Highly stereoselective N-terminal functionalization of small peptides by chiral phase-transfer catalysis

Article abstract of DOI:10.1002/anie.200390167

Virtually complete chirality transfer has been realized in the N-terminal alkylation of small, Schiff-base activated peptides under mild phase-transfer conditions, in which finely tuned chiral quaternary ammonium salts are used as catalysts. Repeated exte

Full text of DOI:10.1002/anie.200390167

Angewandte
Chemie
471; c) J. M. Fraile, J. I. GarcÌa, B. Lµzaro, J. A. Mayoral, Chem.
absorption in the membrane. The active Pyc site was reported
to be an efficient catalyst for the ORR,[3b,7] and hence, the
purging O2 is essential for the formation of H2O2 during the
reaction. The control experiment in pure H2O2 gave only
about 47% conversion with poor selectivity (Table 1). How-
ever, the assistance of Pyc and [Ru(bpy)3]2þ in the SOR was
supported by the indirect electrochemical studies mentioned
earlier. The efficiency of the SOR was then evaluated by
putting a 4.5 î 2 cm j NPycxÀRu(bpy) j in a mixture of CH3CN
(30 mL), H2O (40 mL), and 17 mm RSCH3 (R ¼ Ph,
PhCOCH3, and PhOCH3) at pH 1, with constant purging of
O2 under illumination (500 W halogen lamp) for 3h. The
products were analyzed simply by evaporation of the solution
of the separated reaction product in CHCl3 with a rotary-
vacuum system. All reactions gave a single product of
sulfoxide (that is, no sulfone was observed on the TLC plate
and was further confirmed by NMR and mass spectroscopic
studies) in > 90% yield. The high selectivity of the current
approach was clearly demonstrated. Finally, three repeated
experiments were performed with PhSCH3 to test the
recyclability of the j NPycxÀRu(bpy) j system, and almost
the same yield was observed.
In conclusion, we have demonstrated a clean and highly
selective photochemical oxidation of sulfide to sulfoxide on a
novel heterogeonous multicomponent nafion membrane
containing a Pyc catalyst and a [Ru(bpy)3]2þ photosensitizer.
The high sulfoxide selectivity, lack of pollution, ease of
product separation, and recyclable nature of the muticompo-
nent membrane has a clear advantage over classical ap-
proaches. Further investigations are currently underway to
expand the scope of this reaction to sulfide compounds
containing more complicated organic structures and to a
macroscale synthesis.
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references therein.
[4] The stability experiment was checked by continuously stirring the
j NPycxÀ j membrane (ca. 0.1 cm2) in a solution of about 99%
ethanol for 90 days. The membrane did not show any change in
weight, which illustrates the Pyc-modified nafion membrane has a
relatively rigid structure.
[5] a) W. Adam, J. E. Arg¸ello, A. B. PeÊÿÊory, J. Org. Chem. 1998,
63, 3905; b) N. Somasundaram, C. Srinivasan, J. Photochem.
Photobiol. 1998, 115, 169; c) K. Chiba, Y. Yamaguchi, M. Tada,
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Org. Chem. 2002, 67, 1036.
[6] K. C. Pillai, A. S. Kumar, J.-M. Zen, J. Mol. Catal. A 2000, 160,
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Goodenough, J. Appl. Electrochem. 1992, 22, 140.
Stereoselective Alkylation
Highly Stereoselective N-Terminal
Functionalization of Small Peptides by Chiral
Phase-Transfer Catalysis**
Experimental Section
Photochemical experiments were carried out at pH 1 (adjusted with
HCl) in a mixture of CH3CN and H2O (3:4, ca. 70 mL) in a closed
round-bottomed flask sealed with a gasket-septum under constant
purging of O2 gas. Cyclic voltammetric (CV) experiments were
performed using a CHI workstation with a three-electrode system of
working (0.071 cm2), reference (Ag/AgCl), and counter (Pt disc,
0.071 cm2) electrodes between À0.4 to 1.4 V. A negative current in the
cyclovoltammograms denotes an anodic response, while a positive
current denotes a cathodic current. The oxidized product was
separated into CHCl3 and then analyzed by NMR spectroscopic (in
CDCl3) and mass spectrometric techniques after rotary-vacuum
evaporation. The yield of the products was determined on the basis
of the ratio between the molar weight of the reactant and the product.
