Asymmetric synthesis of calyculin C. 1. Synthesis of the C1-C25 fragment

Article abstract of DOI:10.1021/jo960314y

We report our synthesis of the C₁-C₂₅ fragment of serine/threonine phosphatase PP1 and PP2A inhibitor, calyculin C. Synthetic efforts were directed initially toward the synthesis of a spiroketal core fragment (7), which culminated in completion of the bottom half of the natural product. The synthesis of fragment 7 and subsequent elaboration relied on an allylboration strategy for introduction of chirality. The C₁-C₈ fragment representing the potentially unstable tetraene moiety was introduced as a separate entity.

Full text of DOI:10.1021/jo960314y

J . Org. Chem. 1996, 61, 6139-6152
6139
Asym m etr ic Syn th esis of Ca lycu lin C. 1. Syn th esis of th e C1-C25
F r a gm en t
Gerard R. Scarlato,1 J ohn A. DeMattei,2 Lee S. Chong, Anthony K. Ogawa, Mavis R. Lin, and
Robert W. Armstrong*
Department of Chemistry and Biochemistry, University of California, Los Angeles, California 90095
Received February 15, 1996X
We report our synthesis of the C1-C25 fragment of serine/threonine phosphatase PP1 and PP2A
inhibitor, calyculin C. Synthetic efforts were directed initially toward the synthesis of a spiroketal
core fragment (7), which culminated in completion of the bottom half of the natural product. The
synthesis of fragment 7 and subsequent elaboration relied on an allylboration strategy for
introduction of chirality. The C1-C8 fragment representing the potentially unstable tetraene moiety
was introduced as a separate entity.
In tr od u ction
The calyculins represent a novel class of secondary
metabolites isolated from the marine sponge Discodermia
calyx which was collected in the Sea of Sagami off the
coast of J apan.3 This unique class of compounds is
represented by eight different related structures which
vary by substitution at C32 and by the olefin geometry of
the tetraene moiety3c (see Figure 1). Ishihara and others
have shown that one of these metabolites, calyculin A,
is a selective inhibitor of serine/threonine phosphatases
PP1 and PP2A (2.0 and 1.0 nM, respectively), two of the
four main classes of phosphatases in the cytosol of human
cells.4 The relative stereochemistry of calyculin A was
established by X-ray crystallography. The absolute ster-
eochemistry was subsequently elucidated by Hamada and
Shiori through the synthesis of a C33-C37 acid fragment
that was identical by 1H NMR but opposite in its specific
rotation to a degradation product isolated from a mixture
of calyculins A, B, E, and F.5 Work done by Fusetani3b
has suggested identical solution conformations for both
calyculins A and C. By the use of an NOE correlation
involving the C30-N3 portion of each natural product,
Fusetani3b has assigned the relative stereochemistry of
the C32-methyl in calyculin C. Both calyculins A and C
have similar potency in starfish Asterina pectinifera, sea
urchin Hemicetrotus pulcherrimus, and L1210 leukemia
assays. Within this family of PP1 and PP2A inhibitors
are the microcystins,6 nodularin,7 motuporin,8 tautomy-
cin,9 and okadaic acid.10
F igu r e 1.
Our interest in the synthesis of calyculin C stems from
ongoing work toward the synthesis, structure-activity
relationships (SAR), and conformational studies involving
tautomycin and nodularin. Using a combination of
molecular modeling and 2D-NMR analysis, we have
derived an overlay of the proposed ground state struc-
tures of calyculin, tautomycin, microcystin, nodularin,
and okadaic acid in an effort to understand the common
structural motifs associated with these diverse natural
products. The recent elucidation of the X-ray structure
of a cocrystal of PP1 and microcystin should provide
assistance in developing a comprehensive analysis of
these inhibitors.11
X Abstract published in Advance ACS Abstracts, August 1, 1996.
(1) Taken in part from the Ph.D. Thesis of Gerard R. Scarlato,
University of California, Los Angeles, 1990.
(2) Taken in part from the Ph.D. Thesis of J ohn A. DeMattei,
University of California, Los Angeles, 1994.
(3) (a) Kato, Y.; Fusetani, N.; Matsunaga, S.; Hashimoto, K.; Fujita,
S.; Furuya, T. J . Am. Chem. Soc. 1986, 108, 2780. (b) Kato, Y.;
Fusetani, N.; Matsunaga, S.; Hashimoto, K.; Koseki, K. J . Org. Chem.
1988, 53, 3930. (c) Matsunaga, S.; Fujiki, H.; Sakata, D. Tetrahedron
1991, 47, 2999.
(4) Ishihara, H.; Martin, B. L.; Brautigan, D. L.; Karaki, H.; Ozaki,
H.; Kato, Y.; Fusetani, N.; Watabe, S.; Hashimoto, K.; Uemura, D.;
Hartsborne, D. J . Biochem. Biophys. Res. Commun. 1989, 159, 871.
(5) Hamada, Y.; Tanada, Y.; Yokokawa, F.; Shiori, T. Tetrahedron
Lett. 1991, 32, 5983.
(6) Honkanen, R. E.; Zwiller, J .; Moore, R. E.; Daily, S. L.; Khatra,
B. S.; Dukelow, M.; Boynton, A. L. J . Biol. Chem. 1990, 265, 19401.
(7) Botes, D. P.; Wessels P. L.; Kruger, H.; Runnegar, M. T. C.;
Santikarn, S.; Smith, R. J .; Barna, J . C. J .; Williams, D. H. J . Chem.
Soc. Perkin Trans. 1 1985, 2747.
(8) Schreiber, S. L.; Valentekovich, R. J . J . Am Chem. Soc. 1995,
117, 9069.
Related to our specific interest in calyculin C, the C17-
phosphate provides a unique structural motif that orga-
nizes the hydrogen-bonding network of the compound
that greatly influences its tertiary structure. This struc-
tural motif is exhibited through X-ray structural3a and
2D-NMR analysis. The synthesis of the natural product,
in addition to salient analogs, would be of great interest
in our efforts toward understanding the enzymes.
Retr osyn th esis
Retrosynthetic analysis of the calyculin backbone
revealed several possibilities for disconnection involving
(9) Cheng, X. C.; Kihara, T.; Kusakbe, H.; Magea, J .; Kobayashi,
Y.; Fang, R. P.; Ni, Z. F.; Shen, Y. C.; Ko, K.; Yamaguchi, I.; Isono, K.
J . Antibiot. 1987, 40, 907.
(10) Tachibana, K.; Scheuer, P. J .; Tsukitani, Y.; Kikuchi, H. ;
Engen, D. V.; Clardy, J .; Gopichand, Y.; Schmitz, F. J . J . Am. Chem.
Soc. 1981, 103, 2469.
S0022-3263(96)00314-3 CCC: $12.00 © 1996 American Chemical Society

6140 J . Org. Chem., Vol. 61, No. 18, 1996
Scarlato et al.
Sch em e 1
carbon-carbon bonds. Our strategy centered on an
initial disconnection at the C25-C26 double bond which
divided the natural product into two halves of similar
functional density. Coupling at this junction was per-
ceived to provide the most convergent synthetic approach,
a strategy which was employed in our initial model
studies.12 This approach paralleled other synthetic ef-
forts, most notably the two completed syntheses of
calyculin A.13,14 In maintaining our desired degree of
convergence, a synthetic design addressing the C1-C25
fragment 2 as a whole was adopted.
C17-phosphate, which is resistant toward chemical and
enzymatic hydrolysis, required the judicious choice of
blocking groups. Our plan, therefore, called for incorpo-
ration of the phosphate downstream in the overall
synthesis. Equal consideration was given to the potential
instability toward isomerization of the C1-C9 cyanotet-
raene moiety.15 This potential photolability and reactiv-
ity toward oxygen prompted the disconnection at the C8-
C9 olefin, thereby allowing for its late introduction into
the synthesis of the bottom half of the molecule. The
above primary concerns gave a C9-C25 polyhydroxylated
spiroketal fragment as the initial target compound in the
synthesis of the C1-C25 portion of calyculin. Dissection
of the C9-C25 system yielded two primary components:
the C15-C25 spiroketal fragment 7 whose synthesis was
pivotal for success and the C9-C14 polypropionate side
chain which was foreseen as resulting from homologation
of spiroketal 7 via stereoselective allylborations. Con-
sideration of the spiroketal core focused on a concerted
spirocyclization reaction derived from fully protected open
chain precursor 8. Such a strategy led to the identifica-
tion of the C20-C21 bond as an aldol retron which afforded
a high degree of stereochemical control with respect to
C21.16
Several functionalities within the C1-C25 bottom half
strongly influenced our synthetic plan (Scheme 1). The
(11) Goldberg, J .; Huang, H.; Kwon, Y.; Greengard, P.; Nairn, A.
C.; Kuriyan, J . Nature 1995, 376, 745.
(12) Preliminary communications from this laboratory on this
subject, see: (a) Zhao, Z.; Scarlato, G. R.; Armstrong, R. W. Tetrahedron
Lett. 1991, 32, 1609. (b) Armstrong, R. W.; DeMattei, J . A. Tetrahedron
Lett. 1991, 32, 5749.
(13) For completed total syntheses of both enantiomers of calyculin
A, see: (a) Evans, D. A.; Gage, J . R.; Leighton, J . L. J . Am. Chem.
Soc. 1992, 114, 9434. (b) Tanimoto, N.; Gerritz, S. W.; Sawabe, A.;
Noda, T.; Filla, S. A.; Masamune, S. Angew. Chem. 1994, 106, 674.
(14) For other efforts directed toward the synthesis of calyculins,
see: (a) Evans, D. A.; Gage, J . R.; Tetrahedron Lett. 1990, 31, 6129.
(b) Evans, D. A.; Gage, J . R. J . Org. Chem. 1992, 57, 1958. (c) Evans,
D. A.; Gage, J . R.; Leighton, J . L.; Kim, A. S. J . Org. Chem. 1992, 57,
1961. (d) Evans, D. A.; Gage, J . R.; Leighton, J . L. J . Org. Chem. 1992,
57, 1964. (e) Duplanter, A. J .; Nantz, M. H.; Roberts, J . C.; Short, R.
P.; Somfai, P.; Masamune, S. Tetrahedron Lett. 1989, 30, 7357. (f)
Vaccaro, H. A.; Levy, D. E.; Sawabe, A.; J aetsch, T.; Masamune, S.
Tetrahedron Lett. 1992, 33, 1937. (g) Hara, O.; Hamada, Y.; Shiori, T.
Synlett 1991, 283. (h) Yokokawa, F.; Hamada, Y.; Shiori, T. Synlett
1992, 149. (i) Smith, A. B., III; Duan, J . J .-W.; Hull, K. G.; Salvatore,
B. A. Tetrahedron Lett. 1991, 32, 4855. (j) Smith, A. B., III; Salvatore,
B. A.; Hull, K. G.; Duan, J . J .-W. Tetrahedron Lett. 1991, 32, 4859. (k)
Barrett, A. G. M.; Malecha, J . W. J . Org. Chem. 1991, 56, 5243. (l)
Barrett, A. G. M.; Edmunds, J . J .; Horita, K.; Parkinson, C. J . J . Chem.
Soc., Chem. Commun. 1992, 1236. (m) Barrett, A. G. M.; Edmunds, J .
J .; Hendrix, J . A.; Horita, K.; Parkinson, C. J . J . Chem. Soc., Chem.
Commun. 1992, 1238. (n) Barrett, A. G. M.; Edmunds, J . J .; Hendrix,
J . A.; Malecha, J . W.; Parkinson, C. J . J . Chem. Soc., Chem. Commun.
1992, 1240.
Examination of the spiroketal core suggested a re-
quirement for orthogonality with respect to four sets of
hydroxyl protecting groups. The C21-hydroxyl protecting
group assumed a critical role in an overall strategy based
on a final deprotection step in the total synthesis. The
desire to reserve the C16- and C23-hydroxyls as latent
members of the spiroketal suggested the choice of mild
acid-labile protecting groups to accommodate a sequential
(15) Matsunaga, S.; Fujiki, H.; Sakata, D. Tetrahedron 1991, 47,
2999.
(16) Fukuyama, T.; Akasaka, K.; Karanewsky, D. S.; Wang, C-L.
J .; Schmid, G.; Kishi, Y. J . Am. Chem. Soc. 1979, 101, 262.

Asymmetric Synthesis of Calyculin C. 1
J . Org. Chem., Vol. 61, No. 18, 1996 6141
Sch em e 2
Sch em e 3
of an allylborane derived from (-)-B-methoxydiisopi-
nocampheylborane (MeOB(Ipc)2) to propionaldehyde 14
at -78 °C in the presence of BF3‚Et2O afforded homoal-
lylic alcohol 15 as a single diastereomer in high yield
after DMS workup.20 The issue of C23-hydroxyl protection
proved significant as the eventual open chain C15-C25
fragment was likely to possess great diversity in terms
of protection functionality.
deprotection-cyclization reaction. C17-Hydroxyl protec-
tion was designed to allow for its downstream removal
and introduction of the phosphate moiety. Finally, the
nature of the C25-oxidation state and subsequent protec-
tion was considered. Early results supported the use of
a protected C25-alcohol1 in the synthesis of the C1-C25
fragment.
Model experiments on various blocking groups sug-
gested that tetrahydropyran (THP) would provide an
ideal choice for C23-protection. Although the choice of
THP complicated NMR analysis of subsequent products,
its mild acid lability accommodated a strategy employing
deprotection conditions as a means of effecting spirocy-
clization in a two-reaction-one-step process. The choice
of tert-butyldiphenylsilyl (TPS) as the C25-hydroxyl pro-
tecting group was again made on the basis of experimen-
tal work on model compounds and its compatibility with
our overall protecting group scheme. Preliminary work
revealed that 4-methoxybenzyl (PMB) failed to survive
the proposed Lewis acid spirocyclization conditions, while
the TPS system remained intact. We also felt that the
selective removal of a TPS protecting group on a 1°
alcohol in the presence of 2° benzoyl or silyl groups was
in accord with literature precedent.21
The aldol coupling of ketone 13 with aldehyde 17
proceeded in acceptable yield and with excellent stereo-
selectivity (10:1). Similar high selectivity was also
observed in a condensation used by Kishi in the synthesis
of monensin.16 Stereochemical assignments were con-
clusively made post-spirocyclization due to complications
arising from the THP group in the acyclic precursors.
Other substrates bearing different C17- and/or C23-hy-
droxyl protecting groups did not condense or showed a
low degree of diastereoselectivity. Spirocyclization was
achieved in excellent yield by treatment of ketone 17 with
ZnBr2 at room temperature (Scheme 4). In this one-pot
transformation, the THP and isopropylidene moieties
were concomitantly removed, and the ketone was con-
verted to a ketal. The resulting product contained only
a single free hydroxyl to be used in elaboration of the
side chain. It should be noted that attempted cyclization
with a free C21-hydroxyl led to isolation of â-eliminated
starting material, limiting the variability with regard to
choice of substrate. The stereochemical integrity of the
spiroketal product 19 was verified by extensive NOE
difference analysis.22 Discussion of the relevant NOE
Syn th esis of th e en t-Sp ir ok eta l Cor e F r a gm en t
(C15-C25
)
At the outset of our efforts toward the total synthesis
of calyculin, the absolute configuration had not yet been
established for the natural product.5 Although initial
studies resulted in the stereospecific synthesis of the
enantiomer of the desired C15-C25 spiroketal fragment,1
it nonetheless laid a foundation for future work.
The synthesis of 13 was initiated by condensation of
silyl enol ether 1117 with 2,3-O-isopropylidene-L-glycer-
aldehyde.18 The reaction proceeded under Felkin-Ahn
stereochemical control,19 affording the desired ketone 12a
as the minor product (Scheme 2). The reaction of model
ketones bearing varying protecting groups at the C17-
hydroxyl with isobutyraldehyde led to the choice of (2-
methoxyethoxy)methyl (MEM) (eq 1). The MEM group
(1)
was found to be stable to the Lewis acid (ZnBr2) condi-
tions used for spirocyclization. Extended reaction times
and greater stoichiometries of Lewis acid resulted in the
loss of MEM in spiroketal containing substrates.
The synthesis of aldehyde 17 was founded on a ste-
reoselective allylboration strategy (Scheme 3). Addition
(17) Noyori, R.; Yokoyama, K.; Sakata, J . J . Am. Chem. Soc. 1977,
99, 1265.
(18) Hubschwerlen, C.; Specklin, J -L. Org. Synth. 1993, 72, 1.
(19) Cherest, M.; Felkin, H.; Prudent, N. Tetrahedron Lett. 1968,
2199.
(20) Brown, H. C.; Bhat, K. S. J . Am. Chem. Soc. 1986, 108, 5919
and references cited therein.
(21) Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic
Synthesis; J ohn Wiley and Sons: New York, 1991; p 83.

