One-pot enantioselective synthesis of tryptophan derivatives via phase-transfer catalytic alkylation of glycine using a cinchona-derived catalyst

Article abstract of DOI:10.1055/s-0032-1317382

Tryptophans are building blocks for many natural products. This paper describes the enantiospecific synthesis of ring-A substituted tryptophan derivatives from commercially available gramines using chiral phase-transfer conditions. This one-pot reaction avoids protecting/deprotecting the indolylic nitrogen of gramine by choosing a chemoselective quaternization reagent, 4-(trifluoro-methoxy)benzyl bromide, to produce an electrophilic salt intermediate, which is subsequently alkylated in good yield with high enantiomeric excess. Georg Thieme Verlag KG Stuttgart · New York.

Full text of DOI:10.1055/s-0032-1317382

LETTER
▌2687
letter
One-Pot Enantioselective Synthesis of Tryptophan Derivatives via Phase-
Transfer Catalytic Alkylation of Glycine Using a Cinchona-Derived Catalyst
Chiral Tryptophan Derivatives
Robert Todd, Matthew Huisman, Nazim Uddin, Sarah Oehm, M. Mahmun Hossain*
Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee, 3210 N. Cramer Street, Milwaukee, WI 53211-3029, USA
Fax +1(920)2295530; E-mail: mahmun@uwm.edu
Received: 12.07.2012; Accepted after revision: 18.09.2012
substrate 1a, glycine Schiff base 3, catalyst 4, and 50%
Abstract: Tryptophans are building blocks for many natural prod-
aqueous NaOH/CH2Cl2 resulted in a disappointing race-
ucts. This paper describes the enantiospecific synthesis of ring-A
mic mixture of product with a chemical yield of 15% and
reaction time of 50 hours (5a; Scheme 1). Such alkylation
substituted tryptophan derivatives from commercially available
gramines using chiral phase-transfer conditions. This one-pot reac-
tion avoids protecting/deprotecting the indolylic nitrogen of gra- using gramine has been thoroughly studied in achiral sys-
mine by choosing a chemoselective quaternization reagent, 4-(trifluoro-
methoxy)benzyl bromide, to produce an electrophilic salt interme-
diate, which is subsequently alkylated in good yield with high enan-
tems, with an intermediate 3-methylene indolenine
(Scheme 1) being identified.6
tiomeric excess.
O
Ot-Bu
Key words: asymmetric synthesis, one-pot, organocatalysis, phase
transfer, tryptophan
NMe2
NaOH/H2O (20 equiv), 3
4 (1 equiv)
NC(Ph)2
CH2Cl2, r.t.
N
H
N
H
Optically active tryptophans have been regarded as im-
portant components in the areas of both synthetic and me-
dicinal chemistry.1 Ring-A substituted tryptophans have
been utilized in the design and synthesis of many biologi-
cally active compounds, including indole-based alkaloids,
which have recently been receiving attention for their
anti-cancer properties.2 Several methods are known to ef-
fectively synthesize enantiopure tryptophans, but most
strategies are only suitable for a particular species of tryp-
tophan.3 Many of these methods use stoichiometric
amounts of chiral auxiliaries and extensive multistep syn-
theses, and often involve problematic separation of iso-
mers obtained in the alkylation and annulation steps.3 In
recent years, asymmetric phase-transfer catalysis (PTC)
has been established as a powerful tool in the synthesis of
chiral mono- and di-substituted α-amino acids.4,5 To date,
the only reported asymmetric substitution of this type uti-
lizes a relatively unstable Boc-protected indole to synthe-
size α-methyl tryptophan in 78% yield and 91% ee,5e but
there has not been a general synthesis of chiral trypto-
phans via PTC reported. In this paper, we describe a sim-
ple, cost-effective, one-pot synthetic procedure that can
be used to prepare chiral tryptophan derivatives via a
phase-transfer-catalyzed (PTC) asymmetric alkylation re-
action. We believe that this approach is the most econom-
ical and versatile process for synthesizing these important
chiral building blocks.
