Highly diastereoselective synthesis of 3-indolylglycines via an asymmetric oxidative heterocoupling reaction of a chiral nickel(ii) complex and indoles

Article abstract of DOI:10.1039/c3cc38908a

The asymmetric synthesis of 3-indolylglycine derivatives was achieved by an oxidative heterocoupling reaction. This method for the selective C-3 functionalization of unprotected indoles with the chiral equivalent of a nucleophilic glycine nickel(ii) complex afforded adducts with high diastereoselectivities. The decomposition of adducts readily afforded 3-indolylglycine derivatives in high yields.

Full text of DOI:10.1039/c3cc38908a

ChemComm
View Article Online
View Journal | View Issue
COMMUNICATION
Highly diastereoselective synthesis of 3-indolylglycines
via an asymmetric oxidative heterocoupling reaction
of a chiral nickel(II) complex and indoles†
Daizong Lin,a Jiang Wang,a Xu Zhang,ab Shengbin Zhou,a Jie Lian,ab
Hualiang Jianga and Hong Liu*ab
Cite this: Chem. Commun., 2013,
49, 2575
Received 13th December 2012,
Accepted 5th February 2013
DOI: 10.1039/c3cc38908a
www.rsc.org/chemcomm
The asymmetric synthesis of 3-indolylglycine derivatives was achieved limit their applications. In spite of the fact that the approaches
by an oxidative heterocoupling reaction. This method for the selective of enzymatic resolution and asymmetric synthesis have been
C-3 functionalization of unprotected indoles with the chiral equivalent described, developing highly enantioenriched synthetic methods
of a nucleophilic glycine nickel(II) complex afforded adducts with high of 3-indolylglycines is of urgent need.
diastereoselectivities. The decomposition of adducts readily afforded
3-indolylglycine derivatives in high yields.
The oxidative heterocoupling reaction, considered to be one
type of C–H functionalization, has been developed in recent
decades.5 Importantly, a new C–C bond is formed by direct
Optically active non-proteinogenic amino acids are versatile oxidative coupling of two electron-rich carbons (the indole C-3
motifs in natural products, asymmetric chemical investigations and the a carbon of the carbonyl group), thereby avoiding the
as well as medicinal and peptide/peptidomimetic chemistry.1 prefunctionalization or protection of the substrates. This reaction
Among non-proteinogenic amino acids, 3-indolylglycine and its has many merits: excellent tolerability of functional groups;
derivatives have attracted appreciable attention due to their wide high levels of regioselectivity (exclusively coupling at the indole
application in organic synthesis and drug discovery.2 Accord- 3-position); and the potential to scale-up production. On the other
ingly, the development of efficient methods in their preparation hand, chiral nickel(II) complexes of the Schiff base of glycine
is of considerable interest in academia and industry. Symmetric have been widely used to synthesize optically active non-
syntheses and resolution are achieved initially.3 O’Donnell et al. proteinogenic amino acids via aldol,6 Michael addition,7
demonstrated that a nucleophilic reaction of an indole and an Mannich,8 and C-alkylation9 reactions. Given our recent involve-
equivalent of glycine with a leaving group affords 3-indolylglycin- ment in the asymmetric synthesis of optically active amino acids
amide as racemic mixtures.3a Janczuk et al. also reported an via nucleophilic reactions of the nickel(II) complex and electron-
achiral electrophilic substitution of indole and imide, and deficient substrates,10 we sought to further extend the scope of
described an enzymatic resolution.3b However, compared with substrates to electron-rich indoles and aimed to develop a new
symmetric preparation, the asymmetric synthesis represents the synthetic protocol of 3-indolylglycines via the oxidative hetero-
most direct approach. Several enantioselective syntheses of coupling reaction of a nickel(II) complex (Scheme 1). This
3-indolylglycine have been described;4 Wanner et al. reported a method exhibits the following advantages: (i) predictable stereo-
chiral phosphoric acid-catalyzed Friedel–Crafts reaction of sub- chemical outcome; (ii) high diastereoselectivity; (iii) operationally
stituted glyoxyl imines with indoles;4a Ji et al. also described a convenient reaction procedures; (iv) low-cost material; (v) easy and
diastereoselective Friedel–Crafts alkylation of indoles and a virtually complete recovery of ligands (S)-BPB. Herein, we present
chiral imine.4b Nevertheless, most of those methods are Friedel– an asymmetric oxidative coupling reaction of the chiral nickel(II)
Crafts reactions using chiral Lewis acid catalysts or involving complex and unprotected indoles, as a general method leading to
chiral amine auxiliaries. Hence, existing problems (e.g., control optically active 3-indolylglycine.
