Figure 1.
Ni0-mediated ring-closing reaction as the last step, yielding
only 17% and 1% of the 17- and 16-membered ring systems,
respectively. Here we report two different routes to the DEF
ring system of complestatin. One utilizes a macrolactamiza-
tion as the last step of the synthesis, while the more efficient
route utilizes an intramolecular palladium-catalyzed ring
closure to the 17-membered ring system of complestatin.
Both routes afford access to the 16-membered ring system
of chloropeptin by ring contraction of the 17-membered DEF
ring system of complestatin.
Scheme 1
The DEF ring system allows disconnection at two sites:
the biaryl linkage or a peptide bond. Disconnection at a
peptide bond allows formation of the biaryl linkage by a
Suzuki reaction followed by macrolactamization to give the
17-membered DEF ring system. However, a potentially more
versatile route involves formation of the peptide backbone
prior to the intramolecular Pd-catalyzed Sukuzi reaction.
Synthesis of the phenylglycinol dipeptide unit 5 started
with 4-methoxystyrene as the substrate for the Sharpless
aminohydroxylation6 (Scheme 1). Using (DHQD)2PHAL as
the ligand, the correct regioisomer was obtained in 56% yield
with an 88% ee (determined by formation of the Mosher
ester). Compound 1 was selectively iodinated at the 3-posi-
tion ortho to the methoxy group using Ag2SO4/I2.7 Removal
of the Cbz group required harsher conditions than anticipated.
Hydrogenation using H2/Pd on carbon or transfer hydrogena-
tion using Pd/C with 1,4-cyclohexadiene were unsuccessful.
The use of bromocatecholborane yielded only 20% of the
desired amine, but cleavage of the Cbz group with Me3SiI8
in acetonitrile gave the amine 3 (90% yield), which was
coupled with Boc-D-phenylalanine, using EDCI and HOBt
with NMM in acetonitrile. The phenylglycinol unit was
converted to the tert-butyldiphenylsilyl ether 5, which served
as the precursor to the aryl boronate.
The second component, 6-bromo-D-tryptophan, was syn-
thesized by an enantioselective ene reaction (Schemes 2 and
3). 2,5-Dibromoaniline was reacted with p-toluenesulfonyl
chloride and pyridine to produce the sulfonamide, which was
further reacted with allyl bromide and K2CO3 at 80 °C to
yield N-allyl-2,5-dibromo-N-(tolylsulfonyl)aniline (7). Com-
pound 7 was then reacted with Pd(OAc)2, PPh3, and Ag2-
(5) (a) Carbonnelle, A.; Zamora, E. G.; Beugelmans, R.; Roussi, G.
Tetrahedron Lett. 1998, 39, 4471. (b) Beugelmans, R.; Roussi, G.; Zamora,
E. G.; Carbonnelle, A. Tetrahedron 1999, 55, 5089.
(6) (a) Li, G.; Chang, H. T.; Sharpless, K. B. Angew. Chem., Int. Ed.
Engl. 1996, 35, 451. (b) Li, G.; Angert, H. H.; Sharpless, K. B. Angew.
Chem., Int. Ed. Engl. 1996, 35, 2813. (c) Reddy, K. L.; Sharpless, K. B. J.
Am. Chem. Soc. 1998, 120, 1207.
9
CO3 in an intramolecular Heck reaction in acetonitrile to
(7) Sy, W. Tetrahedron Lett. 1993, 34, 6223.
(8) (a) Lott, R. S.; Chauhan, V. S.; Stammer, C. H. J. Chem. Soc., Chem.
Commun. 1979, 495. (b) Ihara, M.; Taniguchi, N.; Nogochi, K.; Fujumoto,
K.; Kametani, T. J. Chem. Soc., Perkin Trans. 1 1988, 1277.
(9) Sakamoto, T.; Kondo, Y.; Uchiyama, M.; Yamanaka, H. J. Chem.
Soc., Perkin Trans. 1 1993, 1941.
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Org. Lett., Vol. 1, No. 9, 1999