Ring-closing metathesis/isomerization/pictet-spengler cascade via ruthenium/chiral phosphoric acid sequential catalysis

Article abstract of DOI:10.1021/ol302215u

Chiral phosphoric acid worked together with Hoveyda-Grubbs II catalyst enabling highly efficient synthesis of enantioenriched tetrahydro-β- carbolines (up to 98% yield, 99% ee) through a ring-closing metathesis/ isomerization/Pictet-Spengler cascade reaction via sequential catalysis.

Full text of DOI:10.1021/ol302215u

ORGANIC
LETTERS
2012
Vol. 14, No. 19
5022–5025
Ring-Closing Metathesis/Isomerization/
PictetꢀSpengler Cascade via Ruthenium/
Chiral Phosphoric Acid Sequential Catalysis
Quan Cai, Xiao-Wei Liang, Shou-Guo Wang, Jun-Wei Zhang, Xiao Zhang, 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
slyou@sioc.ac.cn
Received August 9, 2012
ABSTRACT
Chiral phosphoric acid worked together with HoveydaꢀGrubbs II catalyst enabling highly efficient synthesis of enantioenriched tetrahydro-β-
carbolines (up to 98% yield, 99% ee) through a ring-closing metathesis/isomerization/PictetꢀSpengler cascade reaction via sequential catalysis.
The chiral tetrahydro-β-carboline ring system is widely
PictetꢀSpengler reaction has been recognized as one of the
most direct and efficient methods for construction of
tetrahydro-β-carboline frameworks.2 Its catalytically en-
antioselective version has attracted enormous attention
and witnessed significant progress during the past decade.3
Studies by Jacobsen,4 List,5 Hiemstra,6 and many others7
have realized highly enantioselective PictetꢀSpengler type
reactions. Notably, Dixon et al. recently designed a cas-
cade employing gold(I)/chiral phosphoric acid binary
catalysts enabling the enantioselective PictetꢀSpengler
type reaction in a highly efficient manner.8 However, to
date, most of the reported methods are accomplished by
the treatment of tryptamine with carbonyl functionality in
the presence of a chiral acidic catalyst. Recently, Nielsen
etal. reportedanalternative route to tetrahydro-β-carboline
by devising a Ru-catalyzed tandem ring-closing metathesis
distributed in natural products and pharmaceuticals.1 The
(1) For reviews, see: (a) Somei, M.; Yamada, F. Nat. Prod. Rep. 2004,
21, 278. (b) Kawasaki, T.; Higuchi, K. Nat. Prod. Rep. 2005, 22, 761. (c)
O’Connor, S. E.; Maresh, J. J. Nat. Prod. Rep. 2006, 23, 532. For
selected examples, see: (d) Yu, J.; Wang, T.; Liu, X.; Deschamps, J.;
Flippen Anderson, J.; Liao, X.; Cook, J. M. J. Org. Chem. 2003, 68,
7565. (e) Shen, Y.-C.; Chen, C.-Y.; Hsieh, P.-W.; Duh, C.-Y.; Lin,
Y.-M.; Ko, C.-L. Chem. Pharm. Bull. 2005, 53, 32. (f) Liao, X.; Zhou, H.;
Yu, J.; Cook, J. M. J. Org. Chem. 2006, 71, 8884. (g) Ma, J.; Yin, W.;
Zhou, H.; Cook, J. M. Org. Lett. 2007, 9, 3491.
(2) (a) Pictet, A.; Spengler, T. Ber. Dtsch. Chem. Ges. 1911, 44, 2030.
(b) Tatsui, G. J. Pharm. Soc. Jpn 1928, 48, 92. (c) Cox, E. D.; Cook, J. M.
Chem. Rev. 1995, 95, 1797. (d) Chrzanowska, M.; Rozwadowska, M. D.
Chem. Rev. 2004, 104, 3341.
(3) For reviews, see: (a) You, S.-L.; Cai, Q.; Zeng, M. Chem. Soc.
Rev. 2009, 38, 2190. (b) Lorenz, M.; Van Linn, M. L.; Cook, J. M. Curr.
€
Org. Synth. 2010, 7, 189. (c) Stockigt, J.; Antonchick, A. P.; Wu, F.;
Waldmann, H. Angew. Chem., Int. Ed. 2011, 50, 8538.