6142 J . Org. Chem., Vol. 61, No. 18, 1996
Scarlato et al.
Sch em e 4
Sch em e 5
assignments relating to proof of structure will be pre-
sented below.
Con str u ction of th e C15-C25 Sp ir ok eta l Cor e
Elucidation of the absolute stereochemistry of the
calyculins5 necessitated the synthesis of spiroketal 26
which was enantiomeric with respect to 19. The route
to 19 suffered two potential drawbacks: (1) the aldol
reaction to afford 12a yielded the undesired diastereomer
as the major product and (2) the yield of the second aldol
to generate 18 was mediocre. We believed that both
issues would be redressed by the use of allylboration
technology. To this end, we sought to develop methodol-
ogy that utilized the potentially novel dianion equivalent
of tetramethylethylene in our spiroketal synthesis. Al-
though formation of allylboranes from several substituted
allyl systems had been reported, no examples had
employed a tetrasubstituted olefin. This offered a sig-
nificant opportunity to expand on current methodology.23
Tetramethylethylene provided a unique synthon in that
the product from the first allylboration could be used to
generate a second boronane derived from a symmetric
allylic anion (eq 2). Success to this end would result in
the head and tail homologation of a previously unfunc-
tionalized allylic system, a method that could prove
general in its application to other targets containing a
gem-dimethyl moiety.
de (results not included). Bromination of 22 readily
afforded the allylic bromide. However, we were unable
to generate an allylic anion for subsequent condensations.
Even attempted conversion to other organometallic re-
agents (Mg, e.g.) failed to provide condensation products
with simple aldehydes.
A significant effort was also made to enhance the
convergence of the overall synthesis by targeting ketone
27 as a means of limiting the number of linear steps in
elaboration of the polypropionate chain attached to the
ketal (eq 3). The aldol condensation of 27 proved
(2)
Addition of allylborane 20 to 2,3-O-isopropylidene-D-
glyceraldehyde24 afforded alcohol 21 in high yield and
with excellent stereoselectivity (Scheme 5). When the
enantiomeric ligand was reacted with the above alde-
hyde, excellent diastereoselectivity and yields were also
observed in spite of the substrate-borane mismatch.20
This is in stark contrast to the unsubstituted allylborane
reagent where the mismatched case gave only about 80%
(3)
problematic, and difficulties in generating the appropri-
ate allylborane species from derivatives of 21 necessitated
convergence on the previously established route to the
spiroketal core.25 Protection of the C17-hydroxyl afforded
MEM ether 22 which was ozonized to ketone 23 in high
(22) Neuhaus, D.; Williamson, M. The Nuclear Overhauser Effect
in Structural and Conformational Analysis; VCH: New York, 1989.
(23) Brown, H. C.; J adhav, P. K.; Bhat, K. S. J . Am. Chem. Soc.
1988, 110, 1535.
(24) Schmid, C. R.; Bryant, J . D. Org. Synth. 1993, 72, 6.

Asymmetric Synthesis of Calyculin C. 1
J . Org. Chem., Vol. 61, No. 18, 1996 6143
Sch em e 6
F igu r e 2.
yield. Subsequent condensation with aldehyde 2426
afforded an aldol adduct which was benzoylated to yield
open chain spiroketal precursor 25. Treatment with
trifluoroacetic acid (TFA) at 0 °C effected the desired
tandem deprotection-cyclization to generate spiroketal
26 whose analytical data were identical to those of
enantiomeric spiroketal 19 with the exception of optical
rotation which was opposite in sign.
The relative and absolute stereochemistry of 26 was
obtained from analysis of NOE difference experiments22
(Figure 2). Under the assumption that the pyran exists
in a chair conformation, the two new stereocenters
generated in the aldol-spirocyclization sequence allow
for eight possible diastereomers of the spiroketal to exist.
Six of these structures were subsequently eliminated due
to strong NOE correlations observed between the aro-
matic benzoate hydrogens and the C23-methine, suggest-
ing an R-configuration at C21. An NOE correlation
between the C42-methyl and C21-methine provided cor-
roboration for the previous conclusion, thereby establish-
ing a trans-diaxial relationship between the C42-methyl
and C21-benzoate. Final evidence for the proposed struc-
ture of 26 was found in the NOE data surrounding the
C44-methyl. Given a syn-relationship between the C16-
and C17-methine hydrogens,27 enhancements linking the
C44-methyl with the C16-methine, the C17-methine, and
both C20-hydrogens strongly supported the claim that all
four sets of hydrogens were syn-facial with respect to the
furan ring. The sum of all NOE data served as verifica-
tion of the proposed spiroketal structure 26.
the acetonide methyls and ketal carbon serve to indicate
the relationship of the 1,3-diol system bound in the
isopropylidene framework. The observed 13C NMR chemi-
cal shifts for 33 were 24.0 and 25.5, which was indicative
of an anti relationship29,30 and, unfortunately, the un-
desired stereochemistry at C15. Evidently the nature of
the spiroketal dictated that nucleophilic addition to the
C15-aldehyde 28 exclusively followed the Felkin-Ahn
model,19 and all attempts at chelation control were
overridden by this bias.
Inversion at C15 was effected by reoxidation under
Swern conditions28 to ketone 30, and subsequent reduc-
tion with LiBH4 to afford alcohol 31 in good overall yield.
Reduction attempts involving NaBH4 resulted in isolation
of the saturated alcohol which presumably arose from
olefin migration followed by sequential 1,4-1,2 reduction.
Diisobutylaluminum hydride in toluene at -78 °C led to
concomitant removal of the benzoyl group as well as
ketone reduction. NOE analysis22 and 13C NMR chemical
shift correlation29,30 of acetonide 34, derived from a
similar deprotection-isopropylidination sequence as pre-
viously mentioned, corroborated the assignment of ster-
eochemistry (Scheme 7). Clean conversion of 31 to the
C15-methyl ether (32) was accomplished in superb yield
by reaction with an excess of KH/CH3I and 18-crown-6
at 0 °C in THF. This success prompted the introduction
of a 13C label at C15-methyl ether in accordance with our
previously outlined plan related to the study of serine/
threonine phosphatases.
In tr od u ction of th e C9-C14 P olyp r op ion a te Ch a in
Extension of the polypropionate chain from spiroketal
26 was initiated by Swern oxidation28 to aldehyde 28 in
excellent yield (Scheme 6). Allylation of the resulting
aldehyde was found to proceed optimally via addition of
an allylmagnesium bromide-ZnCl2 mixture at -78 °C.
Simple addition of allyl Grignard resulted in competitive
debenzoylation, and use of allylsilanes proved less ef-
ficient in alkylation. The stereochemical identity of 29
was again verified by NOE study of isopropylidene 33
derived from removal of MEM and subsequent formation
of the 1,3-acetonide. Utilizing the work of Rychnovsky29
and Evans,30 the stereochemical relationship between the
C15- and C17-hydroxyls was shown to be anti. Empirical
evidence has shown that the 13C NMR chemical shifts of
(25) Numerous attempts to effect coupling proved unfruitful due to
difficulties in generating the required boronate reagent despite a
variety of strategies and methods.
(26) Aldehyde 24 is stable toward chromatography, but undergoes
â- elimination in the precense of mildly basic conditions (NEt3, e.g.)
(27) C16-stereochemistry was derived from glyceraldehyde, and the
syn-relationship with the C17-methine was established through NOE
data (Figure 1).
(28) Mancuso, A. J .; Swern, D. Synthesis 1981, 165.
(29) (a) Rychnovsky, S. D.; Skalitzky, D. J . Tetrahedron Lett. 1990,
31, 945. (b) Rychnovsky, S. D.; Rogers, B.; Yang, G. J . Org. Chem. 1993,
58, 3511.
(30) Evans, D. A.; Rieger, D. L.; Gage, J . R. Tetrahedron Lett. 1990,
31, 7099.
Incorporation of the C11-C12 carbons proceeded with
ozonolysis of 32, followed by reaction with the crotylbo-
rane derived from trans-2-butene and (+)-MeOB(Ipc)2,
affording homoallylic alcohol 35 (Scheme 8).20 The ster-

6144 J . Org. Chem., Vol. 61, No. 18, 1996
Scarlato et al.
Sch em e 7
Sch em e 9
Sch em e 8
The completion of C9-C25 spiroketal fragment 41
signaled the need to consider a strategy for incorporation
of the phosphate in compliance with the overall protect-
ing group strategy. Our initial approach relied on base
cleavage of a global benzoate protection scheme in
conjunction with delayed introduction of the tetraene
moiety. â-Cyanoethoxy protection of phosphorus31 at the
phosphate oxidation state appeared compatible and was
proposed to facilitate a single final deprotection step.
Model studies incorporating such a strategy led to
complications given problematic deprotection of the
phosphate under Horner-Emmons olefination conditions
(eq 4). 4-Methoxybenzyl protection of the phosphate was
eochemical identity of the newly introduced chiral centers
was verified by an X-ray crystal structure of 35.39
Ozonolysis of benzoylated spiroketal 36 afforded an
aldehyde substrate for the final allylboration20 to alcohol
37. The stereochemical outcome of this reaction was
disappointing in that it yielded only a ∼1.3:1 ratio of
separable diastereomers (37 and 38, respectively). The
structures of the desired product and its C10,C11-diaster-
eomer were inferred from 13C NMR analysis of acetonides
39 and 40 involving the C11- and C13-hydroxyls.29,30 The
13C chemical shifts assigned to the acetonide methyls
were 30.0 and 19.3 for the major product (39), provided
strong evidence for a syn 1,3-diol relationship (Scheme
9). Corroboration for this hypothesis lies in 13C data
obtained likewise from the C11,C13-acetonide of the minor
diastereomer (40) in which chemical shifts of 24.6 and
23.6 suggested an anti relationship.
(4)
examined with little success in studies designed to model

Asymmetric Synthesis of Calyculin C. 1
J . Org. Chem., Vol. 61, No. 18, 1996 6145
Sch em e 10
Sch em e 11
olefination at C9. This evidence suggested that perhaps
the phosphate was detrimental to the success of conden-
sation reactions, which prompted convergence on the silyl
protection strategy utilized by Evans.13a A series of
deprotection and reprotection reactions initiating at
benzoate 36 afforded olefin 41 (Scheme 10). Ozonolysis
of 41 led to aldehyde 42 whose spectral data were
identical to those of an advanced target in the synthesis
of ent-calyculin A reported by Evans.13a
In cor p or a tion of th e C1-C9 Tetr a en e
Our plan for the introduction of the C1-C9 portion of
calyculin was based on two key issues relative to the
perceived instability of the cyanotetraene moiety. Con-
cern for the geometric integrity of the C2-C3 double bond
suggested the use of Stille cross-coupling as sp2-sp2 bond
formation32 precluded difficulties related to selectivity.
The other issue to be addressed was the need for
E-selective formation of the C8-C9 olefin. Horner-
Emmons olefination provided an excellent method of
generating a homologated product with the desired
geometry. Phosphonate 6 provided a target bearing
functionality that met both of the above synthetic con-
cerns. It was also our belief that the extent of conjuga-
tion would have little effect on the Horner-Emmons
olefination and no foreseeable impact on the subsequent
Stille cross-coupling. However, the design of phospho-
nate 6 provided sufficient flexibility in its potential for
facile extension to a stannyl diene species if the need
arose.
The synthesis of 6 proceeded from known allylic alcohol
4333 via initial silylation (44) followed by trapping of the
lithiated intermediate species with tributyltin chloride
affording 45 in excellent yield (Scheme 11). In the course
of synthetic work involving vinyl tin compounds, it was
observed, not unexpectedly, that the tin-carbon bond
was readily hydrolyzed in the presence of even weakly
acidic media. Desilylation under basic conditions (TBAF)
was necessary to avoid the unwanted hydrolysis previ-
ously mentioned, and subsequent mesylation afforded 47
in reasonable yield. Initial work directed toward the
synthesis of phosphonate 6 indicated a need to introduce
the phosphonate functionality prior to methylation as
direct displacement of 2°-electrophiles proved unsuccess-
ful. Direct displacement of the allylic mesylate, therefore,
with sodium dimethyl phosphite34 was followed by R-me-
thylation to provide the target phosphonate 6 in good
overall yield.
With the desired phosphonate in hand, coupling stud-
ies designed to model the proposed C8-C9 double-bond
formation were undertaken (eq 5). In order to mimic the
branching observed at the aldehyde R-carbon, two sys-
tems were selected for study. Isobutyraldehyde served
as a simple preliminary model, while an aldehyde derived
from Brown allylboration of phenylacetaldehyde20 af-
forded a system that more adequately mimicked the local
functionality with respect to the C9-aldehyde in 42.
Multiple attempts at coupling onto the latter model
aldehyde using phosphonate 6 under a myriad of reaction
conditions failed to yield the desired olefin. Our original
hypothesis was that the tributyltin moiety affected the
nucleophilic behavior of 6. Conclusive evidence for the
ineffectiveness of monoene phosphonate in our hands was
provided in the successful coupling of the hydrolyzed
substrate. However, it should be noted that Masamune
used phosphonate 6 successfully in the total synthesis
(31) Kossel, H.; Seliger, H. Fortschr. Chem. Org. Naturst. 1975, 32,
297.
(32) Stille, J . K.; Groh, B. L. J . Am. Chem. Soc. 1987, 109, 813.
(33) Baker, R.; Castro, J . L. J . Chem. Soc., Perkin Trans. 1 1990,
47.
(34) Michaelis, A.; Becker, T. Chem. Ber. 1897, 30, 1003.

