Synthesis of the South unit of cephalostatin. 7. Total syntheses of (+)- cephalostatin 7, (+)-cephalostatin 12, and (+)-ritterazine K

Article abstract of DOI:10.1021/ja9817141

Transformation of alcohol 4 to α-azidoketone 6, a hexacyclic steroid beating the requisite functionality and spiroketal stereochemistry of the symchiral South portion of cephalostatin 7 (10) is described. Reaction of a 1:1 mixture of α-azidoketones 5 and

Full text of DOI:10.1021/ja9817141

J. Am. Chem. Soc. 1999, 121, 2071-2084
2071
Synthesis of the South Unit of Cephalostatin. 7. Total Syntheses of
(+)-Cephalostatin 7, (+)-Cephalostatin 12, and (+)-Ritterazine K1
Jae Uk Jeong, Chuangxing Guo,* and P. L. Fuchs*
Contribution from the Department of Chemistry, Purdue UniVersity, West Lafayette, Indiana 47907
ReceiVed May 18, 1998
Abstract: Transformation of alcohol 4 to R-azidoketone 6, a hexacyclic steroid bearing the requisite functionality
and spiroketal stereochemistry of the symchiral South portion of cephalostatin 7 (10) is described. Reaction of
a 1:1 mixture of R-azidoketones 5 and 6 with sodium hydrogen telluride is followed by cleavage of the protecting
groups cephalostatin 12 (9), cephalostatin 7 (10), and ritterazine K (11).
Table 1. Dihydroxylation of the Olefins 12 and 13
Introduction
yield
(%)
C25 nat/epi
ratio
Cephalostatin 7 (10)2 belongs to a family of 43 trisdecacyclic
pyrazines, characterized by the groups of Pettit at Arizona State
University and Fusetani at the University of Tokyo.3 Pettit
hypothesized that the pyrazine core structure was assembled
via dimerization and oxidation of steroidal R-aminoketones, a
well-known reaction in the laboratory.4,5 In the preceding paper,6
we detailed the conversion of hecogenin acetate 1 to a pair of
homoallylic alcohols 3, 4 (via key aldehyde 2) and the
conversion of the former (3) to the North azide 5 (Scheme 1).
In this paper we describe the synthesis of the South R-azide 6
from homoallyl alcohol 47 and the completion of the total
syntheses of cephalostatin 7 (10), cephalostatin 12 (9), and
ritterazine K (11).1 The South skeleton was found to be one of
the most basic assemblies in the cephalostatin/ritterazine family
as it is present in 18 out of 43 members.
substrate
conditions
12
13
13
13
13
13
Sharpless AD-mix-R, 0 °C, 16 h10 40 16S/16R 1:2
Sharpless AD-mix-R, 0 °C, 16 h10 95 17S/17R 2.5:1
Sharpless AD-mix-â, 0 °C, 16 h10 95 17S/17R 1:2
(S,S)-15,11 -78 °C, 1 h
(R,R)-15,11 -78 °C, 1 h
(DHQ)2-PYR,10 0 °C, 16 h
90 17S/17R 1:1.8
90 17S/17R 2:1
90 17S/17R 2.5:1
Osmylation of the Terminal Olefin
Deoxygenation of the C23 alcohol moiety of homoallyl alcohol
4 was accomplished via xanthate 12 (Scheme 2). Xanthate 12
was highly disposed toward formation of triene 14 since both
the C-O and C-H bonds are allylically activated; therefore,
the reaction was conducted by rapid addition of 12 and AIBN
to a preheated oil bath containing the appropriate tin hydride
reagent. Even under these optimized conditions, tributyltin
hydride still afforded a mixture of the desired 1,5 diene 13
accompanied by inseparable triene 14. Fortunately, utilization
of the more reactive8 triphenyltin hydride smoothly provided
13 without a trace of triene 14 (Scheme 2).
Previous studies on osmylation of (R)-configured C23 TBDPS
ethers resulted in stereocontrol at C25 with good selectivity.6,9,10
However, when C23 was substituted with (S)-configured xanthate
12, or unsubstituted (13), the results were far less satisfactory
(Scheme 3 and Table 1). Further indication of the lack of a
usable diastereotopic environment without a TBDPS ether at
(1) Cephalostatin Synthesis. 15. Portions of this work have been
communicated in Articles 6 and 9 of this series: Jeong, J. U.; Fuchs, P. L.
Tetrahedron Lett. 1995, 36, 2431. Jeong, J. U.; Sutton, S. C.; Kim, S.; Fuchs,
P. L. J. Am. Chem. Soc. 1995, 117, 10157. For additional syntheses of
cephalostatin-related pyrazines, see: (a) Pan, Y.; Merriman, R. L.; Tanzer,
L. R.; Fuchs, P. L. Bioorg. Med. Chem. Lett. 1992, 2, 967. (b) Heathcock,
C. H.; Smith, S. C. J. Org. Chem. 1994, 59, 6828. (c) Kramer, A.; Ullmann,
U.; Winterfeldt, E. J. Chem. Soc., Perkin Trans. 1 1993, 2865. (d) Ganesan,
A. Angew. Chem., Int. Ed. Engl. 1996, 35, 611. (e) Drogemuller, M.;
Jantelat, R.; Winterfelt, E. Angew. Chem., Int. Ed. Engl. 1996, 35, 1572.
(f) Guo, C.; Bhandaru, S.; Fuchs, P. L.; Boyd, M. R. J. Am. Chem. Soc.
1996, 118, 10672. (g) LaCour, T. G.; Guo, C.; Bhandaru, S.; Boyd, M. R.;
Fuchs, P. L. J. Am. Chem. Soc. 1998, 120, 692. (h) Dro¨gemu¨ller, M.;
Flessner, T.; Jaulelat, R.; Scholz, U.; Winterfeldt, E. Eur. J. Org. Chem.
1998, 2811.
(2) Pettit, G. R.; Kamano, Y.; Inoue, M.; Dufresne, C.; Boyd, M. R.;
Herald, C. L.; Schmidt, J. M.; Doubek, D. L.; Christie, N. D. J. Org. Chem.
1992, 57, 429.
(3) (a) Pettit, G. R.; Xu, J.-P.; Ichihara, Y.; Williams, M. D.; Boyd, M.
R. Can. J. Chem 1994, 72, 2260 and references therein. (b) Fukuzawa, S.;
Matsunaga, S.; Fusetani, N. J. Org. Chem. 1997, 62, 4484 and references
therein.
C
23 was that the inseparable mixture of diols 17S/17R gave no
indication of being a diastereomeric mixture when assayed by
300 MHz proton and 50 MHz carbon NMR with CDCl3 as
solvent. Ultimately, it was discovered that the product ratio could
be assessed by 300 MHz NMR in C6D6 (17S ) δ 1.01; 17R )
δ 1.03). An alternative mode of analysis was via C6D6 NMR
of the C25,26 diphenylsilyl acetonide derivatives 18S/18R (Ph2-
SiCl2, Et3N, CH2Cl2, 0 to 25 °C, >90% yield). In this case one
proton of the C26 methylene AB patterns could be accurately
integrated (18S ) δ 3.76; 18R ) δ 3.74).
(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.
(5) (a) Edwards, O. E.; Purushothaman, K. K. Can. J. Chem,. 1964, 42,
712. (b) Doorenbos, N. J.; Dorn, C. P. J. Pharm. Sci. 1965, 54, 1219. (c)
Ohta, G.; Koshi, K. Chem. Pharm. Bull. 1968, 16, 1487. (d) Wolloch, A.;
Zibiral, E. Tetrahedron 1976, 32, 1289.
Since (R)-configured C23 TBDPS ether 19 resulted in a 4:1
ratio of stereocontrol at C25,6 we also investigated osmylation
(6) Kim, S.; Sutton, S. C.; Guo, C.; LaCour, T. G.; Fuchs, P. L. J. Am.
Chem. Soc. 1999, 121, 2056.
(7) More than 15 g of alcohol 4, the Stanyl allylation product from the
pentacyclic aldehyde 2, was accumulated during synthesis of the North unit.
For detail, see preceding paper.
(9) Jeong, J. U.; Fuchs, P. L. J. Am. Chem. Soc. 1994, 116, 773.
(10) (a) Crispino, G.; Jeong, K.-S.; Kolb, H. C.; Wang, Z.-M.; Xu, D.;
Sharpless, K. B. J. Org. Chem. 1993, 58, 3785. (b) Kolb, H. C.;
VanNieuwenhze, M. S. Chem. ReV. 1994, 94, 2483.
(8) Newcomb, M. Tetrahedron 1993, 49, 1151.
10.1021/ja9817141 CCC: $18.00 © 1999 American Chemical Society
Published on Web 02/24/1999

2072 J. Am. Chem. Soc., Vol. 121, No. 10, 1999
Jeong et al.
Scheme 1
Scheme 2
Scheme 3
Scheme 4
of trityl ether 21, p-methoxybenzoate 23,11 and tri(isopropyl)-
silyl ether 25, with a view to later deoxygenation of the C23
position (Scheme 4 and Table 2). In the event, these substrates
did not afford improved stereospecificity, necessitating consid-
eration of other options for stereocontrol.
The Nitro Aldol Approach to C-25 Stereocontrol
In an effort to avoid the difficulty inherent in osmylation of
the terminal olefin, we explored introduction of the C25 (S)
stereocenter starting with optically pure nitroacetonide 34 which
was derived from (S)-2-methylglycidol 27.12 Treatment of
acetonide 34 and aldehyde 2 with KF13 in i-PrOH at 25 °C
provided an equilibrium mixture of diastereomeric â-nitro
alcohols 35 (68%) along with unreacted aldehyde 2 (32%,
Scheme 5). Attempts to obtain C23 alcohol 38 directly via
(11) (a) Corey, E. J.; Noe, M. C.; Guzman-Perez, A. J. Am. Chem. Soc.
1995, 117, 10817. (b) Corey, E. J.; Guzman-Perez, A.; Noe, M. C. J. Am.
Chem. Soc. 1995, 117, 10805. (c) Corey, E. J.; Guzman-Perez, A.; Noe,
M. C. Tetrahedron Lett. 1995, 36, 3481. (d) Corey, E. J.; Guzman-Perez,
A.; Noe, M. C. J. Am. Chem. Soc. 1994, 116, 12109.

Synthesis of the South Unit of Cephalostatin
J. Am. Chem. Soc., Vol. 121, No. 10, 1999 2073
Scheme 5
Scheme 6
Table 2. Dihydroxylation of Substrates with C23 (R) Configuration
The target acetonide 40 was prepared from the ketone 37 via
reduction to alcohols 38, preparation of xanthates 39, followed
by deoxygenation to acetonide 40.
yield
(%)
C-25 nat/epi
ratio
substrate
conditions
Unfortunately, all attempts to cleave acetonide 40 were
uniformly unsuccessful due to the intervention of a Ferrier-type
process which readily occurred even under “neutral” conditions
providing aromatized furans 43 and/or 44 (Scheme 6).15 The
only reaction condition that gave evidence for diol 45 or
spiroketals (not shown) derived therefrom involved DDQ
oxidation, but even in that case the aromatization product 43
was the major species observed. Buffered DDQ failed to produce
any improvement.
13
19
21
23
25
Sharpless AD-mix-R, 0 °C, 16 h10 95 17S/17R 2.5:1
(S,S)-15,11 -78 °C, 1 h 956 20S/20R 4:1
Sharpless AD-mix-R, 0 °C, 4 days 40 22S/22R 2.2:1
Sharpless AD-mix-R, 0 °C, 16 h
95 24S/24R 2.8:1
94 26S/26R 3:1
(S,S)-15,11 -78 °C, 1 h
denitration of 35 were unsuccessful, presumably due to the free
hydroxy group at C23, but the nitro group was easily removed
from R-nitroketone 36 with Ph3SnH in the presence of AIBN
(or ACN) to give ketone 37. R-Nitroketone 36 can be obtained
from â-nitro alcohol mixture 35 by the Dess-Martin oxidation.14
An Alternative Approach Employing â-Ketosulfone
Chemistry
(12) For preparation of 34, commercially available (S)-2-methylglycidol
27 was protected as benzyl ether 28 followed by epoxide opening with
LiOH in t-BuOH-H2O at reflux to provide 1,2-diol 29, which was converted
to acetonide 30. Cleavage of the benzyl ether of 30 by hydrogenation
followed by Swern oxidation of the resultant alcohol 31 provided aldehyde
32. Aldehyde 32 was converted to oxime 33, which was oxidized to the
desired nitroacetonide 34 by using Petrini’s protocol (see: Ballini, R.;
Marcantoni, E.; Petrini, M. Tetrahedron Lett. 1992, 4835). For experimental
procedure, see Supporting Information.
Since the nitro-aldol approach was unsuccessful, a new
scheme involving â-ketosulfone chemistry was explored (Scheme
7). The idea was to mask the C25 alcohol as a ketone before the
spiroketal formation and to create the C25 stereochemistry at a
(15) Ireland, R. E.; Meissner, R. S.: Rizzacasa, M. A. J. Am. Chem.
Soc. 1993, 115, 7166 and references therein.
(13) (a) Stevens, R. V.; Beaulieu, N.; Chan, W. H.; Daniewski, A. R.;
Takeda, T.; Waldner, A.; Willard, P. G.; Zutter, U. J. Am. Chem. Soc. 1986,
108, 1039. (b) Williams, T. M.; Mosher, H. S. Tetrahedron Lett. 1985,
6269 and references therein.
(16) Commercially available glycidol 52 was protected as MOM ether
53, followed by epoxide opening to give phenyl sulfide 54 (2 steps, 70%)
and oxone oxidation to afford sulfone 56 (90%). In our initial attempt,
oxidation of the hydroxyl in 56 was found to be problematic. For
experimental procedure, see Supporting Information.
(14) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155