(4) (a) Taylor, M. S.; Jacobsen, E. N. J. Am. Chem. Soc. 2004, 126,
10558. (b) Raheem, I. T.; Thiara, P. S.; Peterson, E. A.; Jacobsen, E. N.
J. Am. Chem. Soc. 2007, 129, 13404. (c) Mergott, D. J.; Zuend, S. J.;
Jacobsen, E. N. Org. Lett. 2008, 10, 745. (d) Raheem, I. T.; Thiara, P. S.;
Jacobsen, E. N. Org. Lett. 2008, 10, 1577. (e) Klausen, R. S.; Jacobsen,
E. N. Org. Lett. 2009, 11, 887. (f) Lee, Y.; Klausen, R. S.; Jacobsen, E. N.
Org. Lett. 2011, 13, 5564.
(7) For selected recent examples, see: (a) Rueping, M.; Volla,
C. M. R.; Bolte, M.; Rabbe, G. Adv. Synth. Catal. 2011, 353, 2853. (b)
Wu, X.; Dai, X.; Fang, H.; Nie, L.; Chen, J.; Cao, W.; Zhao, G. Chem.;
Eur. J. 2011, 17, 10510. (c) He, Y.; Lin, M.; Li, Z.; Liang, X.; Li, G.;
Antilla, J. C. Org. Lett. 2011, 13, 4490. (d) Cheng, D.-J.; Wu, H.-B.;
Tian, S.-K. Org. Lett. 2011, 13, 5636. (e) Duce, S.; Pesciaioli, F.;
Gramigna, L.; Bernardi, L.; Mazzanti, A.; Ricci, A.; Bartoli, G.;
Bencivenni, G. Adv. Synth. Catal. 2011, 353, 860. (f) Huang, D.; Xu,
F.; Lin, X.; Wang, Y. Chem.;Eur. J. 2012, 18, 3148.
(8) (a) Muratore, M. E.; Holloway, C. A.; Pilling, A. W.; Storer, R. I.;
Trevitt, G.; Dixon, D. J. J. Am. Chem. Soc. 2009, 131, 10796. (b)
Holloway, C. A.; Muratore, M. E.; Storer, R. I.; Dixon, D. J. Org. Lett.
2010, 12, 4720.
(5) Seayad, J.; Seayad, A. M.; List, B. J. Am. Chem. Soc. 2006, 128,
1086.
(6) (a) Wanner, M. J.; van der Haas, R. N. S.; de Cuba, K. R.; van
Maarseveen, J. H.; Hiemstra, H. Angew. Chem., Int. Ed. 2007, 46, 7485.
(b) Sewgobind, N. V.; Wanner, M. J.; Ingemann, S.; de Gelder, R.; van
Maarseveen, J. H.; Hiemstra, H. J. Org. Chem. 2008, 73, 6405. (c)
Wanner, M. J.; Boots, R. N. A.; Eradus, B.; de Gelder, R.; van
ꢀ
Maarseveen, J. H.; Hiemstra, H. Org. Lett. 2009, 11, 2579. (d) Herle,
B.; Wanner, M. J.; van Maarseveen, J. H.; Hiemstra, H. J. Org. Chem.
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r
10.1021/ol302215u
Published on Web 09/18/2012
2012 American Chemical Society

(RCM)/isomerization/N-acyliminium cyclization sequence.9
The tandem reactions provide racemic tetrahydro-β-
carbolines in good yields from readily available starting
materials.
reaction into an enantioselective version (Scheme 1). To be
noted, Huang et al. recently showed that chiral phosphoric
acid could catalyze the isomerization of R, β-unsaturated
lactam to N-acyl iminium in an enantioselective N-H
functionalization of indoles.12 In this paper, we report a
highly efficient synthesis of enantioenriched indolizinoin-
doles through a RCM/isomerization/PictetꢀSpengler (PS)
cascade reaction via ruthenium/chiral phosphoric acid
sequential catalysis.
