Synthesis of the north 1 unit of the cephalostatin family from hecogenin acetate 1

Article abstract of DOI:10.1021/ja9817139

Hecogenin acetate (1) was converted to North 1 azidoketone 5 involving several key transformations: (1) conversion of cyclic sulfate 33b to allylic alcohol 40 via Reich iodoso olefination; (2) E-ring annulation via intermolecular oxygen alkylation of high

Full text of DOI:10.1021/ja9817139

2056
J. Am. Chem. Soc. 1999, 121, 2056-2070
Synthesis of the North 1 Unit of the Cephalostatin Family from
Hecogenin Acetate1
Seongkon Kim, Scott C. Sutton, Chuangxing Guo, Thomas G. LaCour, and P. L. Fuchs*
Contribution from the Department of Chemistry, Purdue UniVersity, West Lafayette, Indiana 47907
ReceiVed May 18, 1998
Abstract: Hecogenin acetate (1) was converted to North 1 azidoketone 5 involving several key transforma-
tions: (1) conversion of cyclic sulfate 33b to allylic alcohol 40 via Reich iodoso olefination; (2) E-ring annulation
via intermolecular oxygen alkylation of highly functionalized secondary alcohol 40 using rhodium-catalyzed
decomposition of an R-diazophosphonoacetate to provide R-alkoxyphosphonoacetate 52, with subsequent
intramolecular Wadsworth-Emmons reaction to provide alkoxydihydrofuran 53; and (3) establishment of the
C20 stereochemistry by chromium(II) reduction of tertiary bromide 86 to a 9:1 mixture of diastereomeric
spiroketals 90R/90â, separated as silyl ethers 91R/91â. Conversion of 91R to R-azidoketone 5 was uneventful.
Introduction
In the context of the total synthesis of cephalostatin 7 (10),
a biomimetic approach involved conversion of appropriately
protected R-azidoketones 5 and 6 to R-aminoketones 7 and 8
followed by statistical combination to cephalostatins 126 (9)
and 7 (10) and ritterazine K (11).3b The specific synthetic
strategy involved conversion of hecogenin acetate 1 to the
pentacyclic dihydrofuran-aldehyde 2 which served as the
common intermediate for preparation of both hemispheres (3
and 4) of the target pyrazines (Scheme 1). Recent SAR studies
on cephalostatins and their analogues reveal that the North part
is not only the most common unit in the cephalostatin family
but is also strongly associated with the most potent antitumor
activity.1g,7
Cephalostatin 7 (10)2 is a potent member of a family of 45
trisdecacyclic pyrazines, characterized by the groups of Pettit
at Arizona State University and Fusetani at the University of
Tokyo.3 These materials were isolated from the marine tube
worm Cephalodiscus gilchristi, and more recently from the
tunicate Ritterella tokioka. In particular, cephalostatin 7 (10)
exhibits extreme potency with GI50 (growth inhibition concen-
tration) of 0.1-1 nM against a number of cancer cell lines (e.g.,
non-small cell lung HOP62, small cell lung DMS-273, renal
RXF-393, brain U-251 and SF-295, and leukemia CCRF-CEM,
HL-60, and RPM1-8226).2 In his seminal contribution detailing
the structure of cephalostatin 1, 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
Conversion of Hecogenin Acetate 1 to Aldehyde 28
Reduction of 1 with DIBAL at low temperature followed by
acylation provides rockogenin diacetate 12 in 88% overall yield
(Scheme 2). Isolation of 12 by recrystallization removed the
hexane-soluble minor C12 R-acetate as well as tigogenin acetate
(as 1 in Scheme 2 but X ) H, H) present in the starting
material.9 By use of a procedure similar to Dauben’s,10 diacetate
12 was converted to pseudorockogenin triacetate 13 in 79% yield
by pyridinium hydrochloride catalyzed reaction with acetic
anhydride, and thence into keto ester 14 by oxidation with
chromium trioxide in acetic acid. Treatment of 14 in benzene
with basic alumina effected â-elimination of the pentanoate side
chain, thereby providing the desired enone 15 in 71% yield from
13 on a large scale.
(1) Cephalostatin synthesis. 13. Portions of this work have been
communicated in Article 9 of this series: 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.; Jautelat, 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. (b) Pettit, G. R.; Tan, R.; Xu, J.-p.;
Ichihara, Y.; Williams, M. D.; Boyd, M. R. J. Nat. Prod. 1998, 61, 955
and references therein. (c) Fukuzawa, S.; Matsunaga, S.; Fusetani, N.
Tetrahedron 1995 51, 6707 and references therein. (d) Fukuzawa, S.;
Matsunaga, S.; Fusetani, N. J. Org. Chem. 1997, 62, 4484
Allylic bromination of enone 15 with NBS11 stereoselectively
yielded bromo enone 16 (Scheme 3). Three typical solvents for
(6) Pettit, G. R.; Ichihara, Y.; Xu, J.; Boyd, M. R.; Williams, M. D.
Bioorg. Med. Chem. Lett. 1994, 4, 1507.
(7) Guo, C.; LaCour, T. G.; Fuchs, P. L. Bioorg. Med. Chem. Lett. 1999,
9, 419.
(8) For a preliminary account of this phase of the work see: Kim, S.;
Fuchs, P. L. Tetrahedron Lett. 1994, 35, 7163.
(9) Tigogenin acetate comprises ∼5% of commercial 1. We have
subsequently found that reduction at 0 °C with NaBH4/CeCl3 (Gemal, A.
L.; Luche, J.-L. J. Am. Chem. Soc. 1981, 103, 5454), acetylation, and
recrystallization provides 12 (90%) in an operationally more convenient
manner.
(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.
(10) Ring opening of spiroketal 11 is based upon the general method of
Micovic and Diatak (see: Synthesis 1990, 591) and Dauben and Fonken
(Dauben, W. G.; Fonken, G. J. J. Am. Chem. Soc. 1954, 76, 4618).
10.1021/ja9817139 CCC: $18.00 © 1999 American Chemical Society
Published on Web 03/02/1999

Synthesis of the North 1 Unit of the Cephalostatin Family
J. Am. Chem. Soc., Vol. 121, No. 10, 1999 2057
Scheme 1
free radical reactions, CCl4, benzene, and cyclohexane, were
tested on both small and large scales. All small scale reactions
produced 16 in good yield (75-85%). However, the yield in
benzene decreased significantly upon scale-up. In both CCl4
and cyclohexane, the reaction could be performed on a 10-20
g scale and at higher concentrations (0.02-0.03 M) without
significant reduction in the yield of 16, thereby imparting a
significant preparative advantage. Cyclohexane was the preferred
solvent due to the cost and toxicity associated with CCl4. The
reaction also returned 15% of unreacted enone 15. Extended
reaction time (2 h) or increased amounts of NBS (1.2 equiv)
simply increased the proportion of unwanted dibromide 17.
Scheme 3
Scheme 2
Because of separation difficulties, the crude mixture of 15/
16/17 was epoxidized with alkaline hydrogen peroxide.12 After
treatment with acetic anhydride to reacetylate some C3 alcohol
that arose in the epoxidation step, a mixture of three products
was isolated. The reaction afforded dienone 18 (5-10%) that
likely resulted from elimination of 16, epoxide 19 (10%) from
oxidation of enone 15, and the desired epoxyketone 20 (55-
60%) as a single stereoisomer. Products derived from dibromide
17 did not survive the reaction.
Although the D-ring oxidation state was secured, completion
of the D-ring functionality proved extremely challenging.
Elimination of bromoepoxide 20 to vinyl epoxide 21 was only
(11) Templeton, J. F.; Yan, Y. Org. Prep. Proced. Int. 1992, 24, 159.
(12) Julian, P. L.; Meyer, E. W.; Karpel, W. J.; Waller, I. R. J. Am.
Chem. Soc. 1950, 72, 5145.

2058 J. Am. Chem. Soc., Vol. 121, No. 10, 1999
Kim et al.
Scheme 4
Scheme 5
a TES ether with the same silyl triflate technology, the TMS
series was carried forward. This approach presumably succeeded
because of the sterically confined nature of the silicon moiety.15
When olefin 26 was exposed to mCPBA in CH2Cl2 for extended
periods, the starting material was recovered in over 90% yield.
The olefin was also unreactive to mCPBA even at higher
reaction temperatures.16 The low reactivity of the olefin 26 was
again apparent when repeated infusions of an excess of the
highly reactive oxidant dimethyldioxirane17 required 10 days
to effect epoxidation of 26, affording 27 in a meager 30% yield
(60% recovered 26). Fortunately, osmylation18 of olefin 26
stereospecifically generated diol 28 in nearly quantitative yield
(Scheme 4). Attempts to use catalytic OsO4 were fruitless.
Cyclic sulfates19 have been known for a number of years and
have been exploited as electrophilic epoxide equivalents. An
excellent review by Lohray19d explains the features that dis-
tinguish cyclic sulfates from epoxides. Although they are less
strained (∼5 vs ∼27 kcal/mol), five-membered cyclic sulfates
contain a better leaving group. They occasionally show comple-
mentary regioselectivity to epoxides in nucleophilic ring-opening
reactions and appear more reactive than the corresponding
epoxides. Sharpless19a recently developed a facile conversion
of 1,2-diols into cyclic sulfates that has resulted in ready avail-
ability of this class of compounds. In 1993, Shing19c described
the reaction of cyclic sulfate 29 with selenide anion to generate
trans-diaxial seleno alcohol 30 after hydrolysis of the sulfate
salt (Scheme 5). Regiospecific oxidative elimination of sele-
noxide 31 led to allylic alcohol 32 in good yield.
marginally successful even after substantial optimization, yield-
ing a mixture of starting material 20, desired product 21, and
dienylic alcohol 22 (resulting from further transformation of
21) (Scheme 4). Many attempts were made to suppress the
second elimination. After much experimentation it was found
that warming 20 in neat DBU with LiF (10 equiv) provided
complete conversion to 21 without any evidence for formation
of 22, although the low yield (50%) was troublesome.
This route was rapidly abandoned after finding that hydrolysis
of vinyl epoxide 21 yielded an unacceptable 1:1 mixture of 1,4-
diol 23 and target diol 24. The low yield of 21 in conjunction
with the failure to effect regiospecific epoxide opening neces-
sitated reformulation of the synthetic plan.
The revised plan involved establishment of the trans C16,17
oxygenation pattern prior to introduction of the C14,15 double
bond. Reductive cleavage of bromoepoxide 20 with ultrasoni-
cated zinc/copper couple13 proved highly effective at generating
tertiary allylic alcohol 25, which was then protected as its TMS
ether 26.14 While the wisdom of selecting a TMS protecting
group was open to serious question, the issue was settled on a
pragmatic basis. Since it proved impossible to even introduce
Two variants of the above strategy were next attempted for
synthesis of the key allylic alcohol 40. As anticipated, conver-
sion of diol 28 to cyclic sulfate 33b through cyclic sulfite 33a
(not shown) occurred smoothly with use of the Sharpless
protocol (Scheme 6).19a However, attempts to introduce the
requisite olefin functionality with base-catalyzed elimination of
Scheme 6
(13) (a) Nicolaou, K. C.; Duggan, M. E.; Ladduwahetty, T. Tetrahedron
Lett. 1984, 25, 2069. (b) Sarandeses, L. A.; Mourino, A.; Luche, J. L. J.
Chem. Soc. Chem. Commun. 1991, 818.
(14) Smith, A. B., III; Lupo, A. T., Jr.; Ohba, M.; Chen, K. J. Am. Chem.
Soc. 1989, 111, 6648.
(15) A similar example can be found in Paul Wender’s total synthesis
of (+)-resiniferatoxin. A hindered TMS ether survived HF treatment.
Wender, P. A.; Jesudason, C. D.; Nakahira, H.; Tamura, N.; Tebbe, A. L.;
Ueno, Y. J. Am. Chem. Soc. 1997, 119, 12976.
(16) Kishi, B. Y.; Aratani, M.; Tanino, H.; Fukuyama, T.; Goto, T. J.
Chem. Soc. Chem. Commun. 1972, 64.
(17) (a) Murray, R. W.; Jeyaraman, R. J. Org. Chem. 1985, 50, 2847.
(b) For review, see: Adam, W.; Curci, R.; Edwards, J. O. Acc. Chem. Res.
1989, 22, 205.
(18) Allen, W. S.; Bernstein, S. J. Am. Chem. Soc. 1956, 78, 1909.
(19) (a) Sharpless, K. B.; Gao, Y. J. Am. Chem. Soc. 1988, 110, 7538.
(b) Ramaswamy, S.; Prasad, K.; Repic, O. J. Org. Chem. 1992, 57, 6344.
(c) Shing, T. K. M.; Tai, V. W. F. J. Chem. Soc. Chem. Commun. 1993,
995. (d) For review, see: Lohray, B. B. Synthesis 1992, 1035.

Synthesis of the North 1 Unit of the Cephalostatin Family
J. Am. Chem. Soc., Vol. 121, No. 10, 1999 2059
Scheme 7
Scheme 8
Having established the D-ring oxidation pattern, efforts were
next focused upon synthesis of the E-ring present in the North
1 segment of the cephalostatins. Based on the retrosynthetic
analysis (Scheme 7), R-alkoxy phosphonate ester 43 was
required for E-ring annulation via an intramolecular Wad-
sworth-Emmons reaction. Previously published model studies23
had indicated difficulty with the specificity of olefin osmylation
as a means of establishing the C25,26 diol. Therefore, we en-
visaged construction of intermediate 42, bearing an appropriately
configured acetonide in an effort to avoid osmylation of a remote
C25,26 olefin.24 The appealing feature of this plan was the
potential (ultimately not realized) for incorporation of the 25S
stereocenter via reuse of the previously excised side chain or
adoption of an appropriate “chiral pool” starting material.
Establishment of the requisite C-O bond of compound 43 (see
dashes, Scheme 7) was projected to occur via OH insertion into
the rhodium carbenoid derived from an R-diazoketophosphonate
with methodology developed by Moody.25
Since Moody has shown that unhindered primary alcohol 48
reacts slowly with R-diazoketophosphonate 44 to afford R-al-
koxyketophosphonate 49,25 we investigated the reaction of
secondary neopentyl alcohol 40 with 44 before proceeding with
construction of the optically active R-diazoketophosphonate
required for synthesis of 43 (Scheme 8). Surprisingly, reaction
of 44 with 40 in the presence of dirhodium tetraacetate was
faster by a factor of 20 than reaction with the simple alcohol
48. Unfortunately, the product was not the desired R-alkoxyke-
tophosphonate 45, but was rather phosphonate-ester 46, formed
as a ∼1:1 mixture of diastereomers in 92% yield. While this
product is formally in accord with a mechanism involving Wolff
rearrangement26 of 44 to ketene 47 with trapping by 40, the
fact that the slower-reacting Moody substrate 48 does not also
form ketene adducts akin to 46 poses an interesting problem
for future mechanistic study.27
From the failure of the model study above, it became apparent
that assembling R-diazoketophosphonate 43 would be extremely
difficult. To overcome this problem, the insertion reactions of
R-diazophosphonate-ester 51 were explored (Scheme 9). It has
been shown that the ester moiety is less prone to rearrange than
the keto group in the rhodium(II) catalyzed diazophosphonate
reaction with alcohols28 and we were pleased to see that reaction
sulfate 33b were completely unrewarding. The only product
isolated from these reactions was epoxy alcohol 36, which may
have arisen by intramolecular oxygen silylation of the ketone
enolate (i.e. via 34). No attempts were made to detect the
putative silyl enol ether intermediate since an acidic workup
was necessary to hydrolyze sulfate monoester 35. Compound
36 also resulted from the action of NaSePh on sulfate 33b.
To avoid the base lability problem, we investigated the SN2
chemistry of substrate 33b with iodide ion to introduce the
C14,15 olefin. Treatment of sulfate 33b with excess TBAI
(tetrabutylammonium iodide) in toluene at reflux afforded iodo
ammonium sulfate 37 in 90% yield (Scheme 6). Oxidation of
37 with mCPBA in CH2Cl2 provided key intermediate allylic
alcohol 40 after protonolysis of ammonium sulfate 39. This
reaction is thought to proceed via syn-elimination of hypoiodous
acid from iodoso intermediate 37, a reaction originally developed
by Reich20 that is vastly under-exploited in complex synthe-
sis21,22 relative to the standard sulfoxide and selenoxide proto-
cols. Also remarkable is that selective protonolytic cleaVage of
ammonium sulfate 39 to alcohol 40 can be effected without
concomitant hydrolysis of the TMS ether moiety.
(23) (a) Jeong, J. U.; Fuchs, P. L. J. Am. Chem. Soc. 1994, 116, 773. (b)
Jeong, J. U.; Fuchs, P. L. Tetrahedron Lett. 1994, 35, 5385.
(24) See following article: Jeong, J. U.; Guo, C.; Fuchs, P. L. J. Am.
Chem. Soc. 1999, 121, 2071.
(25) (a) Moody, C. J.; Sie, E. R. H. Tetrahedron 1992, 48, 3991. (b)
Cox, G. G.; Miller, D. J.; Moody, C. J.; Sie, E. H. B. Tetrahedron 1994,
50, 3195 and references cited therin.
(26) (a) Corbel, B.; Hernot, D.; Haelters, J.-P.; Sturtz, G. Tetrahedron
Lett. 1987, 28, 6605. (b) Cossy, J.; Belotti, D.; Thellend, A.; Pete, J. P.
Synthesis 1988, 720. (c) Andriamiadanarivo, R.; Pujol, B.; Chantegrel, B.;
Deshayes, C.; Doutheau, A. Tetrahedron Lett. 1993, 34, 7923.
(27) It seems possible that a bidentate ligating effect of the â-hydroxy
ketone is responsible for enhancement of the Wolff reaction or its operational
equivalent.
(20) Reich, H. J.; Peake, S. L. J. Am. Chem. Soc. 1978, 100, 4888.
(21) For additional examples of the synthetic potential of this strategy,
see: (a) Macdonald, T. L.; Narasimhan, N.; Burka, L. T. J. Am. Chem.
Soc. 1980, 102, 7760. (b) McCabe, P. H.; deJenga, C. I.; Stewart, A.
Tetrahedron Lett. 1981, 22, 3679. (c) Zefirov, N. S.; Zhdankin, V. V.;
Makhon’kova, G. V.; Dan’kov, Y. V.; Koz’min, A. S. J. Org. Chem. 1985,
50, 1872. (d) Citterio, A.; Gandolfi, M.; Giordano, C.; Castaldi, G.
Tetrahedron Lett. 1985, 26, 1665. (e) Holmes, C. P.; Bartlett, P. A. J. Org.
Chem. 1989, 54, 98. (f) Knapp, S.; Naughton, A. B. J.; Dhar, T. G. M.
Tetrahedron Lett. 1992, 33, 1025; see also ref 19.
(22) For an improved procedure for oxidation of iodides to iodoso
intermediates with dimethyldioxirane see: Mahadevan, A.; Fuchs, P. L. J.
Am. Chem. Soc. 1995, 117, 3272.

