Catalytic asymmetric activation of a Csp3-H bond adjacent to a nitrogen atom: A versatile approach to optically active α-alkyl α-amino acids and C1-alkylated tetrahydroisoquinoline derivatives

Article abstract of DOI:10.1002/anie.201105123

Simple and efficient: A one-pot oxidative and catalytic enantioselective alkylation of α-C sp 3-H bonds adjacent to a nitrogen atom was realized for the first time. This novel strategy provides a simple, efficient, and environmentally friendly access to d

Full text of DOI:10.1002/anie.201105123

DOI: 10.1002/anie.201105123
À
C H Activation
À
Catalytic Asymmetric Activation of a Csp3 H Bond Adjacent to a
Nitrogen Atom: AVersatile Approach to Optically Active a-Alkyl a-
Amino Acids and C1-Alkylated Tetrahydroisoquinoline Derivatives**
Gen Zhang, Yaohu Zhang, and Rui Wang*
À
The catalytic enantioselective activation of a Csp3 H bond to
À
form a new C C bond provides a potent strategic approach
for the synthesis of numerous complex chiral molecules, and is
at the forefront of current chemical research.[1] Despite the
À
Scheme 1. Catalytic asymmetric activation of C H bonds adjacent to a
nitrogen atom.
substantial progress that has been made in this field, this
transformation to date has largely been achieved by metal
carbene and nitrene insertion.[2] However, a variety of
deficiencies such as the use of expensive transition metals,
harsh reaction conditions, and poor stereoselectivities have
limited the laboratory and industrial applications of these
methods. Thus, the development of an alternative approach is
particularly appealing.
amines, for the synthesis of optically active a-alkyl a-amino
acids and C1-alkylated tetrahydroisoquinolines.
Glycine is the most simple and least expensive natural
amino acid, and contains a prochiral carbon at the a position.
À
Therefore, the development of a method for the direct a-C H
It was not until very recently that the cross-dehydrogen-
functionalization of glycine would provide a convenient way
to generate large arrays of diverse a-amino acid derivatives,[6]
which are of great importance and have applications in the
synthesis of biologically active peptides, natural products, and
organocatalysts. Recently, Li and co-workers introduced
functionalities such as aryl, vinyl, alkynyl, and indolyl
specifically to the a position of relatively unreactive glycine
amides.[7] However, glycine esters, unlike glycine amides, did
not undergo the CDC reaction, and an alkyl group could not
be introduced. Huang and Xie recently used a transition
metal/amine catalyst under oxidative conditions to solve this
problem, but either the enantioselectivity or yield was poor.[8]
The importance of optically active amino acid derivatives and
the lack of successful systems for catalytic asymmetric CDC
reactions of glycine derivatives with b-ketoesters, combined
with our long-standing interest in the synthesis of amino
acids,[9] lead us to focus on the study of CDC reactions of
glycine esters with a-substituted b-ketoesters. Based on the
À
À
ative coupling (CDC) of C H bonds to give new C C bonds
was developed.[3] This reaction is more atom economical and
environmentally friendly than other cross-coupling reactions,
and can be considered as a complementary strategy to the
À
existing direct C H bonds activations. Considerable advances
in this field have recently been achieved.[4,5] However, a
catalytic enantioselective variant of this transformation has,
to the best of our knowledge, remained elusive, especially for
À
the catalytic asymmetric alkylation of an a-Csp3 H bond
adjacent to a nitrogen atom, even though it presents a
powerful method for amine functionalization. In view of this
limitation, and considering that under oxidizing conditions, a
À
hydride can be abstracted from the C H bond adjacent to a
nitrogen atom to form a cationic intermediate that could react
À
with a nucleophile, thus leading to the formation of a new C
C bond (Scheme 1), we embarked on the study of asymmetric
CDC reactions for the a alkylation of secondary and tertiary
À
concept that the catalytic oxidation of a-Csp3 H bonds of
secondary amines provides reactive imines,[10] and considering
that the nucleophilic addition to imines has been studied
clearly,[11] we believe there is a possibility for this reaction to
proceed.