1a
5a 15%, 0% ee
Br–
O
CH2
N+
N
Ph
Ot-Bu
O
N
Ph
indolenine
3
N
4
Scheme 1 Reaction of gramine 1a with glycinate 3 in the presence
of the catalyst 4 and an external base
The low chemical yield was attributed to the difficult task
of eliminating Me2NH to generate the product. To offset
this matter, 1a was converted into a quaternary salt 2a us-
ing iodomethane, which resulted in a much improved
chemical yield of 75% (5a; Scheme 2), albeit with no
asymmetric induction. The latter result may be due to the
fact that 2a is very soluble in water, and insoluble in di-
chloromethane, which are not ideal conditions for asym-
metric PTC reaction.4,5 In order to improve the
asymmetric induction, we attempted to change the polari-
ty of the quaternary salt, making it very soluble in dichlo-
romethane and partially soluble in water. Upon
introduction of a bulky hydrophobic triisopropylsilyl
(TIPS) protecting group on the indolylic nitrogen of the
substrate (1b; Scheme 2), we were able to improve the
enantioselection (84% ee) of the PTC alkylation reaction
using one equivalent of catalyst (5a; Scheme 2). In addi-
tion, the TIPS group was removed during the alkylation
process.
In this study, a cinchona-derived phase-transfer catalyst
was employed in the first reported PTC synthesis of chiral
tryptophan derivatives, using a glycine Schiff base and
various gramine derivatives. The first experiment, using
SYNLETT 2012, 23, 2687–2691
Advanced online publication: 18.10.2012
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9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0032-1317382; Art ID: ST-2012-R0588-L
© Georg Thieme Verlag Stuttgart · New York

2688
R. Todd et al.
LETTER
O
Ot-Bu
+
NMe2
I–
N(Me)3
NaOH/H2O (20 equiv), 3
4 (1 equiv)
NC(Ph)2
MeI
C6H6, 24 h, r.t.
N
N
N
CH2Cl2, r.t.
R1
R1
R1 = H, 2a
R1 = TIPS, 2b
R1
R1 = H, 1a
R1 = TIPS, 1b
R1 = H, 5a, 75%, 0% ee
R1 = H, 5a, 63%, 84% ee
Scheme 2 Synthesis of quaternary salt 2 by reaction of gramine 1 with MeI, followed by alkylation with glycinate 3 under phase-transfer con-
ditions using catalyst 4 and external base
We screened other commercially available catalysts to de- transformation feasible, but also resulted in both an in-
termine if any were more effective than catalyst 4 for this crease in yield and a reduction in the reaction time (<1 h;
alkylation reaction. From our results, summarized in Scheme 5).
Scheme 3, it was revealed that catalyst 4 (Scheme 2) was
the catalyst of choice for best enantioselection.
In order to further improve the chemical and enantioselec-
tion, a number of variables were studied for the alkylation
Further studies revealed that changing the quaternization reaction in dichloromethane. Increasing the concentration
reagent from iodomethane to 4-(trifluoromethoxy)benzyl of aqueous NaOH from 10 to 50% resulted in an increase
bromide (7) eliminated the need for protection/deprotec- in enantioselection. Changing base from 50% aqueous
tion steps, allowing for the quaternization and chiral al- NaOH to 45% aqueous KOH resulted in an increase in en-
kylation steps to be carried out in one pot (Scheme 4). The antioselection from 65 to 80% ee. The use of other com-
one-pot asymmetric alkylation was a success because the mon bases such as CsOH or Ba(OH)2 did not improve the
salt formed from 7 and gramine 1a was found to be insol- chemical or enantioselection of the product. Further
uble in water, similar to salt 2b. Changing quaternization screening of solvents such as tetrahydrofuran (THF) (6%
reagents from iodomethane to 4-(trifluoromethoxy)ben- ee), dioxane (84% ee) and toluene (71% ee) showed that
zyl bromide (7; Scheme 4), not only rendered a one-pot similar results were obtained with dichloromethane and
O
Ot-Bu
+
I–
N(Me)3
NaOH (50%)
3 (1 equiv), cat* (1 equiv)
NC(Ph)2
CH2Cl2, r.t.