6146 J . Org. Chem., Vol. 61, No. 18, 1996
Scarlato et al.
in maintaining a C17-free hydroxyl species. In the event,
however, that protection of the aforementioned hydroxy
group became necessary, we felt that this strategy
possessed the required flexibility to effect such a change.
Ether 50 was, therefore, desilylated under HF/pyridine
conditions to afford diol 51. The mildly acidic reaction
conditions were thought to preclude nucleophilic attack
onto the tetraene, as might be expected under basic
TBAF deprotection conditions. Dess-Martin oxidation38
yielded the target aldehyde 52 in excellent yield for both
steps. This result established a completed C1-C25 bot-
tom-half fragment that could be utilized in the synthesis
of dephosphocalyculin C.
(5)
Con clu sion
We have successfully completed a synthesis of the C1-
C25 fragment in our effort directed toward the total
synthesis of calyculin C. Our approach to this fragment
was based on initial synthesis of a spiroketal core
followed by subsequent homologation to introduce the
necessary stereochemistry. Principally, these homolo-
gations were accomplished via a chiral allylboration
strategy.20 In the following paper, we report the synthe-
sis of the complementary C26-C37 fragment of calyculin
C and model studies for the construction of the C25-C26
double bond, thereby joining both halves of the natural
product.
of calyculin A.13b In light of the above results, we decided
to harness the flexibility implanted into the design of 6
via conversion to diene 49 which was used by Evans in
his synthesis of calyculin A.13a
The synthesis of diene phosphonate 49 required a tin-
halogen exchange on monoene precursor 6, which was
followed by Stille coupling32 with trans-bis(tributylstan-
nyl)ethylene35 to afford 49. Model studies involving this
particular nucleophile proved efficacious, which provided
a clear avenue to the C1-C25 fragment of calyculin.
Final elaboration to the completed bottom half of the
natural product proceeded with formation of the ylide at
-78 °C, followed by warming and subsequent addition
of aldehyde 42 to afford the desired olefin product.
Completion of a protected C1-C25 fragment involved
submission of the crude product from the preceding
reaction to Stille coupling32 with vinyl iodide 536 to yield
tetraene 50 as a single diastereomer (Scheme 12). Proof
of structure was developed from comparison of spectral
evidence from 50 with the identical intermediate reported
by Evans.13a
Exp er im en ta l Section
Gen er a l. High-resolution FAB mass spectra were obtained
by the Mass Spectroscopy Facilities at the University of
California Riverside. Elemental analysis was obtained from
Desert Analysis of Tuscon, AZ. For CI and FAB mass spectra,
2σ ) 4 ppm.
Solvents and reagents were used as supplied from com-
mercial sources with the following exceptions. Tetrahydrofu-
ran, diethyl ether, and toluene were distilled from sodium
benzophenone ketyl immediately prior to use. Dichloromethane
was distilled from phosphorus pentoxide. Methanol was
distilled from magnesium turnings. Dimethylformamide, di-
methyl sulfoxide, and in some cases diisopropylamine were
distilled from barium oxide and stored over 4Å molecular
sieves. All reactions involving moisture-sensitive reagents
were performed under either a nitrogen or an argon atmo-
sphere.
(4S)-4-[(4S)-2,2-Dim eth yl-1,3-dioxolan -4-yl]-2,2-dim eth yl-
4-h yd r oxybu ta n -3-on e (12a ). To a solution of 2,3-O-isopro-
pylidene-L-glyceraldehyde (9.35 g, 0.072 mol) and enol ether
11 (11.1 g, 0.070 mol) in THF (100 mL) at 0 °C was added a 1
M TBAF (70 mL, 0.070 mol) THF solution. The reaction was
stirred for 2 h, at which time the solvent was removed under
reduced pressure to give a thick oil. Column chromatography
afforded a mixture of ketones 12a :12b (1:5) (12.8 g, 85%
overall yield). For 12a : [R]D ) +4.4 (c 0.01, CHCl3); IR (thin
film) 3506, 2985, 2937, 1708, 1470, 1371, 1217, 1064 cm-1; 1H
NMR (360 MHz, CDCl3) δ 4.05 (2H, m), 3.91 (1H, m), 3.84 (1H,
m), 2.59 (1H, d, J ) 5.3 Hz), 2.19 (3H, s), 1.37 (3H, s), 1.32
Com p letion of th e C1-C25 F r a gm en t to
Dep h osp h oca lycu lin C
In keeping with our interest in SAR work involving
phosphatases PP1 and PP2A, we chose to explore elabor-
ation of fragment 50 to aldehyde 52 which was compat-
ible with our synthetic plans for the synthesis of dephos-
phocalyculin C. Given a strategy that assumed Wittig
coupling to generate the C25-C26 double bond via a fully
deprotected C26-C37 phosphonium salt,37 we felt justified
Sch em e 12

Asymmetric Synthesis of Calyculin C. 1
J . Org. Chem., Vol. 61, No. 18, 1996 6147
(3H, s), 1.20 (3H, s), 1.18 (3H, s); 13C NMR (90 MHz, CDCl3)
δ 214.5, 109.1, 76.8, 76.1, 67.1, 51.0, 26.5, 26.4, 25.4, 21.3, 21.0.
Anal. Calcd for C11H20O4: C, 61.09; H, 9.32. Found: C, 59.16;
H, 9.17. For 12b: 1H NMR (360 MHz, CDCl3) δ 4.14 (1H, ddd,
J ) 7.5, 6.6, 2.6 Hz), 4.03 (1H, dd, J ) 6.5, 6.4 Hz), 3.61 (1H,
dd, J ) 8.3, 2.6 Hz), 3.07 (1H, d, J ) J ) 8.3 Hz), 2.20 (3H, s),
1.39 (3H, s), 1.35 (3H, s), 1.22 (3H, s), 1.17 (3H, s); 13C NMR
(90 MHz, CDCl3) δ 214.3, 109.3, 75.2, 74.7, 66.9, 50.6, 26.7,
25.9, 25.5, 22.0, 20.9. Anal. Calcd for C11H20O4: C, 61.09; H,
9.32. Found: C, 59.11; H, 9.03.
(4S)-4-[(4S)-2,2-Dim eth yl-1,3-dioxolan -4-yl]-2,2-dim eth yl-
1-(((2-m eth oxyeth oxy)m eth yl)oxy)bu tan -3-on e (13). (Meth-
oxyethoxy)methyl chloride (MEMCl) (0.81 mL, 7.1 mmol) was
added to a solution of alcohol 12a (1.4 g, 6.5 mmol) in N,N-
diisopropylethylamine (5 mL) and heated for 12 h at 50 °C.
The amine was removed under reduced pressure, and the
resulting crude product was purified by column chromatog-
-78 °C until the solution turned light blue. Dimethyl sulfide
(DMS) was added at -78 °C, and the mixture was allowed to
warm to rt and stirred for 48 h. The CH2Cl2 and DMS were
removed under reduced pressure, and the resultant liquid was
azeotroped with toluene to give aldehyde 17 (0.53 g, 93%) as
a clear oil.
(1S,5S,6R,7R)-1-[(4S)-2,2-Dim et h yl-1,3-d ioxola n -4-yl]-
1-(((2-m eth oxyeth oxy)m eth yl)oxy)-5-(ben zoyloxy)-7-((2′-
tetr ah ydr opyr an yl)oxy)-9-(ter t-bu tyldiph en ylsiloxy)-2,2,6-
tr im eth yln on a n -3-on e (18). Lithium diisopropylamide (1.70
mL, 1.31 mmol, 0.77 M in THF) was added to a stirring
solution of ketone 13 (0.36 g, 1.2 mmol) in THF (5 mL) at -78
°C. The solution was stirred for 45 min at -40 °C, and the
temperature was then reduced to -78 °C. Aldehyde 17 (0.535
g, 1.2 mmol) in THF (5 mL) was added, and the resulting
mixture was stirred for 5 min. Saturated NH4Cl was added
to the mixture, and the frozen mixture was allowed to warm
to rt. The THF was removed under reduce pressure, and the
aqueous layer was extracted with CH2Cl2. The combined
organic extracts were dried over MgSO4 and chromatographed
to give a mixture of aldolate and starting material which was
carried on as a crude product to the next reaction.
raphy to afford ether 13 (1.55 g, 79%) as a clear oil: [R]D
-34.5 (c 0.014, CHCl3); IR (thin film) 2938, 2933, 1701, 1468,
1369, 1212, 1158, 1107 cm-1 1H NMR (360 MHz, CDCl3) δ
)
;
4.83 (2H, d, J ) 7.0 Hz), 4.14 (1H, m), 3.90 (1H, m), 3.77 (1H,
d, J ) 5.8 Hz), 3.70 (3H, m), 3.52 (2H, m), 3.36 (1H, s), 2.18
(3H, s), 1.35 (3H, s), 1.28 (3H, s), 1.15 (3H, s), 1.13 (3H, s); 13
C
Benzoyl chloride (0.156 mL, 1.3 mmol) was added to a
solution of the above mixture in pyridine (5 mL). The reaction
was heated to 50 °C for 2 h, and the pyridine was removed
under reduced pressure. The resultant material was chro-
matographed to give ketone 18 (0.621g, 60% for two steps):
IR (thin film) 2931, 2359, 2340, 1717, 1472, 1427, 1273, 1157,
NMR (90 MHz, CDCl3) δ 212.2, 108.7, 97.6, 82.7, 76.1,71.6,
68.0, 66.1, 59.0, 51.5, 26.6, 26.1, 25.2, 22.0, 21.0. Anal. Calcd
for C15H28O6: C, 59.19; H, 9.27. Found: C, 58.73; H, 9.20.
(3R,4R)-5-(ter t-Bu tyld ip h en ylsiloxy)-4-h yd r oxy-3-m e-
th ylh exen e (15). A 1.9 M solution of n-butyllithium in THF
(13.5 mL, 0.026 mol) was added via syringe to dry potassium
tert-butoxide (2.64 g, 0.023 mol) and cis-2-butene (7.0 mL, 0.08
mol) in THF (5 mL) at -78 °C, and the resulting mixture was
stirred for 1 h at -40 °C. A solution of (-)-B-methoxydiiso-
pinocampheylborane (10.5 g, 0.033 mol) in toluene (20 mL)
was added to this yellow anionic solution at -78 °C, and the
resulting mixture was stirred for 1 h. Boron trifluoride
etherate (4.4 mL, 0.037 mol) was added to the reaction at -78
°C and stirred for 30 min, after which aldehyde 14 (4 mL, 0.01
mol) was added at -78 °C and stirred for 3 h. then 3 N sodium
hydroxide (7 mL) and 30% H2O2 (7 mL) were added to the
stirring solution, which was allowed to warm to rt. The
reaction mixture was extracted with diethyl ether, and the
organic layer was dried over MgSO4 and chromatographed to
afford olefin 15 (3.8 g, 81%) as a clear oil: [R]D ) +5.5 (c 0.014,
CHCl3); IR (thin film) 3509, 2957, 2929, 1638, 1588, 1472,
1111, 1071 cm-1
.
(2R,3S,4S,6S,8S,9S)-8-(H yd r oxym et h yl)-9-(((2-m et h -
oxyeth oxy)m eth yl)oxy)-2-[2-(ter t-bu tyld ip h en ylsiloxy)-
1-eth yl]-3,10,10-tr im eth yl-1,7-d ioxosp ir o[4.5]d eca n e (19).
Zinc bromide (10 mg) was added to a stirred solution of ketone
18 (50 mg, 0.058 mmol) in CH2Cl2 (5 mL), and the resulting
mixture was stirred at rt for 5 h. The reaction mixture was
concentrated under reduced pressure, and the resultant crude
product was chromatographed to afford spiroketal 19 (33 mg,
80%): [R]D ) +86.4 (c 0.012, CHCl3); IR (thin film) 3488, 3069,
2887, 1713, 1601, 1451, 1427, 1363, 1314, 1278, 1219, 1174,
1
1111, 1084 cm-1; H NMR (360 MHz, C6D6) δ 7.0-8.5 (15H,
m), 5.15 (1H, dt, J ) 3.6, 2.0 Hz), 4.67 (1H, m), 4.24 (2H, m),
4.22 (1H, m), 3.9-4.1 (4H, m), 3.47 (1H, d, J ) 5.7 Hz), 3.26-
3.36 (2H, m), 3.19 (2H, m), 3.06 (3H, s), 1.81 (1H, m), 1.69
(1H, m), 1.46 (1H, m), 1.41 (1H, dd, J ) 14.9, 3.6 Hz), 1.19
1427, 1388, 1111, 1076 cm-1
;
1H NMR (360 MHz, CDCl3) δ
(9H, s), 0.89 (3H, s), 0.69 (3H, d, J ) 7.1 Hz), 0.51 (3H, s); 13
C
7.68 (4H, m), 7.47 (6H, m), 5.79 (1H, ddd, J ) 17.3, 10.5, 7.62
Hz), 5.05 (2H, ddd, J ) 17.3, 10.5, 1.50 Hz), 3.88 (2H, m), 3.76
(1H, dt, J ) 6.1, 2.4 Hz), 3.23 (1H, d, J ) 2.4 Hz), 2.29 (1H,
hex, J ) 6.8 Hz), 1.69 (2H, m), 1.07 (3H, d, J ) 7.0 Hz), 1.05
(9H, s); 13C NMR (90 MHz, CDCl3) δ 141.1, 135.5, 133.1, 132.9,
129.8, 127.8, 114.8, 74.9, 63.7, 43.9, 35.4, 26.8, 19.0, 15.1.
Anal. Calcd for C23H32O2Si: C, 74.95; H, 8.75. Found: C,
75.24; H, 8.68.
(3R,4R)-6-(ter t-Bu tyld ip h en ylsiloxy)-4-(2′-tetr a h yd r o-
p yr a n yl)-3-m eth ylh exen e (16). Dihydropyran (0.635 mL,
6.97 mmol) was added to a solution of alcohol 15 (2.33 g, 6.34
mmol) and pTSA (15 mg) in CH2Cl2 (10 mL) at rt. The reaction
was stirred for 10 min and subsequently neutralized with
triethylamine. The solvent was removed under reduced pres-
sure and the resultant material chromatographed to give 2.8
g of 16 (98%) as a mixture of diastereomers. Anal. Calcd for
C28H40O3Si: C, 74.29; H, 8.91. Found: C, 74.48; H, 8.85.
NMR (90 MHz, C6D6) δ 165.8, 136.0, 136.0, 134.7, 134.5, 132.8,
131.8, 130.2, 129.9, 129.8, 128.6, 128.1, 106.7, 97.5, 87.5, 81.2,
73.0, 72.0, 67.7, 63.9, 62.1, 61.7, 58.7, 50.5, 36.1, 34.9, 27.4,
27.1, 23.0, 19.3, 17.0, 10.1. Anal. Calcd for C41H56O9Si: C,
68.3; H, 7.83. Found: C, 68.41; H, 7.75.
(1R)-1-[(4R)-2,2-Dim eth yl-1,3-d ioxola n -4-yl]-1-h yd r oxy-
2,2,3-tr im eth ylbu t-3-en e (21). To a suspension of potassium
tert-butoxide (13.6 g, 121 mmol, 1.30 equiv) in THF (135 mL)
at -78 °C was added 2,3-dimethyl-2-butene (1.0 M in THF,
167 mL, 167 mmol, 1.80 equiv). 2,2,6,6-Tetramethylpiperidine
(20.3 mL, 120 mmol, 1.30 equiv) followed by n-butyllithium
(2.0 M in hexanes, 60.4 mL, 121 mmol, 1.30 equiv) was added,
and the resulting yellow mixture was allowed to stir at -45
°C for 20 min. The reaction mixture was recooled to -78 °C,
and a solution of (+)-B-methoxydiisopinocampheylborane (38.3
g, 120.8 mmol, 1.30 equiv) in THF (130 mL) was added. The
resulting light yellow mixture was stirred at -78 °C for 5 min
and then allowed to warm to 25 °C over 45 min. The reaction
mixture was recooled to -78 °C, and BF3‚Et2O (17.2 mL, 139
mmol, 1.50 equiv) was added, followed by 2,3-O-isopropylidene-
D-glyceraldehyde (12.2 g, 92.9 mmol, 1.00 equiv) in THF (100
mL). The thick white mixture was stirred at -78 °C for 1 h.
The reaction was quenched by the addition of 3 N aqueous
NaOH (130 mL) followed by 30% aqueous H2O2 (40.0 mL). The
reaction mixture was warmed to 45 °C and stirred for 4 h.
The mixture was cooled and diluted with ethyl acetate (100
mL) and saturated aqueous NaCl (300 mL). The layers were
separated, and the aqueous layer was extracted with ethyl
acetate (3 × 150 mL). The combined organic extracts were
washed with saturated aqueous NaCl (300 mL). The organic
layer was dried over Na2SO4, filtered, and concentrated to give
a clear colorless oil. The oil was chromatographed on silica
(2R,3R)-5-(ter t-Bu tyld ip h en ylsiloxy)-3-((2′-tetr a h yd r o-
p yr a n yl)oxy)-2-m eth ylp en ta n a l (17). Ozone was bubbled
into a solution of ether 16 (0.569 g, 1.26 mmol) in CH2Cl2 at
(35) Corey, E. J .; Wollenberg, R. H. J . Org. Chem. 1975, 40, 3788.
(36) Chalchat, J .-C.; Theron, F.; Vessiere, R. C. R. Acad. Sci. Paris
Ser C 1971, 276, 763.
(37) Ogawa, A. K.; DeMattei, J . A.; Scarlato, G. R.; Tellew, J . E.;
Chong, L. S.; Armstrong, R. W. J . Org. Chem., following paper in this
issue.
(38) (a) Dess, D. B.; Martin, J . C. J . Am. Chem. Soc. 1991, 113, 7277.
(b) Meyer, S. D.; Schreiber, S. L. J . Org. Chem. 1994, 59, 7549.
(39) The author has deposited atomic coordinates for this structure
with the Cambridge Crystallographic Data Centre. The coordinates
can be obtained, on request, from the Director, Cambridge Crystal-
lographic Data Centre, 12 Union Road, Cambridge, CB2 1EZ, UK.

