C O M M U N I C A T I O N S
Scheme 4 a
protected R,ω-dienediol 19; and the aluminum aza-aldol addition
reaction of “20” to 1 to construct the acyclic carbinolamide in
zampanolide (21).
Acknowledgment. This investigation was supported by a grant
awarded by the DHHS (GM-65597). We thank Professors Amos
B. Smith, III, for sharing relevant information prior to publication
and James M. Bobbitt for providing a sample of oxoammonium
salt.8a
Supporting Information Available: Spectroscopic characterization
data for compounds 1-15, 18, 19, and 21 and procedures for
preparation of 1 and 21 and copies of their NMR spectra (PDF). This
References
a (a) Ti(OtBu)4, CH2Cl2, 75 °C, 67%. (b) (i) BSA, PhH; (ii) RuCHPhCl2-
(PCy3)(H2IMes), PhH, 60 °C, 77%; (iii) TBAF, THF, 89%. (c) (Z,E)-
MeCHdCHCHdCHCONH2, THF, DIBALH/hexanes; 1, THF, room
temperature.
(1) Cutignano, A.; Bruno, I.; Bifulco, G.; Casapullo, A.; Debitus, C.; Gomez-
Paloma, L.; Riccio, R. Eur. J. Org. Chem. 2001, 775-778.
(2) (a) Smith, A. B., III; Safonov, I. G. Org. Lett. 2002, 4, 635-637. (b)
Smith, A. B., III; Safonov, I. G.; Corbett, R. M. J. Am. Chem. Soc. 2002,
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(3) Caron, M.; Sharpless, K. B. J. Org. Chem. 1985, 50, 1557-1560.
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1799-1802. (c) Kopecky, D. J.; Rychnovsky, S. D. J. Am. Chem. Soc.
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(5) To be described in more detail in a subsequent full report of this work.
(6) Williams, D. R.; Clark, M. P.; Berliner, M. A. Tetrahedron Lett. 1999,
40, 2287-2290.
(7) Related observations of the solvent effect on stereoselectivity of pyran
formation have been independently made in the Keck laboratory: (a) Keck,
G. E.; Covel, J. A.; Schiff, T.; Yu, T. Org. Lett. 2002, 4, 1189-1192.
For other examples of use of Brønsted acids in related cyclizations, see:
(b) Mohr, P. Tetrahedron Lett. 1993, 34, 6251-6254. (c) Cloninger, M.
J.; Overman, L. E. J. Am. Chem. Soc. 1999, 121, 1092-1093.
(8) (a) Bobbitt, J. M. J. Org. Chem. 1998, 63, 9367-9374. For summaries
of related work in the oxoammonium salt oxidation arena, see: (b)
Rozantsev, E. G.; Sholle, V. D. Synthesis 1971, 190-202. (c) Rozantsev,
E. G.; Sholle, V. D. Synthesis 1971, 401-414. (d) Bobbitt, J. M.; Flores,
M. C. L. Heterocycles 1988, 27, 509-533. (e) Montanari, F.; Quici, S.
In Encyclopedia of Reagents for Organic Synthesis; Paquette, L. A., Ed.;
John Wiley: Chichester, 1995; Vol. 7, pp 4821-4823.
(TLC and 1H NMR evidence), accumulated at longer reaction times.
Limiting the reaction time to ∼12 h (∼50% conversion) minimized
byproduct formation (<5%) and permitted the isolation of 13 and
unreacted 12 as the only components. Importantly, 13 is produced
as an ∼1:1 mixture of C(7) epimers, demonstrating that the two
diastereomers of 12 are comparably competent substrates for the
key closure. Removal of the C(7) TBS ether gave the triol 14. The
chemoselective oxidation of the allylic alcohol in 14 using a
stoichiometric amount of 4-acetylamino-2,2,6,6-tetramethylpiperi-
dine-1-oxoammonium tetrafluoroborate8 to give the diol enone 15
is noteworthy. Final cleavage of the C(20)-C(21) diol with lead
tetraacetate provided (-)-dactylolide [1, spectral data (1H and 13
C
NMR, IR, and HRMS) match those reported for natural and
synthetic (+)-dactylolide9].
