Anodic modification of proline derivatives using a lithium perchlorate/nitromethane electrolyte solution.

Article abstract of DOI:10.1021/ol026713z

[reaction: see text] N-Acyliminium cation of prolines was efficiently generated to accumulate in an undivided cell at 0 degrees C by an anodic oxidation of N-acylprolines or alpha'-phenylsulfanylated N-acylproline derivatives in a lithium perchlorate/nitr

Full text of DOI:10.1021/ol026713z

ORGANIC
LETTERS
2002
Vol. 4, No. 21
3735-3737
Anodic Modification of Proline
Derivatives Using a Lithium Perchlorate/
Nitromethane Electrolyte Solution
Shokaku Kim, Kanako Hayashi, Yoshikazu Kitano, Masahiro Tada, and
Kazuhiro Chiba*
Laboratory of Bio-organic Chemistry, Tokyo UniVersity of Agriculture and Technology,
3-5-8 Saiwai-cho, Fuchu, Tokyo 183-8509, Japan
chiba@cc.tuat.ac.jp
Received August 12, 2002
ABSTRACT
N-Acyliminium cation of prolines was efficiently generated to accumulate in an undivided cell at 0 °C by an anodic oxidation of N-acylprolines
or r′-phenylsulfanylated N-acylproline derivatives in a lithium perchlorate/nitromethane solution. The iminium cation intermediates gave modified
prolines by a reaction with nucleophiles under mild conditions.
There has been considerable interest in the synthesis of
unnatural and/or conformationally constrained amino acids,
peptidomimetics, and small peptide fragments encompassing
these residues.1 Of all the common R-amino acids, proline
plays a particular role in peptide secondary structure forma-
tion.2 Furthermore, the importance of substituted prolines in
the design of new catalysts or in the chemical synthesis of
pharmacologically or biologically interesting molecules is
well recognized.3 From a synthetic standpoint, electrochemi-
cal means are among the most useful methods for the
modification of proline derivatives.4 It has been revealed that
an amide or carbamate is oxidized to generate an iminium
cation and that trapping of the iminium cation with the
methoxy group leads to a product that has been functionalized
on the carbon R to nitrogen.
It is, however, difficult to oxidize the starting material
without affecting some nucleophiles because the oxidation
potentials of nucleophiles are usually lower than those of
the electrolytic substrates. In this regard, Yoshida and co-
workers have shown that the introduction of heteroatoms on
the carbon R to nitrogen leads to the generation of an
iminium cation by anodic oxidation of the heteroatoms
(electron auxiliary) followed by a reaction with carbon
nucleophiles having lower oxidation potential than that of
the amide or carbamate groups.5 Moeller and co-workers
developed new routes to construct functionalized and/or
(1) (a) Gante, J. Angew. Chem., Int. Ed. Engl. 1994, 33, 1699. (b) Giannis,
A.; Kolter, T. Angew. Chem., Int. Ed. Engl. 1993, 32, 1244. (c) Long, R.
D.; Moeller, K. D. J. Am. Chem. Soc. 1997, 119, 12394. (d) Li, W.; Moeller,
K. D. J. Am. Chem. Soc. 1996, 118, 10106.
(2) Takeuchi, Y.; Marshall, G. R. J. Am. Chem. Soc. 1998, 120, 5363.
(3) (a) Parrinello, G.; Stille, J. K. J. Am. Chem. Soc. 1987, 109, 7122.
(b) Hodgson, M.; Parker, D. J. Organomet. Chem. 1987, 325, C27-C30.
(c) Tani, K.; Suwa, K.; Tanigawa, E.; Ise, T.; Yamagata, T.; Tatsuno, Y.;
Otsuka, S. J. Organomet. Chem. 1989, 370, 203. (d) Brunner, H.; Graf, E.;
Leitner, W.; Wutz, K. Synthesis 1989, 743. (e) Baker, G. L.; Fritschel, S.
J.; Stille, J. R.; Stille, J. K. J. Org. Chem. 1981, 46, 2954. (f) For a review,
see: Hanessian, S.; McNaughton-Smith, G.; Lombart, H.-G.; Lubell, W.
D. Tetrahedron 1997, 53, 12789.
(4) (a) Shono, T.; Matsumura, Y.; Tsubata, K. J. Am. Chem. Soc. 1981,
103, 1172. (b) Shono, T. Tetrahedron 1984, 40, 811. (c) Shono, T.
Electroorganic Chemistry as a New Tool in Organic Synthesis; Springer-
Verlag: Berlin, 1984.
(5) (a) Yoshida, J.; Itoh, M.; Isoe, S. J. Chem. Soc., Chem. Commun.
1993, 549. (b) Yoshida, J.; Morita, Y.; Ishichi, Y.; Isoe, S. Tetrahedron
Lett. 1994, 35, 5247. (c) Sugawara, M.; Mori, K.; Yoshida, J. Electrochim.
Acta 1997, 42, 1995.
10.1021/ol026713z CCC: $22.00 © 2002 American Chemical Society
Published on Web 09/17/2002

