Total synthesis of (-)-dactylolide and formal synthesis of (-)-zampanolide via target oriented β-C-glycoside formation

Article abstract of DOI:10.1021/jo8009853

(Chemical Equation Presented) The total synthesis of (-)-dactylolide and formal synthesis of (-)-zampanolide via target oriented β-C-glycoside formation is described. The two key reactions involved a stereoselective reduction of the appropriate oxocarbenium cation and a highly chemo- and diastereoselective ring-closing metathesis protocol for the formation of the macrocyclic core. In addition to the described chemistry, in vitro screening of the antipode of natural dactylolide against the NCI's 60 cancer cell line helped to illuminate the critical importance of the N-acyl hemiaminal side chain of natural zampanolide for its reported potent nanomolar cytotoxicities. Furthermore, by means of the in vitro screen of (-)-dactylolide, a promising cancer therapeutic lead has now emerged for a variety of carcinomas. More specifically, (-)-dactylolide exhibited GI₅₀ values in the nanomolar (25-99 ng/mL) range against the four cell lines HL-60, K-562, HCC-2998, and SF-539, while displaying modest LC₅₀ values.

Full text of DOI:10.1021/jo8009853

Total Synthesis of (-)-Dactylolide and Formal Synthesis of
(-)-Zampanolide via Target Oriented ꢀ-C-Glycoside Formation
Fei Ding and Michael P. Jennings*
Department of Chemistry, The UniVersity of Alabama, Tuscaloosa, Alabama 35487-0336
jenningm@bama.ua.edu
ReceiVed May 7, 2008
The total synthesis of (-)-dactylolide and formal synthesis of (-)-zampanolide via target oriented ꢀ-C-
glycoside formation is described. The two key reactions involved a stereoselective reduction of the
appropriate oxocarbenium cation and a highly chemo- and diastereoselective ring-closing metathesis
protocol for the formation of the macrocyclic core. In addition to the described chemistry, in vitro screening
of the antipode of natural dactylolide against the NCI’s 60 cancer cell line helped to illuminate the critical
importance of the N-acyl hemiaminal side chain of natural zampanolide for its reported potent nanomolar
cytotoxicities. Furthermore, by means of the in vitro screen of (-)-dactylolide, a promising cancer
therapeutic lead has now emerged for a variety of carcinomas. More specifically, (-)-dactylolide exhibited
GI50 values in the nanomolar (25-99 ng/mL) range against the four cell lines HL-60, K-562, HCC-
2998, and SF-539, while displaying modest LC50 values.
Introduction
of 1 and 2 share an enantiomeric relationship with one another.
Thus, the natural (-)-zampanolide can be degraded to the
unnatural (-)-dactylolide (3) or, in the forward sense, (-)-
dactylolide would serve as the macrocyclic precursor of natural
zampanolide as shown in Figure 1. On the basis of the reports
of Riccio and Higa, (+)-2 displayed a modest biological profile
with respect to that of (-)-1, thus initially suggesting that the
N-acyl hemiaminal side chain resident in (-)-1 is required for
the impressive biological activity. However, the enantiomeric
relationship between the macrocyclic cores of 1 and 2 may also
play a dramatic role in the decreased biological profile of 2
First isolated and disclosed in 1996 by Higa and co-workers,1
(-)-zampanolide (1) represented a novel macrolide which
exhibited significant activity against a variety of tumor cell lines.
In particular, 1 has proven to be noticeably active against the
P388, A549, HT29, and MEL28 cell lines with IC50 values
ranging from 1 to 5 ng/mL. Subsequently, Riccio isolated a
structurally related compound, (+)-dactylolide (2), from the
marine sponge Dactylospongia.2 Due to the striking similarities
between 1 and 2, it was postulated that 2 is a potential biogenic
precursor to that of 1. Coupled with potent cytotoxicity and
unusual structures of both 1 and 2, there has been moderate
synthetic interest in these targets culminating in the first total
synthesis by Smith in which the relative and tentative absolute
configuration of 1 and 2 was determined.3,4 By means of Smith’s
account, it was observed that the common macrocyclic cores
(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.
(c) Smith, A. B., III; Safonov, I. G.; Corbett, R. M. J. Am. Chem. Soc. 2002,
124, 11102.
(4) (a) Hoye, T. R.; Hu, M. J. Am. Chem. Soc. 2003, 125, 9576. (b) Aubele,
D. L.; Wan, S. Y.; Floreancig, P. E. Angew. Chem., Int. Ed. 2005, 44, 3485. (c)
Ding, F.; Jennings, M. P. Org. Lett. 2005, 7, 2321. (d) Sanchez, C. C.; Keck,
G. E. Org. Lett. 2005, 7, 3053. (e) Louis, I.; Hungerford, N. L.; Humphries,
E. J.; McLeod, M. D. Org. Lett. 2006, 8, 1117. (f) Loh, T. P.; Yang, J. Y.;
Feng, L. C.; Zhou, Y. Tetrahedron Lett. 2002, 43, 7193. (g) Troast, D. M.; Porco,
J. A., Jr. Org. Lett. 2002, 4, 991.
(1) Tanaka, J.; Higa, T. Tetrahedron Lett. 1996, 37, 5535.
(2) Cutignano, A.; Bruno, I.; Bifulco, G.; Casapullo, A.; Debitus, C.; Gomez-
Paloma, L.; Riccio, R. Eur. J. Org. Chem. 2001, 775.
10.1021/jo8009853 CCC: $40.75
Published on Web 06/28/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 5965–5976 5965

Ding and Jennings
FIGURE 1. Structures and activities of 1, 2, and 3.
correct stereochemistry of the desired ꢀ-C-glycoside.7 As
described in Scheme 2, our initial approach to 4 centered on a
vinyl lithium (5) addition to the protected lactone 8 followed
by an oxocarbenium formation/reduction sequence. The vinyl
lithium species would be derived from the stereodefined iodo-
olefin 6 by means of a lithium halogen exchange. In turn, olefin
6 was envisioned to be the result of a Negishi carboalumination
reaction of the previously reported acetylenic diol 7.8,9 Synthesis
of the other coupling partner 8 would be derived from an
oxidation of lactenone 9, which was envisaged to be the product
of a ring-closing metathesis (RCM) reaction. The initial starting
material leading to the RCM reaction process would be the
previously reported homoallylic alcohol 10.10
SCHEME 1. Retrosynthetic Analyses of (-)-Zampanolide
(1) and (-)-Dactylolide (3)
First Generation Retrosynthetic Analysis of ꢀ-C-Glyco-
side (4). With the initial synthetic blueprint in hand, we
commenced the synthesis of 4 based on the Negishi carboalu-
mination reaction process for the completion of olefin 6. Thus,
treatment of the commercially available (R)-glycidol (11) with
the lithium acetylide•EDA complex provided the homopropar-
gylic diol 7 in 79% yield and set the stage for the zirconium-
catalyzed carboalumination reaction as delineated in Scheme
3.9 Unfortunately, protecting the diol moiety of 7 as TBDPS or
TBS ethers did not allow for the carboalumination reaction and
led to decomposition of the starting material. Much to our
delight, the free diol 7 did indeed undergo carboalumination
with Cp2ZrCl2 and AlMe3 to provide the assumed vinyl
aluminum intermediate and subsequent quenching with I2
allowed for the formation of the iodo-vinylic diol 12 in 45%
yield over the two-step process. Ensuing silylation of the more
accessible primary hydroxyl group with TDBPSCl and imidazole
readily furnished the monoprotected diol 13 in 81% yield.
Completion of the vinylic coupling partner 6 was accomplished
in 72% yield by final protection of the remaining free hydroxyl
moiety as a TES ether via standard silylation protocols (TESCl
and imidazole).
versus that of 1. To the best of our knowledge, no biological
testing of unnatural (-)-dactylolide (3) has been performed (vide
infra). Thus, the unusual structures of both 1 and 2, coupled
with the unclear absolute configuration of 2, and the uncertain
origin of the impressive biological profile of 1 versus that of 2
make this class of natural products attractive targets for total
synthesis and further investigation into their respective biological
profiles.4
The retrosynthetic analysis of both (-)-dactylolide (3) and
(-)-zampanolide (1) is illustrated in Scheme 1. As reported by
Hoye, strategic disconnection at the N-acyl hemiaminal side
chain would allow for the corresponding engagement of an
“aluminum aza-aldol” sequence with the aldehyde moiety to 3
and should furnish the targeted natural product (-)-za-
mpanolide.4a It was expected that disconnection of the macro-
lactone and the enone linkage of 3 would allow for utilization
of olefin metathesis and esterification with 4 and 5 in anticipation
of obtaining the macrolide skeleton.4c,5
With the vinylic coupling partner 6 in hand and in gram
quantities, focus was then shifted to the synthesis of the
protected ꢀ-hydroxy lactone 8 as shown in Scheme 4. Conse-
quently, esterification of the previously reported homoallylic
alcohol 10 with acryloyl chloride and Et3N furnished the acrylate
ester 14 in 88% yield. Ensuing treatment of ester 14 with
Grubbs’ second generation catalyst 15 provided swift access in
91% yield to lactenone 9 by means of a ring-closing metathesis
Results and Discussion
The first major obstacle that was undertaken was the synthesis
of the ꢀ-C-glycoside intermediate 4. We initially surmised that
a two directional approach might provide 4 via the hydride
addition to an incipient oxocarbenium cation as initially
described by Kishi.6 Careful inspection of the two possible
reactive conformers by utilizing the Woerpel models led us to
believe that such a reduction protocol would indeed furnish the
(7) (a) Romero, J. A. C.; Tabacco, S. A.; Woerpel, K. A. J. Am. Chem. Soc.
2000, 122, 168. (b) Ayala, L.; Lucero, C. G.; Romero, J. A. C.; Tabacco, S. A.;
Woerpel, K. A. J. Am. Chem. Soc. 2003, 125, 15521.
(5) (a) Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413. (b) Rivkin,
A.; Cho, Y. S.; Gabarda, A. E.; Yoshimura, F.; Danishefsky, S. J. J. Nat. Prod.