[*] Dr. G. Zhang, Y. Zhang, Prof. Dr. R. Wang
Key Laboratory of Preclinical Study for New Drugs of Gansu
Province, Institute of Biochemistry and Molecular Biology
State Key Laboratory of Applied Organic Chemistry
Lanzhou University, Lanzhou 730000 (China)
E-mail: wangrui@lzu.edu.cn
As 2,3-dichloro-5,6-dicyanoquinone (DDQ) has been
widely used as an efficient oxidant in several recent oxidative
coupling reactions,[12] we started our study with the DDQ-
mediated CDC reaction of ethyl 2-oxocyclopentanecarbox-
ylate (1a) with N-para-methoxyphenyl glycine ester (2a) in
the presence of 10 mol% of Cu(OTf)2 and 12 mol% of a
chiral bisoxazoline (BOX) ligand 4a in dichloromethane. The
reaction gave a moderate yield but poor enantioselectivity
(Table 1, entry 1). However, the replacement of 4a with other
ligands, such as 4b, 4c, and 4e, gave no significant improve-
ment to the stereoselectivity (Table 1, entries 2–4). To our
delight, when 4 f was used as a ligand, both the stereoselec-
tivity and yield were enhanced (78% ee, 75% yield, 4:1 d.r.;
Prof. Dr. R. Wang
State Key Laboratory of Chiroscience
Department of Applied Biology and Chemical Technology
The Hong Kong Polytechnic University
Kowloon, Hong Kong (China)
E-mail: bcrwang@polyu.edu.hk
[**] We are grateful for the grants from the NSFC (20932003 and
90813012) and the Key National S & T Project “Major New Drug
Development” of the Ministry of Science and Technology
(2009ZX09503-017).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201105123.
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Communications
Table 1: Optimization of the reaction conditions.[a]
Table 2: Investigation of the scope of the procedure.[a]
Entry
1
R1 R2 R3
2
R
Ar
3
Yield d.r.[c] ee
[%][b] [%][d]
Entry Metal
L* Solvent t [h] Yield [%][b] d.r.[c] ee [%][d]
1
Cu(OTf)2 4a CH2Cl2
8
8
8
8
47
62
58
71
75
57
48
69
64
51
54
79
80
78
4:1
3:1
7:3
3:1
4:1
3:2
2:1
4:1
2:1
3:2
7:3
4:1
4:1
5:1
15
23
25
45
78
35
17
33
56
27
21
52
84
91[e]
1
2
1a (CH2)3 Et
1a (CH2)3 Et
2a Et 4-
MeOC6H4
2b Et 2,4-
MeOC6H3
2c Et 4-ClC6H4 3c 65
2d Et 4-BrC6H4 3d 61
2e Et C6H5
2 f Me 4-
MeOC6H4
2g Bn 4-
MeOC6H4
3a 78
3b 73
5:1 91
6:1 92
2
3
4
Cu(OTf)2 4b CH2Cl2
Cu(OTf)2 4c CH2Cl2
Cu(OTf)2 4d CH2Cl2
5
6
Cu(OTf)2 4e CH2Cl2 12
Cu(OAc)2 4e CH2Cl2 12
3
4
5
6
1a (CH2)3 Et
1a (CH2)3 Et
1a (CH2)3 Et
1a (CH2)3 Et
3:2 84[e]
3:2 80[e]
4:1 86
5:1 90
7
CuCl2
4e CH2Cl2 12
3e 82
3 f 79
8
9
Zn(OTf)2 4e CH2Cl2 12
Mg(OTf)2 4e CH2Cl2 12
10
11
12
13
14
Sc(OTf)3
Yb(OTf)3
Cu(OTf)2 4e Tol
Cu(OTf)2 4e THF
Cu(OTf)2 4e THF
4 f CH2Cl2 12
4 f CH2Cl2 12
7
1a (CH2)3 Et
3g 72
2:1 96
12
12
24
8
9
1b (CH2)3 Me 2e Et C6H5
1b (CH2)3 Me 2b Et 2,4-
3h 60
3i 74
7:1 89
2:1 84
MeOC6H3
1c (CH2)3 iPr 2a Et 4-
MeOC6H4
1c (CH2)3 iPr 2 f Me 4-
MeOC6H4
1d (CH2)3 tBu 2a Et 4-
MeOC6H4
1e (CH2)3 Bn 2a Et 4-
MeOC6H4
1 f (CH2)3 Allyl 2a Et 4-
MeOC6H4
2a Et 4-
MeOC6H4
2a Et 4-
MeOC6H4
2a Et 4-
MeOC6H4
2a Et 4-
MeOC6H4
[a] Unless otherwise specified, the reaction was performed on a
0.1 mmol scale at room temperature (see the Supporting Information).