Scheme 1. Enantioselective Synthesis of Tetrahydro-β-carbo-
lines via Ru/Chiral Phosphoric Acid (CPA) Sequential Catalysis
Table 1. Screening Chiral Phosphoric Acids for Cascade
RCM/Isomerization/PS Reaction
As we recently succeeded in the development of sequen-
tial catalysis where a ruthenium catalyst and chiral phos-
phoric acid could synergistically catalyze cross-metathesis
(CM) and a FriedelꢀCrafts alkylation reaction,10,11 we
envisioned that a combination of a proper ruthenium
catalyst and chiral phosphoric acid could turn the Nielsen
entrya
1
R
yield (%)b
ee (%)c
1
2
1a
1b
1c
1d
1e
1f
1-naphthyl
50
94
46
92
74
82
89
75
77
80
28
45
55
46
43
55
63
38
35
86
2-naphthyl
3
4-NO2-C6H4
4-biphenyl
(10) For reviews on the combination of transition metal and chiral
phosphoric acid, see: (a) Shao, Z.; Zhang, H. Chem. Soc. Rev. 2009, 38,
2745. (b) Rueping, M.; Koenigs, R.; Atodiresei, I. Chem.;Eur. J. 2010,
16, 9350. (c) Zhou, J. Chem.;Asian J. 2010, 5, 422. (d) Zhong, C.; Shi,
X. Eur. J. Org. Chem. 2010, 2999. For selected examples about the
sequential catalysis of transition metal and chiral phosphoric acid, see:
(e) Sorimachi, K.; Terada, M. J. Am. Chem. Soc. 2008, 130, 14452. (f)
Terada, M.; Toda, Y. J. Am. Chem. Soc. 2009, 131, 6354. (g) Han, Z.-Y.;
Xiao, H.; Chen, X.-H.; Gong, L.-Z. J. Am. Chem. Soc. 2009, 131, 9182.
(h) Liu, X.-Y.; Che, C.-M. Org. Lett. 2009, 11, 4204. (i) Wang, C.; Han,
Z.-Y.; Luo, H.-W.; Gong, L.-Z. Org. Lett. 2010, 12, 2266. (j) Chen, Q.-
A.; Chen, M.-W.; Yu, C.-B.; Shi, L.; Wang, D.-S.; Yang, Y.; Zhou, Y.-
G. J. Am. Chem. Soc. 2011, 133, 16432. (k) Chen, Q.-A.; Wang, D.-S.;
Zhou, Y.-G.; Duan, Y.; Fan, H.-J.; Yang, Y.; Zhang, Z. J. Am. Chem.
Soc. 2011, 133, 6126. (l) Chen, Q.-A.; Gao, K.; Duan, Y.; Ye,
Z.-S.; Shi, L.; Yang, Y.; Zhou, Y.-G. J. Am. Chem. Soc. 2012, 134,
2442. (m) Ren, L.; Lei, T.; Ye, J.-X.; Gong, L.-Z. Angew. Chem., Int. Ed.
2012, 51, 771. For selected examples related to cooperative catalysis of a
transition metal and chiral phosphoric acid, see: (n) Komanduri, V.;
Krische, M. J. J. Am. Chem. Soc. 2006, 128, 16448. (o) Rueping, M.;
Antonchick, A. P.; Brinkmann, C. Angew. Chem., Int. Ed. 2007, 46,
6903. (p) Mukherjee, S.; List, B. J. Am. Chem. Soc. 2007, 129, 11336. (q)
Hu, W.; Xu, X.; Zhou, J.; Liu, W.-J.; Huang, H.; Hu, J.; Yang, L.; Gong,
L.-Z. J. Am. Chem. Soc. 2008, 130, 7782. (r) Xu, X.; Zhou, J.; Yang, L.;
Hu, W. Chem. Commun. 2008, 6564. (s) Li, C.; Wang, C.; Villa-Marcos,
B.; Xiao, J. J. Am. Chem. Soc. 2008, 130, 14450. (t) Li, C.; Villa-Marcos,
B.; Xiao, J. J. Am. Chem. Soc. 2009, 131, 6967. (u) Villa-Marcos, B.; Li,
C. Q.; Mulholland, K. R.; Hogan, P. J.; Xiao, J. Molecules 2010, 15,
2453. (v) Qian, Y.; Xu, X.; Jiang, L.; Prajapati, D.; Hu, W. J. Org. Chem.
2010, 75, 7483. (w) Zhou, S.; Fleischer, S.; Junge, K.; Beller, M. Angew.
Chem., Int. Ed. 2011, 50, 5120. (x) Rueping, M.; Koenigs, R. M. Chem.
Commun. 2011, 47, 304. (y) Jiang, J.; Xu, H.-D.; Xi, J.-B.; Ren, B.-Y.; Lv,
F.-P.; Guo, X.; Jiang, L.-Q.; Zhang, Z.-Y.; Hu, W.-H. J. Am. Chem. Soc.