6148 J . Org. Chem., Vol. 61, No. 18, 1996
Scarlato et al.
gel (5-20% ethyl acetate-hexane) to give 21 as a colorless oil
To a solution of the crude aldolate (17.2 g, 22.6 mmol, 1.00
equiv) in pyridine (50.0 mL) was added benzoyl chloride (5.50
mL). The solution was heated to 55 °C and allowed to stir for
2 h. The reaction was quenched by the addition of saturated
aqueous NaHCO3 (50 mL). The resulting mixture was ex-
tracted with CH2Cl2 (3 × 50.0 mL), and the combined organic
layers were washed with saturated aqueous NaHCO3 (100
mL), dried over Na2SO4, and concentrated to a dark brown
oil. The oil was chromatographed on silica gel (20% ethyl
acetate-hexane) to give compound 25 (15.8 g, 54.4% for the
two steps): Rf 0.65 (40% ethyl acetate in hexane); IR (thin film)
(14.6 g, 73.0%): Rf 0.75 (30% ethyl acetate in hexane); [R]D
)
+7.0 (c 1.36, CHCl3); IR (thin film) 3559, 2985, 2936, 1636,
1454, 1380, 1217, 1064 cm-1 1H NMR (500 MHz, CDCl3) δ
;
4.86 (1H, m), 4.83 (1H, m), 4.10 (1H, m), 3.98 (1H, dd, J )
7.9, 6.7 Hz), 3.69 (1H, dd, J ) 7.9, 7.9 Hz), 3.46 (1H, dd, J )
7.3, 3.7 Hz), 2.46 (1H, d, J ) 7.3 Hz), 1.74 (3H, s), 1.41 (3H,
s), 1.36 (3H, s), 1.12 (3H, s), 1.05 (3H, s); 13C NMR (90 MHz,
CDCl3) δ 150.3, 111.7, 109.1, 74.9, 74.4, 67.8, 43.1, 26.4, 25.8,
24.3, 21.4, 20.1; HRMS NH3CI calcd for MH+ (C12H22O3)
215.1647, found 215.1655 (error 3.6 ppm).
2934, 1717, 1602, 1585, 1472, 1451, 1273, 1111, 1071 cm-1
;
(1R)-1-[(4R)-2,2-Dim eth yl-1,3-dioxolan -4-yl]-1-(((2-m eth -
oxyeth oxy)m eth yl)oxy)-2,2,3-tr im eth ylbu t-3-en e (22). To
a solution of alcohol 21 (6.49 g, 30.3 mmol, 1.00 equiv) in CHCl3
(10 mL) was added diisopropylethylamine (12.0 mL, 68.9
mmol, 2.27 equiv) followed by MEMCl (7.00 mL, 61.3 mmol,
2.02 equiv). The reaction was heated at 55 °C for 2 h. The
dark brown solution was cooled and diluted with saturated
aqueous NaCl (50.0 mL) and CH2Cl2 (50.0 mL). The layers
were separated, and the aqueous layer was extracted with CH2-
Cl2 (3 × 25 mL). The combined organic extracts were washed
with saturated aqueous NaCl, dried over Na2SO4, and con-
centrated to a brown oil. The residue was chromatographed
on silica gel (10-30% ethyl acetate-hexane) to give ether 22
(7.51 g, 82.0%) as a yellow oil: Rf 0.60 (30% ethyl acetate in
hexane); [R]D ) +66.3 (c 1.05, CHCl3); IR (thin film) 2984, 2934,
1636, 1455, 1378, 1249, 1216, 1107 cm-1; 1H NMR (500 MHz,
CDCl3) δ 4.96 (1H, d, J ) 7.3 Hz), 4.78 (2H, s), 4.76 (1H, d, J
) 7.3 Hz), 4.04 (1H, m), 3.86 (1H, dd, J ) 8.5, 6.1 Hz), 3.77
(1H, m), 3.73 (1H, m), 3.52 (3H, m), 3.46 (1H, dd, J ) 8.5, 8.5
Hz), 3.35 (3H, s), 1.73 (3H, s), 1.33 (3H, s), 1.28 (3H, s), 1.08
(3H, s), 1.06 (3H, s); 13C NMR (90 MHz, CDCl3) δ 149.6, 112.0,
107.7, 97.4, 82.9, 77.1, 71.7, 67.8, 67.3, 58.9, 42.9, 26.4, 25.6,
25.5, 21.5, 20.1; HRFABMS calcd for MH+ C16H31O5 303.2171,
found 303.2170 (error 0.5 ppm).
1H NMR (500 MHz, CDCl3) δ 7.97-8.12, 7.29-7.68, 5.69, 4.84,
4.77, 4.72, 4.57, 3.63-4.18, 3.32-3.57, 3.05, 2.11-2.25, 0.91-
1.95; 13C NMR (90 MHz, CDCl3) δ 211.4, 210.8, 165.6, 165.4,
135.5, 135.47, 135.44, 133.9, 133.87, 133.7, 133.5, 133.4, 132.8,
132.6, 130.6, 130.5, 130.0, 129.6, 129.5, 129.4, 128.4, 128.3,
128.2, 127.6, 127.5, 127.4, 108.8, 108.7, 99.4, 97.7, 97.6, 82.0,
81.8, 77.4, 77.0, 76.6, 76.2, 76.0, 75.7, 74.2, 72.2, 71.7, 71.1,
68.0, 67.9, 66.7, 66.6, 64.0, 62.5, 61.0, 60.2, 59.0, 51.8, 51.7,
41.0, 40.4, 40.2, 38.1, 34.7, 34.5, 31.4, 31.0, 26.8, 26.7, 26.2,
26.1, 25.4, 25.2, 25.1, 22.6, 22.4, 20.8, 20.5, 20.3, 19.7, 19.0,
10.9, 10.6; HRFABMS calcd for MNa+ (C49H70O11SiNa)
885.4578, found 885.4585 (error 0.8 ppm).
(2R,3R,5R,7S,8R,9R)-9-(Ben zoyloxy)-7-[2-(ter t-b u t yl-
d ip h en ylsiloxy)et h yl]-2-(h yd r oxym et h yl)-3-(((2-m et h -
oxyet h oxy)m et h yl)oxy)-4,4,8-t r im et h yl-1,6-d ioxa sp ir o-
[4.5]d eca n e (26). To a solution of benzoate 25 (15.8 g, 18.3
mmol, 1.00 equiv) in CH2Cl2 (183 mL) at 0 °C was added
trifluoroacetic acid (21.1 mL, 274 mmol, 15.0 equiv). The
resulting yellow solution was allowed to stir for 20 min; then
the reaction was quenched by the addition of saturated
aqueous NaHCO3 (100 mL). The layers were separated, and
the aqueous layer was extracted with CH2Cl2 (3 × 50 mL).
The combined organic extracts were washed with saturated
aqueous NaHCO3 (100 mL). The organic layer was dried over
Na2SO4, filtered, and concentrated to give a yellow oil. The
oil was chromatographed on silica gel (15% ethyl acetate-
hexane) to give the spiro compound 26 as a colorless oil (11.2
g, 85.0%): Rf 0.45 (40% ethyl acetate in hexane); [R]D ) -64
(c 0.98, CHCl3); IR (thin film) 3489, 2930, 1713, 1472, 1427,
1389, 1276, 1111 cm-1; 1H NMR (500 MHz, C6D6) δ 8.44 (2H,
m), 7.82 (4H, m), 7.21 (9H, m), 5.15 (1H, ddd, J ) 3.6, 3.6, 2.0
Hz), 4.67 (1H, m), 4.28 (1H, d, J ) 5.8 Hz), 4.22 (2H, m), 3.90-
4.10 (4H, m), 3.47 (1H, d, J ) 5.7 Hz), 3.36 (1H, m), 3.25 (1H,
m), 3.19 (2H, m), 3.06 (3H, s), 1.81 (1H, m), 1.69 (2H, m), 1.46
(1H, m), 1.41 (1H, dd, J ) 14.9, 3.7 Hz), 1.19 (9H, s), 0.89 (3H,
s), 0.69 (3H, d, J ) 7.1 Hz), 0.51 (3H, s); 13C NMR (90 MHz,
C6D6) δ 165.8, 136.0, 135.9, 134.7, 134.5, 132.8, 131.8, 130.2,
129.9, 129.8, 128.6, 128.3, 106.7, 97.5, 87.4, 81.2, 73.0, 72.0,
67.7, 63.9, 62.1, 61.7, 58.7, 50.5, 36.1, 34.9, 27.4, 27.1, 23.0,
19.3, 17.0, 10.1; HRFABMS CH2Cl2/NBA calcd for MH+
(C41H57O9Si) 721.3772, found 721.3790 (error 2.5 ppm).
(1R)-1-[2,2-Dim eth yl-1,3-dioxolan -4(R)-yl]-2,2-dim eth yl-
1-(((2-m eth oxyeth oxy)m eth yl)oxy)bu tan -3-on e (23). Ozone
was bubbled through a solution of olefin 22 (8.83 g, 29.2 mmol,
1.00 equiv) in CH2Cl2 (160 mL) and methanol (1.2 mL, 29.2
mmol, 1.00 equiv) at -78 °C. The reaction was monitored by
TLC for the consumption of the olefin at which time dimethyl
sulfide (21.4 mL, 292 mmol, 10.0 equiv) was added. The
solution was allowed to warm to 25 °C and stirred for 12 h.
The solution was concentrated to give a yellow oil. The oil
was chromatographed on silica gel (10% ethyl acetate-hexane)
to give ketone 23 as a colorless oil (7.63 g, 86.2%): Rf 0.30
(30% ethyl acetate in hexane); [R]D ) +37.9 (c 0.965, CHCl3);
IR (thin film) 2984, 2935, 1704, 1370, 1213, 1159, 1110 cm-1
;
1H NMR (500 MHz, CDCl3) δ 4.91 (1H, d, J ) 7.0 Hz), 4.78
(1H, d, J ) 7.0 Hz), 4.16 (1H, ddd, J ) 6.5, 6.5, 5.9 Hz), 3.92
(1H, dd, J ) 8.1, 6.5 Hz), 3.79 (1H, d, J ) 5.9 Hz), 3.71 (3H,
m), 3.53 (2H, m), 3.38 (3H, s), 2.20 (3H, s), 1.37 (3H, s), 1.30
(3H, s), 1.16 (3H, s), 1.15 (3H, s); 13C NMR (90 MHz, CDCl3)
δ 212.3, 108.8, 97.6, 82.7, 76.2, 71.7, 68.0, 66.7, 59.0, 51.5, 26.6,
26.1, 25.2, 22.1, 21.0; HRFABMS calcd for MNa+ (C15H28O6-
Na) 327.1770, found 327.1784 (error 4.2 ppm).
(2R,3R,5R,7S,8R,9R)-9-(Ben zoyloxy)-7-[2-(ter t-b u t yl-
d ip h en ylsiloxy)eth yl]-2-for m yl-3-(2-m eth oxyeth oxym e-
th yl)oxy-4,4,8-tr im eth yl-1,6-d ioxa sp ir o[4.5]d eca n e (28).
To a solution of oxalyl chloride (5.57 mL, 63.9 mmol, 5.00
equiv) in CH2Cl2 (125 mL) at -78 °C was added dropwise
DMSO (9.07 mL, 128 mmol, 10.0 equiv). The solution was
stirred at -78 °C for 5 min; then the alcohol 26 (9.22 g, 12.8
mmol, 1.00 equiv) in CH2Cl2 (25.0 mL) was added dropwise.
The resulting yellow solution was allowed to stir at -40 °C
for 10 min; then the solution was recooled to -78 °C. Tri-
ethylamine (26.7 mL, 192 mmol, 15.0 equiv) was added, and
the resulting white slurry was allowed to warm to rt. The
reaction was diluted with saturated aqueous NaCl (150 mL).
The layers were separated, and the aqueous layer was
extracted with CH2Cl2 (3 × 75 mL). The combined organic
extracts were washed with saturated aqueous NaCl (100 mL).
The organic layer was dried over Na2SO4, filtered, and
concentrated to give a yellow oil. The oil was chromatographed
on silica gel (25% ethyl acetate-hexane) to give aldehyde 28
as a colorless oil (8.59 g, 93.4%): Rf 0.60 (40% ethyl acetate in
hexane); [R]D ) -10.5 (c 1.15, CHCl3); IR (thin film) 2931, 1721,
(1R,5R,6R,7S)-9-[(ter t-Bu t yld ip h en ylsiloxy]-1-(2,2-d i-
m eth yl-1,3-d ioxola n -4(R)-yl)-5-(ben zoyloxy)-1-(((2-m eth -
oxyet h oxy)m et h yl)oxy)-7-(2-t et r a h yd r op yr a n yl)-2,2,6-
t r im et h yln on a n -3-on e (25). To a solution of diisopropyl-
amine (6.00 mL, 43.1 mmol, 1.91 equiv) in THF (17.0 mL) at
-20 °C was added n-butyllithium (2.01 M in hexane, 20.9 mL,
43.1 mmol, 1.91 equiv). The solution was cooled to -78 °C,
and after 5 min at -78 °C the ketone 23 (8.74 g, 28.7 mmol,
1.27 equiv) in THF (20.0 mL) was added. The resulting brown
solution was allowed to stir at -78 °C for 30 min at which
time the aldehyde 24 (10.3 g, 22.6 mmol, 1.00 equiv) in THF
(10.0 mL) was added. After the solution was stirred for 30
min at -78 °C, the reaction was quenched by the addition of
saturated aqueous NaCl (75.0 mL). The layers were sepa-
rated, and the aqueous layer was extracted with ethyl acetate
(3 × 40.0 mL). The combined organic extracts were washed
with saturated aqueous NaCl (40.0 mL), dried over Na2SO4,
and concentrated to give the aldolate as a yellow oil: Rf 0.25
(30% ethyl acetate in hexane).
1451, 1428, 1273, 1111 cm-1 1H NMR (360 MHz, CDCl3) δ
;
9.55 (1H, d, J ) 2.9 Hz), 8.05 (2H, m), 7.68 (4H, m), 7.45 (9H,
m), 5.38 (1H, ddd, J ) 10.9, 10.9, 4.7 Hz), 4.64 (2H, s), 4.42

