C O M M U N I C A T I O N S
Supporting Information Available: Detailed experimental pro-
cedures and tabulated spectroscopic data (1H and 13C NMR, FT-IR,
and HRMS) for all new compounds. This material is available free of
hydroxyl group. Subsequent addition of a solution of tert-butyl-
lithium in pentane (1.7 M, 4.0 equiv) at -78 °C, followed
immediately (<3 s) by quenching with a solution of acetic acid
(30 equiv) in THF, afforded the transannular cyclization product
23 in 30-40% yield.21 Typically, the latter reaction was performed
on scales of 20-25 mg; larger-scale reactions were less efficient.
Selective removal of the allylic diethylisopropylsilyl ether group
within the transannular product 23 was achieved by treatment of
23 with an excess of triethylamine trihydrofluoride in acetonitrile
at -25 °C. The desilylated product was then coupled with the
naphthoic acid 422 in the presence of N,N′-dicyclohexylcarbodiimide
(DCC) in THF, providing the ester 24 (44%, two steps). Addition
of tetrabutylammonium fluoride (6.0 equiv) to a solution of the
ester 24 and the buffering agent o-nitrophenol (6.0 equiv) in THF
at 0 °C cleanly removed the propargylic silyl ether within 24;
subsequent protection of the phenolic hydroxyl group as the
corresponding triethylsilyl ether (TESCl, Et3N, CH2Cl2, -78 °C)
then afforded the highly unstable diol 25. The trans-diol function
within the latter product was transformed to the corresponding
epoxide by tosylation under basic conditions (TsCl, DABCO, CH2-
Cl2, 23 °C), providing N1999A2 in fully protected form (26), a
more stable intermediate relative to others (22 and beyond) in the
sequence. During the latter transformation (25f26) the tosylate
intermediate was observable by TLC analysis, but it did not
accumulate, being transformed to 26 as it was formed. Global
deprotection of the epoxide 26 was accomplished with trifluoro-
acetic acid in a mixture of THF and water at 0 °C.1c In this reaction,
both silyl groups were cleaved within 2 h, and the mesitylene
protective group was removed within 5-8 h. To isolate synthetic
N1999A2, particular workup conditions were necessary. For
example, addition of saturated sodium bicarbonate aqueous solution
led to extensive decomposition of the product. By using pH 7
aqueous phosphate buffer as a quenching solution, decomposition
was minimized. The product was extracted into ether, and the
ethereal solution was dried (Na2SO4) and then concentrated to a
volume of 4-8 mL. Since N1999A2 is an appreciably polar
compound, a rather polar eluent (5% CD3CN-ether) was necessary
for its purification by flash-column chromatography. Although some
decomposition did occur during chromatography, the product
obtained was estimated to be >90% pure by 1H NMR analysis. A
much simpler and more convenient purification procedure was
found serendipitously. When pentane (5 mL) was added to a
solution of synthetic N1999A2 (∼5 mg) in ether (8 mL), a light-
yellow solid precipitated from the solution; solvents were removed,
and the resulting solid was triturated with a 5:1 mixture of ether
and pentane. N1999A2 had not previously been reported to be a
solid. 1H NMR and UV spectra of synthetic (solid) N1999A2 were
identical to published spectra.1a,c Thus, for the second time, the
stereostructure of N1999A2 proposed by Hirama and co-workers
has been confirmed by an unambiguous synthetic route.1b,c A high-
resolution “exact” mass spectrum of synthetic N1999A2 was also
obtained using a Micromass LCT/TOF spectrometer equipped
with an electrospray ionization source (calcd for C27H25ClNO8
[M+NH4]+ 526.1269, found 526.1286). Synthetic N1999A2 was
surprisingly stable. In the solid state, N1999A2 could be left in the
air for 10 min at ambient temperature without evident decomposi-
References
(1) (a) Ando, T.; Ishii, M.; Kajiura, T.; Kameyama, T.; Miwa, K.; Sugiura,
Y. Tetrahedron Lett. 1998, 39, 6495. (b) Kobayashi, S.; Reddy, R. S.;
Sugiura, Y.; Sasaki, D.; Miyagawa, N.; Hirama, M. J. Am. Chem. Soc.
2001, 123, 2887. (c) Kobayashi, S.; Ashizawa, S.; Takahashi, Y.; Sugiura,
Y.; Nagaoka, M.; Lear, M. J.; Hirama, M. J. Am. Chem. Soc. 2001, 123,
11294. (d) Miyagawa, N.; Sasaki, D.; Matsuoka, M.; Imanishi, M.; Ando,
T.; Sugiura, Y. Biochem. Biophys. Res. Commun. 2003, 306, 87.
(2) (a) Edo, K.; Mizugaki, M.; Koide, Y.; Seto, H.; Furihata, K.; Otake, N.;
Ishida, N. Tetrahedron Lett. 1985, 26, 331. (b) Myers, A. G.; Proteau, P.
J.; Handel, T. M. J. Am. Chem. Soc. 1988, 110, 7212. (c) Neocarzinosta-
tin: The Past, Present, and Future of an Anticancer Drug; Maeda, H.,
Edo, K., Ishida, N., Eds.; Springer: Tokyo, 1997.