10
11
12
13
14
15
16
17
18
3j 77
3k 63
3l 49
3m 81
3n 79
3o 71
3p 82
3q 68
3r 70
2:1 91
7:3 88
5:1 91[e]
6:1 90
5:1 92
2:1 90[e]
2:1 90[e]
3:1 90[f]
3:2 81[e]
[b] Yield of the isolated product. [c] The diastereomeric ratio, anti/syn, as
1
determined by H NMR spectroscopy. [d] The ee value for the major
diastereomer. [e] The reaction was carried out at À408C. PMP=para-
methoxyphenyl, Tf=trifluoromethanesulfonyl, THF=tetrahydrofuran.
1g (CH2)4 Et
1h Me Me Et
1i Ph
H
Et
1j Et Me Et
[a] Unless otherwise specified, the reaction was carried out with 1
(0.2 mmol) and 2 (0.1 mmol) in the presence of Cu(OTf)2 (0.01 mmol), 4e
(0.012 mmol), and tetrahydrofuran (2.0 mL) at À408C for 24 h. [b] Yield of
the isolated product. [c] The diastereomeric ratio, anti/syn, as determined
by 1H NMR spectroscopy. [d] The ee value for the major diastereomer.
[e] The reaction was carried out at 08C. [f] The ee value for the minor
diastereomer. Bn=benzyl.
Table 1, entry 5). Other copper salts (Table 1, entries 6 and 7)
and alternative transition metal trifluoromethanesulfonic
salts (Table 1, entries 8–11) led to less-satisfactory reactions.
Solvent optimization results showed that THF was a better
solvent with regard to the enantioselectivity (up to 84% ee;
Table 1, entries 12 and 13). The best outcome for conversion
and enantioselectivity was achieved when the reaction was
carried out at À408C (Table 1, entry 14).
With the best reaction conditions established, the general-
ity of this novel CDC reaction was investigated (Table 2). In
general, the reaction proceeded smoothly to afford the
desired products in good yields and good to excellent
diastereo- and enantioselectivities. For the reaction with
ethyl 2-oxocyclopentanecarboxylate (1a), a wide range of
aromatic-substituted glycine esters 2a–2e were examined
(Table 2, entries 1–5), and it was observed that with both
electron-withdrawing and electron-donating groups on the 4-
position of the phenyl ring of 2 the desired a-alkyl a-amino
acid derivatives were obtained in satisfactory yields of 61–
82% and excellent enantioselectivities (80–92% ee). When
the corresponding methyl ester 2 f and benzyl ester 2g were
employed instead of ethyl ester 2a, coupling products 3 f and
3g, respectively, were also isolated in good yield and high
enantioselectivity (Table 2, entries 6–7).
After testing the generality of this novel CDC reaction
with regard to the series of N-aryl glycine esters 2a–2g with
ethyl 2-oxocyclopentanecarboxylate 1a, various b-ketoesters
were then studied for the synthesis of diverse optically active
a-alkyl a-amino acid derivatives. For the five-membered-ring
cyclic substrate, when ethyl, methyl, isopropyl, tert-butyl,
benzyl, and allyl esters 1a–f were used the reaction proceeded
readily to give coupling products 3b–o in good yield (49–
81%), moderate diastereoselectivity (d.r. 2:1–7:1), and excel-
lent enantioselectivity (84–92% ee; Table 2, entries 8-14).