Asymmetric Synthesis of Calyculin C. 1
J . Org. Chem., Vol. 61, No. 18, 1996 6149
(1H, d, J ) 8.6 Hz), 4.30 (1H, ddd, J ) 12.6, 5.7, 2.4 Hz), 4.10
(1H, dd, J ) 8.6, 2.9 Hz), 3.77 (2H, m), 3.68 (1H, m), 3.62 (1H,
m), 3.54 (2H, m), 3.38 (3H, s), 2.39 (1H, dd, J ) 12.6, 4.7 Hz),
2.18 (2H, m), 1.70 (2H, m), 1.07 (3H, s), 1.06 (9H, s), 0.98 (3H,
d, J ) 6.9 Hz), 0.88 (3H, s); 13C NMR (90 MHz, CDCl3) δ 201.3,
166.0, 135.5, 133.8, 133.7, 133.0, 130.3, 130.2, 129.7, 129.6,
129.5, 128.4, 127.7, 111.0, 96.0, 85.8, 81.2, 74.7, 71.6, 70.8, 67.5,
60.9, 59.0, 48.4, 39.0, 35.3, 32.3, 26.9, 20.3, 19.2, 18.0, 13.5;
HRFABMS CH2Cl2/NBA calcd for M+ (C41H54O9Si) 718.3537,
found 718.3560 (error 3.2ppm).
(2R,3R,5R,7S,8R,9R)-9-[(Ben zoyl)oxy]-7-[2-(ter t-bu tyl-
d ip h en ylsiloxy)eth yl]-2-[1(S)-h yd r oxybu t-3-en yl]-3-(((2-
m e t h o x y e t h o x y )m e t h y l)o x y )4,4,8-t r im e t h y l-1,6-d i-
oxa sp ir o[4.5]d eca n e (31). To a solution of ketone 30 (2.89
g, 3.81 mmol, 1.00 equiv) in THF (10.0 mL) at -10 °C was
added LiBH4 (2.0 M in THF, 2.90 mL, 5.80 mmol, 1.52 equiv).
After 1 h, the reaction was quenched by the addition of
saturated aqueous NaCl (25.0 mL). The mixture was diluted
with ethyl acetate (25.0 mL), and the resulting layers were
separated. The aqueous layer was extracted with ethyl acetate
(3 × 20.0 mL), and the combined organic extracts were washed
with saturated aqueous NaCl (50.0 mL). The organic layer
was dried over Na2SO4, filtered, and concentrtated under
reduced pressure. The resulting oil was chromatographed on
silica gel (15% ethyl acetate-hexane) to give the alcohol 31
(2R,3R,5R,7S,8R,9R)-9-[(Ben zoyl)oxy]-7-[2-(ter t-bu tyl-
d ip h en ylsiloxy)eth yl]-2-[1(R)-h yd r oxybu t-3-en yl]-3-(((2-
m e t h o x y e t h o x y )m e t h y l)o x y )-4,4,8-t r im e t h y l-1,6-d i-
oxa sp ir o[4.5]d eca n e (29). To a solution of aldehyde 28 (8.59
g, 11.9 mmol, 1.00 equiv) in CH2Cl2 (85 mL) at -78 °C was
added a slurry of allylmagnesium bromide (1.0 M in THF, 17.9
mL, 17.9 mmol, 1.50 equiv) and ZnCl2 (1.0 M in THF, 20.9
mL, 20.9 mmol, 1.75 equiv) via cannula. The reaction was
stirred at -78 °C for 15 min; then the reaction was quenched
by the addition of saturated aqueous NaCl (100 mL). The
mixture was filtered, and the filtrate was transferred to a
separatory funnel. The layers were separated, and the aque-
ous layer was extracted with CH2Cl2 (3 × 35 mL). The
combined organic layers were dried over Na2SO4, filtered, and
concentrated to give a light yellow oil. The oil was chromato-
graphed on silica gel (20% ethyl acetate-hexane) to give
alcohol 29 (8.07 g, 88.8%): Rf 0.55 (40% ethyl acetate in
hexane): [R]D ) -64.9 (c 1.26, CHCl3); IR (thin film) 3478,
3071, 2931, 1716, 1472, 1428, 1363, 1277, 1112 cm-1; 1H NMR
(500 MHz, CDCl3) δ 8.12 (2H, m), 7.66 (4H, m), 7.53 (1H, m),
7.35 (8H, m), 5.80 (1H, m), 5.14 (1H, m), 4.96 (2H, m), 4.36
(1H, d, J ) 5.8 Hz), 4.27 (2H, m), 4.04 (1H, m), 3.89 (1H, dd,
J ) 9.6, 5.5 Hz), 3.71 (2H, m), 3.64 (1H, d, J ) 5.5 Hz), 3.56
(1H, br s), 3.39 (4H, m), 3.32 (3H, s), 2.59 (1H, m), 2.23 (1H,
m), 1.88 (1H, m), 1.77 (3H, m), 1.58 (1H, m), 1.02 (9H, s), 1.01
(3H, s), 0.96 (3H, d, J ) 7.2 Hz), 0.87 (3H, s); 13C NMR (90
MHz, CDCl3) δ 165.9, 135.5, 135.4, 135.3, 134.2, 132.8, 130.6,
129.7, 129.5, 129.4, 128.2, 127.6, 127.5, 116.5, 106.6, 97.7, 87.9,
82.6, 72.8, 71.6, 68.3, 67.4, 64.2, 62.5, 58.9, 50.4, 38.0, 35.7,
34.9, 27.3, 26.8, 22.9, 19.0, 16.9, 10.2; HRFABMS CH2Cl2/NBA
calcd for MH+ (C44H61O9Si) 761.4085, found 761.4041 (error
5.8 ppm).
(2.46 g, 85.0%): Rf 0.50 (30% ethyl acetate in hexane); [R]D
-62.8 (c 1.07, CHCl3); IR (thin film) 3531, 2931, 1713, 1471,
1428, 1364, 1277, 1111 cm-1 1H NMR (360 MHz, CDCl3) δ
)
;
8.17 (2H, m), 7.64 (4H, m), 7.51 (1H, m), 7.36 (8H, m), 5.81
(1H, m), 5.16 (1H, m), 4.95 (2H, m), 4.62 (1H, m), 4.58 (1H, d,
J ) 7.2 Hz), 4.48 (1H, d, J ) 7.2 Hz), 4.09 (1H, dd, J ) 5.8,
2.8 Hz), 3.76 (4H, m), 3.64 (1H, m), 3.48 (3H, m), 3.37 (3H, s),
2.37 (2H, m), 1.58-1.92 (5H, m), 1.03 (3H, s), 0.98 (9H, s), 0.93
(3H, d, J ) 7.2 Hz), 0.87 (3H, s); 13C NMR (90 MHz, CDCl3) δ
165.9, 135.6, 135.5, 135.4, 134.0, 133.9, 132.8, 130.7, 129.8,
129.4, 128.3, 127.5, 116.7, 106.4, 96.7, 87.7, 81.0, 72.8, 71.6,
70.3, 67.8, 64.8, 61.3, 59.8, 59.0, 50.6, 38.3, 35.1, 33.9, 27.2,
26.7, 23.3, 21.3, 19.0, 17.1, 10.2; HRFABMS CH2Cl2/NBA calcd
for MH+ (C44H61O9Si) 761.4085, found 761.4122 (error 4.9
ppm).
(2R,3R,5R,7S,8R,9R)-9-[(Ben zoyl)oxy]-7-[2-(ter t-bu tyl-
d ip h en ylsiloxy)eth yl]-2-[1(S)-m eth oxybu t-3-en yl]-3-(((2-
m e t h o x y e t h o x y )m e t h y l)o x y )4,4,8-t r im e t h y l-1,6-d i-
oxa sp ir o[4.5]d eca n e (32). To a solution of 18-crown-6 (2.10
g, 2.69 mmol, 1.00 equiv) in THF (20.0 mL) at 0 °C was added
potassium hydride (350 mg, 8.73 mmol, 3.25 equiv). The
resulting yellow suspension was stirred for 5 min; then
iodomethane (440 µL, 7.02 mmol, 2.61 equiv) was added. The
reaction mixture foamed and was stirred for 5 min. Next the
alcohol 31 (2.05 g, 2.69 mmol, 1.00 equiv) in THF (8 mL) was
added dropwise and stirred for 12 h at 25 °C. The reaction
was quenched by the addition of saturated aqueous NaCl (20.0
mL) and diluted with ethyl acetate (15.0 mL). The layers were
separated, and the aqueous layer was extracted with ethyl
acetate (3 × 10.0 mL). The combined organic extracts were
washed with saturated aqueous NaCl (30.0 mL), dried over
Na2SO4, and concentrated under reduced pressure. The
resulting oil was chromatographed on silica gel (20% ethyl
acetate-hexane) to give the methyl ether 32 (1.84 g, 88.2%):
Rf 0.62 (30% ethyl acetate in hexane). [R]D ) -66.8 (c 1.66,
CHCl3); IR (thin film) 3070, 2929, 1716, 1472, 1451, 1428,
1361, 1277, 1111 cm-1; 1H NMR (500 MHz, CDCl3) δ 8.16 (2H,
m), 7.67 (4H, m), 7.52 (1H, m), 7.38 (8H, m), 5.73 (1H, m),
5.15 (1H, m), 5.02 (2H, m), 4.47 (1H, d, J ) 7.0 Hz), 4.41 (1H,
m), 4.25 (1H, d, J ) 7.0 Hz), 4.02 (2H, m), 3.78 (1H, m), 3.55
(1H, d, J ) 5.1 Hz), 3.23-3.41 (5H, m), 3.35 (3H, s), 3.34 (3H,
s), 2.29 (1H, m), 1.54-2.04 (6H, m), 1.02 (3H, s), 1.01 (9H, s),
0.98 (3H, d, J ) 7.1 Hz), 0.85 (3H, s); 13C NMR (125 MHz,
CDCl3) δ 166.2, 135.4, 135.3, 135.1, 134.1, 134.0, 132.7, 130.8,
129.9, 129.5, 129.4, 128.2, 127.60, 127.58, 106.4, 97.2, 86.9,
83.1, 80.4, 73.0, 71.5, 67.7, 64.1, 62.7, 59.3, 59.0, 50.5, 35.9,
35.0, 34.9, 27.6, 26.7, 22.8, 19.1, 17.6, 10.2; HRFABMS CH2-
Cl2/NBA/NaCl calcd for MNa+ (C45H62O9SiNa) 797.4061, found
797.4105 (error 5.5 ppm).
(2R,3R,5R,7S,8R,9R)-9-[(Ben zoyl)oxy]-7-[2-(ter t-bu tyl-
d ip h en ylsiloxy)eth yl]-2-(1-oxobu t-3-en yl)-3-(2-m eth oxy-
et h oxym et h yl)oxy-4,4,8-t r im et h yl-1,6-d ioxa sp ir o[4.5]-
d eca n e (30). To a solution of oxalyl chloride (2.10 mL, 24.1
mmol, 5.06 equiv) in CH2Cl2 (20.0 mL) at -78 °C was added
dropwise DMSO (3.40 mL, 47.9 mmol, 10.1 equiv). The
solution was stirred at -78 °C for 5 min; then the alcohol 29
(3.62 g, 4.76 mmol, 1.00 equiv) in CH2Cl2 (10.0 mL) was added
dropwise. The resulting yellow solution was allowed to stir
at -40 °C for 10 min; then the solution was recooled to -78
°C. Triethylamine (10.0 mL, 71.7 mmol, 15.1 equiv) was
added, and the resulting white slurry was allowed to warm to
rt. The reaction was diluted with CH2Cl2 (20.0 mL) and
saturated aqueous NaCl (50.0 mL). The layers were sepa-
rated, and the aqueous layer was extracted with CH2Cl2 (3 ×
25 mL). The combined organic extracts were washed with
saturated aqueous NaCl (50.0 mL). The organic layer was
dried over Na2SO4, filtered, and concentrated to give a yellow
oil. The oil was chromatographed on silica gel (15% ethyl
acetate-hexane) to give ketone 30 as a colorless oil (2.89 g,
80.0%): Rf 0.60 (40% ethyl in hexane); [R]D ) -85.5 (c 1.14,
CHCl3); IR (thin film) 3071, 2930, 2857, 1716, 1472, 1428,
1362, 1277, 1112 cm-1; 1H NMR (500 MHz, CDCl3) δ 8.12 (2H,
m), 7.63 (2H, m), 7.53 (1H, m), 7.39 (10H, m,), 5.80 (1H, m),
5.20 (1H, m), 5.06 (1H, m), 4.96 (1H, m), 4.68 (1H, m), 4.55
(1H, d, J ) 4.9 Hz), 4.35 (1H, d, J ) 7.0 Hz), 4.21 (1H, d, J )
7.0 Hz), 4.00 (1H, d, J ) 5.5 Hz), 3.88 (1H, m), 3.77 (1H, m),
3.27-3.54 (9H, m), 1.62-2.02 (5H, m), 1.06 (3H, s), 0.98 (3H,
d, J ) 6.7 Hz), 0.97 (9H, s), 0.88 (3H, s); 13C NMR (90 MHz,
CDCl3) δ 210.1, 165.8, 135.4, 133.8, 132.9, 130.7, 130.3, 129.7,
129.5, 128.3, 127.6, 118.5, 108.9, 96.1, 86.6, 86.5, 72.6, 71.6,
67.4, 65.1, 61.6, 59.0, 50.4, 45.1, 35.5, 34.0, 27.8, 26.7, 22.7,
19.0, 17.3, 10.2; HRFABMS CH2Cl2/NBA calcd for MH+
(C44H59O9Si) 759.3928, found 759.3926 (error 0.3 ppm).
(2R,3R,5R,7S,8R,9R)-9-[(Ben zoyl)oxy]-7-[2-(ter t-bu tyl-
diph en ylsiloxy)eth yl]-2-[(1S,3S,4R)-3-h ydr oxy-1-m eth oxy-
4-m eth ylh ex-5-en yl]-3-(2-m eth oxyeth oxym eth yl)oxy-4,4,8-
t r im et h yl-1,6-d ioxa sp ir o[4.5]d eca n e (35). Ozone was
bubbled through a solution of olefin 32 (1.37 g, 1.76 mmol,
1.00 equiv) in methanol (71.0 µL, 1.76 mmol, 1.00 equiv) and
CH2Cl2 (10.0 mL) at -78 °C. The reaction was monitored by
TLC for the consumption of the olefin at which time dimethyl
sulfide (0.65 mL, 8.9 mmol, 5.0 equiv) was added. The solution
was allowed to warm to 25 °C and stirred for 12 h. The
solution was concentrated to afford the crude aldehyde as a
yellow oil which was used directly in the next reaction.

