Synthesis of C14,15-Dihydro-C22,25-epi north unit of cephalostatin 1 via "red-ox" modifications of hecogenin acetate

Article abstract of DOI:10.1021/ol802122p

The C14,15-Dihydro-C22,25-epi north unit of cephalostatin 1 has been synthesized in 11 operations from commercially available hecogenin acetate via multiple reductions and oxidations. The key transformations include (i) Cr ^VI-catalyzed E-ring o

Full text of DOI:10.1021/ol802122p

ORGANIC
LETTERS
2009
Vol. 11, No. 1
5-8
Synthesis of C14,15-Dihydro-C22,25-epi
North Unit of Cephalostatin 1 via
“Red-Ox” Modifications of Hecogenin
Acetate†
Seongmin Lee,* Daniel Jamieson, and Philip L. Fuchs*
Department of Chemistry, Purdue UniVersity, West Lafayette, Indiana 47907
pfuchs@purdue.edu
Received September 10, 2008
ABSTRACT
The C14,15-Dihydro-C22,25-epi north unit of cephalostatin 1 has been synthesized in 11 operations from commercially available hecogenin
acetate via multiple reductions and oxidations. The key transformations include (i) CrVI-catalyzed E-ring opening, (ii) C17 hydroxylation, and
(iii) a base-triggered cyclization cascade.
The cephalostatins and ritterazines are structurally unique
marine natural products that display extreme cytotoxicity
against various human cancers.1 The targets cephalostatin
1, cephalostatin 7, cephalostatin 12, ritterazine M, and
ritterazine K have been synthesized2 and we and others3 have
been active in the synthesis and testing of analogs. The 45
members of the cephalostatin and ritterazine family, along
with the growing number of analogs and related mono-
steroidal glycosides, provided some insight into the structure-
activity relationships (SARs) and common pharmacophores
of these potent cytotoxins:4 (1) “polarity match” consisting
of polar north domains and less polar south domains with a
connecting pyrazine moiety; (2) bis-spiroketals as prooxo-
carbenium moieties; (3) C17 (north) and C23′ (south)
hydroxyl group; and (4) ∆14 olefin moiety.
† Cephalostatin Support Studies. 36. For 34, see: Lee, J. S.; Cao, H.;
Fuchs, P. L. J. Org. Chem. 2007, 72, 5820. For 35, see: Lee, S.; LaCour,
T. G.; Fuchs, P. L. Chem. ReV. 2008, in press.
Semiempirical calculations for rationalizing the SAR of
the bis-steroidal pyrazines revealed a strong correlation
(1) (a) Pettit, G. R.; Inoue, M.; Herald, D. L.; Krupa, T. S. J. Am. Chem.
Soc. 1988, 110, 2006. (b) Pettit, G. R.; Inoue, M.; Kamano, Y.; Herald,
D. L. Chem. Commun. 1988, 1440. (c) Pettit, G. R.; Xu, J. P.; Schimidt,
J. M. Bioorg. Med. Chem. Lett. 1995, 5, 2027. (d) Fukuzawa, S.; Matsunaga,
S.; Fusetani, N. J. Org. Chem. 1994, 59, 6164. (e) Fukuzawa, S.; Matsunaga,
S.; Fusetani, N. J. Org. Chem. 1995, 60, 608. (f) Fukuzawa, S.; Matsunaga,
S.; Fusetani, N. Tetrahedron 1995, 51, 6707. (g) Fukuzawa, S.; Matsunaga,
S.; Fusetani, N. J. Org. Chem. 1997, 62, 4484. (h) Fukuzawa, S.; Matsunaga,
S.; Fusetani, N. Tetrahedron Lett. 1996, 37, 1447.
(3) (a) Heathcock, C. H.; Smith, S. C. J. Org. Chem. 1994, 59, 6828.
(b) Jautelat, R.; Muller-Fahrnow, A.; Winterfeldt, E. Chem. Eur. J. 1999,
5, 1226. (c) Basler, S.; Brunck, A.; Jautelat, R.; Winterfeldt, E. HelV. Chim.
Acta 2000, 83, 1854, and references therein. (d) Phillips, S. T.; Shair, M. D.
J. Am. Chem. Soc. 2007, 129, 6589. (e) Taber, D. F.; Taluskie, K. V. J.
Org. Chem. 2006, 71, 2797. (f) Betancor, C.; Freire, R.; Perez-Martin, I.;
Prange, T.; Sua´rez, E. Org. Lett. 2002, 4, 1295. (g) Taber, D. F.; Joerger,
J.-M. J. Org. Chem. 2008, 73, 4155. (h) Taber, D. F.; DeMatteo, P. W.;
Taluskie, K. V. J. Org. Chem. 2007, 72, 1492.
(2) (a) LaCour, T. G.; Guo, C.; Boyd, M. R.; Fuchs, P. L. Org. Lett.
2000, 2, 33. (b) Lee, S.; Fuchs, P. L. Org. Lett. 2002, 4, 317. (c) LaCour,
T. G.; Guo, C.; Bhandaru, S.; Boyd, M. R.; Fuchs, P. L. J. Am. Chem. Soc.
1998, 120, 692. (d) Kim, S.; Sutton, S. C.; Guo, C.; LaCour, T. G.; Fuchs,
P. L. J. Am. Chem. Soc. 1999, 121, 2056.
(4) (a) Pettit, G. R.; Tan, R.; Xu, J. P.; Ichihara, Y.; Williams, M. D.;
Boyd, M. R. J. Nat. Prod. 1998, 61, 953, and references therein. (b)
Fukuzawa, S.; Matsunaga, S.; Fusetani, N. J. Org. Chem. 1997, 62, 4484 and
references therein. (c) Yu, W.; Jin, Z. J. Am. Chem. Soc. 2001, 123, 3369.
10.1021/ol802122p CCC: $40.75
Published on Web 12/04/2008
2009 American Chemical Society