2074 J. Am. Chem. Soc., Vol. 121, No. 10, 1999
Jeong et al.
Scheme 7
Scheme 8
when excess SmI2 (5 equiv) was used. Attempts to remove the
MOM group in 62 were fruitless because Ferrier type elimina-
tion again intervened.
Therefore, the MOM group was replaced with the benzyl
group, which can be removed by hydrogenation under neutral
conditions. Fortunately, the technology developed for the MOM
series could be successfully employed on the benzyl protected
series (Scheme 12). The benzyl ether side chain 47b was
prepared in good yield via alcohol 66 with use of the same four-
step sequence. Under optimized conditions, C26 benzyl ether
67 was obtained from the SN2 reaction in 91% yield. For the
subsequent desulfonylation, a smaller excess of SmI2 (3 equiv)
was used, compared to the desulfonylation of MOM ether 61.
The desired benzyl ether 68 was obtained in 86% yield while
the formation of over-reduced ketone 63 was substantially
decreased (<10%). The key debenzylation (H2/Pd-C) afforded
the C26 alcohol 49 in 99% yield as expected.
Scheme 9
Unfortunately, acid-catalyzed spiroketal formation proved to
be unexpectedly problematic (Scheme 13 and Table 3).9,21 The
C25 ketone in 49 makes the proximate hydroxyl less nucleo-
philic, and increases the rigidity in the resultant six-membered
ring. The best conditions employed camphor-sulfonic acid
(CSA) in benzene which slowly provided the desired 6,5-
spiroketal 55 in 33% yield (80% based on recovered 49).
With the C25 ketone 50 in hand, the diastereoselective addition
of methyl anion was tested. According to an MM2 calculation
(CAChe 3.7), the most stable conformation (2.8 kcal/mol lower
than the second most stable conformation) of ketone 50 is as
shown in Schemes 13 and 14. Therefore, equatorial attack of
methyl should give the desired stereochemistry at C25. In the
case of 4-tert-butylcyclohexanone 69, the addition of Me2CuLi22
later stage. The â-ketosulfone 47a was prepared from glycidol
52 (Scheme 8).16 The â-hydroxysulfide 54 was chemoselectively
oxidized to â-ketosulfide 57a upon treatment of o-iodoxybenzoic
acid (IBX, 55) in DMSO.17 The desired side chain 47a was
obtained in 84% yield (for two steps) when sulfide 57a was
oxidized by oxone (3 equiv).18 The 1,2-reduction of pentacyclic
aldehyde 2 and mesylation of the resultant alcohol 58 proceeded
smoothly (Scheme 9).
Attempts to install â-ketosulfone side chain 47a by SN2
reaction of mesylate 46a were unsuccessful, even though the
model study demonstrated that the methyl 4-methoxyaceto-
acetate anion 59 could add to mesylate 46a to give the desired
product 60 in 60% yield when heated in THF at reflux (Scheme
10). Mesylate 46a was transformed to iodide 46b. The same
reaction conditions (THF/reflux) only led to faster decomposi-
tion. Since the substitution reaction was thought to be of the
SN2 type, DMSO was employed as the reaction solvent to
facilitate the substitution.19 Even though mesylate 46a again
showed no reaction, iodide 46b smoothly reacted with â-keto-
sulfone anion 47a within 30 min at room temperature to give
the desired adduct 61 in 86% yield.
23
or MeLi with LiClO4 proceeded mainly through equatorial
addition providing the axial alcohol with good selectivity (>92:
8). However, all the trials on C25 ketone 50 with different methyl
anion reagents afforded predominantly the undesired equatorial
alcohol (Scheme 14). The observed selectivity may be due to
the directing effect of the C26 oxygen, which chelates with metal
ion and induces axial addition of methyl anion.
Establishment of the 6,5-Spiroketal
Concurrent with the above two approaches, we moved
forward with the mixture of the diastereomeric C25 diols 17S/
17R. Treatment of the inseparable 17S/17R mixture with
After the ketosulfone side chain was installed, desulfonylation
was achieved by SmI2 reduction at -78 °C (Scheme 11).20
Significant amounts (33%) of overreduced product 63 formed
(20) (a) Molander, G. A.; Hahn, G. J. Org. Chem. 1986, 51, 1135. (b)
Kunzer, H.; Stahnke, M.; Sayyer, G.; Wiechert, R. Tetrahedron Lett. 1991,
32, 1949.
(21) Williams, D. R.; Jass, P. A.; Gaston, R. D. Tetrahedron Lett. 1993,
34, 3231.
(22) Macdonald, T. L.; Still, W. C. J. Am. Chem. Soc. 1975, 97, 5280.
(23) Ashby, E. C.; Noding, S. A. J. Org. Chem. 1979, 44, 4371.
(17) (a) Frigerio, M.; Santagostino, M.; Sputore, S.; Palmisano, G. J.
Org. Chem. 1995, 60, 7272. (b) Frigerio, M.; Santagostino, M. Tetrahedron
Lett. 1994, 35, 8019.
(18) Trost, B. M.; Curran, D. P. Tetrahedron Lett. 1981, 22, 1287.
(19) Carey, F. A.; Sundberg, R. J. In AdVanced Organic Chemistry, 3rd
ed.; Plenum Press, 1990; Part A, 5.5, p 284.

Synthesis of the South Unit of Cephalostatin
J. Am. Chem. Soc., Vol. 121, No. 10, 1999 2075
Scheme 10
Scheme 11
Scheme 12
Scheme 13
Similar deprotection of the remaining inseparable binary mixture
of S-74/R-74 provided individual samples of triols S-75 (21%
for five steps from 13) and R-75 (19% in five steps from 13)
after chromatographic separation. The stereochemistry of both
S-75 and R-75 was also unambiguously determined by X-ray
analysis.24 The resultant 1:1 ratio for the mixture of 51 and S-73
is consistent with molecular mechanics calculations,25 since these
isomers are predicted to have steric energies within 0.1 kcal/
mol. Similar calculations predict the formation of a 0.8 kcal/
mol less stable, 6,5-spiroketal (25R) diastereomer of 51 (not
shown). A small quantity of this minor isomer may have been
lost during the chromatographic separation.
Table 3. Optimization of Spiroketal Formation
entry
1
reagent/conditions
result
ref
(+)-CSA(cat.) in CH2Cl2, RT, 3.5 h
50 (30%), 65 (25%)
and 49 (25%)
NR
65 (major), 49 (trace) 9
65 (25%), 49 (70%)
9
2
3
4
5
(+)-CSA(cat.) in Et2O, RT, 1 h
(+)-CSA(cat.) in CH3CN, RT, 1 h
(+)-CSA(cat.) in THF, RT, 0.5 h
(+)-CSA(cat.) in benzene, RT, 3.5 h
9
9
9
In addition to providing authentic samples of the above three
spiroketals, this study revealed an interesting reversal in
selectivity for acetate cleavage. As we previously observed,6
when C17 is present as a TMS ether (51) treatment with
potassium bicarbonate in 4:1 methanol/water smoothly resulted
in exclusive deprotection of the less-hindered C3 acetate moiety,
giving C3 alcohol 77 (Scheme 16). However, the fluoride-
mediated cleavage reactions described above resulted in desi-
lylation with concomitant scission of the adjacent C12 acetoxy
moiety, yielding triol 76. Presumably this reaction involved
50 (33%), 65 (15%)
and 49 (47%)
6
7
8
9
PPTs (cat.) in benzene, RT, 2 h
PPTs (cat.) in MeOH, RT, 1 h
silica gel in benzene, RT, 2 days
NR
NR
NR
9, 21
9
CF3CO2H (10 equiv) in Et2O, 0 °C, 1 h decomposition
21
10 CF3SO3H (cat.) in Et2O, -78 °C, 1 h 65 (40%), 49 (50%) 21
camphorsulfonic acid (CSA) in methylene chloride provided a
new inseparable mixture containing three major components
in roughly equal amounts as assayed by NMR (Scheme 15).
Silylation of the new mixture with TBDMS-Cl followed by
chromatography afforded a pure sample of the South spiroketal
51 (27% in three steps from 13). Bis-deprotection of this material
with TBAF in THF at reflux for 3 h yielded a sample of triol
76, whose structure was secured by X-ray crystallography.24
(24) X-ray structural information relating to compounds 76, S-75, and
R-75 can be obtained from the Cambridge Crystallographic Data Centre.
(25) Calculations were performed using a Tektronix CAChe v3.5. For
additional examples of using molecular mechanics for prediction of
spiroketal thermodynamics, see ref 8.

2076 J. Am. Chem. Soc., Vol. 121, No. 10, 1999
Jeong et al.
Scheme 14
Scheme 15
Scheme 16
Scheme 17
activation of the C12 ester via intramolecular hydrogen bonding
from the proximal C17 alcohol followed by nucleophilic deacyl-
ation.
Oxidation of C3 alcohol 77 by the Brown variant of the Jones
oxidation26 afforded ketone 78 in 91% yield (Scheme 17).
Reaction of 78 with phenyltrimethylammonium tribromide
(PTAB) in THF at 0 °C for 10 min provided C2 bromide 80 in
50-60% yield along with the 2,2′-dibromide 81 and the C2
bromide bearing a 5,5-spiroketal 82 resulting from acid-
catalyzed rearrangement of the South 6,5-spiroketal. To prevent
acid-catalyzed rearrangement, C25 alcohol 78 was treated with
DMSO and acetic anhydride27 at 25 °C for 19 h to provide
methylthiomethyl ether 79 in quantitative yield. Bromination
of ketone 79 with PTAB (1.3 equiv) in THF at 0 °C for 20 min
(26) Brown, H. C.; Garg, C. P.; Liu, K.-T. J. Org. Chem. 1971, 36, 387.
(27) Pojer, P. M.; Angyal, S. J. Aust. J. Chem. 1978, 31, 1031.

Synthesis of the South Unit of Cephalostatin
J. Am. Chem. Soc., Vol. 121, No. 10, 1999 2077
Scheme 18
Scheme 19
Scheme 20
afforded a 76% yield of South bromoketone 80, which had
suffered concomitant C25 deprotection without the intervention
of any acid-catalyzed rearrangement to 82.
elimination at C17, therefore full equilibrium between the
spiroketals (88S/88R) was not established at this stage (Scheme
20). Chemoselective oxidation of the C3 alcohol was next
investigated in hopes of separation of the spiroketals. Both
Swern oxidation28 and IBX oxidation17 failed to achieve the
desired transformation although the literature reports cases where
an alcohol was oxidized in the presence of a thioether moiety.
Fortunately, the C3 alcohol could be chemoselectively oxidized
to ketone in 91% yield (7% SM recovered) upon treatment with
pyridine-CrO3 for 5 min. To our surprise and delight, three
different 5/6 spiroketals were successfully isolated from the
mixture (C3 ketone) by column chromatography. They are the
desired South 7 spiroketal 79 (57%), the C25 (R) spiroketal 90
(25%), and spiroketal 89 (10%), which can be converted to the
desired 79 in 90% yield when treated with CSA. The final yields
of spiroketals 79 and 90 were 65 and 25%, respectively. The
stereochemical assignment of spiroketal 90 is based on the fact
that 90 is the only major isomer (25%) that cannot be converted
into the natural spiroketal 79. Thermodynamic product (90)
should adopt the most stable configuration (optimized by MM2)
of the C25 (R) epimer as shown in Scheme 22. On the other
hand, the structure of spiroketal 89, which has a natural
configuration at C25 (S), was proposed by comparing the three
methyl resonances (C18, C21, C27) in the proton NMR (C6D6)
Final Optimized Scheme for Synthesis of the South
Steroid Unit
After two failed attempts at improving the C25 stereospeci-
ficity, we focused on avoiding the undesired 5,5-spiroketal
formation. The scheme started with diol mixture 17S/17R and
involved protection of the C25 alcohol before cyclization
(Scheme 18). To mask the hindered tertiary alcohol at C25, a
variety of protecting groups including acetate, MTM, and silyl
groups were surveyed. The MTM group could be introduced
in high yield and was expected to exhibit reasonable stability
in the upcoming (acidic) spiroketalization reaction (Scheme 19).
Therefore, The primary C26 alcohol in 17S/17R was selectively
acylated in the presence of the tertiary alcohol in nearly
quantitative yield. The MTM group was then affixed to the C25
alcohol affording 86S/86R (97%). The C3, C26 acetates were
cleaved with alkali hydrolysis to give a mixture of diols 87S/
87R in 99% yield.
With the C25 alcohol blocked by the MTM group, only 5/6
spiroketals (mainly 88S/88R) were produced (91% yield plus
9% SM) as an inseparable mixture upon treatment of camphor-
sulfonic acid (CSA) in CH2Cl2 (1 h). Limited reaction time was
given to avoid the possible complication of Ferrier type
(28) Williams, D. R.; Klingler, F. D.; Dabral, V. Tetrahedron Lett. 1988,
29, 3415.

