New oxidative tools for the functionalization of the cephalostatin North 1 hemisphere

Article abstract of DOI:10.1021/ol034551g

(Matrix presented) Dimethyldioxirane (DMDO) C-H oxidation of ketone 17 to hemiketal 18 (82%), bis-dehydration to vinyl ether 21 (77%), and DMDO again provides C-23 axial alcohol 23 (99%). Routine processing, including a double-stereoselective Sharpless AD

Full text of DOI:10.1021/ol034551g

ORGANIC
LETTERS
2003
Vol. 5, No. 13
2247-2250
New Oxidative Tools for the
Functionalization of the Cephalostatin
North 1 Hemisphere†
Jong Seok Lee and Philip L. Fuchs*
Department of Chemistry, Purdue UniVersity, West Lafayette, Indiana 47907
pfuchs@purdue.edu
Received March 30, 2003
ABSTRACT
Dimethyldioxirane (DMDO) C−H oxidation of ketone 17 to hemiketal 18 (82%), bis-dehydration to vinyl ether 21 (77%), and DMDO again provides
C-23 axial alcohol 23 (99%). Routine processing, including a double-stereoselective Sharpless AD reaction (de >98%), gives alcohols 7 and 32.
C-23 deoxy substrate 7 undergoes Suarez hypoiodite oxidative cyclization to (natural) â spiroketal 34, but compound 32, bearing a C-23 silyl
ether, generates unnatural spiroketal 33.
The cephalostatins1 and ritterazines2 comprise a family of
45 structurally unique marine natural products that display
extreme cytotoxicity against human tumors (∼1 nM mean
GI50’s in the 2-day NCI-60 screen and 10-14 M GI50’s in
3-day tests in the Purdue minipanel).3 The total syntheses
of cephalostatin 1 2 and cephalostatin 7 as well as many
analogues have been reported by others4 and us,5 but chem-
ical evidence for the site(s) of reactivity and the mechanism
of action of the bissteroidal pyrazines remain unknown and
no scaleable synthesis for such testing has been achieVed.
Our recent “second-generation” synthesis of the C-23′ deoxy
South 1 hexacyclic spiroketal Do-2 has substantially ame-
liorated the material supply problem with the South 1
hemisphere (12 operations, 23% overall yield from hecogenin
acetate1),6 but access to the North segment (and the South
7 hemisphere 3) remained impractical, standing at ∼34
operations.
As more extensively discussed in our previous publica-
tion,6 we are now pursuing a strategy which retains all 27
carbon atoms of hecogenin acetate 1 and employs specific
† Cephalostatin Support Studies. 24. Oxidations. 2. For previous papers
in these series, see ref 6 and: Lee, S. M.; Fuchs, P. L. J. Am. Chem. Soc.
2002, 124, 13978-13979.
(1) 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.
(2) Fukuzawa, S.; Matsunaga, S.; Fusetani, N. J. Org. Chem. 1997, 62,
4484 and references therein.
(3) LaCour, T. G.; Guo, C.; Ma, S.; Jeong, J. U.; Boyd, M. R.; Matsunaga,
S.; Fusetani, N.; Fuchs, P. L. Bioorg. Med. Chem. Lett. 1999, 9, 2587 and
references therein. Leukemia, renal, and CNS lines are particularly sensitive
to cephalostain 1.
(4) Heathcock, C. H.; Smith, S. C. J. Org. Chem. 1994, 59, 6828 and
references therein. Jautelat, R.; Mu¨ller-Fahrnow, A.; Winterfeldt, E. Chem.
Eur. J. 1999, 5, 1226. Basler, S.; Brunck, A.; Jautelat, R.; Winterfeldt, E.
HelV. Chim. Acta, 2000, 83, 1854 and references therein.
(5) LaCour, T. G.; Guo, C.; Boyd, M. R.; Fuchs, P. L. Org. Lett. 2000,
2, 33.
(6) Li, W.; LaCour, T. G.; Fuchs, P. L. J. Am. Chem. Soc. 2002, 124,
4548.
10.1021/ol034551g CCC: $25.00 © 2003 American Chemical Society
Published on Web 06/06/2003