of reaction stereoselectivity or removal of the chiral ligands) may
Initially, using a simple indole and chiral nickel(II) complex
(S)-1, we isolated 20% of the desired oxidative coupling product
3a with 71% de at ambient temperature with lithium hexamethyl-
disilazide (LiHMDS) as the base and copper(II) acetylacetonate
(Cu(acac)2) as the oxidant (Table 1, entry 1), based on the condi-
tions reported in the literature.11 According to this result, we chose
to study (S)-1 and indole 2a as a model substrate for optimizing
reaction conditions (Table 1). To improve the diastereoselectivity
of the target complex, we reduced the temperature to À40 1C.
a State Key Laboratory of Drug Research, CAS Key Laboratory of Receptor Research,
Shanghai Institute of Materia Medica, Chinese Academy of Sciences,
555 Zuchongzhi Road, Shanghai 201203, P. R. China. E-mail: hliu@mail.shcnc.ac.cn
b Department of Medicinal Chemistry, China Pharmaceutical University,
24 Tongjiaxiang, Nanjing, 210009, P. R. China
† Electronic supplementary information (ESI) available: Experimental details and
additional spectra. CCDC 909566. For ESI and crystallographic data in CIF or
other electronic format see DOI: 10.1039/c3cc38908a
c
This journal is The Royal Society of Chemistry 2013
Chem. Commun., 2013, 49, 2575--2577 2575

View Article Online
Communication
ChemComm
acetate (Cu(OAc)2), ferric acetylacetonate (Fe(acac)3), iodine, and
2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) (entries 6–9)
(see the ESI† for the optimization of copper(II) oxidants). The
ideal solvent for the oxidant reaction was tetrahydrofuran (THF)
(entries 10–12). The effect of temperature was then investigated.
The adduct 3a was formed in higher yield at À40 1C than at
other temperatures (entries 13–16). Furthermore, adding the
oxidant at À40 1C and then allowing the reaction to warm to
room temperature before quenching afforded a slightly higher
yield (63%, entry 17) than that of the corresponding reaction at
À40 1C (entry 5). From this viewpoint, we chose LDA as the
base, Cu(acac)2 as the oxidant, THF as the solvent, and a
temperature range from À40 1C to ambient temperature to
probe the generality of this asymmetric reaction (entry 17). To
confirm the stereochemical generation of the reaction, we
crystallized the optically pure product 3a. The absolute configu-
ration of 3a was determined to be (S, 2S) by X-ray crystallo-
graphy12 (Fig. S1 in the ESI†). Then, a radical mechanism of this
reaction was proposed in the ESI† (Scheme S1).
Scheme 1 Asymmetric synthesis of 3-indolylglycines via oxidative heterocoupling
reaction of nickel(II) complex and indoles.
With the optimal reaction conditions identified, we next
explored the generality of the substrate. Various indoles were
investigated, and most of them afforded the products 3 in
moderate yields with high diastereoselectivities. The results
are summarized in Table 2. Investigation of the electronic effect
showed that the indole with an electron-donating group or
halogen substituted at the 5-position of the indole was well
tolerated in this reaction (entries 1–5). However, the yield
decreased rapidly if an indole with an electron-withdrawing
group at the 5-position was adopted. This was due to a reduction
in the electron density at the carbon atom at the 3-position of the
indole by an electron-withdrawing group at the 5-position of the
Table 1 Optimization of the reaction conditionsa
Entry Base
