C O M M U N I C A T I O N S
Scheme 3. Total Synthesis of the S Atropisomer of Complestatina
rotation between complestatin and isocomplestatin, was resolved
by re-measurement of the rotation of an authentic sample of
isocomplestatin, generously provided by Dr. Singh. The value
obtained by us, [R]26D ) +25.9 (c ) 0.14, 2:1 MeOH:0.01 N NaOH
versus -60° recorded previously),5 is nearly identical to that
documented for natural complestatin (+24.5 (c ) 0.13, 2:1 MeOH:
0.01 N NaOH)).20
Stereoselective synthesis of complestatin and examination of
biological activity of isocomplestatin are in progress.
Acknowledgment. Financial support was provided by the NIH
(GM-57212). T.S. was supported as a JSPS postdoctoral fellowship.
We are grateful to Dr. S. B. Singh of Merck Research Laboratories
for authentic samples and helpful discussions.
Supporting Information Available: Experimental procedures and
spectral, analytical data for all compounds (PDF). This material is
References
(1) (a) Kaneko, I.; Fearon, D. T.; Austen, K. F. J. Immunol. 1980, 124, 1194-
1198. (b) Kaneko, I.; Kamoshida, K.; Takahashi, S. J. Antibiot. 1989, 42,
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(2) (a) Seto, H.; Fujioka, T.; Furihata, K.; Kaneko, I.; Takahashi, S.
Tetrahedron Lett. 1989, 30, 4987-4990. (b) Jayasuriya, H.; Salituro, G.
M.; Smith, S. K.; Heck, J. V.; Gould, S. J.; Singh, S. B.; Homnick, C. F.;
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(3) (a) Matsuzaki, K.; Ikeda, H.; Ogino, T.; Matsumoto, A.; Woodruff, H.
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H.; Omura, S. J. Antibiot. 1997, 50, 66-69.
a Reaction conditions: (a) 1.1 equiv of 8, 1.2 equiv of HATU, THF 0-22
°C, 4 h, 85%; (b) 1 equiv of PdCl2(dppf)‚CH2Cl2, 10 equiv of K2CO3, 10:1
dioxane:H2O, 80 °C, 1.5 h, 63%; (c) 10 equiv of LiOH, 7:1 THF:H2O,
0 °C, 2 h, >98%.
(4) Deng, H.; Jung, J.-K.; Liu, T.; Kuntz, K. W.; Snapper, M. L.; Hoveyda,
A. H. J. Am. Chem. Soc. 2003, 125, 9032-9034.
(5) Singh, S. B.; Jayasuriya, H.; Salituro, G. M.; Zink, D. L.; Shafiee, A.;
Heimbuch, B.; Silverman, K. C.; Lingham, R. B.; Genilloud, O.; Teran,
A.; Vilella, D.; Felock, P.; Hazuda, D. J. Nat. Prod. 2001, 64, 874-882.
(6) Although not explicitly stated nor structurally illustrated, this finding
implies that complestatin bears the (S)-biaryl atropisomer.
(7) For related synthetic studies, see: (a) Gurjar, M. K.; Tripathy, N. K.
Tetrahedron Lett. 1997, 38, 2163-2166. (b) Carbonnelle, A.-C.; Zamora,
E. G.; Beugelmans, R.; Roussi, G. Tetrahedron Lett. 1998, 39, 4471-
4472. (c) Elder, A. M.; Rich, D. H. Org. Lett. 1999, 1, 1443-1446. (d)
Kai, T.; Kajimoto, N.; Konda, Y.; Harigaya, Y.; Takayanagi, H.
Tetrahedron Lett. 1999, 40, 6289-6292. (e) Smith, A. B.; Chruma, J. J.;
Han, Q.; Barbosa, J. Bioorg. Med. Chem. Lett. 2004, 14, 1697-1702.
