T. M. Hansen, et al. / Bioorg. Med. Chem. Lett. 13 (2003) 2127–2130
2129
4. Compounds 2 and 7 were first synthesized as described in:
C. S. Lee, PhD. Thesis, University of Minnesota, 1999. An
enhanced synthetic route is described in ref 3a, and will be
detailed further in due course.
5. Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron
Lett. 1975, 16, 4467.
6. (a) Fujii, K.; Hatano, K.; Nakamura, K.; Umeyama, H.
Jpn. Kokai Tokkyo Koho, 2001, JP 2001064238. (b) Fujii, K.;
Hatano, K.; Oka, A. Jpn. Kokai Tokkyo Koho, 2000, JP
2000355505. (c) Pou, T. E.; Fouquay, S. Fr. Demande, 1998,
FR 2755152.
7. Experimental for 8: A 1 dram vial was charged sequentially
with alkyne 7 (3.0mg, 2.3 mmol), vinyl iodide 3 (1.6 mg, 3.0
mmol) in freshly distilled and de-gassed THF (0.3 mL), freshly
distilled and de-gassed Et3N (0.1 mL, 702 mmol), PdCl2(PPh3)2
(0.16 mg, 0.23 mmol), and anhydrous CuI (0.04 mg, 0.21
mmol). The vial was flushed with N2 and capped. The reaction
mixture was stirred vigorously for 3.5 h at which time, the
reaction was judged to be complete by TLC. Saturated aqu-
eous NH4Cl and ethyl acetate were added. The layers were
separated and the aqueous layer was extracted with ethyl ace-
tate (5Â4 mL). The combined organic layers were dried
(Na2SO4), filtered, and concentrated by rotary evaporation.
The residue was purified by preparative TLC (ethyl acet-
ate!ethyl acetate/ethanol, 10:1, v/v) to provide 8 (2.6 mg, 1.5
mmol, 67%) as a white film: Rf=0.2 (ethyl acetate/ethanol, 9:1,
v/v); [a]D23 +23.4 (c 2.95, CHCl3); IR (neat, cmÀ1) 3369, 2928,
1830, 1772, 1702, 1654; 1H NMR (CDCl3, 500 MHz) d 7.65 (t,
J=6.5 Hz, 4H), 7.56 (s, 1H), 7.45–7.36 (m, 7H), 6.72 (ddd,
J=16.0, 10.0, 6.5 Hz, 1H), 6.28 (m, 2H), 6.10 (dt, J=5.5, 16.0
Hz, 1H), 5.93 (m, 2H), 5.70(d, J=16.0Hz, 1H), 5.57 (dd,
J=7.5, 15.5 Hz, 1H), 5.40(d, J=9.0Hz, 1H), 5.33 (m, 1H),
5.03–4.97 (m, 2H), 4.91 (d, J=12.0Hz, 1H), 4.82 (s, 1H), 4.66
(s, 1H), 4.52 (dd, J=3.5, 9.5 Hz, 2H), 4.44 (t, J=7.0Hz, 1H),
4.33 (br s, 2H), 4.23 (d, J=3.0Hz, 2H), 4.19 (d, J=11.0Hz,
1H), 4.04 (d, J=5.5 Hz, 2H), 3.99 (m, 1H), 3.79 (app q, J=5.0
Hz, 1H), 3.70(t, J=5.0Hz, 3H), 3.66 (m, 9H), 3.59 (m, 3H),
3.35 (s, 3H), 3.32 (s, 3H), 3.30(s, 3H), 2.98 (d, J=15.5 Hz,
1H), 2.93 (dd, J=5.5, 13.0Hz, 1H), 2.77 (d, J=12.5 Hz, 1H),
2.73 (d, J=13.0Hz, 1H), 2.62 (d, J=4.5 Hz, 1H), 2.58–2.43
(m, 7H), 2.38–2.29 (m, 3H), 2.11–2.01 (m, 1H), 1.99 (s, 3H),
1.96–1.81 (m, 4H), 1.80(s, 3H), 1.77–1.63 (m, 3H), 1.58–1.53
(m, 6H), 1.43 (m, 9H), 0.99 (d, J=7.0Hz, 3H), 0.89 (s, 9H),
0.76 (d, J=6.5 Hz, 3H), 0.07 (s, 3H), 0.03 (s, 3H); 13C NMR
(75 MHz, CDCl3) d 173.4, 165.5, 162.7, 161.2, 159.1, 144.2,
142.1, 141.6, 138.2, 137.7, 137.2, 136.2, 135.6, 134.1, 133.7,
133.5, 132.2, 129.6, 129.5, 127.6, 120.9, 119.1, 119.0, 112.2,
110.0, 107.2, 105.3, 99.7, 96.0, 89.1, 87.0, 83.3, 80.5, 79.2, 77.8,
77.1, 73.3, 73.2, 72.0, 70.9, 70.5, 70.4, 69.4, 69.0, 68.7, 67.1,
65.8, 63.4, 61.7, 59.9, 56.5, 56.1, 55.5, 55.1, 47.8, 41.2, 40.4,
39.2, 39.1, 39.0, 36.9, 35.5, 35.1, 34.3, 33.6, 32.5, 31.6, 30.3,
29.6, 29.1, 28.1, 26.9, 26.6, 25.7, 24.5, 19.2, 18.1, 14.1, 13.4,
13.2, 5.9, 0.94,-4.6,-4.7; HRMS(ESI) m/z calcd for:
C95H134O19N4Si2S [(M+H)+]: 1723.8902; found: 1723.8935.