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Angew. Chem. Int. Ed. 2011, 50, 10429 –10432

More importantly, six-membered-ring cyclic substrate, ethyl
2-oxocyclohexanecarboxylate 1g was also a suitable substrate
for this novel CDC reaction (Table 2, entry 15). In addition,
the less-reactive acyclic substrates 1h–j also reacted com-
pletely with 2a to afford the desired products in good
diastereoselectivity and excellent enantioselectivity. The
absolute configuration of products was determined from the
X-ray structure of a known compound (see the Supporting
Information for details).
Encouraged by the outstanding results achieved above, we
wished to extend the application of this effective catalytic
system to the asymmetric synthesis of other useful organic
molecules, such as C1-alkylated tetrahydroisoquinolines, with
their potential versatility as active determining building
blocks with wide utility in organic synthesis and pharmaceut-
ical chemistry.[13] Also, the efficient construction of the
optically pure form of these compounds have not been
achieved, to date. Owing to our continuous interest in
phosphorus-containing nucleophiles,[14] we chose acetyl phos-
phates, which are Horner–
that the irreversible hydrogen transfer could be so rapid that
TEMPO cannot capture this radical cation, however, a little
of this radical cation can be captured by 2,6-di-tert-butyl-4-
methylphenol (BHT; about 20%, the yield of 3 decreased
from 78 to 59%). After formation of the iminium intermedi-
ate 9, the electrophilic addition to the prepared chiral lewis-
acid-bonded nucleophile II, occurs to give the final product 3
(Scheme 3). To support the proposed mechanism, the imi-
nium intermediate 9 was synthesized by oxidation of N-PMP
glycine esters 2 with DDQ, and then iminium 9 was added to a
mixture of 4e, Cu(OTf)2, and 2-oxocyclopentanecarboxylate
1a in THF. To our delight, the reaction proceeded well to
afford the final coupling product without any loss of
enantioselectivity or yield (see the Supporting Information
for the details).
In summary, we have developed a one-pot, oxidative, and
enantioselective cross-coupling reaction of N-substituted
glycine esters with a-substituted b-ketoesters for the synthesis
of various a-alkyl a-amino acids catalyzed by a chiral BOX/
Wadsworth–Emmons
(HWE) reagents with rela-
tively low reactivity,[15] to
react with N-aryl tetrahydroi-
soquinolines under the same
reaction conditions. Satisfac-
torily, the reaction generally
proceeded smoothly to afford
various C1-alkylated tetrahy-
droisoquinolines 7 in good
yields (72–80%) and excel-
lent diastereo- and enantiose-
lectivities (up to 19:1 d.r., up
to 90% ee; Scheme 2).
The possible reaction
pathways are presumed to
involve single-electron trans-
fer (SET).[16] When DDQ
reacts with the N-PMP gly-
Scheme 3. Proposed mechanism for the one-pot asymmetric oxidative reaction.
cine esters 2, a single-electron
transfer from 2 would occur
to afford the radical cation 8, and then hydrogen transfer
would proceed to provide iminium 9. To check the interme-
diacy of a radical cation TEMPO, a radical inhibitor, was
added to this reaction system; there was no significant change
in the yield of the coupling product and the addition product
of N-aryl glycine esters with TEMPO was not formed. These
results indicate that a radical cation might be involved but
CuII complex. More importantly, this novel strategy was
extended to asymmetric synthesis of C1-alkylated tetrahy-
droisoquinolines by the reaction of Horner–Wadsworth–
Emmons reagents with N-aryl tetrahydroisoquinolines.
Received: July 21, 2011
Published online: September 13, 2011
Keywords: amino acids · asymmetric synthesis ·
.