Solution Oxidant
Temp/1C Yield (%) deb (%)
1
2
3
4
5
6
7
8
LiHMDS THF Cu(acac)2 rt
20
35
22
5
59
42
0
71
92
LiHMDS THF
NaHMDS THF
Cu(acac)2 À40
Cu(acac)2 À40
Cu(acac)2 À40
Cu(acac)2 À40
Cu(OAc)2 À40
97
NaH
LDA
LDA
LDA
LDA
LDA
LDA
LDA
LDA
LDA
LDA
LDA
LDA
LDA
THF
THF
THF
THF
THF
THF
NDc
>99
98
Table 2 Oxidative coupling reaction of nickel(II) complex (S)-1 with indoles 2a
Iodine
DDQ
À40
À40
ND
ND
ND
ND
ND
89
97
98
>99
>99
>99
0
9
Fe(acac)3 À40
Trace
0
0
23
34
42
47
22
10
11
12
13
14
15
16
17d
CH2Cl2 Cu(acac)2 À40
DME
Et2O
THF
THF
THF
THF
THF
Cu(acac)2 À40
Cu(acac)2 À40
Cu(acac)2 rt
Cu(acac)2
0
Cu(acac)2 À20
Cu(acac)2 À60
Entry
3
R1
R2
Yield (%)
deb (%)
Cu(acac)2 À40 to rt 63
1
2
3
4
5
6
7
8
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
H
H
H
H
H
H
H
H
H
H
Me
COOEt
Ph
Me
H
5-OMe
5-F
63
60
40
35
33
Trace
62
56
60
54
65
55
74
60
>99
>99
>99
>99
>99
NDc
>99
99
>99
98
98
96
97
a
Reactions were run with 0.20 mmol of (S)-1, 0.80 mmol of 2a in 10 mL
of solvent with 0.66 mmol of base for 0.5 h, then 0.3 mmol of oxidant
b
was added over 1 h. Determined by chiral HPLC analysis (see the ESI
5-Cl
5-Br
5-NO2
4-Me
5-Me
6-Me
7-Me
H
c
d
for details). ND not detected. Reactions were run with 0.20 mmol of
(S)-1, 0.80 mmol of 2a in 10 mL of THF with 0.66 mmol of LDA for 0.5 h
at À40 1C, then 0.3 mmol of Cu(acac)2 was added, and raised to room
temperature naturally over 1 h. (The optimization of the equivalents of
the base, oxidants and indole, see the ESI for details).
9
10
11
12
13
14
This condition afforded the adduct (S, 2S)-3a with high diastereo-
selectivity (92% de, entry 2). Various alternative bases were then
screened. A higher yield and diastereoselectivity was observed
with lithium diisopropylamide (LDA) as the base than with
LiHMDS, sodium hexamethyldisilazide (NaHMDS) and sodium
hydride (NaH) (entries 2–5). Cu(acac)2 demonstrated the best
performance among the screened oxidants such as copper(II)
H
H
OMe
97
a
Reactions were run with 0.20 mmol of (S)-1, 0.80 mmol of 2 in 10 mL
of THF with 0.66 mmol of LDA for 0.5 h at À40 1C, then 0.3 mmol of
Cu(acac)2 was added, and raised to room temperature naturally over
b
1 h. Determined by chiral HPLC analysis (see the ESI for details).
c
ND: not detected.
c
2576 Chem. Commun., 2013, 49, 2575--2577
This journal is The Royal Society of Chemistry 2013

View Article Online
ChemComm
Communication
and Proteins in Organic Chemistry, ed. A. B. Hughes, Wiley-VCH,
Weinheim, 2009, vol. 1 and 2.
2 (a) T. Kouko, K. Matsumura and T. Kawasaki, Tetrahedron, 2005,
61, 2309; (b) M. T. Rudd, J. A. McCauley, J. W. Butcher, J. J. Romano,
C. J. McIntyre, K. T. Nguyen, K. F. Gilbert, K. J. Bush, M. K. Holloway,
J. Swestock, B. L. Wan, S. S. Carroll, J. M. DiMuzio, D. J. Graham,
S. W. Ludmerer, M. W. Stahlhut, C. M. Fandozzi, N. Trainor,
D. B. Olsen, J. P. Vacca and N. J. Liverton, ACS Med. Chem. Lett.,
2011, 2, 207; (c) H. Mizoguchi, H. Oguri, K. Tsuge and H. Oikawa,
Org. Lett., 2009, 11, 3016; (d) F. Yan, X. X. Cao, H. X. Jiang, X. L. Zhao,
J. Y. Wang, Y. H. Lin, Q. L. Liu, C. Zhang, B. A. Jiang and F. Guo,
J. Med. Chem., 2010, 53, 5502; (e) C. Tardy, M. L. Facompre,
W. Laine, B. Baldeyrou, D. Garcia-Gravalos, A. Francesch,
C. Mateo, A. Pastor, J. A. Jimenez, I. Manzanares, C. Cuevas and
C. Bailly, Bioorg. Med. Chem., 2004, 12, 1697; ( f ) N. K. Garg,
R. Sarpong and B. M. Stoltz, J. Am. Chem. Soc., 2002, 124, 13179.
3 (a) M. J. O’Donnell and W. D. Bennett, Tetrahedron, 1988, 44, 5389;