2078 J. Am. Chem. Soc., Vol. 121, No. 10, 1999
Jeong et al.
Scheme 21
Scheme 22
conformations shown in Scheme 22 are at least 1 kcal/mol more
stable than the alternative chair conformations. Therefore, the
C22 of 89 bears an S-configuration if methyl-27 is axial.
In the key acid-catalyzed spiroketal formation step (Scheme
21), protonation of C20,22 enol ether occurs principally from the
R-face, affording oxonium ion 91 (20R,25S). The kinetically
unfavorable but thermodynamically more stable oxonium ion
92 (20S,25S) leads to the desired spiroketal 95 (20S,22R,25S)
which is calculated to be 4.1 kcal/mol more stable than spiroketal
96 (20S,22S,25S).29 The desired spiroketal 95 (20S,22R,25S) was
the major product after equilibration at 25 °C for 1 h, which
indicates that reversable deprotonation of C20 in oxonium ions
91/92 is facile under these conditions, and intermediates 91/92
readily interconvert via the enol ether 87S. The oxonium ion
with a 21R-methyl (92 (20S,25S)) was calculated to be favored
by 3.6 kcal/mol because the 21â-methyl in 91 (20R,25S)
interacts with the 18-methyl. Therefore, the natural spiroketal
95 (20S,20R,25S), whose energy is more than 4.1 kcal/mol lower
than any other epimers at C20 and/or C22, is the predominant
product upon treatment of acid. Interestingly, the equibration
process in the 17-deoxy analogues30 requires elevated temper-
ature (80 °C). The presence of the C17 TMS ether group not
only makes the R-face of the C20,22 enol ether less accessible to
the attack of a proton, but more importantly, apparently
inductively increases the acidity of the C20 methine poton in
the oxonium ions (91/92).31 The isomerization of 89 (or 94) to
form the natural 79 (or 95) was slower than that for the other
isomers. This is presumably due to steric retardation (21â-
methyl) of the acid-catalyzed spiroketal opening.
Table 4. Proton NMR Resonances in C6D6 (ppm)
compound
C-18 (s)
C-21 (d)
C-27 (s)
MTM ether 79 (20S,22R,25S)
MTM ether 90 (20S,22R,25R)
MTM ether 89 (20R,22S,25S)
alcohol 51 (20S,22R,25S)
0.77
0.80
1.22
1.14
1.11
1.11
0.97
0.91
1.05
1.00
1.12
1.36
1.33
1.00
1.13
alcohol 72 (20S,22R,25R)
of 79, 90, 89, 51, and 72 (Table 4). The chemical shift (1.22
ppm) of methyl-18 of 89 is 0.45 ppm further downfield than
that of naturally configured 79 (0.77 ppm), indicating a C20â
stereochemistry in 89. A similar chemical shift change (0.62
ppm, Table 4, preceding paper) of methyl-18 was observed
between the North 1 pentaol (compound 92R, preceding paper)
and its C20 epimer (compound 92â, preceding paper). The
chemical shift (1.33 ppm) of methyl-27 of 89 is 0.22 ppm more
downfield than that of 79 (1.12 ppm), suggesting an axial
methyl-27 in 89. A similar chemical shift difference of methyl-
27 can be found between 79 and 90 and between the C25
alcohols 51 and 72. According to MM2 calculations, the chair
(29) MM2 calculation was performed using CAChe v.3.7.
(30) Jeong, J. U.; Fuchs, P. L. Tetrahedron Lett. 1994, 35, 5385.
(31) Equilibration between kinetically favored 93/94 and more stable
95 involves the enol ether 87S. Its formation, the elimination of the C20
methine proton was believed to be the slowest step in the proposed
mechanism.

Synthesis of the South Unit of Cephalostatin
J. Am. Chem. Soc., Vol. 121, No. 10, 1999 2079
Scheme 23
In the final improved scheme, the overall yield from diol 17S/
17R to the ketone 79 was doubled (from 25 to 54%) without
adding more steps compared to the earlier synthetic route
(Schemes 4, 17).
cleaved ketones 79 and 98 were recovered in 36 and 15% yields
from this reaction. Individual treatment of protected 99-101
with TBAF (15 equiv) in THF at reflux for 3 h provided the
first synthetic samples of cephalostatin 7 (10), cephalostatin 12
(9), and ritterazine K (11), each in approximately 80% yield
(Scheme 23). Samples of each of the three synthetic materials
were provided to Pettit at Arizona State, who confirmed the
identity of cephalostatins 7 and 12 by direct NMR and
chromatographic comparison.34 Pyridine-d5 proton and carbon
NMR data for compound 11 are identical with those reported
by Fusetani for natural ritterazine K.35
Completion of the synthesis of the South R-azidoketone 6
involved reaction of R-bromoketone 80 with 4 equiv of
tetramethylguanidinium azide (TMGA) in nitromethane at 25
°C for 4 h (Scheme 22). This solvent was the key to avoiding
competitive decomposition (to 97) of the initially formed
R-azidoketone 6. In this instance, the isolated yield of 6 was
95% with nitromethane,6,32 as compared to 30-40% along with
60-70% of R-aminoenone 97 (via base-catalyzed nitrogen
elimination from 6) when employing acetonitrile or dichlo-
romethane as the reaction solvent.
Conclusion
The “one pot” syntheses of cephalostatin 7 (10), cephalostatin
12 (9), and ritterazine K (11) were the first synthetic preparations
of these materials. The sequence also provided a sufficient
quantity of the steroidal units for the preparation of other
cephalostatins and ritterazines. Since cephalostatin 7 (10) and
cephalostatin 1 share the same North half, this work also paved
the way to the first total synthesis of cephalostatin 1,1f,g the
most potent member in this family.
Pyrazine Synthesis
The total synthesis of cephalostatin 7 (10) involved in situ
reduction of R-azidoketones 5 and 6 to R-aminoketones 7 and
8 followed by statistical combination to produce cephalostatins
7 (10) and 12 (9) and ritterazine K 11 (Scheme 1). Pyrazine
formation was accomplished by treating a 1:1 mixture of
R-azidoketones 56a and 66b in ether with 6 equiv of ethanolic
NaHTe33 for 1 h at 25 °C, followed by adding silica gel as a
mild acid catalyst and allowing the mixture to stir in ethyl acetate
while exposed to the air for 18 h. Chromatography of the
reaction mixture afforded the protected pyrazines 99, 100, and
101 in 35, 14, and 23% isolated yields, respectively. Azide-
Experimental Section
General Procedures. See the preceding paper.
C2 Azide 6. To a solution of bromide 80 (25 mg, 0.038 mmol) in
CH3NO2 (2 mL) was added TMGA32 (24 mg, 0.153 mmol) at 25 °C.
The reaction mixture was stirred for 4 h. After concentration, the residue
(32) (a) Li, C.; Arasappan, A.; Fuchs, P. L. Tetrahedron Lett. 1993, 34,
3535. (b) Li, C.; Shih, T.-L.; Jeong, J. U.; Arasappan, A.; Fuchs, P. L.
Tetrahedron Lett. 1994, 35, 2645.
(33) Suzuki, H.; Kawaguchi, T.; Takaoka, K. Bull. Chem. Soc. Jpn. 1986,
59, 665.
(34) We are extremely grateful to Professor G. R. Pettit and Dr. Jun-
Ping Xu of Arizona State for comparisons of synthetic cephalostatins 7
(10) and 12 (9) with the natural materials.
(35) Fukuzawa, S.; Matsunaga, S.; Fusetani, N. Tetrahedron 1995 51,
6707.