2060 J. Am. Chem. Soc., Vol. 121, No. 10, 1999
Kim et al.
Scheme 9
Scheme 11
of 51 with allylic alcohol 40 provided the desired insertion prod-
uct 52 as a 1:1 mixture of diastereomers. Although this sub-
strate represented the most highly functionalized alcohol which
had been transformed to an R-alkoxyphosphonate at the time,
subsequent studies from our group have revealed that the
Moody protocol is a highly versatile strategy for the construc-
tion of complex targets.1f,29 Due to the difficulty associated with
isolation and separation,30 52 was carried through the intra-
molecular Wadsworth-Emmons reaction without additional
purification. Treatment of the crude 52 with sodium hydride in
THF for 10 min at 0 °C smoothly afforded the five-mem-
bered intramolecular Wadsworth-Emmons product 53 in
75% yield for the two-step procedure. The facile transfor-
mation of 40 to alkoxydihydrofuran-ester 53 was surprising,
since the assembly of the densely functionalized E-ring was
initially judged to be one of the most difficult tasks of the
synthesis.
Completion of the synthesis of key intermediate 2 was
uneventful (Scheme 10). Lithium borohydride reduction31 of 53
provided a mixture of allylic alcohols 54a/54b which only differ
in that 54a suffered acetate cleavage at C3 during borohydride
treatment. This mixture was selectively reoxidized to a corre-
sponding mixture of aldehydes 55/2 with MnO2. A final acetic
anhydride treatment was employed on the crude aldehydes 55/2
to convert the minor amount of 55 to the key pentacyclic
aldehyde 2. The overall yield for these three steps was 61%,
resulting in an overall 9% yield of 2. Subsquent studies on larger
scales have resulted in 7-8% yields for the 20-step sequence
from hecogenin acetate 1 to aldehyde 2.
Table 1
yield
(ratio 3:4)
entry
reagents
conditions
1
2
3
4
5
methallyl
stannane
methallyl
stannane
methallyl-
(-)-IPc2B35
methallyl
stannane
methallyl
stannane
BF3‚Et2O, CH2Cl2,
-78 °C, 1 h
80%
(1.6:1.0)a
>95%
(1.3:1.0)
69%
(1.7:1.0)b
NRc,36
5.0 M LiClO4,34
Et2O, 25 °C, 1 h
THF, -78 °C, 1 h
(-)-Binaphthol, MS
Ti(O-iPr)4, CH2Cl2
(+)-Binaphthol, MS
Ti(O-iPr)4, CH2Cl2
NRc
a In large scale reactions the yields dropped below 50% due to the
acid lability of 2. b The 3-Ac was also cleaved during workup. c Even
at 25 °C, no reaction was observed after 2 d.
and 4 in nearly quantitative yield. Asymmetric methallylation
technology was also explored with the hope that double
diastereoselection would be possible. Use of Brown’s chiral
methallyl boron reagent35 gave a slightly better ratio of
diastereomeric homoallyl alcohols (1.7:1), but the chemical
yields were disappointingly low (65-75%) due in part to
concomitant cleavage of the C3 acetate. Unfortunately, no
reaction was observed under Keck’s conditions36 (Table 1,
entries 4, 5). Since the unnatural diastereomer 4 served as
progenitor of the South portion of cephalostatin 7 (10) via
deoxygenation,37 the readily separable mixture of alcohols 3
and 4 was perfectly acceptable at this juncture. Further stocks
of “North” alcohol 3 could be secured via Mitsunobu inver-
sion.38 Reaction of 4 with formic acid and triphenylphosphine
in the presence of diethyl azodicarboxylate smoothly afforded
formate 56 in 76% yield. Heating this material in methanol at
reflux provided natural alcohol 3 in 87% yield.
Scheme 10
Synthesis of the North 1 Spiroketal32
Various procedures examined for addition of methallylstan-
nane to aldehyde 2 (Scheme 11) are summarized in Table 1.
The more polar major adduct 3 was hydrolyzed to the C3,12,-
17,23 tetraol 57 and the C23 stereochemistry was secured by
X-ray crystallography.33 The best methallyl stannane reaction
involved 5 M LiClO4 in ether,34 affording a 1.3:1 mixture of 3
(33) X-ray structural information relating to compounds 57, 72, and 82
can be obtained from the Cambridge Crystallographic Data Centre.
(34) Henry, K. J., Jr.; Grieco, P. A.; Jagoe, C. T. Tetrahedron Lett. 1992,
33, 1817.
(35) (a) Racherla, U. S.; Liao, Y.; Brown, H. C. J. Org. Chem. 1992,
57, 6614. (b) Brown, H. C.; Jadhav, P. K.; Bhat, K. S. J. Am. Chem. Soc.
1988, 110, 1535. (c) Brown, H. C.; Bhat, K. S.; Randad, R. S. J. Org.
Chem. 1987, 52, 320. (d) Jadhav, P. K.; Bhat, K. S.; Perumal, P. T.; Brown,
H. C. J. Org. Chem. 1986, 51, 432. (e) Brown, H. C.; Jadhav, P. K.; Perumal,
P. T. Tetrahedron Lett. 1984, 25, 5111. (f) Brown, H. C.; Jadhav, P. K. J.
Org. Chem. 1984, 49, 4091. (g) Brown, H. C.; Jadhav, P. K. J. Am. Chem.
Soc. 1983, 105, 2092.
(36) (a) Keck, G. E.; Tarbet, K. H.; Geraci, L. S. J. Am. Chem. Soc.
1993, 115, 8467. (b) Keck, G. E.; Krishnamurthy, D.; Grier, M. J. Org.
Chem. 1993, 58, 6543. (c) Keck, G. E.; Geraci, L. S. Tetrahedron Lett.
1993, 34, 7827. (d) Costa, A. L.; Piazza, M. G.; Tagliavini, E.; Trombini,
C.; Ronchi, A. U. J. Am. Chem. Soc. 1993, 115, 7001.
(28) Georgian, V.; Boyer, S. K.; Edwards, B. J. Org. Chem. 1980, 45,
1686.
(29) Bhandaru, S.; Fuchs, P. L. Tetrahedron Lett. 1995, 36, 8347.
(30) The Rf value of compound 52 is almost the same as that of
diazophosphonate 51 which was used in excess, so the mixture was used
directly in the Wadsworth-Emmons reaction.
(31) (a) Brown, H. C.; Narasimhan, S.; Choi, Y. M. J. Org. Chem. 1982,
47, 4702. (b) Brown, H. C.; Narasimhan, S. J. Org. Chem. 1982, 47,
1606.
(32) For a preliminary account of this phase of the work, see: Kim, S.;
Sutton S. C.; Fuchs, P. L. Tetrahedron Lett. 1995, 36, 2427.

Synthesis of the North 1 Unit of the Cephalostatin Family
J. Am. Chem. Soc., Vol. 121, No. 10, 1999 2061
Scheme 12
Table 2. Asymmetric Dihydroxylation of Terminal Alkenes
entry
substrate
conditions
yield (%)
ratio
C25 nat/epi
1
2
3
4
5
6
58
3
3
3
61
61
(S,S)-63, -100 °C, 0.5ha,23
(S,S)-63, -95 °C, 1 h
Sharpless AD-mix-R, 25 °C, 24 h
Sharpless AD-mix-â, 25 °C, 24 h
Sharpless AD-mix-R, 25 °C, 24 h
(S,S)-63, -95 °C, 1 h
98%
95%
∼25% conv
∼25% conv
∼30% conv
95%
59S/59R
60S/60R
60S/60R
60S/60R
62S/62R
62S/62R
8:1
2:1
2:1
1:4
1:2
4:1
Scheme 13
Having unambiguously determined the C23 stereochemistry
of the homoallylic alcohol 57, attention was turned toward
establishment of the C25,26 diol functionality. With the acid-
sensitive, electron-rich dihydrofuran moiety making most elec-
trophilic methods (epoxidation, halohydroxylation)39 doubtful,
it seemed prudent to employ osmylation.
An osmylation model study23a (Scheme 12 and Table 2, entry
1) with 17-deoxy-14,15-dihydro olefin 58 required symchiral
Corey ligand 6340 to provide reasonable diastereoselection (59S/
59R ∼ 8:1). Consequently, we first examined reaction of alcohol
3 using these conditions. While neither this reaction nor the
Sharpless AD procedure41 was acceptable for alcohol 3 (Table
2, entries 2-4), ligand 63 provided a usable 4:1 ratio of
inseparable diols 62S/62R when the reaction was conducted on
tert-butyldiphenylsilyl ether 61 (98% from 3 by the method of
Hardinger,42 Table 2, entry 6).
With the inseparable 4:1 mixture of diols 62S/62R as well
as the corresponding mixture of tetraols 66S/66R (prepared via
desilylation of the C17,23 diol mixture 62S/62R) in hand, the
stage was set to study acid-catalyzed spiroketal formation. A
serious concern was the possibility of ionization of the C17
oxygen substituent via a Ferrier-type process43 that could result
in unwanted side products via intermediate 65 (Scheme 13).
In a model study23a lacking the ∆14,15 unsaturation and the
C17 oxygen moiety, cyclization of diol 59S (Scheme 12) under
acidic conditions was unproductive. However, model triol 68S
underwent cyclization at 25 °C to provide an 8:1 mixture of
spiroketals 69â and 70â both bearing the unnatural â-methyl
configuration at C20 (Scheme 14). Brief heating of the reaction
mixture at 80 °C provided 69â in near quantitative yield. It was
hoped that in the real system, the tertiary C17 TMS ether might
prevent protonation from the R-face of the molecule, thereby
giving the natural R-methyl configuration at C20 (64R or 67R).
Initial acid-mediated cyclization studies were conducted on
the inseparable mixture of TBDPS protected diols 62S/62R.
When mild acids (pyridinium p-toluenesulfonate ) PPTs or
lutidinium p-toluenesulfonate) were employed, there was no
reaction as expected due to the combined steric and inductive
effects of the C17 and C26 oxygens. When the PPTs reaction
was heated at reflux at 80 °C, or when stronger acids (Nafion-
(37) Jeong, J. U.; Fuchs, P. L. Tetrahedron Lett. 1995, 36, 2431. See
also ref 24.
(38) (a) Dodge, J. A.; Trujillo, J. I.; Presnell, M. J. Org. Chem. 1994,
59, 234. (b) Caine, D.; Kotian, P. L. J. Org. Chem. 1992, 57, 6587. (c)
Hughes, D. L.; Reamer, R. A.; Bergan, J. J.; Grabowski, E. J. J. J. Am.
Chem. Soc. 1988, 110, 6487.
(39) (a) Johnson, W. S.; Chan, M. F. J. Org. Chem. 1985, 50, 2598. (b)
Ichikawa, Y.; Isobe, M.; Bai, D. L.; Goto, T. Tetrahedron 1987, 43,
4737.
(40) Corey, E. J.; Jardine, P. D.; Virgil, S.; Yuen, P. W.; Connell, R. D.
J. Am. Chem. Soc. 1989, 111, 9243.
(41) Sharpless, K. B.; Amberg, W.; Bennani, Y. L.; Crispino, G. A.;
Hartung, J.; Jeong, K.-S.; Kwong, H.-L.; Morikawa, K.; Wang, Z.-M.; Xu,
D.; Zhang, X.-L. J. Org. Chem. 1992, 57, 2768
(42) Hardinger, S. A.; Wijaya, N. Tetrahedron Lett. 1993, 34, 3821.
(43) Ireland, R. E.; Meissner, R. S.; Rizzacasa, M. A. J. Am. Chem. Soc.
1993, 115, 7166 and references therein.

