.
Angewandte
Communications
Table 4: Selective synthesis of the regioisomers 18 and 19 from specific
precursors 16 and 16’.[a]
Entry
8
Vinyl bromide
Product
Yield [%][b]
1
2
3
4
5
6
7
8
8a (X=H)
8a
8b (X=F)
8b
8c (X=Cl)
8c
8d (X=Br)
8e (X=Me)
8e (X=Me)
8 f (X=OMe)
8 f
16
16’
16
16’
16
16’
16
16
16’
16
16’
18a
19a
18b
19b
18c
19c
18d
18e
19e
18 f
19 f
92
91
95
86
92
85
82
89
78
86
79
9
10
11
[a] Reaction conditions: 8, CuI (5 mol%), DMEDA (10 mol%), K2CO3
(2 equiv), toluene, 1108C; then ZnCl2 (2.2 equiv), toluene, 908C. [b] The
combined yield of two operations without isolation of the enehydrazine
intermediate.
Scheme 2. Synthesis of the complex carbon skeletons in indole alka-
loids through interrupted indolizations. a) CuI (5 mol%), DMEDA
(10 mol%), K2CO3 (2 equiv), toluene, 1008C, 30 h; ZnCl2 (2.0 equiv),
toluene, 908C, 1 h. b) CuI (5 mol%), DMEDA (10 mol%), K2CO3
(2 equiv), toluene, 808C, 40 h; then ZnCl2 (2.0 equiv), toluene, 908C,
1 h. c) CuI (5 mol%), 1,10-phenanthroline (10 mol%), K2CO3 (2 equiv),
toluene, 1108C, 40 h; then ZnCl2 (2.0 equiv), toluene, 908C, 1 h.
our approach was able to generate one isomerically pure
product just by choosing a specific vinyl bromide. Under the
standard reaction conditions, 18 and 19 were produced in
good to excellent yields from 16 and 16’, respectively.
The unique advantage of our new approach was further
demonstrated by its application to the synthesis of complex
carbon framework in indole alkaloids. Remarkably, treatment
of 8a and 8 f with the vinyl iodide 21[17] produced the natural
products desoxyeseroline[18] (22) and esermethole[19] (23),
respectively, in good yields (Scheme 2A and B). It is note-
worthy that the free secondary amine in 21 did not interfere
with the reaction owing to the high chemoselectivity of the
coupling chemistry between phenylhydrazine and 21. More-
over, the excellent chemoselectivity guaranteed the success of
the interrupted Fischer indolizations[20] and fulfilled one-step
divergent preparations of indole alkaloids 22 and 23 from the
same vinyl iodide 21. Notably, desoxyeseroline and esermet-
hole are in the same family of alkaloids as physostigmine (26),
which is a commercial API known to treat myasthenia gravis,
glaucoma, Alzheimerꢀs disease, and delayed gastric empty-
ing.[21] Either of the alkaloids can be readily converted into
the drug molecule according to well-established proce-
dures.[22] In addition, we found the coupling chemistry was
also compatible with the primary amine in the vinyl bromide
24.[23] Although our standard reaction conditions did not work
well with this challenging substrate, tuning of the ligand from
DMEDA to 1, 10-phenanthroline[24] led to efficient produc-
tion of 25 in 71% yield (Scheme 2C). Therefore, our coupling
chemistry provided a new way for quick construction of the
tetracyclic pyrrolidinoindoline scaffold 25, which is the key
structural motif in the Strychnos alkaloid minfiensine[25] (27)
and the Akuammiline alkaloid vincorine[26] (28).
direct formation of the enehydrazine intermediate through
copper-catalyzed coupling of phenylhydrazines and vinyl
halides. The chemistry tolerates ester functional groups, free
hydroxy groups, and free amines. It allowed us to not only
fulfill selective synthesis of isomeric indoles but also to
develop interrupted indolizations to conveniently synthesize
the pyrrolidinoindoline framework. Therefore, our approach
is expected to have great potential in quick construction of
complex carbon skeletons in indole alkaloids, especially those
bearing quaternary carbon centers. What is worth pointing
out is that the formation of the enehydrazine intermediate,
without scrambling the double bond, opens a new avenue for
the challenging asymmetric synthesis of indoles and indolines,
which presumably could be achieved through either substrate
or reagent control of the [3,3] sigmatropic rearrangement in
the Fischer indole synthesis.[27] Relevant studies on this
strategy and its synthetic applications are underway in our
laboratory.
Received: September 4, 2012
Revised: October 17, 2012
Published online: December 6, 2012
À
Keywords: C N coupling · copper · heterocycles ·
natural products · synthetic methods
.
[1] a) R. J. Sundberg, Indoles, Academic Press, London, 1996; b) A.
Rahman, Indole Alkaloids, Harwood Academic Publisher,
Amsterdam, 1998; c) “Indole and its Derivatives”: A. Joule in
Science of Synthesis: Methods of Molecular Transformations
In summary, we created a new entry into the Fischer
indole synthesis and it overcomes the regioselectivity problem
with the classic Fischer indolization. Our approach is based on
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Angew. Chem. Int. Ed. 2013, 52, 1266 –1269