2004, 67, 139. (c) Deiters, A.; Martin, S. F. Chem. ReV. 2004, 104, 2199. (d)
Grubbs, R. H. Tetrahedron 2004, 60, 7117. (e) Gradillas, A.; Perez-Castells, J.
Angew. Chem., Int. Ed. 2006, 45, 6086.
(8) Van Horn, D. E.; Negishi, E.-I. J. Am. Chem. Soc. 1978, 100, 2252.
(9) Heathcock, C. H.; McLaughlin, M.; Medina, J.; Hubbs, J. L.; Wallace,
G. A.; Scott, R.; Claffey, M. M.; Hayes, C. J.; Ott, G. R. J. Am. Chem. Soc.
2003, 125, 12844.
(6) Lewis, M. D.; Cha, J. K.; Kishi, Y. J. Am. Chem. Soc. 1982, 104, 4976.
(10) Su, Q.; Panek, J. S. Angew. Chem., Int. Ed. 2005, 44, 1223.
5966 J. Org. Chem. Vol. 73, No. 15, 2008

Synthesis of (-)-Dactylolide and (-)-Zampanolide
SCHEME 2. First Generation Retrosynthesis of 4
SCHEME 3. Synthesis of Protected Olefin Diol 6
SCHEME 4. Synthesis of Bisbenzyl-Protected Lactone 8
reaction.11–13 With 15 in hand, diastereoselective introduction
of the ꢀ-hydroxy group was envisioned to arise via an
expoxidation/regioselective ring-opening sequence. The driving
force behind the introduction of the hydroxy moiety was
twofold. First, we postulated that the reactive conformer of the
oxocarbenium reduction required the hydroxyl group to be C3
axial position as described by Woerpel.7 Thus, diastereoselective
introduction of such a functional group would require a 1,3-
anti relationship in compounds 17 and 8. Second, the natural
products 1 and 3 required an exo-methylene moiety in that
specific location of the ꢀ-C-glycoside and the hydroxyl group
would serve as an appropriate olefinic surrogate this early in
the synthetic sequence. Consequently, stereoselective epoxida-
tion of 9 with basic H2O2 was quite successful and afforded
the epoxylactone 16 as a single diastereomer in 68% yield.
Subsequent regioselective ring opening of 16 was ac-
complished under Miyashita’s conditions (Ph2Se2, HOAc, and
NaBH4)14 and furnished the ꢀ-hydroxy lactone 17 in excellent
yield.15 The first attempted protection of the free hydroxyl group
of 17 as a benzyl ether was unsuccessful under standard basic
conditions (BnBr, TBAI, NaH) and led to starting material
decomposition. However, treatment of 17 with the benzyl
trichloroacetimidate [BnO(CdNH)CCl3] reagent16 and TFA
efficiently provided the protected lactone 8 in excellent yield.
(11) Diez-Martin, D.; Kotecha, N. R.; Ley, S. V.; Mantegani, S.; Menendez,
J. C.; Organ, H. M.; White, A. D.; Banks, B. J. Tetrahedron 1992, 48, 7899.
(12) Ghosh, A. K.; Cappiello, J.; Shin, D. Tetrahedron Lett. 1998, 39, 4651.
(13) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1,
953.
(14) Miyashita, M.; Suzuki, T.; Hoshino, M.; Yoshikoshi, A. Tetrahedron
1997, 53, 12469.
(15) Miyazawa, M.; Matsuoka, E.; Sasaki, S.; Oonuma, S.; Maruyama, K.;
Miyashita, M. Chem. Lett. 1998, 109.
J. Org. Chem. Vol. 73, No. 15, 2008 5967

Ding and Jennings
SCHEME 5. Attempted Synthesis of Lactol 18
SCHEME 6. Second Generation Synthetic Blueprint to ꢀ-C-Glycoside 4
With the two coupling partners 6 and 8 in hand, our attention
As delineated in Scheme 7, deprotonation of the previously
was focused on first a lithium-halogen exchange of 6 and final
nucleophilic addition to 8 to afford lactol 18 en route to the
ꢀ-C-glycoside 4, as illustrated in Scheme 5. Unfortunately, the
sequential lithium-halogen exchange followed by addition to
8 did not progress as predicted based on the observed two final
products 9 and 19. As a result of the isolation of 9 and 19, it
was assumed that the lithium-halogen exchange did proceed
to afford the vinyl lithium intermediate. However, the vinyl
lithium species did not perform as a nucleophile as hoped, but
functioned as a base and furnished the R,ꢀ-unsaturated lactone
9 via a presumed ꢀ-elimination of the benzyloxide anion. After
multiple unsuccessful attempts of adding the vinyl lithium
intermediate (derived from 6) to lactone 8, we decided to
abandon the current route and redesigned a synthetic blueprint
to take advantage of a nucleophilic addition of a less complex
reagent to a more elaborated lactone.
Second Generation Retrosynthetic Analysis of ꢀ-C-Gly-
coside (4). Our second synthetic blueprint of the ꢀ-C-glycoside
(C8-C20 subunit) 4 was designed to enlist a strategy based on
a tandem organometallic allyl group addition to the correspond-
ing lactone 20 followed by a diastereoselective axial reduction
of an in situ generated oxocarbenium cation to forge the cis-
2,6-disubstituted 4-exo-methylene tetrahydropyran ring after
oxidation/olefination of the free hydroxyl moiety at C8 as shown
in Scheme 6. We envisioned that the lactone 20 would be the
product of an oxidation (similar to that of 17) after a chemose-
lective RCM reaction from the acrylate 21, which in turn would
be derived from a Brown allylation of the R,ꢀ-unsaturated
aldehyde 22. Finally, a stereoselective introduction of the
required methyl group via a two-step thiolate addition-sub-
sequent Grignard addition-thiolate elimination protocol would
allow for the formation of 22 starting from the R,ꢀ-acetylenic
ester 23.
reported propargylic alcohol 2417 with n-BuLi followed by
electrophilic capture of ethyl chloroformate furnished the R,ꢀ-
acetylenic ester 23 in a virtually quantitative (94%) yield.
Subsequent conjugate addition of the thiolate anion derived from
benzenethiol and NaOMe in MeOH diastereoselectively (9:1)
provided the (Z)-R,ꢀ-unsaturated ester 23. Replacement of the
vinylic thiol ether by means of a copper-promoted MeMgBr
addition followed by phenyl thiolate anion displacement afforded
the R,ꢀ-olefinic ester 26 with complete retention of configuration
with a 87% yield over the two-step procedure from 24.18
Subsequent reduction of the ester moiety to the allylic alcohol
27 was readily accomplished with DIBAL, and the correspond-
ing free hydroxyl group was reoxidized to aldehyde 22 under
slightly basic PCC conditions (buffered with NaOAc) in a
combined yield of 89% from ester 26. An asymmetric
allylation-oxidation of 22 utilizing Brown’s Ipc2Ballyl reagent19
furnished the homoallylic alcohol 28 with 90% de. Ensuing
acrylate ester formation under the standard protocol (acryloyl
chloride, Et3N, DMAP) afforded the dienic ester 21 in 79%
yield. Subjecting the acrylate ester 21 to Grubbs’ catalyst 1513
readily allowed for the formation of lactenone 29 via a
chemoselective ring-closing olefin metathesis.
As shown in Scheme 8, an ensuing stereoselective epoxidation
of the corresponding lactenone intermediate 29 with basic
hydroperoxide provided the epoxy lactone 30. A subsequent
(16) Wessel, H. P.; Iversen, T.; Bundle, D. R. J. Chem. Soc., Perkin Trans.
1 1985, 2247.
(17) Nicolaou, K. C.; Jung, J.; Yoon, W. H.; Fong, K. C.; Choi, H.-S.; He,
Y.; Zhong, Y.-L.; Baran, P. S. J. Am. Chem. Soc. 2002, 124, 2183.
(18) Hollowood, C. J.; Yamanoi, S.; Ley, S. V. Org. Biomol. Chem. 2003,
1, 1664.
(19) (a) Racherla, U. S.; Brown, H. C. J. Org. Chem. 1991, 56, 401. (b)
Jadhav, P. K.; Bhat, K. S.; Perumal, P. T.; Brown, H. C. J. Org. Chem. 1986,
51, 432.
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Synthesis of (-)-Dactylolide and (-)-Zampanolide
SCHEME 7. Synthesis of Lactenone 29 via a Chemoselective Ring-Closing Metathesis
SCHEME 8. Synthesis of ꢀ-C-Glycoside 36 via Oxocarbenium Reduction Derived from 31
regioselective reduction of the oxirane under Miyashita’s
condition as above afforded intermediate 20 and set the stage
for the tandem nucleophilic addition-oxocarbenium cation
generation-diastereoselective reduction sequence in anticipation
of providing the vital ꢀ-C-glycoside component. As observed
in Scheme 5, we chose not to protect the free hydroxyl moiety
of 20, due to the concerns of a ꢀ-elimination as occurred with
lactone 8. Thus, nucleophilic addition of allyl magnesium
bromide to ꢀ-hydroxy lactone 20 furnished the lactol 31, which
was immediately transformed into the oxocarbenium cation in
the presence of TFA and consequently reduced with Et3SiH to
furnish the allyl ꢀ-C-glycoside 32 with a 76% yield from 20.
As described in Scheme 8, it is believed that the more reactive
oxocarbenium conformer places the hydroxyl group at C8 in
the axial position while the C6 substituent favors the pseu-
doequatorial position. This is in agreement with Woerpel’s
observation that the C3 hydroxyl moiety prefers the axial position
during the reduction of monosubstituted oxocarbenium cations.7
To avoid removal of the TBS groups during the reduction, TFA
was employed instead of BF3•OEt2 as used in Kishi’s conven-
tional procedure.6,20 Unexpectedly, the C13 hydroxyl group was
concomitantly protected as a TES ether under these conditions.
