi, J. Org. Chem. 1987, 52, 1429–1437.
[9] CCDC 791575 contains the supplementary crystallographic data for
16.These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/
cif.
[10] S. Bhandaru, P. L. Fuchs, Tetrahedron Lett. 1995, 36, 8347–8350.
[11] The 23(R) stereochemistry of the major adduct 4 was confirmed by
X-ray crystallography of its 3-hydroxyl derivative (CCDC 791577,
see Supporting Information).
thetic strategies for the synthesis of pyrazine bis
and other marine natural steroids are in progress.
ACHTUNGTRENUN(NG steroids)
Acknowledgements
The authors are grateful to the Chinese Academy of Sciences (KJ952J10-
512) and the National Natural Science Foundation (29772051,
2107222210) of China for their financial support.
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Keywords: cephalostatin 1 · natural products · spiroketal ·
steroids · synthesis design
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À
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Received: December 9, 2010
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Published online: February 16, 2011
790
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Chem. Asian J. 2011, 6, 786 – 790