Total synthesis of (+)-dactylolide

Article abstract of DOI:10.1021/ol051040g

(Chemical Equation Presented) The development of an approach leading to the total synthesis of dactylolide is described. The key features of this route include a catalytic asymmetric allylation, a diastereoselective pyran annulation, and a Horner-Wadswort

Full text of DOI:10.1021/ol051040g

ORGANIC
LETTERS
2005
Vol. 7, No. 14
3053-3056
Total Synthesis of (+)-Dactylolide
Carina C. Sanchez and Gary E. Keck*
Department of Chemistry, UniVersity of Utah, 315 South 1400 East RM 2020,
Salt Lake City, Utah 84112-0850
keck@chemistry.utah.edu
Received May 5, 2005
ABSTRACT
The development of an approach leading to the total synthesis of dactylolide is described. The key features of this route include a catalytic
asymmetric allylation, a diastereoselective pyran annulation, and a Horner−Wadsworth−Emmons macrocyclization.
Dactylolide (1) was one of the many cytotoxic metabolites
isolated from the Vanuatu sponge Dactylospongia sp. by
Riccio and co-workers in 2001.1 Dactylolide was shown to
have cytotoxicity toward L1210 cell lines (63% inhibition
at 3.2 µg/mL) and SK-OV-3 cell lines (40% inhibition at
3.2 µg/mL). Spectroscopic investigations led to the sugges-
tion of structure 1 (Figure 1) for this material, although the
configuration at C19 was not established. The major archi-
tectural elements of dactylolide consist of a highly unsatu-
rated but moderately functionalized 20-membered macro-
lactone, a 2,6-cis-disubstituted methylene tetrahydropyran,
and two trisubstituted olefins.
stereocenters and culminated in the first total synthesis of
the molecule.3 Hoye and Hu later disclosed a synthesis of
(-)-dactylolide as a precursor to zampanolide.4 Most re-
cently, during the preparation of this manuscript, the groups
of Floreancig as well as Jennings have both reported total
syntheses of dactylolide.5,6
Our interest in dactylolide stemmed from its molecular
structure. Recent work in our laboratories has provided an
exceptionally facile access to stereodefined 2,6-cis-4-meth-
ylene tetrahydropyrans.7 We wished to further explore the
scope of this reaction by exploring the use of R,â-unsaturated
aldehydes in the transformation, an issue which would by
necessity be addressed in the context of a synthesis of
dactylolide.
The route chosen for experimental investigation is outlined
schematically in Figure 2. We envisioned application of a
Horner-Wadsworth-Emmons macrocyclization to close the
20-membered macrolactone. The phosphonate required for
this step was in turn envisioned to arise from another
Horner-Wadsworth-Emmons reaction between aldehyde 4
In 2002, Smith and Safonov reported the results of
synthetic investigations on zampanolide2 (2) and dactylolide
which established the relative configuration of the dactylolide
(1) Cutignano, A.; Bruno, I.; Bifulco, G.; Casapullo, A.; Debitus, C.;
Gomez-Paloma, L.; Riccio, R. Eur. J. Org. Chem. 2001, 775.
(2) Tanaka, J.; Higa, T. Tetrahedron Lett. 1996, 37, 5535.
(3) (a) Smith, A. B., III; Safonov, I. G.; Corbett, R. M. J. Am. Chem.
Soc. 2001, 123, 12426. (b) Smith, A. B., III; Safonov, I. G. Org. Lett. 2002,
4, 635.
(4) Hoye, T. R.; Hu, M. J. Am. Chem. Soc. 2003, 125, 9576.
(5) Floreancig, P. E.; Aubele, D. L.; Wan, S. Angew. Chem., Int. Ed.
2005, 44, 3485.
(6) Jennings, M. P.; Ding, F. Org. Lett. 2005, 7, 2321-2324.
(7) Keck, G. E.; Covel, J. A.; Yu, T.; Schiff, T. Org. Lett. 2002, 4, 1189.
Figure 1. (+)-Dactylolide and (-)-zampanolide.
10.1021/ol051040g CCC: $30.25
© 2005 American Chemical Society
Published on Web 06/07/2005

