Expedient access to the okadaic acid architecture: A novel synthesis of the C1-C27 domain

Article abstract of DOI:10.1021/jo001433n

A newly designed synthetic entry to the C1-C27 domain of okadaic acid has been developed. This incorporates substantial improvements in the preparations of the key okadaic acid building blocks representing the C3-C8, C9-C14, and C16-C27 portions. The synthesis of the C3-C8 lactone used (R)-glycidol as the origin of the C4 stereogenic center and featured a late-stage optional incorporation of the C7 hydroxyl group. The complementary C9-C14 fragment was synthesized in a concise route from (R)-3-tert-butyldimethylsilyloxy-2-methylpropanal and propargyl bromide. Assembly of the C3-C14 spiroketal-containing intermediate from the constituent fragments revealed a dramatic effect of C7 functionalization upon spiroketalization efficiency. In contrast, both (9E)- and (9Z)-enones converged readily to the C8 spiroketal upon treatment with acid. Modifications to the central C16-C27 fragment of okadaic acid included the early replacement of benzylic protecting groups by more suitable functionalities to facilitate both the generation of the C15-C27 intermediate and the deprotection of the final products. These modular building blocks were deployed for the synthesis of the C1-C27 scaffold of 7-deoxyokadaic acid. This work demonstrates improvements in the formation of versatile okadaic acid intermediates, as well as a reordering of fragment couplings. This alternative order of coupling was designed to promote the late stage incorporation of nonnatural lipophilic extensions from the C27 terminus.

Full text of DOI:10.1021/jo001433n

J . Org. Chem. 2001, 66, 925-938
925
Exp ed ien t Access to th e Ok a d a ic Acid Ar ch itectu r e: A Novel
Syn th esis of th e C1-C27 Dom a in
Amy B. Dounay, Rebecca A. Urbanek,† Valerie A. Frydrychowski, and Craig J . Forsyth*
Department of Chemistry, University of Minnesota, Minneapolis, Minnesota 55455
forsyth@chem.umn.edu
Received October 3, 2000
A newly designed synthetic entry to the C1-C27 domain of okadaic acid has been developed. This
incorporates substantial improvements in the preparations of the key okadaic acid building blocks
representing the C3-C8, C9-C14, and C16-C27 portions. The synthesis of the C3-C8 lactone
used (R)-glycidol as the origin of the C4 stereogenic center and featured a late-stage optional
incorporation of the C7 hydroxyl group. The complementary C9-C14 fragment was synthesized in
a concise route from (R)-3-tert-butyldimethylsilyloxy-2-methylpropanal and propargyl bromide.
Assembly of the C3-C14 spiroketal-containing intermediate from the constituent fragments revealed
a dramatic effect of C7 functionalization upon spiroketalization efficiency. In contrast, both (9E)-
and (9Z)-enones converged readily to the C8 spiroketal upon treatment with acid. Modifications to
the central C16-C27 fragment of okadaic acid included the early replacement of benzylic protecting
groups by more suitable functionalities to facilitate both the generation of the C15-C27 intermediate
and the deprotection of the final products. These modular building blocks were deployed for the
synthesis of the C1-C27 scaffold of 7-deoxyokadaic acid. This work demonstrates improvements
in the formation of versatile okadaic acid intermediates, as well as a reordering of fragment
couplings. This alternative order of coupling was designed to promote the late stage incorporation
of nonnatural lipophilic extensions from the C27 terminus.
The marine natural product okadaic acid (1)1 has
attracted significant attention in recent years because
of its engaging architecture and its broad range of
biological activities. This interest has culminated in three
reported total syntheses to date,2-4 as well as other
innovative synthetic approaches.5 Although first isolated
as a potential anticancer agent,6 okadaic acid has sub-
sequently been characterized as a causative agent of
diarrhetic shellfish poisoning,7 a nonphorbol ester type
of tumor promoter,8 and a potent inhibitor of select
serine-threonine phosphatases.9 Ultimately, inhibition of
phosphatases may be the cause of many or all of the
observed cellular responses to okadaic acid exposure.
Because of the increasing recognition of the vital roles
of okadaic acid-sensitive phosphatases in a variety of
cellular processes,10 elucidation of the structural basis
of enzyme binding by okadaic acid is an important
objective. Previous structure-activity relationship (SAR)
studies using naturally occurring analogues and semi-
synthetic derivatives of okadaic acid11 have been limited
by a lack of designed structural variants. SAR data11 and
computational studies12 suggest that potent inhibition of
PP1 and PP2A by 1 requires the C1 carboxylate, the
hydroxyls at C2, C24, and C27, and the terminal lipo-
philic domain. In contrast, 7-deoxyokadaic acid (2) main-
tains much of the phosphatase inhibitory activity of 1.11d
Although it is generally believed that the carboxylate
may mimic the phosphate group of endogenous phospho-
† Current address: AstraZeneca Pharmaceuticals, 1800 Concord
Pike, Wilmington, DE 19850.
(1) Tachibana, K.; Scheuer, P. J .; Tsukitani, Y.; Kikuchi, H.; Van
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1981, 103, 2469.
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963. (b) Isobe, M.; Ichikawa, Y.; Bai, D.-L.; Masaki, H.; Goto, T.
Tetrahedron 1987, 43, 4767 and references therein.
(3) (a) Forsyth, C. J .; Sabes, S. F.; Urbanek, R. A. J . Am. Chem.
Soc. 1997, 119, 8381. (b) Urbanek, R. A.; Sabes, S. F.; Forsyth. C. J . J .
Am. Chem. Soc. 1998, 120, 2523. (c) Sabes, S. F.; Urbanek, R. A.;
Forsyth, C. J . J . Am. Chem. Soc. 1998, 120, 2534.
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Suganuma, M.; Fujiki, H. Cancer Res. 1993, 53, 239. (e) Fujiki, H.;
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H.; Matsushima, R.; Iida, Y.; Ojika, M.; Yamada, K.; Uemura, D.;
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Lindvall, M. K.; Pihko, P. M.; Koskinen, A. M. P. J . Biol. Chem. 1997,
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National Meeting of the American Chemical Society, Boston, MA.;
American Chemical Society: Washington, DC, 1998; ORGN 368.
10.1021/jo001433n CCC: $20.00 © 2001 American Chemical Society
Published on Web 01/09/2001

926 J . Org. Chem., Vol. 66, No. 3, 2001
Dounay et al.
Sch em e 1
peptide substrates and the lipophilic domain may con-
tribute positive hydrophobic-hydrophobic interactions
between the natural product and the enzymes, a detailed
structural basis for binding and inhibition is not known.
In particular, the hypothesis that 1 utilizes bimodal
carboxylate-liphophilic binding for potent phosphatase
inhibition has not been thoroughly evaluated by empirical
study. A series of analogues that preserves the C1-C27
core of 1 or 2, but substitutes unique hydrophobic tails
for the natural C28-C38 domain, would be useful for
probing the role of the C28-C38 lipophilic portion of
okadaic acid in binding to phosphatases.
In the course of adapting the synthesis of 1 to the
construction of strategically designed analogues, a num-
ber of opportunities for improving the synthetic approach
have emerged. We report here the full details of recent
modifications in our synthetic route that provide im-
proved access to key okadaic acid intermediates13,14 as
well as expedient access to a C1-C27 okadaic acid
scaffold amenable to combinatorial elaboration.
quired an aldehyde (3) and a ketophosphonate (5) that
could be joined under mild conditions15 to provide the
entire carbon skeleton of the natural product, which could
be converted to 1 in only four additional steps, including
a sensitive final reductive scission of the benzyl ethers
at C7, C24, and C27 (Scheme 1).3 The C1-C14 fragment
(3) was derived from spiroketal 7, which was obtained
from lactone 10 and alkyne 12 using an approach similar
to that used in Isobe’s first total synthesis of 1.2a The
C15-C38 fragment (5) was obtained in several steps after
the cerium-mediated coupling of aldehyde 9 with the
C28-C38 domain represented by alkyl bromide 13.
This convergent approach to 1 could be readily applied
to the synthesis of designed structural variants of the
natural product. However, opportunities to improve upon
the original preparation of each of the fragments were
recognized. Careful scrutiny of our previously reported
synthesis of the C1-C14 domain (3) suggested that
improvements within the synthesis of this fragment alone
might dramatically enhance the overall synthetic access
to okadaic acid and its analogues. To this end, more
efficient routes to two of the early synthetic intermedi-
ates, lactone 10 and alkyne 12, were sought. Lactone 10
had been previously prepared in eight steps from D-2-
acetoxy-triacetylglucal, and alkyne 12 was derived from
diethyl L-tartrate in 14 steps.16 Additionally, improve-
ment upon the modest yield of the acid-catalyzed forma-
tion of the C3-C14 spiroketal was also desired.
Resu lts a n d Discu ssion
Syn th etic Design . The synthesis of 1 developed in
our laboratories was designed to be directly applicable
to the preparation of an array of nonnatural analogues
of okadaic acid. Thus, key design features include con-
vergence, flexibility, and minimization of post-coupling
transformations. The synthetic strategy employed re-
(15) Blanchette, M. A.; Choy, W.; Davis, J . T.; Essenfeld, A. P.;
Masamune, S.; Roush, W. R.; Sakai, T. Tetrahedron Lett. 1984, 25,
2183.
(13) (a) Dounay, A. B.; Forsyth, C. J . Org. Lett. 1999, 1, 451. (b)
Dounay, A. B.; Urbanek, R. A.; Sabes, S. F.; Forsyth, C. J . Angew.
Chem., Int. Ed. Engl. 1999, 38, 2258.
(16) Our syntheses of these intermediates3 were closely modeled
after the seminal work of Isobe and co-workers.2
(14) Urbanek, R. A. Ph.D. Thesis, University of Minnesota, 1998.

Expedient Access to the Okadaic Acid Architecture
J . Org. Chem., Vol. 66, No. 3, 2001 927
Sch em e 2
Sch em e 3
ated synthesis of the C3-C8 lactone (Scheme 3).13a
Epoxide 17 was opened with the acetylide anion derived
from benzyl propargyl ether (16) under Yamaguchi
conditions17 to provide secondary alcohol 18. Hydrogena-
tion of 18 gave diol 19, which was oxidized with PCC to
give lactone 11, the C3-C8 domain for 7-deoxy analogues
of 1. Davis’ chiral oxaziridine18 was employed for the
diastereoselective installation of the C7 hydroxyl group.
A variety of conditions were surveyed to optimize this
oxidation, and ultimately, treatment of the lithium
enolate of lactone 11 with (+)-(2R,8S)-camphorsulfonyl-
oxaziridine19 in the presence of TMEDA followed by a
careful quench with CSA provided R-hydroxy lactone 20
in moderate yield. The hydroxyl group could be protected
as a benzyl ether using the corresponding trichloro-
acetimidate to yield the known okadaic acid intermediate
10 via this abbreviated route. Alternatively, the C7
hydroxyl group could also be masked as a TBS ether (21)
to avoid the problematic final cleavage of benzyl ethers.3,4,20
This abbreviated route not only leads to the C3-C8
intermediate in markedly improved overall yield, but the
inherent flexibility of this approach also provides for
access to 7-deoxy analogues of 1 as well as derivatives
that retain the C7 hydroxyl group.
Minor modifications in our synthesis of the C15-C27
fragment were also warranted. Specific complications
that could conceivably be avoided via reengineering of
functional group deployment include the propensity of
the C16 hydroxyl group to undergo premature spiro-
ketalization and the problematic final reductive deben-
zylation.
In addition to the opportunities to modify the prepara-
tion of each fragment, an alternative order of fragment
coupling would support the facile construction of ana-
logues of okadaic acid bearing unnatural variable exten-
sions at the C27 position.Our original synthesis of 1
relied upon the early coupling of C16-C27 and C28-C38
fragments via a moderate yielding cerium-mediated
process. This approach allows for easy late-stage incor-
poration of C1-C14 domains that may vary in function-
alization, as illustrated by the total syntheses of both 13
and its naturally occurring 7-deoxy analogue 213b (Scheme
1). However, this ordering of fragment coupling and the
organocerium methodology are impractical for the ef-
ficient incorporation of a library of nonnatural lipophilic
domains. Hence, the sequence of events for coupling the
three domains has been reversed to allow for elaboration
of an aldehyde derived from the C1-C27 alcohol (14) near
the end of the synthesis, after formation of the C14-C15
bond (Scheme 2). For ease of synthetic access, 14 lacks
the C7 hydroxyl group of okadaic acid.13 Because the C7
alcohol of 1 does not appear to contribute substantially
to its biological activity, omission of this functional group
is warranted.11d In this new synthetic design, it was
envisioned that alcohol 14 would be obtained via the mild
and stereoselective Horner-Wadsworth-Emmons cou-
pling of the C1-C14 aldehyde 4 with the C15-C27
ketophosphonate 15.
Im p r oved Syn th esis of C9-C14 Alk yn e. As part of
an effort to streamline the synthesis of the C3-C14
fragment of okadaic acid, abbreviated routes to the C9-
C14 alkyne (12) have also been explored. One new
approach to this key intermediate is illustrated in
Scheme 4. Silylated propargyl chloride 2221 and vinyl
stannane 2322 underwent palladium-mediated coupling
to afford allylic alcohol 24. This coupling proceeded in
(17) Yamaguchi, M.; Hirao, I. Tetrahedron Lett. 1983, 24, 391.
(18) Davis, F. A.; Kumar, A. J . Org. Chem. 1992, 57, 3337.
(19) Davis, F. A.; Towson, J . C.; Weismiller, M. C.; Lal, S.; Carroll,
P. J . J . Am. Chem. Soc. 1988, 110, 8477.
(20) Ichikawa, Y.; Isobe, M.; Goto, T. Agric. Biol. Chem. 1988,
52, 975.
Syn th esis of th e C1-C14 Dom a in . Mod ified Ap -
p r oa ch to th e C3-C8 La cton e. An improved route to
the C1-C14 fragment of 1 began with a novel, abbrevi-
(21) Brandsma, L. Preparative Acetylenic Chemistry; Elsevier:
Amsterdam, 1988; pp 121-122.