N
N
TIPS
H
2b
5a
Cl–
Cl–
N+
N+
HO
HO
N
N
5% ee
F
0% ee
Br–
F
F
Br–
N+
N+
O
O
CH3
Br–
CH3
N+
N
N
47% ee
F
F
F
9% ee
Scheme 3 Results obtained by using some commercially available phase-transfer catalysts in the alkylation reaction
Synlett 2012, 23, 2687–2691 © Georg Thieme Verlag Stuttgart · New York

LETTER
Chiral Tryptophan Derivatives
2689
O
Ot-Bu
NMe2
aq NaOH (20 equiv)
3 (1 equiv), 4 (20 mol%)
NC(Ph)2
7 (1 equiv)
CH2Cl2
r.t., 30 min
CH2Cl2, r.t.
N
R1
N
R1
1a
5a, 72%, 65% ee
BrH2C
OCF3
7
Scheme 4One-pot synthesis of chiral tryptophanate 5a by reaction of gramines 1a with glycinate 3 and catalyst 4, using quaternization reagent
7 under ambient conditions
tion rates and selectivity were achieved with higher base
X–
+
concentrations, the effect of water on the enantioselectiv-
ity was also studied (Table 1).7 We discovered that a min-
imum of six equivalents of water was needed to achieve
excellent enantioselection of the product (Table 1, entry
2). In these reactions, a minimum 20 mol% of catalyst 4
was required for optimal chemical and enantioselection.8
NMe2
NMe2R
RX
CH2Cl2, r.t.
N
H
N
H
1a
Br
Br
RX = MeI
Once the alkylation variables were optimized, we began
structure–activity relationship (SAR) studies of catalyst 4
(Scheme 6) in the asymmetric one-pot alkylation of 1a
F3CO
Rxn time: 18 h
6 h
5 min
Table 1 Effect of Varying the Amount of Water on the Reaction
Scheme 5 Screening of quaternization reagents using gramine 1a un-
der ambient conditions
Entry
H2O (equiv)
Time (h)
Yield (%)a
ee (%)b
dioxane, leading to slightly higher enantioselectivity.
Lowering the reaction temperature from 25 to –30 °C re-
sulted in a further increase in enantioselection (80% ee af-
ter 2 h at 25 °C, 84% ee after 8 h at –30 °C). However,
further cooling (–78 °C) increased the reaction time to
15 h but gave no additional improvement in enantioselec-
tion. The low temperature reactions were run in dichloro-
methane because of the relatively high freezing point of
dioxane. Although we had determined that increased reac-
1
2
3
100
6
8
18
19
80
80
85
92
83
3
>95
a Yield determined by HPLC analysis.
b Determined by chiral HPLC analysis (Chiralcel OD column; IPA–
heptane, 5%; 254 nm DAD; 1 mL/min flow rate; 40 °C column tem-
perature).
O
Ot-Bu
NMe2
1) 4-(F3CO)C6H4CH2Br,
NC(Ph)2
CH2Cl2, r.t., 30 min
2) Ph2CNCH2CO2t-Bu
cat* (20 mol%), KOH (20 equiv)
H2O (6 equiv), –30 °C, 12 h
N
N
H
H
1a
5a
counter-ion effect
N-benzyl group effect
Cl–
Br–
N
N
O
O
F
F
N
N
F
60% ee
70% ee
Scheme 6 Structure–activity relationship studies in the asymmetric alkylation of gramine 1a with glycinate 3 with external base in a one-pot
reaction
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 2687–2691