Figure 2. Retrosynthetic analysis.
and â-ketophosphonate 5. The pyran subunit 4 would be
prepared using the pyran annulation reaction as previously
mentioned. We anticipated that the pyran annulation reaction
between the hydroxy allylsilane 6 and R,â-unsaturated
aldehyde 7 would lead to the desired 4-methylene tetra-
hydropyran with the required cis stereochemistry. For the
preparation of the enal 7, we planned to use the catalytic
asymmetric allylation (CAA) based trisubstituted olefin
synthesis previously developed in our laboratories.8 The other
component necessary for the pyran annulation reaction,
hydroxy allylsilane 6, would arise from a CAA reaction of
the appropriate aldehyde with the known 2-(trimethylsilyl-
methyl)allyltri-n-butylstannane reagent 15.7,9
NMO, 91% yield) then afforded the R,â-unsaturated aldehyde
needed for the pyran annulation. The preparation of the
hydroxyallylsilane component (Scheme 2) for the pyran
annulation was effected via a catalytic asymmetric allylation
reaction using stannane 15 and (S)-BITIP catalyst to afford
the desired hydroxy allylsilane 6 in 91% yield and with 95%
ee.7
The stage was now set for the pyran annulation reaction.
We were delighted to find that the pyran annulation between
aldehyde 7 and hydroxy allylsilane 6 proceeded in excellent
yield (85%) and provided the desired pyran 16 as a single
1
diastereomer (by H and 13C NMR). This pyran is thus
available to us in six steps with an overall yield of 50% from
The preparation of aldehyde 7 commenced with the CAA
reaction of aldehyde 9 with the functionalized stannane 10,
to give the desired (R)-homoallylic alcohol 8 in 75% yield
and 93% ee after chromatographic purification (Scheme 1).
After conversion of the free hydroxyl to the corresponding
silyl ether 11 by reaction with TBSCl and imidazole (96%
yield), an isomerization was employed to secure the E
unsaturated ester 12 (97%, 32:1 E/Z).
Scheme 1. Synthesis of R,â-Unsaturated Aldehyde 7
This isomerization is an exceptional reaction and deserves
some comment. We believe that the high level of stereo-
selectivity observed is a kinetic phenomenon associated with
a preferred pathway for formation of the U shaped internally
chelated enolate anion with sodium as counterion. The use
of DBU to effect this transformation resulted in a 9:1 mixture.
After extended reaction times, the sodium hydride process
also afforded a 9:1 mixture.
With the E stereochemistry of the unsaturated ester
secured, reduction to the alcohol was effected using LAH
(93% yield). Oxidation using the method of Ley (TPAP-
(8) Keck, G. E.; Yu, T. Org. Lett. 1999, 1, 289.
(9) (a) Kang, K.-T.; Hwang, S. S.; Kwak, W. Y.; Yoon, U. C. Bull.
Korean Chem. Soc. 1999, 20, 801. (b) Clive, D. L. J.; Paul, C. C.; Wang,
Z. J. Org. Chem. 1997, 62, 7028. (c) The 2-(chloromethyl)allylsilane
precursor to 15 is commercially available (Aldrich).
3054
Org. Lett., Vol. 7, No. 14, 2005