conformation-constrained peptidomimetics by introducing
silyl groups as electron auxiliaries to lower the oxidation
potential that enabled anodic substitution of the silyl group
with a methoxy group that worked as a trigger for following
Lewis-acid-catalyzed cyclization reactions via N-acyliminium
cation for the construction of peptidomimetics.6 On the other
hand, Yoshida, Suga, and co-workers reported a “cation-
pool” method that can electrochemically generate and
stabilize iminium cations of carbamates in divided electrolytic
cells at low temperatures (lower than -47 °C) followed by
a reaction with nucleophiles in the absence of an electrolytic
current.7
On the other hand, electrolysis of compound 1 conducted
under constant current conditions (2 mA, 2.2 F/mol) at 0 °C
followed by the addition of thiophenol 2 (3 equiv) success-
fully gave the desired product 3 in 91%. On the other hand,
the product was scarcely obtained under other typical
electrolytic conditions, such as tetralkylammonium tosylate
in acetonitrile or in nitromethane. Anodic generation of
1
iminium cation of 1 was confirmed9 by H NMR (δH 9.14,
CHdN+) and 13C NMR (δc 195.0, CdN+) spectra in CDCl3/
CH3NO2 (1:1) in the presence of lithium perchlorate (0.5
M) and acetic acid at 25 °C (electrolyzed solution was diluted
with CDCl3 just after electrolysis, TMS as an internal
standard at 0 ppm).
In anodic oxidation systems, a divided cell is often
introduced to avoid cathodic re-reduction of electrogenerated
products or their undesired reactions with cathodic products,
but the application of higher electrolytic potentials is
generally required, and there is an accumulation of electro-
generated acid accompanied by the generation of the
products. This gave us the incentive to develop an extended,
simple electrochemical method that would enable anodic
generation and accumulation of unstable N-acyliminium
cations of prolines in an undivided system for their diverse
functionalization. In this case, an electrolytic medium would
play an important role to avoid the re-reduction and
decomposition of the reactive intermediates. Furthermore,
if we can also introduce an electron auxiliary that converts
to the corresponding N-acyliminium cation under neutral,
lower oxidation potential conditions, it should further open
the door for the introduction of varied functional groups in
the proline residues of peptides. We herein report a new
method for the introduction of nucleophiles on the carbon
R′ to nitrogen of proline derivatives including phenyl-
sulfanylated ones as a precursor of the iminium cations.
This result suggested that the intermediate generated by
anodic oxidation of compound 1 was highly stabilized in
the reaction media, which also assisted the progress of the
following C-S bond-forming reaction. The oxidation po-
tential of 3 was lowered to Eox 1.2 V vs Ag/AgCl, which
enabled us to try the oxidative C-S bond cleavage in the
presence of electron-rich olefins. As described in Scheme
2, the anodic oxidation of compound 3 allowed the prepara-
Scheme 2
Initially, an introduction of the phenylsulfanyl group in
the R-position of MOC-pyrrolidine 1 was investigated
(Scheme 1). Electrolysis of MOC-pyrrolidine 1 was per-
tion of the alkylated products. Oxidative C-C bond forma-
tion of 3 with allyltrimethylsilane 4 (1.2 equiv) in lithium
perchlorate/nitromethane resulted in an 89% yield of allylated
product 5; in addition, treatment with 1-phenyl-1-(trimethyl-
silyloxy)ethylene 6 provided the expected product 7 in an
83% yield.
Scheme 1
The introduction reaction of the sulfur atom on the R′-
position to the nitrogen of proline derivatives and the C-C
bond formation reaction were carried out according to the
same conditions (Scheme 3). Anodic oxidation of amide 8
or carbamate 9 led to the formation of the corresponding
proline derivatives with the phenylsulfanyl group and af-
forded the allylated products in high yield. Although it is
generally difficult to generate cationic intermediates of
N-acylprolines followed by C-C bond formation triggered
by anodic C-S bond cleavage, the desired reaction success-
fully occurred in this media system. It was presumed that
the lowered oxidation potential based on the introduction of
thiophenol to iminium cations and the electrolytic reaction
media with moderate Lewis acidity led to the aimed oxidative
C-S bond fission followed by a nucleophilic attack of the
carbon nucleophile under a mild condition.
formed in a 1 M lithium perchlorate/nitromethane electrolyte
solution8 in the presence of 50 mM AcOH using an undivided
cell, a glassy carbon anode and a platinum cathode. Because
of the higher oxidation potential of 1 (Eox 1.9 V vs Ag/AgCl)
compared with that of thiols, electrooxidation of 1 in the
presence of thiophenols did not give the desired product.
(6) Sun, H.; Moeller, K. D. Org. Lett. 2002, 4, 1547.
(7) (a) Yoshida, J.; Suga, S.; Suzuki, S.; Kinomura, N.; Yamamoto, A.;
Fujiwara K. J. Am. Chem. Soc. 1999, 121, 9546. (b) Suga, S.; Suzuki, S.;
Yoshida, J. J. Am. Chem. Soc. 2002, 124, 30.
(8) (a) Chiba, K.; Tada, M. J. Chem. Soc., Chem. Commun. 1994, 2485.
(b) Chiba, K.; Miura, T.; Kim, S.; Kitano, Y.; Tada, M. J. Am. Chem. Soc.
2001, 123, 11314.
(9) Yamamoto, Y.; Nakada, T.; Nemoto, H. J. Am. Chem. Soc. 1992,
114, 121 and ref 7a.
3736
Org. Lett., Vol. 4, No. 21, 2002