This novel silylation reaction, presumably derived from the
siliconate intermediate reagent, proceeds readily even at -78
°C. In all reality, this procedure allows for the silylation of free
hydroxyl groups under acidic conditions (even with labile silicon
groups such as the TES group) with concomitant hydride transfer
to a reactive intermediate (i.e., oxocarbenium cation).21 Selective
deprotection of the TES group was unsuccessful upon the
treatment of 32 with PPTS in methanol and other selective re-
agents such as Pd/C22 and DDQ23 also failed to provide the
(20) (a) Lewis, M. D.; Cha, J. K.; Kishi, Y. J. Am. Chem. Soc. 1982, 104,
4976. (b) Kraus, G. A.; Molina, M. T.; Walling, J. A. J. Chem. Soc., Chem.
Commun. 1986, 1568.
(21) The silylation of the axial C3 hydroxyl during oxocarbenium reduction
with Et3SiH has also been observed in three other instances within our laboratory;
see: (a) Sawant, K. B.; Ding, F.; Jennings, M. P. Tetrahedron Lett. 2007, 48,
5177. (b) Sawant, K. B.; Jennings, M. P. J. Org. Chem. 2006, 71, 7911. (c)
Sawant, K. B.; Ding, F.; Jennings, M. P. Tetrahedron Lett. 2006, 47, 939.
(22) Rotulo-Sims, D.; Prunet, J. Org. Lett. 2002, 4, 4701.
(23) Tanemura, K.; Suzuki, T.; Horaguchi, T. J. Chem. Soc., Perkin Trans.
1 1992, 2997.
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Ding and Jennings
SCHEME 9. First Generation Retrosynthetic Analysis of Triene 5
SCHEME 10. Attempted Synthesis of 46 via Pd Cross-Coupling
free hydroxy pyran. In lieu of selective deprotection, global
desilylation of 32 was carried out with TBAF and the corre-
sponding 1,2-diol 33 was reprotected as the acetonide 34 in
81% yield over two steps. Oxidation of the free hydroxyl group
resident in 34 was accomplished with PCC to afford ketone
35. Subsequent transformation of the carbonyl moiety, via the
methylene Wittig reagent, to the cis-2,6-disubstituted 4-exo-
methylene tetrahydropyran unit 36, which possessed all the
functionality required for the synthesis of 3. The relative
configuration of the ꢀ-C-glycoside subunit 36 was confirmed
by NOE enhancements as shown in Scheme 8.
hydroboration or a hydrozirconationftransmetalation of 44.24
The vinyl iodide 40 would be the product of a Negishi anti-
carboalumination-iodination procedure of the homopropargylic
alcohol 41.25
With our design in mind for the completion of 5 by means
of a Pd-catalyzed cross-coupling reaction, we initiated the
synthesis of vinyl iodide 40 via a Negishi anti-carboalu-
mination-iodination reaction sequence from commercially
available 41, as illustrated in Scheme 10. Interestingly, when
AlMe3 was used as a solution in hexane in conjunction with
Cp2ZrCl2 under the reported conditions25 (ClCH2CH2Cl and 48 h
at reflux), the anti-carboalumination/iodination reaction of 41
provided 45 in a low yield (∼30%) and as a 3:1 mixture of Z
to E isomers. Much to our delight, we found that using the neat
AlMe3 reagent provided a much higher yield and virtually
isomerically pure vinyl iodide 45 under identical conditions.
With 45 in hand, an ensuing silylation of the free hydroxyl group
with TBSCl and imidazole furnished the protected electrophilic
First Generation Retrosynthetic Analysis of Triene (5).
With the completion of the ꢀ-C-glycoside 36, our next objective
was the completion of the triene subunit 5. We initially
envisaged that 5 would be derived from 37 after a series of
protecting group shuffles and final oxidation of an allylic primary
alcohol at C1 as described in Scheme 9. In turn, 37 would be
the product of a vinyl Grignard addition to the labile aldehyde
moiety of 38. The conjugated diene was envisioned to be the
product of a Pd-catalyzed cross-coupling reaction with either
the boronate 42 or zincate 43 and vinyl iodide 40. Both of the
nucleophilic coupling partners would be derived from either a
(24) For the seminal contribution from the Negishi laboratory, see: (a)
Negishi, E.; Okukado, N.; King, A. O.; Van Horn, D. E.; Spiegel, B. I. J. Am.
Chem. Soc. 1978, 100, 2254. For a review on the synthetic utility of the zirconium
transmetalation to zinc process, see: (b) Wipf, P.; Kendall, C. Chem.sEur. J.
2002, 8, 1778.
(25) Ma, S.; Negishi, E.-I. J. Org. Chem. 1997, 62, 784.
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Synthesis of (-)-Dactylolide and (-)-Zampanolide
SCHEME 11. Second Generation Retrosynthetic Analysis of Triene 5
SCHEME 12. Successful Completion of the Required Triene 5
coupling partner 40 in a 88% yield and set the stage for the
Pd-catalyzed cross-coupling between 42 and 40. Initial hy-
droboration of 44 with catecholborane readily provided the in
situ formed vinyl boronate 42, which subsequently underwent
Pd-catalyzed cross-coupling with 40 via Pd(PPh3)4 and aq
K2CO3 to furnish 46 as an isomerically pure diene but in a very
low yield of 22%. After multiple unsuccessful attempts of
improving the yield for the cross-coupling by changing the base
(i.e., aq NaOH, NaHCO3, CsF) and catalyst [Pd(PPh3)2Cl2 and
Pd(dppf)Cl2] involved for the synthesis of 46, we decided to
investigate the possibility of utilizing a Negishi cross-coupling
in place of the traditional Suzuki reaction.26
Similar to the hydroboration of 44, we attempted a hydrozir-
conation of 44 with Schwartz’s reagent27 followed by trans-
metalation of the vinyl zirconcene with ZnCl2 in anticipation
of forming the vinyl (or bisvinyl) zinc compound 43 followed
by an ensuing Pd-catalyzed cross-coupling with 40 to provide
the much desired diene 46. Unfortunately, we isolated only ∼5%
of the desired diene 46, with major decomposition of the vinyl
iodide 40. Since the two Pd-catalyzed cross-couplings failed to
provide any useful amounts of 46, we decided to abandon this
specific synthetic plan and redesign a new route to the C1-C9
portion of 1.
Second Generation Retrosynthetic Analysis of Triene
(5). Our second approach to the “triene northern hemisphere”
C1-C9 subunit 4 focused on a diastereoselective Horner-Emmons
olefination in anticipation of providing the conjugated (E,Z)-
diene 49 (Scheme 11), which in turn would allow for the
introduction of the final terminal alkene moiety (as an incon-
sequential mixture of hydroxyl epimers at C7) via a vinyl
Grignard addition to the corresponding aldehyde 48.
With the failed Pd-catalyzed cross-coupling route described
above, attention was then focused on a second approach to the
triene C1-C9 subunit. Accordingly, the known R,ꢀ-unsaturated
aldehyde 5028 was treated with the corresponding Horner-
Emmons reagent which afforded the expected (E,Z)-conjugated
ester 51 in a virtually quantitative yield with an E/Z ratio of
∼10:1 as shown in Scheme 12. Subsequent HF-pyridine-
mediated desilylation of the TBS group resident in 51 furnished
the free hydroxyl intermediate 49 in a 90% yield over two steps.
Ensuing Dess-Martin oxidation29 of the corresponding ho-
moallylic alcohol afforded the labile aldehyde 48 with a modest
61% yield. Presumably due to the highly acidic nature of the
R-proton, addition of the vinyl Grignard reagent allowed for
the formation of the desired allylic alcohol 47 as an inconse-
quential racemic mixture at C7 with a moderate yield of 49%.
Lastly, protection of the allylic alcohol as a TBS ether (TBSCl,
imidazole) and hydrolysis (NaOH, EtOH) of the ester group
provided the conjugated acid 5, which positioned us for the
convergence of the two synthetic intermediates 4 and 5, followed
by the completion of the targeted compound 2.
Total Synthesis of (-)-Dactylolide via a Chemo- and
Diastereoselective RCM Process. To commence the conver-
gence of 4 and 5, selective access to the stereogenic secondary
alcohol of 36 was essential as delineated in Scheme 13. Along
this line, the acetonide protecting group resident in 36 was
cleaved under acidic conditions (TFA) to furnish diol 52 in 95%
yield, and subsequently, the primary hydroxyl group of 52 was
selectively reprotected as a TBS ether under standard conditions
in virtually a quantitative yield providing 4. The first attempted
coupling of 4 and 5 utilizing DCC was unsuccessful, giving
the desired ester 53 in low yield along with inseparable
impurities. Fortunately, esterification proceeded smoothly under
Yamaguchi conditions utilizing 2 equiv of 5, affording the
hexaenic ester intermediate 53 as a diastereomeric 3:1 mixture.30
Apparently the two C7 epimers of acid 5 display distinct kinetic
reactivity toward the enantiopure alcohol 4. An ensuing ring-
closing olefin metathesis was then attempted on bis-TBS-
protected hexaene 53, employing a variety of reaction condi-
(26) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457.
(27) Schwartz, J.; Labinger, J. A. Angew. Chem., Int. Ed. Engl. 1976, 15,
333.
(29) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155.
(30) Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M. Bull.
Chem. Soc. Jpn. 1979, 52, 1989.
(28) McLaughlin, M. J.; Hsung, R. P. J. Org. Chem. 2001, 66, 1049.
J. Org. Chem. Vol. 73, No. 15, 2008 5971

Ding and Jennings
SCHEME 13. Completion of 3 and Formal Synthesis of 1 via a Highly Chemoselective RCM
tions. In general, Grubbs’ first generation catalyst31 led to
recovery of the starting material, while the second generation
catalyst resulted in decomposed starting material even at room
temperature. At this point, we conjectured that the TBS
protecting group on allylic alcohol was impeding the ring
closure.32 Unfortunately, cleavage of the silyl ethers was
problematic, due to sensitive functional groups present in 53
giving rise to decomposed products under various reaction
conditions including many fluoride reagents and weak acids.