2690
R. Todd et al.
LETTER
glycinate 3 (1 equiv),
cat. 4 (0.2 equiv),
KOH, H2O (6 equiv)
7
CO2t-Bu
NMe2R
NMe2
air-stable gramines
25 °C, 1 h
CH2Cl2
CH2Cl2, –30 °C
NC(Ph)2
O
O
Ot-Bu
Ot-Bu
NC(Ph)2
NC(Ph)2
MeO
N
N
H
H
8
5a
(75% yield, 91% ee)
(80% yield, 92% ee)
O
O
Ot-Bu
Ot-Bu
NC(Ph)2
NC(Ph)2
Br
N
N
H
MeO
H
9
10
(65% yield, 95% ee)
(73% yield, 90% ee)
Scheme 7 Optimal asymmetric alkylation conditions of various gramines
and 3 in dichloromethane at –30 °C using solid KOH with
six equivalents of water. The study revealed that both the
bromide counter-anion and the N-anthracenyl group play
an intimate role in the ability of catalyst 4 to induce high
enantioselection. Changing the counter-anion from bro-
mide to chloride resulted in a decrease in enantioselection
to 60% (Scheme 6), which may be due to increased solu-
bility of the catalyst in water. Substituting the anthracenyl
group with a less bulky 3,4,5-trifluorobenzyl group also
resulted in a decrease in enantioselection to 70% (Scheme
6). Steric influences were believed to be a contributing
factor toward increasing enantiodifferentiation.4,5
References and Notes
(1) (a) Dalpozzo, R.; Bartoli, G. Curr. Org. Chem. 2005, 9, 163.
(b) Mori, M. J. Organomet. Chem. 2004, 689, 4210.
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(d) Gribble, G. W. Pure Appl. Chem. 2003, 75, 1417.
(e) Meister, A. Biochemistry of the Amino Acids; Academic
Press: New York, 1965, 202.
(2) (a) Rahman, A.; Basha, A. Indole Alkaloids; Harwood
Academic Publishers: Amsterdam, 1998, 141. (b) Gupta, R.
R.; Kumar, M.; Gupta, V. Heterocyclic Chemistry II: Five-
Membered Heterocycles; Springer Publishing: New York,
1999, 193. (c) Physicians’ Desk Reference, 51st ed.;
Medical Economics, Co: Oradell (NJ, USA), 1997, 2395.
(d) Physicians’ Desk Reference, 51st ed.; Medical
After optimizing the reaction with gramine 1a, which re-
sulted in a good yield and excellent enantiomeric excess,
we expanded the scope of our study to other gramine-type
substrates, specifically ring-A substituted gramines such
as 5-methoxy, 6-methoxy, and 5-bromogramine (Scheme
7).8 All the gramines tested are commercially available
and provided good yields with excellent optical purity.
Economics, Co: Oradell (NJ, USA), 1997, 1723. (e) For a
review on medicinal chemistry of vinblastine, see: Borman,
L. S.; Kuehne, M. E.; Pearce, H. L. In The Alkaloids:
Antitumor Bisindole Alkaloids from Catharanthus roseus
(L.), Vol. 37; Brossi, A., Ed.; Academic Press Inc: San
Diego, 1990, 133.
(3) (a) Kieffer, M.; Repka, L.; Reisman, S. J. Am. Chem. Soc.
2012, 134, 5131. (b) Zheng, B.; Ding, C.; Hou, X.; Dai, L.
Org. Lett. 2010, 12, 1688. (c) Jain, H. D.; Zhang, C.; Zhou,
S.; Zhou, H.; Ma, J.; Liu, X.; Liao, X.; Deveau, A. M.;
Dieckhaus, M.; Johnson, M. A.; Smith, K. S.; Macdonald, T.
L.; Kakeya, H.; Osada, H.; Cook, J. M. Bioorg. Med. Chem.
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2007, 9, 3491. (f) Li, X.; Yin, W.; Sarma, P. V. V. S.; Zhou,
H.; Ma, J.; Cook, J. M. Tetrahedron Lett. 2004, 45, 8569.
(g) Castle, S. L.; Srikanth, G. S. C. Org. Lett. 2003, 5, 3611.