928 J . Org. Chem., Vol. 66, No. 3, 2001
Dounay et al.
Sch em e 4
Sch em e 5
ture with n-butyllithium converted the allene into alkyne,
increasing the alkyne:allene ratio to g 20:1.29 Subjection
of the mixture of epimeric alcohols (28) to anisaldehyde
dimethyl acetal and TsOH caused in situ desilylation and
acetal formation to give the chromatographically sepa-
rable anisylidenes (12R)-29 and (12S)-30.30,31 Regiose-
lective reductive opening of the desired anisylidene acetal
30, followed by silylation provided alkyne 12. In principle,
reductive opening of anisylidene acetal 29 followed by
inversion of configuration of the C12 secondary alcohol
and silylation should allow for efficient conversion of 29
into alkyne 12. However, preliminary efforts to invert the
carbinol stereocenter under Mitsunobu conditions have
been unsuccessful due to the competitive elimination of
the activated alcohol. Likewise, oxidation to the ketone
as a prelude to asymmetric reduction was also problem-
atic. Nevertheless, this approach provides the C9-C14
alkyne intermediate via a remarkably short route that
is readily scalable.
F or m a tion of th e C3-C14 Sp ir ok eta l. The remain-
ing goal with respect to improving the overall synthesis
of the C1-C14 domain was to enhance the yield of
spiroketalization. To determine the utility of C7 variants
for formation of spiroketals, alkyne 12 was treated with
n-butyllithium followed by lactone 21 or 11 to generate
the corresponding δ-hydroxy ynones, which were con-
verted to silyl ethers 31 or 32, respectively (Scheme 6).
Conjugate addition of dimethylcuprate to 31 or 32
provided nearly quantitative yields of enones 33 or 34,
respectively, each as an approximate 1:1 mixture of (E,Z)-
isomers. TsOH-induced spiroketalization of the (E,Z)-
mixture of 33 generated (8R)-spiroketal 35 in 31% yield,
comparable to the yield obtained for the analogous
transformation in the total synthesis of 1 in which a
benzyloxy substituent was present at the C7 position.3
Similar yields of 35 were obtained by subjecting chro-
matographically separated samples of (E)-33 and (Z)-33
to the ketalization conditions. However, treatment of the
(E,Z)-mixture of the 7-deoxy enones 34 under the same
modest yield when carried out using Pd2dba3‚CHCl3 and
PPh3 in THF at 50 °C. The use of TMS-protected
propargyl bromide instead of 22, DMF rather than THF,
and Pd(PPh3)4 in place of Pd2dba3‚CHCl3 provided no
improvement in reaction yield.23 Sharpless asymmetric
epoxidation24,25 of 24 was followed by hydroxy-directed
dimethyl cuprate opening of epoxide 25 to effect the regio-
and stereoselective installation of the C13 methyl group.26
Diol 26 was then protected as an anisylidene acetal,
which was treated with trifluoroacetic acid and sodium
cyanoborohydride to induce regioselective reductive open-
ing of the anisylidene to the secondary alcohol.27 The
alkyne was cleanly desilylated and the free secondary
alcohol was silylated to complete the shortened synthesis
of alkyne 12.3c
This alternative route to the C9-C14 alkyne repre-
sents an improvement upon our original synthesis of this
intermediate, but a more readily scalable route was
desired that avoids both the noxious organotin inter-
mediate and the asymmetric epoxidation, which gave
variable yields and enantioselectivities in our hands.
Therefore, further refinements toward alkyne 12 were
explored (Scheme 5). Treatment of readily available
aldehyde 273b with propargyl bromide and zinc provided
alcohol 28 (1:1 diastereomeric ratio) along with minor
amounts of its allenic isomer (∼6:1 alkyne:allene) in
excellent combined yield.28 Reaction of the product mix-
(22) J ung, M. W.; Light, L. A. Tetrahedron Lett. 1982, 3851.
(23) The use of ligands that may provide enhanced yields for the
Stille coupling has not been explored. See: Farina, V. Pure Appl. Chem.
1996, 68, 73.
(24) Gao, Y.; Hanson, R. M.; Klunder, J . M.; Ko, S. Y.; Masamune,
H.; Sharpless, K. B. J . Am. Chem. Soc. 1987, 109, 5765.
(25) The enantiomeric excess (ee) was determined by formation of
the (R)-MTPA ester [Dale, J . A.; Dull, D. L.; Mosher, H. S. J . Org.
Chem. 1969, 34, 2543.] under standard conditions [(S)-MTPACl,
DMAP, CH2Cl2] and subsequent analysis. 1H NMR spectroscopic
analysis in CDCl3 at 500 MHz showed a diastereomeric pair of doublet
of doublets at δ ) 4.62 and δ ) 4.75, corresponding to the major and
minor epoxide products, respectively. Integration of these signals
showed an 18:1 ratio, corresponding to 89% ee.
(26) Lipshutz, B. H.; Kozlowski, J .; Wilhelm, R. S. J . Am. Chem.
Soc. 1982, 104, 2305. 1H NMR spectroscopy of the crude reaction
mixture in CDCl3 at 500 MHz showed an >8:1 ratio of 1,3-diol to 1,2-
diol, as determined by the integration of the methyl doublets at δ )
0.89 and δ ) 0.99. The mixture of diols was treated with NaIO4 to
induce oxidative cleavage of the 1,2-diol in order to facilitate purifica-
tion of 26.
(28) For alternative methods which may provide diastereoselectivity,
see: (a) Ikeda, N.; Arai, I.; Yamamoto, H. J . Am. Chem. Soc. 1986,
108, 483. (b) Marshall, J . A.; Wang, X. J . Org. Chem. 1992, 57, 1242.
(c) Marshall, J . A.; Grant, C. M. J . Org. Chem. 1999, 64, 696, and
references therein.
(29) Isomeric ratio was determined by 1H NMR spectroscopy.
(30) Carbon numbers correspond to the okadaic acid skeleton.
(31) Chromatographic separation of the anisylidene acetals from
anisaldehyde, a byproduct of the reaction, was facilitated by treatment
of the crude mixture with NaBH4 in MeOH, which reduced anisalde-
hyde to p-methoxybenzyl alcohol.
(27) J ohansson, R.; Samuelsson, B. J . Chem. Soc., Perkin Trans. 1
1984, 2371.

Expedient Access to the Okadaic Acid Architecture
J . Org. Chem., Vol. 66, No. 3, 2001 929
Sch em e 6
Sch em e 7
conditions generated (8R)-spiroketal 36 in significantly
higher yield (76%). The structure of 36 was confirmed at
this stage via correlation with a deoxygenation product
obtained from the corresponding (8R,7R)-7-benzyloxy-
spiroketal used in the total synthesis of 1.32 This demon-
strates that (E)-34 isomerizes to an appreciable extent
to the corresponding (Z)-isomer en route to 36. Because
the starting enone configuration has little impact on the
overall efficiency of bicyclodehydration, the limited yield
of spiroketal 35 obtained via the conjugate addition-
spiroketalization sequence may largely be attributable
to the presence of the substituent at C7. Hence, focusing
synthetic efforts toward a novel 7-deoxy C1-C14 inter-
mediate lacking the biologically dispensable11d and syn-
thetically cumbersome C7 hydroxyl group of 1 was war-
ranted. This intermediate was useful for the synthesis
of 7-deoxyokadaic acid (2)13b and may serve as well for
its analogues.
634 gave an approximately equimolar ratio of three
chromatographically separable products, 39, 40a , and
40b. Separate treatment of each of the alcohol products
under Barton deoxygenation conditions35 showed that
40a and 40b converged to the single product 42 upon
deoxygenation, indicating that they were epimeric at the
newly formed C3 stereocenter, whereas 41, the product
of deoxygenation of 39, was diastereomeric with 42. At
this stage, 40a and 40b were assigned the (2R)-config-
uration, based on literature precedent,3,34 which included
the observation that a similar ratio (∼2:1) of (2R,2S)-
isomers was obtained in the synthesis of 1. The low level
of diastereoselectivity in the lactate enolate addition may
reflect the dominant effect of the large chiral substituent
adjacent to the aldehyde. Oxidative cleavage of the
p-methoxybenzyl ether of 42 with DDQ in the presence
of a phosphate buffer (pH ) 7.0) afforded primary alcohol
43, which was cleanly oxidized to aldehyde 4 using TPAP/
NMO. Thus, the synthesis of the 7-deoxy-C1-C14 frag-
ment of okadaic acid was achieved in 15 steps and 8.1%
overall yield from commercially available R-(+)-glycidol,
which represents a significant improvement over our
previous synthesis of the corresponding intermediate (cf.
3, Scheme 1) in 25 steps and 0.6% overall yield from
diethyl L-tartrate in the synthesis of 1.
Com p letion of C1-C14 Dom a in . Completion of the
synthesis of the 7-deoxy-C1-C14 fragment required
installation of the protected R-hydroxy-R-methyl carboxyl-
ate functionality at the C3 position. Desilylation of 36
with TBAF followed by oxidation of the resultant alcohol
with TPAP/NMO33 gave aldehyde 38 (Scheme 7). Treat-
ment of 38 with the lithium enolate of lactate pivalidene
(32) Spiroketal A used in the total synthesis of 13 and spiroketal
36 were both converted to diol B (vide infra) to confirm the structure
of 36.
(34) Seebach, D.; Naef, R.; Calderari, G. Tetrahedron 1984, 40, 1313.
(35) Barton, D. H. R.; McCombie, S. W. J . J . Chem. Soc., Perkin
Trans. 1 1975, 1574.
(33) Ley, S.; Norman, J .; Griffith, W. P.; Marsden, S. P. Synthesis
1994, 639.

930 J . Org. Chem., Vol. 66, No. 3, 2001
Dounay et al.
Sch em e 8
Sch em e 10
Sch em e 9
afforded a diastereomeric mixture of alcohols, which were
oxidized under Swern conditions36 to afford ketone 49.
Acidic methanolysis of 49 under Dean-Stark conditions
efficiently cleaved both the tert-butyldimethylsilyl ether
and the anisylidene acetal and provided the mixed
methyl ketal at C19 in only one step. Essentially one
isomer was generated at the newly formed acetal center
Syn th esis of a Mod ified C16-C27 Cen tr a l Cor e.
The synthesis and functionalization of the C16-C27 bis-
pyran core of okadaic acid and its derivatives have also
been altered. One previously reported difficulty was the
premature spiroketalization of the C16 oxygen onto the
C19 ketal center to form the 1,3-dioxaspiro[4.5]decane
system irreversibly.3b,14 This event occurred both during
formation of the mixed methyl ketal (44 to 44a to 45 in
Scheme 8) as well as during the oxidative removal of the
p-methoxybenzyl group at C16 (46 to 46a to 47 in Scheme
9). Although conditions to prevent this spiroketalization
have been identified,14 use of a different functional group
altogether at the C16 position could completely eliminate
concerns over premature spiroketalization. To this end,
an olefin was selected to replace the p-methoxybenzyloxy
group at C16, with the aim that oxidative cleavage of the
olefin would lead directly to the C16 aldehyde. This new
tactic would preclude undesired side reactions associated
with the presence of a free C16-primary alcohol at any
step in the synthetic sequence.
Final cleavage of benzyl ethers was another difficulty
encountered in each of the reported syntheses of 1.3,4,20
For this reason, the new synthetic plan called for
replacement of the benzyl ethers at the C24 and C27
positions with silyl ethers. The silyl ethers would be labile
under much milder conditions, and the steric differentia-
tion between the C24 and C27 positions should favor
selective liberation of the C27 alcohol, as required for our
targeted C1-C27 intermediate.
1
(19R), as analyzed by H NMR spectroscopy. The result-
ant diol was monoprotected as its primary tert-butyl-
dimethylsilyl ether 50 in 66% yield for the two steps. In
the initial route, cleavage of the C23 silyl ether was best
performed in a separate step prior to assembly of the
mixed methyl ketal to bypass formation of spiroketal
45.3b In the present modification, with an olefin at C16,
the silyl ether could be removed concomitantly with
mixed ketal formation at C19 in reasonable yields.
Alcohol 50 was oxidized to the ketone under modified
Swern conditions,36 and subsequent methylenation37
provided exocyclic olefin 51 in 75% yield for the two steps.
Replacement of the C24 benzyl ether with a tert-butyl-
dimethylsilyl ether at this stage proved optimal. The
debenzylation was effected with lithium di-tert-butyl-
biphenylide (LiDBBP)38 to give the corresponding second-
ary alcohol in moderate yield. The free C24 alcohol was
cleanly converted into bis-silyl ether 52, a versatile
precursor to a variety of analogues of okadaic acid.
Completion of the synthesis of the C15-C27 inter-
mediate required installation of the â-ketophosphonate
functionality. Selective oxidative cleavage of the mono-
(36) Mancuso, A. J .; Swern, D. Synthesis 1981, 165.
(37) Miljkovic, M.; Glisin, D. J . Org. Chem. 1975, 40, 3357.
(38) (a) Freeman, P. K.; Hutchinson, L. L. J . Org. Chem. 1980, 45,
1924. (b) Ireland, R. E.; Smith, M. G. J . Am. Chem. Soc. 1988, 110,
854.
The modified synthesis of the C16-C27 core began
with aldehyde 483b (Scheme 10). Treatment of 48 with
the Grignard reagent derived from 1-bromo-3-butene

Expedient Access to the Okadaic Acid Architecture
J . Org. Chem., Vol. 66, No. 3, 2001 931
Sch em e 11
The advanced synthetic product representing the C1-
C27 core of 7-deoxy okadaic acid (54) is a potentially
valuable intermediate to probe the relationship between
okadaic acid structure and biological activity. Several
derivatives of okadaic acid have been assayed previously
for their phosphatase inhibitory activity, including com-
pounds representing the C1-C1411a and C15-C3811a,d
portions of 1. These domains alone do not maintain
enzyme inhibitory activity that is comparable to that of
the parent compound. However, intact C1-C27 portions
of 1 or 2, or unnatural derivatives bearing variable
lipophilic extensions from the C27 position have not been
available for comparable studies. Advanced intermediate
54 was designed to be deployed to further advance such
empirical investigations via the divergent synthesis of a
series of potential phosphatase inhibitors.42 Toward this
end, 54 was selectively deprotected with TBAF to give
the primary alcohol 14 due to the differential steric
environment about the two silyl ethers.43 It is anticipated
that oxidation of this alcohol to the corresponding alde-
hyde would provide a useful intermediate for the chemo-
selective addition of organometallic coupling partners
to C27 in the presence of the C1 carboxylate. Indeed,
preliminary studies on model systems representing the
C16-C27 portion of 1 bearing an aldehyde at C27 indi-
cate that Nozaki-Hiyama-Kishi coupling may provide a
reliable method for introducing a variety of lipophilic
appendages at C27.44
substituted olefin at C16 of 52 in the presence of the C25-
disubstituted olefin yielded the C16 aldehyde in moderate
yield. Addition of lithiated methyl dimethyl phosphonate
to the C16 aldehyde followed by Dess-Martin oxidation39
gave â-ketophosphonate 15 and completed the synthesis
of this modified C15-C27 okadaic acid core. The newly
developed approach to 52 circumvents several potentially
problematic transformations encountered in our total
synthesis of 1.3 Furthermore, the unique ketophospho-
nate 15 may be employed for the preparation of novel
analogues of the natural product.
Con clu sion s
This work summarizes a number of distinct synthetic
innovations that support the facile generation of okadaic
acid and its analogues. Improvements in the C3-C14
fragment, some of which have been previously com-
municated,13 are fully detailed here. These include a
versatile new and abbreviated preparation of the C3-
C8 lactone intermediate of okadaic acid and its 7-deoxy
analogues. This route avoids the extensive manipulations
that were previously used2,3 to obtain this simple building
block from carbohydrate starting materials, and allows
for either the incorporation or omission of C7 function-
alization. The complementary C9-C14 alkynyl coupling
partner was similarly obtained in only a few steps from
commercially available materials. The joining of these
fragments under standard conditions provided ynone
Michael acceptors as a prelude to the introduction of the
C10 methyl group. Both the (E)- and (Z)-enones derived
from nonstereoselective conjugate addition of dimethyl-
cuprate converged to the C8 spiroketal upon treatment
with acid, thus demonstrating that productive (E) to (Z)
Com p letion of th e C1-C27 Dom a in of 7-Deoxy-
ok a d a ic Acid . After successful syntheses of the C1-C14
(4) and C15-C27 (15) domains, completion of the con-
vergent synthesis of the C1-C27 portion simply required
formation of the C14-C15 alkene, followed by a few
further transformations. Nearly equimolar amounts of
aldehyde 4 and â-ketophosphonate 15 were subjected
to the Masamune-Roush modified conditions15 of the
Horner-Wadsworth-Emmons olefination to provide the
C1-C27 enone 53 in moderate yield (Scheme 11). Stereo-
and chemoselective reduction of the carbonyl at C16
with the (S)-CBS oxazaborolidine reagent and catechol
borane40 at -78 °C provided the desired (16R)-alcohol
along with the chromatographically separable (16S)-
alcohol as a minor side product (∼9:1, 16R:16S). The
(16R)-alcohol was treated with TsOH in benzene to effect
intramolecular trans-ketalization to the bis-TBS-ether
54, forming the desired C19 spiroketal center with
complete stereocontrol.41 The stereoselectivities observed
in this reduction-spiroketalization process suggest that
the previously reported minor product of the similar
sequence in the synthesis of 13c resulted from the reduc-
tion step, not the subsequent spiroketalization.
(42) Wipf, P.; Cunningham, A.; Rice, R. L.; Lazo, J . S. Bioorg. Med.
Chem. 1997, 5, 165.
(43) The regioselectivity of the mono-desilylation of 54 was verified
by acetylation of 14 to give monoacetate 55 coupled with extensive
NMR spectroscopic studies, which are summarized in the Supporting
Information.
(44) Nozaki-Hiyama-Kishi couplings with a C16-C27 model alde-
hyde (i) and various vinyl and alkynyl iodides have demonstrated that
this C-C bond formation is useful for providing the corresponding
secondary alcohols (ii).
(39) (a) Dess, D. B.; Martin, J . C. J . Am. Chem. Soc. 1991, 113, 7277.
(b) Ireland, R. E.; Liu, L. J . Org. Chem. 1993, 58, 2899.
(40) (a) Corey, E. J .; Helal, C. J . Angew. Chem., Int. Ed. 1998, 37,
1986. (b) Corey, E. J .; Bakshi, R. K.; Shibata, S.; Chen, C.-P. Singh, V.
K. J . Am. Chem. Soc. 1987, 109, 7925.
(41) The desired stereoisomer was formed with dr >95:5, as only
a
single product was observed by 1H NMR spectroscopy (CDCl3,
500 MHz).