6150 J . Org. Chem., Vol. 61, No. 18, 1996
Scarlato et al.
To a suspension of potassium tert-butoxide (310 mg, 2.76
mmol, 1.57 equiv) in THF (8.0 mL) at -78 °C was added trans-
2-butene (550 mg, 9.80 mmol, 5.57 equiv). n-Butyllithium (2.0
M in hexanes, 1.35 mL, 2.70 mmol, 1.54 equiv) was added,
and the resulting yellow mixture was allowed to stir at -45
°C for 20 min. The reaction mixture was recooled to -78 °C,
and a solution of (+)-B-methoxydiisopinocampheylborane (850
mg, 2.69 mmol, 1.53 equiv) in THF (2.0 mL) was added. The
resulting light yellow mixture was stirred at -78 °C for 35
min. BF3‚Et2O (440 µL, 3.58 mmol, 2.03 equiv) was added
followed by the above-mentioned aldehyde (1.368 g, 1.76 mmol,
1.00 equiv) in THF (5.0 mL). The thick white mixture was
stirred at -78 °C for 1 h. The reaction was quenched by
addition of 3 N aqueous NaOH (10 mL) followed by 30%
aqueous H2O2 (10 mL). The reaction mixture was warmed to
25 °C and stirred for 1 h. The mixture was cooled and diluted
with ethyl acetate (20 mL) and saturated aqueous NaCl (20
mL). The layers were separated, and the aqueous layer was
extracted with ethyl acetate (3 × 10 mL). The combined
organic extracts were washed with saturated aqueous NaCl
(25 mL). The organic layer was dried over Na2SO4, filtered,
and concentrated to give a clear colorless oil. The oil was
chromatographed on silica gel (15% ethyl acetate-hexane) to
give 35 as a colorless oil (880 mg, 60.0% for the two steps): Rf
0.50 (30% ethyl acetate in hexane) [R]D ) -103 (c 1.50, CHCl3);
IR (thin film) 3498, 3070, 2931, 1714, 1472, 1452, 1428, 1278,
To a suspension of potassium tert-butoxide (69 mg, 0.62
mmol, 1.5 equiv) in THF (5.0 mL) at -78 °C was added trans-
2-butene (120 mg, 2.1 mmol, 5.2 equiv). n-Butyllithium (2.0
M in hexanes, 310 µL, 0.62 mmol, 1.5 equiv) was added, and
the resulting yellow mixture was allowed to stir at -45 °C for
20 min. The reaction mixture was recooled to -78 °C, and a
solution of (+)-B-methoxydiisopinocampheylborane (210 mg,
0.66 mmol, 1.6 equiv) in THF (2.0 mL) was added. The
resulting light yellow mixture was stirred at -78 °C for 35
min. BF3‚Et2O (81 µL, 0.66 mmol, 1.5 equiv) was added
followed by the crude aldehyde (390 mg, 0.41 mmol, 1.0 equiv)
in THF (5.0 mL). The thick white mixture was stirred at -78
°C for 1 h. The reaction was quenched by addition of 3 N
aqueous NaOH (10 mL) followed by 30% aqueous H2O2 (10
mL). The reaction mixture was warmed to 25 °C and stirred
for 1 h. The mixture was cooled and diluted with ethyl acetate
(20 mL) and saturated aqueous NaCl (20 mL). The layers were
separated, and the aqueous layer was extracted with ethyl
acetate (3 × 10 mL). The combined organic extracts were
washed with saturated aqueous NaCl (25 mL). The organic
layer was dried over Na2SO4, filtered, and concentrated to give
a clear colorless oil. The oil was chromatographed on silica
gel (15% ethyl acetate-hexane) to give the diastereomers 37
(170 mg, 40%) and 38 (130 mg, 30%). For 37: Rf 0.30 (30%
ethyl acetate in hexane). [R]D ) -58 (c 0.75, CHCl3); IR (thin
film) 3425, 2928, 1713, 1451, 1429, 1277, 1112 cm-1; 1H NMR
(400 MHz, CDCl3) δ 8.03-8.10 (4H, m), 7.26-7.58 (16H, m),
5.82 (1H, m), 5.64 (1H, m), 5.08 (3H, m), 4.62 (1H, d, J ) 6.7
Hz), 4.54 (1H, d, J ) 6.7 Hz), 4.42 (1H, m), 4.10 (1H, m), 3.30-
3.77 (9H, m), 3.51 (3H, s), 3.33 (3H, s), 2.69 (1H, br s), 2.40
(1H, m), 2.11 (1H, m), 1.40-1.89 (7H, m), 1.15 (3H, d, J ) 6.8
Hz), 1.06 (3H, s), 0.96 (3H, d, J ) 6.8 Hz), 0.89 (15H, m); 13C
NMR (100 MHz, CDCl3) δ 166.3, 165.9, 139.1, 135.5, 133.9,
133.8, 132.8, 132.7, 130.8, 130.6, 129.9, 129.6, 129.5, 129.4,
128.3, 128.2, 127.6, 116.2, 106.6, 97.9, 87.7, 84.2, 79.1, 76.6,
73.1, 72.7, 71.7, 67.9, 64.5, 61.7, 60.5, 59.0, 50.5, 40.5, 39.6,
35.3, 34.2, 31.4, 27.8, 26.7, 23.1, 19.0, 17.8, 17.7, 11.3, 10.0;
HRFABMS CH2Cl2/NBA/NaCl calcd for MNa+ (C58H78O12SiNa)
1017.5160, found 1017.5104 (error 5.5 ppm).
1
1112 cm-1; H NMR (500 MHz, CDCl3) δ 8.16 (2H, m), 7.64
(4H, m), 7.51 (1H, m), 7.35 (8H, m), 5.82 (1H, m), 5.15 (1H,
m), 5.07 (2H, m), 4.44 (2H, m), 4.36 (1H, d, J ) 6.6 Hz), 4.18
(1H, dd, J ) 9.6, 4.9 Hz), 3.97 (1H, m), 3.75 (1H, m), 3.67 (1H,
m), 3.51 (3H, m), 3.41 (3H, s), 3.35 (3H, s), 3.28-3.42 (3H, m),
3.01 (1H, d, J ) 4.4 Hz), 2.16 (1H, m), 1.38-1.93 (7H, m), 1.03
(6H, m), 0.99 (9H, s), 0.97 (3H, d, J ) 7.1 Hz), 0.88 (3H, s); 13
C
NMR (125 MHz, CDCl3) δ 166.2, 140.8, 135.5, 135.4, 134.1,
134.0, 132.7, 129.9, 129.5, 128.1, 127.6, 115.1, 106.5, 97.8, 87.7,
83.2, 79.8, 73.1, 71.7, 71.5, 67.8, 64.2, 62.5, 59.9, 58.9, 50.6,
44.4, 35.8, 34.8, 34.2, 27.7, 26.8, 22.8, 19.0, 17.6, 16.0, 10.2;
HRFABMS CH2Cl2/NBA/NaCl calcd for MNa+ (C48H68O10SiNa)
855.4479, found 855.4500 (error 2.4 ppm).
(2R,3R,5R,7S,8R,9R)-9-(b en zoyloxy)-7-[2-(ter t-b u t yl-
diph en ylsiloxy)eth yl]-2-[(1S,3S,4R)-3-(ben zoyloxy)-1-m eth -
oxy-4-m eth ylh ex-5-en yl]-3-(2-m eth oxyeth oxym eth yl)oxy-
4,4,8-tr im eth yl-1,6-d ioxa sp ir o[4.5]d eca n e (36). To a sol-
ution of the alcohol 35 (880 mg, 1.06 mmol, 1.00 equiv) in
pyridine (20 mL) was added benzoyl chloride (1.00 mL, 8.61
mmol, 8.16 equiv). The solution was heated to 60 °C and
allowed to stir for 2 h. The reaction was quenched by the
addition of saturated aqueous NaHCO3 (50 mL). The resulting
mixture was extracted with CH2Cl2 (3 × 50 mL), and the
combined organic layers were washed with saturated aqueous
NaHCO3 (100 mL), dried over NaSO4, and concentrated to a
dark brown oil. The oil was chromatographed on silica gel
(20% ethyl acetate-hexane) to give 36 (1.00 g, 99%): Rf 0.40
(30% ethyl acetate in hexane). [R]D ) -76.9 (c 0.854, CHCl3);
IR (thin film) 3070, 2930, 1716, 1602, 1584, 1451, 1363, 1274,
[3S,4S,5S,6S,8S,8(2R,3R,5R,7S,8R,9R)]-8-{9-[(Ben zoyl)-
oxy]-7-[2-(ter t-bu tyld ip h en ylsiloxy)eth yl]-3-((2-m eth oxy-
eth oxy)m eth oxy)-4,4,8-tr im eth yl-1,6-d ioxa sp ir o[4.5]d ec-
2-y l}-6-(b e n z o y lo x y )-4-h y d r o x y -8-m e t h o x y -3,5-d i -
m eth yloct-1-en e (38). For 38: Rf 0.20 (30% ethyl acetate in
hexane). [R]D ) -58 (c 0.96, CHCl3); IR (thin film) 3507, 3060,
2931, 1714, 1601, 1451, 1362, 1276, 1112 cm-1; 1H NMR (400
MHz, CDCl3) δ 8.01-8.12 (4H, m), 7.26-7.54 (16H, m), 5.84
(1H, m), 5.42 (1H, m), 5.09 (3H, m), 4.69 (1H, d, J ) 6.7 Hz),
4.60 (1H, d, J ) 6.7 Hz), 4.44 (1H, m), 4.12 (1H, dd, J ) 9.0,
5.1 Hz), 3.34-3.65 (9H, m), 3.41 (3H, s), 3.36 (3H, s), 2.62 (1H,
br s), 2.32 (1H, m), 1.41-2.02 (8H, m), 1.06 (3H, s), 0.97 (3H,
d, J ) 6.9 Hz), 0.93 (3H, d, J ) 6.8 Hz), 0.88 (15H, m); 13C
NMR (100 MHz, CDCl3) δ 167.0, 166.3, 141.8, 135.5, 135.4,
133.8, 133.6, 133.0, 132.7, 130.6, 130.2, 129.9, 129.7, 129.5,
128.4, 128.1, 127.5, 115.3, 106.6, 97.9, 87.5, 84.3, 78.3, 74.3,
73.7, 73.1, 71.8, 68.0, 64.7, 61.4, 60.4, 59.1, 50.5, 41.0, 39.3,
35.0, 34.0, 33.5, 27.7, 26.6, 23.1, 18.9, 17.7, 16.5, 10.0, 8.7;
HRFABMS CH2Cl2/NBA/NaCl calcd for MNa+ (C58H78O12SiNa)
1017.5160, found 1017.5117 (error 4.3 ppm).
[3R,4R,5S,6S,8S,8(2R,3R,5R,7S,8R,9R)]-8-{9-[(ter t-Bu -
tyld im eth ylsiloxy]-7-[2-(ter t-bu tyld im eth ylsiloxy)eth yl]-
3-h yd r oxy-4,4,8-t r im et h yl-1,6-d ioxa sp ir o[4.5]d ec-2-yl}-
4,6-b is (t er t -b u t y ld im e t h y ls ilo x y )-8-m e t h o x y -3,5-d i-
m eth yloct-1-en e (41). To a solution of the dibenzoate 37 (482
mg, 0.484 mmol, 1.00 equiv) in CH2Cl2 (10 mL) at -78 °C was
added allylmagnesium bromide (1.0 M in Et2O, 3.9 mL, 3.9
mmol, 8.1 equiv). The solution was allowed to warm to 25 °C
over 30 min; then the reaction was quenched by the addition
of H2O (4.0 mL). The resulting slurry was filtered, and the
funnel was rinsed with CH2Cl2 (2 × 10 mL). The filtrate was
poured in to a separatory funnel and diluted with CH2Cl2 (20
mL) and saturated aqueous NaCl (30 mL). The layers were
separated, and the aqueous layer was extracted with CH2Cl2
(2 × 20 mL). The combined organic extracts were washed with
saturated aqueous NaCl (30 mL), dried over Na2SO4, and
concentrated under reduced pressure to afford the crude triol
as an oil which was used directly in the next step.
1
1112 cm-1; H NMR (500 MHz, CDCl3) δ 7.97-8.21 (4H, m),
7.26-7.66 (16H, m), 5.85 (1H, m), 5.45 (1H, m), 5.05-5.14 (3H,
m), 4.64 (1H, d, J ) 6.8 Hz), 4.54 (1H, d, J ) 6.8 Hz), 4.48
(1H, m), 4.11 (1H, dd, J ) 9.1, 5.0 Hz), 3.33-3.68 (8H, m),
3.48 (3H, s), 3.36 (3H, s), 2.55 (1H, m), 1.41-1.86 (7H, m), 1.06
(6H, m), 0.89 (15H, m); 13C NMR (125 MHz, CDCl3) δ 166.3,
166.1, 139.3, 135.4, 133.8, 133.7, 132.7, 130.7, 130.0, 129.9,
129.5, 128.3, 128.1, 127.5, 115.8, 106.5, 98.0, 87.9, 84.1, 78.2,
74.1, 73.0, 71.7, 67.8, 64.6, 61.5, 60.3, 59.0, 50.4, 42.4, 35.1,
34.1, 33.4, 27.8, 26.6, 23.1, 18.9, 17.7, 15.9, 10.0.
[3R,4R,5S,6S,8S,8(2R,3R,5R,7S,8R,9R)]-8-{9-[(Ben zoyl)-
oxy]-7-[2-(ter t-b u t yld ip h en ylsiloxy)et h yl]-3-(((2-m et h -
oxyet h oxy)m et h yl)oxy)4,4,8-t r im et h yl-1,6-d ioxa sp ir o-
[4.5]d ec-2-yl}-6-(b en zoyloxy)-4-h yd r oxy-8-m et h oxy-3,5-
d im eth yloct-1-en e (37). Ozone was bubbled through
a
solution of olefin 36 (387 mg, 0.413 mmol, 1.00 equiv) in CH2-
Cl2 (10.0 mL) at -78 °C. The reaction was monitored by TLC
for the consumption of the olefin at which time dimethyl sulfide
(100 µL, 1.4 mmol, 3.3 equiv) was added. The solution was
allowed to warm to 25 °C and stirred for 12 h. The solution
was concentrated to afford a crude aldehyde as a yellow oil
which was used directly in the next reaction.

