A biomimetically inspired, efficient synthesis of the south 7 hemisphere of cephalostatin 7

Article abstract of DOI:10.1021/ja0531935

Synthesis of the South 7 hemisphere of cephalostatin 7 is described applying a second-generation synthetic strategy, which retains all the existing carbons in hecogenin acetate 1. TFAT (trifluoroacetyl trifluoromethanesulfonate)-assisted E-ring opening yi

Full text of DOI:10.1021/ja0531935

Published on Web 09/03/2005
A Biomimetically Inspired, Efficient Synthesis of the South 7 Hemisphere of
Cephalostatin 7
Jong Seok Lee* and Philip L. Fuchs*
Department of Chemistry, 560 OVal DriVe, Purdue UniVersity, West Lafayette, Indiana 47907
Received May 16, 2005; E-mail: pfuchs@purdue.edu
Scheme 1. Biomimetic Strategy of North 1 and South 7
Our quest to supply multigram quantities of cephalostatin
analogues to the clinic has featured improved syntheses of several
Southern hemispheres, including ritterazine GN,1 23′-deoxy cepha-
lostatin 1, and 17-hydroxy, 23-deoxy cephalostatin 1. Combining
these segments with the North 1 segment has given a series of potent
agents exhibiting promising cell-line specificity.2
Completing the goal requires a vastly improved preparation of
South 7 and several variants of the North 1 hemisphere. Our
approach to these materials involves conversion of the plant-derived,
hecogenin acetate 1 to spiroketals 2H and 2OH.3 In concept,
electrophilic opening of 2H or 2OH could give the corresponding
oxonium ions 3H or 3OH. Furthermore, the enol from 3H may
serve as a precursor to 4OH. Conversion of 4H and 4OH to key
polyols 7H and 7OH requires elimination to 5 followed by
dihydroxylation to D-ring dienes 6. Cephalostatin-related steroidal
D-ring dienes have previously been subjected to [4 + 2] reactions
with singlet oxygen,4 but this communication reports the first
appropriately oxygenated, stereodefined substrates that deliver a
synthetically relevant outcome.
Scheme 2. Synthesis of Dienes 15a-c and 16a-d
Olefinic polyols 7H and 7OH each have the potential of being
in equilibrium with four diastereomeric hemiketals, of which 8 and
10 appear preordained to suffer mild acid-catalyzed cyclization to
9 and 11, respectively. Alternatively, ionization of the C-14 tertiary
allylic alcohol of 7 may result in capture of the C-22 ketone
followed by kinetic closure of the spiroketal, again potentially
yielding 9 and 11 or their diastereomers (Scheme 1).
Acid-catalyzed ring-opening reactions of steroidal spiroketals are
generally based upon the seminal 1939-1940 Marker protocol.5
The reaction conditions are quite severe (Ac2O, 200 °C, 10 h), and
substrates such as 2 bearing a D-ring olefin decompose when
subjected to these conditions. Our new procedure involves low
temperature (-30 to -40 °C) treatment of spiroketals with tri-
fluoroacetyltriflate (TFAT) for 2 h, followed by cold, aqueous
workup.6 Application of this protocol to steroid 2H gave dihydro-
furan 12. If one allows the reaction to reach room temperature, the
product is ring-opened diene 13, which has unfortunately suffered
equilibration of the doubly activated C-20 stereocenter (Scheme
2). The problem was avoided by reaction of 143b,7 with TFAT to
provide dienyl trifluoroacetate 15a in high yield with no loss of
C-20 stereochemistry. Mild hydrolysis and Swern oxidation (Hu¨nig’s
base is essential to avoid C-20 isomerization) afforded the
equilibration-sensitive ketone 15c with only a trace epimerization
at C-20 (Scheme 2).
The biomimetic hypothesis was initially tested with dienes 15a-
c, which added singlet oxygen in high yield, but gave no facial
preference (Table 1, entries 1-3). Molecular modeling of C-22
propylene glycol ketals prefigured the singlet oxygen reaction as a
function of the conformational bias of the C-21 methyl moiety.
Specifically, it appears that the natural C-21R methyl ketal exists
as a group of three low-energy conformers, which shield the top
face of the D-ring diene, while the corresponding five conformers
of the â-methyl isomer block the bottom face (Figure 1).
In the event, C-22 ketals 16a-c (from 15c in 91, 53, and 91%
yield, respectively)8,9 smoothly underwent [4 + 2] cycloaddition
of singlet oxygen in 80-98% yield (entries 4-6), stereospecifically
providing R-face adducts. In striking contrast, but consistent with
the model in Figure 1, unnatural C-21 methyl ketal 16d gave only
the expected â-adduct 20d-â (entry 7).
With selective cycloaddition achieved, biomimetic synthesis of
the South 7 hemisphere was next addressed. Conversion of terminal
olefin 14 to differentially protected C-25,26 diol 21a-r (not shown)
was accomplished in three operations with 93% yield and >4.3:1
de with either C-25 selectivity as a function of catalyst in the
Sharpless AD reaction (see Supporting Information).
Cleavage of the isolable and characterized peroxide 22a-r (see
Supporting Information) with Zn/HOAc provided diol 23a-r in 86%
yield (Scheme 3). The stage was now set to deprotect ketal 23a-r
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10.1021/ja0531935 CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
Table 1. [4 + 2] Cycloaddition of Steroidal D-ring Dienes with Singlet Oxygen
a Calculated by crude 1H NMR spectrum; ns ) not separated. b Isolated yields. c Structure confirmed by X-ray crystallography. See Supporting Information.
In conclusion, the above synthesis affords a new, practical route
to the South 7 hemisphere 28 in 20% overall yield over 16
operations from hecogenin acetate 1. This compares with our first-
generation synthesis that required 25 operations with an overall
yield of 2%.11 In addition, this communication provides a biomi-
metic strategy potentially appropriate for a vastly improved
synthesis of the crucial North 1 hemisphere and its analogues.
Figure 1. Molecular models of C-22 propylene glycol ketals.
Acknowledgment. This work was supported by the National
Institute of Health (CA 60548). We thank Dr. Phillip Fanwick and
Arlene Rothwell for providing the X-ray and MS data.
Scheme 3. Completion of Synthesis of South 7 (28)
Supporting Information Available: Extended discussion, experi-
mental procedures, and 1H, 13C spectra. This material is available free
of charge via the Internet at http://pubs.acs.org.
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