932 J . Org. Chem., Vol. 66, No. 3, 2001
Dounay et al.
was added, and the THF was removed by rotary evaporation.
The residue was diluted with ethyl acetate, and the resulting
emulsion was filtered under vacuum. The separated aqueous
residue was extracted with ethyl acetate (3 × 75 mL), and the
combined organic layers were washed with H2O and saturated
aqueous NaCl (75 mL each), dried over Na2SO4, filtered, and
concentrated. The residue was purified by silica gel column
chromatography (hexanes/ethyl acetate, 4:1, v/v) to yield 18
(6.83 g, 14.9 mmol, 93%) as a clear, colorless oil: Rf 0.35
(hexanes/ethyl acetate, 4:1, v/v); [R]26D ) +3.9 (c 1.27, CHCl3);
IR (neat) 3435, 3031, 2930, 2857, 1428, 1360, 1070, 823, 702
isomerization occurs under the spiroketalization reaction
conditions. Furthermore, the efficiency of spiroketaliza-
tion was found to be dramatically affected by substitution
at the C7 position. The utility of this approach to the C1-
C14 domain for natural product synthesis has been
demonstrated by the total synthesis of 7-deoxy-okadaic
acid.13b The synthesis of the central domain of okadaic
acid was similarly revised to both overcome problems
encountered in previous total synthesis efforts and to
provide ready access to nonnatural products. Early
replacement of the benzylic ethers at C16 and C24 with
alternative functional groups led to the versatile bispyran
intermediate 52, representing the C16-C27 core of 1 and
its analogues. Targeting a C1-C27 truncated form of 2,
52 was elaborated into the C1-C27 enone using the end-
game strategy employed in the total syntheses of 13 and
2.13b Finally, the choice of silyl ethers to protect the C24
and C27 hydroxyls allowed for the selective and mild
liberation of the C27 hydroxyl group. Ongoing efforts
include the chemoselective functionalization of the C27
position to generate a series of nonnatural products with
variable lipophilic side chain extensions. Such compounds
may be instrumental for defining the role of the C28-
C38 lipophilic domain and exploiting the potential of the
bimodal carboxylate-lipophilic binding of okadaic acid-
like molecules with their phosphatase receptors.45
1
cm-1; H NMR (CDCl3, 300 MHz) δ 7.66 (apparent d, J ) 6.0
Hz, 4H), 7.40-7.32 (m, 11H), 4.52 (s, 2H), 4.11 (s, 2H), 3.88
(m, 1H), 3.73 (ddd, J ) 14.1, 9.9, 4.2 Hz, 1H), 2.52 (m, 3H),
1.07 (s, 9H); 13C NMR (CDCl3, 75 MHz) (overlapping signals
in aromatic region) δ 135.7, 133.2, 130.0, 128.6, 128.2, 128.0,
83.0, 78.3, 71.7, 70.5, 66.6, 57.8, 27.0, 23.8, 19.4. Anal. Calcd
for C29H34O3Si: C, 75.94; H, 7.47. Found: C, 76.03; H, 7.28.
(2S)-1-ter t-Bu tyld ip h en ylsilyloxy-2,6-h exa n ed iol (19).
To a stirred solution of 18 (7.0 g, 15 mmol) in ethyl acetate
(200 mL) was added Pd(OH)2 on carbon (812 mg of 20% Pd
catalyst, 1.52 mmol). The reaction flask was repeatedly evacu-
ated and flushed with H2. After a H2 atmosphere (1 atm) was
established in the reaction flask, the suspension was vigorously
stirred for 6 h and then filtered through Celite with ethyl
acetate (300 mL). The filtrate was concentrated, and silica gel
column chromatography (hexanes/ethyl acetate, 2:1, v/v) of the
residue gave 19 (4.4 g, 12 mmol, 78%) as a clear, colorless oil:
Rf 0.15 (hexanes/ethyl acetate, 2:1, v/v); [R]27D ) +15.2 (c 0.46,
CHCl3); IR (neat) 3351, 3048, 2932, 1472, 1461, 1427, 1261,
1112, 824, 703 cm-1; 1H NMR (CDCl3, 500 MHz) δ 7.68 (dd, J
) 6.5, 1.5 Hz, 4H), 7.47-7.39 (m, 6H), 3.74 (m, 1H), 3.67 (dd,
J ) 10.5, 3.5 Hz, 1H), 3.62 (t, J ) 6.0 Hz, 2H), 3.50 (dd, J )
10.5, 8.0 Hz, 1H), 2.62 (s, 1H), 1.55-1.39 (m, 7H), 1.07 (s, 9H);
13C NMR (CDCl3, 125 MHz) δ 135.6, 132.2, 129.9, 128.0, 71.9,
68.0, 62.7, 32.6, 32.4, 27.0, 21.7, 19.3; HRFABMS calcd for
Exp er im en ta l Section
Gen er a l Meth od s. Unless otherwise noted, all reactions
were carried out under an Ar or N2 atmosphere using oven-
dried glassware and standard syringe, cannula, and septa
techniques. Diethyl ether, THF, and benzene were distilled
from Na/benzophenone under N2. Toluene was distilled from
Na under N2. CH2Cl2, CH3CN, Et3N, i-Pr2NEt, i-Pr2NH,
C
18H23O3Si [M - t-Bu]+ 315.1416, found 315.1409.
(5S)-6-ter t-Bu t yld ip h en ylsilyloxy-5-h yd r oxyh exa n o-
ic Acid δ-La cton e (11). To a stirred rt solution of 19 (4.30 g,
11.5 mmol) in CH2Cl2 (125 mL) were added crushed 4 Å
molecular sieves (3.0 g). PCC (8.7 g, 40 mmol) was added in
two equal portions, allowing a 3 h reaction time between
additions. The reaction mixture was allowed to stir for 16 h
before being filtered through silica gel with ethyl acetate (350
mL). The filtrate was concentrated, and the residue was
purified by silica gel column chromatography (hexanes/ethyl
acetate, 4:1, v/v) to yield 11 (3.14 g, 8.6 mmol, 75%) as a clear,
.
TMSCl, and BF3 OEt2 were distilled from CaH2 under N2.
Toluene solutions of (S)-methyl oxazaborolidine were pur-
chased from Strem Chemicals, Newburyport, MA. (2R,8S)-
Camphorsulfonyloxaziridine was prepared from (1S)-(+)-
camphorsulfonic acid following the procedure by Davis and co-
workers.19 Dess-Martin periodinane was freshly prepared in
our laboratory following the original procedure by Dess and
Martin.39 Solutions of n-butyllithium in hexanes and methyl-
lithium in diethyl ether (Aldrich) were titrated according to
the procedure of Watson and Eastman.46 Flash chromatogra-
phy was performed using Baker Flash silica gel 60 (40 µm) or
ICN silica gel 32-63 and the solvent systems indicated.
Analytical TLC was performed with 0.25 mm or 0.50 mm EM
silica gel 60 F254 plates that were analyzed by fluorescence
upon 254 nm irradiation or by staining upon heating with
anisaldehyde reagent (450 mL 95% EtOH, 25 mL concentrated
H2SO4, 15 mL of acetic acid, and 25 mL of anisaldehyde). High-
resolution mass spectrometric data were obtained by the
University of Minnesota Mass Spectrometry Laboratory using
CI, FAB, and MALDI techniques. Elemental analyses were
performed by M-H-W Laboratories (Phoenix, AZ).
C3-C8 La ct on es. (2S)-6-Ben zyloxy-1-ter t-b u t yld i-
p h en ylsilyloxy-4-p en tyn -2-ol (18). To a stirred -78 °C
solution of benzyl propargyl ether (16, 4.70 g, 32.0 mmol) in
THF (100 mL) was added n-butyllithium (11.7 mL of a 2.60
M solution in hexanes, 30.4 mmol). The resulting solution was
stirred for 15 min before being added via cannula to a solution
of 17 (5.00 g, 16.0 mmol) in THF (60 mL) at -78 °C. Freshly
distilled boron trifluoride diethyl etherate (2.3 mL, 16.0 mmol)
was added dropwise, and the resulting solution was stirred
at -78 °C for 40 min. Saturated aqueous NaHCO3 (20 mL)
colorless oil: Rf 0.45 (hexanes/ethyl acetate, 2:1, v/v); [R]26
)
D
+9.8 (c 2.0, CHCl3); IR (neat) 2955, 2931, 2857, 1738, 1240,
1133, 823, 704 cm-1 1H NMR (CDCl3, 500 MHz) δ 7.66 (m,
;
4H), 7.43 (m, 6H), 4.40 (m, 1H), 3.77 (ddd, J ) 15.5, 11.0, 4.5
Hz, 2H), 2.65-2.39 (m, 2H), 1.94-2.00 (m, 2H), 1.75-1.86 (m,
2H), 1.06 (s, 9H); 13C NMR (CDCl3, 125 MHz) δ 171.2, 135.6,
133.1, 130.0, 127.8, 80.2, 65.6, 29.9, 26.8, 24.4, 19.3, 18.3;
HRFABMS calcd for C22H29O3Si [M + H]+ 369.1885, found
369.1862.
Hyd r oxy La cton e 20. To a stirred -78 °C solution of
diisopropylamine (84 µL, 0.60 mmol) in THF (1 mL) under Ar
was added n-butyllithium (0.23 mL of a 2.4 M solution in
hexanes, 0.54 mmol). After 30 min, TMEDA (0.20 mL, 1.4
mmol) was added, followed by 11 (100 mg, 0.27 mmol) in THF
(2 mL). After an additional 30 min, a solution of (+)-(2R,8S)-
camphorsulfonyloxaziridine (93 mg, 0.41 mmol) in THF (2 mL)
was added. The reaction was warmed to -40 °C and main-
tained at this temperature for 2 h, before camphorsulfonic acid
(126 mg, 0.544 mmol) in THF (2 mL) was added. The reaction
mixture was concentrated, and the crude residue was purified
by silica gel column chromatography (hexanes/ethyl acetate,
5:1 to 2:1, v/v). The resulting product was dissolved in ether,
and the insoluble residual sulfonimine was removed by filtra-
tion. The filtrate was concentrated to provide 20 (64 mg, 0.17
mmol, 61%) as a clear, colorless oil: Rf 0.31 (hexanes/ethyl
acetate, 2:1, v/v); [R]25D ) +10.3 (c 3.2, CHCl3); IR (neat) 3450,
3080, 3040, 2920, 2850, 1740, 1475, 1430, 1100, 690 cm-1; 1H
NMR (CDCl3, 500 MHz) δ 7.65 (ddd, J ) 8.0, 1.5, 1.5 Hz, 4H),
(45) Takai, A.; Tsuboi, K.; Koyasu, M.; Isobe, M. Biochem. J . 2000,
350, 81-88.
(46) Watson, S. C.; Eastman, J . F. J . Organomet. Chem. 1967, 9,
165.