forded the desired â-ketophosphonate 5 (70% over three
steps).
Scheme 2. Pyran Annulation
The â-ketophosphonate 5 and the aldehyde 17 were then
united by means of a Horner-Wadsworth-Emmons reaction
(Scheme 4). Many different conditions were examined to
Scheme 4. Horner-Wadsworth-Emmons Reaction
effect this transformation, and the use of Paterson’s Ba(OH)2
procedure12 proved superior to reactions using more standard
bases (KOtBu) or reaction under Masamune’s conditions.13
We were delighted to find that the Horner-Wadsworth-
Emmons reaction worked extremely well to generate the
desired enone 20 in a 79% yield.
aldehyde 9. Selective deprotection of the BPS group followed
using TBAF/AcOH.10 Oxidation using TPAP/NMO then
provided the sensitive pyran aldehyde 17.
At this point, we became concerned about potential
problems associated with the presence of the keto group at
C7. We reasoned that the acidity of the protons R to the
ketone at C6 would be significantly enhanced since they are
also γ with respect to the R,â-unsaturated aldehyde. If the
ketone were to be left unprotected, the anticipated ease of
removal of these protons could negatively impact upon the
desired Horner-Wadsworth-Emmons macrocyclization.
To preclude these potential problems, we decided to reduce
and protect the ketone. The next issue that arose was the
choice of protecting group for the alcohol. In looking at the
projected synthesis, it can be seen that the alcohol at C20
was protected as a PMB ether. This PMB group must be
removed and the resulting alcohol oxidized. The alcohol at
C7 would also have to be deprotected and oxidized in one
of the penultimate steps of the synthesis. Thus, we elected
to protect this alcohol as the PMB ether in hopes that we
could deprotect and oxidize both alcohols in the same
operation.
The synthesis of the â-ketophosphonate 5 began with
intermediate 18 (Scheme 3).11 DIBAL-H reduction of the
Scheme 3. Synthesis of â-Ketophosphonate 5
Luche reduction of the ketone provided the alcohol which
was immediately subjected to PMB protection (Scheme 5).
We examined a variety of methods for installing the PMB
ether; however most of these failed or gave poor yields. Use
of the PMB imidate and triflic acid resulted in decomposition
of the alcohol substrate. Use of KH and PMBBr resulted in
only trace amounts of product formation. It was ultimately
found that KHMDS, PMBBr, and triethylamine worked
ester to the alcohol, followed by protection as the BPS ether
generated the disilyl ether. Selective deprotection of the TBS
ether was accomplished using CSA/MeOH. This three-step
sequence was carried out in 75% yield. Oxidation of the
resulting alcohol 19 was problematic and the only reagent
found to work well in this case was CrO3/pyridine. The use
of PCC, Dess-Martin periodinane, TPAP-NMO, and PDC
all failed, a result which may be attributed to the sensitive
nature of the desired â-γ unsaturated system. Fortunately,
addition of the lithiate of methyl dimethyl phosphonate into
this aldehyde occurred without incident. Oxidation of the
resulting alcohol using Dess-Martin periodinane then af-
(10) Higashibayashi, S.; Shinko, K.; Ishizu, T.; Hashimoto, K.; Shira-
hama, H.; Nakata, M. Synlett 2000, 1306.
(11) Still, W. C.; Gennari, C.; Nogues, J. A.; Pearson, D. A. J. Am. Chem.
Soc. 1984, 106, 260.
(12) (a) Paterson, I.; Yeung, K.-S. Tetrahedron Lett. 1993, 34, 5347.
(b) Paterson, I.; Yeung, K.-S.; Smaill, J. B. Synlett 1993, 774.
(13) Masamune, S.; Roush, W. R.; Sakai, T.; Blanchette, M. A.; Choy,
W.; Davis, J. T.; Essenfeld, A. P. Tetrahedron Lett. 1984, 25, 2183.
Org. Lett., Vol. 7, No. 14, 2005
3055