Takashi Ooi, Eiji Tayama, and Keiji Maruoka*
Peptide modification is an essential yet flexible synthetic
concept for screening targets efficiently and optimizing lead
structures in the application of naturally occurring peptides as
pharmaceuticals.[1,2] The introduction of side chains directly to
a peptide backbone is a powerful method for preparing
nonnatural peptides. The achiral glycine subunit has generally
8]
been used for this purpose[3] and glycine enolates,[4 radi-
11]
cals,[9
and glycine cation equivalents[12,13] have been ex-
Received: July 17, 2002
Revised: August 27, 2002 [Z19755]
[*] Prof. K. Maruoka, Dr. T. Ooi, E. Tayama
Department of Chemistry, Graduate School of Science
Kyoto University, Sakyo, Kyoto, 606-8502 (Japan)
Fax: (þ81)75-753-4041
[1] a) M. C. CarreÊo, Chem. Rev. 1995, 95, 1717; b) Sulfur Centered
Reactive Intermediates in Chemistry and Biology, (Eds.: C.
Chatgilialoglu, K. D. Asmus), Nato ASI series, Plenum, New
E-mail: maruoka@kuchem.kyoto-u.ac.jp
[**] This work was supported in part by a Grant-in-Aid for Scientific
Research from the Ministry of Education, Culture, Sports, Science
and Technology, Japan.
¬
York, 1990; c) M. Hudlicky, Oxidations in Organic Chemistry,
ACS Monograph 186, American Chemical Society, Washington,
DC, 1980.
[2] a) H. S. Schultz, H. B. Freyermuth, S. R. Bu, J. Org. Chem. 1963,
28, 1140; b) T. Indrasena, R. S. Varma, Chem. Commun. 1997,
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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Communications
Table 1: Effect of the chiral C2-symmetricquaternary ammonium salts on
the diastereoselectivity of the phase-transfer benzylation of 2a.[a]
ploited as reactive intermediates. However, controlling the
stereochemical outcome of these processes in an absolute
sense is difficult, especially in the modification of linear
peptides, and hence the development of an efficient, practical,
and general approach to establish sufficient stereoselectivity
has been eagerly awaited.[7d,14] Although the stereoselective
phase-transfer alkylation of Schiff-base-activated small pep-
tides 2, which involves chirality transfer between two adjoin-
ing amino acid residues, appears to be an attractive method,[6]
it has never been developed to a useful level due to the lack of
well-designed chiral catalysts.[15,16] Here we present the first
solution to this problem, in which the optically pure, C2-
symmetric quaternary ammonium salt 1 is used as the catalyst
(Scheme 1).[17] By fine-tuning the catalyst structure, a variety
of new side chains can be attached to the growing peptide N
terminus with remarkable stereoselectivity. This newly cre-
ated chirality can be transferred efficiently to an adjacent
amino acid residue, allowing the asymmetric construction of
nonnatural oligopeptides.
Entry
Catalyst
Reaction
time [h]
Yield [%][b]
de [%][c]
1
2
3
4
5
6
TBAB
4
4
6
8
4
6
85
88
83
43
98
97
8
55
20
81
86
97
(S,S)-1a
(R,R)-1a
(S,S)-1b
(S,S)-1c
(S,S)-1d
[a] The reactions were carried out with 1.1 equivalents PhCH2Br in the
presence of 2 mol% TBAB or 1 in 50% aqueous KOH/toluene (volume
ratio¼1:3) at 08C under argon. [b] Yield of isolated product. [c] The
diastereomericexcess of 3a (R¼CH2Ph) was determined by 1H NMR
spectroscopy and by HPLC analysis with a chiral column (Daicel
Chiralcel OD) and hexane/2-propanol as solvent. The absolute config-
uration of 3a was determined by comparison of the 1H NMR spectrum
and the HPLC retention time with those of the independently synthesized
authenticsample.