À
C H activation · 2,3-dichloro-5,6-dicyanoquinone ·
homogeneous catalysis
À
À
[1] For recent reviews of C H activation, see: a) “C H Activation”:
Topics in Current Chemistry (Eds.: J. Q. Yu, Z. Shi), Springer,
Berlin, 2010; b) K. Godula, D. Sames, Science 2006, 312, 67;
c) R. G. Bergman, Nature 2007, 446, 391; d) K. R. Campos,
Chem. Soc. Rev. 2007, 36, 1069; e) J. C. Lewis, R. G. Bergman,
J. A. Ellman, Acc. Chem. Res. 2008, 41, 1013; f) X. Chen, K. M.
Scheme 2. The CDC reaction for the asymmetric synthesis of chiral C1-
alkylated tetrahydroisoquinolines.
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Communications
Engle, D.-H. Wang, J.-Q. Yu, Angew. Chem. 2009, 121, 5196;
Angew. Chem. Int. Ed. 2009, 48, 5094; g) S.-I. Murahashi, D.
Zhang, Chem. Soc. Rev. 2008, 37, 1490.
[8] J. Xie, Z.-Z. Huang, Angew. Chem. 2010, 122, 10379; Angew.
Chem. Int. Ed. 2010, 49, 10181.
[9] a) H. Wang, R. Wang, H. Nie, R. Zhang, J.-T. Qiao, Peptides
2000, 89, 7; b) H.-M. Liu, X.-F. Liu, J.-L. Yao, C.-L. Wang, Y. Yu,
R. Wang, J. Pharmacol. Exp. Ther. 2006, 319, 308.
À
[2] For recent reviews of carbene and nitrene insertion into C H
bonds: a) H. M. L. Davies, Angew. Chem. 2006, 118, 6574;
Angew. Chem. Int. Ed. 2006, 45, 6422; b) H. M. L. Davies,
R. E. J. Beckwith, Chem. Rev. 2003, 103, 2861; c) H. M. L.
Davies, J. R. Manning, Nature 2008, 451, 417; d) P. Mꢀller, C.
Fruit, Chem. Rev. 2003, 103, 2905.
[10] a) S. Suga, S. Suzuki, J. Yoshida, J. Am. Chem. Soc. 2002, 124, 30;
b) S.-I. Murahashi, T. Naota, H. Taki, J. Chem. Soc. Chem.
Commun. 1985, 613; c) A. H. ꢄll, J. S. M. Samec, C. Brasse, J.-E.
Bꢂckvall, Chem. Commun. 2002, 1144; d) S.-I. Murahashi, Y.
Okano, H. Sato, T. Nakae, N. Komiya, Synlett 2007, 1675.
[11] a) K. Juhl, N. Gathergood, K. A. Jørgensen, Angew. Chem. 2003,
115, 1536; Angew. Chem. Int. Ed. 2003, 42, 1498; b) D. A. Evans,
D. Seidel, J. Am. Chem. Soc. 2005, 127, 9958; c) M. Agostinho, S.
Kobayashi, J. Am. Chem. Soc. 2008, 130, 2430; d) T. Tsubogo, Y.
Yamashita, S. Kobayashi, Angew. Chem. 2009, 121, 9281; Angew.
Chem. Int. Ed. 2009, 48, 9117; e) M. Hatano, T. Horibe, K.
Ishihara, J. Am. Chem. Soc. 2010, 132, 56.
[12] a) W. Tu, P. E. Floreancig, Angew. Chem. 2009, 121, 4637;
Angew. Chem. Int. Ed. 2009, 48, 4567; b) L. Liu, P. E. Floreancig,
Angew. Chem. 2010, 122, 6030; Angew. Chem. Int. Ed. 2010, 49,
5894; c) C. Guo, J. Song, S. W. Luo, L.-Z. Gong, Angew. Chem.
2010, 122, 5690; Angew. Chem. Int. Ed. 2010, 49, 5558; d) Y.
Hayashi, T. Itoh, H. Ishikawa, Angew. Chem. 2011, 123, 4006;
Angew. Chem. Int. Ed. 2011, 50, 3920; e) S.-L. Zhang, H.-X. Xie,
J. Zhu, H. Li, X.-S. Zhang, J. Li, W. Wang, Nat. Commun. 2011, 2,
211.