between bioactivity and enthalpy of oxacarbenium ion
formation.5 Our efforts for calculation-guided design and
synthesis of cephalostatin analogs led to the finding of the
hyperactive C25-epi-ritterostatin GN1N (2), which is ∼100
times more cytotoxic than ritterostatin GN1N (1), thereby
being more potent than cephalostatin 1 (3, Figure 1), the
formations to deliver the target hemispheres. Herein, we
report progress toward the synthesis of C25-epi north 1 (6)
from hecogenin acetate 5 via Red-Ox modifications (Scheme
1).
Scheme 1. Red-Ox Strategy
Red-Ox synthesis of the C25-epi north 1 6 started from
commercially available plant-derived 5 (Scheme 2). Boro-
hydride reduction of hecogenin acetate 5 at -78 °C followed
by acetylation afforded rockogenin acetate 7 in a nearly
quantitative yield.
7
The action of t-BuNO2/BF3·OEt2 on 5/6 spiroketal 7
regioselectively delivered C23 oxime 8 which was then
hydrolyzed in the presence of acid to unveil ketone 9.
Obtaining a workable stereoisomeric excess at C23 relied
on (S)-CBS reduction8 (C23R (axial OH) 86% 10; C23S
(equatorial OH) 14%). Regio- and stereoselective triethyl-
silane reduction of 5/6 spiroketal 10 resulted in the formation
of F-ring-opened diol 11 in 94% yield. Selective tosylation
of the primary alcohol in the presence of the secondary
alcohol using catalytic 1,4-diazabicyclo[2.2.2]octane (DAB-
CO) followed by C23 benzoylation furnished 12, which was
then subjected to a sequential iodination and DBU-mediated
E2 elimination to give terminal olefin 13a.
With olefin 13a in hand, we investigated C25,26-oxyfunc-
tionalization using Sharpless asymmetric dihydroxylation.9 As
expected from previous studies, 10 stereoselective dihydroxyl-
ation of the olefin moiety was especially difficult. A reasonable
excess of C25R stereoisomer was obtained only when using
(DHQ)2PHAL ligand and C23-substituted substrate (Table 1).
The stereochemistry at C25 was unambiguously determined by
single crystal X-ray crystallography. The diol 14a was subjected
to sequential protection of the primary alcohol with an acetyl
Figure 1. Effect of C25 stereochemistry on the cytotoxicity of
cephalostatin analogs.
(6) (a) Li, W.; LaCour, T. G.; Boyd, M. R.; Fuchs, P. L. J. Am. Chem.
Soc. 2002, 124, 4548. (b) Lee, S.; Fuchs, P. L. Org. Lett. 2002, 4, 313. (c)
Lee, J. S.; Fuchs, P. L. J. Am. Chem. Soc. 2005, 127, 13122. (d) Lee, J. S.;
Fuchs, P. L. Org. Lett. 2003, 5, 2247.
most potent member of the cephalostatin family. Simply by
comparing these three compounds (1, 2, and 3), most organic
chemists would consider that C25-epi-cephalostatin 1 (4)
would be a logical one to prepare. Calculations5 also predict
that the C25-epi-cephalostatin 1 (4) should be in the
hyperactive class.
In conjunction with our quest to achieve an efficient second
generation synthesis of the north unit of cephalostatin
analogs,6 we have developed a “Red-Ox” strategy where
multiple oxidations/reductions are employed as key trans-
(7) (a) Gonzalez, A. G.; Frerire, R.; Garcia-Estrada, M. G.; Suarez, E.
Tetrahedron 1972, 28, 1289. (b) Barton, D. H. R.; Sammes, P. G.; Taylor,
M. V.; Werstiuk, E. J. Chem. Soc. C 1970, 1977. (c) Lee, S.; Fuchs, P. L.
Can. J. Chem. 2006, 84, 1442. (d) Betancor, C.; Freire, R.; Perez-Martin,
I.; Prange, T.; Suarez, E. Org. Lett. 2002, 4, 1295.
(8) (a) Corey, E. J.; Bakshi, R. K.; Shibata, S. J. Am. Chem. Soc. 1987,
109, 5551. (b) Corey, E. J.; Roberts, B. E. J. Am. Chem. Soc. 1997, 119,
12425.
(9) Sharpless, K. B.; Amberg, W.; Bennani, Y. L. J. Org. Chem. 1992,
57, 2768.
(10) (a) Jeong, J. U.; Guo, C.; Fuchs, P. L. J. Am. Chem. Soc. 1999,
121, 2071. (b) Kim, S. K.; Sutton, S. C.; Guo, C.; LaCour, T. G.; Fuchs,
P. L. J. Am. Chem. Soc. 1999, 121, 2056.
(5) LaCour, T. G. Ph.D. Thesis, 2001, Purdue University.
6
Org. Lett., Vol. 11, No. 1, 2009

