An expedient total synthesis of (-)-dactylolide and formal synthesis of (-)-zampanolide

Article abstract of DOI:10.1021/ol0504897

(Chemical Equation Presented) A highly convergent and efficient total synthesis of (-)-dactylolide and formal synthesis of (-)-zampanolide is reported.

Full text of DOI:10.1021/ol0504897

ORGANIC
LETTERS
2005
Vol. 7, No. 12
2321-2324
An Expedient Total Synthesis of
(
−
−
)-Dactylolide and Formal Synthesis of
)-Zampanolide
(
Fei Ding and Michael P. Jennings*
Department of Chemistry, The UniVersity of Alabama,
Tuscaloosa, Alabama 35487-0336
jenningm@bama.ua.edu
Received March 7, 2005 (Revised Manuscript Received May 2, 2005)
ABSTRACT
A highly convergent and efficient total synthesis of (−)-dactylolide and formal synthesis of (−)-zampanolide is reported.
First isolated and disclosed in 1996 by Higa and co-workers,1
zampanolide (1) represented a novel macrolide that exhibited
significant activity against a variety of tumor cell lines. In
particular, 1 has proven to be active against the P388, A549,
HT29, and MEL28 cell lines with IC50 values ranging from
1 to 5 ng/mL.1 However, extensive biological tests have not
been performed because of the lack of material, as only 3.9
mg were isolated from 0.480 kg (wet weight) of the marine
sponge Fasciospongia rimosa. Subsequently, Riccio isolated
a structurally related compound, dactylolide (2), from the
marine sponge Dactylospongia.2 However, 2 only displayed
a modest biological profile (63% and 40% inhibition of
L1210 and SK-OV-3 tumor cell lines at 3.2 µg/mL) with
respect to that of 1, thus suggesting that the N-acyl hemi-
aminal side-chain resident in 1 is required for the impressive
biological activity.
relationship to one another. Thus, the natural (-)-zampano-
lide can be degraded to the unnatural (-)-dactylolide, or in
the forward sense, (-)-dactylolide would serve as the
macrocyclic precursor of natural zampanolide.
The retrosynthetic analysis of both (-)-dactylolide (2) and
(-)-zampanolide is illustrated in Scheme 1. As reported by
Hoye, strategic disconnection at the N-acyl hemi-aminal side
chain would allow for the corresponding engagement of an
“aluminum aza-aldol” sequence with the aldehyde moiety
Scheme 1
In addition to a highly unsaturated macrolactone, both
naturally occurring cytotoxins also feature a cis-2,6-disub-
stituted 4-exo-methylene tetrahydropyran ring system. Coupled
with potent cytotoxicity and unusual structures of both 1 and
2, there has been moderate synthetic interest in these targets.3
By means of Smith’s account, it was observed that the
common macrocyclic cores of 1 and 2 share an enantiomeric
(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/ol0504897 CCC: $30.25
© 2005 American Chemical Society
Published on Web 05/13/2005