(b) A. Janczuk, W. Zhang, W. H. Xie, S. Z. Lou, J. P. Chong and
P. G. Wang, Tetrahedron Lett., 2002, 43, 4271; (c) J. E. Mangette, X. M.
Chen, R. Krishnamoorthy, A. S. Vellekoop, A. J. Csakai, F. Camara,
W. D. Paquette, H. J. Wang, H. Takahashi, R. Fleck and G. P. Roth,
Tetrahedron Lett., 2011, 52, 1292; (d) G. Desimoni, G. Faita, M. Mella,
M. Toscanini and M. Boiocchi, Eur. J. Org. Chem., 2008, 6232;
(e) M. Kitamura, D. Lee, S. Hayashi, S. Tanaka and M. Yoshimura,
J. Org. Chem., 2002, 67, 8685; ( f ) N. Sakai, J. Asano, Y. Shimano and
T. Onakahara, Tetrahedron, 2008, 64, 9208; (g) M. Oikawa, M. Ikoma
and M. Sasaki, Eur. J. Org. Chem., 2011, 4654; (h) A. N. Mirskova,
E. V. Rudyakova, I. B. Rozentsveig, A. G. Stupina, G. G. Levkovskaya and
A. I. Albanov, Pharm. Chem. J., 2001, 35, 311.
4 (a) M. J. Wanner, P. Hauwert, H. E. Schoemaker, R. de Gelder, J. H. van
Maarseveen and H. Hiemstra, Eur. J. Org. Chem., 2008, 180; (b) D. M. Ji
and M. H. Xu, Chem. Commun., 2010, 46, 1550; (c) T. Andreassen,
L. K. Hansen and O. R. Gautun, Eur. J. Org. Chem., 2008, 4871;
(d) M. Johannsen, Chem. Commun., 1999, 2233; (e) J. F. Hang,
H. M. Li and L. Deng, Org. Lett., 2002, 4, 3321; ( f ) M. Abid,
L. Teixeira and B. Torok, Org. Lett., 2008, 10, 933; (g) S. Shirakawa,
R. Berger and J. L. Leighton, J. Am. Chem. Soc., 2005, 127, 2858;
(h) Q. Kang, Z. A. Zhao and S. L. You, Tetrahedron, 2009, 65, 1603.
5 (a) J. M. Richter, B. W. Whitefield, T. J. Maimone, D. W. Lin,
M. P. Castroviejo and P. S. Baran, J. Am. Chem. Soc., 2007,
129, 12857; (b) M. P. DeMartino, K. Chen and P. S. Baran, J. Am.
Chem. Soc., 2008, 130, 11546; (c) P. S. Baran and J. M. Richter, J. Am.
Chem. Soc., 2004, 126, 7450; (d) Y. L. Hu, H. Jiang and M. Lu, Green
Chem., 2011, 13, 3079.
Scheme 2 Decomposition of nickel(II) complex 3 to release 3-indolylglycine
derivatives 4.
indole (entry 6). Then, our focus was turned to evaluation of the
steric effects. Indoles bearing a methyl substituent at the 4-, 5-, 6-
or 7-position of the indole ring were suitable substrates and
afforded the corresponding products with excellent diastereo-
selectivity (98–99% de) (entries 7–10). Nevertheless, a 3-methyl
indole did not afford the desired products under this condition,
which confirmed that the reaction occurred selectively at the
3-position of the indole. It is noticeable that the diastereoselec-
tivities and chemical yields were not decreased by substitution at
the indole 2-position next to the reaction site, regardless of the
steric and electronic effect of the substituted group (entries 11–13).
Furthermore, the disubstitution at the indole 2- and 5-positions
did not affect the diastereoselectivity (97% de) (entry 14).
Disassembly of the diastereomerically pure complex (S, 2S)-3
under an acidic condition (THF/methanol/HCl) afforded the
target amino acid (S)-3-indolylglycine derivatives 4 in good ee
values (97–98% ee) and yields (85–93%) at room temperature
(Scheme 2). The chiral ligand (S)-BPB was recovered readily in
quantitative yield and could be reused via a simple procedure.
The specific rotation of the recovered (S)-BPB is the same as
that of the fresh-prepared (S)-BPB.
In conclusion, we successfully developed a practical and
highly efficient diastereoselective route to synthesize 3-indolyl-
glycine derivatives via the oxidative heterocoupling reaction of
unprotected indoles and chiral equivalent of nucleophilic
glycine. A broad range of indoles could be employed under
an operationally simple condition. The resulting adducts were
converted into the target amino acids in high yields. Moreover,
the method provided opportunities for the reaction of extensive
nucleophilic carbons and chiral nickel(II) complexes for the
synthesis of various chiral non-proteinogenic amino acids.