be obtained using L-Selectride. Reductive cleavage to 11
followed by protecting group manipulation and elimina-
tion via the nitroselenoxide afforded silyl ether-olefin 12
(Scheme 1).
The parallel studies next examined osmylation of olefins
6 and 12, respectively. The Purdue group employed double
stereoselection via catalytic asymmetric dihydroxylation of
6, which delivered a pair of spiroketals in ∼6:1 selectivity
both bearing the 25S configuration.7,11 In comparison, stoi-
chiometric osmylation of 12 gave a 1:2 mixture favoring the
unnatural 25R stereochemistry.8
Application of the Suarez reaction to the C-23,26-dipro-
tected diol mixture 13 generated a 28/72 mixture of the two
5/5 ring spiroketals 14/15 in 83% yield. In stark contrast,
similar treatment of the C-26 protected substrate 7 generated
a single diastereomeric spiroketal 8, which was shown to
have the desired 22-natural stereochemistry (Scheme 2).
Figure 1.
oxidation reactions to introduce common features found in
both cephalostatin hemispheres (Figure 1).
Our revised approach to the North 1 and South 7 segments
is based upon the Suarez cyclization we employed for the
synthesis and structure correction of Ritterazine M.7 A related
model study has recently appeared from the Suarez group.8
We have found that it is essential to define the “gestalt”
effects of the entire steroid upon chemistry occurring at a
supposedly remote site. In this light, comparison of the
Suarez study8 with our current investigation is particularly
instructive.
Scheme 2
Our study began with compound 4,9 having C12 and
C14-15 in the required oxidation state. Reductive cleavage
of the spiroketal gave alcohol 5, which was converted to
olefin 6 through the intermediate iodide (Scheme 1).
These and other experiments (Vide infra) proVe that a
C14-15 olefin is required to achieVe stereospecific asym-
metric dihydroxylation at C25,26.
The new Purdue synthesis begins with our improved
transformation of hecogenin acetate 16 to â-hydroxyketone
17 in a one-pot 94% yield.9 Dimethyldioxirane has been
effectively used for the oxidation of tertiary C-H bonds in
steroids,12 and application of this reagent to spiroketal 17
smoothly provides diol 18 in 82% yield (15.7 g).14 Initial
experiments to effect bis-dehydration of 18 were quite
unrewarding. For example, treatment of hemiketal 18 with
2.1 equiv of BF3‚OEt2 in CH2Cl2 from -10 to +25 °C for
18 h gave dienone 19 in 27% yield. Attempts to intercept
Scheme 1
(11) Originally this mixture was misassigned as a mixture of stereoiso-
mers at C25,7 but the minor isomer is actually the C22â spiroketal and can
be equilibrated quantitatively to the natural C22R configuration under acidic
conditions (Lee, S. M. Unpublished results).
(12) Adam, W.; Bialas, J.; Hadjiarapoglou, L. Chem. Ber. 1991, 124,
124. Iida, T.; Yamaguchi, T.; Nakamori, R.; Hikosaka, M.; Mano, N.; Goto,
J.; Nambara, T. J. Chem. Soc., Perkin Trans. 1 2001, 2229. Bovicelli, P.;
Lupattelli, P.; Fiorini, V.; Mincione, E. Tetrahedron Lett. 1993, 34, 6103.
Dixon, J. T.; Holzapfel, C. W.; van Heerden, F. R. Synth. Commun. 1993,
23, 135. Bovicelli, P.; Lupattelli, P.; Fiorini, V.; Mincione, E. Tetrahedron
Lett. 1993, 34, 6103. Bovicelli, P.; Lupattelli, P.; Fracassi, D.; Mincione,
E. Tetrahedron Lett. 1994, 35, 935.
(13) Ley, S. V.; Anthony, N. J.; Armstrong, A.; Brasca, M. G.; Clarke,
T.; Culshaw, D.; Greck, C.; Grice, P.; Jones, A. B.; Lygo, B.; Madin, A.;
Sheppard, R. N.; Slawin, A. M. Z.; Williams, D. J. Tetrahedron 1989, 45,
7161. Ley, S. V.; Anderson, J. C.; Blaney, W. M.; Jones, P. S.; Lidert, Z.;
Morgan, E. D.; Robinson, N. G.; Santafianos, D.; Simmonds, M. S. J.;
Toogood, P. L. Tetrahedron 1989, 45, 5175. Bernsmann, H.; Hungerhoff,
B.; Fechner, R.; Fro¨hlich, R.; Metz, P. Tetrahedron Lett. 2000, 41, 1721.
(14) X-ray structural information relating to compounds 18, 20, and 26
can be obtained from the Cambridge Crystallographic Data Centre.
The Suarez group started with compound 10 having C12
and C14 in the fully reduced state. This material was con-
verted to the C23 ketone via the nitroimine.10 Similar to pre-
vious cases, reduction of the spiroketal C-23 ketone was
highly selective (5:95) for the (unnatural) equatorial alco-
hol, although a 63:37 ratio favoring the axial alcohol could
(7) Lee, S. M.; Fuchs, P. L. Org. Lett. 2002, 4, 317. Lee, S. M.; LaCour,
T. G.; Lantrip, D.; Fuchs, P. L. Org. Lett. 2002, 4, 313.
(8) Betancor, C.; Freire, R.; Perez-Martin, I.; Prange, T.; Suarez, E. Org.
Lett. 2002, 4, 1295.
(9) LaCour, T. G.; Guo, C.; Bhandaru, S.; Boyd, M. R.; Fuchs, P. L. J.
Am. Chem. Soc. 1998, 120, 692.
(10) Barton, D. H. R.; Sammes, P. G.; Taylor, M. V.; Werstiuk, E. J.
Chem. Soc. 1970, 1977. Gonzalez, A. G.; Freire, R.; Garcia-Estrada, M.
G.; Salazar, J. A.; Suarez, E. Anal. Quim. 1971, 67, 903. Gonzalez, A. G.;
Freire, R.; Garcia-Estrada, M. G.; Salazar, J. A.; Suarez, E. Tetrahedron
1972, 28, 1289.
2248
Org. Lett., Vol. 5, No. 13, 2003