Expedient Access to the Okadaic Acid Architecture
J . Org. Chem., Vol. 66, No. 3, 2001 933
7.47-7.38 (m, 6H), 4.45 (dddd, J ) 10.5, 4.5, 4.5, 4.5 Hz, 1H),
4.13 (ddd, J ) 12.5, 6.5, 1.5 Hz, 1H), 3.81 (dd, J ) 11.0, 5.0
Hz, 1H), 3.72 (dd, J ) 11.0, 3.5 Hz, 1H), 3.23 (d, J ) 1.0 Hz,
1H), 2.38 (m, 1H), 2.06 (m, 2H), 1.87 (dddd, J ) 12.0, 12.0
12.0, 4.5 Hz, 1H), 1.06 (s, 9H); 13C NMR (CDCl3, 125 MHz) δ
174.2, 135.5, 132.8, 129.8, 127.7, 82.1, 67.8, 65.2, 27.2, 26.7,
24.0, 19.2; HRFABMS calcd for C22H29SiO4 [M + H]+ 385.1835,
found 385.1855.
were washed with H2O and saturated aqueous NaCl (50 mL
each). The combined aqueous phases were extracted with
diethyl ether, and the organic phases were combined, dried
over Na2SO4, filtered, and concentrated. Silica gel column
chromatography (hexanes/ethyl acetate, 5:1 to 2:1, v/v) yielded
epoxide 25 (5.80 g, 31.9 mmol, 86% yield, 89% ee25): Rf 0.24
(hexanes/ethyl acetate, 2:1, v/v); [R]25 ) -11 (c 2.1, CHCl3);
D
IR (neat) 3400, 2950, 2175, 1410, 1245, 840 cm-1 1H NMR
;
ter t-Bu tyld im eth ylsilyloxy La cton e 21. To a stirred 0
°C solution of 20 (250 mg, 0.65 mmol) in CH2Cl2 (10 mL) under
Ar were added 2,6-lutidine (200 µL, 1.9 mmol) and tert-
butyldimethylsilyltriflate (300 mg, 1.14 mmol). The reaction
mixture was warmed to rt. After 1.5 h, saturated aqueous
NH4Cl (5 mL) was added. The separated aqueous phase was
washed with ethyl acetate (3 × 10 mL), and the combined
organic extracts were washed with H2O and saturated aqueous
NaCl (10 mL each), dried over Na2SO4, filtered, and concen-
trated. The crude residue was purified by silica gel column
chromatography (hexanes/ethyl acetate, 8:1, v/v) to provide 21
(306 mg, 0.61 mmol, 94%) as a clear colorless oil, which was
stored in a benzene matrix at -20 °C: Rf 0.70 (hexanes/ethyl
acetate, 2:1, v/v); [R]26D ) +21.0 (c 2.7, CHCl3); IR (neat) 2955,
(500 MHz, CDCl3) δ 3.96 (ddd, J ) 12.5, 5.5, 2.5 Hz, 1H), 3.68
(ddd, J ) 12.5, 7.5, 4.0 Hz, 1H), 3.16 (ddd, J ) 5.0, 5.0, 2.0
Hz, 1H), 3.13 (ddd, J ) 4.0, 2.5, 2.5 Hz, 1H), 2.67 (dd, J )
17.5, 4.5 Hz, 1H), 2.57 (dd, J ) 18.0, 5.0 Hz, 1H), 1.74 (dd, J
) 7.5, 5.5 Hz, 1H), 0.16 (s, 9H); 13C NMR (125 MHz, CDCl3) δ
100.4, 87.3, 60.9, 57.7, 52.8, 22.6, -0.15. Anal. Calcd for
C9H16O2Si: C, 58.65; H, 8.75. Found: C, 58.73; H, 8.62.
Diol 26. CuCN (6.56 g, 73.2 mmol) was azeotropically dried
with benzene (25 mL) at rt under vacuum and then placed
under Ar. Diethyl ether (55 mL) was added, and the resultant
mixture was cooled to -78 °C. Methyllithium (74.9 mL of a
1.76 M solution in diethyl ether, 132 mmol) was added
dropwise via a pressure-equalizing addition funnel, and the
resulting mixture was warmed to -15 °C and stirred vigor-
ously until all of the CuCN dissolved (∼20 min), resulting in
a pale green solution. A solution of epoxide 25 (2.22 g, 12.2
mmol) in diethyl ether (6 mL) was added, and the resultant
mixture was stirred at -10 to -15 °C for 1 h. Diethyl ether
(100 mL) and saturated aqueous NH4Cl (75 mL) were added.
The resultant mixture was warmed to rt and filtered to give a
cloudy suspension. The separated organic phase was washed
with saturated aqueous NH4Cl, H2O, and saturated aqueous
NaCl (2 × 50 mL each). The combined aqueous phases were
extracted with diethyl ether and the combined organic phases
were dried over Na2SO4, filtered, and concentrated to give
crude 26 (2.43 g, 12.2 mol, 100%) as an off-white solid. 1H NMR
analysis in CDCl3 showed a >8:1 ratio of regioisomeric diols.
To this crude material were added THF (70 mL), H2O (55 mL),
and NaIO4 (652 mg, 3.05 mmol) at rt. The resultant solution
was stirred for 1 h and then was diluted with diethyl ether
(200 mL), and the phases were separated. The organic phase
was washed with saturated aqueous NaHCO3 (100 mL) and
saturated aqueous NaCl (100 mL). The combined aqueous
phases were extracted with diethyl ether and the combined
organic phases were dried over Na2SO4, filtered, and con-
centrated. Silica gel column chromatography (hexanes/ethyl
acetate, 5:1 to 2:1 to 1:1, v/v) of the residue afforded 26 (1.79
g, 8.91 mmol, 73%) as an amorphous white solid: Rf 0.41
(hexanes/ethyl acetate, 1:1, v/v); [R]26D ) -18.0 (c 3.0, CHCl3);
2930, 2857, 1755, 1472, 1428, 1253, 1147, 1114, 837, 702 cm-1
;
1H NMR (CDCl3, 500 MHz) δ 7.67 (m, 4H), 7.45-7.38 (m, 6H),
4.51 (m, 1H), 4.16 (dd, J ) 9.0, 6.0 Hz, 1H), 3.75 (d, J ) 4.5
Hz, 2H), 2.16 (m, 1H), 2.04 (m, 1H), 1.99-1.91 (m, 2H), 1.07
(s, 9H), 0.92 (s, 9H), 0.18 (s, 3H), 0.14 (s, 3H); 13C NMR (CDCl3,
125 MHz) δ 171.7, 135.8, 133.2, 130.4, 128.0, 80.3, 69.4, 65.8,
29.2, 27.0, 26.0, 23.9, 19.5, 18.5, -4.5, -5.3; HRFABMS calcd
for C28H43O4 Si2Na [M + Na]+ 521.2519, found 521.2548.
C9-C14 Alk yn e. En yn e 24. To a round-bottomed flask
under Ar containing vinyl stannane 2322 (25.1 g, 84.5 mmol)
was added a solution of 3-chloro-1-(trimethylsilyl)-1-propyne
2221 (13.7 g, 92.9 mmol) in THF (170 mL). This solution was
deoxygenated by bubbling a stream of Ar through it for 10 min.
.
To the resultant solution were added Pd2(dba)3 CHCl3 (890 mg,
845 µmol) and triphenylphosphine (443 mg, 1.69 mmol). This
deep burgundy mixture was heated to 50 °C with stirring for
24 h, cooled to rt, and stirred for an additional 36 h. The THF
was removed under reduced pressure, and the crude residue
was filtered through Celite and rinsed with hexanes. Silica
gel column chromatography (hexanes/ethyl acetate, 8:1 to 5:1
to 2:1, v/v) of this residue gave enyne 24 (5.57 g, 33.2 mmol,
39%) as a pale oil: Rf 0.39 (hexanes/ethyl acetate 2:1, v/v); IR
(neat) 3300, 2960, 2180, 1415, 1295 cm-1; 1H NMR (300 MHz,
CDCl3) δ 5.87 (ddddd, J ) 15.3, 5.7, 5.7, 1.8, 1.8 Hz, 1H), 5.64
(ddddd, J ) 15.3, 5.4, 5.4, 1.5, 1.5 Hz, 1H), 4.10 (dddd, J )
5.7, 1.5, 1.5, 1.5 Hz, 2H), 2.98 (dddd, J ) 5.4, 1.5, 1.5, 1.5 Hz,
2H), 2.09 (s, 1H), 0.13 (s, 9H); 13C NMR (75 MHz, CDCl3) δ
130.8, 125.8, 103.5, 86.9, 63.0, 22.8, -0.06; HRCIMS calcd for
C9H20OSiN [M + NH4]+ 186.1314, found 186.1319.
IR (neat) 3340, 2960, 2170, 1410, 1240, 1020, 830 cm-1 1H
;
NMR (500 MHz, CDCl3) δ 3.73 (m, 1H), 3.67 (m, 2H), 2.89 (m,
1H), 2.85 (br s, 1H), 2.57 (dd, J ) 17.0, 4.0 Hz, 1H), 2.43 (dd,
J ) 17.0, 7.5 Hz, 1H), 1.84 (m, 1H), 0.90 (d, J ) 7.0 Hz, 1H),
0.16 (s, 9H); 13C NMR (125 MHz, CDCl3) δ 102.7, 88.0, 74.9,
67.2, 39.4, 27.3, 13.6, 0.02. Anal. Calcd for C10H20O2Si: C,
59.95; H, 10.06. Found: C, 59.76; H, 10.27.
Ep oxid e 25.47 To a stirred solution of (+)-diethyltartrate
(1.84 g, 8.90 mmol) in CH2Cl2 (160 mL) under Ar was added
crushed 4 Å molecular sieves (∼ 10 g). This mixture was cooled
to -20 °C, and Ti(OiPr)4 (2.19 mL, 7.42 mmol) was added,
followed by tert-butyl hydroperoxide (13.5 mL of a ∼5.5 M
solution in decane, ∼74 mmol). The resultant mixture was
stirred for 30 min before a solution of allylic alcohol 24 (6.23
g, 37.1 mmol) in CH2Cl2 (25 mL) was added dropwise via
cannula. The resulting mixture was stirred at -20 °C for an
additional 7.5 h, then stored at this temperature without
stirring for an additional 14 h. The mixture was warmed to 0
°C, filtered, and slowly poured into a 0 °C solution of FeSO4‚
7H2O (12.2 g) and tartaric acid (3.7 g) in H2O (40 mL). The
two-phase mixture was stirred vigorously at rt for 30 min. The
separated aqueous layer was extracted with diethyl ether, and
the combined organic phases were cooled to 0 °C. A precooled
0 °C solution of 30% NaOH (w/v) in saturated aqueous NaCl
(15 mL) was added, and the mixture was stirred vigorously at
0 °C for 20 min. The solution was diluted with H2O (100 mL),
and the phases were separated. The combined organic phases
An isylid en e 26a . To a 0 °C solution of diol 26 (2.33 g, 11.7
mmol) in CH2Cl2 (120 mL) was added anisaldehyde dimethyl
acetal (2.21 mL, 12.9 mol) followed by camphorsulfonic acid
(136 mg, 585 µmol). The resulting solution was warmed to rt
and stirred for 2 h, diluted with diethyl ether (250 mL) and
washed with saturated aqueous NH4Cl, H2O, and saturated
aqueous NaCl (2 × 75 mL each). The combined aqueous phases
were extracted with diethyl ether, and the organic phase was
dried over Na2SO4, filtered, and concentrated. Silica gel column
chromatography (hexanes/ethyl acetate, 8:1 to 5:1, v/v) yielded
anisylidene 26a (3.51 g, 10.9 mmol, 93%) as a white crystalline
solid (hexanes/ethyl acetate): mp 39-40 °C; Rf 0.43 (hexanes/
ethyl acetate, 5:1, v/v); [R]26 ) -16 (c 1.6, CHCl3); IR (neat)
D
2950, 2825, 2170, 1610, 1515, 1460, 1240, 1110 cm-1; 1H NMR
(300 MHz, CDCl3) δ 7.43 (d, J ) 9.0 Hz, 2H), 6.88 (d, J ) 9.0
Hz, 2H), 5.47 (s, 1H), 4.09 (dd, J ) 11.4, 4.8 Hz, 1H), 3.80 (s,
3H), 3.58 (m, 1H), 3.50 (dd, J ) 11.4, 11.4 Hz, 1H), 2.65 (dd,
J ) 17.0, 4.8 Hz, 1H), 2.56 (dd, J ) 17.0, 5.7 Hz, 1H), 2.03 (m,
1H), 0.86 (d, J ) 7.0 Hz, 1H), 0.16 (s, 9H); 13C NMR (125 MHz,
CDCl3) δ 159.9, 131.0, 127.4, 113.6, 103.1, 101.1, 86.6, 81.0,
(47) Freshly distilled (+)-diethyltartrate and Ti(OiPr)4, activated
molecular sieves, and efficient stirring were crucial for high yields and
enantioselectivities in this reaction.