2080 J. Am. Chem. Soc., Vol. 121, No. 10, 1999
Jeong et al.
was purified by flash column chromatography on silica gel (1:6 EtOAc/
18.66*, 20.8*, 20.9*, 22.3*, 26.8, 27.4, 27.6, 29.2, 33.9, 34.1*, 35.2,
35.9, 39.1, 43.3*, 50.1*, 58.3, 72.8*, 73.3*, 75.8*, 94.0*, 98.4, 113.9,
117.2*, 140.2, 149.7, 160.0, 168.7, 169.2; MS (CI) 583 (M + H -
HOCS2CH3)+; HRMS (FAB, NBA) calculated for C34H51O6Si 583.3455,
found 583.3413.
hexanes) to provide 23 mg (96%) of azide 6: Rf ) 0.16 (1:3 EtOAc/
1
hexanes); H NMR (C6D6, 300 MHz) δ 0.31 (s, 9H), 0.32 (s, 3H),
0.98 (s, 3H), 1.03 (d, J ) 7.2 Hz, 3H), 1.12 (s, 3H), 1.80 (s, 3H),
3.14-3.28 (m, 2H), 3.75 (d, J ) 11.1, 1H), 4.78 (d, J ) 2.2 Hz, 1H),
5.16 (dd, J ) 11.7, 4.6 Hz, 1H), 5.33 (t, J ) 2.3 Hz, 1H); 13C NMR
(C6D6, 75 MHz) δ 2.3*, 9.1*, 11.3*, 19.8*, 20.7*, 25.1*, 26.9, 27.4,
28.2, 28.7, 32.6, 33.9*, 36.2, 43.0, 44.2, 44.9*, 46.7*, 49.5*, 56.3, 63.0*,
65.9, 68.9, 73.3*, 89.9*, 93.2, 107.7, 117.6*, 158.2, 168.9, 202.8; MS
(EI) 615 (M)+; HRMS (EI) calculated for C32H49N3O7Si 615.3340,
found 615.3321.
Olefin 13. A solution of xanthate 12 (66 mg, 0.10 mmol), Ph3SnH
(195 mg, 0.56 mmol), and a catalytic amount of AIBN (1.6 mg, 0.01
mmol) in toluene (100 mL) was heated at reflux with a preheated oil
bath. After 5 min, the solution was cooled to 25 °C and concentrated
under reduced pressure. The residue was purified by flash column
chromatography (2% EtOAc/hexanes to 8% EtOAc/Hex) on silica gel
to provide 50 mg (90%) of the product 13: Rf ) 0.57 (1:6 EtOAc/
Cephalostatin 12 (9), Cephalostatin 7 (10), and Ritterazine K
(11). Individual samples of protected pyrazines 99, 100, and 101 with
15 equiv of TBAF in THF were heated at reflux for 1-3 h. After
removing THF, the residue was dissolved in EtOAc. The organic layer
was washed with saturated aqueous NH4Cl (×2) and brine and dried
over MgSO4. After filtration and evaporation, the residue was subjected
to silica gel chromatography to give cephalostatin 12 (9) and ritterazine
K (11) each in approximately 80% yield. Cephalostatin 7 (10) was
chromatographed on prep TLC (1:3 EtOAc/hexanes).
1
Hex); H NMR (CDCl3, 300 MHz) δ 0.61 (s, 9H), 0.85 (s, 3H), 1.05
(s, 3H), 1.58 (s, 3H), 1.73 (s, 3H), 2.00 (s, 3H), 2.02 (s, 3H), 4.62-
4.75 (m, 3H), 4.96 (d, J ) 2.1 Hz, 1H), 5.03 (dd, J ) 11.7, 4.7 Hz,
1H), 5.37 (t, J ) 2.3 Hz, 1H); 13C NMR (C6D6, 50 MHz) δ 2.3*, 9.9*,
12.1*, 18.6*, 21.5*, 21.8*, 22.9*, 26.0, 27.9, 28.1, 28.5, 30.0, 34.6,
34.8*, 35.2, 36.0, 36.7, 44.1*, 51.0*, 59.1, 73.6*, 74.4*, 94.4*, 99.6,
107.0, 111.1, 118.6*, 145.5, 155.1, 159.4, 169.4, 170.0; MS (CI) 585
(M+H)+; HRMS (CI, isobutane) calculated for C34H52O6Si 585.3611,
found 585.3572.
1
Cephalostatin 7 (10): Rf ) 0.38 (1:10 MeOH/CH2Cl2); H NMR
(300 MHz, C6D6) δ 0.59 (3H, s), 0.61 (3H, s), 0.90 (3H, s), 1.00 (3H,
d, J ) 6.9 Hz), 1.03 (3H, d, J ) 6.9 Hz), 1.18 (3H, s), 1.19 (3H, s),
1.29 (3H, s), 2.4-2.7 (2H, m), 2.85-3.2 (3H, m), 2.44 (1H, s), 3.70
(1H, d, J ) 11 Hz), 3.76 (1H, s), 3.97 (1H, s), 4.08 (1H, dd, J ) 12.0,
5.2 Hz), 4.48 (1H, s), 4.82 (1H, s), 4.89 (1H, s), 5.39 (1H, s), 5.46
(1H, s). MS (FAB, NBA) 929 (M + H)+; HRMS (FAB, NBA)
Diols 17S/R. AD-mix-R (200 mg) was dissolved in t-BuOH (0.6
mL) and H2O (0.6 mL) at 25 °C. The clear orange solution was cooled
to 0 °C and olefin 13 (30 mg, 0.05 mmol) was added. After being
stirred for 16 h at 0 °C, the reaction mixture was quenched with Na2-
SO3 (220 mg) and H2O (2 mL) and then stirred for 1 h at 25 °C. The
mixture was extracted with CH2Cl2. The combined extract was washed
with brine followed by drying over MgSO4. After concentration, the
residue was purified by flash column chromatography on silica gel (1:6
EtOAc/hexanes to 1:3 EtOAc/hexanes) to provide 30 mg (95%) of
inseparable diastereomeric diols 17S and 17R (ratio; 2.5:1, based on
1H NMR integration of C26 methyl): Rf ) 0.06 (1:3 EtOAc/hexanes);
1H NMR of a mixture of diastereomeric diols 17S and 17R (C6D6, 300
MHz) δ 0.23 (s, 9H), 0.50 (s, 3H), 1.01 (R at C26) and 1.03 (S at C26)
(two s (ratio: 1:2.5), 3H), 1.24 (s, 3H), 1.69 (s, 3H), 1.88 (s, 3H),
3.13-3.24 (m, 2H), 4.64-4.78 (m, 1H), 5.19 (d, J ) 2.5 Hz, 1H),
5.35-5.41 (m, 2H); 13C NMR (C6D6, 50 MHz) δ 2.3*, 9.8*, 12.1*,
18.6*, 21.5*, 21.8*, 21.9, 23.9*, 27.8, 28.1, 28.5, 30.0, 34.6, 34.8*,
36.0, 36.6, 44.0*, 51.0*, 59.1, 70.5, 72.5, 73.6*, 74.4*, 94.5*, 99.5,
107.2, 118.3*, 155.4, 159.8, 159.9, 169.5, 170.1; MS (CI) 619 (M +
H)+; HRMS (CI, isobutane) calcd for C34H54O8Si 619.3666, found
619.3665.
calculated for C54H76N2O11 929.5527, found 929.5518. [R]23 +97 (
D
10° (c 0.03, MeOH); lit.2 [R]D +106° (c 0.244, MeOH).
Cephalostatin 12 (9): Rf ) 0.36 (1:10 MeOH/CH2Cl2);1H NMR
(300 MHz, C5D5N) δ 0.73 (6H, s, H19), 1.33 (6H, s, H18), 1.35 (6H, d,
J ) 7.2 Hz, H21), 1.64 (6H, s, H27), 2.35 (2H, J ) 11.4, H24a), 3.07
(2H, d, J ) 16.8 Hz, H1b), 3.71 (2H, dd, J ) 11.4, 4.8 Hz, H26a), 3.81
(2H, dd, J ) 11.2, 4.6 Hz, H26b), 4.04 (2H, dd, J ) 11.2, 4.6 Hz, H12),
4.71 (2H, br s, 12OH), 4.80 (2H, m, H23), 5.24 (2H, s, H16), 5.63 (2H,
s, H15), 6.25 (2H, s, H17), 6.60 (2H, br s, H26), 8.12 (2H, d, J ) 7.6 Hz,
23OH). MS (FAB, NBA) 945 (M + H)+; HRMS (FAB, NBA)
calculated for C54H76N2O12 945.5477, found 945.5411. [R]23D +151 (
10° (c 0.025, MeOH); lit.36 [R]D +157.5° (c 0.40, MeOH).
Ritterazine K (11): Rf ) 0.42 (1:10 MeOH/CH2Cl2);1H NMR (300
MHz, C6D6) δ 0.61 (6H, s, H19), 0.93 (6H, s, H27), 1.02 (6H, d, J )
6.9 Hz, H21), 1.19 (6H, s, H18), 2.53 (2H, d, J ) 16.8 Hz, H1b), 2.62
(2H, dd, m, H4b), 2.92 (2H, dd, J ) 17.8, 5.1 Hz, H4a), 3.03 (2H, br d,
J ) 11.4 Hz, H26b), 3.17 (2H, d, J ) 16.8 Hz, H1a), 3.49 (2H, s, OH),
3.72 (2H, d, J ) 11.3 Hz, H26a), 3.98 (2H, s, OH), 4.07 (2H, dd, J )
11.6, 5.1 Hz, H12), 4.91 (2H, s, H16), 5.40 (2H, s, H15);13C NMR (75
MHz, C6D6) δ 8.2 (C21), 11.8 (C19), 13.0 (C18), 27.0 (C27), 27.7 (C23),
28.3 (C6), 29.0 (C7), 29.2 (C11), 33.3 (C24), 34.0 (C8), 35.8 (C4), 36.3
(C10), 41.8 (C5), 46.0 (C1), 48.5 (C20), 52.9 (C9), 56.0 (C13), 65.8 (C25),
70.2 (C26), 75.7 (C12), 93.3 (C17), 93.7 (C16), 107.9 (C22), 120.0 (C15),
148.6 (C2), 148.9 (C3), 154.8 (C14); MS (FAB, NBA) 913 (M + H)+;
HRMS (FAB, NBA) calculated for C54H76N2O10 913.5578, found
Diastereomeric â-Nitro Alcohols 35. To a solution of aldehyde 2
(31 mg, 0.057 mmol) and nitro compound 34 (25 mg, 0.143 mmol)38
in i-PrOH (1 mL) was added KF (6.6 mg, 0.114 mmol) at 25 °C. After
being stirred for 12-24 h, the solution was concentrated and the residue
was subjected to flash column chromatography on silica gel (1:12 to
1:6 EtOAc/hexanes) to provide 28 mg (68%) of diastereomeric â-nitro
alcohols 35 along with 10 mg (32%) of recovered aldehyde 2 and 13
1
mg of nitro compound 34: Rf ) 0.42 (1:3 EtOAc/hexanes); H NMR
of one of the diastereomers (CDCl3, 300 MHz) δ 0.08 (s, 9H), 0.85 (s,
3H), 1.04 (s, 3H), 1.35 (s, 3H), 1.42 (s, 3H), 1.52 (s, 3H), 1.71 (s, 3H),
2.00 (s, 3H), 2.02 (s, 3H), 3.23 (d, J ) 10.9 Hz, 1H), 3.80 and 4.37
(two d, JAB ) 9.5 Hz, 1H each), 4.63-4.77 (m, 1H), 4.78 (d, J ) 3.2
Hz, 1H), 4.83 (dd, J ) 11.0, 3.1 Hz, 1H), 4.97 (d, J ) 1.9 Hz, 1H),
4.97-5.03 (m, 1H), 5.32 (br t, J ) 1.8 Hz, 1H); MS (EI) 719 (M)+;
HRMS (EI) calculated for C37H57NO11Si 719.3701, found 719.3715.
Diastereomeric r-Nitro Ketones 36. To a solution of R-nitro
alcohols 35 (375 mg, 0.52 mmol) in CH2Cl2 (25 mL) was added Dess-
Martin periodinane (553 mg, 1.30 mmol)14 at 25 °C. After 30 min, the
solution was concentrated, and the residue was dissolved in EtOAc
followed by washing with cold 5% aqueous NaOH solution and brine.
After drying over MgSO4 and concentration, column chromatography
on silica gel (1:8 EtOAc/Hex) provided 373 mg (quant) of 36: Rf )
0.51 (1:3 EtOAc/hexanes); 1H NMR (CDCl3, 300 MHz) δ 0.08 (s, 9H),
0.86 (s, 3H), 1.05 (s, 3H), 1.41 (s, 3H), 1.44 (s, 3H), 1.50 (s, 3H), 2.00
(s, 3H), 2.01 (s, 3H), 2.02 (s, 3H), 3.97 and 4.07 (two d, JAB ) 9.7 Hz,
1H each), 5.02 (dd, J ) 11.6, 4.7 Hz, 1H), 5.13 (d, J ) 2.6 Hz, 1H),
5.42 (t, J ) 2.2 Hz, 1H), 5.56 (s, 1H); MS (CI) 718 (M+H)+.
913.5566; [R]23 +83 ( 10° (c 0.1, MeOH); lit.35 [R]D +74° (c 0.1,
D
MeOH).
Xanthate 12. To a solution of alcohol 437 (700 mg, 1.17 mmol) in
CS2 (3 mL) and THF (3 mL) at 0 °C was added hexane-washed NaH
(140 mg, 5.85 mmol). 20 min later, MeI (0.3 mL, 4.82 mmol) and
TMEDA (0.8 mL) were added to the reaction mixture. After being
stirred for 1 h at 0 °C, the reaction mixture was concentrated, and the
residue was dissolved in EtOAc and H2O. The mixture was extracted
with EtOAc and dried over MgSO4. After concentration, the residue
was purified by flash column chromatography on silica gel (1:20 EtOAc/
hexanes) to provide 785 mg (97%) of xanthate 12: Rf ) 0.29 (1:8
EtOAc/Hex); 1H NMR (CDCl3, 300 MHz) δ 0.62 (s, 9H, OTMS), 0.84
(s, 3H), 0.97 (s, 3H), 1.71 (s, 3H), 1.77 (s, 3H), 1.99 (s, 3H), 2.01 (s,
3H), 2.52 (s, 3H, SCH3), 2.77 (dd, J ) 14.6, 8.8 Hz, 1H), 4.83 (brs,
2H), 4.98-5.03 (m, 2H), 5.39 (t, J ) 2.3 Hz, 1H), 6.38 (dd, J ) 8.7,
5.7 Hz, 1H); 13C NMR (C6D6, 75 MHz) δ 1.6*, 9.2*, 11.3*, 18.1*,
(36) Pettit, G. R.; Ichihara, Y.; Xu, J.-P.; Boyd, M. R.; Williams, M. D.
Bioorg. Med. Chem. Lett. 1994, 4, 1507.
(38) See Supporting Information for the preparation of nitro compounds
(37) For the preparation of 4, see the preceding paper.
34, 47a, and 47b.

