Enantioselective construction of spiroindolenines by Ir-catalyzed allylic alkylation reactions

Article abstract of DOI:10.1021/ja105111n

With 2-methyl-1,2,3,4-tetrahydroquinoline-derived phosphoramidite ligand (R,R_a)-L₆, Ir-catalyzed intramolecular C-3 allylic alkylation of indoles has been realized to afford highly enantioenriched spiroindolenine derivatives in 92-98

Full text of DOI:10.1021/ja105111n

Published on Web 08/02/2010
Enantioselective Construction of Spiroindolenines by Ir-Catalyzed Allylic
Alkylation Reactions
Qing-Feng Wu, Hu He, Wen-Bo Liu, and Shu-Li You*
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences, 345 Lingling Lu, Shanghai 200032, China
Received June 20, 2010; E-mail: slyou@mail.sioc.ac.cn
Scheme 1. Pd- and Ir-Catalyzed Intramolecular Allylic Alkylation
Abstract: With 2-methyl-1,2,3,4-tetrahydroquinoline-derived phos-
phoramidite ligand (R,Ra)-L6, Ir-catalyzed intramolecular C-3 allylic
alkylation of indoles has been realized to afford highly enantioen-
riched spiroindolenine derivatives in 92-98% yields with up to
>99/1 dr and 97% ee.
The spiroindolenine and spiroindoline units are privileged hetero-
cyclic motifs that form the structural core for a large family of alkaloid
natural products such as koumine, perophoramidine, and commune-
sins.1 Consequently, enormous efforts have been devoted to the develop-
ment of efficient synthetic protocols for the construction of these skeletons.2
The synthesis of indolenines from indoles features a straightforward
Table 1. Optimization of the Reaction Conditionsa
route and ready availability of starting materials but is faced with the
difficulty of constructing a quaternary stereocenter Via a dearomati-
zation process.3 In 2005, Tamaru and co-workers reported a C-3
selective Pd-catalyzed allylation of 1H-indoles promoted by trieth-
ylborane using allylic alcohols.4 Soon after, Trost and Quancard
described an enantioselective Pd-catalyzed C-3-alkylation of various
3-substituted indoles to construct a range of indolenine and indoline
derivatives bearing quaternary stereocenters.3b Rawal and co-workers
recently extended the reaction to 2,3-disubstituted indoles.3c Since Ir-
catalysts have been successfully applied to the allylic alkylation of
indoles at C-3 and N-1 by us and Hartwig,5,6 we envisaged that the
spiroindolenines might be accessed via Ir-catalyzed intramolecular
allylic alkylation of indoles. As an inspiration, Bandini and co-workers
reported a highly enantioselective Pd-catalyzed intramolecular allylic
alkylation for the synthesis of tetrahydro-ꢀ-carbolines and tetrahydro-
γ-carbolines (Scheme 1).7 Recently, we found the spiroindolenine
substructures could be formed through intramolecular allylic alkylation
by extending the linker. Herein, we describe the first highly enanti-
oselective synthesis of spiroindolenines via Ir-catalyzed asymmetric
allylic alkylation reaction.
At the outset, we utilized a well-developed Ir-catalytic system
including [Ir(COD)Cl]2 and phosphoramidite L1 (Table 1) as catalyst.8
In the presence of 2 mol % of [Ir(COD)Cl]2, 4 mol % of L1, and 2
equiv of Cs2CO3, reaction of 1a in THF for 1.5 h gave spiroindolenine
2a in 70% yield, 76/24 dr, and 95% ee (entry 1, Table 1). Screening
various bases, DABCO, K3PO4, DBU, Et3N, DIEA, DBN, and BSA
(entries 2-8, Table 1), confirmed that Cs2CO3 was optimal. Next, we
examined several chiral ligands, as summarized in Table 1. Ligands
L2, L3, and L5 could catalyze the reaction in excellent ee’s, but with
only moderate dr ratios. To our delight, after screening two ligands
developed in our group, L6 and L7,5b we found that catalyst derived
from L6 gave satisfactory results in terms of yield, dr, and ee (entry
13, Table 1). Varying the solvent (DCM, toluene, dioxane, DME, and
Et2O) influenced the outcome considerably. Refluxed DCM gave the
best result, affording 2a in 95% yield, >99/1 dr, and 96% ee (entry
15, Table 1).