934 J . Org. Chem., Vol. 66, No. 3, 2001
Dounay et al.
72.7, 55.3, 33.9, 25.0, 12.4, 0.04. Anal. Calcd for C18H28O3Si:
C, 67.88; H, 8.23. Found: C, 67.87; H, 8.37.
isolated as a colorless, crystalline solid (pentane/ether): mp
95-97 °C; Rf 0.47 (hexanes/ethyl acetate, 4:1, v/v); [R]25
)
D
Alcoh ol 26b. To a 0 °C solution of anisylidene 26a (3.47 g,
10.8 mmol) in DMF (90 mL) containing 4 Å molecular sieves
(∼6.5 g) under Ar was NaBH3CN (6.77 g, 108 mmol) followed
by a cannula addition over 30 min of a 0 °C solution of
trifluoroacetic acid (16.6 mL, 216 mmol) in DMF (70 mL),
which had been dried over 4 Å molecular sieves for ∼20 min.
The resulting mixture was stirred at 0 °C for an additional 30
min then at rt for 4.5 h, at which time TLC showed almost
complete disappearance of 26a . The mixture was filtered, and
the filtrate was cooled to 0 °C before saturated aqueous
NaHCO3 (225 mL) was added cautiously. The aqueous phase
was extracted with CH2Cl2 (6 × 50 mL). The organic phase
was washed with saturated aqueous NaHCO3, H2O, and
saturated aqueous NaCl (100 mL each). The organic phase was
dried over Na2SO4, filtered, and concentrated under reduced
pressure. Silica gel column chromatography (hexanes/ethyl
acetate, 5:1, v/v) of the residue gave recovered 26a (208 mg,
646 µmol), alcohol 26b (2.87 g, 8.86 mmol, 82%, 88% based on
recovered 26a ), and the regioisomeric anisylidene-opening
product (408 mg, 1.26 mmol, 12%). Alcohol 26b was indistin-
guishable by TLC (Rf 0.30 in hexanes/ethyl acetate, 5:1, v/v)
and 1H NMR spectroscopy from an authentic sample.3c The
-15.3 (c 2.0, CHCl3); IR (neat) 3275, 3066, 2966, 2862, 2122,
1615, 1590, 1518, 1460, 1402, 1371, 1303, 1249, 1110 cm-1
;
1H NMR (CDCl3, 300 MHz) δ 7.47 (d, J ) 9.0 Hz, 2H), 6.91 (d,
J ) 9.0 Hz, 2H), 5.50 (s, 1H), 4.10 (dd, J ) 11.4, 4.8 Hz, 1H),
3.80 (s, 3H), 3.60 (m, 1H), 3.50 (t, J ) 11.4 Hz, 1H), 2.64 (ddd,
J ) 17.2, 3.9, 2.7 Hz, 1H), 2.53 (ddd, J ) 17.2, 5.7, 2.7 Hz,
1H), 2.12-2.06 (m, 1H), 2.05 (t, J ) 2.5 Hz, 1H), 0.84 (d, J )
6.6 Hz, 3H); 13C NMR (CDCl3, 75 MHz) δ 160.0, 142.1, 130.9,
127.5, 113.6, 101.2, 80.9, 72.7, 70.1, 55.3, 33.4, 23.4, 12.4;
HRCIMS calcd for
247.1325. Anal. Calcd for C15H18O3: C, 73.15; H, 7.37. Found:
C, 73.26; H, 7.10.
C
15H18O3 [M + H]+ 247.1334, found
Alcoh ol 30a . To a stirred 0 °C solution of 30 (1.72 g, 6.99
mmol) in DMF (60 mL) over 4 Å molecular sieves under Ar
was added NaBH3CN (4.39 g, 69.9 mmol). A solution of
trifluoroacetic acid (10.78 mL, 139.8 mmol) in DMF (50 mL)
that had been stirred over 4 Å molecular sieves at 0 °C under
Ar for 20 min was added via cannula over 30 min. The reaction
mixture was stirred at 0 °C for 30 min, then warmed to rt.
After 6 h, the mixture was filtered through a fritted glass
funnel and cooled to 0 °C, and saturated aqueous NaHCO3 was
added. The crude mixture was extracted with CH2Cl2 (3 × 100
mL), and the combined organic phase was washed with
saturated aqueous NaHCO3 (50 mL), H2O (50 mL), and
saturated aqueous NaCl (50 mL), dried over Na2SO4, filtered,
and concentrated by rotary evaporation. The crude mixture
was purified by flash column chromatography on silica gel
(hexanes/ethyl acetate, 4:1, v/v) to give 30a (1.18 g, 4.78 mmol,
68%) as a colorless oil, which was indistinguishable from the
an authentic sample3c by TLC, specific rotation, 1H and 13C
NMR, and HRCIMS.
observed specific rotation ([R]24 ) + 8.3 (c 1.7, CHCl3)) is
D
consistent with an 89% enantiomeric excess obtained in the
Sharpless asymmetric epoxidation.
An isylid en e 30. To a stirred rt solution of aldehyde 27 (384
mg, 1.90 mmol) in DMF (25 mL) were added Zn pieces (185
mg, 2.85 mmol), followed by propargyl bromide (254 µL, 2.85
mmol) and water (0.5 mL). The Zn dissolved and the solution
became cloudy before completion of the reaction. After 8 h,
the reaction mixture was poured into saturated aqueous NH4Cl
(100 mL), extracted with diethyl ether (4 × 75 mL), dried over
Na2SO4, filtered, and concentrated by rotary evaporation. The
crude mixture was purified by silica gel flash chromatography
(hexanes/ethyl acetate, 6:1, v/v) to give 28 (410 mg) as a 6:1
mixture of alkyne and allene, with an approximately 1:1
mixture of alcohol diastereomers. This mixture was dissolved
in THF (200 mL) under Ar, and cooled to -78 °C before
n-butyllithium in hexanes (2.17 mL of a 2.63 M solution in
hexanes, 5.71 mmol) was added. After 3 h at -78 °C, saturated
aqueous NH4Cl (10 mL) was added, and the mixture was
warmed to rt. The reaction mixture was extracted with ether
(3 × 100 mL), and the combined organic phase was dried over
Na2SO4, filtered, and concentrated by rotary evaporation. The
crude product was purified by flash column chromatography
on silica gel (hexanes/ethyl acetate, 4:1, v/v) to give 28 (405
mg, 1.67 mmol, 88%) as a >20:1 mixture of alkyne to allene,
C1-C14 Ald eh yd e. Yn on e 11a . To a stirred -78 °C
solution of alkyne 12 (1.0 g, 3.1 mmol) in THF (30 mL) under
Ar was added n-butyllithium (1.05 mL of a 2.80 M solution in
hexanes, 2.94 mmol). After the mixture was stirred for 45 min,
a solution of lactone 11 (680 mg, 1.84 mmol) in THF (15 mL)
was added via cannula. After 50 min, saturated aqueous NH4-
Cl (5 mL) was added, and the mixture was allowed to warm
to rt. The mixture was extracted with ethyl acetate (2 × 40
mL), and the combined organic extracts were washed with H2O
and saturated aqueous NaCl (30 mL each). The organic
fraction was dried over Na2SO4, filtered, and concentrated. The
residue was purified by silica gel column chromatography
(hexanes/ethyl acetate, 8:1, v/v) to give 11a (1.10 g, 1.60 mmol,
87%) as a clear, colorless oil: Rf 0.30 (hexanes/ethyl acetate,
4:1, v/v); [R]26 ) +9.2 (c 6.6, CHCl3); IR (neat) 3510, 2950,
D
2850, 2210, 1675, 1605, 1508, 1455, 1420, 1355, 1295, 1240,
1
1
as determined by H NMR spectroscopy.
1100 cm-1; H NMR (CDCl3, 500 MHz) δ 7.68 (ddd, J ) 8.0,
To a stirred solution of 28 (360 mg, 1.49 mmol) in CH2Cl2
(25 mL) under Ar at rt were added p-anisaldehyde dimethyl
acetal (383 µL, 2.23 mmol) and p-toluenesulfonic acid (71 mg,
0.37 mmol). The solution turned dark violet. After 9 h,
triethylamine (∼2 mL) was added, and the mixture was
concentrated by rotary evaporation. The crude residue was
dissolved in methanol (50 mL) and cooled to 0 °C, and NaBH4
(84 mg, 2.2 mmol) was added. After 1 h, saturated aqueous
NH4Cl (10 mL) was added, and the mixture was extracted with
ethyl acetate (3 × 100 mL). The organic phase was washed
with H2O (50 mL) and saturated aqueous NaCl (50 mL), dried
(Na2SO4), filtered, and concentrated by rotary evaporation. The
crude mixture was purified by flash chromatography on silica
gel (pentane/Et2O, 5:1, v/v) to give 29 (164 mg, 666 µmol, 45%)
and 30 (137 mg, 556 µmol, 38%). Anisylidene 29 was isolated
1.5, 1.5 Hz, 4H), 7.42 (m, 6H), 7.27 (d, J ) 9.0 Hz, 2H), 6.89
(d, J ) 8.5 Hz, 2H), 4.46 (d, J ) 11.0 Hz, 1H), 4.40 (d, J )
11.0 Hz, 1H), 3.91 (m, 2H), 3.80 (s, 3H), 3.73 (m, 1H), 3.66
(dd, J ) 10.5, 4.0 Hz, 1H), 3.51 (dd, J ) 9.5, 7.0 Hz, 1H), 3.47
(dd, J ) 9.0, 5.5 Hz, 1H), 3.36 (dd, J ) 9.5, 6.0 Hz, 1H), 2.56
(m, 5H), 2.03 (m, 1H), 1.83 (dddd, J ) 14.0, 14.0, 7.5, 7.5 Hz,
1H), 1.70 (dddd, J ) 14.5, 14.5, 8.0, 8.0 Hz, 1H), 1.43 (m, 2H),
1.09 (s, 9H), 0.95 (d, J ) 7.5 Hz, 3H), 0.16 (s, 9H); 13C NMR
(CDCl3, 125 MHz) δ 187.7, 159,1, 135.6, 133.2, 130.6, 129.9,
129.1, 127.8, 113.8, 92.0, 82.1, 72.7, 72.2, 71.6, 71.5, 68.0, 55.3,
45.3, 39.0, 32.0, 26.9, 25.5, 20.1, 19.3, 13.7, 0.4. Anal. Calcd
for C40H56O6Si2: C, 69.73; H, 8.19. Found: C, 69.97; H, 8.00.
Bis-Tr im eth ylsilyl Eth er 32. To a solution of 11a (460
mg, 669 µmol) in CH2Cl2 (15 mL) under Ar at 0 °C was added
triethylamine (470 µL, 3.35 mmol), followed by chlorotrimeth-
ylsilane (170 µL, 1.34 mmol), and 4-N,N-(dimethylamino)-
pyridine (8 mg, 67 µmol). After the mixture was stirred for 35
min, saturated aqueous NH4Cl (5 mL) was added, and the
mixture was diluted with ethyl acetate (20 mL). The organic
phase was separated and washed with H2O and saturated
aqueous NaCl (10 mL each) and then dried over NaSO4,
filtered, and concentrated. The residue was purified by silica
gel column chromatography (hexanes/ethyl acetate, 8:1, v/v)
to give 32 (495 mg, 651 µmol, 97%) as a clear, colorless oil: Rf
as a colorless oil: Rf 0.53 (hexanes/ethyl acetate, 4:1, v/v); [R]25
D
) +0.94 (c 2.4, CHCl3); IR (neat) 3289, 2964, 2853, 2121, 1616,
1588, 1518, 1463, 1249 cm-1 1H NMR (CDCl3, 300 MHz) δ
;
7.45 (d, J ) 8.3 Hz, 2H), 6.91 (d, J ) 8.3 Hz, 2H), 5.48, (s,
1H), 4.15-4.06 (m, 3H), 3.81 (s, 3H), 2.54 (ddd, J ) 16.8, 5.8,
2.8 Hz, 1H), 2.42 (ddd, J ) 16.8, 9.5, 2.8 Hz, 1H), 2.01 (t, J )
2.8 Hz, 1H), 1.88 (m, 1H), 1.23 (d, J ) 7.0 Hz, 3H); 13C NMR
(CDCl3, 75 MHz) 160.1, 131.1, 128.4, 127.5, 113.7, 101.8, 79.8,
73.6, 70.1, 55.3, 33.1, 22.6, 10.7; HRCIMS calcd for C15H18O3
[M + H]+ 247.1334, found 247.1338. Anisylidene 30 was
0.30 (hexanes/ethyl acetate, 8:1, v/v); [R]26 ) +0.5 (c 3.1,
D

Expedient Access to the Okadaic Acid Architecture
J . Org. Chem., Vol. 66, No. 3, 2001 935
CHCl3); IR (neat) 2950, 2850, 2210, 1660, 1600, 1500, 1415,
Hz), 1.00 (d, J ) 7.0 Hz); 13C NMR (CDCl3, 125 MHz) δ 159.1,
136.3, 130.8, 129.1, 124.5, 113.7, 94.8, 72.7, 72.0, 70.7, 68.4,
66.2, 55.3, 38.6, 35.0, 33.3, 26.3, 23.0, 18.6, 13.9; HRFABMS
calcd for C22H33O5 [M + H]+ 377.2328, found 377.2352.
Alcoh ols 39, 40a , a n d 40b. To a stirred rt solution of 37
(62 mg, 0.17 mmol) in CH2Cl2 (8 mL) were added crushed 4 Å
molecular sieves (60 mg) and tetrapropylammonium perruth-
enate (3.0 mg, 8.3 µmol), followed by 4-methylmorpholine
N-oxide (49 mg, 0.42 mmol). After 30 min, the reaction mixture
was concentrated under a stream of N2. Filtration through
silica gel (hexanes/ethyl acetate, 2:1, v/v) gave 38 (56 mg, 0.15
mmol, 90%) as a clear, colorless oil. This was used directly
without further purification: Rf 0.50 (hexanes/ethyl acetate,
2:1, v/v); 1H NMR (CDCl3, 500 MHz) δ 9.54 (s, 1H), 7.23 (d, J
) 9.0 Hz, 2H), 6.87 (d, J ) 8.5 Hz, 2H), 5.31 (s, 1H), 4.43 (d,
J ) 12.0 Hz, 1H), 4.39 (d, J ) 12.0 Hz, 1H), 4.16 (dd, J )
12.0, 2.5 Hz, 1H), 3.85 (m, 1H), 3.80 (s, 3H), 3.51 (m, 2H), 1.96-
1.65 (m, 6H), 1.74 (s, 3H), 1.55 (ddd, J ) 13.0, 13.0, 4.5 Hz,
1H), 1.33 (dddd, J ) 12.5, 12.5, 12.5, 4.0 Hz, 1H), 1.28 (t, J )
4.5 Hz, 1H), 1.01 (d, J ) 7.5 Hz, 3H); 13C NMR (CDCl3, 125
MHz) δ 202.3, 159.1, 137.0, 130.6, 129.1, 123.7, 113.7, 95.2,
75.1, 72.8, 71.7, 68.6, 55.3, 38.6, 34.8, 33.2, 25.2, 23.0, 18.3,
13.8.
1
1235, 1095, 1020 cm-1; H NMR (CDCl3, 500 MHz) δ 7.69 (d,
J ) 6.5 Hz, 4H), 7.41 (m, 6 H), 7.26 (d, J ) 8.5 Hz, 2H), 6.89
(d, J ) 8.5 Hz, 2H), 4.45 (d, J ) 11.5 Hz, 1H), 4.40 (d, J )
11.5 Hz, 1H), 3.90 (dd, J ) 11.5, 5.0 Hz, 1H), 3.812 (s, 3H),
3.70 (m, 1H), 3.58 (dd, J ) 5.5, 10.5 Hz, 1H), 3.47 (m, 2H),
3.36 (dd, J ) 9.0, 6.0 Hz, 1H), 2.56 (m, 4H), 2.02 (ddd, J )
12.0, 6.0, 6.0 Hz, 1H), 1.75 (m, 1H), 1.68 (m, 2H), 1.41 (m, 1H),
1.06 (s, 9H), 0.95 (d, J ) 6.5 Hz, 3H), 0.15 (s, 9H), 0.61 (s,
9H); 13C NMR (CDCl3, 125 MHz) δ 187.8, 159.1, 135.6, 133.6,
133.5, 130.6, 129.7, 129.1, 127.7, 113.8, 91.8, 82.1, 72.7, 72.2,
71.5, 67.9, 55.3, 45.6, 39.0, 33.4, 26.9, 25.5, 20.0, 19.2, 13.8,
0.4, 0.3. Anal. Calcd for C43H64O6Si3: C, 67.85; H, 8.47.
Found: C, 68.22; H, 8.30.
Sp ir ok eta l 36. To a -78 °C solution of CuI (860 mg, 4.51
mmol) in THF (15 mL) under Ar was added methyllithium
(5.0 mL of a 1.8 M solution in diethyl ether, 9.0 mmol). The
mixture was allowed to warm slowly to -40 °C until a clear
and colorless solution formed. The solution was cooled to -78
°C, and a solution of 32 (1.0 g, 1.3 mmol) in THF (30 mL) was
added via cannula. After 25 min, saturated aqueous NH4Cl (6
mL) was added, and the mixture was allowed to warm to rt.
The mixture was stirred until the aqueous phase became
bright blue. The mixture was extracted with ethyl acetate (2
× 30 mL), and the combined organic phases were washed with
H2O and saturated aqueous NaCl (20 mL each), dried over
Na2SO4, filtered, and concentrated. Silica gel column chroma-
tography (hexanes/ethyl acetate, 8:1, v/v) of the residue
provided a 1:1 mixture of E and Z isomers 34 (990 mg, 1.28
mmol, 99%) as a clear, colorless oil: Rf 0.28 and 0.30 (hexanes/
ethyl acetate, 8:1, v/v).
To a stirred -78 °C solution of diisopropylamine (310 µL,
2.21 mmol) in THF (8 mL) under Ar was added n-butyllithium
(0.85 mL of a 2.6M solution in hexanes, 2.21 mmol). After 30
min, a solution of cis-(S)-lactate pivalidene 34 (350 mg, 2.21
mmol) in THF (8 mL) was added via cannula. After 45 min, a
solution of 38 (80 mg, 0.22 mmol) in THF (8 mL) was added
via cannula. The resulting solution was allowed to stir for 20
min before saturated aqueous NH4Cl was added. The mixture
was allowed to warm to rt and diluted with ethyl acetate (30
mL), washed with H2O and saturated aqueous NaCl (10 mL
each), and dried over Na2SO4. The solution was filtered,
concentrated, and purified by silica gel column chromatogra-
phy (hexanes/ethyl acetate, 3:1, v/v) to give a mixture of 39,
40a , and 40b (114 mg, 0.216 mmol, 100%). Further silica gel
chromatography (hexanes/ethyl acetate, 10:1 to 3:1, v/v) al-
lowed for separation of the three products: Alcohol 39: Rf 0.10
(hexanes/ethyl acetate, 4:1, v/v); IR (neat) 3478, 2962, 2935,
1795, 1613, 1514, 1247, 1089, 975 cm-1; 1H NMR (CDCl3, 500
MHz) δ 7.27 (d, J ) 8.5 Hz, 2H), 6.87 (d, J ) 9.0 Hz, 2H), 5.32
(s, 1H), 5.15 (s, 1H), 4.46 (s, 2H), 4.00 (m, 1H), 3.78 (m, 2H),
3.78 (s, 3H), 3.71 (ddd, J ) 11.0, 7.5, 3.5 Hz, 1H), 3.23 (t, J )
9.0 Hz, 1H), 2.61 (d, J ) 4.0 Hz, 1H), 2.01-1.20 (m, 7H), 1.70
(s, 3H), 1.44 (s, 3H), 0.99 (s, 9H); 13C NMR (CDCl3, 125 MHz)
δ 174.3, 159.0, 135.8, 131.0, 129.2, 124.4, 113.7, 107.4, 95.1,
81.4, 76.5, 72.7, 72.5, 70.0, 69.1, 55.3, 38.6, 35.1, 34.3, 33.0,
25.8, 23.7, 22.9, 18.4, 15.9, 13.8; HRFABMS calcd for C30H45O8
[M + H]+ 533.3114, found 533.3113. Alcohol 40a : Rf 0.15
(hexanes/ethyl acetate, 4:1, v/v); IR (neat) 3483, 2936, 1794,
To a solution of (E,Z)-34 (670 mg, 863 µmol) in benzene (25
mL) was added TsOH‚H2O (16 mg, 86 µmol). After the solution
was stirred for 2.5 h at rt, saturated aqueous NaHCO3 (5 mL)
was added, and the mixture was diluted with ethyl acetate
(15 mL). The organic phase was washed with H2O and
saturated aqueous NaCl (15 mL each), dried over Na2SO4,
filtered, and concentrated. Silica gel chromatography (hexanes/
ethyl acetate, 8:1, v/v) provided 36 (400 mg, 653 µmol, 76%)
as a clear, colorless oil: Rf 0.30 (hexanes/ethyl acetate, 8:1,
v/v); [R]24D ) -39.0 (c 2.8, CHCl3); IR (neat) 2930, 2850, 1615,
1508, 1455, 1422, 1240, 1110, 990, 815, 695 cm-1 1H NMR
;
(CDCl3, 500 MHz) δ 7.70 (ddd, J ) 5.5, 4.0, 1.5 Hz, 4H), 7.38
(m, 6H), 7.28 (d, J ) 8.5 Hz, 2H), 6.87 (d, J ) 8.5 Hz, 2H),
5.34 (s, 1H), 4.50 (d, J ) 11.0 Hz, 1H), 4.45 (d, J ) 11.0 Hz,
1H), 3.89 (m, 1H), 3.80 (s, 3H), 3.79 (m, 2H), 3.71 (dd, J )
10.5, 5.5 Hz, 1H), 3.52 (dd, J ) 10.0, 7.0 Hz, 1H), 3.37 (t, J )
9.0 Hz, 1H), 1.98-1.77 (m, 5H), 1.73 (s, 3H), 1.65 (m, 2H), 1.50
(ddd, J ) 14.0, 14.0, 4.5 Hz, 1H), 1.20 (dddd, J ) 11.5, 11.5,
11.5, 3.5 Hz, 1H), 1.07 (s, 9H), 1.02 (d, J ) 6.5 Hz, 3H); 13C
NMR (CDCl3, 125 MHz) 159.0, 135.9, 135.7, 133.9, 130.9,
129.5, 129.2, 127.6, 124.8, 113.7, 94.6, 72.7, 72.3, 70.8, 68.7,
67.8, 55.3, 38.7, 35.2, 33.4, 27.8, 26.9, 23.0, 19.3, 18.7, 14.0;
HRFABMS calcd for C38H51O5Si [M + H]+ 615.3506, found
615.3557. Anal. Calcd for C38H50O5Si: C, 74.46; H, 7.43.
Found: C, 74.63; H, 7.55.
1
1612, 1513, 1248 cm-1; H NMR (CDCl3, 500 MHz) δ 7.25 (d,
J ) 9.0 Hz, 2H), 6.88 (d, J ) 8.5 Hz, 2H), 5.39 (s, 1H), 5.30 (s,
1H), 4.45 (s, 2H), 3.98 (ddd, J ) 11.5, 3.0, 3.0 Hz, 1H), 3.89 (t,
J ) 3.5 Hz, 1H), 3.81 (s, 3H), 3.75 (dd, J ) 9.5, 5.0 Hz, 1H),
3.67 (ddd, J ) 10.5, 7.0, 3.0 Hz, 1H), 2.68 (t, J ) 8.0 Hz, 1H),
2.35 (d, J ) 3.5 Hz, 1H), 1.98-1.40 (m, 9H), 1.72 (s, 3H), 1.32
(s, 3H), 1.00 (d, 7.0 Hz, 3H), 0.94 (s, 9H); 13C NMR (CDCl3,
125 MHz) δ 175.4, 159.1, 136.3, 130.7, 129.1, 129.0, 124.2,
113.8, 110.5, 95.4, 81.4, 72.7, 72.2, 69.8, 69.2, 55.3, 38.5, 34.9,
34.5, 33.1, 23.9, 23.3, 22.9, 20.3, 18.2, 14.0; HRFABMS calcd
for C30H45O8 [M + H]+ 533.3114, found 533.3138. Alcohol
40b: Rf 0.20 (hexanes/ethyl acetate, 4:1, v/v); IR (neat) 3542,
2943, 1790, 1613, 1514, 1247 cm-1; 1H NMR (CDCl3, 500 MHz)
δ 7.29 (d, J ) 8.0 Hz, 2H), 6.87 (d, J ) 9.0 Hz, 2H), 5.43 (s,
1H), 5.29 (s, 1H), 4.50 (d, J ) 11.0 Hz, 1H), 4.44 (d, J ) 11.0
Hz, 1H), 3.90 (ddd, J ) 11.0, 3.0, 3.0 Hz), 3.82 (m, 1H), 3.81
(s, 3H), 3.69 (ddd, J ) 11.0, 7.5, 3.5 Hz, 1H), 3.51 (dd, J ) 6.5,
3.5 Hz, 1H), 3.33 (t, J ) 9.0 Hz, 1H), 2.90 (d, J ) 8.5 Hz, 1H),
1.96-1.42 (m, 9H), 1.71 (s, 3H), 1.49 (s, 3H), 1.02 (d, J ) 7.0
Hz, 3H), 0.91 (s, 9H); 13C NMR (CDCl3, 125 MHz) δ 173.8,
159.0, 136.0, 131.0, 129.4, 123.9, 113.6, 109.3, 95.1, 80.9, 76.9,
72.6, 72.4, 69.5, 68.6, 55.3, 38.6, 35.0, 34.5, 33.0, 27.5, 23.3,
22.8, 22.0, 18.0, 13.9; HRFABMS calcd for C30H45O8 [M + H]+
533.3114, found 533.3107.
Alcoh ol 37. To a stirred 0 °C solution of 36 (160 mg, 261
µmol) in THF (6 mL) was added TBAF (365 µL of a 1.0 M
solution in THF, 365 µmol). The solution was allowed to warm
to rt, and after 15 h, saturated aqueous NH4Cl (1 mL) was
added. The mixture was diluted with ethyl acetate (10 mL),
and the aqueous phase was extracted with ethyl acetate (2 ×
5 mL). The combined organic extracts were washed with H2O
and saturated aqueous NaCl, dried over Na2SO4, filtered, and
concentrated. Silica gel chromatography (hexanes/ethyl ac-
etate, 8:1 to 2:1, v/v) yielded 37 (82 mg, 220 µmol, 84%) as a
clear, colorless oil: Rf 0.30 (hexanes/ethyl acetate, 2:1, v/v);
[R]26D ) -18.6 (c 3.4, CHCl3); IR (neat) 3461, 2941, 2865, 1675,
1614, 1516, 1614, 1516, 1455, 1375, 1246, 1094, 1037, 978
1
cm-1; H NMR (CDCl3, 500 MHz) δ 7.26 (d, J ) 9.0 Hz, 2H),
6.87 (d, J ) 9.0 Hz, 2H), 5.34 (s, 1H), 4.47 (d, J ) 12.0 Hz,
1H), 4.41 (d, J ) 12.0 Hz, 1H), 3.80 (s, 3H), 3.78 (m, 2H), 3.63
(dd, J ) 9.0, 4.0 Hz, 1H), 3.51 (m, 1H), 3.48 (dd J ) 9.0, 6.5
Hz, 1H), 3.44 (m, 1H), 1.95-1.82 (m, 4H), 1.72 (s, 3H), 1.63
(m, 2H), 1.48 (m, 1H), 1.31 (dddd, J ) 13.5, 13.5, 13.5, 4.0