2062 J. Am. Chem. Soc., Vol. 121, No. 10, 1999
Kim et al.
Scheme 14
Scheme 16
attempted. Unfortunately, only complex mixtures were isolated
without any sign of the debrominated products 64R,â. This was
surprising since tin hydride cleavage of model compound 75 to
spiroketals 76R,â was an excellent reaction.23a
H, TfOH, HClO4, BF3‚2HOAc) were employed, complex
mixtures resulted. The proton NMR spectra of these mixtures
contained signals for the desired spiroketal 64R, albeit in very
low yield (<10%). Due to the complexity of the product mixture
as well as the poor yield of the desired product, this approach
was not synthetically viable. Cyclization of a 4:1 diastereomeric
mixture of tetraols 66S/66R prepared via desilylation of the 4:1
62S/62R mixture was also unfruitful. Further acid-catalyzed
cyclizations were not attempted.
Scheme 17
Scheme 15
A number of other methods were investigated, including
photochemical protocols47-51 (Scheme 18, Table 3). It is known
that alkyl halides can be reduced by irradiation in an appropriate
solvent with or without reducing additives. Electron transfer
within the initial radical pair cage is postulated to afford
carbenium ion intermediates responsible for alkene and nucleo-
philically substituted sideproducts. Irradiation of 71S at 254 nm
in alcoholic solvent provided olefin 77 as the only product
(65%), without a trace of the desired 64. Another attempt in
the presence of tin hydride52 at 350 nm gave the same result.
Reductions via cationic intermediates under various conditions
such as NaCNBH3/ ZnCl253 or SnCl253 and Et3SiH/Lewis acids54
were next attempted. Unfortunately, 71S was inert to these
conditions. Reduction under basic conditions was also explored.
However, these methods (including Birch reduction,55 trans-
metalation by t-BuLi, Zn/Cu alloy, and lithium biphenylide)
showed either no reaction or decomposition.
While reaction of the 4:1 62S/62R diol mixture with a variety
of acids was unrewarding, NBS-mediated spirocyclization23a
cleanly afforded the C20 brominated 5/5 spiroketal 71S (77%),
chromatographically separable from its diastereomer 71R (15%)
which resulted from cyclization of the minor diol 62R (Scheme
15). The structure of 71S was confirmed by X-ray of alcohol
7233 obtained by methanolysis of the C3 acetate.
Since the bulky R-face silyl ether at C17 might have been
responsible for retarding the reduction of the R-face C20
bromide, deprotection of the TMS group was explored (Scheme
19). Surprisingly, the C23 TBDPS group was also cleaved under
mild conditions (TBAF/0 °C). Careful examination via TLC
showed that deprotection of both silicon groups occurred
essentially simultaneously. The resultant bromo-triol 78 was too
unstable for further manipulation. When a large excess of TBAF
Attempts to incorporate iodide at C20 by using either NIS44
or the highly reactive IDCP (Iodonium di-Collidine Perchlor-
ate)45 were not successful (Scheme 16). Presumably these
reactions were unsuccessful due to the bulkiness of the reagents
which retarded reaction at the enol ether moiety, thereby leading
to the unwanted ketone 73 via oxidative fragmentation46 of the
C25,26 diol (Scheme 16).
Stereoselective Reduction of Hindered Bromides
(47) Kropp, P. Acc. Chem. Res. 1984, 17, 131.
(48) Shibata, I.; Nakamura, K.; Baba, A.; Matsuda, H. Tetrahedron Lett.
1992, 33, 5709.
(49) Vedejs, E.; Duncan, S. M.; Haight, A. R. J. Org. Chem. 1993, 58,
3043.
(50) Barton, D. H. R.; Jang, D. O.; Jaszberenyi, J. C. Synlett 1991, 435.
(51) Barton, D. H. R.; Jang, D. O.; Jaszberenyi, J. C. Tetrahedron Lett.
1992, 33, 5709.
Stereoselective reductive cleavage of the tertiary C20 bromide
71S provided the most severe challenge of the entire synthesis.
To obtain the natural R-methyl configuration at C20, we wished
to debrominate 71S to 64R as shown in Scheme 17. To this
end, triphenyltin hydride reduction of bromide 71S was initially
(44) (a) Konradsson, P.; Mootoo, D. R.; Mcdevitt, R. E.; Reid, B. F. J.
Chem. Soc. Chem. Commun. 1990, 270. (b) Veeneman, G. H.; Van Leeuwe,
S. H.; Van Boom, J. H. Tetrahedron Lett. 1990, 31, 1331. (c) Merritt, J.
R.; Reid, B. F. J. Am. Chem. Soc. 1992, 114, 8334. (d) Olah, G. A.; Wang,
Q.; Sandford, G.; Prakash, G. K. S. J. Org. Chem. 1993, 58, 3194.
(45) Lemieux, R. U.; Morgan, A. R. Can. J. Chem. 1965, 43, 2190.
(46) Beebe, T. R. J. Org. Chem. 1981, 46, 1927.
(52) Kahne, D.; Yang, D.; Lim, J. J.; Miller, R.; Paguaga, E. J. Am.
Chem. Soc. 1988, 110, 8716.
(53) (a) Kim, S.; Kim, Y.; Ahn, K. H. Tetrahedron Lett. 1983, 24, 3369.
(b) Kim, S.; Ko, J. S. Synth. Commun. 1985, 15, 603.
(54) Doyle, M. P.; Mcoster, C. C.; West, C. T. J. Org. Chem. 1976, 41,
1393.
(55) Berkowitz, D. B. Synlett 1990, 649.

Synthesis of the North 1 Unit of the Cephalostatin Family
J. Am. Chem. Soc., Vol. 121, No. 10, 1999 2063
Scheme 18
Scheme 21
Table 3. Initial Debromination Experiments with Bromide 71S
entry
reagents
Bu3SnH
conditions
AIBN, 80 °C
Rayonet (350 nm), RT, 1 h
AIBN, 50 °C
AIBN, 80 °C
AIBN, 80 °C
results
Table 4. Reduction of 71S in DMSO
1
2
3
4
5
6
complex
77 65%
71S recov
complex
complex
complex
Bu3SnH
Ph3SnH
Ph3SnH
Bu2SnH2
71S + reagents
temp
(°C)
entry
1
and H donora
time
48 h
results
20 equiv Cr(OAc)2;
80 equiv n-PrSH
4 equiv Cr(OAc)2;
40 equiv EDb
4 equiv CrCl2;
10 equiv n-PrSH
4 equiv CrCl2;
100 equiv n-PrSH
4 equiv CrCl2;
10 equiv Ph3SnH
5 equiv CrCl2;
50
25
25
25
25
25
64â (30%)
48
AIBN, 80 °C
2
3
4
5
6
5 min
24 h
5 h
77 (99%)
no reaction
7
Rayonet (350 nm), RT,1 h
77 60%
64 [R/â ) 1:7]
(80%)
50
8
9
PhSiH3
AIBN, 80 °C
AIBN, 110 °C
71S recov
complex
H3PO2/Et3N51
30 min 64 [R/â ) 1:2]
(30%)
77 (50%) + 64â
(5%)
6 h
100 equiv t-BuSH
was used in the presence of acid, elimination of bromide 71S
occurred to give olefinic triol 79 in good yield.
Although hydrogenation of olefin 79 might be expected to
produce 64â bearing the unnatural â-methyl configuration at
C20, several protocols were attempted with 79, including H2/
a DMSO was degassed by Ar which was pretreated with basic
pyrogallol solution. b ED ) ethylenediamine.
halogenation, inversion was observed.60 It is generally held that
the stereochemistry of such reductions is strongly influenced
by thermodynamics at the stage of the radical intermediate.61
This reaction signaled the beginning of the explosive growth
of radical technology pioneered by the Barton school. Interest-
ingly, with the advent of the now standard tin hydride protocols,
chromium(II) mediated reductions have seen few applications
in recent years. Of particular interest with reference to deha-
logenation of 71S was the prospect of generating the tris-â--
alkoxy radical at lower reaction temperatures than via the tin
hydride procedures.
Bromide 71S was treated with excess Cr(OAc)2 in the
presence of n-propyl mercaptan (Scheme 21, Table 5, entry 1).
While the reaction was unacceptably slow, it was extremely
rewarding to isolate a C20 reduction product for the first time
(30% yield) in addition to recovered starting material (60%).
While the C20 stereochemistry (64R or 64â) was initially
indeterminate, nOe studies indicated a proximal relationship
between the C23 methine and the C20 methine, which suggested
Scheme 19
Pd/60psi,56 diimide,57 and [Ir(cod)(Pcy3)Py]PF6/H2.58 Unfortu-
nately, no 64 was observed.
In 1966, Barton reported that bromohydrin 80 could be re-
duced to alcohol 81 with retention of stereochemistry by using
chromium acetate in the presence of a hydrogen atom transfer
agent (Scheme 20).59 In another example of chromium(II) de-
Scheme 20
Scheme 22
(56) Paulvannan, K.; Stille, J. R. Tetrahedron Lett. 1993, 34, 6673.
(57) Vedejs, E.; Buchanan, R. A. J. Am. Chem. Soc. 1989, 111, 8426.
(58) (a) Crabtree, R. H.; Davis, M. W. J. Org. Chem. 1986, 51, 2655.
(b) Stork, G.; Kahne, D. E. J. Am. Chem. Soc. 1983, 105, 1072.
(59) (a) Barton, D. H. R.; Basu, N. K.; Hesse, R. H.; Morehouse, F. S.;
Pechet, M. M. J. Am. Chem. Soc. 1966, 88, 3016. (b) Barton, D. H. R.;
Basu, N. K. Tetrahedron Lett. 1964, 43, 3151.
(60) (a) Bachi, M. D.; Epstein, J. W.; Minzly, Y.; Loewenthal, H. E. J.
Org. Chem. 1969, 34, 126. (b) House, H. O.; Zaiko, E. J. Org. Chem. 1977,
42, 3780. (c) Hook, J. M.; Mander, L. N.; Urech, R. J. Am. Chem. Soc.
1980, 102, 6628. (d) Hook, J. M.; Mander, L. N.; Urech, R. J. Org. Chem.
1984, 49, 3250.
(61) (a) Hanson, J. R.; Premuzic, E. Angew. Chem., Int. Ed. Engl. 1968,
247. (b) Hanson, J. Synthesis 1974, 1.
(62) Kochi, J. K.; Mocadlo, P. E. J. Am. Chem. Soc. 1966, 88, 4094.

2064 J. Am. Chem. Soc., Vol. 121, No. 10, 1999
Kim et al.
Scheme 23
Table 5. Dependence of Stereoselectivity on Substrate Structure and Conditions
entry
SM
R
R′
X
no. of equiv of n-PrSH
solvent, temp
time (h)
products [ratio]a(yield)
1
2
3
4
5
6
7
8
9
71S
87
86
86
86
TMS
H
H
H
H
H
H
H
TMS
H
H
H
H
H
TBS
H
H
â -OAc
100
100
100
200
200
200
200
200
100
DMSO, 25 °C
DMSO, 25 °C
DMSO, 25 °C
DMF, -15 °C
DMF, -40 °C
DMSO, 25 °C
DMF, -15 °C
DMF, 25 °C
6
0.5
0.5
2.5
6
12
2
64 [R/â ) 1:7] (80%)
â -OAc
89 [R/â ) 3.5:1] (90%)
90 [R/â ) 3.6:1] (87%)
O
O
O
O
O
O
O
90 [R/â ) 9:1] (84%) (recov 13% 86)
90 [R/â ) 6:1] (80%) (recov 15% 86)
91R (60%) + 91â (15%) (+10% 88)
NR
93 [R/â ) 5.5:1] (90%)
NR
88
86R
86R
85
6
12
TBS
DMSO, 25 °C
a Ratio for inseparable diastereomers estimated by NMR.
that the product had the unnatural â-methyl configuration 64â.
This assignment was ultimately secured by single-crystal X-ray
analysis of bis-desilylated triol diacetate 82.33
of the C26-OH was unnecessary, as NBS-mediated oxidation64
of the 3,17,26-triol derived from 71R proceeded smoothly at
C3 to give diol 86R in high yield.
Although â-face quenching with thiol would give 64R bearing
the more stable natural R-methyl configuration at C20, the
R-configured radical from bromide 71S may have been quenched
by excess thiol to give 64â before equilibration to the more
stable â-configured radical precursor of 64R.
The breakthrough to achieve the correct C20 stereochemistry
involved conducting the chromium-mediated reductiVe cleaVage
on the C17 alcohol (Scheme 23 and Table 6). For example,
while reduction of 71S (17-OTMS) generated a 1:7 mixture of
64R and 64â (Table 4, entry 4 ) Table 5, entry 1), reaction of
87 afforded a 3.5:1 ratio of 89R to 89â in 90% yield (Table 5,
entry 2). This structural feature carried over to the C3-keto
series, with essentially identical results being obtained for
dehalogenation of ketone 86 (17-OH) to 90R and 90â (entry
3). Furthermore, a substantially improved ratio of 9:1 for the
C20 diastereomers 90R,â was attained simply by carrying out
the reduction in DMF at -15 °C (entry 4), although even lower
temperature gave sluggish reaction with diminished selectivity
(entry 5). While the ketodiols 90R/90â were not readily sep-
arable, protection of the C26 neopentyl alcohols as TBS ethers
enabled surprisingly facile isolation of the pure keto-alcohols
91R and 91â (Scheme 23, R ) H, R′ ) TBDMS, X ) O) in
76% and 8% overall yields from 86, respectively. The C3
acetates 89R/89â could be likewise separated as their 26-OTBS
ethers 92R and 92â (70% and 20%, respectively, from 87).
Substantial effects on reduction rate were apparent for the
silyloxy groups at both C17 and C26. Reaction of 87 (17-OH)
proceeded far more quickly than had that of 71S (17-OTMS).
Reduction of 86 (17R,26R diol) was much faster than that of
88 (17R-OH, 26R-OTBDMS), although no change in selectivity
was evident (both gave a ∼3.5:1 C20R/â ratio, entries 2 and
5). Interestingly, 86R (17R,26â diol, the 25R epimer of 86) also
exhibited a slower rate than did 86 (entries 6 and 7), raising
In an effort to mediate the selectivity of the chromium(II)
system, a number of experiments were undertaken. The reactiv-
ity of Cr(OAc)2 was greatly improved by adding ethylenedi-
amine,62 but the product was olefin 77 (Table 4, entry 2).
Attempts involving CrCl2 were initially disappointing as no
reaction occurred (entry 3). Finally, we noted that reduction
proceeded smoothly (80%) proVided that a large excess of thiol
was employed (entry 4). These observations indicated that the
thiol might act not only as a hydrogen atom donor but also as
a ligand, thereby enhancing the reducing power of chromium-
(II). The NMR spectra of the products revealed a disappointing
1:7 ratio of the long sought 64R in addition to its inseparable
diastereomer 64â. Repeating the reaction with more sterically
demanding H-atom donors was unsatisfactory (entries 5,6).
Faced with an apparently impossible separation of the C20
diastereomers, it seemed prudent to delay bromide reduction
until after introduction of the ketone at C3. Accordingly, the
C26 hydroxyl of 71S was converted to C26 TBDMS ether 83,
followed by cleavage of the C3 acetate which afforded alcohol
84 (Scheme 22). Oxidation to ketone 85 followed by selective
bis-desilylation with H2SiF663 provided diol 86 in 83% overall
yield for the four-step procedure. Further reduction substrates
were generated by mono-desilylation of 71S to give 87 (17-
63
OH, 94% from 71S via H2SiF6 cleavage, see Scheme 23),
(63) Pilcher, A. S.; Hill, D. K.; Shimshock, S. J.; Waltermire, R. E.;
DeShong, P. J. Org. Chem. 1992, 57, 2492.
(64) Corey, E. J.; Ishiguro, M. Tetrahedron Lett. 1979, 79, 2745-2748.
reprotection of the C26-OH of 86 to afford 88, and conversion
of 71R to 86R. In this case, it was found that prior protection