[13] a) M. Chrzanowska, M. D. Rozwadowska, Chem. Rev. 2004, 104,
3341; b) K. W. Bentley, Nat. Prod. Rep. 2004, 21, 395.
[14] a) D. Zhao, Y. Yuan, A. S. C. Chan, R. Wang, Chem. Eur. J. 2009,
15, 2738; b) L. Hong, W. Sun, C. Liu, D. Zhao, R. Wang, Chem.
Commun. 2010, 46, 2856.
[15] a) W. S. Wadsworth, W. D. Emmons, J. Am. Chem. Soc. 1961, 83,
1733; b) B. E. Maryanoff, A. B. Reize, Chem. Rev. 1989, 89, 863.
[16] a) N. J. Leonard, G. W. Leubner, J. Am. Chem. Soc. 1949, 71,
3408; b) S.-I. Murahashi, N. Komiya, H. Terai, Angew. Chem.
2005, 117, 7091; Angew. Chem. Int. Ed. 2005, 44, 6931.
[3] For reviews on CDC reactions, see: a) C.-J. Li, Z. Li, Pure Appl.
Chem. 2006, 78, 935; b) C.-J. Li, Acc. Chem. Res. 2009, 42, 335;
c) C. Scheuermann, Chem. Asian J. 2010, 5, 436.
À
[4] For CDC reactions of benzylic C H bonds, see: a) Z. Li, L. Cao,
C.-J. Li, Angew. Chem. 2007, 119, 6625; Angew. Chem. Int. Ed.
2007, 46, 6505; b) F. Benfatti, M. G. Capdevila, L. Zoli, E.
Benedetto, G. Cozzi, Chem. Commun. 2009, 5919; c) A. Pintꢁr,
A. Sud, D. Sureshkumar, M. Klussmann, Angew. Chem. 2010,
122, 5124; Angew. Chem. Int. Ed. 2010, 49, 5004; d) D. J. Covell,
M. C. White, Angew. Chem. 2008, 120, 6548; Angew. Chem. Int.
Ed. 2008, 47, 6448; e) T. D. Beeson, A. Mastracchio, J. B. Hong,
K. Ashton, D. W. Macmillan, Science 2007, 316, 582.
À
[5] For CDC reactions of a-C H bonds of second and tertiary
amines, see: a) Z. Li, C.-J. Li, J. Am. Chem. Soc. 2004, 126,
11810; b) Z. Li, P. D. MacLeod, C.-J. Li, Tetrahedron: Asymme-
try 2006, 17, 590; c) Z. Li, C.-J. Li, Org. Lett. 2004, 6, 4997; d) O.
Baslꢁ, C.-J. Li, Org. Lett. 2008, 10, 3661; e) I. Ibrahem, J. S. M.
Samec, J. E. Bꢂckvall, A. Cꢃrdova, Tetrahedron Lett. 2005, 46,
3965; f) N. Sasamoto, C. Dubs, Y. Hamashima, M. Sodeoka, J.
Am. Chem. Soc. 2006, 128, 14010; g) S.-I. Murahashi, T. Nakae,
H. Terai, N. Komiya, J. Am. Chem. Soc. 2008, 130, 11005.
[6] a) K. Maruoka, T. Ooi, Chem. Rev. 2003, 103, 3013; b) P. Beak,
W. J. Zajdel, D. B. Reitz, Chem. Rev. 1984, 84, 471.
[7] a) L. Zhao, C.-J. Li, Angew. Chem. 2008, 120, 7183; Angew.
Chem. Int. Ed. 2008, 47, 7075; b) L. Zhao, O. Basle, C.-J. Li, Proc.
Natl. Acad. Sci. USA 2009, 106, 4106; c) S.-I. Murahashi, A.
Mitani, K. Kitao, Tetrahedron Lett. 2000, 41, 10245.
10432 www.angewandte.org
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