Ag-catalyzed diastereo- and enantioselective synthesis of β-substituted tryptophans from sulfonylindoles

Article abstract of DOI:10.1021/ol100161n

The asymmetric catalytic synthesis of β-substituted tryptophan derivatives was realized in high diastereo- and enantioselectivity by the reaction of glycine derivatives with sulfonylindoles in the presence of catalyst derived from AgCl and a commercially available chiral monodentate phosphoramidite ligand. The resulting adduct was readily converted to β-substituted tryptophan in 95% overall yield for two steps, which presented a highly efficient route to chiral β-substituted tryptophan.

Full text of DOI:10.1021/ol100161n

ORGANIC
LETTERS
2010
Vol. 12, No. 8
1688-1691
Ag-Catalyzed Diastereo- and
Enantioselective Synthesis of
ꢀ-Substituted Tryptophans from
Sulfonylindoles
Bao-Hui Zheng, Chang-Hua Ding, Xue-Long Hou,* and Li-Xin Dai
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, 354 Fenglin Road, Shanghai 200032, China
xlhou@mail.sioc.ac.cn
Received January 22, 2010
ABSTRACT
The asymmetric catalytic synthesis of ꢀ-substituted tryptophan derivatives was realized in high diastereo- and enantioselectivity by the reaction
of glycine derivatives with sulfonylindoles in the presence of catalyst derived from AgCl and a commercially available chiral monodentate
phosphoramidite ligand. The resulting adduct was readily converted to ꢀ-substituted tryptophan in 95% overall yield for two steps, which
presented a highly efficient route to chiral ꢀ-substituted tryptophan.
Tryptophan as an essential amino acid is an important
structural unit and synthetic intermediate of various natural
products.1 Among them, ꢀ-substituted tryptophans as a
useful class of compounds are found in biologically active
molecules and natural products such as telomycine,2a
streptonigrine,2b lavendamycine,2c fumitremorgin,2d and
cyclomarines.2e The ꢀ-substituted tryptophans have also been
used in the research of peptide-receptor relationships by
means of replacing natural amino acids.3 Although this
structural scaffold is important in organic synthesis, only one
asymmetric catalytic version appeared for the synthesis of
ꢀ-substituted tryptophans with low diastereoselectivity.4
Furthermore, the reports for the enantioselective route to
these compounds have been limited.5 ꢀ-Substituted tryp-
tophans are composed of two parts, an R-amino acid moiety
and an indole core. Glycine derivatives have served as
precursors in the synthesis of R-amino acids for a long
(1) (a) Hamaker, L. K.; Cook, J. M. In Alkaloids: Chemical and
Biological PerspectiVes; Pelletiers, S. W., Ed.; Elsevier Science: New York,
1995; Vol. 9, p 23. (b) Lounasmaa, M.; Hanhinen, P.; Westersund, M. In
Alkaloids; Cordell, G. A., Ed.; Academic: San Diego, CA, 1999; Vol. 52,
p 103.
(3) (a) Huang, Z.; He, Y. B.; Raynor, K.; Tallent, M.; Reisine, T.;
Goodman, M. J. Am. Chem. Soc. 1992, 114, 9390. (b) Haskell-Luevano,
C.; Boteju, L. W.; Miwa, H.; Dickinson, C.; Gantz, I.; Yamada, T.; Hadley,
M. E.; Hruby, V. J. J. Med. Chem. 1995, 38, 4720. (c) Haskell-Luevano,
C.; Toth, K.; Boteju, L.; Job, C.; Castrucci, A. M. de L.; Hadley, M. E.;
Hruby, V. J. J. Med. Chem. 1997, 40, 2740. (d) Bonner, G. G.; Davis, P.;
Stropova, D.; Edsall, S.; Yamamura, H. I.; Porreca, F.; Hruby, V. J. J. Med.
Chem. 2000, 43, 569.
(2) (a) Sheehan, J. C.; Mania, D.; Nakamura, S.; Stock, J. A.; Maeda,
K. J. Am. Chem. Soc. 1968, 90, 462. (b) Gould, S. J.; Weinreb, S. M.
Fortschr. Chem. Org. Naturst. 1982, 41, 77. (c) Doyle, T. W.; Balitz, D. M.;
Grulich, R. E.; Nettleton, D. E.; Gould, S. J.; Tann, C.-h.; Moews, A. E.
Tetrahedron Lett. 1981, 22, 4595. (d) Loevezijn, A.; Maarseveen, J. H.;
Stegman, K.; Visser, G. M.; Koomen, G.-J. Tetrahedron Lett. 1998, 39,
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Frankmoelle, W.; Kauffman, C. A.; Fenical, W.; Lobkovsky, E.; Clardy, J.