Synthesis of the North 1 Unit of the Cephalostatin Family
J. Am. Chem. Soc., Vol. 121, No. 10, 1999 2065
Scheme 24
along with up to 25% of R-aminoenone 96 resulting from
competitive enolization and fragmentation67 of azidoketone 5.
Experimental Section
General Methods. All reactions were performed under a positive
pressure of argon at 25 °C with magnetic stirring unless otherwise
noted.Tetrahydrofuran (THF) and diethyl ether (Et2O) were distilled
from sodium benzophenone ketyl; benzene, toluene, CH2Cl2, dimethyl
sulfoxide (DMSO), and dimethylformamide (DMF) were distilled from
calcium hydride. Acetonitrile (CH3CN), chloroform (CHCl3), and
methanol (CH3OH) were spectra-grade. Ethyl acetate (EA) was reagent
grade. Hexane (Hex) was distilled (95% hexanes). Thin-layer chroma-
tography (TLC) was performed on silica gel 60 F-254 plates (EM
reagents, 0.25 mm). Preparative column chromatography (sgc) was
performed with 230-400 mesh silica gel. NMR spectra were deter-
mined in chloroform-d1 (CDCl3) at 300 (proton) and 75 MHz (carbon)
unless otherwise noted [benzene-d6 (C6D6), pyridine-d5 (C5D5N),
methanol-d4 (CD3OD), or deuterium oxide (D2O) were alternate
solvents] and are reported in parts per million (ppm, δ) referenced to
internal CHCl3 (7.26 and 77.00 ppm), C6D5H (7.15 ppm), CD2HOD
(3.30 and 49.00 ppm), C5D4HN (8.71 and 149.5 ppm), or HOD (4.65
ppm). Peak multiplicities are abbreviated as follows: s (singlet), d
(doublet), t (triplet), q (quartet), m (multiplet), b (broad), ap (apparent),
and ABq (AB quartet). In APT spectral lists, chemical shifts of carbons
with one or three attached hydrogens are marked with an asterisk; the
unmarked chemical shifts represent carbons with zero or two attached
hydrogen atoms. Mass spectra were run by the Purdue Campus-wide
Mass Spectrometry Facility; peaks are reported as m/z. Microanalyses
were performed by the Purdue Chemistry Department Microanalytical
Laboratory.
Table 6. Proton NMR Resonances in Pyridine-d5
compd
C-19 (s)
C-18 (s)
C-21 (d)
C-27 (s)
CSTAT 7 (10)2
CSTAT 12 (9)6
94R
0.75
0.73
0.78
0.80
1.31
1.33
1.31
1.93
1.33
1.35
1.34
1.65
1.61
1.63
1.63
1.63
94â
the possibility that the 26R-OH facilitates the reaction by
coordinating with the reagents. Finally, the combination of
silyloxy groups at both C17R and C26R appeared to completely
block access to C20 since reduction of 85 is impossibly slow
(entry 8). While a more complete understanding of the
mechanistic implications of these observations awaits further
refinement,65 it is apparent that a free alcohol moiety at C17
appears to be an absolute structural requirement for production
of the desired stereochemistry.
While the stereochemical assignment of all of the hexacyclic
compounds ultimately rested on the X-ray of 82 (desilylated
64â), the four methyl resonances in the proton NMR (pyridine-
d5) of pentaols 94R and 94â (from deprotection of 92R and
92â, respectively) were particularly informative when compared
to the published data from natural products cephalostatin 7 (10)2
and the “North dimer” cephalostatin 12 (9, Scheme 24). As can
be seen in Table 6, the methyl resonances of 94R, assigned the
natural configuration at C20, had essentially identical chemical
shifts to the North segments of the two reference cephalostatins.
Furthermore, compound 91R was used to complete the synthesis
of both cephalostatins 7 (10) and 126 (9), thus removing any
ambiguity about the structure of the spiroketal array.1
Bromo Epoxide 20. A mixture of enone 15 (15 g, 36 mmol, from
1 via modification of the method of Dauben and Micovic8,10,68), NBS
(7.4 g, 41 mmol), and a catalytic amount of benzoyl peroxide (0.40 g,
1.8 mmol) in cyclohexane (1.8 L) was heated at reflux for 3 h and
then cooled. Succinimide was removed by filtration and the solvent
evaporated under reduced pressure. The resulting oil was composed
(by NMR) of unreacted starting enone 15 (∼15%), γ-bromo enone 16
(∼75%), and dibromide 17 (<5%). This ternary mixture was dissolved
in 400 mL of methanol, cooled to 0 °C, and treated with 4 N NaOH
(0.6 mL) and then immediately with a 30% H2O2 solution (0.65 mL).
The mixture was then stirred at 0 °C for 24 h. The reaction was acidi-
fied with 5% HCl to pH 3, extracted into EA, and evaporated to give
a pale brownish oil. The residue was reacetylated (Ac2O/pyr), and sgc
(25% EA in Hex) afforded bromo epoxide 20 (10.5 g, 57%), epoxy
ketone 19 (10%), and ketone 18 (5%). Compound 20: 1H NMR δ
4.79 (1H, dd), 4.66 (1H, m), 4.3 (1H, d, J ) 5.4 Hz), 3.85 (1H, s),
2.01 (3H, s), 2.00 (3H, s), 2.0 (3H, s), 1.45 (3H, s), 0.9 (3H, s),
2.0-0.9 (remaining H, m); 13C NMR (50 MHz) δ 204.1, 171.7, 171.1,
74.2*, 73.7*, 71.9, 63.7*, 53.2*, 49.6*, 47.9*, 47.5, 45.2*, 36.86, 36.2,
34.1, 31.6*, 31.0, 28.6, 27.7, 27.1 27.0*, 22.0*, 21.7*, 13.8*, 12.5*;
MS (FAB) 451 (M - HOAc, base); HRMS (FAB) calcd for C25H35O6-
Completion of the synthesis of R-azidoketone 5 simply
involved treatment of ketone 91R with phenyltrimethylammo-
nium perbromide (PTAB) in THF for short reaction times to
afford R-bromoketone 95 (80%, 94% based on recovered 91R)
which was subjected to reaction with tetramethylguanidinium
azide (TMGA) in nitromethane66 (Scheme 25). This protocol
Br 451.1484, found 451.1465; [R]23 -40.5° (CHCl3, c 8); mp 185-
D
187 °C.
17: 1H NMR δ 6.66 (1H, d), 4.91 (1H, dd), 4.87 (1H, m), 4.68
(1H, m), 4.14 (2H, AB, two d), 2.00 (3H, s), 2.02 (3H, s), 1.41 (3H,
s), 0.93 (3H, s), 2.2-0.8 (remaining H’s, m).
Scheme 25
18: 1H NMR δ 7.21 (1H, d), 6.03 (1H, b, s), 4.62 (1H, m), 4.23
(1H, dd), 2.22 (3H, s), 1.96 (3H, s), 1.21 (3H, s), 0.92 (3H, s), 2.4-
0.6 (remaining H’s, m); 13C NMR δ 193.2, 170.8, 170.6, 167.8, 153.3,
143.8, 120.9, 75.2, 73.2, 58.1, 52.0, 44.2, 37.0, 35.9, 34.8, 33.8, 29.1,
28.0, 27.8, 27.3, 27.2, 21.5, 21.4, 14.5, 12.2; MS (EI) 414 (M), 354
(M - HOAc, base), (CI) 415 (M + H, base), 355 (M + H - HOAc);
HRMS (EI) calcd for C25H34O5 414.2406, found 414.2400.
19: 1H NMR δ 4.87 (1H, dd), 4.63 (1H, m), 3.49 (1H, s), 2.01 (3H,
s), 1.98 (3H, s), 1.97 (3H, s), 1.21 (3H, s), 0.82 (3H, s), 2.3-0.6
(remaining H’s, m).
smoothly generated R-azidoketone 5 in 75-85% yield (nearly
quantitative on small scales). This can be contrasted with other
azide reactions such as sodium azide in DMF that produced 5
(65) A study of factors influencing the course of the chromium(II) medi-
ated reduction is in progress and will be the subject of a future report.
(66) (a) Li, C.; Arasappan, A.; Fuchs, P. L. Tetrahedron Lett. 1993, 22,
3545. (b) Li, C.; Shih, T. L.; Jeong, J. U.; Arasappan, A.; Fuchs, P. L.
Tetrahedron Lett. 1994, 35, 2645.
(67) Magnus, P.; Miknis, G. F.; Press: N. J.; Grandjean, D.; Taylor, G.
M.; Harling, J. J. Am. Chem. Soc. 1997, 119, 6739.
(68) (a) Kaneko, K.; Niitsu, K.; Yoshida, N.; Mitsuhashi, H. Phytochem-
istry 1980, 19, 299. (b) Tschesche, R.; Schwinum, E. Chem. Ber. 1967,
100, 464.

2066 J. Am. Chem. Soc., Vol. 121, No. 10, 1999
Kim et al.
Vinyl Epoxide 21 and Dienyl Alcohol 22. A solution of bromo
epoxide 20 (73 mg, 0.14 mmol) was stirred with LiF (109 mg) and
Li2CO3 (207 mg) in DMF at 100 °C for 48 h. The reaction mixture
was cooled and diluted with EA. The organic layer was washed with
H2O, dried, and concentrated to give pale yellow oil; sgc (EA/Hex)
afforded 21 and 22 as well as SM 20 (20:21:22 ) 0.5:1.0:0.3). Vinyl
epoxide 21: 1H NMR δ 5.68 (1H, brd, J ) 0.9 Hz), 4.91 (1H, dd),
4.66 (1H, m), 3.98 (1H, s), 2.04 (3H, s), 2.03 (3H, s), 2.02 (3H, s),
1.43 (3H, s), 0.86 (3H, s), 2.2-0.6 (remaining H, m); 13C NMR (50
MHz) δ 204.9, 171.1, 170.1, 161.8, 119.6*, 74.5*, 73.7*, 71.4, 65.1*,
54.1, 50.4*, 44.3*, 37.1, 36.2, 34.3*, 34.2, 29.5, 28.2, 27.7, 27.2*, 26.9,
21.9*, 21.7*, 16.4*, 12.3*; MS (EI) 430 (M), 387 (M - COCH3, base),
(CI) 431 (M + H), 371 (M + H - HOAc, base); HRMS (EI) calcd for
C25H34O6 430.2355, found 430.2339.
22: 1H NMR (200 MHz) δ 6.70 (1H, d, J ) 5.7 Hz), 5.95 (1H, d,
J ) 6.0 Hz), 5.46 (1H, dd), 4.72 (1H, m), 3.50 (1H, s), 2.62 (1H, s),
2.30 (3H, s), 2.07 (3H, s), 2.02 (3H, s), 1.08 (3H, s), 0.81 (3H, s),
2.2-0.6 (remaining H, m); 13C NMR (50 MHz) δ 211.4, 171.9, 171.1,
140.1, 134.8*, 133.2, 132.7*, 91.2, 73.6*, 71.3*, 51.5, 50.3*, 44.3*,
38.0, 36.5, 34.3, 30.1, 29.0, 28.8*, 27.8, 25.6, 21.9*, 21.8*, 19.0*, 13.4*;
MS (EI) 387 (M - COCH3), 327 (M - COCH3-HOAc, base), (CI)
431 (M + H), 413 (M + H - H2O), 353 (M + H - H2O - HOAc,
base).
Tertiary Allylic Alcohol 25. Zinc dust (253 mg, 3.87 mmol) and
CuI (270 mg, 1.4 mmol) were sonicated in 50% EtOH (10 mL). After
formation of a black suspension (0.5 h), a solution of bromo epoxide
20 (221 mg, 0.43 mmol) in a minimum of THF was added and
sonication was continued until TLC indicated consumption of 20 (∼15
h). Addition of saturated NH4Cl, filtration, extraction with EA, and
sgc afforded 25 (183 mg, 99%). 1H NMR δ 6.25 (1H, dd, J ) 5.9, 1.7
Hz), 5.91 (1H, dd, J ) 5.7, 3.3 Hz), 5.42 (1H, dd), 4.68 (1H, m), 3.70
(1H, s), 2.45(1H, m), 2.25 (3H, s), 2.1 (3H, s), 2.05 (3H, s), 0.9 (3H,
s), 0.85 (3H, s), 2.0-1.0 (remaining H, m); 13C NMR (50 MHz) δ
211.5, 172.4, 171.1, 138.1*, 132.1*, 90.6, 73.7*, 72.7*, 55.3*, 55.1,
53.8*, 45.1*, 36.8, 36.1, 34.2, 31.9, 31.5*, 28.8*, 28.7, 27.7, 27.2, 21.9*,
21.7*, 13.3*, 12.6*; MS (EI) 432 (M), 269 (M - COCH3 - 2HOAc,
base), (CI) 433 (M + H), 415 (M + H - H2O, base); HRMS (EI)
calcd for C25H36O6 432.2511, found 432.2494. Anal. Calcd for
C25H36O6: C, 69.42; H, 8.39. Found: C, 69.05; H, 8.74. [R]25D - 50.6°
(CHCl3, c 12); mp 70-73 °C (foam).
) 4.5 Hz, D2O exchangeable), 5.08 (1H, d), 4.7 (1H, m), 4.24 (1H,
dd, J ) 6.0, 4.5 Hz), 4.14 (1H, m), 3.0 (1H, brd, J ) 1.5 Hz), 2.2 (3H,
s), 2.0 (3H, s), 1.98 (3H, s), 0.98 (3H, s), 0.85 (3H, s), 0.2 (9H, s),
2.1-0.9 (remaining H, m); 13C NMR (50 MHz) δ 218.3, 171.1, 170.1,
89.5, 82.9*, 74.3*, 73.9*, 71.0*, 53.7, 52.7*, 52.5*, 45.0*, 36.9, 36.1,
34.2, 31.7, 31.0*, 28.7, 28.5*, 27.7, 27.0, 21.9*, 21.8*, 12.7*, 12.5*,
1.9*; MS (EI) 538 (M), 435 (M - COCH3 - HOAc, base), (CI) 539
(M + H), 479 (M + H - HOAc - H2O, base); HRMS (EI) calcd for
C28H46O8Si 538.2961, found 538.2955. Anal. Calcd for C28H46O8Si:
C, 62.42; H, 8.61; Si, 5.21. Found: C, 62.16; H, 8.94; Si, 4.87. [R]23
D
- 22.0° in CH2Cl2 (c 11).
Cyclic Sulfate 33. To a well-stirred solution of diol 28 (0.20 g, 0.37
mmol) in pyridine at 0 °C was added SOCl2 (0.8 mL) dropwise over
5 min. The ice bath was removed and the mixture was stirred for 30
min, diluted with EA, and washed with saturated CuSO4, then passed
through silica to give 33a. The sulfite 33a was dissolved in CH3CN
and cooled to 0 °C, and NaIO4 (120 mg, 0.56 mmol) was added
followed by a catalytic amount (5%) of RuCl3 hydrate and 10 mL of
H2O. After 10 min, the mixture was diluted with CH2Cl2 and worked
up to afford 33b (219 mg, 99%) as a white solid. 1H NMR δ 5.23 (1H,
brt, J ) 5.7, 5.4 Hz), 4.96 (1H, dd), 4.78 (1H, d, J ) 5.7 Hz), 4.67
(1H, m), 2.4 (3H, s), 2.01 (3H, s), 1.92 (3H, s), 1.26 (3H, s), 0.87 (3H,
s), 0.12 (9H, s), 2.0-0.9 (remaining H, m); 13C NMR (50 MHz) δ
204.3, 171.0, 170.1, 89.7, 87.4*, 84.2*, 73.6*, 73.0*, 53.2, 52.4*, 52.0*,
44.9*, 36.8, 36.2, 34.1, 31.3*, 31.0, 30.8*, 28.4, 27.6, 26.5, 21.8*, 21.2*,
12.5*, 12.2*, 2.3*; MS (EI) 557 (M - COCH3), 497 (M - COCH3 -
HOAc), (CI) 601 (M + H); HRMS (EI) calcd for C28H44O10S1Si
600.2425, found 600.2404. Anal. Calcd for C28H44O10S1Si: C, 55.98;
H, 7.4; S, 5.34; Si, 4.67. Found: C, 56.10; H, 7.55; S, 5.23; Si, 4.45.
[R]23 - 54.0° in CH2Cl2 (c 12); mp: 202-204 °C.
D
33a (a pair of diastereomers): 1H NMR δ 5.43 and 5.08 (H-15, brt),
5.01 and 4.59 (H-16, d), 4.98 (H-12, dd), 4.69 (H-3, m), 2.42 and 2.38
(Me-21, s), 2.01 (C-3 OAc, s), 1.92 (C-12 OAc, s), 1.42 and 1.09 (Me-
18, s), 0.87 (Me-19, s), 0.15 and 0.12 (OTMS, s)
Hydroxy Epoxide 36. To a CH2Cl2 solution of cyclic sulfate 33 (6
mg, 0.01 mmol) was added DBU (4 mg, 0.03 mmol). After 10 h, the
mixture was poured into ice-cold sulfuric acid solution (1 N) and
extracted with CH2Cl2. The combined organic layers were washed with
brine and dried over MgSO4. After evaporation of solvent, crude
epoxide 36 (5.5 mg) was obtained as an oil. 1H NMR δ 4.82 (1H, dd),
4.81 (1H, d), 4.18 (1H, s), 3.63 (1H, br, s), 2.02 (3H, s), 1.99 (3H, s),
1.97 (3H, s), 1.40 (3H, s), 0.83 (3H, s).
TMS Ether 26. To a solution of alcohol 25 (270 mg, 1.4 mmol) in
pyridine at 0 °C was added TMSOTf (0.86 mL, 4.4 mmol). The mixture
was stirred for 1 h, then partitioned between EA and saturated NaHCO3.
The organic layer was washed with saturated CuSO4, dried (Na2SO4),
and evaporated, and sgc (10% EA in Hex) afforded 26 as a white foam
Allylic Alcohol 40. To a solution of cyclic sulfate 33 (0.24 g, 0.39
mmol) in toluene (∼0.01 M) was added tetrabutylammonium iodide
(1.1 g, ∼7 equiv). The mixture was stirred for 15 h at reflux and then
cooled. Precipitated TBAI was removed by filtration and washed twice
with toluene. The combined organic filtrates were evaporated in vacuo.
The residue was dissolved in CH2Cl2, and 60% mCPBA (336 mg, ∼3
equiv) was added. After 3 h, the mixture was poured into cold H2O.
The organic layer was washed successively with saturated NaHCO3
and dried (Na2SO4). After concentration under reduced pressure, the
yellowish residue was dissolved in THF (10 mL) to which H2O (0.1
mL) had been added. The clear solution was carefully acidified to pH
3 with concentrated H2SO4 and stirred for 2 h (until TLC analysis
indicated all the ammonium salt had been hydrolyzed), then diluted
with EA, washed with saturated NaHCO3, dried (Na2SO4), and
concentrated to afford a yellow oil in which only 40 was observed by
1H NMR analysis. Sgc (15% EA in Hex) gave 40 (81%) as a white
1
(1.41 g, 94%). H NMR δ 6.04 (1H, dd, J ) 6.0, 1.5 Hz), 5.87 (1H,
dd, J ) 6.0, 3.6 Hz), 5.40 (1H, dd), 4.67 (1H, m), 2.35 (1H, m), 2.19
(3H, s), 2.01 (3H, s), 1.98 (3H, s), 0.81 (3H, s), 0.71 (3H, s), 0.15 (9H,
s), 2.0-0.8 (remaining H, m); 13C NMR (50 MHz) δ 212.0, 172.0,
170.0, 136.2*, 134.1*, 94.0, 73.9*, 73.8*, 56.2*, 56.0, 53.8*, 45.0*,
30.5, 36.0, 34.0, 32.0, 31.9*, 29.0, 28.0, 27.0, 26.5*, 22.0*, 12.5*, 2.0*;
MS (EI) 461 (M - COCH3, base), (CI) 505 (M + H), 415 (M + H -
H2O - TMS, base); HRMS (CI) calcd for C28H44O6Si 504.2906, found
504.2888.
Epoxide 27. To a solution of allyl TMS ether 26 (10 mg, 0.02 mmol)
in CH2Cl2 was added an excess of 0.1 M dimethyldioxirane in acetone.
The mixture was stirred during 10 d with fresh DMDO added
repeatedly. The solvent was evaporated, and sgc gave 27 (3 mg, 30%)
1
1
and 26 (6 mg, 60%). H NMR δ 5.12 (1H, dd), 4.65 (1H, m), 3.45
foam. H NMR δ 5.46 (1H, dd, J ) 2.1, 2.1 Hz), 5.26 (1H, dd), 5.13
(2H, m), 2.25 (3H, s), 2.05 (3H, s), 1.98 (3H, s), 1.01 (3H, s), 0.85
(3H, s), 0.17 (9H, s), 2.0-0.8 (remaining H, m); 13C NMR (50 MHz)
δ 209.7, 171.2, 170.3, 89.4, 74.1*, 73.8*, 57.4*, 53.9*, 53.5*, 52.7*,
47.0, 45.1*, 36.7, 36.3, 34.2, 31.9, 31.3*, 28.7, 27.9*, 27.7, 27.4, 21.9*,
21.8*, 14.7*, 12.5*, 2.2*.
Diol 28. To a solution of olefin 26 (1.39 g, 2.75 mmol) in pyridine
was added OsO4 (840 mg, 3.3 mmol). The mixture was stirred for 10
h, then hydrolyzed with saturated NaHSO3 for 5 h. CH2Cl2 was added,
and the precipitate was collected by filtration (Celite) and washed with
warm CH2Cl2. The combined filtrates were washed twice with saturated
CuSO4, dried (Na2SO4), and concentrated; sgc (35% EA in Hex)
provided 28 (1.43 g, 96%) as a white foam. 1H NMR δ 5.82 (1H, d, J
(1H, brd, J ) 2.7 Hz), 4.69 (2H, m), 2.26 (3H, s), 2.02 (3H, s), 2.01
(3H, s), 1.12 (3H, s), 0.85 (3H, s), 0.16 (9H, s), 2.1-0.9 (remaining
H, m); 13C NMR (50 MHz) δ 217.5, 171.1, 170.0, 155.6, 122.2*, 88.4,
83.5*, 73.7*, 73.3*, 57.7, 50.5*, 44.3*, 37.0, 36.1, 35.0*, 34.2, 30.0,
28.5*, 28.4, 27.7, 27.1, 21.9*, 21.9*, 17.3*, 12.3*, 2.2*; MS (EI) 520
(M), 477 (M - COCH3), (CI) 521 (M + H), 503 (M + H - H2O,
base); HRMS (EI) calcd for C28H44O7Si 520.2856, found 520.2882.
Anal. Calcd for C28H44O7Si: C, 64.58; H, 8.52; Si, 5.39. Found: C,
64.81; H, 8.73; Si, 5.13; [R]23 +9.60° in CH2Cl2 (c 9).
D
Iodide 37: 1H NMR δ 5.03 (1H, brs), 4.94 (1H, dd), 4.69 (1H, m),
4.12 (1H, dd), 2.86 (8H, m), 2.43 (3H, s), 2.01 (3H, s), 1.88 (3H, s),
1.24 (3H, s), 0.82 (3H, s), 0.21 (9H, s).