Scheme 3
Scheme 5
tained at the first step has a [R]25 value of -65.4°, while
D
the one derived from phenylsulfanyl-N-acetylproline methyl
ester 10 has a value of -65.3°. This result showed that no
significant racemization occurred in the anodic introduction
of thiophenol. Furthermore, it is thought that this electrolytic
system has the potential for use in a wide variety of peptides
having a pyrrolidine skeleton in a facile way.
In conclusion, a practical new pathway to the synthesis
of substituted proline derivatives has been developed. It was
found that amides and carbamates of pyrrolidine derivatives
were efficiently generated and trapped by nucleophiles in a
lithium perchlorate/nitromethane solution (Scheme 6). The
Furthermore, the application of a direct C-C bond
formation of iminium cations with 4 was also investigated.
After the completion of anodic oxidation of 8 or 9 in lithium
perchlorate/nitromethane in the presence of acetic acid (2.2
F/mol) at 0 °C followed by the addition of allyltrimethyl-
silane at ambient temperature, the desired products 12 or 13
were produced in good yield, respectively (Scheme 4).
Scheme 6. Proposed Reaction Mechanism
Scheme 4
introduction of thiophenol as a nucleophile lowered the
oxidation potential of proline derivatives, leading to the
oxidative C-S bond fission followed by the intermolecular
C-C bond-forming reaction with a nucleophilic attack of
carbon nucleophiles under mild conditions.
To elucidate optical purity through the electro-oxidative
conversion of proline derivatives, a comparison of two
N-acetyl-L-proline methyl esters was carried out (Scheme
5).10 Compound 8 was prepared by treating L-proline methyl
ester with acetic anhydride and pyridine, and it was oxidized
in lithium perchlorate/nitromethane to give phenylsulfanyl-
N-acetylproline methyl ester 10 by the addition of thiophenol.
Subsequent reduction of 10 with Et3SiH and TFA in CHCl3
yielded compound 8. N-Acetyl-L-proline methyl ester ob-
Supporting Information Available: Experimental pro-
cedures, spectroscopic data for compounds 3, 10, and 11,
1
and H NMR spectra of compounds 3, 7, and 10-13. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(10) Wong, P. L.; Moeller, K. D. J. Am. Chem. Soc. 1993, 115, 11434.
OL026713Z
Org. Lett., Vol. 4, No. 21, 2002
3737