Finally and much to our delight, aqueous HCl in MeOH was
found to be the most satisfactory condition, providing the diol
54 in 80% yield. Subsequently subjecting the corresponding
intermediate 52 to 10 mol % of catalyst 15 in a 1 mM solution
in CH2Cl2 allowed for successful ring closure within 1 h at rt
to afford the diastereomerically pure (with regards to the alkene
geometries, but as an insignificant 3:1 diastereomeric mixture
at C7) macrolactone 53 in a 93% yield. Pleased by this result,
the very late-stage intermediate 55 was then subjected to
Dess-Martin periodinane (DMP), thus enabling the oxidation
of both the primary and the allylic alcohols and consequently
removing the redundant C7 stereogenic center to afford (-)-
dactylolide (3) as a single diastereomer. It is worth noting that
the bisoxidation with DMP and the subsequent workup of 3
was conducted under strict anhydrous conditions as not to
hydrate the labile aldehyde moiety (see the Experimental Section
for details). The spectral data (1H NMR, 500 MHz; 13C NMR,
TABLE 1. Comparison Data between (-)-Zampanolide,
(-)-Dactylolide, and (+)-Dactylolide
cell line
(-)-zampanolide
(-)-dactylolide
(+)-dactylolide
A549/ATCC
HT29
SK-Mel-28
SK-OV-3
P388
1-5 ng/mL
1-5 ng/mL
1-5 ng/mL
1.72 µg/mL
0.101 µg/mL
2.0 µg/mL
1.8 µg/mL
3.2 µg/mLa
3.2 µg/mLb
1-5 ng/mL
L1210
a IC50 or GI50 values. b GI40 value. c GI63 value.
dactylolide could readily be converted to (-)-zampanolide via
the “aluminum aza-aldol” sequence as reported by Hoye.4a
In Vitro Evaluation of (-)-Dactylolide. As mentioned in
the Introduction, the biological profile comparison between nat
1 and nat 2 is not the correct approach to evaluate the true
importance of the N-acyl aminal side chain of 1 (remember that
nat 1 and unnat 2 share the same enantiomeric macrocyclic
core). Initially, we surmised that the enantiomeric relationship
of the macrocyclic cores (Figure 1) may play a major role in
the decreased biological activity of nat 2 versus nat 1. With
this in mind, we synthesized the unnat 2 and sent a 7 mg sample
to the NCI for in vitro evaluation versus the 60-cell panel. The
results from this screening are highlighted in Tables 1 and 2.
As shown in Table 1, a direct comparison between (-)-
zampanolide, (-)-dactylolide (unnat), and (+)-dactylolide has
been made. The data strongly suggest that the N-acyl hemi-
aminal side chain of zampanolide does indeed play a dramatic
role in the nanomolar IC50 values against the four cell lines
tested. Our sample of (-)-dactylolide, in a direct comparison
with (-)-zampanolide against the A549, HT29, and SK-Mel-
28 lines, was 10- to 1000-fold less active (GI50) than that of
(-)-zampanolide. These results suggest that the “double”
hydrogen bonding network of (-)-zampanolide might be crucial
for the reported nanomolar activities. On the basis of the limited
125 MHz), optical rotation ([R]rt -136, c 1.2, MeOH), and
D
HRMS data of synthetic (-)-dactylolide were in complete
agreement with those previously reported.2–4 Finally, (-)-
(31) Schwab, P.; France, M. B.; Ziller, J. W.; Grubbs, R. H. Angew. Chem.,
Int. Ed. Engl. 1995, 34, 2039.
(32) Hoye reported ring closure via olefin metathesis at the same C8-C9
alkene with a compound that is structurally related to 53. Similar obstacles with
respect to ring-closing olefin metathesis have been described; see: Matsuya, Y.;
Kawaguchi, T.; Nemoto, H. Org. Lett. 2003, 5, 2939.
5972 J. Org. Chem. Vol. 73, No. 15, 2008

Synthesis of (-)-Dactylolide and (-)-Zampanolide
TABLE 2. NCI 60 Cell Line In Vitro Data for (-)-Dactylolide
Conclusion
cell line
cancer type
GI50
GI50 [M]
LC50 [M]
6.03 × 10-5
In conclusion, we have completed a highly convergent total
synthesis of (-)-dactylolide and a formal synthesis of (-)-
zampanolide. Key features of the synthetic strategy included a
chemo- and diastereoselective 20-membered macrocyclization
via a ring-closing olefin metathesis utilizing Grubbs’ second
generation catalyst and a tandem nucleophilic addition-di-
astereoselective axial reduction of an in situ generated oxocar-
benium cation to forge the central ꢀ-C-glycoside subunit. The
prospect of a late-stage addition of the amide framework to (-)-
dactylolide now allows for the synthesis of a variety of
analogues to examine bioactivity of structurally diverse “zam-
panolide-like” compounds against a variety of tumor cell lines.
In addition, in vitro screening of the antipode of natural
dactylolide against the NCI’s 60 cancer cell line helped to
illuminate the critical importance of the N-acyl hemiaminal side
chain of natural zampanolide with respect to the potent
nanomolar cytotoxicities as reported by Tanaka and Higa.
Furthermore, by means of the in vitro screen of (-)-dactylolide,
a promising cancer therapeutic lead has now emerged for a
variety of carcinomas. More specifically, (-)-dactylolide ex-
hibited GI50 values in the nanomolar (25-99 ng/mL) range
against the four cell lines HL-60, K-562, HCC-2998, and SF-
539, while displaying modest LC50 values. These results
underscore the importance that (+)-dactylolide was only tested
on one human tumor cell line and clearly illustrates the need
for synthetic natural product molecules (or in this case the
antipode) for the undertaking of in vitro biological testing. By
simply synthesizing (-)-dactylolide and providing the NCI with
a small sample for testing, a promising therapeutic has now
emerged. Further investigations into determining the mechanism
of action against a variety of tumors for 3 are underway and
will be reported in due course.
CCRF-CEM
HL-60(TB)
K-562
RPMI-8226
SR
Leukemia
Leukemia
Leukemia
Leukemia
Leukemia
0.148 µg/mL 3.84 × 10-7
0.094 µg/mL 2.43 × 10-7 >1.00 × 10-4
0.025 µg/mL 6.38 × 10-8 >1.00 × 10-4
0.117 µg/mL 3.05 × 10-7 >1.00 × 10-4
0.175 µg/mL 4.54 × 10-7 >1.00 × 10-4
HOP-92
Non-Small 0.193 µg/mL 5.02 × 10-7
3.51 × 10-5
Cell Lung
COLO 205
HCC-2998
HCT-116
HCT-15
HT29
Colon
Colon
Colon
Colon
Colon
Colon
Colon
CNS
0.147 µg/mL 3.81 × 10-7
0.077 µg/mL 2.00 × 10-7
0.133 µg/mL 3.46 × 10-7
0.174 µg/mL 4.53 × 10-7
0.101 µg/mL 2.63 × 10-7
0.222 µg/mL 5.76 × 10-7
0.173 µg/mL 4.50 × 10-7
0.231 µg/mL 6.02 × 10-7
0.099 µg/mL 2.58 × 10-7
5.12 × 10-5
3.16 × 10-5
5.49 × 10-6
4.62 × 10-5
4.87 × 10-5
8.57 × 10-5
4.69 × 10-5
9.56 × 10-5
2.50 × 10-5
4.07 × 10-5
4.07 × 10-5
3.18 × 10-5
7.14 × 10-5
KM12
SW-620
SF-268
SF-539
SNB-75
U251
LOX IMVI
M14
IGROV1
OVCAR-3
786-0
SN12C
PC-3
DU-145
MCF7
NCI/ADR-RES Breast
MDA-MB-435 Breast
BT-549
T-47D
CNS
CNS
CNS
0.120 µg/mL 3.12 × 10-7 >1.00 × 10-4
0.200 µg/mL 5.19 × 10-7
Melanoma 0.266 µg/mL 6.92 × 10-7
Melanoma 0.108 µg/mL 2.81 × 10-7
Ovarian
Ovarian
Renal
0.185 µg/mL 4.81 × 10-7
0.316 µg/mL 8.22 × 10-7 >1.00 × 10-4
0.324 µg/mL 8.41 × 10-7
0.286 µg/mL 7.43 × 10-7
0.149 µg/mL 3.86 × 10-7
0.133 µg/mL 3.47 × 10-7
0.076 µg/mL 1.98 × 10-7
8.01 × 10-5
6.52 × 10-5
8.03 × 10-5
2.32 × 10-5
5.20 × 10-5
Renal
Prostate
Prostate
Breast
0.269 µg/mL 6.99 × 10-7 >1.00 × 10-4
0.122 µg/mL 3.16 × 10-7 >1.00 × 10-4
Breast
Breast
0.121 µg/mL 3.15 × 10-7
3.74 × 10-5
0.295 µg/mL 7.67 × 10-7 >1.00 × 10-4
bioassay data from Riccio, our data were compared to that of
(+)-dactylolide against only one cell line. The natural (+)-
dactylolide showed a GI40 value of 3.2 µg/mL against the SK-
OV-3 line, whereas (-)-dactylolide exhibited a GI50 of 1.8 µg/
mL. This result demonstrates that the unnatural (-)-dactylolide
is roughly 2- to 3-fold times more active against this specific
line than that of (+)-dactylolide and helps shed some preliminary
light on the structural relationship between (-)-zampanolide,
(-)-dactylolide, and (+)-dactylolide.
In addition to the comparisons shown in Table 1, the NCI in
vitro assay data provided a much more detailed biological profile
of the unnatural (-)-dactylolide, as shown in Table 2. First,
only values of <0.350 µg/mL were placed into the table as the
higher values GI50 were not included. A few trends are readily
observable as described below.