the putative D-ring enone by adding triethylsilane to the
above conditions provided a 75:11 mixture of 19 and
isomeric spiroketal 20 in 86% yield.14 Under many conditions
(see the Supporting Information), 20 is the exclusive product
and yields in excess of 95% may be obtained.
Scheme 4a
After much experimentation, it was discovered that reac-
tion of diol 18 with 4 equiv of thionyl chloride and 20 equiv
of pyridine in toluene at -50 °C afforded the long-sought
crystalline vinyl ether 21 in 77% yield. This labile material
was immediately subjected to DMDO oxidation and under-
went quantitative oxidative cyclization to the requisite C-23
axial alcohol 23, presumably via the intermediacy of non-
observed epoxide 22 (Scheme 3).
a Key: cat. BF3‚OEt2 (5 mol %), PhSH (1.5 equiv), CH2Cl2, -40
°C, 30 min; (b) dark, 1.1 equiv of PhSeH, cat. BF3‚OEt2 (10 mol
%), CH2Cl2, -30 to -10 °C, 20 min; (c) 2.5 equiv of PhSeH, cat.
BF3‚OEt2 (10 mol %), CH2Cl2, -30 °C, 2 h, sun lamp; (d) 1.1
equiv of PhSeH, sun lamp, 2 h, -30 to -20 °C; (e) 70% m-CPBA
(1.0 equiv), CH2Cl2, 25 °C, 10 min.
Scheme 3a
After an unsuccessful survey of methods designed to use
the axial C-23 alcohol to axially oxygenate the C-25 position
(see the Supporting Information), we returned to the strategy
we had previously applied in the ritterazine M synthesis.7
Conversion of the diol (not shown) from the Sharpless
AD reaction of olefin 30 gives a high yield of C-26 acetate
31(Scheme 5). Presumably, this interesting transformation
Scheme 5a
a Key: (a) (i) hν, CH2Cl2, (ii) evap, add 3:1 HOAc/H2O, (iii)
add H2CrO4; (b) DMDO (750 mL), CH2Cl2 (50 mL), 25 °C, 7 days;
(c) TMSCl (1 equiv), NaI (1 equiv), CH3CN, 30 min, 25 °C, or
DMF, 85 °C, or AcOH/CH2Cl2 (1:3), 25 °C, 8 h, 99%; (d) 4 equiv
of SOCl2, 20 equiv of pyridine, toluene, -50 °C, 40 min; (e)
DMDO, -50 °C, 30 min, >99%.
The synthetic plan envisaged dehydration of 23 to dienyl
ether 27 in preparation for introduction of the C-17 hydroxyl
group via hydroboration. The first try involved conversion
of hemiacetal 23 to sulfide 24 in 71% yield using standard
conditions for this transformation.13 We next examined
introduction of the selenide moiety in hopes of generating a
selenoxide leaving group which might eliminate to 27 under
milder conditions. Treatment of lactol 23 with 1.1 equiv of
phenylselenol in the presence of boron trifluoride etherate
gave the expected selenide 25 in 43% yield along with ever-
increasing amounts of 26, the product of reductive cleavage,
in addition to an equivalent amount of diphenyl diselenide.
Compound 26 and diphenyl diselenide could be obtained in
83% yield by running the reaction of 23 with 2.5 equiv of
selenol with irradiation by a sun lamp. Compound 26 has
been verified by X-ray,14 thereby also securing the structure
of alcohol 23.
Oxidation of 24 or 25 with 1 equiv of m-CPBA provided
neither the expected sulfoxide, selenoxide, nor diene 27.
Presumably, the putative allylic sulf- (selen-) oxide suffered
spiroketal-assisted ionization to the enone-oxonium ion
followed by pinacol rearrangement of the C-23 hydride to
the C-22 position, thereby yielding ketone 28 in ∼60% yield
(Scheme 4).
a Key: (i) 1.2 equiv of NaBH4, MeOH, CH2Cl2, -78 °C, 9 h,
R/â ) 1:20, (ii) 3 equiv of Ac2O, 12 equiv of pyridine, cat. DMAP,
CH2Cl2, rt, 8 h, 99%; (b) 9 equiv of BF3‚OEt2, 9 equiv of Et3SiH,
CH2Cl2, 0 °C to rt, 36 h; (c) (i) 2.5 equiv of PPh3, 3 equiv of I2, 5
equiv of imidazole, Et2O, CH3CN, 0 °C to rt, 2.5 h, (ii) DBU,
CH3CN, reflux, 3 h, 83% in two steps; (d) 3 equiv of K3Fe(CN)6,
3 equiv of K2CO3, 0.1 equiv of (DHQ)2‚PHAL, 0.014 equiv of
K2OsO4‚2H2O, tBuOH, H2O, 0 °C, 17 h; (e) K2CO3, THF, H2O,
rt, 3 h, 72% in two steps, C25-S/-R ) 7.8:1; (f) 1.7 equiv of
TBDMSOTf, 3 equiv of TEA, CH2Cl2, 0 °C, 4 h, 78%; (g) 2.6
equiv of PhI(OAc)2, 2.2 equiv of I2, UV lamp (300 nm), cyclo-
hexane, 40 °C, 2 h; (h) HCl gas, CH2Cl2, rt, 8 h, 99%.
involves sequential double transacylation from C-23. Sub-
strate 32 suffers kinetic Suarez cyclization conditions; now
the unnatural isomer 33 is favored over 34 by a 12.5:1 ratio.
Thermodynamic equilibration of these two isomers demon-
strates that the minor isomer 34 can be completely conVerted
to the unnatural spiroketal 33.
The route for completing the cephalostatin North 1 hemi-
sphere is now becoming fairly well defined after integrating
Org. Lett., Vol. 5, No. 13, 2003
2249