Synthesis of the North 1 Unit of the Cephalostatin Family
J. Am. Chem. Soc., Vol. 121, No. 10, 1999 2067
Sulfate 39: 1H NMR δ 5.83 (1H, brs), 5.28 (1H, brs), 5.12 (1H,
dd), 4.69 (1H, m), 3.57 (8H, m), 2.28 (3H, s), 2.02 (3H, s), 1.99 (3H,
s), 1.18 (3H, s), 0.82 (3H, s), 0.18 (9H, s).
H’s, m); MS (EI) 546 (M, base), 486 (M - HOAc), (CI) 546 (M), 457
(M + H - HOTMS, base); HRMS (EI) calcd for C30H46O7Si 546.3013,
found 546.3018.
r-Phosphonate Esters 46. A solution of the diazophosphonate
ketone 44 (16 mg, 0.075 mmol) in benzene was added to a mixture of
a catalytic amount of Rh2(OAc)4 and the allylic alcohol 40 (13 mg,
0.025 mmol) in benzene at reflux over 15 min. The solvent was removed
by evaporation, and sgc yielded R-phosphonate esters 46 (17 mg,
Homoallylic Alcohols 3 and 4 (from 2). A solution of aldehyde 2
(0.21 g, 0.39 mmol) in 5.0 M LPDE (lithium perchlorate diethyl ether)
was treated with methallylstannane (0.27 g, 0.78 mmol). After 1 h, the
mixture was poured into cold water and EA. The aqueous layer was
extracted twice with EA. The combined organic layers were washed
with brine, dried, and evaporated to give an oil (1.3:1 3:4 by 1H NMR),
and sgc (1% THF/CH2Cl2) afforded 3 (126 mg) and 4 (100 mg).
Compound 3: 1H NMR (C6D6) δ 5.35 (1H, brs), 5.29 (1H, dd), 5.14
(1H, brd, J ) 2.4 Hz), 4.78 (1H, brs), 4.76 (1H, brs), 4.64 (1H, m),
4.47 (1H, m), 2.45 (2H, m), 1.8 (3H, s), 1.68 (3H, s), 1.66 (3H, s),
1.59 (3H, s), 1.14 (3H, s), 0.44 (3H, s), 0.19 (9H, s), 2.04-0.5
(remaining H, m); 13C NMR (C6D6) δ 169.3, 168.7, 159.1, 154.0, 141.6,
117.5*, 113.2, 108.0, 98.9, 93.7*, 73.6*, 72.8,*, 65.0*, 58.2, 50.3*,
43.6, 43.4*, 35.9, 35.3, 34.1*, 33.9, 29.3, 27.8, 27.4, 27.1, 22.4*, 21.0*,
20.8*, 17.8*, 11.4*, 8.8*, 1.6*; MS (EI) 600 (M), 545 (M - C4H7);
1
>98%) as a diastereomeric mixture. H NMR δ 5.60 (2H, d, J ) 2.4
Hz), 5.32 (2H, brt), 5.22 (2H, dd), 4.69 (2H, m), 4.13 (4H, m), 3.05
(2H, m), 2.15 (3H, s), 2.14 (3H, s), 2.02 (6H, s), 2.0 (6H, s), 1.56 (6H,
two dd), 1.31 (6H, m), 1.14 (3H, s), 1.12 (3H, s), 0.85 (6H, s), 0.19
(9H, s), 2.0-0.8 (remaining H, m); 13C NMR (50 MHz) δ 209.3, 208.5,
171.1, 170.4, 170.1, 170.1, 169.4, 169.3, 159.7, 159.6, 117.4*, 117.4*,
89.6, 89.4, 83.8*, 83.6*, 73.7*, 73.1*, 63.3, 63.1, 63.0, 58.4, 58.2, 50.7*,
44.4*, 41.9*, 41.1*, 39.3*, 38.4*, 37.0, 36.2, 35.1*, 34.2, 29.8, 29.2*,
29.2*, 28.3, 27.7, 26.9, 21.9*, 21.8*, 17.3*, 16.9*, 16.8*, 16.8*, 12.3*,
12.2*, 12.1*, 11.9*, 11.8*, 2.8*.
Dihydrofuran Ester 53. A solution of the diazophosphonate ester
51 (645 mg, 2.58 mmol) in benzene was added dropwise via syringe
drive over 5 to 6 h to a mixture of a catalytic amount (3-4%) of Rh2-
(OAc)4 and the allylic alcohol 40 (450 mg, 0.86 mmol) in benzene at
reflux. The solvent was removed by evaporation, and sgc of a portion
of the residue for analytical purposes provided 52 as a diastereomeric
mixture. The crude product 52 was used directly for the synthesis of
53 by slow addition of NaH (155 mg, 1.5 equiv) in THF at 0 °C. After
30 min, EA and H2O were added, the aqueous layer was extracted with
EA, and the combined organic layers were washed with brine and dried.
Solvent removal and sgc (10% EA in Hex) gave 53 (380 mg, 75%).
1H NMR δ 5.45 (1H, app t, J ) 2.4 Hz), 5.14 (1H, d, J ) 2.4 Hz),
5.04 (1H, dd), 4.68 (1H, m), 4.29 (2H, q), 2.02 (6H, s), 1.98 (3H, s),
1.35 (3H, t), 1.07 (3H, s), 0.86 (3H, s), 0.09 (9H, s), 2.04-0.9
(remaining H, m); 13C NMR (50 MHz) δ 171.1, 170.0, 161.7, 160.2,
142.8, 126.8, 117.6*, 98.5, 93.9*, 73.9*, 73.7*, 61.5, 58.9, 50.8*, 44.4*,
37.0, 36.2, 34.8*, 34.2, 29.9, 28.4, 27.7, 27.2, 21.9*, 21.9*, 18.2*, 14.7*,
12.4*, 11.2*, 2.0*; MS (EI) 588 (M), 528 (M - HOAc); HRMS (EI)
calcd for C32H48O8Si 588.3118, found 588.3097. Anal. Calcd for
C55H55O5Si: C, 65.28; H, 8.22; Si, 4.77. Found: C, 65.61; H, 8.57; Si,
4.51. [R]24D -57.5° in CH2Cl2 (c 10) mp 90-94 °C (typically used as
the crude foam).
HRMS (EI) calcd for C34H52O7Si 600.3482, found 600.3458; [R]23
24.4° (CH2Cl2, c 6).
-
D
4: 1H NMR (C6D6) δ 5.41 (1H, brt), 5.32 (1H, dd), 5.15 (1H, brd,
J ) 2.4 Hz), 4.80 (1H, brs), 4.86 (1H, brs), 4.67 (1H, m), 4.54 (1H,
m), 2.55 (2H, m), 1.85 (3H, s), 1.74 (3H, s), 1.73 (3H, s), 1.70 (3H, s),
1.23 (3H, s), 0.51 (3H, s), 0.19 (9H, s), 2.04-0.5 (remaining H, m);
13C NMR (C6D6) δ 169.4, 168.7, 159.6, 154.1, 141.8, 117.4*, 113.4,
108.1, 98.8, 93.6*, 73.5*, 72.9*, 65.1*, 58.4, 50.2*, 43.4*, 43.1, 36.0,
35.3, 34.2*, 33.9, 29.3, 27.8, 27.4, 27.0, 22.3*, 21.0*, 20.8*, 17.8*,
11.4*, 8.7*, 1.6*; MS (EI) 600 (M), 485 (M - C4H7 - HOAc, base),
(CI) 601 (M + H), 511 (M + H - HOTMS, base); HRMS (EI) calcd
for C34H52O7Si 600.3482, found 600.3494; [R]22 -39.6° (CH2Cl2, c
D
0.5).
Alcohol 3 (from 56). Formate 56 (40 mg, 0.064 mmol) in MeOH
(10 mL) was heated at reflux for 15 h, then cooled and concentrated.
Sgc gave 3 (33 mg, 87%).
Formate 56 (from 4). A toluene (0.8 mL) solution of alcohol 4 (50
mg, 0.083 mmol), PPh3 (109 mg, 0.417 mmol), and formic acid (19
mg, 0.42 mmol) was treated with diethyl azodicarboxylate (DEAD, 73
mg, 0.42 mmol). After 2 h, concentration and sgc (10% EA/Hex) gave
1
40 mg (77%) of formate 56. H NMR δ 8.07 (1H, s), 5.78 (1H, t),
5.39 (1H, brs), 5.02 (1H, s), 5.00 (1H, dd), 4.80 (1H, s), 4.73 (1H, s),
4.70 (1H, m), 2.48 (2H, m), 2.01 (3H, s), 1.99 (3H, s), 1.74 (3H, s),
1.71 (3H, s), 1.02 (3H, s), 0.83 (3H, s), 0.02 (9H, s), 2.2-0.8 (remaining
H’s, m); 13C NMR δ 170.7, 169.7, 160.1, 159.1, 149.4, 139.8, 117.3,
114.1, 111.9, 98.0, 93.6, 73.8, 73.4, 65.6, 58.2, 50.6, 44.1, 39.6, 36.6,
35.9, 34.3, 33.9, 29.5, 28.1, 27.3, 26.9, 22.6, 21.6, 21.5, 17.8, 12.0,
8.8, 1.6; MS (EI) 628 (M, base), 583 (M - OCHO), (CI) 629 (M +
H), 583 (M + H - HOCHO, base); HRMS (EI) calcd for C35H52O8Si
628.3431, found 628.3443.
52: 1H NMR δ 5.58 (1H, brs), 5.06 (1H, two dd), 4.69 (2H, m),
4.54 (1H, brs), 4.4-4.1 (6H, m), 2.30 (3H, two s), 2.01 (6H, four s),
1.21 and 1.18 (3H, two s), 1.82 (3H, s), 0.17 (9H, s).
Dihydrofuran Aldehyde 2. A mixture of dihydrofuran ester 53 (0.41
g, 0.70 mmol) and 2.0 M LiBH4 (1.3 mL, 2.6 mmol) in THF was stirred
at reflux for 5 h. The solution was quenched with cold H2O and the
water layer was extracted twice with EA. The combined organic layers
were washed with brine, dried (Na2SO4), passed through silica gel, and
evaporated. The residual oil (54a/54b) was redissolved in EA and MnO2
(1.21 g) was added. Vigorous stirring was continued for 3 h. The
mixture was filtered (Celite) and the filtrate was evaporated and
acetylated (Ac2O/Et3N/DMAP) to afford pentacyclic aldehyde 2 (232
mg, 61%) as a white foam. 1H NMR δ 9.69 (1H, s), 5.45 (1H, dd, J )
2.4, 2.1 Hz), 5.15 (1H, d, J ) 2.4 Hz), 5.03 (1H, dd), 4.67 (1H, m),
2.04 (3H, s), 2.01 (3H, s), 2.01 (3H, s), 1.07 (3H, s), 0.85 (3H, s), 0.09
(9H, s), 2.04-0.9 (remaining H’s, m); 13C NMR (50 MHz) δ 182.4*,
171.1, 170.0, 160.2, 150.1, 132.5, 117.5*, 98.3, 94.0*, 73.7*, 73.7*,
58.9, 50.8*, 44.4*, 37.0, 36.2, 34.8*, 34.2, 30.0, 28.4, 27.7, 27.1, 21.9*,
18.1*, 12.4*, 9.4*, 2.1*; MS (EI) 544 (M), 515 (M - CHO), (CI) 545
(M + H), 395 (M + H - 2HOAc - HCOH, base); HRMS (EI) calcd
Tetraol 57. Alcohol 3 and K2CO3 in MeOH was refluxed for 5 h to
1
afford 57, which was crystallized from MeOH/Hex (1:3.5). H NMR
(CD3OD) δ 5.33 (1H, brt), 4.69 (1H, brs), 4.65 (1H, brs), 4.41 (1H,
app t, J ) 7.3 Hz), 3.84 (1H, dd), 3.5 (1H, m), 2.30 (2H, brd), 2.13
(1H, s), 1.68 (3H, s), 1.66 (3H, s), 1.00 (3H, s), 0.87 (3H, s), 2.1-0.7
(remaining H, m); MS (FAB, NBA matrix) 467 (M + Na); HRMS
(FAB, KIPEG/NBA/NaI matrix) calcd for C27H40O5 + Na 467.2773,
found 467.2759; mp 160 °C dec.
TBDPS Ether 61. To a solution of AgNO3 (30 mg, 2 equiv) and
alcohol 3 (53 mg, 0.089 mmol) in DMF was added TBDPSCl (47 µL,
2 equiv). A white precipitate formed immediately. After 15 min, the
mixture was diluted with EA and H2O. The organic layer was dried,
and sgc provided pure 61 (73 mg, 98%) as a colorless oil. 1H NMR δ
7.72 (4H, m), 7.38 (6H, m), 5.40 (1H, brt), 5.0 (1H, brd, J ) 2.4 Hz),
4.96 (1H, dd), 4.68 (1H, m), 4.53 (1H, brs), 4.51 (1H, brs), 4.42 (1H,
dd), 2.02 (3H, s), 2.00 (3H, s), 1.36 (3H, s), 1.07 (3H, s), 1.05 (9H, s),
for C30H44O7Si 544.2856, found 544.2850; [R]23 - 50.3° in CH2Cl2
D
(c 6).
54a: 1H NMR δ 5.40 (1H, br, t), 5.07 (1H, d, J ) 2.4 Hz), 5.03
(1H, dd), 4.17 (2H, d), 3.60 (1H, m), 2.01 (3H, s), 1.65 (3H, s), 1.08
(3H, s), 0.85 (3H, s), 0.09 (9H, s), 2.1-0.8 (remaining H’s, m); MS
(EI) 504 (M, base), 444 (M - HOAc), (CI) 504, 415 (M + H -
HOTMS, base); HRMS (EI) calcd for C28H44O6Si 504.2907, found
504.2917.
0.94 (3H, s), 0.84 (3H, s), 0.03 (9H, s), 2.4-0.7 (remaining H, m); 13
C
NMR (50 MHz, C6D6) δ 170.0, 170.0, 159.8, 154.6, 141.5, 136.9*,
136.9*, 134.8, 134.5, 130.5*, 130.5*, 118.4*, 114.3, 109.4, 99.5, 93.5*,
74.4*, 73.5*, 67.7*, 59.2, 51.0*, 44.5, 44.1*, 36.7, 36.0, 34.8*, 34.6,
30.0, 28.5, 28.1, 27.7*, 22.8*, 21.7*, 21.5*, 20.1, 18.5*, 12.1*, 9.6*,
2.6*; MS (FAB, DTT/DTE matrix) 839 (M); HRMS (FAB, KIPEG/
DTT/DTE matrix) calcd for C50H70O7Si2 839.4738, found 839.4657.
54b: 1H NMR δ 5.40 (1H, br, t), 5.07 (1H, d, J ) 2.4 Hz), 5.03
(1H, dd), 4.69 (1H, m), 4.18 (2H, br, d), 2.04 (3H, s), 2.01 (3H, s),
1.65 (3H, s), 1.08 (3H, s), 0.85 (3H, s), 0.09 (9H, s), 2.1-0.9 (remaining