Experimental Section
5,6-Bis(tert-butyldimethylsilanyloxy)hex-2-ynoic acid ethyl
ester (23): To a solution of alkyne 24 (7.37 g, 22.5 mmol) in THF
(63 mL) at -78 °C was added BuLi (1.6 M in hexanes, 21 mL,
33.7 mmol) dropwise and stirred for 15 min. Then, ethyl chloro-
formate (6.45 mL, 67.5 mmol) was added, and the solution was
warmed to rt and stirred for 45 min before being quenched with a
saturated NaHCO3 solution (60 mL). The aqueous phase was
extracted with Et2O (3 × 60 mL). The organic layers were
combined, dried over Na2SO4, and concentrated under reduced
pressure. Flash column chromatography (silica, 2% EtOAc in
hexanes) afforded the pure alkynoate (Rf ) 0.40, 2% EtOAc in
hexanes) as a colorless oil (9.5 g, 94%): 1H NMR (360 MHz,
CDCl3) δ 4.21 (q, J ) 7.2 Hz, 2H), 3.87 (m, 1H), 3.59 (dd, J )
10.2, 4.9 Hz, 1H), 3.48 (dd, J ) 10.2, 6.9 Hz, 1H), 2.65 (dd, J )
17.0, 4.7 Hz, 1H), 2.43 (dd, J ) 17.0, 6.6 Hz, 1H), 1.29 (t, J )
7.2, 3H), 0.89 (s, 18H), 0.12 (s, 3H), 0.08 (s, 3H), 0.06 (s, 6H);
13C NMR (90 MHz, CDCl3) δ 154.9, 87.2, 74.8, 71.4, 66.7, 62.1,
35.2, 26.1, 25.0, 23.3, 18.3, 14.2, -4.3, -4.6, -5.1, -5.2; [R]20
The first is that (-)-dactylolide exhibits GI50 values in the
nanomolar (25-99 ng/mL) range against the four cell lines HL-
60, K-562, HCC-2998, and SF-539. This is important to note
due to the fact that (+)-dactylolide was only tested on one
human line and clearly illustrates the need for synthetic natural
product molecules for the undertaking of in vitro biological
testing. By simply synthesizing (-)-dactylolide and providing
the NCI with a small sample for testing, a promising cancer
therapeutic has now emerged for a variety of carcinomas. A
second important fact that was uncovered by the NCI was that
(-)-dactylolide exhibits extensive growth inhibition (GI50) but
is not excessively cytotoxic against most all of the leukemia
and breast cell lines (and even other tumor lines as delineated
-6.4 (c 0.90, CH2Cl2); IR (CH2Cl2) 1710, 1471, 1115, 1082 cm-1D
;
HRMS (ESI) calcd for C20H41O4Si2 (M + H)+ 401.2543, found
401.2528.
5,6-Bis(tert-butyldimethylsilanyloxy)-3-methylhex-2-enoic acid
ethyl ester (26): To a stirred solution of NaOMe (61 mg, 1.1 mmol)
in MeOH (54 mL) were added PhSH (2.86 mL, 28.0 mmol) and
alkynoate 23 (9.0 g, 22.5 mmol) and stirred for 20 h at rt. The
reaction mixture was then filtered through a silica plug with Et2O
as eluent. The filtrate was then concentrated under reduced pressure.
Flash column chromatography (silica, 10% EtOAc in hexanes)
afforded the alkenoate 25 (Rf ) 0.40, 10% EtOAc in hexanes) as
in Table 2) due to the higher LC50 concentrations >1.00 × 10-4
.
Our next challenges include deciphering the true nature of the
N-acyl hemiaminal side chain of 1 and understanding the
mechanism of action of (-)-dactylolide and (-)-zampanolide
analogues against specific tumor cell lines. The results from
these future studies will be reported in due course.
J. Org. Chem. Vol. 73, No. 15, 2008 5973

Ding and Jennings
1
a pale yellow oil (10.35 g, 90%): H NMR (360 MHz, CDCl3) δ
chromatography (silica, 2% EtOAc in hexanes) afforded the acrylate
7.51 (m, 2H), 7.35 (m, 3H), 5.94 (s, 1H), 4.21 (m, 2H), 3.63 (m,
1H), 3.33 (dd, J ) 10.0, 5.0 Hz, 1H), 3.15 (dd, J ) 10.0, 5.6 Hz,
1H), 1.29 (t, J ) 7.2 Hz, 3H), 0.82 (s, 9H), 0.79 (s, 9H), -0.01 (s,
3H), -0.04 (s, 3H), -0.09 (s, 6H); 13C NMR (90 MHz, CDCl3) δ
166.1, 156.9, 135.6, 131.5, 129.4, 115.9, 71.8, 67.6, 60.1, 41.8,
18.3, 15.5, 14.3, -4.2, -4.6, -5.2, -5.3; HRMS (ESI) calcd for
C21H38O3Si (M + H)+ 366.2590, found 366.2593.
21 (Rf ) 0.40, 10% EtOAc in hexanes) as a colorless oil (5.12 g,
1
79%): H NMR (360 MHz, CDCl3) δ 6.37 (dd, J ) 17.2, 1.3 Hz,
1H), 6.07 (dd, J ) 17.2, 10.0 Hz, 1H), 5.78 (dd, J ) 10.0, 1.3 Hz,
1H), 5.68 (m, 2H), 5.24 (dd, J ) 9.3, 1.2 Hz, 1H), 5.06 (m, 2H),
3.75 (ddd, J ) 12.5,11.6, 5.6 Hz, 1H), 3.48 (dd, J ) 10.0, 5.4 Hz,
1H), 3.38 (dd, J ) 10.0, 6.1 Hz, 1H), 2.40 (m, 2H), 2.31 (dd, J )
13.9, 6.0 Hz, 1H), 2.06 (dd, J ) 13.9, 6.5 Hz, 1H), 1.75 (d, J )
1.1 Hz, 3H), 0.89 (s, 9H), 0.85 (s, 9H), 0.04 (s, 6H), 0.03 (s, 3H),
0.0 (s, 3H); 13C NMR (90 MHz, CDCl3) δ 165.7, 138.3, 133.7,
130.8, 129.5, 125.7, 118.2, 71.8, 70.7, 67.3, 45.0, 39.6, 26.2, 26.1,
A solution of MeMgBr (3.0 M in Et2O, 473 µL, 1.42 mmol)
was added dropwise into a suspension of CuI (296 mg, 1.56 mmol)
in THF (4.7 mL) at -78 °C. The reaction mixture was warmed to
rt and then recooled to -78 °C. Next, a solution of the thioether
25 (0.50 g, 0.98 mmol) in THF (0.5 mL) was added, and the
resultant solution was warmed to 0 °C and allowed to stir for 1 h.
Water (0.5 mL) was then added, and the mixture was diluted with
Et2O (20 mL). The organic phase was separated and then dried
over Na2SO4. The resultant organic phase was then filtered through
a silica plug, which was then eluted with Et2O (10 mL). The
combined organics were concentrated under reduced pressure to
afford the product 26 (Rf ) 0.55, 10% EtOAc in hexanes) as a
18.6, 18.3, 17.7, -4.2, -4.6, -5,08, -5.13; [R]20 -8.2 (c 0.17,
D
CH2Cl2); IR (CH2Cl2) 1715, 1409, 1201 cm-1; HRMS (ESI) calcd
for C25H48O4Si2Na (M + Na)+ 491.2989, found 491.2995.
To a solution of acrylate 21 (2.29 g, 4.90 mmol) in CH2Cl2 (300
mL) was added Grubbs’ second generation catalyst (0.208 g, 0.245
mmol), and the solution was heated under reflux for 16 h until
completion by TLC analysis. The solvent was removed under
reduced pressure, and flash column chromatography (silica, 20%
EtOAc in hexanes) afforded the lactenone 29 (Rf ) 0.28, 20%
EtOAc in hexanes) as a colorless oil (2.06 g, 96%): 1H NMR (360
MHz, CDCl3) δ 6.87 (dddd, J ) 13.2, 8.5, 3.6, 1.4 Hz, 1H), 6.03
(ddd, J ) 13.2, 1.7, 1.7 Hz, 1H), 5.40 (dd, J ) 8.4, 0.9 Hz, 1H),
5.15 (m, 1H), 3.77 (ddd, J ) 11.6, 5.2, 1.4 Hz, 1H), 3.51 (dd, J )
10.0, 5.1 Hz, 1H), 3.39 (dd, J ) 10.0, 6.5 Hz, 1H), 2.37 (m, 3H),
2.08 (dd, J ) 13.5, 7.0 Hz, 1H), 1.76 (d, J ) 1.4 Hz, 1H), 0.89 (s,
9H), 0.88 (s, 9H), 0.05 (s, 12H); 13C NMR (90 MHz, CDCl3) δ
164.6, 144.9, 140.6, 124.9, 122.0, 75.0, 72.4, 67.1, 44.6, 29.9, 26.2,
26.1, 18.5, 18.3, 18.1, -4.2, -4.5, -5.09, -5.12; [R]20D -12.2 (c
0.17, CH2Cl2); IR (CH2Cl2) 1719, 1424 cm-1; HRMS (ESI) calcd
for C23H45O4Si2 (M + H)+ 441.2856, found 441.2860.
1
colorless oil (395 mg, 97%): H NMR (360 MHz, CDCl3) δ 5.70
(s, 1H), 4.14 (m, 2H), 3.81 (m, 1H), 3.54 (dd, J ) 9.9, 5.0 Hz,
1H), 3.37 (dd, J ) 9.9, 6.8 Hz, 1H), 2.45 (dd, J ) 12.7, 3.8 Hz,
1H), 2.18 (d, J ) 1.4 Hz, 3H), 2.15 (dd, J ) 12.7, 7.9 Hz, 1H),
1.26 (t, J ) 7.0 Hz, 3H), 0.89 (s, 9H), 0.86 (s, 9H), 0.05 (s, 6H),
0.03 (s, 3H), 0.0 (s, 3H); 13C NMR (90 MHz, CDCl3) δ 166.8,
156.9, 118.5, 71.8, 67.3, 59.6, 46.2, 26.2, 26.0, 25.7, 19.7, 18.5,
18.3, 15.5, 14.3, -4.2, -4.7, -5.1, -5.2; [R]20 -7.7 (c 2.35,
D
CH2Cl2); IR (CH2Cl2) 1713, 1653, 1474, 1226, 1154, 1094 cm-1
;
HRMS (ESI) calcd for C21H45O4Si2 (M + H)+ 417.2856, found
417.2860.
8,9-Bis(tert-butyldimethylsilanyloxy)-6-methylnona-1,5-dien-
4-ol (28): To a stirred solution of (-)-Ipc2BOMe (10.0 g, 31.9
mmol) in anhydrous Et2O (32 mL) at 0 °C was added allylmag-
nesium bromide (1.0 M solution in ether, 29.0 mL), and the reaction
mixture was stirred at rt for 1 h before being cooled to -78 °C.