A more convergent construction of dactylolide (1) as well as its
subsequent conversion to the naturally occurring, acyclic carbino-
lamide zampanolide (21) is outlined in Scheme 4. Epoxide 7b and
the trienoic acid 185 were coupled by the action of Ti(OtBu)4 to
provide the ring-closing metathesis substrate 19 (∼1:1 dr). The
vicinal diol was protected in situ with excess bis-trimethylsilylac-
etamide (BSA)5 in benzene, and RuCHPhCl2(PCy3)(H2IMes)10 was
directly added. Each diastereoisomer smoothly cyclized at 60 °C,
and each gave rise to only a single C(8)-C(9) alkene of E-
geometry. All three silyl ethers were removed to provide triol 14
(68% from 19). Finally, (-)-dactylolide (1) was converted to the
related natural product, zampanolide (21),11 and its C(20) epimer
(∼1:1 ratio) by the aza-aldol addition of the species derived from
titration of (Z,E)-sorbamide with 1 equiv of DIBALH (cf., 20).
Studies to further delineate the stereochemical aspects of this
transformation are continuing.5
In conclusion, our synthesis shows that the Ti(IV)-promoted ring
opening of “Sharpless epoxides” by carboxylic acids, even in
settings where both components are structurally complex, is
sufficiently versatile to serve as a key coupling strategy. Both the
convergent bimolecular union between 7b and 18 (Scheme 4) and
the intramolecular macrolactonization within 12 (Scheme 3)
demonstrate this point. Other notable features include the proton-
catalyzed, cis-selective construction of pyran 4 from enal 2 and
allylic silane 3; the selective oxidation of triol 14 by an oxoam-
monium ion; the efficient RCM reaction of the in situ (TMS)-
(9) It is more than a curiosity that we have observed varying amounts of the
hydrate 16 in the proton NMR spectra (CDCl3) of different samples of
dactylolide. The propensity of the aldehyde to hydrate, presumably
heightened by both the electronic effect and the hydrogen-bonding network
(cf., ref 12) afforded by the R-acyloxy substituent, is quite likely related
to the stability of the unusual acyclic carbinolamide in zampanolide (21).
It is also relevant that an initial oxidative cleavage of 15 with n-Bu4N+-
-
IO4 in methanol/CH2Cl2 provided 1 along with a portion of the methyl
hemiacetal 17. Moreover, 17 (both epimers) survived silica gel chroma-
tography, again attesting to the predisposition of the free aldehyde in 1 to
form stable adducts with protic nucleophiles. The existence of methanol
adduct(s) was first detected for methanol solutions of 1 by both mass
spectrometry and NMR analyses during the isolation/characterization
work.1 We observed that the 1H NMR spectrum of a solution of 1 in
CD3OD gave no evidence of any free aldehyde; a mixture of diastereo-
meric hemiacetals was present instead. The value of the specific rotation
we obtained for our synthetic sample of 1 ([R]RTD ) -128°/-129°, c )
0.39/0.26, MeOH) differed from values previously reported for both
natural1 ([R]RTD ) +30°, c ) 1.0, MeOH) and synthetic2 ([R]RTD ) +235°,
c ) 0.52, MeOH; recently remeasured at a second concentration as +240°,
c ) 0.2, MeOH; private communication with A. B. Smith, III) dactylolide
(1). (+)-Dactylolide synthesized in the Smith laboratory2 was the opposite
antipode of that described here. The question of the absolute configuration
of natural dactylolide is still open, because the specific rotation of the
natural sample differs so greatly from that of each synthetic antipode.
(10) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1, 953-
956.
(11) Isolation: (a) Tanaka, J.; Higa, T. Tetrahedron Lett. 1996, 37, 5535-
5538. Synthesis: (b) Smith, A. B., III; Safonov, I. G.; Corbett, R. M. J.
Am. Chem. Soc. 2001, 123, 12426-12427 and ref 12b.
(12) (a) Bussolari, J. C.; Beers, K.; Lalan, P.; Murray, W. V.; Gauthier, D.;
McDonnell, P. Chem. Lett. 1998, 787-788. (b) Troast, D. M.; Porco, J.
A., Jr. Org. Lett. 2002, 4, 991-994.
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