Highly Enhanced Enantioselectivity in the Memory of Chirality via Acyliminium Ions

Article abstract of DOI:10.1021/ol025865r

(Matrix Presented) Electrochemical oxidation of N-acylated serine derivative 1b in methanol gave optically active methoxylated compound 2b with an enantiomeric excess of up to 80%. The bulky o-phenyl benzoyl N-protecting group was found to be the main con

Full text of DOI:10.1021/ol025865r

ORGANIC
LETTERS
2002
Vol. 4, No. 11
1875-1877
Highly Enhanced Enantioselectivity in
the Memory of Chirality via Acyliminium
Ions†
G. Ng’ang’a Wanyoike, Osamu Onomura, Toshihide Maki, and
Yoshihiro Matsumura*
Department of Pharmaceutical Sciences, Graduate School of Biomedical Sciences,
Nagasaki UniVersity, 1-14 Bunkyo-machi, Nagasaki City, Nagasaki 852-8521, Japan
matumura@net.nagasaki-u.ac.jp
Received March 13, 2002
ABSTRACT
Electrochemical oxidation of N-acylated serine derivative 1b in methanol gave optically active methoxylated compound 2b with an enantiomeric
excess of up to 80%. The bulky o-phenyl benzoyl N-protecting group was found to be the main contributing factor for the enhanced
enantioselectivity. The mechanistic aspect of this methoxylation reaction was investigated and found to proceed via a retention mechanism.
The synthesis of optically active compounds on the basis of
“memory of chirality” continues to attract much attention in
asymmetric synthesis.1 Memory of chirality can be defined
as a phenomenon in which the chirality of a starting material
having a chiral sp3-carbon is preserved in the reaction product
even though the reaction proceeds at the chiral carbon as a
reaction center through reactive intermediates such as car-
banion, singlet monoradicals,2 biradicals,3 or carbenium
ions.4,5 Reactions involving all the above intermediates except
the carbenium ion have been reported to proceed well
affording products with very high enantiomeric excesses.
In the first memory of chirality via carbenium ion
chemistry, we reported the generation of optically active 2a
(39% enantiomeric excess (ee)) when N-benzoylated serine
derivative 1a was electrochemically oxidized (eq 1),4a but
the ee was generally low.
To increase the enantioselectivity, we envisioned that the
modification of the N-protecting group could enhance the
ee since protecting groups of amino compounds are known
to affect selectivity of the reactions6 especially asymmetric
reactions.7 On the basis of this hypothesis, we synthesized a
serine derivative 1b bearing a bulky o-phenylbenzoyl group
† This paper is dedicated to Professor Hans J. Scha¨fer on the occasion
of his 65th birthday.
(1) Kawabata, T.; Chen, J.; Suzuki, H.; Nagae, Y.; Kinoshita, T.;
Chancharunee, S.; Fuji, K. Org. Lett. 2000, 2, 3883-3885.
(2) (a) Schmalz, H. G.; de Koning, C. B.; Bernicke, D.; Siegel, S.;
Pfletchinger, A. Angew. Chem., Int. Ed. 1999, 38, 1620-1623. (b) Sauer,
S.; Schumacher, A.; Barbosa, F.; Giese, B. Tetrahedron Lett. 1998, 39,
3685-3688. (c) Giese, B.; Wettstein, P.; Stahelin, C.; Barbosa, F.;
Neuburger, M.; Zehnder, M.; Wessig, P. Angew. Chem., Int. Ed. 1999, 38,
2586-2587.
(4) (a) Matsumura, Y.; Shirakawa, Y.; Satoh, Y.; Umino, M.; Tanaka,
T.; Maki, T.; Onomura, O. Org. Lett. 2000, 2, 1689-1691. (b) Matsumura,
Y.; Tanaka, T.; Wanyoike, G. N.; Maki, T.; Onomura, O. J. Electroanal.
Chem. 2001, 507, 71-74. (c) Davies, S. G.; Donohoe, T. J. Synlett 1993,
323-332.
(5) The original chirality is conformationally memorized in those reactive
intermediates. Thus, the well-known retention of configuration caused by
neighboring effects in carbocation chemistry is excluded from the definition.
(3) Griesbeck, A. G.; Kramer, W.; Lex, J. Angew. Chem., Int. Ed. 2001,
40, 577-579.
10.1021/ol025865r CCC: $22.00 © 2002 American Chemical Society
Published on Web 04/30/2002