The aldehyde 22 (7.18 g, 19.3 mmol) was then added dropwise
into the Ipc2Ballyl solution and allowed to stir for 1 h and then
warm slowly to rt. An aqueous solution of NaOH (3 M, 12.8 mL)
was then added, followed by slow addition of a 30% H2O2 solution
(25.5 mL). The mixture was refluxed for 3 h to complete the
oxidation process. After being cooled to rt, the biphasic solution
was separated, and the aqueous layer was extracted with ether (3
× 50 mL). The combined organics were dried over Na2SO4 and
concentrated under vacuum to yield the crude product. Flash column
chromatography (silica, 10% EtOAc in hexanes) afforded the
homoallylic alcohol 28 (Rf ) 0.50, 20% EtOAc in hexanes) as a
colorless oil (5.70 g, 71%) along with other isomers (two diaster-
eomers for each of the Z/E isomers, 88% combined yield, 90%
6-[4,5-Bis(tert-butyldimethylsilanyloxy)-2-methylpent-1-enyl]-
4-hydroxytetrahydropyran-2-one (20): To a solution of the
lactenone 29 (0.600 g, 1.36 mmol) in MeOH (6.8 mL) was added
an aqueous H2O2 solution (30%, 488 mg, 4.58 mmol). The solution
was cooled to 0 °C, and an aqueous NaOH solution (6.0 M, 0.14
mL, 0.82 mmol) was added dropwise and stirred for 10 min. The
reaction mixture was then warmed to rt and kept stirring for 0.5 h,
before being diluted with Et2O (15 mL) and H2O (15 mL).
Concentrated aqueous HCl solution was added to adjust the pH to
4. The aqueous layer was extracted with Et2O (2 × 15 mL), and
the combined organics were washed with brine (10 mL). After being
dried over Na2SO4, the organic solution was concentrated under
reduced pressure. The residue was redissolved in benzene (3.4 mL),
and the resultant solution was refluxed for 15 min using a
Dean-Stark apparatus to remove water. After solvent evaporation,
flash column chromatography (silica, 20% EtOAc in hexanes)
afforded the epoxide 30 (Rf ) 0.32, 20% EtOAc in hexanes) as a
colorless viscous oil (515 mg, 83%): 1H NMR (360 MHz, CDCl3)
δ 5.22 (ddd, J ) 18.7, 8.8, 3.0 Hz, 1H), 5.21 (d, J ) 1.5, 1H),
3.75 (ddd, J ) 11.8, 5.0, 1.8 Hz, 1H), 3.66 (dd, J ) 6.8, 3.9 Hz,
1H), 3.58 (d, J ) 4.1 Hz, 1H), 3.50 (dd, J ) 10.0, 5.1 Hz, 1H),
3.37 (dd, J ) 10.0, 6.6 Hz, 1H), 2.33 (m, 2H), 2.05 (m, 2H), 1.73
(d, J ) 0.7 Hz, 3H), 0.89 (s, 9H), 0.87 (s, 9H), 0.044 (s, 3H),
0.040 (s, 6H), 0.035 (s, 3H); 13C NMR (90 MHz, CDCl3) δ 167.9,
140.5, 123.8, 72.2, 70.7, 67.1, 52.3, 49.3, 44.4, 30.1, 26.2, 26.1,
1
de): H NMR (360 MHz, CDCl3) δ 5.81 (m, 1H), 5.25 (dd, J )
8.5, 1.0 Hz, 1H), 5.12 (m, 2H), 4.41 (dd, J ) 14.6, 6.3 Hz, 1H),
3.77 (ddd, J ) 12.2, 11.2, 5.6 Hz, 1H), 3.49 (dd, J ) 10.0, 4.5 Hz,
1H), 3.41 (dd, J ) 10.0, 4.4 Hz, 1H), 2.31 (dd, J ) 11.4, 6.5 Hz,
1H), 2.28 (m, 2H), 2.05 (dd, J ) 11.4, 6.7 Hz, 1H), 1.72 (d, J )
1.2 Hz, 3H), 0.90 (s, 9H), 0.88 (s, 9H), 0.055 (s, 3H), 0.047 (s,
6H), 0.045 (s, 3H); 13C NMR (90 MHz, CDCl3) δ 136.1, 134.7,
130.2, 118.0, 72.3, 68.0, 67.2, 44.9, 42.3, 26.2, 26.1, 18.6, 18.4,
17.6, -4.05, -4.50, -5.05, -5.11; [R]20D -10.1 (c 1.3, CH2Cl2);
IR (CH2Cl2) 1471, 1120, 1092 cm-1; HRMS (ESI) calcd for
C22H46O3Si2Na (M + Na)+ 437.2883, found 437.2885.
18.6, 18.3, 18.0, -4.2, -4.5, -5.08, -5.10, -5.12; [R]20 +34.2
D
(c 0.37, CH2Cl2); IR (CH2Cl2) 1738, 1473, 1363, 1112, 1080, 1013
cm-1; HRMS (ESI) calcd for C23H45O5Si2 (M + H)+ 457.2806,
found 457.2805.
6-[4,5-Bis(tert-butyldimethylsilanyloxy)-2-methylpent-1-enyl]-
5,6-dihydropyran-2-one (29): To a stirring solution of alcohol 28
(5.70 g, 13.8 mmol), Et3N (4.29 mL, 30.4 mmol), and DMAP (84
mg, 0.70 mmol) in CH2Cl2 (138 mL) at rt was added acryloyl
chloride (2.23 mL, 27.6 mmol) dropwise, and the resulting solution
was stirred for 16 h, before brine (100 mL) was added. The aqueous
layer was extracted with CH2Cl2 (2 × 50 mL), and the combined
organics were washed with brine (50 mL) and dried over Na2SO4,
and the solvent was removed under reduced pressure. Flash column
To a solution of (PhSe)2 (482 mg, 1.55 mmol) in EtOH (8.2
mL) under Ar at rt was added NaBH4 (118 mg, 3.09 mmol) and
stirred for 5 min before being cooled to 0 °C. HOAc (176 µL, 3.09
mmol) was then added dropwise, and the solution was allowed to
stir for 5 min before a solution of epoxide 30 (471 mg, 1.03 mmol)
in EtOH (6.2 mL) was added. The reaction mixture was stirred for
15 min and then diluted with EtOAc (36 mL). The organic solution
was washed with brine (9 mL), and the aqueous layer was then
extracted with EtOAc (2 × 9 mL). The combined organic solution
5974 J. Org. Chem. Vol. 73, No. 15, 2008

Synthesis of (-)-Dactylolide and (-)-Zampanolide
was dried over Na2SO4 and concentrated under reduced pressure.
Flash column chromatography (silica, 1:1 EtOAc:hexanes) afforded
the alcohol 20 (Rf ) 0.30, 1:1 EtOAc/hexanes) as a pale yellow
oil (368 mg, 78%): 1H NMR (360 MHz, CDCl3) δ 5.42 (ddd, J )
8.8, 8.8, 3.4 Hz, 1H), 5.28 (d, J ) 8.6 Hz, 1H), 4.37 (ddd, J ) 7.6,
3.9, 3.9 Hz, 1H), 3.76 (ddd, J ) 11.6, 5.5, 5.5 Hz, 1H), 3.50 (dd,
J ) 10.1, 5.5 Hz, 1H), 3.38 (dd, J ) 10.1, 6.4 Hz, 1H), 2.71 (dd,
J ) 17.7, 4.9 Hz, 1H), 2.61 (ddd, J ) 17.7, 3.4, 1.3 Hz, 1H), 2.34
(dd, J ) 13.4, 4.9 Hz, 1H), 2.07 (dd, J ) 13.4, 7.0 Hz, 1H), 1.93
(ddd, J ) 14.2, 3.9, 3.9 Hz, 1H), 1.82 (dd, J ) 14.2, 3.4 Hz, 1H),
1.76 (s, 3H), 0.88 (s, 9H), 0.86 (s, 9H), 0.04 (s, 12H); 13C NMR
(90 MHz, CDCl3) δ 170.7, 139.6, 125.3, 73.0, 72.2, 67.1, 63.0,
44.5, 38.9, 36.3, 26.2, 26.1, 18.5, 18.3, 17.9, -4.21, -4.50, -5.10,
134.8, 128.4, 117.1, 109.1, 108.9, 78.0, 75.7, 74.8, 69.5, 43.8, 41.0,
40.2, 27.2, 26.0, 17.7; HRMS (EI) calcd for C18H28O3 (M+)
292.2038, found 292.2031.
7-Hydroxy-5-methylhepta-2,4-dienoic acid ethyl ester (49):
To a solution of triethyl phosphonoacetate (6.91 mL, 34.5 mmol)
in THF (34 mL) was added LiHMDS (1.0 M in THF, 34.5 mL,
34.5 mmol) dropwise, and the reaction was allowed to stir for 15
min at 0 °C. A solution of the enal 50 (3.95 g, 17.2 mmol) in THF
(52 mL) was then added, and the reaction mixture was warmed to
rt and stirred for 1 h, before being diluted with Et2O (100 mL) and
quenched with H2O (30 mL). The aqueous solution was extracted
with Et2O (3 × 30 mL), and the combined organics were dried
over Na2SO4 and concentrated under reduced pressure. Flash
column chromatography (silica, 5% EtOAc in hexanes) afforded
the dienoate 51 (Rf ) 0.40, 10% EtOAc in hexanes) as a colorless
-5.12; [R]20 +14.3 (c 0.20, CH2Cl2); IR (CH2Cl2) 1728, 1424
D
cm-1; HRMS (ESI) calcd for C23H47O5Si2 (M + H)+ 459.2962,
1
found 459.2960.
oil (5.03 g, 98%): H NMR (360 MHz, CDCl3) δ 7.54 (dd, J )
15.3, 11.8 Hz, 1H), 6.05 (d, J ) 11.6 Hz, 1H), 5.75 (d, J ) 15.1
Hz, 1H), 4.19 (g, J ) 7.5 Hz, 2H), 3.70 (t, J ) 6.5 Hz, 2H), 2.50
(t, J ) 6.6 Hz, 2H), 1.90 (s, 3H), 1.29 (t, J ) 7.4 Hz, 3H), 0.87 (s,
9H), 0.04 (s, 6H); 13C NMR (90 MHz, CDCl3) δ 167.7, 147.1,
141.1, 125.7, 119.5, 61.9, 60.2, 39.2, 36.7, 26.2, 25.2, 14.5, -5.1;
IR (CH2Cl2) 1704, 1637, 1156, 1101 cm-1; HRMS (ESI) calcd for
C16H31O3Si (M + H)+ 299.2042, found 299.2047.