(8) The R-ketoamide terminus must be present prior to macrocyclization;
otherwise, removal of amine protecting groups (e.g., NBoc), as effected
in the total synthesis of chloropeptin I (ref 4), could cause rearrangement
to the less strained macrocycle.
tion conditions and methyl ester hydrolysis delivered 2 (via 18) as
a single stereoisomer in 63% yield (for two steps).18
The stereochemical identity of the atropisomer of the tryptophan
moiety of 2 is based on the signature chemical shift of the H2 proton
(δ 5.18 ppm) and was ascertained by extensive nOe experiments
(Scheme 3). We measured the optical rotation to be [R]26D ) +36.0
(c ) 0.15, 2:1 MeOH:0.01 N NaOH). Moreover, through nOe
studies and comparison of the chemical shift values with those for
complestatin (1) and chloropeptin I (3),18 we rigorously established
that the integrity of the remaining stereogenic centers has been
preserved.19
(9) Taniguchi, M.; Anjiki, T.; Nakagawa, M.; Hino, T. Chem. Pharm. Bull.
1984, 32, 2544-2554.
Analysis of the related spectral and physical data18 clearly
indicates that the material synthesized according to the route shown
in Scheme 3 (2) is not complestatin; 2 is also different from the
compound reported to be isocomplestatin.5 Collectively, the above
(10) Abbreviations: dppf ) 1,1′-bis(diphenylphosphino)ferrocene; EDC ) 1-[3-
(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride; HOAt )
1-hydroxy-7-azabenzotriazole; HATU ) 2-(1-H-7-azabenzotriazol)-1,1,3,3-
methyluronium hexafluorophosphate; DEPBT ) 3-(diethyloxyphospho-
ryloxy)-1,2,3-benzotriazin-4(3H)-one.
1
(11) (a) Ishiyama, T.; Murata, M.; Miyaura, N. J. Org. Chem. 1995, 60, 7508-
7510. (b) Ishiyama, T.; Itoh, Y.; Kitano, T.; Miyaura, N. Tetrahedron
Lett. 1997, 38, 3447-3450.
(12) Olah, G. A.; Narang, S. C. Tetrahedron 1982, 38, 2225-2277.
(13) Pearson, A. J.; Chelliah, M. V.; Bignan, G. C. Synthesis 1997, 536-541.
(14) (a) Kometani, T.; Watt, D. S.; Ji, T. Tetrahedron Lett. 1985, 26, 2043-
2046. (b) Kometani, T.; Watt, D. S.; Ji, T.; Fitz, T. J. Org. Chem. 1985,
50, 5384-5387.
(15) Li, H.; Jiang, X.; Ye, Y.; Fan, C.; Romoff, T.; Goodman, M. Org. Lett.
1999, 1, 91-93.
(16) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457-2483.
(17) Bois-Choussy, M.; Cristau, P.; Zhu, J. Angew. Chem., Int. Ed. 2003, 42,
4238-4241.
(18) See the Supporting Information for details of all spectral and physical
data.
(19) In contrast to 13 and 14 (Table 1), repeated attempts to isomerize 2 led
to decomposition (perhaps due to higher ring strain versus 1).
(20) Subsequent re-examination of optical rotation of different batches of
isocomplestatin by Dr. Singh supports the validity of this measurement.
observations and comparison of H NMR spectra of 13, 14, 1, 2,
and an authentic sample of isocomplestatin18 indicate that the
compound labeled as isocomplestatin is the same as complestatin,
and that the correct atropisomer of complestatin, yet to be isolated
as a natural product, is 2. These studies offer strong evidence that
1 (Scheme 1) is complestatin.
The above findings explain why the chemical shifts for H2 of
the tryptophan moiety for complestatin and isocomplestatin were
reported to appear at δ 4.2 ppm.5 Furthermore, observations
presented herein address the claim that complestatin and isocom-
plestatin rearrange to chloropeptin I (TFA). That isocomplestatin
is complestatin provides a rationale for why their tryptophan H3
protons are at the same chemical shifts (complicated by the apparent,
but nonexistent, discrepancy between the 2001 paper5 and the 1989
disclosure2a). The remaining issue, the distinctly different optical
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