ether moiety imparted by the C-23 silyl ether. Application
of forcing conditions on 38 only serves to generate a plethora
of products, probably via the Ferrier pathway. This problem
was solved in our (lengthy) first-generation synthesis via a
two-step bromocyclization/reduction strategy.16 Kinetic bro-
mination from the R-face yields oxonium ion 39, which
suffers stereospecific cyclization to 40. Subsequent chro-
mium(II)-mediated reductive cleavage then provides a ∼10:1
separable mixture from which C-20 methyl compound 41
can be obtained in 70% yield (Figure 2).
The results previously discussed above can now be
contrasted with the findings of this paper. While C-17, C23
bis-deoxy compound 7 smoothly affords spiroacetal 8 bearing
the C-22 natural configuration via the Suarez hypoiodite
reaction, it is clear that the C-23 silyl ether is a dominant
negatiVe control element, since alcohol 32 completely favors
the unnaturally configured spiroacetal 33 under thermody-
namic conditions. Thus, the key question remaining to be
tested is whether 42, bearing the requisite C-17 oxygen
functionality and a C-20 R-methyl will be cyclize to natural
spiroketal 43 or its unwanted isomer 44. Put another way, is
geminal substitution required at C-20 (intermediate 39) to
ensure formation of â-face spiroketal 40, or can oxonium
intermediate 42 bearing a C-17 silyl ether and an R-face C-20
methyl moiety overcome the deleterious effect of the C-23
silyl ether (Figure 7)?
Figure 2.
Acknowledgment. We thank the National Institutes of
Health (CA 60548) for funding. Arlene Rothwell provided
the MS data.
the current work with our earlier efforts. We have previously
demonstrated that C-23 deoxy diol 35 thermodynamically
cyclizes to a ∼1:1 mixture of the natural South 7 spiroacetal
36 and the 22-epi, 23-deoxy North 1 spiroacetal 37 when
treated with catalytic camphor sulfonic acid, a result predicted
by molecular mechanics modeling calculations.15 However,
the “real”, oxygenated substrate 38 is very unreactive because
of the combined steric and electronic deactivation of the enol
Supporting Information Available: Experimental pro-
cedures and copies of 1H and 13C NMR spectra. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL034551G
(16) Kim, S.; Sutton, S. C.; Fuchs, P. L. Tetrahedron Lett. 1995, 36,
2427; see also ref 9.
(15) Jeong, J. U.; Fuchs, P. L. Tetrahedron Lett. 1995, 36, 2431.
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