Asymmetric Synthesis of Calyculin C. 1
J . Org. Chem., Vol. 61, No. 18, 1996 6151
The crude triol was dissloved in THF (15 mL), and TBAF
(1.0 M, 0.50 mL, 0.50 mmol, 1.0 equiv) was added. The
solution turned brown and was allowed to stir for 12 h. The
solution was concentrated to dryness and chromatographed
on silica gel (5% methanol in CH2Cl2) to give the 260 mg of a
tetrol. To a solution of the tetrol (250 mg, 0.456 mmol, 1.00
equiv) in CH2Cl2 (20 mL) at -78 °C was added 2,6-lutidine
(350 µL, 3.00 mmol, 6.58 equiv) followed by TBSOTf (570 mL,
2.48 mmol, 5.44 equiv). The solution was warmed to 0 °C over
1 h; then the reaction was quenched by the addition of
saturated aqueous NaHCO3 (20 mL). The combined organic
extracts were washed wilth saturated aqueous NaCl (30 mL),
dried over Na2SO4, and concentrated under reduced pressure.
The resulting oil was chromatographed on silica gel (ethyl
acetate-hexane) to give 234 mg of a MEM ether product. To
a solution of the MEM ether (230 mg, 0.229 mmol, 1.00 equiv)
in CH2Cl2 (10 mL) was added ZnBr2 (40 mg, 0.18 mmol, 0.78
equiv). The suspension was allowed to stir at 25 °C for 24 h
at which time the solvent was removed under reduced presure.
The resulting oil was chromatographed on silica gel (5% ethyl
acetate-hexane) to give 41 (147 mg, 35% for four steps): Rf
0.90 (10% ethyl acetate in hexane). [R]D ) -54.0 (c 0.92,
CHCl3); IR (thin film) 3510, 2953, 2929, 1472, 1361, 1255, 1097
(E)-3-(Tr ibu tylsta n n yl)-2-m eth ylp r op en -1-ol (46). To a
solution of silyl ether 45 (3.0 g, 6.3 mmol) at 0 °C in THF (40
mL) was added dropwise TBAF (6.3 mL, 6.3 mmol, 1 M in
THF). After 10 min at 0 °C, the reaction mixture was warmed
to rt, stirred for an additional 40 min, and quenched via
addition of a saturated aq NH4Cl solution (∼1 mL). The
resulting mixture was concentrated at reduced pressure and
dissolved in ether (25 mL). The organic phase was washed
with H2O (20 mL), dried over MgSO4, and concentrated.
Purification via column chromatography on silica gel (20%
ethyl acetate-hexanes) afforded 46 (2.2 g, 92%): IR (thin film)
3312, 2955, 2922, 1521, 1464, 1456, 1374 cm-1; 1H NMR (360
MHz, CDCl3) δ 5.80 (1H, s), 4.07 (2H, d, J ) 4.2 Hz), 1.77 (3H,
s), 1.46-1.50 (6H, m), 1.27-1.33 (6H, m), 0.85-0.95 (15H, m);
13C NMR (90 MHz, CDCl3) δ 152.3, 120.7, 68.8, 29.2, 27.3, 21.3,
13.7, 10.0.
(E)-3-(Tr ibu tylstan n yl)-1-(m eth an esu lfon yloxy-2-m eth -
yl-2-p r op en e (47). To a solution of alcohol 46 (257 mg, 0.713
mmol) at 0 °C in ethyl ether (10 mL) were added triethylamine
(198 µL, 1.42 mmol), DMAP (2 mg), and methanesulfonyl
chloride (61 µL, 0.78 mmol). The mixture was warmed to rt
and stirred for 30 min, at which time the suspension was
filtered. The resulting organic layer was washed with H2O (2
× 5 mL), dried over Na2SO4, and concentrated to afford
mesylate 47 (287 mg, 92%). Purity of the product was
established by 1H NMR, and therefore, the crude product was
carried on without purificaton: IR (thin film) 2956, 2926, 1603,
1251 cm-1; 1H NMR (360 MHz, CDCl3) δ 6.00 (1H, s), 4.66 (2H,
s), 3.01 (3H, s), 1.84 (3H, s), 1.46-1.51 (6H, m), 1.27-1.33 (6H,
m), 0.85-0.90 (15H, m); 13C NMR (90 MHz, CDCl3) δ 145.7,
131.1, 76.0, 37.8, 29.3, 21.1, 13.6, 10.0.
(E)-3-(Tr ibu tylsta n n yl)-2-m eth yl-1-(d im eth ylp h osp h o-
n o)-2-p r op en e (48). Dimethyl phosphite (2.5 mL, 27 mmol)
was added slowly to a suspension of sodium hydride (1.085 g,
27.1 mmol, 60% oil dispersion) in THF (45 mL). This mixture
was stirred for 2 h and cannulated into a solution of mesylate
47 (1.986 g, 4.52 mmol) in THF (5 mL). The resulting mixture
was heated to 45 °C and stirred for 1 h. The mixture was then
concentrated, and the resulting crude product was suspended
in ether (100 mL). The suspension was washed with saturated
aq NH4Cl (2 × 75 mL), H2O (1 × 75 mL) and dried over Na2-
SO4, and concentrated. Purification via column chromatog-
raphy on silica gel (0-25% ethyl acetate-35% triethylamine-
hexane) afforded phosphonate 48 (1.18 g, 58%): IR (thin film)
2955, 2925, 1603, 1465, 1457, 1375, 1256, 1183 cm-1; 1H NMR
(360 MHz, CDCl3) δ 5.69 (1H, dt, J ) 27.0, 5.0 Hz), 3.73 (6H,
d, J ) 10.9 Hz), 2.74 (2H, d, J ) 22.3 Hz), 1.91 (3H, d, J ) 3.2
Hz), 1.45-1.51 (6H, m), 1.27-1.33 (6H, m), 0.86-0.92 (15H,
m); 13C NMR (90 MHz, CDCl3) δ 143.6 (d, J ) 43 Hz), 129.9
(d, J ) 48 Hz), 52.7 (d, J ) 27 Hz), 38.6 (d, J ) 532 Hz), 25.6,
29.1, 27.3, 13.7, 10.1; HRFABMS calcd for MH+ (C18H40O3PSn)
455.1737, found 455.1737 (error 0.0 ppm).
cm-1 1H NMR (360 MHz, CDCl3) δ 5.90 (1H, m), 4.97 (2H,
;
m), 4.58 (1H, m), 4.28 (1H, m), 3.98 (1H, dd, J ) 8.8, 4.0 Hz),
3.63 (3H, d, J ) 141.1 Hz), 3.61 (2H, m), 3.36-3.54 (5H, m),
2.43 (1H, m), 1.87 (1H, m), 1.75 (1H, dd, J ) 14.2, 4.0 Hz),
1.56-1.70 (4H, m), 1.49 (1H, dd, J ) 14.2, 1.8 Hz), 1.28 (1H,
m), 1.10 (3H, s), 1.05 (3H, d, J ) 7.1 Hz), 0.92 (9H, s), 0.89
(9H, s), 0.88 (12H, s), 0.87 (9H, s), 0.83 (3H, d, J ) 7.1 Hz),
0.78 (3H, d, J ) 6.6 Hz), 0.14 (3H, s), 0.09 (3H, s), 0.06 (6H,
s), 0.05 (3H, s), 0.03 (6H, s), 0.02 (3H, s); 13C NMR (90 MHz,
CDCl3) δ 141.5, 113.6, 108.5, 87.9, 80.2, 78.9, 77.6, 70.6, 68.2,
65.3, 60.5, 60.5, 60.4, 60.1, 60.0, 59.9 (-O13CH3), 59.6, 56.0, 49.3,
43.9, 42.4, 37.3, 35.5, 33.8, 30.4, 26.3, 26.0, 25.98, 25.93, 25.88,
22.1, 18.5, 18.3, 18.2, 18.1, 16.6, 16.0, 10.5, 10.1, -3.7, -3.8,
-3.9, -4.3, -4.7, -5.0, -5.4; HRFABMS NaCl calcd for MNa+
(C48H100O8NaSi4) 940.64266, found 940.6408 (error 2.0 ppm).
(E)-1-(ter t-Bu tyld im eth ylsiloxy)-3-iod o-2-m eth yl-2-p r o-
p en e (44). To a solution of alcohol 43 (4.96 g, 25.0 mmol) at
0 °C in CH2Cl2 (50 mL) were added triethylamine (7.0 mL,
50.1 mmol), TBS-Cl (4.15 g, 27.5 mmol), and DMAP (62 mg, 2
mol %). The resulting mixture was warmed to rt and stirred
for 18 h. The solvent was removed under reduced pressure,
and the resulting crude product was suspended in ether (50
mL). The suspension was washed with saturated aq NH4Cl
(100 mL) and 5% aqueous NaHCO3 (50 mL), dried over MgSO4,
and concentrated to afford 44 as a crude oil (7.5 g, 97%). The
1
product was deemed pure by H NMR and carried on without
purification: IR (thin film) 2954, 2928, 1464, 1362, 1279, 1251,
1
1143, 1106 cm-1; H NMR (500 MHz, CDCl3) δ 6.20 (1H, s),
4.10 (2H, s), 1.78 (3H, s), 0.90 (9H, s), 0.05 (6H, s); 13C NMR
(90 MHz, CDCl3) δ 146.8, 75.9, 67.1, 31.6, 25.8, 25.7, 22.6, 21.2,
18.8, 14.1; HRFABMS calcd for M+ (C10H21IOSi) 312.0408,
found 312.0406 (error 0.6 ppm).
(E)-1-(Tr ibu tylsta n n yl)-2-m eth yl-3-(d im eth ylp h osp h o-
n o)-1-bu ten e (6). To a solution of phosphonate 48 (1.18 g,
2.6 mmol) at -78 °C in THF (25 mL) was added n-butyllithium
(1.36 mL, 2.73 mmol, 2 M in pentane). The orange solution
was stirred at -78 °C for 15 min, at which time iodomethane
(187 µL, 3.0 mmol) in THF (1 mL) was added. The mixture
was allowed to warm to rt over 40 min and then poured into
H2O (50 mL). The aqueous layer was extracted with ether (2
× 75 mL), and the combined organics were washed with brine
(50 mL), dried over Na2SO4, and concentrated. Purification
via column chromatography on silica gel (20% ethyl acetate-
35% triethylamine-hexane) afforded phosphonate 6 (1.08 g,
(E)-1-(ter t-Bu tyld im eth ylsiloxy)-2-m eth yl-3-(tr ibu tyl-
sta n n yl)-2-p r op en e (45). To a solution of vinyl iodide 44
(8.60 g, 26.6 mmol) at -78 °C in THF (200 mL) was added
dropwise tert-butyllithium (32.4 mL, 55.1 mmol, 1.7 M in
pentane) over a period of 30 min. The mixture was stirred at
-78 °C for 30 min, at which time tributyltin chloride (8.2 mL,
28.9 mmol) was added slowly. This mixture was stirred at
-78 °C for 30 min and then warmed to rt. After stirring at rt
for 15 min, the mixture was concentrated under reduced
pressure. The resulting crude product was suspended in
hexanes (150 mL) and washed with H2O (2 × 50 mL). The
organic layer was then dried over Na2SO4, concentrated, and
purified by column chromatography on silica gel (20% triethyl-
amine in hexanes) to afford vinylstannane 45 (15.7 g, 77%):
IR (thin film) 2955, 2926, 1250, 1136, 1103 cm-1; 1H NMR (360
MHz, CDCl3) δ 5.89 (1H, s), 4.07 (2H, s), 1.71 (3H, s), 1.51-
1.45 (6H, m), 1.34-1.27 (6H, m), 0.9-0.8 (24H, m), 0.06 (6H,
s); 13C NMR (90 MHz, CDCl3) δ 157.7, 120.1, 68.9, 29.2, 27.3,
26.0, 21.0, 18.4, 13.7, 10.0, -5.3; HRFABMS calcd for M+
(C22H48OSiSn) 475.2496, found 475.2491 (error 1.0 ppm).
89%): IR (thin film) 2955, 2925, 1457, 1250, 1183 cm-1 1H
;
NMR (360 MHz, CDCl3) δ 5.75 (1H, dt, J ) 27.0, 5.0 Hz), 3.71
(3H, d, J ) 10.7 Hz), 3.70 (3H, d, J ) 10.3 Hz), 2.78 (1H, dq,
J ) 23.1, 7.3 Hz), 1.90 (3H, d, J ) 2.8 Hz), 1.45-1.51 (6H, m),
1.35 (3H, d, J ) 7.3 Hz), 1.27-1.33 (6H, m), 0.87-0.92 (15H,
m); 13C NMR (90 MHz, CDCl3) δ 149.7 (d, J ) 36 Hz), 127.4
(d, J ) 46 Hz), 53.1 (d, J ) 28 Hz), 52.8 (d, J ) 28 Hz), 42.7
(d, J ) 529 Hz), 29.1, 27.3,24.0, 14.4, 13.7, 10.1; HRFABMS
calcd for M+ (C19H42O3PSn) 469.1893, found 469.1893 (error
0.0 ppm).
(1E ,3E )-1-(Tr ib u t ylst a n n yl)-4-m e t h yl-5-(d im e t h yl-
p h osp h on o)-1,3-h exa d ien e (49). To a solution of stannane
6 (107 mg, 0.23 mmol) in THF (3 mL) at 0 °C was added