Scheme 2a
Scheme 3a
a (a) n-BuLi (2.0 equiv), THF, -78 °C, 15 min, then ClCOOEt
(4.0 equiv), rt, 45 min, 100%. (b) PhSH (1.2 equiv), NaOMe (5
mol %), MeOH, rt, 20 h, 90%. (c) MeMgBr (1.5 equiv), CuI (1.6
equiv), THF, -78 °C to rt, 1 h, 97%. (d) DIBAL-H (2.2 equiv),
CH2Cl2, -78 °C, 2 h, 95%. (e) PCC (2.0 equiv), NaOAc (0.8 equiv),
CH2Cl2, rt, 1 h, 94%. (f) (i) (-)-Ipc2BOMe (1.65 equiv), allylMgBr
(1. 5 equiv), Et2O, 0 °C to rt, 1 h, then 8, -78 °C, 1 h; (ii) H2O2
(3.0 equiv), NaOH (2.2 equiv), H2O/Et2O, reflux, 3 h, 88%, 90%
de. (g) acryloyl chloride (2.0 equiv), Et3N (2.2 equiv), DMAP (5
mol %), CH2Cl2, rt, 16 h, 79%. (h) 10 (5 mol %), CH2Cl2, reflux,
18 h, 96%.
a (a) (i) H2O2 (3.5 equiv), NaOH (0.6 equiv), MeOH, 0 °C, 10
min, then rt, 0.5 h; (ii) PhH, reflux, 1 h, 83%. (b) (PhSe)2 (1.5
equiv), NaBH4 (3.0 equiv), EtOH, rt, 5 min, then HOAc (3.0 equiv),
0 °C, 5 min, then epoxide, 15 min, 78%. (c) (i) allylMgBr (3.0
equiv), Et2O, -78 °C, 0.5 h. (ii) Et3SiH (10 equiv), TFA (5 equiv),
CH2Cl2, -78 °C to -40 °C, 0.5 h, 76%. (d) (i) TBAF (4.0 equiv),
THF, 6 h. (e) 2,2-dimethoxypropane (5.0 equiv), TsOH (0.1 equiv),
CH2Cl2, rt, 16 h, 81%. (f) PCC (2.0 equiv), NaOAc (0.8 equiv)
CH2Cl2, rt, 1.5 h, 74%. (g) Ph3PMeBr (2.0 equiv), n-BuLi (2.0
equiv), THF, -78 °C, 15 min, then 0 °C, 20 min, then 15, rt, 1.5
h, 78%. TFA ) tirfluoroacetic acid, TsOH ) p-toluenesulfonic acid,
PCC ) pyridinium chlorochromate.
to 2 and should furnish the targeted natural product (-)-
zampanolide. It was expected that disconnection of the
macrolactone and the enone linkage of 2 would allow for
utilization of olefin metathesis and esterification with 3 and
4 in anticipation of obtaining the macrolide skeleton.
Our synthetic blueprint of the C8-C20 subunit (3) was
designed to enlist a strategy based on a tandem organome-
tallic allyl group addition to the corresponding lactone
followed by a diastereoselective axial reduction of an in situ
generated oxocarbenium cation to forge the cis-2,6-disub-
stituted 4-exo-methylene tetrahydropyran ring.4 Our 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, which
in turn would allow for the introduction of the final terminal
alkene moiety (as an inconsequential mixture of hydroxyl
enantiomers at C7).
deprotonation of the known propargylic alcohol 55 with
n-BuLi followed by electrophilic quench with ethyl chloro-
formate furnished the acetylenic ester 6 in a virtually
quantitative yield. Ensuing conjugate addition of the thiolate
anion derived from benzenethiol upon treatment with NaOMe
in MeOH selectively provided the (Z)-R,â-unsaturated ester.6
Replacement of the vinylic phenyl thiol ether by means of a
copper-promoted MeMgBr addition afforded the methylated
R,â-olefinic ester 7 with complete retention of configuration
with an 87% yield over the three-step procedure from 5.
Subsequent reduction of the ester moiety to the allylic alcohol
was readily accomplished with DIBAL, and the correspond-
ing free hydroxyl group was reoxidized to aldehyde 8 under
slightly basic PCC conditions (buffered with NaOAc) in a
combined yield of 89% from ester 7.
The approach to the synthesis of the central cis-pyran of
1 and 2 is shown in Schemes 2 and 3. Toward this end,
An asymmetric allylation-oxidation of 8 utilizing Brown’s
reagent7 provided the homo-allylic alcohol 9 with 90% de
(3) (a) Smith, A. B., III; Safonov, I. G.;. Corbett, R. M. J. Am. Chem.
Soc. 2001, 123, 12426. (b) Hoye, T. R.; Hu, M. J. Am. Chem. Soc. 2003,
125, 9576. (c) Smith, A. B., III; Safonov, I. G. Org. Lett. 2002, 4, 635. (d)
Smith, A. B., III; Safonov, I. G.;. Corbett, R. M. J. Am. Chem. Soc. 2002,
124, 11102. (e) Troast, D. M.; Porco, J. A., Jr. Org. Lett. 2002, 4, 991. (f)
Loh, T. P.; Yang, J. Y.; Feng, L. C.; Zhou, Y. Tetrahedron Lett. 2002, 43,
7193.
(5) 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.
(6) Hollowood, C. J.; Yamanoi, S.; Ley, S. V. Org. Biomol. Chem. 2003,
1, 1664.
(7) (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.
(4) Lewis, M. D.;. Cha, J. K.; Kishi, Y. J. Am. Chem. Soc. 1982, 104,
4976.
2322
Org. Lett., Vol. 7, No. 12, 2005