2068 J. Am. Chem. Soc., Vol. 121, No. 10, 1999
Kim et al.
1
Diols 62S/62R. To a solution of [S,S] Corey ligand 63 (310 mg, 1.3
equiv) in CH2Cl2 (0.03 M) at -78 °C was added OsO4 (1 equiv) in
one portion. After 30 min, the mixture was cooled to -98 °C and a
precooled solution of TBDPS ether 61 (420 mg, 0.50 mmol) in
CH2Cl2 was added by cannula over 5 min. After 1 h, powdered NaHSO3
was added, the reaction was warmed, and the solvent was removed in
vacuo. The residue was taken up in aqueous THF and refluxed for 11
h. The solids were filtered off and washed with EA, and the combined
filtrates were washed with brine and dried. The inseparable mixture of
crude diols 62S/62R (S-C25:R-C25 ) 4:1) was purified by sgc (414
(6.5 mg, 75%). H NMR δ 4.05 (1H, brt), 4.95 (1H, dd), 4.90 (1H,
brd), 4.89 (1H, app t), 4.71 (1H, m), 2.69 (2H, m), 2.09 (3H, s), 1.98
(3H, s), 1.97 (3H, s), 1.25 (3H, s), 1.01 (9H, s), 0.95 (3H, s), 0.91 (3H,
s), -0.09 (9H, s), 2.2-0.8 (remaining H, m); 13C NMR (50 MHz) δ
206.3, 171.1, 170.1, 160.4, 152.5, 136.7*, 136.4*, 133.9, 133.5, 130.4*,
130.2*, 128.1*, 128.1*, 128.1*, 117.6*, 109.9, 98.3, 92.7*, 74.1*, 73.8*,
64.7*, 58.7, 50.7*, 49.5, 44.4*, 36.9, 36.2, 34.8*, 34.3, 31.5*, 30.0,
28.5, 27.7, 27.4*, 27.1, 21.9*, 19.8, 18.4*, 12.3*, 8.7*, 2.2*; MS (FAB,
NBA) 840 (M); HRMS (FAB, NBA) calcd for C49H67O8Si2 840.4453,
found 840.4497.
1
mg, 95%). H NMR δ 7.8 (4H, m), 7.4 (6H, m), 5.43 (1H, brs), 4.95
Olefin 77. Procedure 1: A solution of bromide 71S (10 mg, 0.01
mmol) in a quartz tube containing excess NaHCO3 in i-PrOH was
irradiated at 254 nm for 1 h (Rayonet reactor). The mixture was
concentrated and sgc afforded 77 (65%). Procedure 2: (Note: Argon
was carefully deoxygenated by passing through a basic pyrogallol
solution followed by drying.) To a solution of bromoketal 71S (45 mg,
0.050 mmol) in dimethyl sulfoxide (3 mL, redistilled) containing
ethylenediamine (0.11 mL, 1.9 mmol) was added Cr(OAc)2 (89 mg,
0.47 mmol). After 30 min, the mixture was poured into ice water and
extracted into EA. Concentration and sgc provided 77 (40 mg, 99%).
1H NMR δ 7.76-7.34 (10H, m), 5.41 (1H, brs), 5.18 (1H, s), 5.12
(1H, s), 4.99 (1H, dd), 4.95 (1H, d, J ) 2.1 Hz), 4.68 (1H, m), 4.26
(1H, dd), 3.05 and 2.93 (2H, AB, two d, J ) 11.1 Hz), 2.01 (6H, s),
1.57 (3H, s, overlap with H2O), 1.13 (3H, s), 1.06 (9H, s), 0.84 (3H,
s), 0.10 (9H, s), 2.0-0.8 (remaining H, m); 13C NMR δ 2.4, 11.9, 14.2,
17.9, 19.1, 21.4, 21.5, 25.5, 28.0, 29.4, 33.8, 34.4, 35.8, 36.5, 40.2,
44.1, 50.8, 56.5, 60.4, 69.7, 73.4, 74.3, 75.4, 80.3, 91.3, 92.4, 110.9,
111.4, 119.9, 127.5, 129.8, 133.5, 134.0, 135.9, 136.1, 151.5, 155.1,
169.7, 170.6; MS (FAB, NBA) 871.8 (M); HRMS (FAB, NBA) calcd
for C50H70O9Si2 871.4637, found 871.4625.
(H-12, two dd), 4.87 (1H, s), 4.65 (2H, m), 3.35 (1H, s), 3.15 (2H, m),
2.02 and 2.00 (3H, two s (1:4)), 1.95 (3H, two s), 1.65 (3H, s), 1.24
(3H, s), 1.05 (9H, two s), 0.96 (3H, s), 0.82 (3H, s), 0.02 and 0.03
(OTMS, two s (1:4)); 13C NMR, the peaks at δ 162, 118, 111, 98, 72,
71, 23, 18, 8 all show the same 1:4 ratio; MS (FAB, DTT/DTE
matrix) 872 (M); HRMS (FAB, KIPEG/DTT/DTE matrix) calcd for
C50H72O9Si2 873.4792, found 873.4727.
Tetraols 66S/66R. To a solution of 62S/62R (40 mg, 0.046 mmol)
in THF was added TBAF (0.18 mL, 4 equiv) in THF. After 2 h, the
solution was poured into saturated NH4Cl and extracted with EA.
The organic layer was washed with brine and dried, and sgc (20%
MeOH in CH2Cl2) afforded tetraols 66S/66R (24 mg, 93%). 1H NMR
(CD3OD) δ 5.43 (1H, br, s), 5.12 (1H, dd), 4.68 (3H, m), 3.42 (1H, br,
s), 3.35 (1H, br, s), 2.00 (3H, s), 1.99 (3H, s), 1.70 (3H, s), 1.22 (3H,
s), 0.87 (3H, s); 13C NMR δ 171.4, 170.8, 159.9, 153.9, 148.3, 117.8,
107.9, 95.6, 95.0, 73.4, 72.9, 70.8, 63.7, 57.0, 52.2, 50.2, 44.0, 42.8,
36.7, 35.8, 34.4, 33.8, 29.6, 28.0, 27.3, 25.2, 24.7, 21.6, 21.6, 21.5,
20.3, 18.6, 18.5, 13.7, 12.0, 8.0; MS (FAB, NBA matrix) 585 (M +
Na); HRMS (FAB, NBA matrix) calcd for C31H46O9 + Na 585.3040,
found 585.3046.
General Procedure for Cr(II) Mediated Reductions. NB: Argon
was deoxygenated by passing through a basic pyrogallol solution
followed by drying. Failure to follow this precaution resulted in little
or no reduction. The substrate in DMSO or DMF was deoxygenated
by purging with argon for 40 min. Propanethiol was added, and the
chromous salt was added in one portion. The reaction was partitioned
between water and EA, dried (Na2SO4), concentrated, and (if needed)
purified by sgc.
Bromospiroketals 71S and 71R. To a solution of diols 62S/62R
(4:1 ratio; 100 mg, 0.114 mmol) in THF at -78 °C was added NBS
(31 mg, 1.5 equiv) in one portion, followed by warming to 0 °C. After
1 h, saturated Na2S2O3 and saturated NaHCO3 were added, the aqueous
layer was extracted with EA, and the combined organic layers were
dried (Na2SO4). Evaporation and sgc afforded bromospiroketal 71S
(83.5 mg, 77%). 1H NMR δ 7.93 (4H, m), 7.4 (6H, m), 5.54 (1H, brt),
5.41 (1H, dd,), 4.83 (1H, brd, J ) 1.8 Hz), 4.71 (1H, m), 4.71 (1H,
dd), 3.04 and 3.11 (2H, AB, two d, J ) 11.4 Hz), 2.03 (3H, s), 2.01
(3H, s), 1.90 (3H, s), 1.53 (3H, s), 1.09 (3H, s), 1.05 (9H, s), 0.85 (3H,
s), 0.20 (9H, s), 2.2-0.8 (remaining H’s, m); 13C NMR (50 MHz) δ
171.1, 170.1, 162.7, 136.6*, 136.3*, 135.6, 134.1, 130.2*, 130.0*,
128.1*, 127.8*, 117.0*, 114.8, 96.0, 86.4*, 83.0, 81.6, 80.0*, 73.8*,
73.8*, 69.9, 58.9, 49.6*, 44.5*, 40.5, 37.3, 36.0, 34.6*, 34.3, 29.8, 28.5,
27.8, 27.5*, 27.0*, 26.7, 25.5*, 22.0*, 21.9*, 19.9, 18.4*, 12.1*, 3.8*;
MS (FAB, DTT/DTE matrix) 871 (M + H - HBr); HRMS (FAB,
KIPEG/DTT/DTE matrix) calcd for C50H71O9Si2 871.4637, found
Debrominated Spiroketals 64r/64â. Bromospiroketal 71S (50 mg,
0.053 mmol) in DMSO (2 mL, redistilled) containing propanethiol (0.50
mL, 5.3 mmol) was reduced with CrCl2 (27 mg, 0.21 mmol) according
to the general procedure to afford 64 (â/R ) 7:1 by NMR) as a colorless
1
oil (80%, 37 mg). H NMR (major peaks only) δ 7.8-7.4 (10H, m),
5.4 (1H, brt), 5.05 (1H, dd), 4.7 (1H, d, J ) 2.4 Hz), 4.7 (1H, m), 4.03
(1H, dd), 3.13, 3.01 (2H, AB, two d, J ) 11.1 Hz), 2.74 (1H, q), 2.05
(3H, s), 2.01 (3H, s), 1.41 (3H, s), 1.15 (3H, s), 1.1 (9H, s), 0.97 (3H,
d, J ) 7.5 Hz), 0.83 (3H, s), 0.06 (9H, s), 2.1-0.8 (remaining H, m);
13C NMR (50 MHz, C6D6; major peaks only) δ 170.1, 169.6, 159.8,
136.8*, 136.5*, 135.3, 134.9, 130.6*, 119.3*, 113.9, 95.9, 91.5*, 81.5,
75.5*, 75.4*, 75.4*, 73.6*, 70.3, 58.2, 50.9*, 50.1*, 44.1*, 40.2, 36.8,
36.0, 34.6, 34.5*, 30.1, 28.6, 28.1, 28.0*, 26.9, 26.2*, 21.7*, 21.5*,
20.1, 17.3*, 12.0*, 9.3*, 3.4*; MS (FAB, DTT/DTE matrix) 872.5 (M,
weak), 813 (M - HOAc); HRMS (FAB, DTT/DTE matrix) calcd for
C50H72O9Si2 - HOAc 813.4582, found 813.4565.
871.4621; [R]25 - 11.2° in CH2Cl2 (c 5); mp 145-146 °C.
D
Further elution provided 71R (16.5 mg, 15%): 1H NMR δ 7.82 (4H,
m), 7.41 (6H, m), 5.51 (1H, brt), 5.39 (1H, dd, J ) 11.4, 4.6 Hz), 4.82
(1H, d, J ) 1.8 Hz), 4.71 (1H, m), 4.69 (1H, dd), 3.28 (1H, d), 3.04
(1H, t), 2.73 (1H, d), 2.27 (1H, t), 2.03 (3H, s), 2.01 (3H, s), 1.90 (3H,
s), 1.47 (3H, s), 1.04 (9H, s), 0.87 (3H, s), 0.84 (3H, s), 0.19 (3H, s);
13C NMR δ 170.6, 169.6, 162.7, 136.2, 135.9, 134.8, 133,7, 129.9,
129.6, 127.7, 127.5, 116.3, 114.0, 95.6, 86.3, 82.0, 81.9, 79.3, 73.4,
73.4, 67.9, 58.5, 49.2, 44.1, 36.7, 35.7, 34.2, 33.9, 29.4, 29.3, 28.1,27.4,
27.1 (3C), 26.6, 26.2, 24.4, 21.6, 21.5, 19.5, 18.1, 11.7, 3.4; MS (FAB,
DTT/DTE) 871 (M + H - HBr); HRMS (FAB, DTT/DTE) calcd for
C50H71O9Si2 871.4637, found 871.4641.
Bromotriol 78. Deprotection of the 17-OTMS of 71S (10 mg, 0.011
mmol) was performed as for 66 except 3 equiv of TBAF at 0 °C for
1
15 min sufficed; sgc afforded 78 (6.1 mg, 91%). H NMR (C6D6) δ
5.24 (1H, brt), 5.09 (1H, brs), 5.05 (1H, dd), 4.95 (1H, dd), 4.70 (1H,
m), 4.5 (1H, brs), 3.3, 3.1 (2H, AB, two d), 2.3 (2H, m), 2.1 (3H, s),
1.78 (3H, s), 1.71 (3H, s), 1.41 (3H, s), 1.2 (3H, s), 0.45 (3H, s), 2.0-
0.2 (remaining H, m). This compound was too unstable for further
characterization.
Bromospiroketal Diol 72. Selective monodeacetylation of 71S was
1
performed by our standard protocol1g to afford 72. H NMR δ 7.85
(4H, m), 7.41(6H, m), 5.53 (1H, brs), 5.40 (1H, dd), 4.82 (1H, brd, J
) 2.7 Hz), 4.70 (1H, app q), 3.68 (1H, m), 3.06 (2H, AB, brq), 2.02
(3H, s), 1.91 (3H, s), 1.53 (3H, s), 1.09 (3H, s), 1.05 (9H, s), 0.84 (3H,
s), 0.20 (9H, s), 2.2-0.8 (remaining H, m).
Ketone 73. To a solution of 62S/62R (4:1 ratio; 10 mg, 0.011 mmol)
in CH3CN was added IDCP (iodonium dicollidine perchlorate, 18 mg,
3 equiv) in one portion. After 3 h, saturated Na2S2O3 and NaHCO3
were added, the aqueous layer was extracted with EA, and the combined
organic layers were dried (Na2SO4). Evaporation and sgc afforded 73
Olefinic Triol 79. TBAF (0.3 mL, 10 equiv) in THF was added to
a solution of 71S (27 mg, 0.028 mmol) in THF containing 4 equiv of
AcOH. After 24 h, the mixture was poured into saturated NH4Cl and
extracted with EA. The organic layer was washed with saturated NaCl
and dried (Na2SO4), and sgc (20% MeOH in CH2Cl2) afforded 79 (14.3
1
mg, 85%). H NMR (CD3OD) δ 5.54 (1H, brs), 5.41 (1H, brt), 5.32
(1H, brs), 4.65 (1H, m), 4.49 (1H, d, J ) 2.4 Hz), 4.29 (1H, dd), 3.40
(2H, AB, two d, overlap with MeOH), 2.31 (1H, dd), 2.01 (3H, s),
2.00 (3H, s), 1.12 (3H, s), 1.10 (3H, s), 0.87 (3H, s), 2.12-0.9