(h) Ma, C.; Liu, X.; Li, X.; Flippen-Anderson, J.; Yu, S.;
Cook, J. M. J. Org. Chem. 2001, 66, 4525. (i) Wang, H.;
Usui, T.; Osada, H.; Ganesan, A. J. Med. Chem. 2000, 43,
1577. (j) Drury, W.; Ferraris, D.; Cox, C.; Young, B.;
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Liu, R.; Yu, P.; Zhao, S.; Cook, J. M. J. Org. Chem. 1997,
62, 9298. (l) Yamada, S.; Yamamoto, M.; Hongo, C.;
Chibata, I. J. Agric. Food Chem. 1975, 23, 653.
In conclusion, a systematic study of substrate, catalyst, re-
agents, and reaction conditions led to a simple, enantiose-
lective synthesis of L-tryptophan derivatives using chiral
phase-transfer catalysis in a one-pot fashion.
Acknowledgment
We are grateful to the Graduate School of UWM for support of this
research through grant RGI-101X170. We thank the UWM Office
of Undergraduate Research for summer support of Sarah Oehm
through SURF. We also thank the Aldrich Chemical Company for
supplying some of the chemicals.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnoIufproig
m
iotSrat
ungIifoop
r
t
Synlett 2012, 23, 2687–2691
© Georg Thieme Verlag Stuttgart · New York

LETTER
Chiral Tryptophan Derivatives
authentic samples.9
2691
(4) For reviews in chiral PTC, see: (a) Maruoka, K.; Ooi, T.
Angew. Chem. Int. Ed. 2007, 46, 4222. (b) Maruoka, K. Pure
Appl. Chem. 2005, 77, 1285. (c) Lygo, B.; Andrews, B. Acc.
Chem. Res. 2004, 37, 518. (d) Maruoka, K.; Ooi, T. Chem.
Rev. 2003, 103, 3013. (e) O’Donnell, M. J. Aldrichimica
Acta 2001, 34, 3.
(5) (a) Christiansen, M.; Butler, A.; Hill, A.; Andrus, M. Synlett
2009, 653. (b) Barraja, P.; Diana, P.; Carbone, A.;
Cirrincione, G. Tetrahedron 2008, 64, 11625. (c) Lee, Y.-J.;
Lee, J.; Kim, M.-J.; Kim, T.-S.; Park, H.-g.; Jew, S.-s. Org.
Lett. 2005, 7, 1557. (d) O’Donnell, M. J. Acc. Chem. Res.
2004, 37, 506. (e) Ooi, T.; Takeuchi, M.; Kameda, M.;
Maruoka, K. J. Am. Chem. Soc. 2000, 122, 5228. (f) Pirrung,
M. G.; Krishnamurthy, N. J. Org. Chem. 1993, 58, 957.
(g) O’Donnell, M. J.; Eckrich, T. M. Tetrahedron Lett. 1978,
47, 4625.
tert-Butyl 2-(Diphenylmethyleneamino)-3-(5-methoxy-
1H-indol-3-yl)propanoate (Scheme 6; Compound 8): 1H
NMR (300 MHz, CDCl3): δ = 8.19 (s, 1 H), 7.59 (d, J =
7.9 Hz, 2 H), 7.27–7.43 (m, 4 H), 7.15–7.20 (m, 3 H), 6.93
(s, 1 H), 6.78–6.83 (m, 2 H), 6.61 (d, J = 7.5 Hz, 2 H), 4.33
(dd, J = 8.7, 4.5 Hz, 1 H), 3.69 (s, 3 H), 3.44 (dd, J = 14.1,
4.5 Hz, 1 H), 3.30 (dd, J = 14.1, 8.7 Hz, 1 H), 1.47 (s, 9 H).
13C NMR (75 MHz, CDCl3): δ = 171.4, 170.1, 153.6, 139.6,
136.1, 131.1, 130.0, 128.7, 128.3, 128.0, 127.9, 127.6,
124.0, 112.0, 111.8, 111.6, 100.5, 81.0, 66.6, 55.7, 45.2,
29.3, 28.0. HRMS: m/z [M + H]+ calcd. for C29H30N2O3:
455.2335; found: 455.2353.