followed by successive acrylate ester formation under the
standard protocol (acryloyl chloride, Et3N, DMAP) afforded
the dienic-ester. Subjecting the acrylate ester to Grubbs’
carbene catalyst 108 readily allowed for the formation of
lactenone 11 via a ring-closing olefin metathesis9 with a
combined yield of 67% over two steps from 9.
Scheme 4a
As shown in Scheme 3, an ensuing stereoselective epoxi-
dation of the corresponding lactenone intermediate 11 with
basic hydroperoxide provided the epoxy-lactone followed by
a subsequent regioselective reduction of the oxirane by means
of the in situ generated PhSeH10 afforded intermediate 12
and set the stage for the tandem nucleophilic addition-
oxonium cation generation-diastereoselective reduction
sequence in anticipation of providing the vital â-C-glycoside
component. Thus, nucleophilic addition of allylmagnesium
bromide to â-hydroxy lactone 12 furnished the lactol, which
was immediately transformed into the oxocarbenium cation
in the presence of TFA and consequently reduced with Et3-
SiH to furnish the cis-2,6-disubstituted tetrahydropyran 13
with a 76% yield from 12.11 To avoid removal of the TBS
groups during the reduction, TFA was employed instead of
BF3•OEt2 as used in Kishi’s conventional procedure. Unex-
pectedly, the C13 hydroxyl group was concomitantly protected
as a TES ether under these conditions.
Selective deprotection of the TES group was unsuccessful
upon the treatment of 13 with PPTS in methanol, and other
selective reagents such as Pd/C12 and DDQ13 also failed to
provide the free hydroxy-pyran. In lieu of selective depro-
tection, global desilylation of 13 was carried out with TBAF,
and the corresponding 1,2-diol was reprotected as the
acetonide 14 in 81% yield over two steps. Oxidation of the
free hydroxyl group resident in 14 was accomplished with
PCC, and ketone 15 was subsequently transformed via the
methylene Wittig reagent to the cis-2,6-disubstituted 4-exo-
methylene tetrahydropyran unit 16, which possessed all the
functionality required for the synthesis of 2. The relative
configuration of the â-C-glycoside subunit 16 was confirmed
by NOE enhancements as shown in Scheme 3.
a (a) triethyl phosphonoacetate (2.0 equiv), LiHMDS (2.0 equiv),
THF, 0 °C, 15 min, 98%. (b) pyridine-HF (10 equiv), THF, rt, 4 h,
92%. (c) Dess-Martin periodinane (1.5 equiv), CH2Cl2, rt, 1 h,
61%. (d) vinylMgBr (2.5 equiv), THF, -78 °C, 2 h, 49%. (e)
TBSCl (2.0 equiv), imidazole (3.0 equiv), DMF, 20 h, 85%. (f)
NaOH (1.0 M, 2.5 equiv), EtOH, 0 °C to rt, 20 h, 95%. LiHMDS
) lithium salt of 1,1,1,3,3,3-hexamethyldisilazane, Dess-Martin
periodinane ) 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxo-3-
(1H)-one, TBSCl ) tert-butyldimethylsilyl chloride.
for the formation of the desired allylic alcohol 19 as an
inconsequential racemic mixture at C7 with a moderate yield.
Finally, protection of the allylic alcohol as a TBS ether
(TBSCl, imid.) and hydrolysis (NaOH, EtOH) of the ester
group provided the conjugated acid 4, which positioned us
for the convergence of the two synthetic intermediates 3 and
4, followed by the completion of the targeted compound 2.
To commence the convergence of 3 and 6, selective access
to the stereogenic secondary alcohol of 3 was essential.
Along this line, the acetonide protecting group was cleaved
under acidic conditions (TFA), and the primary hydroxyl
group was selectively reprotected as a TBS ether under
standard conditions in a quantitative yield.The first attempted
coupling 3 and 4 utilizing DCC was unsuccessful, giving
the desired ester 20 in low yield along with inseparable
impurities. Fortunately, esterification proceeded smoothly
under Yamaguchi conditions15 utilizing two equivalents of
4, affording the hexaeneic ester intermediate 20 as a
diastereomeric 3:1 mixture. Apparently, the two C7 epimers
of acid 4 displayed distinct kinetic reactivity toward the
enantiopure alcohol 3. Ring-closing olefin metathesis was
then attempted on bis-TBS-protected hexaene 20 employing
a variety of reaction conditions. In general, Grubbs’ first-
generation catalyst 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.16 Unfortunately,
cleavage of the silyl ethers was problematic, because of
sensitive functional groups present in 20 giving rise to
With the C8-C20 intermediate in hand, attention was
focused on the synthesis of the triene C1-C9 subunit.
Accordingly, the known R,â-unsaturated aldehyde 1714 was
treated with the corresponding Horner-Emmons reagent,
which afforded the expected (E,Z)-conjugated ester. Subse-
quent HF-pyridine-mediated desilylation of the TBS group
furnished the free hydroxyl intermediate 18 in a 90% yield
over two steps. Dess-Martin oxidation of the corresponding
homoallylic alcohol afforded the labile aldehyde with a
modest 61% yield. Because of the highly acidic nature of
the R-proton, addition of the vinyl Grignard reagent allowed
(8) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1,
953.
(9) Ghosh, A. K.; Cappiello, J.; Shin, D. Tetrahedron Lett. 1998, 39,
4651.
(10) Miyashita, M.; Suzuki, T.; Hoshino, M.; Yoshikoshi, A. Tetrahedron
1997, 53, 12469.
(11) Kraus, G. A.; Molina, M. T.; Walling, J. A. J. Chem. Soc., Chem.
Commun. 1986, 1568.
(12) Rotulo-Sims, D.; Prunet, J. Org. Lett. 2002, 4, 4701.
(13) Tanemura, K.; Suzuki, T.; Horaguchi, T. J. Chem. Soc., Perkin
Trans. 1 1992, 2997.
(15) Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M. Bull.
Chem. Soc. Jpn. 1979, 52, 1989.
(16) Hoye reported ring closure via olefin metathesis at the same C8-
C9 alkene with a compound that is somewhat structurally related to 20.
Similar obstacles with respect to ring-closing olefin metathesis have been
described, see: Matsuya, Y.; Kawaguchi, T.; Nemoto, H. Org. Lett. 2003,
5, 2939.
(14) McLaughlin, M. J.; Hsung, R. P. J. Org. Chem. 2001, 66, 1049.
Org. Lett., Vol. 7, No. 12, 2005
2323