8. Experimental for 1: A 1 dram vial was charged sequentially
with alkyne 2 (2.3 mg, 2.4 mmol), vinyl iodide 3 (4.1 mg, 7.7
mmol) in freshly distilled and de-gassed THF (0.5 mL), freshly
distilled and de-gassed Et3N (0.1 mL, 0.7 mmol), PdCl2(PPh3)2
(0.16 mg, 0.23 mmol), and anhydrous CuI (0.04 mg, 0.2 mmol).
The vial was flushed with N2 and capped. The reaction mix-
ture was stirred vigorously for 3.5 h at which time, the reaction
was judged to be complete by TLC. Saturated aqueous NH4Cl
and ethyl acetate (2 mL) were added, the layers were separated
and the aqueous layer was extracted with ethyl acetate (5Â4
mL). The combined organic layers were dried (Na2SO4), fil-
tered, and concentrated by rotary evaporation. The residue
was purified by preparative TLC (ethyl acetate!ethyl acetate/
ethanol, 3:1, v/v) to provide 1 (1.2 mg, 0.9 mmol, 38%) as a
white film: TLC (silica gel, ethyl acetate/ethanol, 2:1, v/v)
Scheme 4. Sonogashira coupling of 2 and 3.
affinity probes for elucidating the molecular basis of
phorboxazoles’ remarkable biological activities is cur-
rently being evaluated in our laboratories.
Acknowledgements
This work was supported by the NIH (R01GM55756
and R01CA99950) and a Bristol-Myers Squibb Award
in Synthetic Organic Chemistry (C.J.F.). We thank Mr.
Y. Lu, Mr. J. Chen, Dr. C. S. Lee, Dr. R. D. Cink, Dr.
F. Ahmed, Dr. J. Klassen, and Dr. M. Christmann for
early experimental contributions.
References and Notes
1. (a) Searle, P. A.; Molinski, T. F. J. Am. Chem. Soc. 1995,
117, 8126. (b) Searle, P. A.; Molinski, T. F.; Brezezinski, L. J.;
Leahy, J. W. J. Am. Chem. Soc. 1996, 118, 9422. (c) Molinski,
T. F. Tetrahedron Lett. 1996, 37, 7879.
2. (a) Forsyth, C. J.; Ahmed, F.; Cink, R. D.; Lee, C. S. J. Am.
Chem. Soc. 1998, 19, 5597. (b) Evans, D. A.; Fitch, D. M.;
Smith, T. E.; Cee, V. J. J. Am. Chem. Soc. 2000, 122, 10033.
(c) Smith, A. B., III; Verhoest, P. R.; Minbiole, K. P.; Schel-
haas, M. J. Am. Chem. Soc. 2001, 123, 10942. (d) Gonzalez,
M. A.; Pattenden, G. Angew. Chem. Int. Ed. 2003, 42, 1255. (e)
Williams, D. A.; Kiryanov, A. A.; Emde, U.; Clark, M. P.;
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1258.
3. (a) Portions of this work are described in the PhD. Thesis of
T. M. Hansen, University of Minnesota, 2002. (b) Hansen, T.
M.; Engler, M. M.; Forsyth, C. J. Abstracts of Papers, 222nd
National Meeting of the American Chemical Society: Chicago,
IL, Aug 2001; American Chemical Society: Washington D.C.,
2001, ORGN 199. (c) The biological activity of 2 has been
reported: Uckun, F. M.; Forsyth, C. J. Bioorg. Med. Chem.
Lett. 2001, 11, 1181 and references cited within.