Synthesis of the South Unit of Cephalostatin
J. Am. Chem. Soc., Vol. 121, No. 10, 1999 2081
Ketone 37. A solution of R-nitro ketone 36 (79 mg, 0.11 mmol)
and Ph3SnH (77 mg, 0.22 mmol) in degassed benzene (5 mL) was
heated at reflux for 1 h in the presence of AIBN. After concentration,
flash column chromatography on silica gel (4% to 10% EtOAc/hexanes)
provided 60 mg (81%) of ketone 37: Rf ) 0.30 (1:6 EtOAc/hexanes);
1H NMR (CDCl3, 300 MHz) δ 0.07 (s, 9H), 0.86 (s, 3H), 1.05 (s, 3H),
1.36 (s, 6H), 1.40 (s, 3H), 1.95 (s, 3H), 2.02 (s, 6H), 2.79 and 3.15
(two d, J ) 17.2 Hz, 1H each), 3.89 and 3.98 (two d, JAB ) 8.8 Hz,
1H each), 4.62-4.77 (m, 1H), 5.03 (dd, J ) 11.6, 4.3 Hz, 1H), 5.11
(br s, 1H), 5.42 (br s, 1H); 13C NMR (C6D6, 75 MHz) δ 1.3*, 11.1*,
11.3*, 11.7*, 20.7*, 20.9*, 25.1*, 26.9, 27.3*, 27.4, 27.7, 29.3, 33.8,
34.2*, 35.2, 35.9, 43.3*, 49.6, 50.2*, 58.7, 72.8*, 73.1*, 73.9, 79.4,
93.8*, 98.5, 108.6, 117.2*, 123.6, 149.3, 159.7, 168.6, 169.3, 194.1.
Diastereomeric Alcohols 38. To a solution of ketone 37 (53 mg,
0.079 mmol) in THF (2 mL) was added 2 M LiBH4 in THF (0.05 mL,
0.095 mmol) at 0 °C. The mixture was stirred for 1 h at 0 °C and
quenched with H2O followed by extraction with EtOAc. After drying
over MgSO4 and concentration, flash column chromatography on silica
gel (1:6 EtOAc/hexanes) provided 46 mg (87%) of diastereomeric
tography (10% EtOAc/hexanes; silica gel was treated with Et3N) to
give 196 mg (89%) of iodide 46b, stable at 25 °C.
Mesylate 46a: Rf ) 0.28 (25% EtOAc/hexanes); 1H NMR (300
MHz, CDCl3) δ 5.39 (1H, br t), 5.09 (1H, d), 5.01 (1H, dd), 4.74 (2H,
s), 4.68 (1H, m), 3.03 (3H, s), 2.03 (3H, s), 2.00 (3H, s), 1.72 (3H, s),
1.07 (3H, s), 0.84 (3H, s), 0.07 (9H, s).
Iodide 46b: Rf ) 0.22 (10% EtOAc/hexanes); 1H NMR (300 MHz,
CDCl3) δ 5.39 (1H, br t), 5.05 (1H, d), 4.99 (1H, dd), 4.66 (1H, m),
3.80 (2H, s), 2.00 (3H, s), 1.98 (3H, dd), 1.57 (3H, s), 1.02 (3H, s),
0.83 (3H, s), 0.07 (9H, s); 13C NMR (75 MHz, CDCl3) δ 170.6, 169.7,
159.7, 149.6, 117.2, 111.3, 98.1, 93.8, 73.8, 58.6, 50.5, 44.0, 36.6, 35.9,
34.4, 33.9, 29.5, 28.1, 27.3, 26.8, 21.6, 21.5, 17.6, 12.0, 9.6, 1.9; MS
(FAB, DTT/DTE) 567 (M + H - HOTMS); HRMS (FAB, DTT/DTE)
calcd for C27H46IO5 567.1608, found 567.1619.
C26 Alcohol 49. To an EtOAc (3 mL) solution of C26 benzyl ether
68 (18 mg, 0.026 mmol) was added Pd/C (5 mg (10%), ∼3% w/w).
The solution was stirred under hydrogen (1 atm) for 30 min, then filtered
through Celite. The filtrate was concentrated and purified by column
chromatography (35% EtOAc/hexanes) affording 16 mg (quant) of C26
1
1
alcohols 38: Rf ) 0.32 and 0.36 (1:3 EtOAc/hexanes); H NMR of
alcohol 49. Rf ) 0.20 (35% EtOAc/hexanes); H NMR (300 MHz,
one of the diastereomers (CDCl3, 300 MHz) δ 0.10 (s, 9H), 0.85 (s,
3H), 1.04 (s, 3H), 1.38 (s, 3H), 1.41 (s, 3H), 1.44 (s, 3H), 1.67 (s, 3H),
2.00 (s, 3H), 2.02 (s, 3H), 3.60 (br s, 1H), 3.79 and 3.87 (two d, JAB
) 8.5 Hz, 1H each), 4.63-4.75 (m, 2H), 5.00-5.08 (m, 2H), 5.39 (br
t, J ) 2.0 Hz, 1H).
CDCl3) δ 5.34 (1H, br t), 5.01 (1H, dd), 4.94 (1H, d, J ) 2.4 Hz), 4.68
(1H, m), 4.23 (2H, s), 3.03 (1H, br s), 2.58 (2H, m), 2.48 (2H, m),
2.02 (2H, s), 2.00 (3H, s), 1.59 (3H, s), 1.02 (3H, s), 0.85 (3H, s), 0.04
(9H, s); 13C NMR (75 MHz, CDCl3) δ 208.8, 170.7, 169.8, 159.3, 151.6,
117.3, 108.1, 98.4, 93.5, 73.9, 73.4, 68.3, 58.2, 50.6, 44.1, 36.6, 35.9,
34.8, 34.3, 33.9, 29.8, 29.5, 28.1, 27.4, 27.0, 21.6, 21.5, 20.7, 17.9,
12.0, 9.1, 1.7. MS (EI) 602 (M+, base peak); MS (CI) 603 (M + H),
513 (M + H - HOTMS, base peak); HRMS (EI) calcd for C33H50O8-
Si 602.3275, found 602.3247.
Acetonide 40. To a solution of diastereomeric alcohols 38 (209 mg,
0.31 mmol) in CS2 (3 mL) and THF (3 mL) was added NaH (60%
dispersion in mineral oil, 50 mg, 1.2 mmol) at 0 °C. 30 min later,
TMEDA (1 mL) and MeI (0.5 mL, 8 mmol) were added at 0 °C. After
being stirred for 2 h at 0 °C, the mixture was concentrated and the
residue was dissolved in EtOAc and H2O. The mixture was extracted
with EtOAc, and then dried over MgSO4. After concentration, flash
column chromatography on silica gel (1:18 EtOAc/hexanes) provided
220 mg of inseparable diastereomeric xanthates 39 (91%): 1H NMR
(partial) of a mixture of two diastereomeric xanthates (CDCl3, 300 MHz)
δ 0.028 and 0.033 (2 s, TMS), 2.54 and 2.55 (2 s, SMe), 3.68 (dd, J
) 18.4, 8.6 Hz), 3.86 (dd, J ) 8.6, 6.2 Hz), 4.60-4.78 (m, 1H), 4.95-
5.05 (m, 1H), 6.30-6.44 (m, 1H).
6,5-Spiroketal 50. To a benzene (1 mL) solution of C26 alcohol 49
(8.6 mg, 0.014 mmol) was added CSA (0.6 mg, 0.026 mmol). After
the mixture was stirred for 4.5 h, Na2CO3 (solid, 10 mg) was added.
Benzene was evaporated to give a yellow residue, which was purified
by column chromatography (20% EtOAc/hexanes) affording 2.8 mg
(33%) of desired spiroketal 50 as a single diastereomer and 4 mg (47%)
1
of starting material. Rf ) 0.31 (20% EtOAc/hexanes); H NMR (300
MHz, CDCl3) δ 5.42 (1H, br t), 4.95 (1H, dd), 4.70 (1H, m), 4.69 (1H,
d), 4.19 (1H, d), 3.92 (1H, d), 2.70 (1H, m), 2.49 (1H, m), 2.27 (1H,
m), 2.02 (3H, s), 1.97 (3H, s), 1.15 (3H, s), 0.89 (3H, d), 0.86 (3H, s),
0.09 (9H, s); 13C NMR (75 MHz, CDCl3) δ 208.0, 170.7, 169.9, 160.7,
116.4, 107.8, 93.0, 90.5, 74.0, 73.4, 67.3, 56.4, 50.6, 46.5, 44.0, 36.8,
35.8, 35.0, 34.9, 33.9, 31.4, 30.4, 29.8, 29.5, 28.1, 27.4, 26.5, 21.5,
21.4, 20.3, 12.0, 9.2, 2.3; MS (EI) 602 (M+), 544 (M - CO2CH2); MS
(CI) 603 (M + H), 453 (M + H - HOAc - HOTMS, base peak);
HRMS (EI) calcd for C33H50O8Si 602.3275, found 602.3287.
Alcohols 51 and 72 from Ketone 50. To a Et2O (0.5 mL) solution
of LiClO4 (0.1 M) at -78 °C was added in one portion C25 ketone (2.8
mg, 0.0046 mmol), followed by MeLi in ether (8.7 µL (0.8 M), 0.0070
mmol). The solution was stirred for 10 min, then quenched by addition
of saturated NH4Cl solution (1 mL). The aqueous layer was extracted
with Et2O (2 × 10 mL). The combined organic layers were washed
with brine (10 mL), dried over MgSO4, and concentrated. Column
chromatography (25% EtOAc in hexanes) afforded 1.5 mg (52%) of
undesired C25 (R) alcohol 72, 0.3 mg (10%) of desired C25 (S) alcohol
51, and 0.9 mg (32%) of starting material 50.
A solution of xanthates 39 (155 mg, 0.20 mmol), Ph3SnH (470 mg,
1.34 mmol) and 2,2′-azobiscyclohexylnitrile (3 mg, 0.01 mmol) in
toluene was heated at reflux (the oil bath was preheated at 135 °C).
After 20 min, the solution was cooled to 25 °C and concentrated under
reduced pressure. Flash column chromatography (2% to 8% EtOAc/
hexanes) on silica gel provided 119 mg (90%) of the desired product
1
40: Rf ) 0.50 (1:3 EtOAc/hexanes); H NMR (CDCl3, 300 MHz) δ
0.06 (s, 9H), 0.85 (s, 3H), 1.05 (s, 3H), 1.28 (s, 3H), 1.40 (s, 3H), 1.58
(s, 3H), 1.73 (s, 3H), 2.00 (s, 3H), 2.02 (s, 3H), 3.71 and 3.81 (two d,
JAB ) 8.4 Hz, 1H each), 4.61-4.73 (m, 1H), 4.96 (d, J ) 2.0 Hz, 1H),
5.03 (dd, J ) 11.6, 4.7 Hz, 1H), 5.37 (br t, J ) 1.9 Hz, 1H); 13C NMR
(C6D6, 75 MHz) δ 1.5*, 9.1*, 11.4*, 17.8*, 20.8*, 21.0*, 21.8, 24.3*,
27.1*, 27.1, 27.2*, 27.4, 27.8, 29.3, 33.9, 34.1*, 35.3, 35.9, 36.6, 43.4*,
50.3*, 58.4, 72.8*, 73.7*, 74.0, 80.3, 93.7*, 98.9, 106.0, 108.9, 117.8*,
154.7, 158.7, 168.7, 169.2; MS (CI) 659 (M + H)+; HRMS (EI)
calculated for C37H58O8Si 658.3901, found 658.3894.
C26 Iodide 46b. To aldehyde 2 (280 mg, 0.51 mmol) in THF (10
mL) was added slowly at -25 °C LiBH4 (0.51 mmol) in THF (0.26
mL, 2 M). After 5 min, the reaction was quenched by addition of
saturated NH4Cl solution (5 mL). The mixture was extracted with CH2-
Cl2 (3 × 30 mL). The combined organic layers were washed with brine
(3 × 30 mL), dried over MgSO4, and concentrated. The crude product
58 (∼300 mg) was dissolved in CH2Cl2 (4 mL) and cooled to 0 °C
and Et3N (95 µL, 0.68 mmol) and MsCl (32 µL, 0.41 mmol) were
added. After being stirred for 10 min, ice-cold saturated NaHCO3
solution (10 mL) was added. The resulting mixture was extracted with
CH2Cl2 (3 × 30 mL). The combined organic layers were washed with
brine (3 × 30 mL) and concentrated. The residue was passed through
a short pad of silica gel (deactivated by Et3N, 10% EtOAc/hexanes) to
give 260 mg (80% for two steps) of the desired mesylate 46a (slowly
decomposed at 25 °C). To the mesylate 46a (21 mg, 0.32 mmol) in
acetone (20 mL) at 0 °C was added NaI (58 mg, 0.38 mmol). After 30
min, the solution was concentrated and purified by column chroma-
Desired C25 (S) alcohol 51 (less polar): identical to that obtained
from the CSA catalyzed cyclization of the diols 17S/R.
Undesired C25 (R) alcohol 72 (more polar): Rf ) 0.20 (25% EtOAc/
hexanes); 1H NMR (300 MHz, C6D6) δ 5.32 (1H, br s), 5.17 (1H, dd,
J ) 11.2, 4.7 Hz), 4.77 (1H, br s), 4.66 (1H, m), 3.72 (1H, d, J ) 11
Hz), 3.19 (1H, m), 2.32 (1H, q, J ) 6.4 Hz), 1.75 (3H, s), 1.70 (3H,
s), 1.15 (3H, s), 1.12 (3H, s), 1.00 (3H, d, J ) 6.5 Hz), 0.48 (3H, s),
0.28 (9H, s).
Adduct 61. To a DMSO (6.4 mL) solution of MOM-protected
â-ketosulfone 47a (165 mg, 0.64 mmol)38 was added NaH (60% in
mineral oil, 26 mg, 0.64 mmol) in one portion. The mixture was stirred
for 15 min, then iodide 46b (105 mg, 0.16 mmol) was added. After
0.5 h, the reaction was quenched by addition of ice-cold H2O (2 mL).
The aqueous layer was extracted with CH2Cl2 (3 × 30 mL). The
combined organic layers were washed with brine (3 × 30 mL) and
H2O (30 mL), dried over MgSO4, and concentrated. Column chroma-