Scheme 5. Preparation of 22
Scheme 6. Completion of the Synthesis
extremely well to provide the desired product 21 in 94%
yield over two steps.14
With this operation implemented, attention was turned
toward forming the phosphono-aldehyde needed for the
Horner-Wadsworth-Emmons macrocyclization (Scheme 5).
Selective deprotection of the TBS ether ensued using PPTs
in EtOH in 74% yield. Other methods such as HF‚pyr and
CSA/MeOH provided diminished yields.
displayed spectral and analytical data in excellent agreement
with those previously reported for the natural material as
well as with data described from previous synthetic efforts.17
In conclusion, dactylolide was synthesized in 18 steps
(longest linear sequence) from aldehyde 9 (20 linear steps
from commercially available 2-butene-1,4-diol) and in 7.1%
overall yield. This is the highest yielding synthesis reported
to date.
Acylation of the alcohol with diethylphosphonoacetic acid
was now required. The conditions used for this reaction were
those of the modified Keck-Boden macrolactonization that
we had reported on previously.15 The phosphonate product
was expected to be (and indeed was) very polar, therefore
utilizing a polymer-bound DCC (PS-DCC) rather than DCC
itself would simplify the workup as well as isolation and
purification of the phosphonate. This acylation was found
to occur very rapidly using the PS-DCC reagent in combina-
tion with DMAP and DMAP hydrochloride to provide a
quantitative yield of the desired phosphono ester. Our
attention now turned to deprotection of BPS ether 22
(Scheme 6). This was easily accomplished using HF and
pyridine to give the free alcohol in 74% yield. Oxidation of
the resulting alcohol to the aldehyde was accomplished using
TPAP-NMO.
With the phosphono aldehyde successfully synthesized,
the Horner-Wadsworth-Emmons macrocyclization could
now be attempted. The phosphono-aldehyde was subjected
to 1.2 equivalents of NaHMDS at -78 °C with subsequent
warming to 0 °C.2,16 This led to the desired macrocycle 23
in a 60% isolated yield. Only removal of the PMB ethers
and oxidation were now required to complete the synthesis
of dactylolide.
Acknowledgment. Financial support from the National
Institutes of Health (through GM-28961) and by Pfizer, Inc.,
in the form of a Diversity in Organic Chemistry Fellowship
(to C.C.S.) is gratefully acknowledged.
Supporting Information Available: Full experimenal
details as well as spectral data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL051040G
(14) Roush, W. R.; Holson, E. B. Org. Lett. 2002, 4, 3719.
(15) Keck, G. E.; Sanchez, C. C.; Wager, C. A. Tetrahedron Lett. 2000,
41, 8673.
(16) We originally investigated the use of a macrolactonization reaction
to close the 20-membered macrolactone. Many macrolactonization methods
failed to provide the desired macrolactone. Further details will be provided
in a full account of this work.
(17) The optical rotation that we measured was [R]20 ) +134 (c )
D
0.065, MeOH). Smith reported a rotation of +235 (c ) 0.52, MeOH). Hoye
reported a rotation of -128 (c ) 0.39, MeOH) for the unnatural enantiomer
of dactylolide. Floreancig reported an optical rotation of +163 (c ) 0.29,
MeOH). Jennings reported a rotation of -136 (c ) 1.2, MeOH) for the
unnatural enantiomer of dactylolide. The optical rotation reported for the
natural material is +30 (c ) 1.0, MeOH). The reason for this deviation in
rotations is unclear, but we believe an explanation may be found in the
presence of the highly conjugated and enolizable ketone and ester functions
in the C1-C10 region. Enolization could occur using a proton at C6, C10, or
both. Enol formation using the C5 methyl group is also possible. The precise
enol content and composition in turn could depend on the exact batch of
solvent used, the history of the sample, the polarimeter cell, etc. Since such
highly conjugated enols would be expected to have large rotations, it can
be seen that even small variations in enol content could lead to large
variations in the measured optical rotation.
Deprotection of both PMB ethers proceeded smoothly by
reaction with DDQ (84% yield), and Dess-Martin oxidation
of the resulting diol followed to generate the natural product
dactylolide. This double oxidation also occurred without
incident and in high (91%) yield. Our synthetic dactylolide
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Org. Lett., Vol. 7, No. 14, 2005