We gratefully acknowledge financial support from National
Basic Research Program of China (Grants 2009CB940903,
2009CB918502, and 2012CB518005), the National Natural Science
Foundation of China (Grants 20721003, 91229204, and 81025017),
National S&T Major Projects (2012ZX09103-101-072), China-EU
Science and Technology Cooperation Project (1109) and Silver
Project (260644).
6 (a) Y. N. Belokon, A. G. Bulychev, S. V. Vitt, Y. T. Struchkov,
A. S. Batsanov, T. V. Timofeeva, V. A. Tsyryapkin, M. G. Ryzhov,
L. A. Lysova, V. I. Bakhmutov and V. M. Belikov, J. Am. Chem. Soc.,
1985, 107, 4252; (b) V. A. Soloshonok, D. V. Avilov and V. P. Kukhar,
Tetrahedron, 1996, 52, 12433; (c) Y. N. Belokon, K. A. Kochetkov,
N. S. Ikonnikov, T. V. Strelkova, S. R. Harutyunyan and
A. S. Saghiyan, Tetrahedron: Asymmetry, 2001, 12, 481.
7 (a) V. A. Soloshonok, C. Z. Cai, T. Yamada, H. Ueki, Y. Ohfune and
V. J. Hruby, J. Am. Chem. Soc., 2005, 127, 15296; (b) V. A. Soloshonok,
H. Ueki, R. Tiwari, C. Cai and V. J. Hruby, J. Org. Chem., 2004,
69, 4984.
8 V. A. Soloshonok, D. V. Avilov, V. P. Kukhar, L. V. Meervelt and
N. Mischenko, Tetrahedron Lett., 1997, 38, 4671.
9 (a) V. A. Soloshonok, X. Tang, V. J. Hruby and L. Van Meervelt, Org.
Lett., 2001, 3, 341; (b) S. M. Taylor, T. Yamada, H. Ueki and
V. A. Soloshonok, Tetrahedron Lett., 2004, 45, 9159; (c) V. A.
Soloshonok, Y. N. Belokon, N. A. Kuzmina, V. I. Maleev, N. Y.
Svistunaova, V. A. Solodenko and V. P. Kukhar, J. Chem. Soc., Perkin
Trans. 1, 1992, 1525; (d) V. A. Soloshonok, X. Tang and V. J. Hruby,
Tetrahedron, 2001, 57, 6375.
10 (a) J. Wang, D. Z. Lin, S. B. Zhou, X. Ding, V. A. Soloshonok and
H. Liu, J. Org. Chem., 2011, 76, 684; (b) J. Wang, S. B. Zhou, D. Z. Lin,
X. Ding, H. L. Jiang and H. Liu, Chem. Commun., 2011, 47, 8355;
(c) J. Wang, J. M. Shi, X. D. Zhang, D. Z. Lin, H. L. Jiang and H. Liu,
Synthesis, 2009, 1744; (d) J. Wang, D. Z. Lin, J. M. Shi, X. Ding,
L. Zhang, H. L. Jiang and H. Liu, Synthesis, 2010, 1205.
Notes and references
1 (a) T. Kawasaki, H. Enoki, K. Matsumura, M. Ohyama, M. Inagawa
and M. Sakamoto, Org. Lett., 2000, 2, 3027; (b) C. D. Hupp and
J. J. Tepe, J. Org. Chem., 2009, 74, 3406; (c) R. A. Hughes and C. J. 11 (a) P. S. Baran and J. M. Richter, J. Am. Chem. Soc., 2005, 127, 15394;
Moody, Angew. Chem., Int. Ed., 2007, 46, 7930; (d) J. Singh,
P. Conzentino, K. Cundy, J. A. Gainor, C. L. Gilliam, T. D. Gordon, J. A.
(b) J. M. Richter, Y. Ishihara, T. Masuda, B. W. Whitefield, T. Llamas,
A. Pohjakallio and P. S. Baran, J. Am. Chem. Soc., 2008, 130, 17938.
Johnson, B. A. Morgan, E. D. Schneider, R. C. Wahl and D. A. Whipple, 12 CCDC 909566 contains the supplementary crystallographic data for
Bioorg. Med. Chem. Lett., 1995, 5, 337; (e) Amino Acids, Peptides,
this paper.
c
This journal is The Royal Society of Chemistry 2013
Chem. Commun., 2013, 49, 2575--2577 2577