2-Allyl-6-[4,5-bis(tert-butyldimethylsilanyloxy)-2-methylpent-
1-enyl]-4-triethylsilanyloxytetrahydropyran (32): To a solution
of lactone 20 (57 mg, 0.12 mmol) in Et2O (1.2 mL) at -78 °C was
added allylMgBr (1.0 M in Et2O, 0.37 mL, 0.37 mmol) dropwise,
and the suspension was stirred for 0.5 h, before being quenched
with H2O (1.2 mL) and then diluted with EtOAc (25 mL). The
mixture was dried over Na2SO4, and the solvents were removed
under reduced pressure to afford the hemiketal 31 (Rf ) 0.60, 1:1
EtOAc:hexanes) as a colorless oil (53 mg). This material was used
without further purification.
To a solution of the silyl ether 51 (298 mg, 1.0 mmol) in THF
(10 mL) was added a Py•HF solution (65% in Py, 0.3 mL, ∼10.0
mmol) and stirred for 4 h. The reaction mixture was then diluted
with Et2O (30 mL) and quenched with a saturated NaHCO3 solution
(10 mL) along with solid NaHCO3 until no gas was evolved. The
aqueous layer was extracted with EtOAc (3 × 10 mL), and the
combined organics were dried over Na2SO4. Evaporation of solvents
afforded the alcohol 49 (Rf ) 0.30, 1:1 EtOAc/hexanes) as a pale
To a solution of the hemiketal 31 (53 mg, 0.11 mmol) in CH2Cl2
(1.1 mL) were added Et3SiH (0.18 mL, 1.1 mmol) in one portion
and TFA (41 µL, 0.55 mmol) sequentially. The solution was then
warmed to -40 °C and kept stirring for 0.5 h, before being
quenched with a saturated NaHCO3 solution (1.1 mL). The mixture
was diluted with Et2O (25 mL) and dried over Na2SO4. The solvents
were then removed under reduced pressure. Flash column chro-
matography (silica, 5% EtOAc in hexanes) afforded the tetrahy-
dropyran 32 (Rf ) 0.50, 10% EtOAc in hexanes) as a pale yellow
1
yellow oil (169 mg, 92%) without further purification: H NMR
(360 MHz, CDCl3) δ 7.54 (dd, J ) 15.1, 11.7 Hz, 1H), 6.09 (d, J
) 11.7 Hz, 1H), 5.77 (d, J ) 15.5 Hz, 1H), 4.17 (q, J ) 7.2 Hz,
2H), 3.72 (t, J ) 6.7 Hz, 2H), 2.55 (t, J ) 6.7 Hz, 2H), 1.90 (s,
3H), 1.27 (t, J ) 7.2 Hz, 3H); 13C NMR (90 MHz, CDCl3) δ 167.9,
146.4, 140.5, 126.1, 119.7, 60.9, 60.4, 36.2, 24.7, 14.5; IR (CH2Cl2)
1704, 1637, 1154 cm-1; HRMS (ESI) calcd for C10H17O3 (M +
H)+ 185.1178, found 185.1168.
1
oil (55 mg, 76%): H NMR (360 MHz, CDCl3) δ 5.84 (m, 1H),
5.20 (d, J ) 7.9 Hz, 1H), 5.07 - 4.99 (m, 2H), 4.54 (ddd, J )
13.5, 8.3, 5.2 Hz, 1H), 4.18 (m, 1H), 3.88 (m, 1H), 3.75 (ddd, J )
11.8, 11.8, 5.8 Hz, 1H), 3.52 - 3.36 (m, 2H), 2.33 - 2.25 (m,
2H), 2.13 (dd, J ) 13.3, 6.8 Hz, 1H), 2.01 (dd, J ) 13.3, 6.8 Hz,
1H), 1.70 (s, 3H), 1.64 - 1.19 (m, 4H), 0.96 (t, J ) 8.0 Hz, 9H),
0.89 (s, 9H), 0.87 (s, 9H), 0.58 (q, J ) 8.0 Hz, 6H), 0.045 (s, 3H),
0.041 (s, 3H), 0.035 (s, 6H); 13C NMR (90 MHz, CDCl3) δ 135.5,
135.3, 129.1, 116.5, 72.7, 71.3, 69.3, 67.5, 65.2, 44.9, 40.9, 39.8,
38.9, 26.2, 26.1, 18.6, 17.9, 7.1, 5.1, -4.2, -4.5, -5.06, -5.14;
[R]20D -3.3 (c 0.30, CH2Cl2); IR (CH2Cl2) 1471, 1081 cm-1; HRMS
(ESI) calcd for C32H67O4Si3 (M + H)+ 599.4347, found 599.4353.
2-Allyl-6-[3-(2,2-dimethyl-[1,3]dioxolan-4-yl)-2-methylprope-
nyl]-4-methylenetetrahydropyran (36): To a stirred solution of
MePh3PBr (129 mg, 0.36 mmol) in anhydrous THF (2.1 mL) at
7-Hydroxy-5-methylnona-2,4,8-trienoic acid ethyl ester (47):
To a stirred solution of alcohol 49 (1.00 g, 5.43 mmol) in CH2Cl2
at 0 °C was added Dess-Martin periodinane (15% in CH2Cl2, 17
mL, 8.14 mmol), and the reaction mixture was warmed to rt and
allowed to stir for 1 h. After completion by TLC analysis, the
reaction was quenched with isopropanol (6 mL) and the mixture
was filtered through a silica gel plug using EtOAc as the eluent.
The combined organics were concentrated under reduced pressure.
Flash column chromatography (silica, 30% EtOAc in hexanes)
afforded the aldehyde 48 (Rf ) 0.35, 30% EtOAc in hexanes) as a
1
pale yellow oil (602 mg, 61%): H NMR (360 MHz, CDCl3) δ
n
9.59 (t, J ) 1.8 Hz, 1H), 7.39 (dd, J ) 15.1, 11.7 Hz, 1H), 6.21 (d,
J ) 11.7 Hz, 1H), 5.83 (d, J ) 15.1 Hz, 1H), 4.16 (q, J ) 7.2 Hz,
2H), 3.40 (s, 2H), 1.89 (s, 3H), 1.25 (t, J ) 7.2 Hz, 3H); 13C NMR
(90 MHz, CDCl3) δ 197.5, 167.2, 139.2, 139.0, 127.8, 121.4, 60.5,
47.9, 25.3, 14.4; IR (CH2Cl2) 1718, 1706, 1638, 1158 cm-1; HRMS
(ESI) calcd for C10H15O3 (M + H)+ 183.1021, found 183.1036.
To a solution of aldehyde 48 (67 mg, 0.37 mmol) in THF (2.8
mL) at -78 °C was added vinylMgBr (1.0 M in THF, 0.93 mL,
0.93 mmol), and the reaction mixture was stirred for 2 h, before
being quenched with a saturated NH4Cl solution (0.9 mL), warmed
to rt, and diluted with EtOAc (20 mL). The organic solution was
dried over Na2SO4 and concentrated under reduced pressure. Flash
column chromatography (silica, 30% EtOAc in hexanes) afforded
the allylic alcohol 47 (Rf ) 0.50, 1:1 EtOAc/hexanes) as a brown
-78 °C was added BuLi (1.5 M solution in hexanes, 0.24 mL)
dropwise, and the reaction mixture was stirred for 15 min, before
being warmed to 0 °C for 20 min. A solution of ketone 35 (53 mg,
0.18 mmol) in THF (2.1 mL) was then added, and the reaction
was allowed to stir at rt for 1.5 h until consumption of the starting
material as determined by TLC analysis. The reaction was then
quenched with H2O (4 mL), and the aqueous layer was extracted
with ether (3 × 4 mL). The combined organic solution was dried
over Na2SO4 and concentrated under reduced pressure. Flash
column chromatography (silica, 5% EtOAc in hexanes) afforded
the methylene tetrahydropyran 36 (Rf ) 0.45, 20% EtOAc in
hexanes) as a slightly yellow oil (41 mg, 78%): 1H NMR (500 MHz,
CDCl3) δ 5.83 (m, 1H), 5.30 (dd, J ) 7.5, 1.0 Hz, 1H), 5.06 (m,
2H), 4.73 (dd, J ) 1.5, 1.5 Hz, 2H), 4.22 (ddd, J ) 13.2, 6.1, 6.1
Hz, 1H), 4.01 (m, 1H), 4.00 (dd, J ) 7.6, 5.7 Hz, 1H), 3.54 (dd, J
) 7.5, 7.5 Hz, 1H), 3.36 (m, 1H), 2.41 (dd, J ) 14.0, 6.3 Hz, 2H),
2.27-2.12 (m, 2H), 2.03 (ddd, J ) 11.5, 11.5, 1.2 Hz, 1H), 1.92
(ddd, J ) 11.5, 11.5, 1.2 Hz, 1H), 1.72 (d, J ) 1.0 Hz, 3H), 1.41
(s, 3H), 1.35 (s, 3H); 13C NMR (90 MHz, CDCl3) δ 144.6, 135.7,
1
oil (38 mg, 49%): H NMR (360 MHz, CDCl3) δ 7.53 (dd, J )
15.1, 11.7 Hz, 1H), 6.11 (d, J ) 11.7 Hz, 1H), 5.88 (m, 1H), 5.77
(d, J ) 15.1 Hz, 1H), 5.25 (d, J ) 17.2 Hz, 1H), 5.11 (d, J ) 10.4
Hz, 1H), 4.17 (d, J ) 7.1 Hz, 2H), 2.62 (dd, J ) 13.4, 8.2 Hz,
1H), 2.41 (dd, J ) 13.4, 5.4 Hz, 1H), 1.91 (s, 3H), 1.27 (t, J ) 7.1
J. Org. Chem. Vol. 73, No. 15, 2008 5975

Ding and Jennings
Hz, 3H); 13C NMR (90 MHz, CDCl3) δ 167.7, 145.7, 140.5, 140.3,
126.7, 120.0, 115.3, 71.6, 60.3, 40.6, 25.3, 14.5; IR (CH2Cl2) 1707,
1640, 1632, 1157 cm-1; HRMS (ESI) calcd for C12H19O3 (M +
H)+ 211.1334, found 211.1334.