tert-Butyl 2-(Diphenylmethyleneamino)-3-(6-methoxy-
1H-indol-3-yl)propanoate (Scheme 6; Compound 9): 1H
NMR (300 MHz, CDCl3): δ = 8.39 (s, 1 H), 7.63–7.71 (d, J
= 7.9 Hz, 2 H), 7.28–7.41 (m, 4 H), 7.18–7.25 (m, 3 H), 6.84
(d, J = 2.4 Hz, 2 H), 6.67–6.80 (m, 3 H), 4.36 (dd, J = 8.4,
4.8 Hz, 1 H), 3.82 (s 3 H), 3.46 (dd, J = 14.1, 4.8 Hz, 1 H),
3.27 (dd, J = 14.1, 8.4 Hz, 1 H), 1.48 (s, 9 H). 13C NMR (75
MHz, CDCl3): δ = 171.5, 170.2, 156.1, 139.6, 136.7, 136.2,
130.1, 128.7, 128.1, 128.0, 127.9, 127.6, 122.0, 119.4,
111.7, 109.0, 94.4, 80.9, 66.8, 55.6, 45.2, 29.4, 28.0. HRMS:
m/z [M + H]+ calcd. for C29H30N2O3: 455.2335; found:
455.2349.
(6) Joule, J. A.; Mills, K. Heterocyclic Chemistry, 5th ed.; John
Wiley & Sons: Chichester, 2010, 324.
(7) Dobish, M. C.; Johnston, J. N. Org. Lett. 2010, 12, 5744.
(8) Synthesis of tert-Butyl 2-(Diphenylmethyleneamino)-3-
(1H-indol-3-yl)propanoate (Scheme 6; Compound 5a);
Typical Procedure: To a solution of gramine (0.300 g, 1.7
mmol, 1 equiv) in CH2Cl2 (10 mL) was added 4-
(trifluoromethoxy)benzyl bromide (0.430 g, 1.7 mmol, 1
equiv) and the mixture was stirred for 30 min. N-
(Diphenylmethylene)glycine tert-butyl ester (0.502 g, 1.7
mmol, 1 equiv) and O-allyl-N-(9-
tert-Butyl 3-(5-Bromo-1H-indol-3-yl)-2-(diphenyl-
methyleneamino)propanoate (Scheme 6; Compound 10):
1H NMR (300 MHz, CDCl3): δ = 8.09 (s, 1 H), 7.80–7.90 (d,
J = 7.9 Hz, 2 H), 7.60–7.70 (m, 3 H), 7.18–7.41 (m, 9 H),
7.00 (s, 1 H), 6.65 (d, J = 3.32 Hz, 2 H), 4.24 (dd, J = 8.4,
4.8 Hz, 1 H), 3.36 (dd, J = 14.1, 4.8 Hz, 1 H), 3.21 (dd,
J = 14.1, 8.4 Hz, 1 H), 1.45 (s, 9 H). 13C NMR (75 MHz,
CDCl3): δ = 171.0, 170.2, 135.9, 134.5, 130.0, 129.9, 128.6,
128.3, 128.2, 128.0, 127.9, 127.4, 124.4, 124.3, 121.6,
112.4, 112.2, 112.0, 81.0, 66.4, 28.9, 28.0. HRMS: m/z [M +
H]+ calcd. for C28H27BrN2O2: 503.1334; found: 503.1297.
(9) Tarzia, G.; Balsamini, C.; Spadoni, G.; Duranti, E. Synthesis
1988, 514.
anthracenylmethyl)cinchoninium bromide (0.209 g, 0.3
mmol, 0.2 equiv) were added to the solution. The reaction
mixture was then cooled to –30 °C. While stirring, solid
KOH (2.0 g, 36 mmol, 20 equiv) and deionized H2O (0.2
mL, 11.1 mmol, 6 equiv) were added to the reaction mixture,
which was stirred for an additional 12 h at –30 °C. The
reaction mixture was concentrated by rotary evaporation and
the products were isolated by column chromatography
(silica gel; EtOAc–pentane, 10%) providing 5a (0.580 g,
80% yield) as a yellow oil. The identity of 5a was confirmed
by comparing its spectra to those of 1H NMR spectra from
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 2687–2691

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