Synthesis of the North 1 Unit of the Cephalostatin Family
J. Am. Chem. Soc., Vol. 121, No. 10, 1999 2069
(remaining H, m); 13C NMR (50 MHz, CD3OD) δ 172.8, 172.6, 160.0,
155.4, 119.8*, 114.8, 114.0, 93.8*, 89.1, 83.7, 80.3*, 76.0*, 75.2*,
70.0, 56.6, 52.3*, 45.6*, 40.6, 38.0, 37.1, 36.4*, 35.2, 31.0, 29.5, 28.7,
27.7, 26.4*, 21.8*, 21.5*, 19.8*, 12.5*; MS (FAB, NBA) 583 (M +
Na); HRMS (FAB, NBA) calcd for C31H42O9 + Na 583.2883, found
583.2894.
inferior results and led to decomposition of the diol product. The
solution used here was prepared 8 days in advance and stored in a
polypropylene bottle). The reaction was allowed to stir for 1.5 h while
1
monitoring by H NMR, then was quenched by addition of saturated
NaHCO3 solution. The CH3CN was removed in vacuo and the yellow
oil was dissolved in Et2O (75 mL). The Et2O layer was washed with
brine and dried (Na2SO4). Sgc (30% to 40% EA/Hex) afforded 121
Spiroketal Triol 82. Exhaustive desilylation of spiroketals 64 (7:
1â/R, 25 mg, 0.029 mmol) was performed as for 66 to provide 82 (13
1
mg (93%) of 86 as a white foam. H NMR δ 1.01 (s, 9H), 1.06 (s,
1
mg, 81%), which was subjected to single-crystal X-ray analysis. H
3H), 1.09 (s, 3H), 1.56 (s, 3H), 1.97 (s, 3H), 2.01 (s, 3H), 2.92 (dd, J
) 12, 8.9 Hz, 1H), 3.16 (dd, J ) 12, 5.1 Hz, 1H), 4.92 (dd, J ) 11,
5.1 Hz, 1H), 5.01 (dd, J ) 11, 8.1 Hz, 1H), 5.11 (d, J ) 1.5 Hz, 1H),
5.53 (brs, 1H), 5.64 (s, 1H), 7.40-7.49 (m, 6H), 7.81-7.84 (m, 2H),
7.87-7.90 (m, 2H), 0.8-2.2 (remaining H, m); 13C NMR δ 11.5, 13.2,
19.6, 21.9, 25.3, 26.8 (3C), 27.3, 27.6, 27.8, 28.5, 28.6, 34.3, 36.5,
38.1, 38.2, 39.6, 44.7, 46.5, 53.6, 54.1, 69.6, 77.8 (2C), 82.0, 90.2 (2C),
115.3, 121.2, 128.1 (2C), 128.3 (2C), 130.3, 130.7, 132.2, 133.6, 135.9
(2C), 136.2 (2C), 154.1, 170.5, 211.4; MS (FAB, NBA) 835 (M + H);
HRMS (FAB, NBA) calcd for C45H60BrO8Si 835.3241, found 835.3267;
NMR (CD3OD) δ 5.36 (1H, brt), 5.15 (1H, dd), 4.63 (1H, m), 4.30
(1H, d, J ) 2.4 Hz), 3.90 (1H, dd), 3.30, 3.22 (2H, AB, two d, J )
11.1 Hz), 2.83 (1H, m), 2.67 (1H, q), 2.17 (2H, m), 2.02 (3H, s), 1.97
(3H, s), 1.44 (3H, s), 1.20 (3H, s), 1.13 (3H, d, J ) 7.5 Hz), 0.87 (3H,
s), 2.0-0.8 (remaining H, m); MS (FAB, DTT/DTE matrix) 585 (M
+ Na); HRMS (FAB, DTT/DTE matrix) calcd for C31H46O9 + Na
585.3040, found 585.3009; mp 196-199 °C.
TBS Ether 83. To a solution of 71S (170 mg, 0.178 mmol) in DMF
(3 mL) was added imidazole (42 mg, 0.62 mmol) and tert-butyldi-
methylsilyl chloride (67 mg, 0.45 mmol). After 5 h, the reaction was
cooled to 0 °C and water was added followed by Et2O. The aqueous
layer was extracted with Et2O and the combined organic layers were
washed with water and dried, and sgc (10% EA/Hex) afforded 83 (180
[R]24 +44.5° in CH2Cl2 (c 20).
D
Ketodiol 86R. The minor diastereomer 71R (0.320 g, 0.336 mmol,
collected from several NBS mediated spiroketalizations of 62S/62R)
was hydrolyzed as per 84. The 3,26-diol product (0.300 g, 0.330 mmol)
was dissolved in 10% aqueous DME (7 mL) and treated with NBS
(0.117 g, 0.66 mmol, 2 equiv) for 4 h, then diluted with EtOAC, washed
with water, dried (Na2SO4), and concentrated to give crude 3-keto,26-
OH,17-OTMS ether. To a solution of this silyl ether (0.295 g, 0.325
mmol) in CH2Cl2 (6.5 mL) was added BF3‚OEt2 (49 µL, 0.39 mmol,
1.2 equiv) dropwise over 2 min. After 1.5 h, the mixture was diluted
with EtOAC, washed with aqueous NaHSO3, dried (Na2SO4), and
concentrated. Sgc (50:1 to 20:1 CH2Cl2/THF) afforded 0.250 g (90%)
1
mg, 95%) as a white foam. H NMR δ -0.12 (s, 6H), 0.19 (s, 9H),
0.79 (s, 9H), 0.85 (s, 3H), 1.00 (s, 3H), 1.05 (s, 9H), 1.54 (s, 3H), 1.90
(s, 3H), 2.01 (s, 3H), 2.02 (s, 3H), 3.01 (d, J ) 9.9 Hz, 1H), 3.16 (d,
J ) 9.9 Hz, 1H), 4.68-4.76 (m, 1H), 4.82 (d, J ) 2.7 Hz, 1H), 4.86
(dd, J ) 18, 8.1 Hz, 1H), 5.43 (dd, J ) 12, 4.5 Hz, 1H), 5.54 (t, J )
2.0 Hz, 1H), 7.36-7.41 (m, 6H), 7.80-7.83 (m, 2H), 7.90-7.93 (m,
2H), 0.5-2.2 (remaining H, m); 13C NMR: δ -5.7 (2C), 3.3 (3C),
11.6, 17.8, 18.2, 19.5, 21.4, 21.5, 25.5, 25.7, 25.9 (3C), 26.2, 26.4,
27.0 (3C), 27.3, 28.1, 29.3, 33.8, 34.1, 35.5, 36.8, 39.8, 44.0, 49.1,
58.4, 69.3, 73.4, 79.8, 81.5, 83.4, 85.6, 95.6, 114.5, 116.6, 127.3 (2C),
127.6 (2C), 129.2, 129.6, 134.0, 135.5, 135.8 (2C), 136.2 (2C), 162.0,
169.6, 170.6; MS (FAB, NBA) 985 (M + H - HBr); HRMS (FAB,
NBA) calcd for C56H85O9Si3 985.5501, found 985.5471.
1
of 86R as offwhite solids. H NMR δ 0.76 (s, 3H), 1.01 (s, 9H), 1.06
(s, 3H), 1.09 (s, 3H), 1.55 (s, 3H), 1.93 (s, 3H), 2.01 (s, 3H), 2.70 (dd,
J ) 10.5, 1.5 Hz, 1H), 3.02 (apt, J ) 11 Hz, 1H), 3.30 (dd, J ) 11.3,
1.5 Hz, 1H), 4.83 (dd, J ) 11.5, 7.3 Hz, 1H), 4.94 (dd, J ) 10.7, 5.1
Hz, 1H), 5.06 (d, J ) 1.5 Hz, 1H), 5.48 (brs, 1H), 5.64 (s, 1H), 7.40-
7.51 (m, 6H), 7.80-7.85 (m, 2H); 13C NMR δ 11.1 (q), 12.8 (q), 19.1
(s), 21.4 (q), 23.6 (q), 26.3 (q, 3C), 26.9 (q), 27.3 (t), 28.0 (t), 28.1 (t),
33.8 (d), 35.6 (t), 36.0 (s), 37.66 (t), 37.75 (t), 44.2 (t), 46.0 (d), 53.1
(d), 53.7 (s), 67.4 (t), 75.2 (s), 75.8 (d), 77.0 (d), 81.6 (s), 89.7 (d),
90.4 (s), 114.5 (s), 120.5 (d), 127.7 (d, 2C), 127.9 (d, 2C), 130.0 (d),
130.3 (d), 131.5 (s), 132.5 (s), 135.5 (d, 2C), 135.7 (d, 2C), 154.2 (s),
170.0 (s), 210.8 (s); MS (CI) 757/759 (M + H - HBr), (FAB, NBA)
835 (M + H); HRMS (FAB, NBA) calcd for C45H60BrO8Si 835.3241,
found 835.3256.
Alcohol 84. Selective monodeacetylation of 83 (170 mg, 0.159
mmol) as per our standard protocol1g provided 84 (155 mg, 95%) as a
white foam. 1H NMR δ -0.12 (s, 6H), 0.19 (s, 9H), 0.79 (s, 9H), 0.84
(s, 3H), 1.01 (s, 3H), 1.05 (s, 9H), 1.54 (s, 3H), 1.91 (s, 3H), 2.01 (s,
3H), 3.01 (d, J ) 9.9 Hz, 1H), 3.16 (d, J ) 9.9 Hz, 1H), 4.82 (d, J )
2.7 Hz, 1H), 4.86 (dd, J ) 10, 8.1 Hz, 1H), 5.42 (dd, J ) 12, 4.3 Hz,
1H), 5.54 (t, J ) 1.9 Hz, 1H), 7.34-7.40 (m, 6H), 7.80-7.83 (m, 2H),
7.90-7.93 (m, 2H), 0.8-2.2 (remaining H, m); 13C NMR δ -5.7 (2C)
3.3 (3C), 11.7, 17.7, 18.1, 19.4, 21.5, 25.5, 25.9 (3C), 26.1, 26.4, 27.0
(3C), 28.2, 29.4, 31.2, 34.1, 35.5, 37.0, 37.7, 39.8, 44.2, 49.2, 58.4,
69.2, 70.9, 73.5, 79.8, 81.4, 83.4, 85.6, 95.5, 114.5, 116.5, 127.2 (2C),
127.6 (2C), 129.2, 129.5, 134.0, 135.5, 135.7 (2C), 136.1 (2C), 162.0,
169.7; MS (FAB, NBA) 943 (M + H - HBr); HRMS (FAB, NBA)
calcd for C54H83O8Si3 943.5396, found 943.5388.
Diol 87. Following the procedure for desilylation of 85, diol 87 was
1
obtained from 71S in 94% yield. H NMR δ 7.86 (4H, m), 7.73 (6H,
m), 5.61 (1H, s), 5.52 (1H, s), 5.12 (1H, s), 5.02 (1H, dd), 4.91 (1H,
dd), 4.68 (1H, m), 3.17 (1H, dd), 2.94 (1H, br, t), 2.04 (3H, s), 2.02
(3H, s), 1.98 (3H, s), 1.52 (3H, s), 1.08 (9H, s), 0.86 (3H, s); 13C NMR
δ 171.0, 170.5, 154.6, 136.3, 135.9, 133.7, 132.3, 130.7, 130.3, 128.4,
128.1, 120.9, 115.4, 90.3, 90.2, 82.1, 77.9, 73.6, 69.7, 54.2, 54.1, 44.7,
39.7, 36.6, 36.5, 34.4, 34.1, 32.0, 28.8, 28.4, 27.7, 26.8, 25.3, 23.0,
21.9, 21.8, 19.6, 14.5, 13.3, 12.3.
Ketone 85. To a solution of 84 (140 mg, 0.137 mmol) in Et2O (3.6
mL) and CH2Cl2 (1.0 mL) at 0 °C was added an aqueous solution of
chromic acid (0.32 mL of 1.3 M, 0.41 mmol). After 15 min, water and
Et2O were added. The aqueous layer was extracted with Et2O and the
combined organic layers were dried and filtered through a 1-in. pad of
1
26-OTBS Ether 88. Following the procedure for silylation of 83,
86 was converted to 88 in 96% yield. 1H NMR δ -0.12 (s, 6H), 0.79
(s, 9H), 1.01 (s, 9H), 1.06 (s, 3H), 1.09 (s, 3H), 1.56 (s, 3H), 1.97 (s,
3H), 2.01 (s, 3H), 2.62 (s, 1H), 2.65 (dd, 1H), 3.03 (dd, J ) 12, 8.9
Hz, 1H), 4.87-5.0 (m, 2H), 5.06 (d, J ) 1.5 Hz, 1H), 5.53 (brs, 1H),
5.57 (s, 1H), 7.40-7.49 (m, 6H), 7.81-7.84 (m, 2H), 7.87-7.90 (m,
2H), 0.8-2.2 (remaining H, m).
silica gel. Concentration gave 85 (136 mg, 97%) as a white foam. H
NMR δ -0.12 (s, 6H), 0.18 (s, 9H), 0.79 (s, 9H), 1.01 (s, 3H), 1.04
(s,9H), 1.56 (s, 3H), 1.91 (s, 3H), 2.02 (s, 3H), 3.01 (d, J ) 9.9 Hz,
1H), 3.16 (d, J ) 9.9 Hz, 1H), 4.82 (d, J ) 2.7 Hz, 1H), 4.86 (dd, J
) 10, 8.1 Hz, 1H), 5.44 (dd, J ) 12, 4.4 Hz, 1H), 5.57 (t, J ) 2.3 Hz,
1H), 7.36-7.42 (m, 6H), 7.79-7.82 (m, 2H), 7.89-7.92 (m, 2H), 0.8-
2.4 (remaining H); 13C NMR δ -5.7 (2C), 3.8 (3C), 11.5, 18.3, 18.7,
20.0, 22.0, 26.1(3C), 26.4, 26.9, 27.5 (3C), 28.9, 29.6, 34.6, 36.2, 38.4,
38.8, 40.3, 44.9, 46.3, 49.3, 58.9, 69.8, 73.7, 79.8, 80.3, 82.0, 83.8,
86.0, 96.1, 115.1, 117.5, 127.8 (2C), 128.2 (2C), 129.7, 130.1, 134.5,
136.0, 136.3 (2C), 136.7 (2C), 161.9, 170.2, 211.7; MS (FAB, NBA)
1023 (M + H); HRMS (FAB, NBA) calcd for C54H81BrO8Si3
1021.4501, found 1021.4640.
C20 Debrominated Diastereomers 89r/89â. Reduction of 87 (0.11
g, 0.13 mmol) in DMSO (2 mL) with 1-propanethiol (1.2 mL, 13 mmol)
and CrCl2 (79 mg, 0.64 mmol) according to the general procedure and
sgc (35% to 40% EA/Hex) afforded 90 mg (87%) of the inseparable
1
89R/â mixture (3.6:1). H NMR δ 7.80 (4H, m), 7.42 (6H, s), 5.53
(1H, s), 5.27 and 5.03 (H-12, two dd (1:3.5)), 4.93 and 4.57 (H-16,
two brd (3.5:1)), 4.19 and 3.83 (H-23, two dd (3.5: 1)), 3.90 and 3.68
(1H, two s (3.5:1)), 3.05 (1H, m), 2.93 (1H, m), 2.02 (3H, s), 1.99
(3H, s), 1.07 (3H, d, J ) 7.2 Hz), 1.01 (9H, s), 0.88 and 0.85 (3H, two
s (3.5:1)).
Ketodiol 86. To a solution of ketotrisilyl ether 85 (160 mg, 0.156
mmol) in CH3CN (13 mL) was added a solution of H2SiF6 in CH3CN
(2.5 mL of 0.063 M, 0.16 mmol). (Note: Direct application of
commercially available 25% aqueous H2SiF6 for this reaction gave