as the N-protecting group. Electrolysis of this compound 1b
in methanol afforded R-methoxylated serine derivative 2b
with an interestingly high ee of up to 80%8 (eq 2).
It was deduced from this result that the methoxylation
process proceeded mainly by introduction of the methoxyl
group from the same side (syn) as the carboxylate group to
afford a retention product 4a. This information was necessary
for inferring the absolute configuration of 2b, but it was not
sufficient because the presence of the methyl group at the
C(5) could have had a directing effect on the incoming
nucleophile due to steric effects. The steric hindrance could
favor the formation of the trans isomer, which was the main
product. To investigate whether the stereochemical course
of reaction of 3 was governed by the chirality at C(5), an
L-allo-threonine derivative 5 was prepared and electrolyzed
under similar reaction conditions (eq 4).
The electrolysis was carried out in methanol at -30 °C
using an excess of base (NaOMe) and platinum as both the
anode and the cathode.9
Having obtained a convenient method for synthesizing
optically active 2b, we finally had to determine the absolute
configuration and hence deduce the reaction mechanism. The
absolute configuration of 2b could not be determined directly
but was inferred on the basis of the following reactions.
Threonine derivative 3 was synthesized and subjected to
electrolysis under the optimized reaction conditions. This
electrolysis afforded R-methoxylated diastereomers 4a and
4b in a 98:2 ratio (eq 3).10,11
Electrolysis of the L-allo-threonine derivative 5 afforded
a mixture of R-methoxylated diastereomers 6a and 6b in a
ratio of 90:10. The strong NOE between methyl protons and
the methoxy protons of 6a, which was absent in the minor
isomer 6b, confirmed the relative stereochemistry of the
major product 6a (Figure 2).
The relative configuration of the oxidation products 4a
and 4b was confirmed by NOE experiments. Particularly
diagnostic were the presence of strong NOE between the
5-methyl group protons and the H(4) and the NOE between
methoxyl protons and H(5) of 4a (Figure 1). In the case of
Figure 2. NOESY for 6a and 6b
This result also shows that the major oxidation product
6a resulted from attack of the methoxide from the much more
(7) Shibasaki, M.; Takamura, M.; Funabashi, K.; Kanai, M. J. Am. Chem.
Soc. 2000, 122, 6327-6328; 2001, 123, 6801-6088.
(8) The ee of 2b was determined by HPLC analysis employing a Daicel
Chiralpak OD.
(9) A solution of serine derivative 1b (0.5 mmol) and NaOMe (5 mmol)
in methanol (10 mL) was put into an undivided cell, stirred continuously,
and cooled to -30 °C. The cell was then equipped with platinum plate
electrodes (1 × 2 cm). Electrolysis of the solution with 2 F/mol at a constant
current (50 mA) afforded 2b (40% yield at 2 F/mol, 74% yield at 8 F/mol)
with a recovery of 1b (no racemization) after the usual workup.4a
(10) Treatment of a 98:2 mixture of 4a and 4b with acidic methanol at
room temperature for 12 h afforded a 37:63 thermodynamic ratio of of 4a
and 4b. Also, an acid treatment of a 90:10 mixture of 6a and 6b in methanol
resulted in the formation of a 63:37 mixture of 6a and 6b.11
(11) The de for the methoxylated product of threonine and allo-threonine
derivatives 3 and 5, respectively, were determined using both Daicel
Chiralpak OD and YMC-Pac SIL HPLC columns.
Figure 1. NOESY for 4a and 4b
4b, these signals were absent but the NOE between the
methoxyl and methyl groups was observed, implying that
these groups had a cis relationship (Figure 1).
(6) Greene, T. W.; Wuts, P. G. M. ProtectiVe Groups in Organic
Synthesis, 2nd ed.; John Wiley and Sons: New York, 1991; pp 315-403,
41-452.
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Org. Lett., Vol. 4, No. 11, 2002

Scheme 1. Reaction Mechanism
a Determined by MOPAC AM1 calculation.
hindered syn side to form (4R,5S)-6a. On the basis of the
stereochemical results of the oxidation products of both
threonine and allo-threonine derivatives, it was deduced that
the chirality at C(4) in 4a and 6a was memorized in the
corresponding iminium ion intermediates. The memorized
chirality made a major contribution to the stereochemical
course of the reaction, while chirality at the adjacent chiral
center C(5) had little effect. It is therefore inferred that the
major oxidation product for 1b is also the R-isomer.
Although the mechanistic details of this reaction are not
well understood, a plausible mechanism for the electro-
chemical oxidation of these non-Kolbe reactions is illustrated
in Scheme 1.
the nucleophilic attack was predominantly from the less
hindered syn side resulting in R-isomer 2b.
In conclusion, we have found that the electrochemical
oxidation of the serine derivative 1b in methanol at -30 °C
afforded optically active R-methoxylated compound 2b with
80% ee, while that of threonine derivative 3 and allo-
threonine derivative 5 afforded R-methoxylated products with
96 and 80% de, respectively. The high ee observed is
attributable to the bulky o-phenylbenzoyl protecting group.
Investigation is under way to find a more efficient protecting
group than the o-phenylbenzoyl group for the improvement
of enantioselectivity.
The initial step involves the oxidative decarboxylation of
1b to form the iminium ion 4, which can be attacked by
nucleophiles (Nu) from the syn or the anti side. The observed
80% ee could be attributable to the presence of the bulky
o-phenyl group beneath the carboxylic group and the fixation
of the conformation of 1b and of iminium ion intermediate
4 at low temperature.12 The restricted rotation could have
favored the formation of a chiral iminium ion with the
conformation of an o-phenyl group similar to that of the
precursor 1b. The bulky o-phenyl group could have pre-
cluded an effective approach from the anti side, and hence
Acknowledgment. This study was supported by a Grant-
in-Aid for Scientific Research on Priority Areas (A), No.
412 (Exploitation of Multi-Element Cyclic Molecules) (Nos.
13029093 and 14044084), from the Ministry of Education,
Culture, Sports, Science, and Technology, Japan, and by a
Grant-in-Aid for Scientific Research (B) (No. 13450375)
from Japan Society for the Promotion of Science.
Supporting Information Available: Experimental pro-
cedures and characterization for 1a, 2b, 3, 4a, 5, and 6a,b.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(12) Electrolysis of 1b at room temperature afforded 2b (57% ee). The
fact that this ee of 2b was lower than that obtained when the reaction was
performed at -30 °C (80% ee) indicated that the facial selectivity was
dependent on the temperature.
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