(3) Ji, N. Ph.D. Thesis, Harvard University, Cambridge, MA, 2006.
(4) For preparation of 5, see: Meng, D.; Bertinato, P.; Balog, A.; Su, D.-S.;
Kamenecka, T.; Sorensen, E. J.; Danishefsky, S. J. J. Am. Chem. Soc.
1997, 119, 10073.
(5) For the use of alkynyl trifluoroborates in epoxide-opening reactions, see:
Yamaguchi, M.; Hirao, I. Tetrahedron Lett. 1983, 24, 391.
(6) Corey, E. J.; Venkateswarlu, A. J. Am. Chem. Soc. 1972, 94, 6190.
(7) Ogawa, Y.; Shibasaki, M. Tetrahedron Lett. 1984, 25, 663.
(8) Parikh, J. R.; Doering, W. v. E. J. Am. Chem. Soc. 1967, 89, 5505.
(9) Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 13, 3769.
(10) Grandjean, D.; Pale, P.; Chuche, J. Tetrahedron Lett. 1994, 35, 3529.
(11) Dabdoub, M. J.; Dabdoub, V. B.; Baroni, A. C. M. J. Am. Chem. Soc.
2001, 123, 9694.
(12) (S)-Glyceraldehyde acetonide (12) was synthesized in one step from (R)-
(-)-2,2-dimethyl-1,3-dioxolane-4-methanol (Alfa Aesar) by the method
of Janson et al. See: Janson, M.; Kvarnstro¨m, I.; Svensson, S. C. T.;
Samuelsson, B. C. B. Synthesis 1993, 129.
(13) Myers, A. G.; Hammond, M.; Wu, Y.; Xiang, J.-N.; Harrington, P. M.;
Kuo, E. Y. J. Am. Chem. Soc. 1996, 118, 10006.
(14) In the absence of any lithium halide additive, Wittig coupling of 13 and
14 using n-butyllithium as base afforded a 1.5:1 mixture of Z- and
E-olefins, respectively. The undesired E-isomer could be transformed into
a 55:45 mixture of E- and Z-isomers, respectively, by UV irradiation.
See Supporting Information for details.
(15) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem. ReV. 1994,
94, 2483.
(16) Brummond and co-workers have reported that the (DHQD)2PYR ligand
was optimal for the enantioselective dihydroxylation of an achiral enyne
substrate. See: Brummond, K. M.; Lu, J.; Petersen, J. J. Am. Chem. Soc.
2000, 122, 4915.
(17) In this application, acetonitrile was found to be a more effective solvent
than dichloromethane, the solvent used by Sen et al. See: Sen, S. E.;
Roach, S. L.; Boggs, J. K.; Ewing, G. H.; Magrath, J. J. Org. Chem.
1997, 62, 6684.
(18) The acetonide protective group proved to be too robust to remove without
decomposition in later-stage synthetic intermediates and was therefore
modified. Model studies established that the mesitylene protective group
was an ideal replacement, being readily removed under acidic conditions
(TFA, THF, H2O, 0 °C).1c
(19) Mesitaldehyde dimethyl acetal (19) was synthesized in one step from
mesitaldehyde as follows: camphorsulfonic acid (10 mg) was added to a
solution of mesitaldehyde (3.00 g, 20.2 mmol, 1 equiv) and trimethyl
orthoformate (3.22 g, 30.4 mmol, 1.5 equiv) in methanol (30 mL) at
23 °C. After stirring at 23 °C for 12 h, the reaction mixture was partitioned
between ether (30 mL) and saturated aqueous sodium bicarbonate solution
(30 mL). The aqueous layer was separated and further extracted with ether
(30 mL). The organic extracts were combined, and the combined solution
was dried over anhydrous sodium sulfate. The dried solution was filtered,
and the filtrate was concentrated to provide mesitaldehyde dimethyl acetal
(19) as a colorless oil (3.90 g, 99%).
(20) Eglinton, G.; Galbreath, A. R. J. Chem. Soc. 1959, 889.
(21) (a) Myers, A. G.; Goldberg, S. D. Angew. Chem., Int. Ed. 2000, 39, 2932.
(b) Myers, A. G.; Hogan, P. C.; Hurd, A. R.; Goldberg, S. D. Angew.
Chem., Int. Ed. 2002, 41, 1062.
1
tion by subsequent H NMR analysis, and solutions of N1999A2
(22) The diethylisopropylsilyl-protected naphthoic acid 4 was synthesized in
two steps from the corresponding triisopropylsilyl-protected naphthoic
acid; see Supporting Information. For synthesis of the triisopropylsilyl-
protected naphthoic acid, see: Ji, N.; Rosen, B. M.; Myers, A. G. Org.
Lett. 2004, 6, 4551.
in ether or DMSO have been stored at -25 °C for 2 months without
detectable decomposition by HPLC analysis.
Acknowledgment. Generous financial support from the National
Institutes of Health and Pfizer, Inc. is gratefully acknowledged.
JA0662467
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