2070 J. Am. Chem. Soc., Vol. 121, No. 10, 1999
Kim et al.
C20 Debrominated Diastereomers 90r/90â. Reduction of 86 (750
mg, 0.90 mmol) in DMF (9 mL) at -25 °C with 1-propanethiol (16
mL, 170 mmol) and CrCl2 (551 mg, 4.49 mmol) according to the
general procedure gave 90R,â (9:1 ratio by NMR). Sgc as for 89
afforded 570 mg (84%) of 90R,â (inseparable) and 100 mg (13%) of
starting material 86. 90R: 1H NMR δ 1.06 (s, 3H), 1.08 (d, J ) 9.0
Hz, 3H), 1.16 (s, 3H), 1.24 (s, 3H), 2.00 (s, 3H), 2.48 (q, J ) 7.1 Hz,
1H), 2.93 (d, J ) 11 Hz, 1H), 3.06 (d, J ) 11 Hz, 1H), 3.92 (s, 1H),
4.20 (dd, J ) 11, 7.8 Hz, 1H), 4.94 (brs, 1H), 5.04 (dd, J ) 11, 5.0
Hz, 1H), 5.56 (brs, 1H), 7.38-7.47 (m, 6H), 7.74-7.76 (m, 2H), 7.81-
7.84 (m, 2H), 0.8-2.4 (remaining H, m); MS (FAB, NBA) 757 (M +
H); HRMS (FAB, NBA) calcd for C45H61O8Si 757.4136, found
757.4080. 90â: 1H NMR δ 5.28 (1H, dd), 4.55 (1H, d), 3.84 (1H, dd).
7.68-7.81 (m, 4H), 0.8-2.4 (remaining H, m); MS (FAB, NBA) 757
(M + H); HRMS (FAB, NBA) calcd for C45H61O8Si 757.4136, found
757.4095.
Pentaol 94r. A THF (2 mL) solution of 92R (11 mg, 0.018 mmol)
and TBAF (55 µL, 0.055 mmol) was heated at reflux for 1 h, cooled,
concentrated, and redissolved in aqueous MeOH (2 mL, 15% H2O).
K2CO3 (25.6 mg, 0.185 mmol) was added and the reaction mixture
was heated at reflux for 1 h. The mixture was diluted with EA (20
mL), washed with brine (2 × 10 mL), and concentrated and sgc (1%
1
MeOH/EA) afforded 8 mg (90%) of pentaol 94R. H NMR (CD3OD)
δ 5.39 (1H, brs), 4.74 (1H, brs), 4.18 (1H, dd, J ) 11.0, 8.0 Hz), 3.77
(1H, dd, J ) 11.0, 4.7 Hz), 3.50 (1H, m), 2.37 (1H, q, J ) 7.1 Hz),
2.23 (1H, dd, J ) 12.0, 8.0 Hz), 1.27 (3H, s), 1.12 (3H, s), 1.07 (3H,
d, J ) 7.2 Hz), 0.89 (3H, s); MS (EI) 460 (M - H2O), 314 (base),
(CI) 461 (M + H - H2O, base); HRMS (EI) calcd for C27H40O7
460.2825, found 460.2835.
C26 TBS Ethers 91r/91â. Ketodiols 90R,â (1.01 g, 1.33 mmol)
were silylated with TBSCl as per 83 to afford, after sgc (15% to 25%
EA/Hex) 1.05 g (90%) of 91R and 0.12 g (10%) of 91â as white foams.
Identical products were obtained by reduction of 88 as per the general
procedure. 91R: Rf ) 0.35 (25% EA/Hex); 1H NMR δ -0.15 (s, 3H),
-0.14 (s, 3H), 0.74 (s, 9H), 1.00 (s, 9H), 1.06 (s, 3H), 1.10 (s, 3H),
1.11 (d, J ) 7.1 Hz, 3H), 1.24 (s, 3H), 1.99 (s, 3H), 2.46 (q, J ) 7.1
Hz, 1H), 2.97 (d, J ) 10 Hz, 1H), 3.10 (d, J ) 10 Hz, 1H), 3.98 (s,
1H), 4.31 (dd, J ) 11, 8.0 Hz, 1H), 4.94 (brs, 1H), 5.03 (dd, J ) 11,
5.2 Hz, 1H), 5.55 (brs, 1H), 7.35-7.44 (m, 6H), 7.72-7.75 (m, 2H),
7.83-7.87 (m, 2H), 0.8-2.4 (remaining H, m); 13C NMR δ -5.8, -5.6,
8.6, 11.2, 13.6, 18.2, 19.2, 21.4, 25.6, 25.9 (3C), 26.6 (3C), 27.4, 28.3
(2C), 33.6, 36.1, 37.5, 37.9 (2C), 44.2, 44.4, 46.1, 52.6, 53.3, 69.1,
73.9, 74.5, 81.8, 89.2, 93.2, 116.4, 122.3, 127.6 (2C), 127.9 (2C), 129.8,
130.1, 132.6, 133.6, 135.5 (2C), 135.9 (2C), 151.2, 170.2, 211.2; MS
(FAB, NBA) 871 (M + H); HRMS (FAB, NBA) calcd for C51H75O8-
Pentaol 94â. Following the same procedure for making 94R, polyol
94â was obtained in 82% yield. 1H NMR (C5D5N) δ 6.56 (1H, s), 6.38
(1H, d, J ) 9.4 Hz), 6.28 (1H, brt), 5.96 (1H, brs), 5.58 (1H, s), 5.44
(1H, brs), 4.59 (2H, m), 3.72 (2H, m), 3.44 (1H, q, J ) 7.5 Hz), 2.80
(1H, dd, J ) 11.5, 8.0 Hz), 1.88 (3H, s), 1.64 (3H, d, J ) 7.5 Hz),
1.60 (3H, s), 0.79 (3H, s); MS (EI) 460 (M - H2O), 314 (base), (CI)
461 (M + H - H2O, base); HRMS (EI) calcd for C27H40O7 460.2825,
found 460.2835.
r-Bromoketone 95. Utilizing standard protocols,1g ketone 91R (84
mg, 0.097 mmol) and PTAB (38 mg, 0.10 mmol) afforded after sgc
73 mg (80%) of R-bromoketone 95 and 12 mg (14%) of starting
1
material 91R. H NMR δ 7.84 (2H, m), 7.73 (2H, m), 7.42 (6H, m),
5.56 (1H, brs), 5.03 (1H, dd, J ) 11.0, 5.1 Hz), 4.93 (1H, brs), 4.71
(1H, dd, J ) 13.0, 6.2 Hz), 4.31 (1H, dd, J ) 10.0, 8.0 Hz), 3.99 (1H,
s), 3.10 (1H, d, J ) 10 Hz), 2.97 (1H, d, J ) 10 Hz), 2.55 (1H, dd, J
) 13, 6.3 Hz), 2.46-2.42 (2H, m), 1.99 (3H, s), 1.23 (3H, s), 1.13
(3H, s), 1.11 (3H, d, J ) 7.1 Hz), 1.10 (3H, s), 1.00 (9H, s), 0.74 (9H,
s), -0.15 (3H, s), -0.16 (3H, s), 2.2-0.8 (remaining H’s, m); 13C NMR
δ 200.5, 170.2, 150.6, 135.9, 135.5, 133.6, 132.6, 130.2, 129.8, 128.0,
127.6, 122.7, 116.4, 93.1, 89.2, 81.9, 74.2, 73.9, 69.1, 53.7, 53.3, 52.2,
50.9, 46.9, 44.2, 43.6, 39.2, 37.5, 33.1, 28.1, 27.8, 27.4, 26.6, 25.9,
25.6, 21.3, 19.2, 18.2, 13.6, 11.9, 8.7, -5.6, -5.8; MS (FAB, NBA)
949 (M + H); HRMS (FAB, NBA) calcd for C51H74BrO8Si2 949.4106,
Si2 871.5001, found 871.5010; [R]24 +47.6° in CH2Cl2 (c 0.5).
D
91â: Rf ) 0.30 (25% EA in Hex); 1H NMR δ -0.14 (s, 3H), -0.13
(s, 3H), 0.69 (d, J ) 7.8 Hz, 3H), 0.74 (s, 9H), 1.04 (s, 3H), 1.08 (s,
9H), 1.16 (s, 3H), 1.38 (s, 3H), 2.07 (s, 3H), 2.45 (q, J ) 7.8 Hz, 1H),
3.09 (d, J ) 10 Hz, 1H), 3.15 (d, J ) 10 Hz, 1H), 3.38 (s, 1H), 3.98
(apparent t, J ) 8.2 Hz, 1H), 4.50 (d, J ) 2.4 Hz, 1H), 5.28 (dd, J )
12, 5.0 Hz, 1H), 5.54 (brs, 1H), 7.34-7.45 (m, 6H), 7.70-7.73 (m,
4H), 0.8-2.4 (remaining H, m); 13C NMR δ 211.3, 172.1, 159.0, 136.1,
134.1, 133.7, 129.9, 129.7, 127.9, 127.6, 119.2, 114.0, 91.5, 90.5, 81.8,
75.2, 74.4, 69.6, 56.6, 49.5, 48.1, 45.8, 44.5, 38.5, 38.3, 38.0, 35.7,
33.9, 29.1, 28.4, 27.4, 27.2, 26.1, 26.0, 21.9, 19.4, 18.3, 16.3, 11.2,
7.8, -5.5, -5.6; MS (FAB, DTT/DTE) 871 (M + H); HRMS (FAB,
DTT/DTE) calcd for C51H75O8Si2 871.5001, found 871.4992.
found 949.4125; [R]23 + 45° in CH2Cl2 (c 1.0).
D
r-Azidoketone 5. TMGA (17 mg, 0.11 mmol) was dissolved in
CH3NO2 (0.8 mL), added to a solution of bromoketone 95 (26 mg,
0.027 mmol) in CH3NO2 (2 mL), and stirred for 6 h. The CH3NO2 was
removed in vacuo and the product was filtered through silica (15%
C26 TBDMS Ethers 92r and 92â. Silylation of 89 and sgc as for
91R/â gave 92R (77%) and 92â (20%). 91R: Rf ) 0.39 (25% EA/
Hex); 1H NMR δ 7.85 (2H, m), 7.73 (2H, m), 7.41 (6H, m), 5.51 (1H,
s), 5.00 (1H, dd, J ) 11.2, 5.1 Hz), 4.93 (1H, s), 4.66 (1H, m), 4.28
(1H, dd, J ) 10.5, 7.9 Hz), 3.94 (1H, s), 3.02 (2H, AB), 2.45 (1H, q,
J ) 7.0 Hz), 2.00 (3H, s), 1.97 (3H, s), 1.20 (3H, s), 1.09 (3H, s), 1.09
(3H, d, J ) 6.9 Hz), 1.00 (9H, s), 0.87 (3H, s), 0.74 (9H, s), -0.15
(3H, s), -0.16 (3H, s); 13C NMR δ 170.6, 170.2, 151.6, 135.9, 135.5,
133.6, 132.6, 130.1, 129.8, 127.9, 127.6, 122.0, 116.4, 93.3, 89.3, 81.8,
74.7, 73.8, 73.3, 69.1, 52.3, 52.9, 44.3, 37.5, 36.3 36.0, 33.7, 28.6,
28.0, 27.2, 26.6, 25.9, 25.6, 21.4, 19.1, 18.2, 13.6, 11.9, 8.7, -3.6,
-5.6, -5.8. 91â: Rf ) 0.32 (25% EA/Hex); 1H NMR δ 7.71 (4H, m),
7.40 (6H, m), 5.52 (1H, br, t), 5.27 (1H, dd, J ) 11.5, 4.6 Hz), 4.69
(1H, m), 4.50 (1H, d, J ) 2.5 Hz), 3.96 (1H, dd, J ) 10.3, 7.9 Hz),
3.50 (1H, s), 2.06 (3H, s), 2.03 (3H, s), 1.39 (3H, s), 1.18 (3H, s), 1.05
(9H, s), 0.88 (3H, s), 0.78 (9H, s), 0.9 (3H, d), -0.15 (3H s), -0.16
(3H, s).
1
EA in Hex) to afford 5 (25 mg, 100%) as a white film. H NMR δ
-0.16 (s, 3H), -0.15 (s, 3H), 0.74 (s, 9H), 1.00 (s, 9H), 1.10 (s, 3H),
1.11 (d, J ) 7.1 Hz, 3H), 1.13 (s, 3H), 1.23 (s, 3H), 1.99 (s, 3H), 2.45
(q, J ) 7.1 Hz, 1H), 2.97 (d, J ) 10 Hz, 1H), 3.10 (d, J ) 10 Hz, 1H),
3.96 (dd, J ) 13, 6.3 Hz, 1H), 3.99 (s, 1H), 4.31 (dd, J ) 10, 8.0 Hz,
1H), 4.93 (brs, 1H), 5.03 (dd, J ) 11, 5.1 Hz, 1H), 5.56 (brs, 1H),
7.36-7.46 (m, 6H), 7.72-7.75 (m, 2H), 7.83-7.86 (m, 2H), 0.8-2.4
(remaining H, m); 13C NMR: δ -5.8, -5.6, 8.7, 12.3, 13.6, 18.2, 19.2,
21.3, 25.6, 25.9 (3C), 26.6 (3C), 27.5, 27.9, 28.2, 33.1, 37.2, 37.5,
43.5, 44.2, 44.9, 47.1, 52.3, 53.3, 63.7, 69.1, 73.9, 74.2, 81.9, 89.2,
93.1, 116.4, 122.7, 127.6 (2C), 128.0 (2C), 129.8, 130.2, 132.6, 133.6,
135.5 (2C), 135.9 (2C), 150.6, 170.2, 204.5; MS (FAB, NBA) 912 (M
+ H); HRMS (FAB, NBA) calcd for C51H74N3O8Si2 912.5015, found
912.4987; [R]22 +64.3° (CH2Cl2, c 1).
D
Acknowledgment. We thank the National Institutes of
Health (CA 60548) for support of this work. Special thanks are
due to Jae Uk Jeong and Rao Bhandaru for valuable discussions
and Patrick Crouse, Lawrence Knox, and Lei Jiang for prepara-
tion of advanced synthetic intermediates. We are grateful to
Arlene Rothwell for MS data.
Debrominated 25R Epimers 93r/â. Reduction of bromide 86R (40
mg, 0.048 mmol) was performed as for the 25S epimer 86, except the
reaction was maintained at 25 °C and required a second charge of CrCl2
after 2.5 h to bring the reaction to completion. Workup and sgc gave
1
93R/â (33 mg, 90%; 5.5:1 ratio by NMR). H NMR δ 0.76 (s, 3H),
1.02 (s, 9H), 1.06 (d, J ) 7.3 Hz, 3H), 1.24 (s, 3H), 1.25 (s, 3H), 2.00
(s, 3H), 2.46 (q, J ) 7.3 Hz, 1H), 2.67 (apt, J ) 7.3 Hz, 1H), 3.06
(brapt, J ) 10.9 Hz, 1H), 3.24 (brd, J ) 10 Hz, 1H), 3.34 (brd, J )
11.5, Hz, 1H), 3.72 and 3.91 (1:5.5, s, 1H), 3.82 and 4.13 (1:5.5, dd,
J ) 11.3, 7.4 Hz, 1H), 4.54 and 4.93 (1:5.5, brs, 1H), 5.02 and 5.28
(5.5:1, dd, J ) 10.9, 5.2 Hz, 1H), 5.50 (brs, 1H), 7.28-7.51 (m, 6H),
Supporting Information Available: NMR spectra of com-
pounds studied (PDF). This material is available free of charge
via the Internet at http://pubs.acs.org.
JA9817139