Having established the requisite stereochemistry at C12,
C23, and C25, we next turned to C17 hydroxylation (Scheme
3). For this transformation, opening of the E-ring was
Scheme 2
Scheme 3
required. While there are a number of tetrahydrofuran ring-
opening methods,11 the steroidal E-ring of 15 was proved
inert returning starting material in most cases. However, the
recently developed CrVI-mediated C-H oxidation12 protocol
smoothly effected E-ring opening to deliver diketone 16 in
84% yield. After extensive experimentation, formation of
C17-OH 18 was finally achieved by TMSI/hexamethyldisi-
lazane-mediated13 thermodynamic silylenol ether 17 forma-
tion followed by oxidation with TFMDO14 generated in situ.
The C17-OH group was introduced in a stereoselective
manner. The use of different bases other than hexamethyl-
disilazane or in situ generated TMSI resulted in no formation
of the silylenolether 17. Removal of the trifluoroacetyl
protecting group of 18 with 1,8-diazabicyclo[5.4.0]undec-
7-ene triggered a cyclization cascade to form hemiacetal 19
as a single stereoisomer. Reduction of the hemiacetal 19 with
Table 1. Asymmetric Dihydroxylation of the C25-Olefin
substrate
X
Y
C14-15
ligand
product 25R:25S
13a
13b
13c
13d
13e
13f
OAc OBz 14r-H (DHQ)2PHAL
14a
OAc OBz 14R-H (DHQD)2PHAL 14b
5:1
1:3
1:1
1:1
1:5
2:1
OBz H
OBz H
OBz H
OBz H
14R-H (DHQ)2PHAL
14c
14R-H (DHQD)2PHAL 14d
14
∆
∆
(DHQ)2PHAL
14e
(11) (a) Tenaglia, A.; Terranova, E.; Waegell, B. J. Org. Chem. 1992,
57, 5523. (b) Carlsen, P.; Katsuki, T.; Martin, V. S.; Sharpless, K. B. J.
Org. Chem. 1981, 46, 3936. (c) Scarborough, R. M.; Smith, A. B. J. Am.
Chem. Soc. 1980, 102, 3904.
14
(DHQD)2PHAL 14f
a OsO4 (2 mol %), ligand (10 mol %), K3Fe(CN)6 (3 equiv), K2CO3 (3
equiv), t-BuOH/H2O (1:1), 0 °C.
(12) (a) Lee, S.; Fuchs, P. L. J. Am. Chem. Soc. 2002, 124, 13978. (b)
Lee, S.; Fuchs, P. L. Org. Lett. 2004, 6, 1437.
(13) (a) Hoeger, C. A.; Okamura, W. H. J. Am. Chem. Soc. 1985, 107,
268. (b) Miller, R. D.; McKean, D. R. Synthesis 1979, n/a, 730.
(14) Mello, R.; Fiorentino, M.; Fusco, C.; Curci, R. J. Am. Chem. Soc.
1989, 111, 6749.
group and the tertiary alcohol with the trifluoroacetyl group to
provide 15 (Scheme 2).
Org. Lett., Vol. 11, No. 1, 2009
7

excess triethylsilane and TMSOTf at -78 °C delivered
C14,15-dihydro-C22,25-epi north 1 (20) in 89% yield.15
In summary, we have developed an efficient synthetic route
for C14,15-dihydro-C22,25-epi north 1 (20) wherein CrVI-
catalyzed E-ring opening, stereoselective C17 hydroxylation,
and a cyclization cascade are used as key reactions. Dihydro-
22,25-epi north 1 (20) was prepared in 11 operations and
4% overall yield from hecogenin acetate. These results
illustrate that the Red-Ox-based synthesis provides an
efficient access to cephalostatin analogs from hecogenin
acetate 5. Further synthetic efforts to convert C17-hyroxy-
C16,22-diketone 18 into C25-epi north 1 (6) and to prepare
cephalostatin analogs containing C14,15-dihydro-C22,25-epi
north 1 hemisphere 20 are in progress, and results will be
reported in due course.
Acknowledgment. This investigation was generously
supported by funds provided by the National Institute of
Health (CA 60548). We acknowledge Arlene Rothwell and
Karl Wood (Purdue University) for providing MS data.
Supporting Information Available: General experimental
procedure and NMR spectra for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(15) The C22 stereochemistry was determined by comparing 1H and
13C NMR spectra of 20 with those of 14,15-dihydro-17-deoxy-22,25-epi
north 1, the structure of which was solved by single crystal X-ray
crystallography (see Supporting Information).
OL802122P
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Org. Lett., Vol. 11, No. 1, 2009