2082 J. Am. Chem. Soc., Vol. 121, No. 10, 1999
Jeong et al.
tography (20% EtOAc/hexanes) gave 5.6 mg (5%) of recovered iodide
R-73: Rf ) 0.38 (1:3 EtOAc/hexanes); 1H NMR of a mixture of major
spiroketals 51, S-73, and R-73 (C6D6, 300 MHz) δ 0.34 (s), 0.52 (s),
0.99 (s), 1.14 (s), 1.75 (s), 1.80 (s), 3.20-3.50 (m), 4.60-4.78 (m),
4.70, 4.79, and 4.80 (three brs), 5.10-5.41 (m, 2H).
46b and 107 mg (86%) of desired adduct 61 (two diastereomers). Rf )
1
0.28 (20% EtOAc/hexanes); H NMR (300 MHz, CDCl3) (selected
peaks) δ 7.9-7.5 (phenyl H’s, m), 5.32 and 5.27 (H-15, two br s),
4.91 and 4.85 (H-16, two d), 4.64-4.60 (CH2 (MOM), two s), 3.40
and 3.37 (Me (MOM), two s), 2.73 (23-CH2, m), 2.01 (3H, s), 1.98
(3H, two s), 1.53 and 1.50 (21-Me, two s), 0.02 and -0.02 (TMS, two
s); MS (FAB, DTT/DTE) 786 (M+).
Isolation of 6,5-Spiroketal 51 from a Mixture of Spiroketals 51/
S-73/R-73. To a solution of spiroketals 51, S-73, and R-73 (555 mg,
0.9 mmol) in dry DMF (9 mL) were added TBDMSCl (677 mg, 4.5
mmol) and imidazole (1.06 g, 6.28 mmol) at 25 °C. The mixture was
stirred for 10 h at 25 °C, followed by addition of ether (50 mL). The
solution was washed with 5% aqueous HCl solution, saturated aqueous
NaHCO3 solution, and brine and dried over MgSO4. After evaporation,
flash column chromatography on silica gel (1:16 to 1:6 EtOAc/hexanes)
provided 180 mg (32%) of 6,5-spiroketal 51 along with a mixture of
5,5-spiroketals S-74 and R-74 (0.5 g) which have a C26 TBDMS ether:
MOM Ether 62. To a THF solution of SmI2 (7.5 mL (0.1 M), 0.75
mmol) at -78 °C, was added dropwise â-ketosulfone 61 (107 mg, 0.14
mmol) in 1:1 THF/MeOH (degassed, 0.5 mL). After 5 min at -78 °C,
the solution was poured into saturated NaHCO3 (20 mL) solution. The
mixture was extracted with CH2Cl2 (3 × 25 mL). The combined organic
layers were then washed with saturated NaHCO3 (2 × 25 mL), dried
over MgSO4, and concentrated. The residue was purified by column
chromatography (20% EtOAc/hexanes) to give 51 mg (58%) of desired
desulfonylation product 62 and 26 mg (33%) of overreduction product
63.
1
Compound 51: Rf ) 0.38 (1:3 EtOAc/hexanes); H NMR (C6D6, 300
MHz) δ 0.35 (s, 9H), 0.52 (s, 3H), 0.99 (s, 3H), 1.05 (d, J ) 7.2 Hz,
3H), 1.14, (s, 3H), 1.75 (s, 3H), 1.80 (s, 3H), 3.25 (dd, J ) 11.4, 2.3
Hz, 1H), 3.76 (d, J ) 11.3 Hz, 1H), 4.65-4.78 (m, 1H), 4.80 (d, J )
2.0 Hz, 1H), 5.22 (dd, J ) 11.6, 4.6 Hz, 1H), 5.39 (t, J ) 2.1 Hz, 1H);
MS (CI) 619 (M + H)+; HRMS (EI) calculated for C34H54O8Si
618.3588, found 618.3600.
1
MOM ether 62: Rf ) 0.33 (20% EtOAc/hexanes); H NMR (300
MHz, CDCl3) δ 5.37 (1H, br s), 5.00 (1H, dd), 4.93 (1H, br d), 4.68
(2H, s), 4.68 (1H, m), 4.18 (2H, s), 3.39 (3H, s), 2.60 (2H, m), 2.40
(2H, m), 2.00 (3H, s), 1.99 (3H, s), 1.59 (3H, s), 1.01 (3H, s), 0.82
(3H, s), 0.04 (9H, s); 13C NMR (75 MHz, CDCl3) δ 206.7, 170.7, 169.8,
159.2, 152.2, 117.4, 107.7, 98.4, 96.5, 93.5, 73.9, 73.4, 72.2, 58.2, 55.8,
50.6, 44.1, 36.6, 35.8, 35.4, 34.3, 33.9, 29.5, 28.1, 27.3, 26.9, 21.6,
21.5, 20.3, 17.8, 12.0, 9.1, 1.7; MS (FAB, DTT/DTE) 646 (M+); HRMS
(FAB, DTT/DTE) calcd for C35H54O9Si 646.3537, found 646.3524.
Preparation of Crystals of 76, S-75, and R-75 for X-ray
Determination. General Procedure: Individual samples of spiroketals
51 or the mixture of S-74 and R-74 with 15 equiv of TBAF in THF
were heated at reflux for 2-4 h. After concentration, the residue was
dissolved in EtOAc. The organic layer was washed with saturated
aqueous NH4Cl (2×) and brine, and dried over MgSO4. After filtration
and evaporation, silica gel chromatography gave 76 (1:3 EtOAc/
hexanes), S-75 (1:30 THF/CH2Cl2), and R-75 (1:30 THF/CH2Cl2) each
in 80-90%. All three alcohols 76, S-75, and R-75 were separately
crystallized from a CH2Cl2/hexanes solution (started at 1:2 (v/v), and
slowly evaporated).
1
Compound 63: Rf ) 0.47 (20% EtOAc/hexanes); H NMR (300
MHz, CDCl3) δ 5.37 (1H, br s), 5.00 (1H, dd), 4.93 (1H, br s), 4.69
(1H, m), 2.60 (2H, t), 2.13 (3H, s), 2.01 (3H, s), 1.99 (3H, s), 1.60
(3H, s), 1.02 (3H, s), 0.83 (3H, s), 0.03 (9H, s); 13C NMR (75 MHz,
CDCl3) δ 207.9, 170.7, 169.8, 159.2, 152.2, 117.4, 107.5, 98.4, 93.5,
73.9, 73.4, 58.2, 50.6, 44.1, 39.9, 36.6, 35.9, 34.3, 33.9, 30.0, 29.5,
28.1, 27.4, 27.0, 21.6, 21.5, 20.8, 17.9, 12.0, 9.1, 1.7; MS (FAB, DTT/
DTE) calcd for C33H50O7Si 586.3326, found 586.3313.
Compound 76: Rf ) 0.18 (1:1 EtOAc/hexanes); 1H NMR (C5D5N,
300 MHz) δ 0.75 (s, 3H), 1.22 (s, 3H), 1.27 (d, J ) 7.3 Hz, 3H), 1.30
(s, 3H), 2.03 (s, 3H), 2.54 (dt, J ) 11.7, 1.6 Hz, 1H), 4.00 (d, J ) 12.2
Hz, 1H), 4.12 (dd, J ) 8.4, 2.1 Hz, 1H), 4.64 (s, 1H, OH), 4.79 (m,
1H), 5.06 (s, 1H, OH), 5.14 (s, 1H), 5.58 (s, 1H), 5.71 (s, 1H, OH);
mp 186-187 °C dec.
Ketosulfone 67. Following the procedure for making 61, adduct 67
was obtained in 91% yield and 40% â-ketosulfone 47b38 was recovered.
Benzyl sulfone 67 (two diastereomers): Rf ) 0.30 (20% EtOAc/
hexanes); 1H NMR (300 MHz, CDCl3) (selected peaks) δ 8.0-7.5 (5H,
m), 7.37 (5H, m), 5.20 (H-15, br t), 4.88 and 4.80 (H-16, two d), 2.80
(2H, t), 2.63 (2H, br t), 2.01 (3H, two s), 1.98 (3H, two s), 1.53 and
1.48 (21-Me, two s), 0.98 and 0.89 (18-Me, two s), 0.83 and 0.79 (19-
Me, two s), 0.02 and -0.03 (TMS, two s); MS (FAB, DTT/DTE) 833
(M+ + H).
Compound S-75: Rf ) 0.36 (1:10 THF/CH2Cl2);1H NMR (C6D6,
300 MHz) δ 0.59 (s, 3H), 0.83 (s, 3H), 0.89 (d, J ) 6.8 Hz, 3H), 1.18
(s, 3H), 1.75 (s, 3H), 3.27 (brs, 1H), 3.37 and 3.51 (two d, JAB )
11.2 Hz, 1H), 3.85-4.00 (m, 1H), 4.70-4.83 (m, 1H), 4.84 (s, 1H),
5.21 (s, 1H); mp 203-204 °C dec.
1
Compound R-75: Rf ) 0.25 (1:10 THF/CH2Cl2); H NMR (C6D6,
300 MHz) δ 0 60 (s, 3H), 0.98 (d, J ) 6.9 Hz, 3H), 1.21 (s, 3H), 1.31
(s, 3H), 1.74 (s, 3H), 3.15-3.23 (m, 2H), 3.62 (brs, 1H), 4.02-4.07
(m, 1H), 4.75-4.81 (m, 1H), 4.97 (s, 1H), 5.38 (s, 1H); mp 215-216
°C dec.
Ketone 68. To a THF (1 mL) suspension of Sm (Aldrich, 27 mg,
0.22 mmol) was added in one portion at 25 °C 1,2-diiodoethane (31
mg, 0.11 mmol). After 1 h, the suspension turned into a deep blue
solution, which was cooled to -78 °C. â-Ketosulfone 67 (30 mg, 0.036
mmol) in 1:1 THF/MeOH (degassed, 0.5 mL) solution was added
dropwise. After 1 min, the solution was poured into saturated NaHCO3
(30 mL). The aqueous layer was extracted with CH2Cl2 (3 × 25 mL).
The combined organic layers were washed with saturated NaHCO3 (2
× 25 mL), dried over MgSO4, and concentrated. Column chromatog-
raphy (20% EtOAc/hexanes) gave 21.5 mg (86%) of desired desulfo-
nylation product 68 and 2.5 mg (8%) of overreduction product 63.
C3 Alcohol 77. A solution of diacetate 51 (102 mg, 0.165 mmol)
and KHCO3 (41 mg, 0.412 mmol) in MeOH (1.6 mL) and H2O (0.4
mL) was heated at reflux for 1 h. After the MeOH was removed, the
mixture was neutralized with saturated aqueous NH4Cl solution and
extracted with CH2Cl2. The combined extract was washed with H2O
and brine and dried over MgSO4. After evaporation, flash column
chromatography on silica gel (1:6 EtOAc/hexanes) provided 95 mg
(quant) of alcohol 77: Rf ) 0.12 (1:3 EtOAc/hexanes); 1H NMR (C6D6,
300 MHz) δ 0.32 (s, 9H), 0.55 (s, 3H), 0.99 (s, 3H), 1.04 (d, J ) 7.2
Hz, 3H), 1.16, (s, 3H), 1.80 (s, 3H), 1.80 (s, 3H), 3.20-3.30 (m, 2H),
3.75 (d, J ) 11.3 Hz, 1H), 3.75 (d, J ) 11.3 Hz, 1H), 4.79 (d, J ) 2.2
1
Benzyl ether 68: Rf ) 0.30 (20% EtOAc in hexanes); H NMR (300
MHz, CDCl3) δ 7.33 (5H, m), 5.33 (1H, t, J ) 2 Hz), 5.03 (1H, dd, J
) 11.4, 4.5 Hz), 4.93 (1H, J ) 2 Hz), 4.68 (1H, m), 4.58 (2H, s), 4.06
(2H, s), 2.63 (2H, m), 2.41 (2H, m), 2.02 (3H, s), 2.00 (3H, s), 1.59
(3H, s), 1.02 (3H, s), 0.85 (3H, s), 0.04 (9H, s); 13C NMR (75 MHz,
CDCl3) δ 207.6, 170.7, 169.8, 159.1, 152.2, 137.2, 128.6*, 128.1*,
127.9*, 117.4*, 107.6, 98.4, 93.4*, 75.0, 73.9*, 73.4(2, o), 58.2, 50.5*,
44.0*, 36.5, 35.8, 35.4, 34.2*, 33.8, 29.5, 28.1, 27.3, 26.9, 21.6*, 21.5*,
20.3, 17.8*, 11.9*, 9.1*, 1.7*; MS (FAB, DTT/DTE) 692 (M+); HRMS
(FAB, DTT/DTE) calcd for C40H57O8Si 693.3823, found 693.3816.
Spiroketals 51, S-73, and R-73. To a solution of the mixture of
diols 17S/R (618 mg, 1.0 mmol) in CH2Cl2 was added (+)-CSA (23
mg, 0.1 mmol) at 25 °C. The mixture was stirred for 1 h at 25 °C and
quenched with solid Na2CO3 (1 g). After filtration and concentration,
flash column chromatography on silica gel (1:6 EtOAc/hexanes)
provided 555 mg (90%) of inseparable major spiroketals 51, S-73, and
Hz, 1H), 5.23 (dd, J ) 11.6, 4.6 Hz, 1H), 5.40 (t, J ) 2.3 Hz, 1H); 13
C
NMR (C6D6, 75 MHz) δ 2.3*, 9.2*, 11.7*, 19.9*, 20.8*, 25.4*, 26.7,
28.2, 29.6, 31.5, 32.6, 34.8*, 35.5, 36.7, 38.0, 44.0*, 46.6*, 50.9*, 56.3,
66.1, 68.8, 70.3*, 70.9*, 74.0*, 89.9*, 93.2, 107.8, 117.1*, 159.5, 169.2.
C3 Keto Alcohol 78. To a solution of alcohol 77 (95 mg, 0.165
mmol) in ether (5 mL) was added chromic acid solution (0.3 mL, 0.18
mmol). After the solution was stirred for 30 min at 25 °C, H2O and
ether were added and the mixture was extracted with ether. The
combined extract was washed with saturated aqueous NaHCO3 solution
and brine and dried over MgSO4. After evaporation, flash column
chromatography on silica gel (1:6 EtOAc/hexanes) provided 86 mg
(91%) of ketone 78: Rf ) 0.20 (1:3 EtOAc/hexanes); 1H NMR (C6D6,