temp
(°C)
yield
(%)b
ee
(%)d
entry ligand
solvent
base
t (h)
drc
1
2
L1
L1
L1
L1
L1
L1
L1
L1
L2
L3
L4
L5
L6
L7
L6
L6
L6
L6
L6
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
DCM
Cs2CO3
50
1.5 75
1.5 48
1.5 62
1.5 68
1.5 63
1.5 67
1.5 41
1.5 56
1.5 74
1.5 72
24 trace
24 40
1.5 95
24 30
76/24 95
61/39 95
74/26 95
68/32 95
77/23 95
66/34 95
70/30 95
75/25 95
84/16 96
81/19 93
DABCO 50
3
4
5
6
K3PO4
DBU
Et3N
DIEA
DBN
50
50
50
50
50
50
50
50
50
50
50
50
7
8
9
BSA
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
10
11
12
13
14
15
16
17
18
19
>99/1 82
96/4 91
80e
97/3
reflux 1.5 95
>99/1 96
>99/1 93
90/10 86
94/6 90
toluene Cs2CO3
dioxane Cs2CO3
DME
Et2O
50
50
50
1.5 84
1.5 73
1.5 60
Cs2CO3
Cs2CO3
reflux 1.5 85
>99/1 93
a Reaction conditions: 0.2 mmol of 1a, 0.4 mmol of base in solvent
(1.0 mL). b Isolated yield of the major diastereoisomer. c Determined by
1H NMR of the crude reaction mixture. d Determined by chiral HPLC
analysis. e Product with opposite configuration was obtained.
In the presence of 2 mol % of [Ir(COD)Cl]2, 4 mol % of L6, and
2 equiv of Cs2CO3 under DCM reflux, various 3-indolyl allyl
carbonates were tested to examine the generality of the reaction. The
results are summarized in Table 2. Reaction of allylic carbonates with
a varying protecting group on the linking N atom (Bn, p-Br-C6H4CH2,
Me, allyl) all gave the spiroindolenine products in good yields with
9
11418 J. AM. CHEM. SOC. 2010, 132, 11418–11419
10.1021/ja105111n  2010 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Reaction Substrate Scope
Scheme 2. Transformation of Product 2a
treatment of 2a with sodium cyanoborohydride afforded the spiroin-
doline 3. The CdC and CdN could be reduced by Pd/C catalyzed
hydrogenation to give spiroindoline 4. Interestingly, for Pd(OH)2/C
catalyzed hydrogenation, the Bn group was also removed. In all cases,
there was no notable loss of the optical purity.10
In summary, we have developed a highly enantioselective synthesis
of spiroindolenine derivatives via Ir-catalyzed intramolecular C-3 allylic
alkylation of indoles. The spiroindolenine derivatives were obtained
in excellent yields with up to >99/1 dr and 97% ee. Further extension
of the reaction scope and development of more efficient catalytic
systems are currently underway in our laboratory.
Acknowledgment. We thank the NSFC (20872159, 20821002,
20923005) and National Basic Research Program of China (973
Program 2009CB825300) for generous financial support.
Supporting Information Available: Experimental procedures and
characterization of the products. This material is available free of charge
via the Internet at http://pubs.acs.org.
References
(1) (a) Chou, T. Q. Chin. J. Physiol. 1931, 5, 345. (b) Liu, C.-T.; Wang, Q.-W.;
Wang, C.-H. J. Am. Chem. Soc. 1981, 103, 4634. (c) Verbitski, S. M.; Mayne,
C. L.; Davis, R. A.; Concepcion, G. P.; Ireland, C. M. J. Org. Chem. 2002,
67, 7124. (d) Numata, A.; Takahashi, C.; Ito, Y.; Takada, T.; Kawai, K.; Usami,
Y.; Matsumura, E.; Imachi, M.; Ito, T.; Hasegawa, T. Tetrahedron Lett. 1993,
34, 2355. (e) Jadulco, R.; Edrada, R. A.; Ebel, R.; Berg, A.; Schaumann, K.;
Wray, V.; Steube, K.; Proksch, P. J. Nat. Prod. 2004, 67, 78.
(2) Selected examples in total synthesis: (a) Magnus, P.; Mugrage, B.; DeLuca,
M. R.; Cain, G. A. J. Am. Chem. Soc. 1989, 111, 786. (b) Magnus, P.;
Mugrage, B.; DeLuca, M.; Cain, G. A. J. Am. Chem. Soc. 1990, 112, 5220.
(c) Fuchs, J. R.; Funk, R. L. J. Am. Chem. Soc. 2004, 126, 5068. (d) Sabahi,
A.; Novikov, A.; Rainier, J. D. Angew. Chem., Int. Ed. 2006, 45, 4317. (e)
Yang, J.; Wu, H.; Shen, L.; Qin, Y. J. Am. Chem. Soc. 2007, 129, 13794.