We initially examined the alkylation of the dipeptide Gly-
l-Phe derivative 2a as a representative system and evaluated
the critical importance of the chiral phase-transfer catalyst in
obtaining high stereoselectivity (Table 1). When a mixture of
2a and tetrabutylammonium bromide (2 mol%) as a typical
achiral ammonium salt in toluene was treated with 50% KOH
aqueous solution and benzyl bromide (1.1 equiv) at 08C for
4 h, the corresponding benzylation product 3a was obtained
in 85% yield. The diastereomer ratio (d,l-3a:l,l-3a) was
determined to be 54:46 (8% diastereomeric excess (de)) by
chiral HPLC analysis (entry 1 in Table 1). In contrast, the
reaction with the chiral quaternary ammonium bromide (S,S)-
1a as the catalyst under similar conditions gave rise to 3a with
a d,l:l,l ratio of 77.5:22.5 (55% de, 88% yield, entry 2).
Here, use of enantiomeric (R,R)-1a led to the preferential
formation of l,l-3a in 20% de (entry 3), indicating that
(R,R)-1a is a mismatched catalyst for this diastereofacial
differentiation of 2a. Significantly, the stereoselectivity was
increased dramatically when the aryl substituent (Ar) on the
3- and 3’-positions of the catalyst was changed. Almost
complete diastereocontrol was achieved with the catalyst
(S,S)-1d, which has 3,5-bis(3,5-di-tert-butylphenyl)phenyl
groups (97% de, entries 4 6).[18] It is worthy of comment that
neither racemization of the preexisting chiral center nor
N-alkylation was observed under the
present biphasic conditions.
In a similar manner a variety of alkyl
halides can be employed as the electro-
phile in this alkylation (Table 2, en-
tries 1 5), where excellent stereoselectiv-
ities were uniformly observed. The effi-
ciency of the transmission of stereochem-
Ph
O
Ph
O
O
O
Ph2C NH
CH2Cl2
Cl–H3N
OtBu
N
OtBu
Ph2C
N
H
N
H
2a
Ph
Ph
TBAB or 1 (2 mol%)
PhCH2Br (1.1 equiv)
O
O
N
OtBu
N
OtBu
Ph2C
+
Ph2C
N
H
N
H
ical information was not affected by the
side-chain structure of the preexisting
toluene/50% KOH aq
0 °C
O
O
Ph
Ph
D,L-3a
L,L-3a
amino acid residues, as clearly demon-
strated in the phase-transfer benzylation
of various dipeptides derived from natu-
ral a-amino acids (Table 2, entries 6 9).
Interestingly, sterically less demanding
(S,S)-1c was found to be a suitable
catalyst for the substrate with the l-pro-
line tert-butyl ester moiety (entry 10).
Ar
Br
Ar
Br
N
N
Ar
(S,S)-1
Ar
(R,R)-1
tBu
tBu
We further examined the stereoselec-
tive alkylation of the dipeptide l-Ala-l-
Phe derivative 4, which would enable the
asymmetric construction of noncoded
a,a-dialkyl-a-amino acid residues at the
peptide terminal (Scheme 2).[19] Thus,
tBu
F
F
F
Ar =
tBu
tBu
1a
1b
1c
1d
reaction of a mixture of 4, benzyl bro-
mide (1.1 equiv), and the catalyst (S,S)-
tBu
1d (2 mol%) in toluene with CsOH¥H2O
(5 equiv) as a solid base at 08C for 1 h
Scheme 1. Catalytic asymmetric alkylation of Schiff-base-activated dipeptide 2a under phase-
transfer conditions. TBAB¼ tetrabutylammonium bromide.