Synthesis of the South Unit of Cephalostatin
J. Am. Chem. Soc., Vol. 121, No. 10, 1999 2083
300 MHz) δ 0.32 (s, 9H), 0.46 (s, 3H), 0.98 (s, 3H), 1.04 (d, J ) 7.2
Hz, 3H), 1.14, (s, 3H), 1.80 (s, 3H), 2.23 (q, J ) 7.0 Hz, 1H), 3.24
(dd, J ) 11.3, 2.6 Hz, 1H), 3.75 (d, J ) 11.3 Hz, 1H), 4.78 (d, J ) 2.1
34.1*, 33.9, 33.0, 29.3, 27.8, 27.4, 27.1, 21.0*, 20.8*, 20.2*, 20.1, 17.9*,
13.9*, 11.3*, 9.1*, 1.6*.
C3,26 Diols 87S/R. To an aqueous MeOH (32 mL, 12% H2O) solution
of MTM ethers 86S/R (460 mg, 0.64 mmol) was added in one portion
KHCO3 (160 mg, 1.6 mmol). The solution was heated at reflux for 2
h, then cooled to 25 °C. The suspension was concentrated and extracted
with CH2Cl2 (3 × 35 mL). The combined organic layers were washed
with brine (2 × 30 mL), dried over MgSO4, and concentrated. Filtration
through a short pad (3 in) of silica gel (40% EtOAc/hexanes) gave
404 mg (quant) of desired diols 87S/R. Rf ) 0.18 (40% EtOAc/
hexanes); 1H NMR (300 MHz, C6D6) δ 5.38 (1H, br t), 5.32 (1H, dd),
5.13 (1H, br d), 4.32 (2H, AB), 3.34 (2H, s), 3.29 (1H, m), 2.63 (1H,
br s), 2.21 (2H, t), 1.84 (3H, s), 1.82 (3H, s), 1.63 (3H, s), 1.19 (3H,
s), 0.97 (3H, s), 0.54 (3H, s), 0.17 (9H, s); 13C NMR (75 MHz, C6D6)
δ 168.9, 159.0, 154.7, 117.7*, 106.2, 98.8, 93.7*, 78.8, 73.9*, 70.5*,
66.9, 66.4, 58.4, 50.6*, 43.9*, 38.0, 36.5, 35.5, 34.2*, 32.4, 31.5, 29.5,
28.1, 27.2, 21.1*, 21.0, 19.9*, 19.8*, 17.9*, 11.6*, 9.2*, 1,6*.
6,5-Spiroketals 88S/R. To a CH2Cl2 (20 mL) solution of diols 87S/R
(285 mg, 0.29 mmol) was added CSA (6.8 mg, 0.0291 mmol). The
solution was stirred for 1 h at 25 °C, then quenched by addition of
Na2CO3 (30 mg), and CH2Cl2 was removed by evaporation. Column
chromatography (30% EtOAc/hexanes) afforded 258 mg (91%) of 6,5-
spiroketals 88S/R and 25 mg (9%) of starting materials 87S/R. Rf )
Hz, 1H), 5.18 (dd, J ) 11.6, 4.6 Hz, 1H), 5.36 (t, J ) 2.3 Hz, 1H); 13
C
NMR (C6D6, 75 MHz) δ 2.3*, 9.2*, 10.4*, 19.9*, 20.8*, 25.3*, 26.8,
28.0, 28.2, 29.0, 32.6, 34.5*, 35.2, 37.5, 44.0, 44.8*, 46.6*, 50.1*, 56.3,
66.0, 68.8, 73.6*, 89.9*, 93.1, 107.8, 117.4*, 158.8, 169.0, 208.2; MS
(CI) 575 (M + H)+; HRMS (EI) calculated for C32H50O7Si 574.3326,
found 574.3320.
MTM Ether 79. To a solution of keto alcohol 78 (25 mg, 0.0435
mmol) in DMSO (0.25 mL) was added Ac2O (0.18 mL) at 25 °C. After
19 h at 25 °C, the mixture was poured into cold saturated aqueous
NaHCO3 solution and extracted with ether. The combined extract was
washed with saturated aqueous NaHCO3 solution, H2O, and brine. After
drying over MgSO4 and concentration, flash column chromatography
on silica gel (1:7 EtOAc/hexanes) provided 28 mg (quant) of MTM
ether 79: Rf ) 0.22 (1% THF/CH2Cl2); 1H NMR (300 MHz, C6D6) δ
5.39 (1H, t, J ) 2.3 Hz), 5.19 (1H, dd, J ) 11.7, 4.6 Hz), 4.82 (1H, d,
J ) 2.3 Hz), 4.44 and 4.36 (1H each, two d, JAB)10.5 Hz), 3.63 (1H,
dd, J ) 12.2, 2.2 Hz), 3.56 (1H, d, J ) 12.2 Hz), 2.10 (3H, s), 1.80
(3H, s), 1.17 (3H, s), 1.09 (3H, d, J ) 7.2 Hz), 0.82 (3H, s), 0.46 (3H,
s), 0.33 (9H, s); 13C NMR (75 MHz, C6D6) δ 207.6, 168.9, 158.8, 117.5,
107.8, 93.2, 89.8, 73.6, 71.6, 66.9, 64.5, 56.3, 50.2, 46.6, 44.8, 44.0,
37.5, 37.5, 35.2, 34.5, 31.3, 29.0, 28.0, 26.8, 21.2, 20.8, 19.9, 13.9,
10.4, 9.2, 2.3; MS (EI) 634 (M+); MS(CI) 635 (M + H, base peak),
545 (M + H - HOTMS); HRMS (EI) calcd for C34H54O7SSi 634.3360;
found 634.3347.
1
0.21 (30% EtOAc/hexanes); H NMR (300 MHz, C6D6) δ 5.42, 5.38
and 5.34 (H-15, three br t), 5.2-5.0 (H-12, m), 4.85 and 4.76 (H-16,
two br s), 4.36, 4.35, and 4.35 (CH2 (MTM), one br s and two AB),
4.1-2.8 (26-CH2, m), 2.04, 2.00, and 1.90 (Me (MTM), three s), 1.77
(12-OAc, three s), 0.57 (19-Me, two s), 0.20 (TMS, 3 s); 13C NMR
(75 MHz, C6D6, major spiroketal) δ 171.0, 159.4, 117.1, 107.8, 89.9,
73.9, 71.6, 70.3, 66.9, 64.5, 56.3, 50.9, 46.7, 38.0, 36.6, 35.4, 34.8,
31.5, 31.3, 29.6, 28.1, 28.0, 26.8, 21.2, 20.0, 11.7, 9.3, 2.3; MS (FAB,
DTT/DTE) 637 (M + H); HRMS (FAB, DTT/DTE) calcd for C34H57O7-
SSi 637.3594, found 637.3581.
Bromide 80. To a solution of MTM ether 79 (32 mg, 0.05 mmol)
in THF (2 mL) was added phenyltrimethylammonium tribromide
(PTAB, 24 mg, 0.064 mmol) at 0 °C. After being stirred for 20 min at
0 °C, the mixture was quenched with brine and extracted with ether.
The combined extract was washed with saturated aqueous NaHCO3
solution and brine and dried over MgSO4. After evaporation, flash
column chromatography on silica gel (1:8 EtOAc/hexanes) provided
25 mg (82%) of bromide 80: Rf ) 0.16 (1:3 EtOAc/hexanes); 1H NMR
(C6D6, 300 MHz) δ 0.31 (s, 9H), 0.31 (s, 3H), 0.98 (s, 3H), 1.03 (d, J
) 7.2 Hz, 3H), 1.10 (s, 3H), 1.80 (s, 3H), 2.23 (dd, J ) 12.6, 6.2 Hz,
1H), 2.33 (q, J ) 7.1 Hz, 1H), 3.24 (dd, J ) 11.3, 2.6 Hz, 1H), 3.74
(d, J ) 11.3 Hz, 1H), 4.10 (dd, J ) 13.4, 6.2 Hz, 1H), 4.77 (d, J ) 2.4
C3 Ketones (79/89/90). To a pyridine/CH2Cl2 (0.8 mL/2 mL) solution
was added in one portion CrO3 (53 mg, 0.53 mmol). After 20 min, the
C3 alcohol (75 mg, 0.12 mmol) in CH2Cl2 (1 mL) was added dropwise.
The suspension was stirred for 2.5 min, then quenched with ice-cold
saturated Na2SO3 (5 mL). The mixture was diluted with Et2O (100 mL),
washed with brine (2 × 30 mL), dried over MgSO4, and concentrated.
Column chromatography (20% EtOAc/hexanes) gave 58 mg (77%) of
C3 ketones 79/89/90 and 11 mg (15%) of starting materials 88S/R. C3
Hz, 1H), 5.15 (dd, J ) 11.6, 4.6 Hz, 1H), 5.32 (t, J ) 2.3 Hz, 1H); 13
C
NMR (C6D6, 75 MHz) δ 2.3*, 9.1*, 10.8*, 19.8*, 20.7*, 25.1*, 26.8,
27.4, 28.2, 28.6, 32.6, 34.0*, 38.3, 43.2, 45.0*, 46.7*, 49.5*, 50.0, 53.6*,
56.2, 65.9, 68.9, 73.2*, 89.9*, 89.9*, 93.1, 107.7, 158.2, 168.8, 197.9;
MS (EI) 652/654 (M)+; HRMS (EI) calculated for C32H49BrO7Si
652.2431, found 652.2464.
1
ketones (mixture of 79/89/90) Rf ) 0.30 (20% EtOAc/hexanes); H
NMR (300 MHz, C6D6) (selected peaks) δ 5.33 and 5.26 (H-15, two
br t), 4.84, 4.76, and 4.74 (H-16, three br s), 2.02, 2.00, and 1.89 (Me
of MTM, three s), 1.79 (OAc, two s), 0.21 (TMS, three s).
Equilibration and Separation of Spiroketals 79/89/90. A mixture
of 6,5-spiroketals 79/89/90 (255 mg, 0.40 mmol) was subjected to
column chromatography (CH2Cl2/THF: 200:1 to 100:1) to give 90 mg
of pure desired (20S,22R,25S) spiroketal 79 and 155 mg of other
spiroketals, which were treated with CSA (10 mol %) in CH2Cl2 (15
mL) for 1 h. The resulting crude spiroketals were purified by column
chromatography (CH2Cl2/THF: 200:1 to 100:1) to give 56 mg of (20S,
22R,25S) spiroketal 79, 65 mg of (20S,22R,25R) spiroketal 90, and 25
mg of (20R,22S,25S) spiroketal 89. Compound 89 could be converted
into 79 (20 mg) upon another treatment with CSA in CH2Cl2. Therefore,
the (20S,22R,25S) spiroketal 79 (166 mg) and its C25 epimer 90 (65
mg) were obtained in 65 and 25% yield, respectively (ca 2.5:1).
Compound 79: Identical to 79 prepared from 78.
C26 Acetates 85S/R from Diols 17S/R. To a pyridine/CH2Cl2 (2
mL, 1:2) solution of diols 17S/R (100 mg, 0.16 mmol) at 0 °C was
added DMAP (1 mg), followed by Ac2O (0.25 mL). After 20 min, the
solution was diluted with CH2Cl2 (20 mL), washed with saturated
NaHCO3 (3 × 10 mL), dried over MgSO4, and concentrated. Column
chromatography (15% EtOAc/hexanes) afforded 107 mg (quant) of C26
acetates 85S/R, with nearly identical spectra. Rf ) 0.21 (15% EtOAc/
hexanes); 1H NMR (300 MHz, C6D6) δ 5.34 (1H, br s), 5.32 (1H, dd),
5.13 (1H, d), 4.65 (1H, m), 3.87 (2H, s), 1.83 (3H, s), 1.68 (3H, s),
1.64 (3H, s), 1.58 (3H, s), 1.19 (3H, s), 0.96 (3H, s), 0.45 (3H, s), 0.18
(9H, s); 13C NMR (75 MHz, C6D6) δ 169.9, 169, 168.7, 159.0, 154.4,
117.6*, 106.5, 98.8, 73.7*, 72.9*, 70.7, 58.4, 50.3*, 43.4*, 36.0, 35.6,
35.3, 34.1*, 33.9, 29,3, 27.8, 27.4, 27.1, 23.8*, 21.0*, 21.0, 20.8*, 20.0*,
17.9*, 11.4*, 9.1*, 1.6*.
C25 MTM Ethers 86S/R. To a DMSO (4 mL) solution of C25 alcohol
85S/R (450 mg, 0.68 mmol) was added Ac2O (2 mL). After 15 h at 25
°C, the solution was diluted with Et2O (100 mL), washed with saturated
NaHCO3 solution (2 × 35 mL) and brine (40 mL), dried over MgSO4,
and concentrated. Column chromatography (10% EtOAc/hexanes) gave
470 mg (96%) of MTM ethers 86S/R. Rf ) 0.23 (10% EtOAc/hexanes);
1H NMR (300 MHz, C6D6) δ 5.39 (1H, br t), 5.35 (1H, dd), 5.17 (1H,
br d), 4.65 (1H, m), 4.36 (2H, s), 3.99 (2H, AB), 1.91 (3H, s), 1.84
(3H, s), 1.66 (3H, s), 1.63 (3H, s), 1.61 and 1.60 (3H, two s (2.5:1)),
1.21 (3H, s), 0.94 (3H, s), 0.44 (3H, s), 0.19 (9H, s); 13C NMR (75
MHz, C6D6) δ 169.4, 169.3, 168.7, 158.8, 154.5, 117.8*, 106.2, 98.8,
93.7*, 76.5, 73.7*, 72.8*, 67.3, 67.2, 58.3, 50.3*, 43.4*, 35.9, 35.3,
Compound 89: Rf ) 0.18 (1% THF/CH2Cl2); 1H NMR (300 MHz,
C6D6) δ 5.25 (1H, s), 5.01 (1H, dd), 4.85 (1H, br s), 4.38 (2H, s), 4.12
(1H, d), 3.38 (1H, d), 2.82 (1H, q), 1.91 (3H, s), 1.77 (3H, s), 1.34
(3H, s), 1.22 (3H, s), 0.91 (3H, d), 0.40 (3H, s), 0.22 (9H, s); 13C NMR
(125 MHz, C6D6) δ 207.9, 169.3, 155.1, 119.9, 109.2, 95.0, 91.2, 75.2,
72.9, 69.0, 66.9, 56.5, 51.1, 48.5, 45.4, 44.3, 37.8, 35.6, 34.3, 31.2,
30.4, 29.0, 28.6, 28.3, 27.5, 21.2, 20.4, 18.0, 14.1, 11.7, 10.7, 2.3; MS
(EI) 634 (M+); MS(CI) 635 (M + H, base peak), 545 (M + H -
HOTMS); HRMS (EI) calcd for C34H54O7SSi 634.3360, found 634.3340.
Compound 90: Rf ) 0.20 (1% THF/CH2Cl2); 1H NMR (300 MHz,
C6D6) δ 5.32 (1H, br t), 5.03 (1H, dd), 4.86 (1H, br s), 4.37 (2H, AB),
3.74 (1H, d), 3.62 (1H, br dd), 2.88 (1H, q), 2.00 (3H, s), 1.75 (3H, s),
1.34 (3H, s), 0.96 (3H, d), 0.60 (3H, s), 0.39 (3H, s), 0.22 (9H, s); 13
C