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10.1021/ol100161n  2010 American Chemical Society
Published on Web 03/24/2010

time.6 On the other hand, sulfonylindoles have been
reported to produce vinylogous imines in situ in the
presence of base,7 which react with various nucleophiles,
such as Grignard reagents,7a Reformatsky reagents,7b
nitroalkanes,7c aldehydes,7d,8a and enamide.8b Recently, we
have focused on the applications of glycine derivatives in
asymmetric catalysis;9 herein we communicate an unprec-
edented Ag-catalyzed asymmetric reaction of glycine deriva-
tives with sulfonylindoles, which offers a general procedure
leading to chiral ꢀ-substituted tryptophans.
Table 1. Screening of the Chiral Ligand for CuClO4-Catalyzed
Reaction of Sulfonylindole 1a with Glycine Ester 2aa
We commenced our study by exposure of sulfonylindole
1a with glycine imine 2a using a catalyst derived from
CuClO4 and various readily available chiral ligands (Table
1). The results revealed that the ligand with different
coordination atom had a great impact on the enantio- and
diastereoselectivity of the reaction. The use of FcPHOX
L1-L510 afforded the corresponding adduct 3aa in high
enantioselectivity (81-90%) and chemical yield but in low
diastereoselectivity (1/1-2/1). The change of electronic
factor of ligands exerted limited effect on both enantio- and
diastereoselectivities, which differs from our early observa-
tion (entries 1-5).9a,b PHOX L611 and Trost’s ligand L712
demonstrated low stereocontrol in the present reaction,
obtaining nearly racemic product (entries 6 and 7). SiocPhox
L8 and L913 developed in our group were also proved to be
unsuitable for the reaction (entries 8 and 9). Finally, we were
pleased to find that diastereoselectivity of the adduct 3aa
was improved greatly by employing commercially available
entry
ligand
yieldb (%)
anti/sync
ee of anti/synd (%)
1
2
3
4
5
6
7
8
L1
L2
L3
L4
L5
L6
L7
L8
L9
L10
L11
84
86
98
82
88
87
83
81
78
59
85
57/43
64/36
71/29
64/36
36/64
60/40
53/47
62/38
57/48
71/29
83/17
83/83
80/73
90/88
81/-
80/97
18/43
2/14
35/23
37/31
86/35
86/-
(5) (a) Behforouz, M.; Zarrinmayeh, H.; Ogle, M. E.; Riehle, T. J.; Bell,
F. W. J. Heterocycl. Chem. 1988, 25, 1627. (b) Boteju, L. W.; Wegner, K.;
Qian, X. H.; Hruby, V. J. Tetrahedron 1994, 50, 2391. (c) Bruncko, M.;
Crich, D. J. Org. Chem. 1994, 59, 4239. (d) Dubois, L.; Mehta, A.; Tourette,
E.; Dodd, R. H. J. Org. Chem. 1994, 59, 434. (e) Shapiro, G.; Buechler,
D.; Marzi, M.; Schmidt, K.; Gomezlor, B. J. Org. Chem. 1995, 60, 4978.
(f) Rodriguez, R.; Vinets, I.; Diez, A.; Rubiralta, M.; Giralt, E. Synth.
Commun. 1996, 26, 3029. (g) Damour, D.; Pulicani, J. P.; Vuilhorgne, M.;
Mignani, S. Synlett 1999, 786. (h) Valdez, S. C.; Leighton, J. L. J. Am.
Chem. Soc. 2009, 131, 14638.
9
10
11
a Molar ratio of 1a/2a/CuClO4/L ) 100/110/10/11, 80 mg of 40 wt %
KF on basic alumina was used as base. b Determined by 1H NMR with
CH3NO2 as the internal standard. c The ratio was determined by 1H NMR.
d Determined by chiral HPLC.
(6) (a) O’Donnell, M. J. Acc. Chem. Res. 2004, 37, 506. (b) Na´jera, C.;
Sansano, J. M. Chem. ReV. 2007, 107, 4584. (c) Hashimoto, T.; Maruoka,
K. Chem. ReV. 2007, 107, 5656.
(7) (a) Ballini, R.; Palmieri, A.; Petrini, M.; Torregiani, E. Org. Lett.
2006, 8, 4093. (b) Palmieri, A.; Petrini, M. J. Org. Chem. 2007, 72, 1863.
(c) Ballini, R.; Palmieri, A.; Petrini, M.; Shaikh, R. R. AdV. Synth. Catal.
2008, 350, 129. (d) Shaikh, R. R.; Mazzanti, A.; Petrini, M.; Bartoli, G.;
Melchiorre, P. Angew. Chem., Int. Ed. 2008, 47, 8707.
monodentate phosphoramidite ligands L10 and L11;14 the
latter was better in terms of both selectivity and yield (entry
10 vs entry 11).