2011, 133, 8428. (z) Xu, X.; Qian, Y.; Yang, L.; Hu, W. Chem. Commun.
2011, 47, 797. (aa) Jiang, G.; List, B. Angew. Chem., Int. Ed. 2011, 50,
9471. (ab) Xu, B.; Zhu, S.-F.; Xie, X.-L.; Shen, J.-J.; Zhou, Q.-L. Angew.
Chem., Int. Ed. 2011, 50, 11483. (ac) Terada, M.; Toda, Y. Angew.
Chem., Int. Ed. 2012, 51, 2093.
4
5
9-anthryl
6
9-phenanthryl
1-pyrenyl
2,4,6-(iPr)3-C6H2
4-tBu-2,6-(iPr)2-C6H2
SiPh3
7
1g
1h
1i
8
9
10
1j
a Reaction conditions: 5 mol % HoveydaꢀGrubbs II, 5 mol % (S)-1,
0.05 mol/L of 2a in toluene, 80 °C. b Isolated yield. c Determined by
HPLC analysis.
We began our study by using readily available trypta-
mine derivative 2a as a model substrate. The Hoveydaꢀ
Grubbs II catalyst was used to accomplish the RCM reac-
tion. With chiral phosphoric acid 1a bearing 1-naphthyl
groups, the proposed cascade RCM/isomerization/PS re-
action indeed proceeded even at 80 °C, affording cycliza-
tion product 3a in 50% yield and 28% ee (entry 1, Table 1).
Inspired by this result, several chiral BINOL-derived
phosphoric acids bearing different substituents at 3,30-
positions were further tested. The results are summarized
in Table 1. To our great delight, all the tested chiral phos-
phoric acids could catalyze the cascade reaction together
with the ruthenium catalyst, affording the cyclization
product generally in good yields and variable enantioselec-
tivity (entries 2ꢀ9, Table 1). Notably, chiral phosphoric
acid 1j, bearing triphenyl silyl groups, displayed optimal
enantioselective control (80% yield, 86% ee, entry 10, Table 1).
(11) (a) Cai, Q.; Zhao, Z.-A.; You, S.-L. Angew. Chem., Int. Ed. 2009,
48, 7428. (b) Cai, Q.; Zheng, C.; You, S.-L. Angew. Chem., Int. Ed. 2010,
49, 8666. For excellent work on the Ru-catalyzed tandem cross-
metathesis and FriedelꢀCrafts sequence, see: (c) Chen, J.-R.; Li,
C.-F.; An, X.-L.; Zhang, J.-J.; Zhu, X.-Y.; Xiao, W.-J. Angew. Chem.,
Int. Ed. 2008, 47, 2489.
(12) Xie, Y.; Zhao, Y.; Qian, B.; Yang, L.; Xia, C.; Huang, H. Angew.
Chem., Int. Ed. 2011, 50, 5682.
Org. Lett., Vol. 14, No. 19, 2012
5023

Table 2. Optimization of the Reaction Conditions for Cascade
RCM/Isomerization/PS Reaction with CPA 1j
Scheme 2. Substrate Scope for Cascade RCM/Isomerization/PS
Reaction
entrya
solvent
additive
t (°C)
yield (%)b
ee (%)c
1
2
3
4
5
6
toluene
benzene
m-xylene
CHCl3
none
none
none
none
none
none
80
80
80
80
80
80
80
48
60
<5
<5
90
86
85
81
ND
ND
81
DCE
c-hexane/
toluene
toluene
toluene
toluene
toluene
7d
8d
9d
10
3 A MS
80
80
80
80
83
84
60
80
86
85
81
85
˚
˚
4 A MS
˚
5 A MS
H2O
(1 equiv)
none
11e
12
13
14
toluene
toluene
toluene
toluene
80
80
82
86
95
86
85
86
84
none
70
none
95
none
reflux
a Reaction conditions: 5 mol % HoveydaꢀGrubbs II, 5 mol % (S)-1j,
0.05 mol/L of 2a, unless noted otherwise. b Isolated yield. c Determined by
HPLC analysis. d With 50 mg of molecular sieves per 0.1 mmol of 2a.
e Reaction with 0.1 mol/L of 2a
It should be noted that this optimal catalyst is consistent
with the work of Dixon and co-workers.8
With Hoveyda-Grubbs II and (S)-1j as the catalysts, the
reaction conditions were further optimized as summarized
in Table 2. Several conventional solvents were examined.