2084 J. Am. Chem. Soc., Vol. 121, No. 10, 1999
Jeong et al.
NMR (125 MHz, C6D6) δ 207.6, 169.1, 155.3, 119.5, 109.2, 94.6, 90.5,
74.8, 71.9, 66.9, 66.6, 56.3, 50.8, 48.4, 45.2, 44.1, 37.6, 37.4, 35.4,
34.2, 30.8, 28.8, 28.0, 27.2, 25.8, 21.2, 20.9, 17.9, 13.9, 11.1, 10.4,
2.2; MS (EI) 634 (M+); MS (CI) 635 (M + H, base peak), 545 (M +
H - HOTMS); HRMS (EI) calcd for C34H54O7SSi 634.3360, found
634.3353.
0.55 (s, 3H, H-19′), 0.85 (s, 9H), 1.81 (s, 3H), 2.02 (s, 3H), 2.47-2.68
(m, 4H), 2.85-3.20 (m, 5H), 3.20-3.28 (m, 2H), 3.76 (d, J ) 11.3,
1H, H-26′b), 4.37 (s, OH), 4.65 (dd, J ) 10.4, 8.1 Hz, 1H, H-23), 4.81
(d, J ) 2.3 Hz, 1H, H-16′), 5.28-5.35 (m, 2H, H-16 and H-12′), 5.39-
5.45 (m, 2H, H-12 and H-15′), 5.59 (s, 1H, H-15); MS (FAB, NBA)
1439 (M + H)+.
Protected Pyrazines 99, 100, and 101. A solution of metallic
tellurium (42 mg, 0.30 mmol) and NaBH4 (29 mg, 0.76 mmol) in
absolute ethanol (1 mL) was heated at reflux under argon for 1 h. After
being cooled to 25 °C, 0.28 mL (0.083 mmol) of the resultant dark red
solution (NaHTe)33 was added to a solution of azido ketones 5 (12.6
mg, 0.014 mmol) and 6 (8.5 mg, 0.014 mmol) in ether (1 mL) at 25
°C. The dark red solution instantly turned black with evolution of
nitrogen. After 1 h, the reaction mixture was exposed to air and stirred
for 1 h. Silica gel (230-400 mesh, 30 mg) and EtOAc (3 mL) were
added and the mixture was stirred for 18 h. After removal of the solvents
by evaporation, silica gel chromatography (1:15 to 1:3 EtOAc/hexanes)
gave protected pyrazines 100 (3.5 mg, 14%), 99 (7.0 mg, 35%), and
101 (3.6 mg, 23%) separately. Azido-cleaved ketones 98 (4.3 mg, 36%)
and 79 (1.2 mg, 15%) were also obtained.
Protected Ritterazine K (101): Rf ) 0.61 (1:1 EtOAc/hexanes);
1H NMR (300 MHz, C6D6) δ 0.35 (s, 18H, OTMS), 0.55 (s, 6H, H-19),
0.99 (s, 6H, H-18), 1.06 (d, J ) 7.1 Hz, 6H, H-21), 1.15 (s, 6H, H-27),
1.82 (s, 6H, OAc), 2.50-2.63 (m, 4H, H-1a and H-4b), 2.88 (dd, J )
18.2, 5.1 Hz, 2H, H-4a), 3.15 (d, J ) 16.7 Hz, 2H, H-1b), 3.25 (dd, J
) 11.3, 2.4 Hz, 2H, H-26a), 3.77 (d, J ) 11.3 Hz, 2H, H-26b), 4.82
(d, J ) 2.3 Hz, 2H, H-16), 5.31 (dd, J ) 11.6, 4.6 Hz, 2H, H-12), 5.43
(t, J ) 2.1 Hz, 2H, H-15); 13C NMR (C6D6) δ 2.3 (OTMS), 9.2 (C21),
11.4 (C19), 19.9 (C18), 20.8 (CH3CO2), 25.1 (C27), 26.8 (C23), 27.7
(C6), 28.2 (C7), 29.1 (C11), 32.6 (C24), 34.5 (C8), 35.3 (C4), 35.5
(C10), 40.5 (C5), 45.6 (C1), 46.6 (C20), 50.3 (C9), 56.3 (C13), 66.0
(C25), 68.8 (C26), 73.6 (C12), 89.9 (C16), 93.2 (C17), 107.8 (C22),
117.5 (C15), 148.2 (C2), 148.6 (C3), 159.1 (C14), 169.0 (CH3CO2);
MS (FAB, DDT/DTE) 1141 (M + H)+; HRMS (FAB, DDT/DTE)
calculated for C64H96N2O12Si2 1141.6580, found 1141.6470.
Protected Cephalostatin 12 (100): Rf ) 0.20 (1:3 EtOAc/hexanes);
1H NMR (300 MHz, CDCl3) δ -0.15 and -0.14 (two s, 12H), 0.74
(s, 18H), 0.85 (s, 6H, H-19), 1.00 (s, 18H), 1.11 (s, 6H, H-18), 1.12
(d, J ) 7.1 Hz, 6H, H-21), 1.24 (s, 6H, H-27), 2.00 (s, 6H), 2.44-2.63
(m, 6H), 2.81 (dd, J ) 18.0, 5.3 Hz, 2H, H-4a), 2.85 (d, J ) 17.0 Hz,
2H, H-1b), 2.97 (d, J ) 10.0 Hz, 2H, H-26b), 3.10 (d, J ) 10.0 Hz,
2H, H-26a), 3.96 (s, 2H, OH), 4.30 (dd, J ) 9.6, 7.2 Hz, 2H, H-23),
4.95 (br s, 2H, H-16), 5.06 (dd, J ) 11.0, 4.8 Hz, 2H, H-12), 5.56 (br
s, 2H, H-15), 7.36-7.76 (m, 4H), 7.84-7.87 (m, 4H); 13C NMR (75
MHz, CDCl3) δ -5.7, -5.6, 8.8, 11.7, 13.5, 18.2, 19.2, 21.3, 25.7,
25.9 (3C), 26.6 (3C), 27.3, 27.9, 28.3, 33.6, 35.2, 36.0, 37.5, 41.5,
44.3, 45.5, 52.6, 53.3, 69.2, 73.9, 74.6, 81.8, 89.4, 93.3, 116.5, 122.4,
127.6 (2C), 128.0 (2C), 129.8, 130.2, 132.7, 133.7, 135.5 (2C), 136.0
(2C), 148.3, 148.5, 151.5, 170.1; MS (FAB, NBA) 1734.8 (M + H)+.
Acknowledgment. We thank the National Institutes of
Health (CA 60548) for support of this work. Special thanks are
due to Mr. Lawrence Knox, Mr. Lei Jiang, and Mr. Patrick
Crouse for conversion of hecogenin acetate to advanced
synthetic intermediates. We are grateful to Arlene Rothwell for
supplying mass spectral data and Dr. P. Fanwick for providing
X-ray structures.
Supporting Information Available: Experimental proce-
dures as well as a characterization check list and NMR spectra
(PDF). This material is available free of charge via the Intenet
at http://pubs.acs.org.
1
Protected cephalostatin 7 (99): Rf ) 0.08 (1:3 EtOAc/hexanes); H
NMR (300 MHz, C6D6) δ -0.11 (s, 3H), -0.09 (s, 3H), 0.34 (s, 9H),
JA9817141