subjecting the corresponding diol intermediate to 10 mol %
catalyst 10 in a 1mM solution in CH2Cl2 allowed for
successful ring closure within 1 h at room temperature to
afford the diastereomerically pure (with regard to the alkene
geometries, but as an insignificant 3:1 diastereomeric mixture
at C7) macrolactone 21. As we were delighted by this result,
the very late stage intermediate 21 was then subjected to
Dess-Martin periodinane, thus enabling the oxidation of
both the primary and allylic alcohols and consequently
removing the redundant C7 stereogenic center to afford (-)-
dactylolide as a single diastereomer. The spectral data (1H
NMR, 500 MHz; 13C NMR, 125 MHz), optical rotation
Scheme 5a
([R]rt -136°, c 1.2, MeOH), and HRMS data of synthetic
D
(-)-dactylolide were in complete agreement with those
previously reported.2,3 Finally, (-)-dactylolide could readily
be converted to (-)-zampanolide via the “aluminum aza-
aldol” sequence reported by Hoye.3
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 macrocycliza-
tion via a ring-closing olefin metathesis utilizing Grubbs’
second-generation catalyst and a tandem nucleophilic addi-
tion-diastereoselective axial reduction of an in situ generated
oxonium cation to forge the cis-2,6-disubstituted 4-exo-
methylene tetrahydropyran ring. 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 “zampanolide-like” com-
pounds against a variety of tumor cell lines.
a (a) 1:1:1 TFA/EtOH/CH2Cl2, 0 °C, 10 min. (b) TBSCl (2.5
equiv), Et3N (4.0 equiv), DMAP (16 mol %), CH2Cl2, 0 °C to rt,
1.5 h, 97%. (c) 4 (2.0 equiv), 2,4,6-Cl3C6H2COCl (3.0 equiv), Et3N
(4.0 equiv), PhMe, rt, 1 h, then 3 (1.0 equiv), DMAP (1.2 equiv),
rt, 1 h, 100%. (d) HCl (1.0 M, 2.0 equiv), 4:1 MeOH/CH2Cl2, rt,
4.5 h, 80%. (e) catalyst 10 (10 mol %), CH2Cl2 (1 mM), rt, 1 h,
93%. (f) Dess-Martin periodinane (4.0 equiv), CH2Cl2, 0 °C to rt,
0.5 h, 90%. TFA ) trifluoroacetic acid, TBSCl ) tert-butyldim-
ethylsilyl chloride, DMAP ) 4-(dimethylamino)pyridine, Dess-
Martin periodinane ) 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benzi-
odoxo-3-(1H)-one.
Acknowledgment. Support was provided by the Univer-
sity of Alabama and the NSF (CHE-0115760) for the
departmental NMR facility. We would also like to thank
Professor Hoye for sharing information with us prior to
publication.
Supporting Information Available: Experimental pro-
cedures and spectroscopic data for compounds 2-4, 6-9,
11-16, 18-21. This material is available free of charge via
the Internet at http://pubs.acs.org.
decomposed products under various reaction conditions,
including many fluoride reagents and weak acids. Finally,
aqueous HCl in MeOH was found to be the most satisfactory
condition, providing the diol in 80% yield. Subsequently
OL0504897
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Org. Lett., Vol. 7, No. 12, 2005