Selected examples of construction of spiroindole skeletons: (f) Ibaceta-
Lizana, J. S. L.; Jackson, A. H.; Prasitpan, N.; Shannon, P. V. R. J. Chem.
Soc., Perkin Trans. 2 1987, 1221. (g) Linnepe, P.; Schmidt, A. M.; Eilbracht,
P. Org. Biomol. Chem. 2006, 4, 302.
(3) (a) Austin, J. F.; Kim, S.-G.; Sinz, C. J.; Xiao, W.-J.; MacMillan, D. W. C.
Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5482. (b) Trost, B. M.; Quancard,
J. J. Am. Chem. Soc. 2006, 128, 6314, and references therein. (c) Kagawa,
N.; Malerich, J. P.; Rawal, V. H. Org. Lett. 2008, 10, 2381. (d) Eastman,
K.; Baran, P. S. Tetrahedron 2009, 65, 3149.
(4) Kimura, M.; Futamata, M.; Mukai, R.; Tamaru, Y. J. Am. Chem. Soc. 2005,
127, 4592.
(5) (a) Liu, W.-B.; He, H.; Dai, L.-X.; You, S.-L. Org. Lett. 2008, 10, 1815.
(b) Liu, W.-B.; He, H.; Dai, L.-X.; You, S.-L. Synthesis 2009, 2076. (c)
Stanley, L. M.; Hartwig, J. F. Angew. Chem., Int. Ed. 2009, 48, 7841.
(6) For reviews: (a) Takeuchi, R.; Kezuka, S. Synthesis 2006, 3349. (b)
Helmchen, G.; Dahnz, A.; Du¨bon, P.; Schelwies, M.; Weihofen, R. Chem.
Commun. 2007, 675. For the first Ir-catalyzed asymmetric allylic alkylation
reaction: (c) Janssen, J. P.; Helmchen, G. Tetrahedron Lett. 1997, 38, 8025.
(7) Bandini, M.; Melloni, A.; Piccinelli, F.; Sinisi, R.; Tommasi, S.; Umani-
Ronchi, A. J. Am. Chem. Soc. 2006, 128, 1424.
(8) (a) Ohmura, T.; Hartwig, J. F. J. Am. Chem. Soc. 2002, 124, 15164. (b)
Lo´pez, F.; Ohmura, T.; Hartwig, J. F. J. Am. Chem. Soc. 2003, 125, 3426.
(c) Kiener, C. A.; Shu, C.; Incarvito, C.; Hartwig, J. F. J. Am. Chem. Soc.
2003, 125, 14272. (d) Raskatov, J. A.; Spiess, S.; Gnamm, C.; Bro¨dner,
K.; Rominger, F.; Helmchen, G. Chem.sEur. J. 2010, 16, 6601.
(9) See the Supporting Information (SI).
a Isolated yields of the major diastereoisomer. b Determined by 1H
NMR of the crude reaction mixture. c Determined by chiral HPLC
analysis. d Isolated yields of the minor diastereoisomer.
excellent dr and ee (92-95% yields, 96/4f99/1 dr, 95-96% ee,
entries 1-4, Table 2). Notably, the allyl protecting group in 1d did
not interfere with the alkylation process. The stereochemistry of the
products was determined by X-ray structural determination of their
enantiopure bromine-containing derivatives.9 Substrates bearing either
an electron-donating group (4-Me, 5-MeO, 6-BnO) (entries 5-7, Table
2) or electron-withdrawing group (6-Br, 5-F) (entries 8-9, Table 2)
on the indole core all led to their corresponding products in excellent
yields, dr, and ee (93-98% yields, 96/4f99/1 dr, 88-94% ee). The
2-substituted indolyl allyl carbonates were also tolerated and afforded
the corresponding products in excellent yields and ee (88-90% yields,
91-97% ee, entries 10-11, Table 2), although in moderate dr.
To test the five-member ring spiroindolenine formation, Bandini’s
substrate, by shortening one carbon in 1a (as shown in Scheme
1),7 was tested in the current catalytic system. Interestingly,
tetrahydro-γ-carboline product was obtained,9 which suggests the
formation of spiroindolenine is likely caused by the favorable six-
member ring product by reacting at the C-3 position over the seven-
member ring product at the C-2 position.
(10) The ee of 4 and 5 were determined after their conversion to N-Ts derivatives
(see the SI for details).
JA105111N
The multifunctionalized spiroindolenine products obtained here
could undergo versatile transformation. As shown in Scheme 2,
9
J. AM. CHEM. SOC. VOL. 132, NO. 33, 2010 11419