Figure 1. Structures of chloptosin (1) and polyoxypeptins A (2)
and B (3).
of alkaloids,3,5 the presence of a chlorine atom at the
6-position in chloptosin is apparently rare. Existing methods
for generating similar structures such as 3a-hydroxypyrrolo-
[2,3-b]indole have suffered from problems related to poor
yields and stereocontrol.4 One notable exception is the
dimethyldioxirane (DMDO)-based oxidation of trytophan
derivatives developed by Danishefsky and co-workers.5
However, our initial efforts utilizing a similar strategy could
not achieve satisfactory results when applied to the substrates
having two chlorines. Recently, partial syntheses of this
pyrroloindoline were reported by us6a and Han6b using a
Davis silyl ether oxidation and Danishefsky’s protocol,
respectively. Unfortunately, these methods lacked satisfactory
stereoselectivity and efficiency when applied to the synthesis
of this dimeric amino acid. Very recently, important meth-
odology was developed in Ley’s lab7 to elaborate similar
hexahydropyrrolo[2,3-b]indol-3a-ols using a selenocycliza-
tion-oxidative deselenation sequence. This method presented
itself as an alternative protocol that may avoid side reactions
associated with the chlorines. Herein, we report our suc-
cessful total synthesis of the challenging C2-symmetrical
amino acid 4 present in chloptosin (1) (Figure 2).
Figure 2. Retrosynthetic analysis of the dimeric amino acid 4 in
chloptosin (1).
According to our synthetic plan, a Zinin benzidine rear-
rangement, intramolecular Heck reaction, and selenocycliza-
tion-oxidative deselenation were designed as the key
reactions, and commercially available m-chloronitrobenzene
(9) and D-serine were used as the starting materials. The
intermediate diamine 8 could be prepared via a Zinin
benzidine rearrangement8 followed by regioselective iodi-
nation. Double mono N-akylations and intramolecular Heck
reactions could achieve the indole derivative 6. The final
dimeric L-6-chloropyrroloindoline derivative 4 could be
elaborated via Ley’s protocol.7
The precursor 7 for the intramolecular Heck reactions was
prepared first (Scheme 1). Treatment of m-chloronitroben-
zene (9) with powdered zinc and sodium hydroxide under
refluxing conditions afforded 1,2-bis(3-chlorophenyl)hydra-
zine (10), which was then efficiently rearranged to 2,2′-
dichlorobiphenyl-4,4′-diamine (11) using hydrochloride acid8
(70% yield in two steps). Regioselective iodination of 11
was carried out by treatment with H2O2 and iodine,9 giving
the desired iodide 8 in 62% yield. Next double mono
N-alkylations were accomplished by reacting 8 with the
bromide 1210 in water and acetone in the presence of
NaHCO3 and Bu4NCl.11 Optimization of this procedure
finally afforded 7 in acceptable yield.
As shown in Figure 2, chloptosin (1) can be disconnected
into one dimeric L-6-chloropyrroloindoline derivative 4 and
two pentapeptides 5. A bidirectional route was then designed
to take advantage of the C2 symmetry of the target.
(3) Recent examples: (a) Depew, K. M.; Marsden, S. P.; Zatorska, D.;
Zatorski, A.; Bornmann, W. G.; Danishefsky, S. J. J. Am. Chem. Soc. 1999,
121, 11953-11963. (b) Nishida, A.; Ushigome, S.; Sugimoto, A.; Arai, S.
Heterocycles 2005, 66, 181-185. (c) Iwaki, T.; Yamada, F.; Funaki, S.;
Somei, M. Heterocyles 2005, 65, 1811-1815. (d) Kawahara, M.; Nishida,
A.; Nakagawa, M. Org. Lett. 2000, 2, 675-678. (e) Sun, W. Y.; Sun, Y.;
Tang, Y. C.; Hu, J. Q. Synlett 1993, 337-338.
(4) Sakai, A.; Tani. H.; Aoyama, T.; Shioiri, T. Synlett 1998, 257-258.
(5) Kamenecka, T. M.; Danishefsky, S. J. Chem. Eur. J. 2001, 7, 41-
63.
(8) Zinin, N. J. Prakt. Chem. 1845, 36, 93.
(6) (a) Hong, W.-X.; Yao, Z.-J. Chin. J. Chem. 2004, 22, 365-370. (b)
Kim, Y.-A.; Han, S.-Y. Synth. Commun. 2004, 34, 2931-2943.
(7) Ley, S. V.; Cleator, E.; Hewitt, P. R. Org. Biomol. Chem. 2003, 1,
3492-3494.
(9) Vaidyanathan, G.; Affleck, D. J.; Zalutsky, M. R. J. Med. Chem.
1994, 37, 3655-3662.
(10) Jurgens, A. R. Tetrahedron Lett. 1992, 33, 4727-4730.
(11) Aubart, K. M.; Heathcock, C. H. J. Org. Chem. 1999, 64, 16-22.
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