936 J . Org. Chem., Vol. 66, No. 3, 2001
Dounay et al.
p-Meth oxyben zyl Eth er 42. To a stirred 0 °C solution of
40 (10 mg, 19 µmol) in THF (2 mL) under Ar was added NaH
(23 mg of 60% NaH in mineral oil, 0.57 mmol). The mixture
was allowed to warm to rt over 40 min before freshly distilled
CS2 (53 µL, 0.91 mmol) was added. After 30 min, methyl iodide
(35 µL, 0.57 mmol) was added. After 20 min, the solution was
cooled to 0 °C, and saturated aqueous NH4Cl (1 mL) was
added. The mixture was warmed to rt, and ethyl acetate (4
mL) was added. The separated organic phase was washed with
H2O and saturated aqueous NaCl (2 mL each), dried over Na2-
SO4, filtered, and concentrated. The residue was azeotropically
dried from benzene (2 × 3 mL) and then dissolved in toluene
(2 mL). To the solution were added 2,2′-azobisisobutyronitrile
(3 mg, 19 µmol) and tri-n-butyltin hydride (20 µL, 76 µmol),
and Ar was bubbled through the resultant solution for 15 min
to remove oxygen. The mixture was then heated to 80 °C under
Ar for 1.5 h. After the solution was cooled to rt, it was diluted
with ethyl acetate (2 mL), washed with H2O and saturated
aqueous NaCl (2 mL each), dried over Na2SO4, filtered, and
concentrated. Silica gel column chromatography (hexanes/ethyl
acetate, 1:0 to 8:1, v/v) yielded 42 (6.8 mg, 13 µmol, 70%) as a
clear, colorless oil: Rf 0.35 (hexanes/ethyl acetate, 4:1, v/v);
the mixture was warmed to rt. The THF was removed by
rotary evaporation and the aqueous phase was extracted with
ethyl acetate. The organic phase was washed successively with
saturated aqueous NH4Cl, H2O, and saturated aqueous NaCl
(50 mL each). The organic phase was dried over Na2SO4,
filtered, and concentrated by rotary evaporation to give the
crude product 48a (3.14 g, 5.25 mmol, 93%) as a diastereomeric
mixture of alcohols. This material was taken to the next step
without further purification.
To a -78 °C solution of oxalyl chloride (687 mL, 7.88 mmol)
in CH2Cl2 (18 mL) under Ar was added a solution of DMSO
(1.12 mL, 15.8 mmol) in CH2Cl2 (3.6 mL) via cannula. The
resultant mixture was stirred for 25 min before a solution of
crude 48a (3.14 g, 5.25 mmol) in CH2Cl2 (6 mL) was added
via cannula. After the mixture was stirred for an additional
1.5 h at -78 °C, triethylamine (4.79 mL, 34.1 mmol) was
added, and the resulting mixture was allowed to warm to 0
°C over 30 min. Saturated aqueous NH4Cl (50 mL) and ethyl
acetate (150 mL) were added. The mixture was warmed to rt,
and the separated organic phase was washed with H2O and
saturated aqueous NaCl (100 mL each). The combined aqueous
phases were extracted with ethyl acetate, and the combined
organic phases were dried over Na2SO4, filtered, and concen-
trated by rotary evaporation. Silica gel chromatography (hex-
anes/ethyl acetate, 5:1 to 2:1, v/v) of the residue gave recovered
aldehyde 48 (871 mg, 1.61 mmol) and 49 (1.91 g, 3.20 mmol,
79% for 2 steps based on recovered starting material) as a pale
[R]26 ) +1.8 (c 1.6, CHCl3); IR (neat) 2960, 2937, 2869, 1793,
D
1611, 1516, 1455, 1375, 1365, 1249, 1173, 980 cm-1; 1H NMR
(CDCl3, 500 MHz) δ 7.28 (d, J ) 8.5 Hz, 2H), 6.87 (d, J ) 8.5
Hz, 2H), 5.33 (s, 1H), 5.31 (s, 1H), 4.49 (d, J ) 11.0 Hz, 1H),
4.44 (d, J ) 11.0 Hz, 1H), 3.92 (m, 1H), 3.82 (dd, J ) 9.0, 4.5
Hz, 1H), 3.80 (s, 3H), 3.69 (ddd, J ) 11.5, 8.0, 3.5 Hz, 1H),
3.32 (t, J ) 8.5 Hz, 1H), 1.99-1.45 (m, 10H), 1.71 (s, 3H), 1.46
oil: Rf 0.38 (hexanes/ethyl acetate, 5:1, v/v); [R]26 ) -6.1 (c
D
1.10, CHCl3); IR (neat) 2920, 1720, 1620, 1520, 1470, 1350,
(s, 3H), 1.24 (m, 1H), 1.03 (d, J ) 6.5 Hz, 3H), 0.92 (s, 9H); 13
C
1
1100 cm-1; H NMR (500 MHz, CDCl3) δ 7.44 (d, J ) 9.0 Hz,
NMR (CDCl3, 125 MHz) δ 175.4, 159.0, 135.6, 131.0, 129.3,
124.5, 113.7, 108.2, 94.8, 78.8, 72.7, 72.4, 69.3, 66.2, 55.4, 42.8,
38.6, 34.9, 34.3, 33.1, 31.5, 24.6, 23.4, 22.9, 18.6, 14.0; HR-
FABMS calcd for C30H45O7 [M + H]+ 517.3165, found 517.3182.
Alcoh ol 43. To a mixture of 42 (19 mg, 37 µmol), CH2Cl2 (5
mL), an aqueous phosphate buffer (pH ) 7, 1.0 mL), and tert-
butyl alcohol (280 µL) was added DDQ (42 mg, 0.185 mmol).
The reaction flask was placed in an aqueous bath, sonicated
for 1 min, and then assayed by TLC. This process was repeated
for a total of 4.5 min of sonication, at which point no starting
material remained. (Note: After cleavage of the p-methoxy-
benzyl ether, care must be taken to prevent acid-catalyzed
conversion of 43 to an undesired tricyclic product.)3c Saturated
aqueous NaHCO3 (1 mL) was added, and the mixture was
diluted with ethyl acetate (5 mL). The organic phase was
washed with saturated aqueous NaHCO3 (3 × 1 mL), H2O,
and saturated aqueous NaCl (2 mL each), dried over Na2SO4,
filtered, and concentrated. The resulting residue was purified
by silica gel column chromatography (hexanes/ethyl acetate/
triethylamine, 4:1:0.004, v/v/v) to give 43 (12 mg, 29 µmol, 79%)
as a clear, colorless oil: Rf 0.05 (hexanes/ethyl acetate, 4:1,
2H), 7.36-7.28 (m, 5H), 6.91 (d, J ) 9.0 Hz, 2H), 5.76-5.84
(m, 1H), 5.54 (s, 1H), 5.03 (ddd, J ) 17.0, 2.5, 1.5 Hz, 1H),
4.98 (ddd, J ) 10.0, 2.8, 1.5 Hz, 1H), 4.90 (d, J ) 12.0 Hz,
1H), 4.62 (d, J ) 12.0 Hz, 1H), 4.21 (dd, J ) 10.0, 5.0 Hz, 1H),
4.06-4.10 (m, 1H), 4.01 (dd, J ) 9.5, 2.5 Hz, 1H), 3.82 (s, 3H),
3.79 (d, J ) 3.5 Hz, 1H), 3.75 (m, 1H), 3.72 (dd, J ) 10.0, 10.0
Hz, 1H), 3.64 (dd, J ) 12.0, 4.0 Hz, 1H), 2.57 (m, 1H), 2.51
(m, 5H), 2.31 (m, 1H), 1.76 (m, 1H), 0.87 (s, 9H), 0.001 (s, 3H),
-0.03 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 209.5, 160.0,
138.7, 137.1, 130.4, 128.3, 127.6, 127.5, 115.2, 113.6, 102.2,
79.3, 77.8, 76.5, 73.5, 72.4, 69.8, 59.7, 55.3, 42.0, 39.3, 27.8,
25.8, 23.2, 18.0, -5.1 (2C). Anal. Calcd for C34H48O7Si: C,
68.42; H, 8.11. Found: C, 68.64; H, 7.98.
P r im a r y TBS Bisp yr a n 50. A solution of 49 (1.05 g, 1.76
mmol) and camphorsulfonic acid (82 mg, 0.35 mmol) in
benzene (20 mL) and methanol (10 mL) was heated at reflux
under N2 for 7 h under a Dean-Stark trap. The solution was
cooled to rt and diluted with methanol (50 mL), and triethyl-
amine was added until the solution was neutral or slightly
basic to pH paper. The solvents were removed under reduced
pressure to yield an orange oil that was used without further
purification. To this crude material in CH2Cl2 (17 mL) under
Ar at rt were added tert-butyldimethylsilyl chloride (796 mg,
5.28 mmol), triethylamine (1.47 mL, 10.6 mmol), and 4-N,N-
(dimethylamino)pyridine (cat.). This mixture was stirred for
5 h and then diluted with ethyl acetate (75 mL). The separated
organic phase was washed with saturated aqueous NH4Cl (2
× 25 mL), H2O (25 mL), and saturated aqueous NaCl (25 mL).
The aqueous phases were combined and extracted with ethyl
acetate (2 × 25 mL). The combined organic phases were dried
(Na2SO4), filtered, and concentrated. Silica gel column chro-
matography (hexanes/ethyl acetate, 5:1, v/v) of the residue
gave silyl ether 50 (573 mg, 1.16 mmol, 66% from ketone 49)
as an off-white solid: mp 66-68 °C; Rf 0.47 (hexanes/ethyl
acetate, 2:1, v/v); [R]25D ) -20.8 (c 1.14, CHCl3); IR (neat) 3460,
v/v); [R]26 ) +4.9 (c 1.5, CHCl3); IR (neat) 3469, 2960, 2930,
D
2873, 1793, 1000 cm-1; H NMR (C6D6, 500 MHz) δ 5.31 (s,
1
1H), 5.28 (br. s, 1H), 4.08 (dddd, J ) 12.0, 9.5, 3.0, 3.0 Hz,
1H), 4.03 (ddd, J ) 11.5, 8.5, 3.5 Hz, 1H), 3.91 (m, 2H), 2.98
(t, J ) 6.0 Hz, 1H), 1.87 (dd, J ) 15.0, 9.5 Hz, 1H), 1.81 (m,
2H), 1.70, (m, 1H), 1.60 (m, 3H), 1.44 (s, 3H), 1.41 (s, 3H), 1.32
(m, 2H), 1.22 (m, 1H), 0.95 (m, 1H), 0.90 (d, J ) 6.5, 3H), 0.83
(s, 9H); 13C NMR (C6D6, 125 MHz) 174.8, 135.0, 124.6, 107.8,
94.8, 78.3, 71.5, 66.0, 65.8, 43.7, 40.1, 34.8, 33.9, 33.6, 31.2,
25.1, 23.1, 22.4, 18.7, 13.1; HRFABMS calcd for C22H37O6 [M
+ H]+ 397.2590, found 397.2559.
C15-C27 Ketop h osp h on a te. Keton e 49. To a three-
necked round-bottom flask containing dry-stirred magnesium
(688 mg, 28.3 mmol) under N2 were added 10 mL of a solution
of 4-bromo-1-butene (2.30 mL, 23.0 mmol) and 1,2-dibromo-
ethane (15 µL) in THF (34 mL). This mixture was heated to
reflux for 5 min, and then the external heating was removed.
The remainder of the bromide solution was added dropwise
over 30 min to maintain reflux. The mixture was then
externally heated at reflux for an additional 30 min. The
Grignard mixture was cooled to rt and added to a solution of
aldehyde 483 (3.07 g, 5.66 mmol) in THF (50 mL) at -78 °C
dropwise via cannula. After the resulting mixture was stirred
for 30 min, saturated aqueous NH4Cl (6 mL) was added and
3030, 2940, 1630, 1455, 1355, 1250, 1100 cm-1 1H NMR
;
(CDCl3, 300 MHz) δ 7.40-7.26 (m, 5H), 5.92-5.79 (m, 1H),
5.05 (ddd, J ) 17.0, 1.5, 1.5 Hz, 1H), 4.98 (m, 1H), 4.85 (d, J
) 12.0 Hz, 1H), 4.75 (d, J ) 12.0 Hz, 1H), 4.16 (dd, J ) 1.0,
1.0 Hz, 1H), 3.98 (dd, J ) 5.0, 5.0 Hz, 1H), 3.88-3.74 (m, 4H),
3.56-3.48 (m, 1H), 3.22 (s, 3H), 2.84 (s, 1H), 2.09-2.02 (m,
2H), 1.92-1.76 (m, 4H), 1.62-1.51 (m, 2H), 0.86 (s, 9H), 0.03
(s, 3H), 0.01 (s, 3H); 13C NMR (CDCl3, 75 MHz) δ 138.4, 138.2,
128.3, 127.6, 127.4, 114.4, 99.1, 78.2, 76.6, 72.4, 71.5, 71.3, 68.8,
63.8, 47.3, 34.8, 32.3, 27.9, 25.8, 25.3, 18.0, -5.6, -5.7. Anal.