The reactions in benzene and m-xylene gave comparable
enantioselectivity but decreased yields, while those in
CHCl3 and DCE led to no detectable products (entries 1ꢀ5,
Table 2). The mixed solvents of cyclohexane and toluene
(1/1) could be tolerated to afford cyclization product 3a in
excellent yield but with slightly decreased enantioselectiv-
ity (90% yield, 81% ee, entry 6, Table 2). When molecular
sieves were tested as the additive (entries 7ꢀ9, Table 2),
cyclization products with excellent yields (82ꢀ98%). For
the aryl allyl amine moiety, substrates containing substi-
tuents such as 3-CF3, 3-OMe, 4-iBu, and 4-OMe on the
benzene ring could all be tolerated with good enantioselec-
tivity (80ꢀ91% ee, 3bꢀ3e, Scheme 2). The substrate
derived from methyl allyl amine also gave product 3f in
82% yield and 74% ee. Substrates bearing different sub-
stituents such as 4-Me, 6-Me, 5-Br, 6-F on the indole core
all proceeded smoothly under the sequential catalysis
(3gꢀ3j, Scheme 2). Interestingly, when substrates having
7-Me on the indole core were used, the enantioselectivity
could be enhanced dramatically. For instance, products
3kꢀq were obtained in excellent yields (91ꢀ96%) and ee
(93ꢀ99%) with various substituents on the allyl amine
such as Ph, 4-iBu-C6H4, 4-Br-C6H4, 3-CF3-C6H4, methyl,
cyclopropyl, and n-butyl groups (3kꢀ3q, Scheme 2). No-
tably, when the substrate derived from simple allyl amine
(R1 = H) was used, only moderate enantioselectivity was
obtained (3r, Scheme 2).13
˚
˚
both 3 A and 4 A MS gave improved yields (83ꢀ84%) but
˚
5 A MS led to a decreased yield (60%). Interestingly, the
addition of 1 equiv of water did not show any deteriorative
effect (entry 10, Table 2), indicating that the reaction is not
sensitive to moisture. Investigation of the reaction tem-
peratures disclosed that the reaction could proceed
smoothly ranging from 70 °C to reflux in toluene, without
an obvious effect on enantioselectivity (entries 12ꢀ14,
Table 2). In general a higher temperature leads to a better
yield in a shorter reaction time. The reaction in refluxed
toluene gave an optimal yield (95%).
Under the optimized reaction conditions (entry 14,
Table 2), the substrate scope of this cascade reaction has
been examined. The results are summarized in Scheme 2.
In general, all the tested substrates with varying substitu-
ents on the indole core and amine proceeded well to give
To shed light on the mechanism of this cascade reaction,
the R,β-unsaturatedlactam 4 was prepared. Treatmentof4
with 5 mol % (S)-1j in refluxed toluene led to 3a in 95%
yield and 87% ee (eq 1). Similar enantioselectivity between
the stepwise and the cascade reaction (entry 14, Table 2)
(13) See the Supporting Information for details.
5024
Org. Lett., Vol. 14, No. 19, 2012

suggested the N-acyl iminium cyclization was mainly
catalyzed by chiral phosphoric acid. On the other hand,
the highyield and enantioselectivity of the cascade reaction
highlight how sequential catalysis is advantageous.
the racemic synthesis. This cascade reaction provides a new
route for tetrahydro-β-carbolines and concepts in design-
ing transition-metal/chiral Brønsted acid sequential catalysis.
Acknowledgment. We thank the National Basic Re-
search Program of China (973 Program 2009CB825300)
and National Natural Science Foundation of China
(20923005, 21025209, 21121062) for financial support.
S.-L.Y. thanks AZ for an unrestricted research grant
(2011 AstraZeneca Excellence in Chemistry Award).
In conclusion, we have developed a cascade RCM/
isomerization/PictetꢀSpengler reaction, utilizing a ruthe-
nium complex and chiral phosphoric acid, with excellent
yields and enantioselectivity. The synergistic effect of the
binary catalytic system allows the enantioselective reaction
to proceed under milder reaction conditions compared to
Supporting Information Available. Detailed experimen-
tal procedures and spectroscopic data for all new com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 19, 2012
5025