580
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Chemie
Table 2: Stereoselective N-terminal alkylation of dipeptides by chiral phase-transfer catalysis.[a]
(S,S)-1d (2 mol%)
afforded 5a in 87% yield and
92% de. The reaction with allyl
bromide under similar conditions
also proceeded smoothly with high
diastereoselectivity (5b; 91% yield,
92% de).
O
O
RX (1.1 equiv)
N
N
Ph2C
Ph2C
L-AA-OtBu
L-AA-OtBu
toluene/50% KOH aq
R
0 °C
2
3
Entry
AA
RX
Reaction
Yield [%][b]
de [%][c]
time [h]
Encouraged by the results, we
extended the chiral phase-transfer
catalysis with (S,S)-1d to the stereo-
selective N-terminal alkylation of
Gly-Ala-Phe derivative 6, that is,
asymmetric synthesis of tripeptides
(Scheme 3). To our surprise, the
benzylation of l,l-6 with (S,S)-1d
under the optimized biphasic con-
ditions resulted in poor diastereo-
selectivity (20% de) with l,l,l-7 as
the major product; however, the
selectivity was enhanced to 93% de
(89% yield) by the use of (R,R)-1d
as a catalyst. The observed stereo-
chemical relationship was totally
opposite to that in the reactions of
dipeptides. This interesting fact was
further supported by the benzyla-
tion of d,l-6, where (S,S)-1d turned
out to be a matched catalyst leading
to almost exclusive formation of
d,d,l-7 under similar conditions
(Scheme 3).
1
2
Phe (2a)
6
6
89
80
98
96
3[d]
4
CH3CH2I
12
8
90
92
98
96
5[d]
6
95
91
6
7
8
9
Leu
Val
Tyr(Bn)
Ala
PhCH2Br
6
12
8
6
8
91
85
90
92
80
96
93
98
93
90[e]
10
Pro
[a] Unless otherwise specified, the reactions were carried out with 1.1 equivalents RX in the presence of
2 mol% (S,S)-1d in 50% aqueous KOH/toluene (volume ratio¼1:3) under the given reaction
conditions. [b] Yield of isolated product. [c] Diastereomeric excess of 3 was determined by 1H NMR
spectroscopy and HPLC analysis of the alkylated peptide with a chiral column (Daicel Chiralpak AD
(entries 1, 3, and 8 10) and Chiralcel OD (entries 2, 4, and 5 7)) and hexane/2-propanol or hexane/
ethanol as solvent. [d] A saturated solution of CsOH was used as the aqueous base. [e] With (S,S)-1c as
catalyst.
Furthermore, we found that this
tendency for stereochemical com-
munication was consistent in the
phase-transfer alkylation of d,d,l-
8, which can be readily prepared
from d,d,l-7 by means of hydrolysis
and successive introduction of a
new glycine subunit by well-estab-
lished methods. The corresponding
protected tetrapeptide d,d,d,l-9
was obtained in 90% yield with
excellent stereochemical control
(94% de) as illustrated in Scheme 4.
We also confirmed that similar
alkylation of l,l,l-8 with (R,R)-1d
as the catalyst furnished l,l,l,l-9 in
87% yield and 92% de, suggesting
that (R,R)-1d is suitable for the
stereoselective N-terminal alkyla-
tion of naturally occurring polypep-
tides.
Scheme 2. Asymmetric construction of terminal a,a-dialkyl-a-amino acid residues.
Our approach based on the use
of chiral quaternary ammonium
salts enables the asymmetric
phase-transfer catalytic alkylation
of peptides. This provides a general
procedure not only for the highly
stereoselective N-terminal func-
tionalization of peptides but also
Scheme 3. Reversal of stereochemical preference in the asymmetric phase-transfer catalytic alkyla-
tion of tripeptide derivative 6.
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Communications
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