6152 J . Org. Chem., Vol. 61, No. 18, 1996
Scarlato et al.
dropwise a solution of I2 (58 mg, 0.23 mmol) in THF (1 mL).
The resulting mixture was allowed to warm to rt over 30 min,
at which time the mixture was partitioned between ether (20
mL) and 10% aqueous Na2S2O3 (10 mL). The organic phase
was dried over Na2SO4, filtered, and concentrated. Purifica-
tion via column chromatography on silica gel (0-5% CH3OH-
CH2Cl2) afforded 63 mg of a yellow oil that was dissolved in
THF (2 mL). To this mixture was added bis(triphenylphos-
phine)palladium(II) chloride (5 mg, 3 mol %), followed by trans-
bis(tributylstannyl)ethylene (200 mg, 0.33 mmol). The reac-
tion mixture was stirred at rt for 20 h, at which time it was
concentrated. The resulting crude product was partitioned
between CH2Cl2 (20 mL) and saturated aqueous NaHCO3 (10
mL). The layers were separated, and the aqueous layer was
extracted with CH2Cl2 (1 × 20 mL). The combined organics
were dried over Na2SO4, filtered, and concentrated. Purifica-
tion via column chromatography on silica gel (0-40% ethyl
acetate-1% triethylamine-hexane) afforded diene 49 (36 mg,
33%). The 1H NMR data matched the identical compound
reported by Evans.13a
[2Z ,4E ,6E ,8E ,10R ,11R ,12S ,13S ,15S ,15(2R ,3R ,5R ,
7S,8S,9R)]-15-[9-(ter t-Bu tyld im eth ylsiloxy)-7-[2-(ter t-bu -
t yld im et h ylsiloxy)et h yl]-3-h yd r oxy-4,4,8-t r im et h yl-1,6-
d ioxosp ir o[4.5]d ec-2-yl]-11,13-b is(ter t-b u t yld im et h ylsi-
loxy)-15-m et h oxy-3,7,8,10,12-p en t a m et h yl-2,4,6,8-p en -
ta d eca tetr a en en itr ile (50). To a solution of phosphonate
49 (36 mg, 0.073 mmol) in THF (0.7 mL) at -78 °C was added
dropwise n-butyllithium (37 µL, 0.073 mmol, 1.95 M in
pentane). The yellow solution was stirred for 2 min at -78 °C
and then warmed to rt over 10 min. A solution of aldehyde
42 (19 mg, 0.021 mmol) in THF (0.5 mL + 2 × 0.5 mL rinses)
was added, and the resulting red solution was stirred at rt.
After 20 min, the reaction was quenched via addition of
saturated aq NH4Cl (2 mL) and H2O (1 mL). This mixture
was extracted with CH2Cl2 (4 × 5 mL). The combined organics
were dried over Na2SO4, filtered, and concentrated to afford a
yellow oil which was dissolved in 1-methyl-2-pyrrolidinone (1.2
mL). To this mixture was added vinyl iodide 5 (15 µL, 0.146
mmol), followed by bis(acetonitrile)palladium(II) chloride (0.5
mg). The resulting black solution was stirred at rt. After 36
h, 0.5 mg of the Pd catalyst was added, and after 42 h, an
additional 0.5 mg of Pd catalyst and 5 µL of 5 were added.
After 80 h, the reaction was quenched via addition of saturated
aqueous NaHCO3 (20 mL). The aqueous phase was extracted
with ether (4 × 10 mL). The combined organics were washed
with H2O (10 mL), dried over Na2SO4, filtered, and concen-
trated. Purification via preparative thin layer chromatography
on silica gel (0-10% ethyl acetate-5% triethylamine-hexane)
afforded tetraene 50 (9 mg, 41%). 1H and 13C data mtached
the enantiomer of 50 which was reported by Evans,13a with
the exception of the methoxy group at C15 which bore a 13C-
label. 50: 1H NMR (500 MHz, CDCl3) δ 6.99 (1H, dd, J )
14.9, 11.2 Hz), 6.81 (1H, d, J ) 15 Hz), 6.33 (1H, d, J ) 11.1
Hz), 6.05 (1H, d, J ) 9.0 Hz), 5.04 (1H, s), 4.56 (1H, m), 4.22
(1H, m), 4.00 (1H, dd, J ) 8.8, 4.1 Hz), 3.87 (1H, m), 3.67 (3H,
d, J ) 140.7 Hz), 3.66 (2H, m), 3.57-3.49 (3H, m), 3.42 (1H,
d, J ) 12 Hz), 2.73 (1H, m), 2.05 (3H, s), 2.00 (3H, s), 1.85
(3H, s), 1.72 (1H, dd, J ) 14.2, 3.9 Hz), 1.57-1.66 (4H, m),
1.47 (1H, m), 1.23 (1H, m), 1.07 (3H, s), 1.00 (3H, d, J ) 7.0
Hz), 0.92 (9H, s), 0.86 (18H, s), 0.85 (12H, s), 0.80 (3H, d, J )
7.0 Hz), 0.74 (3H, d, J ) 7.0 Hz), 0.15 (3H, s), 0.07 (3H, s),
0.06 (3H, s), 0.03 (3H, s), 0.02 (3H, s), 0.01 (3H, s), -0.01 (3H,
s); 13C NMR (125 MHz, CDCl3) δ 156.7, 144.3, 134.4, 133.9,
133.4, 128.5, 124.0, 117.5, 108.5, 94.6, 87.9, 80.2, 77.6, 70.6,
68.4, 65.3, 60.1, 60.0, 59.8, 49.3, 46.2, 37.3, 35.5, 26.4, 26.0,
26.0, 25.9, 22.1, 19.4, 18.6, 18.3, 18.2, 18.1, 16.6, 14.5, 10.1,
-3.5, -3.7, -4.2, -5.0, -5.3; HRFABMS DCM/NBA/NaCl
calcd for MNa+ (C5713CH111NO8Si4Na) 1085.7318, found
1085.7365 (error 4.7 ppm).
(24 mg, 0.023 mmol) in THF (2 mL) was added the above stock
HF solution (0.8 mL). After the solution was stirred for 2.5 h
at rt, the reaction was quenched via addition of saturated
aqueous NaHCO3 (5 mL). The aqueous phase was extracted
with CH2Cl2 (5 × 10 mL). The combined organics were dried
over Na2SO4, filtered, and concentrated. Purification via
preparative thin layer chromatography on silica gel (17% ethyl
acetate-hexane) afforded diol 51 (11.3 mg, 53%, 84% based
on recovered starting material) and starting material 50 (9
mg). 51: Rf 0.44 (20% ethyl acetate-hexane). [R]D ) -99.5
(c 0.22, CHCl3). 1H NMR (500 MHz, CDCl3) δ 7.05 (1H, dd, J
) 14.9, 11.2 Hz), 6.88 (1H, d, J ) 15.0 Hz), 6.39 (1H, d, J )
11.1 Hz), 6.11 (1H, d, J ) 9.1 Hz), 5.17 (1H, s), 4.61 (1H, m),
4.31 (1H, m), 4.02 (1H, m), 3.86 (1H, m), 3.76 (2H, m), 3.66
(3H, d, J ) 140 Hz), 3.57 (4H, m), 2.78 (1H, m), 2.11 (3H, d, J
) 1.3 Hz), 2.05 (3H, s), 1.89 (3H, s), 1.70-1.84 (4H, m), 1.50-
1.60 (3H, m), 1.38 (1H, m), 1.14 (3H, s), 1.07 (3H, d, J ) 7.0
Hz), 0.98 (9H, s), 0.90-0.95 (21H, m), 0.89 (3H, d, J ) 7.2
Hz), 0.80 (3H, d, J ) 3.8 Hz), 0.22 (3H, s), 0.15 (3H, s), 0.13
(3H, s), 0.12 (3H, s), 0.10 (3H, s), 0.06 (3H, s); 13C NMR (125
MHz, CDCl3) δ 156.7, 144.2, 134.5, 133.9, 133.1, 128.5, 124.1,
108.3, 94.7, 87.7, 80.2, 77.7, 70.7, 68.6, 66.0, 61.2, 59.8, 59.8,
59.5, 49.4, 44.9, 38.8, 37.3, 35.3, 30.4, 26.4, 26.0, 25.9, 22.4,
19.4, 18.6, 18.2, 18.1, 16.7, 14.5, 14.0, 14.1, 10.4, -3.5, -3.8,
-3.9, -4.1, -4.7, -5.0; HRFABMS DCM/NBA/NaCl calcd for
MNa+ (C5113CH97NO8Si3Na) 971.6453, found 971.6509 (error
5.7 ppm).
[2E ,4E ,6E ,8E ,10R ,11R ,12S ,13S ,15S ,15(2R ,3R ,5R ,
7S,8S,9R)]-15-[9-(ter t-Bu tyldim eth ylsiloxy)-7-(2-oxoeth yl)-
3-h yd r oxy-4,4,8-t r im et h yl-1,6-d ioxa sp ir o[4.5]d ec-2-yl]-
11,13-b is(t er t -b u t yld im e t h ylsiloxy)-15-m e t h oxy-3,7,8,
10,12-p en ta m eth yl-2,4,6,8-p en ta d eca tetr a en en itr ile (52).
To a solution of diol 51 (12.5 mg, 0.013 mmol) in CH2Cl2 (1
mL) was added pyridine (10 mL), followed by portions of Dess-
Martin periodinane37 (122 mg) over 2.5 h at rt. The reaction
was quenched via addition of saturated aqueous NaHCO3 (1
mL) and 1.5 M Na2S2O3 (1 mL). The layers were separated,
and the aqueous layer was extracted with CH2Cl2 (4 × 5 mL).
The combined organics were dried over Na2SO4, filtered, and
concentrated. Purification via preparative thin layer chroma-
tography on silica gel (20% ethyl acetate-hexane) afforded
aldehyde 52 (12 mg, 98%): 1H NMR (360 MHz, CDCl3) δ 9.75
(1H, d, J ) 2.0 Hz), 6.99 (1H, dd, J ) 11.1, 4.9 Hz), 6.80 (1H,
d, J ) 15.0 Hz), 6.33 (1H, d, J ) 11.1 Hz), 6.05 (1H, d, J ) 9.2
Hz), 5.01 (2H, m), 4.21 (1H, m), 3.97 (1H, dd, J ) 8.2, 4.1 Hz),
3.83 (1H, m), 3.59 (3H, d, J ) 140.7 Hz), 3.43-3.52 (3H, m),
2.97 (1H, d, J ) 12.0 Hz), 2.70 (1H, m), 2.48 (2H, m), 2.05
(3H, s), 1.98 (3H, s), 1.85 (3H, s), 1.73 (1H, dd, J ) 14.3, 3.7
Hz), 1.62 (2H, m), 1.51 (1H, m), 1.20-1.35 (2H, m), 1.06 (3H,
s), 1.00 (3H, d, J ) 6.8 Hz), 0.91 (9H, s), 0.81-0.89 (24H, m),
0.74 (3H, d, J ) 7.0 Hz), 0.15 (3H, s), 0.07 (3H, s), 0.06 (3H,
s), 0.05 (3H, s), 0.03 (3H, s), 0.01 (3H, s).
Ack n ow led gm en t. We thank Prof. Fusetani for a
sample of calyculin C. We thank Kristopher Depew and
Greg Mayeur for their synthetic efforts. Support from
the NSF (CHE 88-58059) is graciously acknow-
ledged.
Su p p or tin g In for m a tion Ava ila ble: Procedures and
characterization data for 14, 24, 33, 34, 39, 40, and 42, an
ORTEP diagram of compound 35, and NMR spectra to indicate
purity of new compounds (74 pages). This material is con-
tained in libraries on microfiche, immediately follows this
article in the microfilm version of the journal, and can be
ordered from the ACS; see any current masthead page for
ordering information.
[ 2 Z , 4 E , 6 E , 8 E , 1 0 R , 1 1 R , 1 2 S , 1 3 S , 1 5 S , 1 5 ( 2 R ,
3R,5R,7S,8S,9R)]-15-[9-(ter t-Bu t yld im et h ylsiloxy)-7-(2-
h yd r oxyeth yl)-3-h yd r oxy-4,4,8-tr im eth yl-1,6-d ioxa sp ir o-
[4.5]dec-2-yl]-11,13-bis(ter t-bu tyldim eth ylsiloxy)-15-m eth -
o x y -3 ,7 ,8 ,1 0 ,1 2 -p e n t a m e t h y l -2 ,4 ,6 ,8 -p e n t a d e c a -
tetr a en en itr ile (51). A stock solution of HF-pyridine was
prepared by addition of HF-pyridine (0.5 mL, Aldrich) to
pyridine (1 mL) and THF (4 mL). To a solution of tetraene 50
J O960314Y