(8) (a) Li, Y.; Shi, F.-Q.; He, Q.-L.; You, S.-L. Org. Lett. 2009, 11,
3182. (b) Guo, Q.-X.; Peng, Y.-G.; Zhang, J.-W.; Song, L.; Feng, Z.; Gong,
With ligand L11, we set out to optimize reaction condi-
tions, and the results are summarized in Table 2. Examination
of glycine imines 2 led to the bulky tert-butyl esters 2b as
optimal substrates, affording the adduct 3ab in 80% yield
with 85/15 dr, 96% ee (entry 1, Table 2, vs entry 11, Table
1). With tert-butyl esters 2b, the effect of solvent was
evaluated, which revealed that the enantio- and diastereo-
selectivities decreased in THF relative to that in CH2Cl2
(entry 2 vs entry 1). The diastereoselectivity was maintained
in DME, while the enantioselectivity was lower (entry 3).
The yield in toluene increased from 80% to 88% while the
L.-Z. Org. Lett. 2009, 11, 4620
.
(9) (a) Yan, X.-X.; Peng, Q.; Zhang, Y.; Zhang, K.; Hong, W.; Hou,
X.-L.; Wu, Y.-D. Angew. Chem., Int. Ed. 2006, 45, 1979. (b) Yan, X.-X.;
Peng, Q.; Li, Q.; Zhang, K.; Yao, J.; Hou, X.-L.; Wu, Y.-D. J. Am. Chem.
Soc. 2008, 130, 14362. (c) Chen, C.-G.; Hou, X.-L.; Pu, L. Org. Lett. 2009,
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12, 1080.
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1995, 60, 10. (b) Richards, C. J.; Damalidis, T.; Hibbs, D. E.; Hursthouse,
M. B. Synlett 1995, 74. (c) Nishibayashi, Y.; Uemura, S. Synlett 1995,
79.
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Roseblade, S. J.; Pfaltz, A. Acc. Chem. Res. 2007, 40, 1402.
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Soc. 1992, 114, 9327. (b) Trost, B. M.; Toste, F. D. J. Am. Chem. Soc.
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Chem. Res. 2006, 39, 747.
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Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.;
Springer: Heidelberg, 2004; Vols. 1-3. (c) Minnaard, A. J.; Feringa, B. L.;
Lefort, L.; de Vries, J. G. Acc. Chem. Res. 2007, 40, 1267.
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Org. Lett., Vol. 12, No. 8, 2010
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Table 2. Optimization of Reaction Conditions for Reaction of
Sulfonylindole 1a with Glycine Ester 2ba
Table 3. Substrate Scope for AgCl-Catalyzed Reaction of
Sulfonylindoles 1 with Glycine Ester 2ba
yieldb
(%)
ee of
anti/sync anti/synd (%)
yieldb
(%) anti/sync antid (%)
ee of
entry
1, R1, R2, R3
1a, Ph, H
entry metal solvent
base
1
2
3
4
5
6
7
87
71
95
80
93
58
88
86
75
90
93
93
91
97/3
92/-
88/-
97/-
91/-
96/-
84/70
89/-
91/96
96/-
86/-
89/-
83/-
98/-
1
2
3
CuClO4 DCM
CuClO4 THF
CuClO4 DME
KF/Al2O3 80
KF/Al2O3 90
KF/Al2O3 90
85/15
78/22
85/15
87/13
87/13
81/19
91/9
96
93
86
96
87
92
86
1b, 4-MeO-C6H4, H, H
1c, 4-Cl-C6H4, H, H
1d, 4-Br-C6H4, H, H
1e, 4-NO2-C6H4, H, H
1f, Me, H, H
96/4
98/2
98/2
95/5
4
5
6
CuClO4 toluene KF/Al2O3 88
AgOAc toluene KF/Al2O3 72
AgOTf toluene KF/Al2O3 70
73/27
96/4
i
1g, Pr, H, H
7
8
9
10
11
AgCl
AgCl
AgCl
AgCl
AgCl
toluene KF/Al2O3 64
8e
9e
10
11
12
13f
1h, nPr, H, H
61/39
62/38
95/5
toluene Et3N
NR
-/-
toluene KOtBu
toluene Cs2CO3
toluene K2CO3
toluene Cs2CO3
toluene Cs2CO3
toluene Cs2CO3
50
87
9
52
9
45/55
97/3
97/3
96/4
98/2
96/4
1i, 2-fural, H, H
1j, Ph, Me, H
1k, Ph, H, 5-Me
1l, Ph, H, 5-Cl
1m, Ph, H, 4-Me
92
93
95
88/12
84/16
90/10
12e AgCl
13f
AgCl
14g AgCl
80
a The reaction was carried out with 1 (0.2 mmol), 2b (0.22 mmol),
AgCl (0.02 mmol), L11 (0.022 mmol), and Cs2CO3 (0.24 mmol) in toluene
(2 mL) at rt. b Isolated yields. c Determined by 1H NMR. d Determined by
chiral HPLC. e L1 as ligand. f Ts was replaced by SO2Ph.