Expedient Access to the Okadaic Acid Architecture
J . Org. Chem., Vol. 66, No. 3, 2001 937
Calcd for C27H44O6Si: C, 65.82; H, 9.00. Found: C, 66.02; H,
8.84.
68%) as a white solid: mp 88-90 °C; Rf 0.19 (hexanes/ethyl
acetate, 5:1, v/v); [R]27 ) -17 (c 1.0, CHCl3); IR (neat) 3460,
D
Keton e 50a . To a stirred -78 °C solution of DMSO (255
µL, 3.60 mmol) in CH2Cl2 (10 mL) under Ar was added
trifluoroacetic anhydride (381 µL, 2.70 mmol) dropwise. The
resultant mixture was stirred for 15 min before a solution of
alcohol 50 (887 mg, 1.80 mmol) in CH2Cl2 (4.5 mL) was added
via cannula. After the mixture was stirred for an additional
1.5 h at -78 °C, triethylamine (700 µL, 5.04 mmol) was added,
and the resulting mixture was stirred at 0 °C for 30 min.
Saturated aqueous NH4Cl (25 mL) and ethyl acetate (100 mL)
were added. The separated organic phase was washed with
H2O and saturated aqueous NaCl (25 mL each). The combined
aqueous phases were extracted with ethyl acetate, and the
combined organic phases were dried over Na2SO4, filtered, and
concentrated. Silica gel column chromatography (hexanes/ethyl
acetate, 5:1, v/v) of the residue gave ketone 50a (784 mg, 1.60
mmol, 89%) as a pale oil: Rf 0.39 (hexanes/ethyl acetate, 5:1,
v/v); [R]26D ) -21.3 (c 1.15, CHCl3); IR (neat) 2920, 1725, 1450,
1250, 1180 cm-1; 1H NMR (CDCl3, 300 MHz) δ 7.45-7.43 (m,
2H), 7.35-7.26 (m, 3H), 5.93-5.80 (m, 1H), 5.09-4.98 (m, 2H),
5.02 (d, J ) 12.3 Hz, 1H), 4.81 (d, J ) 12.3 Hz, 1H), 4.22-
4.16 (m, 1H), 4.12 (dd, J ) 2.7, 2.7 Hz, 1H), 4.10 (d, J ) 10.5
Hz, 1H), 3.96 (m, 2H), 3.74 (dd, J ) 10.0, 10.0 Hz, 1H), 3.23
(s, 3H), 2.10-2.02 (m, 2H), 1.94-1.81 (m, 4H), 1.67-1.53 (m,
2H), 0.81 (s, 9H), 0.03 (s, 3H), -0.04 (s, 3H); 13C NMR (CDCl3,
125 MHz) δ 206.7, 138.1, 138.0, 128.1, 127.6, 127.5, 114.4, 98.7,
83.4, 83.2, 74.3, 73.9, 71.9, 66.5, 47.4, 34.4, 31.8, 27.8, 25.6,
25.3, 17.9, -5.9 (2C). Anal. Calcd for C27H42O6Si: C, 66.09; H,
8.63. Found: C, 65.94; H, 8.77.
2930, 1635, 1250, 1090, 830 cm-1; 1H NMR (CDCl3, 500 MHz)
δ 5.88-5.80 (m, 1H), 5.36 (m, 1H), 5.07 (m, 1H), 5.04 (m, 1H),
4.98 (dd, J ) 10.0, 1.5 Hz, 1H), 4.39 (m, 1H), 4.32 (dd, J )
5.0, 5.0 Hz, 1H), 3.88 (dd, J ) 10.5, 6.0 Hz, 1H), 3.81 (dd, J )
10.5, 5.0 Hz, 1H), 3.65 (m, 1H), 3.21 (dd, J ) 9.5, 9.5 Hz, 1H),
3.19 (s, 3H), 2.45 (d, J ) 3.0 Hz, 1H), 2.08-2.03 (m, 2H), 1.94-
1.87 (m, 2H), 1.82-1.79 (m, 2H), 1.60-1.51 (m, 2H), 0.90 (s,
9H), 0.06 (s, 6H); 13C NMR (CDCl3, 125 MHz) δ 143.8, 138.0,
114.5, 110.6, 99.2, 80.6, 76.7, 71.0, 70.3, 65.2, 47.4, 34.5, 32.2,
27.8, 25.9, 25.2, 18.3, -5.4, -5.4; HRFABMS calcd for C21H39O5-
Si [M + H]+ 399.2567, found 399.2555.
Bis-TBS Eth er 52. To a 0 °C solution of alcohol 51a (150
mg, 377 µmol) in DMF (4 mL) under Ar were added triethyl-
amine (1.05 mL, 7.54 mmol), 4-N,N-(dimethylamino)pyridine
(46 mg, 377 µmol) and tert-butyldimethylsilyl chloride (568 mg,
3.77 mmol). This solution was allowed to warm to rt and
stirred for 22 h. CH2Cl2 (25 mL) was then added, followed by
saturated aqueous NH4Cl (10 mL). The phases were separated,
and the organic phase was washed successively with saturated
aqueous NH4Cl, H2O, and saturated aqueous NaCl (10 mL
each). The combined aqueous washes were extracted with CH2-
Cl2, and the combined organic phases were dried over Na2-
SO4, filtered and concentrated. The residue was purified by
silica gel column chromatography (hexanes/ethyl acetate, 8:1
to 5:1, v/v) to yield silyl ether 52 (181 mg, 354 µmol, 94%) as
a pale oil: Rf 0.50 (hexanes/ethyl acetate, 5:1, v/v); [R]26
)
D
-18.4 (c 1.18, CHCl3); IR (neat) 2960, 1635, 1460, 1360, 1250,
1
1090 cm-1; H NMR (CDCl3, 300 MHz) δ 5.93-5.79 (m, 1H),
Olefin 51. To a stirred rt mixture of methyltriphenylphos-
phonium bromide (1.41 g, 3.96 mmol) in toluene (35 mL) under
N2 was added potassium bis(trimethylsilyl)amide (7.2 mL of
a 0.50 M solution in toluene, ∼3.6 mmol). The deep yellow
mixture was heated to 80-90 °C for 30 min, and then the
resultant deep orange solution was cooled to rt before a
solution of ketone 50a (784 mg, 1.60 mmol) in toluene (9 mL)
was added via cannula. The resultant solution was heated to
80-90 °C for 30 min, then cooled to rt before saturated NH4-
Cl (25 mL) was added. The toluene was removed by rotary
evaporation, and the aqueous phase was extracted with ethyl
acetate (2 × 50 mL). The organic phase was washed with H2O
and saturated aqueous NaCl (2 × 25 mL each). The combined
aqueous phases were extracted with ethyl acetate and the
combined organic extracts were dried over Na2SO4, filtered,
and concentrated. Silica gel column chromatography (hexanes/
ethyl acetate, 15:1, v/v) of the residue gave olefin 51 (656 mg,
1.34 mmol, 84%) as a colorless oil: Rf 0.48 (hexanes/ethyl
acetate, 5:1, v/v); [R]27D ) -10.2 (c 1.66, CHCl3); IR (neat) 2960,
1635, 1455, 1350, 1250, 1085 cm-1; 1H NMR (CDCl3, 500 MHz)
δ 7.43-7.41 (m, 2H), 7.36-7.33 (m, 2H), 7.29-7.26 (m, 1H),
5.91-5.83 (m, 1H), 5.44 (dd, J ) 2.0, 2.0 Hz, 1H), 5.07 (m,
1H), 5.07 (dd, J ) 2.0, 2.0 Hz, 1H), 4.99 (m, 1H), 4.92 (d, J )
12 Hz, 1H), 4.82 (d, J ) 12.0 Hz, 1H), 4.32 (dd, J ) 5.0, 5.0
Hz, 1H), 4.21 (m, 1H), 3.88-3.80 (m, 2H), 3.68 (m, 1H), 3.42
(dd, J ) 9.5, 9.5 Hz, 1H), 3.23 (s, 3H), 2.10-2.06 (m, 2H), 1.93-
1.85 (m, 2H), 1.83-1.78 (m, 2H), 1.63-1.54 (m, 2H), 0.89 (s,
9H), 0.04 (s, 3H), 0.03 (s, 3H); 13C NMR (CDCl3, 125 MHz) δ
143.2, 138.9, 138.2, 128.1, 127.4, 127.3, 114.4, 111.6, 98.9, 80.6,
78.0, 76.9, 73.7, 70.9, 65.2, 47.3, 34.7, 32.2, 27.8, 25.8, 25.6,
18.1, -5.53, -5.57. Anal. Calcd for C28H44O5Si: C, 68.81; H,
9.07. Found: C, 69.00; H, 8.83.
Alcoh ol 51a . To a -60 °C solution of benzyl ether 51 (135
mg, 276 µmol) in THF (3 mL) under Ar was added a solution
of lithium di-tert-butylbiphenylide38 (16.2 mL of a 0.17 M
solution in THF, ∼2.8 mmol) dropwise. After the mixture was
stirred at this temperature for 10 min, saturated aqueous NH4-
Cl (10 mL) was added, and the mixture was warmed to rt and
diluted with diethyl ether (50 mL). The phases were separated,
and the organic phase was washed successively with H2O and
saturated aqueous NaCl (25 mL each). The aqueous washes
were extracted with diethyl ether, and the combined organic
phases were dried over Na2SO4, filtered, and concentrated.
Silica gel column chromatography (hexanes/ethyl acetate, 1:0
to 5:1, v/v) of the residue gave alcohol 51a (75 mg, 0.19 mmol,
5.35 (dd, J ) 2.0, 2.0 Hz, 1H), 5.06 (m, 1H), 5.04 (m, 1H), 4.99
(m, 1H), 4.40 (m, 1H), 4.33 (dd, J ) 5.1, 5.1 Hz, 1H), 3.87 (d,
J ) 5.1 Hz, 2H), 3.71 (m, 1H), 3.20 (dd, J ) 9.5, 9.5 Hz, 1H),
3.21 (s, 3H), 2.12-2.03 (m, 2H), 1.92-1.77 (m, 4H), 1.62-1.51
(m, 2H), 0.97 (s, 9H), 0.93 (s, 9H), 0.15 (s, 3H), 0.11 (s, 3H),
0.094 (s, 3H), 0.087 (s, 3H); 13C NMR (CDCl3, 75 MHz) δ 145.8,
138.3, 114.4, 111.3, 99.0, 80.7, 76.5, 72.0, 71.3, 65.7, 47.4, 34.6,
32.3, 28.0, 25.9 (2C), 25.6, 18.4, 18.2, -4.4, -5.0, -5.4, -5.5.
Anal. Calcd for C27H52O5Si2: C, 63.23; H, 10.22. Found: C,
63.37; H, 10.03.
â-Ketop h osp h on a te 15. To a solution of olefin 52 (74 mg,
0.15 mmol) in THF (1 mL) and H2O (0.5 mL) was added
pyridine (5.9 µL, 72 µmol), followed by sodium periodate (94
mg, 0.44 mmol), and osmium tetraoxide (120 µL of a 76 mM
solution in tert-butyl alcohol, 8.9 µmol). This mixture was
stirred vigorously for 2 h. The reaction was diluted with diethyl
ether (10 mL) and washed successively with saturated aqueous
NaHCO3, H2O, and saturated aqueous NaCl (3 mL each). The
combined aqueous phases were extracted with diethyl ether,
and the combined organic extracts were dried over Na2SO4,
filtered, and concentrated to give a crude oil. Silica gel column
chromatography (hexanes/ethyl acetate, 1:0 to 5:1, v/v) of the
residue afforded recovered olefin 52 (8 mg, 0.02 mmol) and
aldehyde 52a (41 mg, 80 µmol, 55%, 61% based on recovered
52).
To a stirred -78 °C solution of dimethyl methylphosphonate
(120 µL, 1.11 mmol) in THF (2 mL) under Ar was added
n-butyllithium (400 µL of a 2.4 M solution in hexanes, ∼961
µmol) dropwise. The resultant mixture was stirred for 1 h
before a solution of 52a (38 mg, 74 µmol) in THF (0.5 mL) was
added via cannula. The resultant pale yellow solution was
stirred for an additional 50 min, at which time saturated
aqueous NH4Cl (1 mL) was added and the mixture was allowed
to warm to rt. Diethyl ether (10 mL) was added, and the phases
were separated. The organic phase was washed with H2O and
saturated aqueous NaHCO3 (3 mL each). The aqueous phases
were extracted with diethyl ether and the combined organic
phases were dried over Na2SO4, filtered, and concentrated. The
residue was filtered through silica gel (hexanes/ethyl acetate,
2:1, v/v) to yield the crude â-hydroxy phosphonate as an oil.
This material was used without further purification.
To a stirred rt solution of the above alcohols (74 µmol
theoretical) in CH2Cl2 (1.5 mL) were added NaHCO3 (250 mg,
2.96 mmol) and the Dess-Martin periodinane reagent (250
mg, 591 µmol). The resultant mixture was stirred for 1.5 h