mmol), and the reaction mixture was warmed to rt and stirred for
1.5 h until complete by TLC analysis. The reaction was then
quenched with H2O (0.5 mL), and the aqueous layer was extracted
with Et2O (2 × 5 mL). The combined organic washes were dried
over Na2SO4 and concentrated under reduced pressure. Flash
column chromatography (silica, 20% EtOAc in hexanes) afforded
the monoprotected alcohol 4 (Rf ) 0.35, 20% EtOAc in hexanes)
7-(tert-Butyldimethylsilanyloxy)-5-methylnona-2,4,8-trienoic
acid (5): To a stirred solution of the allylic alcohol 47 (195 mg,
0.93 mmol) and TBSCl (280 mg, 1.86 mmol) in DMF (2.0 mL) at
rt was added imidazole (190 mg, 2.79 mmol), and the reaction was
allowed to stir for 20 h, before being diluted with Et2O (40 mL)
and quenched with H2O (10 mL). The organic solution was dried
over Na2SO4 and concentrated under reduced pressure. Flash
column chromatography (silica, 10% EtOAc in hexanes) afforded
the TBS ester (Rf ) 0.32, 10% EtOAc in hexanes) as a pale yellow
1
as a colorless oil (35 mg, 97%): H NMR (360 MHz, CDCl3) δ
5.83 (m, 1H), 5.30 (d, J ) 7.8 Hz, 1H), 5.10 - 5.03 (m, 2H), 4.73
(s, 2H), 4.01 (ddd, J ) 10.8, 7.8, 2.7 Hz, 1H), 3.79 (dddd, J )
13.5, 10.6, 6.7, 3.8 Hz, 1H), 3.59 (dd, J ) 10.0, 3.8 Hz, 1H), 3.44
(dd, J ) 10.0, 6.6 Hz, 1H), 3.36 (m, 1H), 2.43-2.14 (m, 6H), 2.04
(dd, J ) 11.3, 11.3 Hz, 1H), 1.92 (dd, J ) 11.3, 11.3 Hz, 1H),
1.72 (d, J ) 1.2 Hz, 3H), 0.90 (s, 9H), 0.06 (s, 6H); 13C NMR (90
MHz, CDCl3) δ 144.6, 136.0, 134.7, 128.6, 117.3, 108.8, 77.9, 75.7,
70.1, 66.7, 43.4, 40.8, 40.1, 26.1, 18.4, 17.4, -5.2; HRMS (ESI)
calcd for C21H38O3Si (M +H)+ 366.2590, found 366.2593.
(-)-Dactylolide (3): To a solution of the diol 55 (3.6 mg, 9.3
µmol) in CH2Cl2 (100 µL) was added dropwise a Dess-Martin
solution (15% in CH2Cl2, 77 µL, 37.2 µmol) at 0 °C, and the
reaction was allowed to warm to rt. The reaction mixture was stirred
for 0.5 h, then diluted with CH2Cl2 (1.0 mL) and Et2O (2.0 mL).
Pyridine (5 µL, 91 µmol) was added, and the resulting mixture
was filtered through a plug of Celite. The solvents were removed
under reduced pressure, and flash column chromatography (silica,
1:1 EtOAc/hexanes) afforded dactylolide (3) (Rf ) 0.46, 3:2 EtOAc/
1
oil (254 mg, 85%): H NMR (360 MHz, CDCl3) δ 7.53 (dd, J )
15.1, 11.6 Hz, 1H), 6.05 (d, J ) 11.6 Hz, 1H), 5.83 (dd, J ) 10.4,
6.1 Hz, 1H), 5.78 (dd, J ) 10.4, 6.6 Hz, 1H), 5.75 (d, J ) 15.3
Hz, 1H), 5.17 (ddd, J ) 17.1, 1.4, 1.4 Hz, 1H), 5.04 (ddd, J )
10.3, 1.3, 1.3 Hz, 1H), 4.22 (m, 1H), 4.19 (q, J ) 7.1 Hz, 2H),
2.58 (dd, J ) 13.2, 7.7 Hz, 1H), 2.34 (dd, J ) 13.2, 5.4 Hz, 1H),
1.90 (s, 3H), 1.28 (t, J ) 7.1 Hz, 3H), 0.86 (s, 9H), 0.01 (s, 6H);
13C NMR (90 MHz, CDCl3) δ 167.6, 146.2, 141.1, 141.0, 126.1,
119.3, 114.1, 73.0, 60.1, 41.7, 25.9, 25.7, 18.3, 14.4, -2.9, -4.4;
IR (CH2Cl2) 1708, 1631 cm-1; HRMS (ESI) calcd for C18H33O3Si
(M + H)+ 325.2199, found 325.2205.
To a solution of ester (241 mg, 0.74 mmol) in EtOH (3.7 mL)
was added dropwise an aqueous NaOH solution (1.0 M, 1.85 mL)
at 0 °C. The reaction mixture was then warmed to rt and stirred
for 20 h before an aqueous HCl solution was added (1.0 M, 1.85
mL). EtOAc (20 mL) was added and allowed to partition. The
aqueous layer was extracted with EtOAc (2 × 5 mL), and the
organics were combined and dried over Na2SO4, and the solvent
was removed under reduced pressure. The residue was redissolved
in toluene (4 mL) and then rotavapped to afford the acid 5 (Rf )
0.56, EtOAc) as a pale yellow viscous oil (208 mg, 95%): 1H NMR
(360 MHz, CDCl3) δ 7.65 (dd, J ) 15.0, 11.7 Hz, 1H), 6.10 (d, J
) 11.7 Hz, 1H), 5.83-5.74 (m, 2H), 5.18 (ddd, J ) 17.1, 1.4, 1.4
Hz, 1H), 5.06 (ddd, J ) 10.4, 1.4, 1.4 Hz, 1H), 4.25 (dd, J ) 12.7,
6.3 Hz, 1H), 2.60 (dd, J ) 13.2, 7.7 Hz, 1H), 2.36 (dd, J ) 13.2,
5.2 Hz, 1H), 1.93 (s, 3H), 0.86 (s, 9H), 0.01 (s, 3H), 0.00 (s, 3H);
13C NMR (90 MHz, CDCl3) δ 173.1, 148.1, 143.7, 141.2, 126.2,
118.4, 114.4, 73.1, 42.0, 26.0, 18.3, -4.3, -4.7; IR (CH2Cl2) 1718,
1635 cm-1; HRMS (ESI) calcd for C16H28O3Si (M + H)+ 296.1808,
found 296.1811.
1
hexanes) as a colorless solid (3.2 mg, 90%): H NMR (500 MHz,
CDCl3) δ 9.67 (s, 1H), 7.63 (dd, J ) 15.1, 11.6 Hz, 1H), 6.85
(ddd, J ) 16.1, 8.6, 5.9 Hz, 1H), 6.15 (d, J ) 11.6 Hz, 1H), 6.00
(d, J ) 16.2 Hz, 1H), 5.96 (d, J ) 15.1 Hz, 1H), 5.32 (dd, J )
11.4, 2.4 Hz, 1H), 5.24 (d, J ) 8.0 Hz, 1H), 4.75 (s, 2H), 3.97
(ddd, J ) 11.1, 8.1, 2.5 Hz, 1H), 3.95 (d, J ) 14.3 Hz, 1H), 3.32
(dddd, J ) 11.4, 9.1, 2.5, 2.5 Hz, 1H), 3.23 (d, J ) 14.3 Hz, 1H),
2.54 (d, J ) 14.0 Hz, 1H), 2.39-2.27 (m, 3H), 2.17 (ddd, J )
13.2, 1.6, 1.6 Hz, 1H), 2.11 (ddd, J ) 13.0, 1.6, 1.6 Hz, 1H), 1.96
(m, 2H), 1.86 (s, 3H), 1.72 (s, 3H); 13C NMR (90 MHz, CDCl3) δ
199.3, 197.6, 166.5, 146.2, 144.2, 140.6, 131.7, 131.1, 130.7, 125.8,
120.0, 109.5, 76.7, 75.9, 75.5, 45.1, 41.0, 40.6, 39.94, 39.90, 24.3,
16.3; [R]20D ) -136 (c 1.2, MeOH); IR (CH2Cl2) 1722, 1703, 1668,
1638, 1283 cm-1; HRMS (ESI) calcd for C23H29O5 (M + H)+
385.2015, found 385.2023.
Acknowledgment. Support was provided by the University
of Alabama and the NSF (CHE-0115760) for the departmental
NMR facility.
5-(6-Allyl-4-methylenetetrahydropyran-2-yl)-1-(tert-butyldim-
ethylsilanyloxy)-4-methylpent-4-en-2-ol (4): To a solution of the
acetonide 36 (29 mg, 0.1 mmol) in EtOH (0.33 mL) and CH2Cl2
(0.33 mL) at 0 °C was added TFA (0.33 mL) dropwise and stirred
for 10 min. The solvents were removed under reduced pressure,
and the residue was coevaporated with PhMe (2 × 2 mL) to remove
TFA and afforded the crude diol 52.
Supporting Information Available: Experimental proce-
dures and full characterization data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
To a solution of 52, TBSCl (38 mg, 0.25 mmol), DMAP (2 mg,
16 µmol) in CH2Cl2 (1.0 mL) at 0 °C was added Et3N (56 µL, 0.4
JO8009853
5976 J. Org. Chem. Vol. 73, No. 15, 2008