a Molar ratio of 1a/2b/metal/L11/base ) 100/110/10/11/120. 80 mg of
40 wt % KF on basic alumina was used as base. b Determined by 1H NMR
with CH3NO2 as the internal standard. c Determined by 1H NMR.
d Determined by chiral HPLC. e 60 mol % Cs2CO3. f 12 mol % Cs2CO3.
g Ts in 1a was replaced by SO2Ph.
excellent diastereo- and enantioselectivities were achieved
for the isopropyl derivative 1g (entry 7). These results
suggested the importance of steric hindrance in the stereo-
control of the reaction. In the case of sulfonylindole 1h with
linear propyl substituent and 1i bearing a fural substituent,
selectivity was poor under standard conditions, while 91%
ee for 1h and 96% ee for 1i were achieved for anti isomer
albeit with low diastereoselectivity by using L1 as ligand
(entries 8 and 9). The sulfonylindoles with Me or Cl as
substituent at the 2 and 5 positions of indole ring were also
suitable substrates to provide corresponding products, al-
though the stereoselectivities were a bit lower (entries
10-12), while sulfonylindole 1m with Me as substituent at
4 position gave excellent enantioselectivity (entry 13).
The absolute configuration of the adduct 3db was deter-
mined unambiguously as (2S,3S) by X-ray diffraction
analysis of anti-3db. The adduct 3ab was readily converted
to ꢀ-phenyl tryptophan 5 by conventional sequences in 95%
overall yield in two steps, which presented a straightforward
route to ꢀ-substituted tryptophans (Scheme 1).
selectivity was the same as that in CH2Cl2 (entry 4 vs entry
1). The screening of Lewis acid showed that silver salts such
as AgOAc and AgOTf were also able to smoothly catalyze
the Michael reaction albeit with lower enantioselectivity
(entries 5 and 6), while AgCl enhanced the diastereoselec-
tivity but lowered the enantioselectivity (entry 7 vs entry
1). To improve the selectivity further, we studied the impact
of base and identified Cs2CO3 as the best one with dr 97/3
and ee being 92% among the bases we tested (entry 10 vs
entries 8, 9, and 11). The reaction occurred sluggishly in
the presence of weak base such as Et3N and K2CO3 (entries
8 and 11). Much lower diastereoselectivity was provided in
the case of KOtBu as base (entry 9). The chemical yields of
the reaction decreased sharply using substoichiometric or
catalytic amount of base, although the diastereoselectivity
and enantioselectivity were maintained (entries 12 and 13
vs entry 10). The replacement of p-toluenesulfonyl of
sufonylindole 1a by benzenesulfonyl resulted in the slight
decrease of the yield (entry 14 vs entry 10).
The substrate scope was investigated under the optimized
conditions, and the results are compiled in Table 3. A wide
variety of sulfonylindoles were suitable substrates to provide
the adducts 3 with anti-selectivity in 58-95% yields and
high enantioselectivity. Both electron-withdrawing and do-
nating groups at the para-position of the phenyl ring were
tolerated in sulfonylindoles 1 (entries 2-5). The electron-
deficient substrate 1c gave the best result, affording adduct
3cb in 95% yield with 98:2 dr and 97% ee (entry 3).
Although the diastereo- and enantioselectivities were lower
for sulfonylindoles 1f with methyl substitutent (entry 6),
Scheme 1
.
Transformation of Adduct 3ab to ꢀ-Phenyl
Tryptophan
1690
Org. Lett., Vol. 12, No. 8, 2010

In conclusion, we presented a straightforward route to
ꢀ-substituted tryptophans via the asymmetric catalytic reac-
tion of glycine derivatives with sulfonylindoles using a
catalyst derived from AgCl and a commercially available
chiral monodentate phosphoramidite ligand. The investiga-
tions on the reaction mechanism, the extension of substrates,
as well as the applications of the methodology in organic
synthesis are underway.
NSFC (20872161, 20821002, 20932008), Chinese Academy
of Sciences, and Science and Technology Commission of
Shanghai Municipality (10ZR1436800). This paper is dedi-
cated to Professor A. S. C. Chan on the occasion of his 60th
birthday.
Supporting Information Available: General experimental
procedure, spectral data for 3ab-mb, and X-ray analysis
data of 3db (CIF). This material is available free of charge
via the Internet at http://pubs.acs.org.
Acknowledgment. Financially supported by the Major
Basic Research Development Program (2010CB833300),
OL100161N
Org. Lett., Vol. 12, No. 8, 2010
1691