938 J . Org. Chem., Vol. 66, No. 3, 2001
Dounay et al.
before diethyl ether (20 mL), saturated aqueous NaHCO3 (4
mL), and 10% aqueous Na2S2O3 (4 mL) were added. This
mixture was stirred vigorously until the organic layer became
clear (∼20 min). The separated organic phase was washed with
H2O and saturated aqueous NaCl (2 × 5 mL each). The
aqueous phases were extracted with diethyl ether, and the
combined organic phases were dried over Na2SO4, filtered, and
concentrated. Silica gel column chromatography (hexanes/ethyl
acetate, 1:1 to 1:5, v/v) gave â-ketophosphonate 15 (33 mg, 52
µmol, 70% from 52a ) as a pale oil: Rf 0.29 (hexanes/ethyl
v/v) provided 53a (2.9 mg, 2.9 µmol, 95%) as a clear, colorless
oil: Rf 0.05 (hexanes/ethyl acetate, 4:1, v/v); [R]26 ) -12.2 (c
D
0.77, CHCl3); IR (neat) 3465, 2952, 2933, 2857, 3465, 1789,
1458, 1367, 1253, 831, 774 cm-1; 1H NMR (C6H6, 500 MHz) δ
6.03 (dd, J ) 15.0, 8.5 Hz, 1H), 5.71 (dd, J ) 15.0, 6.0 Hz,
1H), 5.53 (t, J ) 1.5 Hz, 1H), 5.50 (s, 1H), 5.34 (s, 1H), 4.95 (s,
1H), 4.59 (d, J ) 9.5 Hz, 1H), 4.39 (t, J ) 4.5 Hz, 1H), 4.13
(m, 2H), 3.83 (m, 3H), 3.77 (dd, J ) 10.5, 5.0 Hz, 1H), 3.55 (t,
J ) 9.5 Hz, 1H), 3.22 (s, 3H), 2.34 (dddd, J ) 14.0, 7.0, 7.0,
7.0 Hz, 1H), 2.24 (m, 2H), 1.97-1.58 (m, 10H), 1.61 (s, 3H),
1.13 (d, J ) 7.0 Hz, 3H), 1.05 (s, 9H), 0.96 (s, 9H), 0.85 (s,
9H), 0.36 (s, 6H), 0.29 (s, 3H), 0.19 (s, 3H); HRMALDIMS calcd
for C49H86O11Si2Na [M + Na]+ 929.5606, found 929.5676.
Sp ir ok eta l 54. To a stirred rt solution of 53a (∼2.5 mg,
2.6 µmol) in benzene (0.8 mL) was added p-toluenesulfonic acid
monohydrate (∼0.1 mg, 0.5 µmol). After the solution was
stirred for 45 min, saturated aqueous NaHCO3 (0.5 mL) was
added, and the mixture was diluted with ethyl acetate (1 mL).
The organic phase was washed with H2O and saturated
aqueous NaCl (0.8 mL each), dried over Na2SO4, filtered, and
concentrated. Silica gel column chromatography (hexanes/ethyl
acetate, 8:1, v/v) of the residue yielded 54 (2.0 mg, 2.4 µmol,
83%) as a clear, colorless oil: Rf 0.40 (hexanes/ethyl acetate,
acetate, 1:5, v/v); [R]25 ) -12 (c 1.5, CHCl3); IR (neat) 2930,
D
1715, 1460, 1250, 1035 cm-1
;
1H NMR (CDCl3, 300 MHz) δ
5.32 (dd, J ) 2.1, 2.1 Hz, 1H), 5.02 (s, 1H), 4.36 (m, 1H), 4.30
(dd, J ) 4.8, 4.8 Hz, 1H), 3.84 (d, J ) 5 Hz, 2H), 3.79 (d, J P-H
) 11.4 Hz, 6H), 3.73-3.67 (m, 1H), 3.15 (s, 3H), 3.15 (m, 1H),
3.10 (d, J P-H ) 22.8 Hz, 2H), 2.63 (dd, J ) 8, 8 Hz, 2H), 2.08-
1.97 (m, 2H), 1.84-1.44 (m, 4H), 0.93 (s, 9H), 0.90 (s, 9H), 0.11
(s, 3H), 0.07 (s, 6H), 0.06 (s, 3H); 13C NMR (CDCl3, 125 MHz)
δ 201.0, 145.7, 111.4, 98.6, 80.7, 76.7, 71.9, 71.1, 65.6, 53.0,
47.4, 41.4 (d, J C-P ) 127 Hz), 38.8, 32.3, 28.6, 25.9, 25.5, 18.4,
18.2, -4.3, -5.0, -5.4, -5.5; HRFABMS calcd for C28H54O9-
PSi2 [M - OCH3]+ 605.3095, found 605.3107.
En on e 53. To a stirred rt solution of 43 (9.0 mg, 23 µmol)
in CH2Cl2 (3 mL) were added crushed 4 Å molecular sieves
(20 mg) and tetrapropylammonium perruthenate (0.4 mg, 1
µmol), followed by 4-methylmorpholine N-oxide (6 mg, 50
µmol). After 30 min, the reaction mixture was concentrated
under a stream of N2. Filtration through a silica gel column
(hexanes/ethyl acetate, 2:1, v/v) gave 4 (8 mg, 20 µmol, 89%)
as a white solid. This was used directly without further
purification: Rf 0.60 (hexanes/ethyl acetate, 4:1, v/v); 1H NMR
(CDCl3, 500 MHz) δ 9.81 (d, J ) 6.0 Hz, 1H), 5.35 (s, 1H),
5.32 (s, 1H), 4.16 (ddd, J ) 19.5, 13.0, 7.0 Hz, 1H), 3.90 (m,
1H), 2.40 (dddd, J ) 24.0, 11.5, 11.5, 6.0 Hz, 1H), 2.04-1.78
(m, 6H), 1.73 (s, 3H), 1.62-1.46 (m, 3H), 1.48 (s, 3H), 1.25 (m,
1H), 1.16 (d, J ) 11.5 Hz, 3H), 0.92 (s, 9H).
4:1, v/v); [R]26 ) +5.0 (c 1.5, CHCl3); IR (neat) 2956, 2930,
D
2854, 1793, 1466, 1364, 1253, 1120, 1082, 1010, 980, 839 cm-1
;
1H NMR (CDCl3, 500 MHz) δ 5.73 (dd, J ) 15.5, 8.5 Hz, 1H),
5.49 (dd, J ) 15.0, 7.0 Hz, 1H), 5.33 (s, 1H), 5.32 (s, 1H), 5.31
(s, 1H), 5.01 (s, 1H), 4.51 (q, J ) 7.5 Hz, 1H), 4.31 (m, 2H),
4.00 (m, 1H), 3.86 (dd, J ) 10.0, 6.0 Hz, 1H), 3.81 (dd, J )
10.5, 5.5 Hz, 1H), 3.72 (ddd, J ) 9.0, 5.5, 3.5 Hz, 1H), 3.63 (m,
1H), 3.41 (t, J ) 10.0 Hz, 1H), 2.29 (m, 1H), 2.16 (m, 1H), 2.00-
1.73 (m, 10H), 1.71 (s, 3H), 1.64-1.54 (m, 3H), 1.47 (s, 3H),
1.32-1.16 (m, 4H), 1.10 (d, J ) 7.0 Hz, 3H), 0.95 (s, 9H), 0.91
(s, 9H), 0.90 (s, 9H), 0.12 (s, 3H), 0.08 (s, 3H), 0.06 (s, 6H);
HRFABMS calcd for C48H83O10Si2 [M + H]+ 875.5524, found
875.5529.
Alcoh ol 14. To a stirred rt solution of 54 (∼1.5 mg, 1.7 µmol)
in THF (0.5 mL) was added TBAF (5 µL of a 1.0 M solution in
THF, 5 µmol). After 3 h, the reaction mixture was concentrated
under a stream of N2. The residue was purified by silica gel
column chromatography (hexanes/ethyl acetate, 2:1, v/v) to
give recovered 54 (0.3 mg, 0.3 µmol) and 14 (∼1 mg, 1.3 µmol,
76%, 95% corrected for recovered starting material) as a clear,
pale yellow oil: Rf 0.33 (hexanes/ethyl acetate, 2:1, v/v); 1H
NMR (CDCl3 500 MHz) δ 5.74 (dd, J ) 15.0, 8.0 Hz, 1H), 5.50
(dd, J ) 15.5, 7.5 Hz, 1H), 5.37 (t, J ) 2.0 Hz, 1H), 5.34 (s,
1H), 5.33 (s, 1H), 5.09 (s, 1H), 4.51 (q, J ) 7.0 Hz, 1H), 4.43
(dd, J ) 10.5, 5.0 Hz, 1H), 4.15 (d, J ) 8.5 Hz, 1H), 3.99 (m,
2H), 3.72 (ddd, J ) 11.0, 5.5, 3.5 Hz, 1H), 3.51-3.44 (m, 3H),
2.29 (q, J ) 7.0 Hz, 1H), 2.16 (m, 1H), 1.99-1.48 (m, 16H),
1.75 (s, 3H), 1.47 (s, 3H), 1.23 (m, 1H), 1.09 (d, J ) 7.0 Hz,
To a stirred rt solution of 15 (11 mg, 19 µmol) in CH3CN
(2 mL) was added LiCl (10 mg, 0.24 mmol) followed by diiso-
propylethylamine (25 µL, 0.14 mmol). After the mixture was
stirred for 10 min, a solution of 4 (9 mg, 25 µmol) in CH3CN
(1 mL) was added. The resulting mixture was stirred for 36 h.
The solvent was removed under a stream of N2, and the
resulting residue was mixture was diluted with ethyl acetate
(4 mL), washed with H2O and saturated aqueous NaCl (1 mL
each), dried over Na2SO4, filtered, and concentrated. Silica gel
column chromatography (hexanes/ethyl acetate, 12:1 to 8:1,
v/v) of the residue gave enone 53 (10 mg, 11 µmol, 58%) as a
clear, colorless oil: Rf 0.55 (hexanes/ethyl acetate, 4:1, v/v);
[R]25D ) -20.0 (c 2.9, CHCl3); IR (neat) 2950, 2930, 1785, 1670
cm-1; 1H NMR (CDCl3, 500 MHz) δ 6.97 (dd, J ) 15.5, 8.5 Hz,
1H), 6.13 (d, J ) 15.5 Hz, 1H), 5.38 (s, 1H), 5.34 (s, 1H), 5.33
(s, 1H), 5.03 (s, 1H), 4.36 (d, J ) 9.5 Hz, 1H), 4.31 (t, J ) 5.0
Hz, 1H), 3.93 (dddd, J ) 11.0, 2.0, 2.0, 2.0 Hz, 1H), 3.85 (m,
3H), 3.67 (m, 1H), 3.18 (s, 3H), 3.18 (m, 1H), 2.67 (ddd, J )
17.0, 10.5, 6.0 Hz, 1H), 2.57 (ddd, J ) 17.0, 10.0, 5.0 Hz, 1H),
2.46 (m, 1H), 2.09 (ddd, J ) 15.5, 10.5, 5.5 Hz, 1H), 1.96-1.74
(m, 10H), 1.71 (s, 3H), 1.61-1.48 (m, 4H), 1.47 (s, 3H), 1.23
(m, 1H), 1.18 (d, J ) 13.0 Hz, 3H), 0.94 (s, 9H), 0.909 (s, 9H),
0.906 (s, 9H), 0.13 (s, 3H), 0.08 (s, 3H), 0.07 (s, 3H), 0.06 (s,
3H); 13C NMR (CDCl3, 125 MHz) δ 199.9, 175.4, 149.8, 145.7,
135.2, 130.8, 128.4, 124.5, 111.5, 108.4, 99.0, 94.8, 80.8, 78.6,
76.6, 72.0, 71.2, 69.9, 66.1, 65.5, 47.5, 43.8, 42.2, 34.7, 34.2,
34.0, 33.3, 32.4, 31.4, 29.7, 29.1, 25.9, 25.6, 25.4, 23.4, 22.8,
18.4, 18.2, 16.3, -4.3, -4.9, -5.3, -5.5; HRFABMS calcd for
3H), 0.95 (s, 9H), 0.91 (s, 9H); HRFABMS calcd for C42H69O10
-
Si [M + H]+ 761.4660, found 761.4658.
Ack n ow led gm en t. We acknowledge financial sup-
port from the NIH (CA62195), as well as generous,
unrestricted research grants from AstraZeneca and
Bristol-Myers Squibb (C.J .F.). We also gratefully ac-
knowledge fellowship support from the University of
Minnesota Graduate School (A.B.D., V.A.F., R.A.U.), the
Stanwood J ohnston Memorial Fellowship (A.B.D.,
R.A.U.), and the American Chemical Society Division
of Medicinal Chemistry (sponsored by Parke-Davis,
A.B.D.) and Division of Organic Chemistry (sponsored
by Organic Syntheses, A.B.D.). We appreciate the
experimental contributions of J . Hao, K. Plummer, C.
Mattingly, and A. Singh. We especially thank Dr. S.
Sabes for invaluable discussions.
C
49H84O11Si2Na [M + Na]+ 927.5450, found 927.5479.
Allylic Alcoh ol 53a . To a stirred rt solution of 53 (3.0 mg,
3.0 µmol) in toluene (0.5 mL) under Ar was added (S)-2-methyl-
CBS-oxazaborolidine (26 µL of a 1.0 M solution in toluene, 26
µmol). The mixture was cooled to -78 °C, and catechol borane
(2 µL, 0.01 mmol) was added. After 10 min, saturated aqueous
NaHCO3 (1 mL) was added, and the mixture was allowed to
warm to rt. Ethyl acetate (2 mL) was added, and the organic
phase was washed with H2O and saturated aqueous NaCl (1
mL each), dried over Na2SO4, filtered, and concentrated. Silica
gel column chromatography (hexanes/ethyl acetate, 8:1 to 4:1,
Su p p or tin g In for m a tion Ava ila ble: NMR spectral data
of all new compounds described in the Experimental Section
as well as derivative 55. This material is available free of
charge via the Internet at http://pubs.acs.org.
J O001433N