Memory of chirality in the electrochemical oxidation of N-o phenylbenzoylated prolinols

Article abstract of DOI:10.3987/COM-08-S(D)10

Memory of chirality in electrochemical carbon-carbon bond cleavage of N-o-phenylbenzoylated (S)-prolinol derivatives was observed. Substituents of the α-position affected the ee of the products. The reaction of α,α-diarylated (S)-prolinol derivatives proc

Full text of DOI:10.3987/COM-08-S(D)10

HETEROCYCLES, Vol. 79, 2009
339
HETEROCYCLES, Vol. 79, 2009, pp. 339 - 345. © The Japan Institute of Heterocyclic Chemistry
Received, 18th August, 2008, Accepted, 29th September, 2008, Published online, 2nd October, 2008.
DOI: 10.3987/COM-08-S(D)10
MEMORY OF CHIRALITY IN THE ELECTROCHEMICAL OXIDATION
OF N-o-PHENYLBENZOYLATED PROLINOLS†
George Ng’aNg’a Wanyoike, Yoshihiro Matsumura, and Osamu Onomura*
Graduate School of Biomedical Sciences, Nagasaki University, 1-14,
Bunkyo-machi, Nagasaki 852-8521, Japan. E-mail: onomura@nagasaki-u.ac.jp
†Dedicated to the memory of Professor Dr. John Daly
Abstract – Memory of chirality in electrochemical carbon-carbon bond cleavage
of N-o-phenylbenzoylated (S)-prolinol derivatives was observed. Substituents of
the α-position affected the ee of the products. The reaction of α,α-diarylated
(S)-prolinol derivatives proceeded smoothly to afford optically active
α-methoxylated pyrrolidine with up to 73% ee.
The synthesis of optically active compounds on the basis of ‘memory of chirality’ continues to attract
much attention in asymmetric synthesis.1 In our previous study, we demonstrated that the decarboxylation
of α-amino acids furnished iminium ions, which were quenched with nucleophiles to afford optically
active compounds via memory of chirality.2 The non-Kolbe electrolysis of N-acylated
oxazolidine-4-carboxylic acid 1 afforded optically active N,O-acetals 3 with up to 83% ee,3 while the
electrochemical oxidation of the proline derivative 2 gave α-methoxylated pyrrolidine 4 in up to 46% ee
(Scheme 1).4
O
O
Me
Me
Me
Me
-2e
CO2H
CO2H
OMe
OMe
N
N
N
N
Pt electrodes
or
or
NaOMe
O
O
O
O
in MeOH
Ph
Ph
Ph
3, up to 83% ee
Ph
4, up to 46% ee
1
2
Scheme 1. Electrochemical oxidation of oxazolidine and proline derivatives
In our continuing study on memory of chirality, we anticipated that electrochemical oxidation of
N-acylamino alcohols might bring about the carbon-carbon (C-C) bond cleavage between the α and β
carbons5 to give iminium ions (Scheme 2) similar to those anodically generated from amino acids and

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HETEROCYCLES, Vol. 79, 2009
trapping of these iminium ions intermediates with nucleophiles such as methanol could afford N,O-acetals
with some memory of chirality. We report herein that the electrochemical C-C bond cleavage of several
N-o-phenylbenzoyl prolinols 5 proceeds more efficiently than that of the proline derivative to afford 4 in
good enantiomeric excess (Scheme 3). The ee (up to 73% ee) was better than that of the non-Kolbe
reaction of proline derivative 2 (up to 46% ee).
R1
O
R3
R1
O
R3
R1
O
R3
cleavage
-e
R4
R2
+
R2
R4
R4
R2
N R5
COR6
N R5
COR6
N R5
COR6
H
H
H
-H+
O
-e
R3
R1
R2
R3
R4
MeOH
-H+
MeO
R4
N R5
N R5
COR6
COR6
Scheme 2. Electrochemical C-C bond cleavage of N-acyl-β-hydroxylamines
R
-2e
Pt electrodes
α
N
R
OMe
N
β
OH
NaOMe
in MeOH
O
O
up to 73% ee
4
5
Ph
Ph
Scheme 3. Electrochemical C-C bond cleavage of prolinol derivatives
The initial study was the electrolysis of N-o-phenylbenzoylated (S)-prolinol 5a as described in (Scheme
4). The electrolysis proceeded to afford α-methoxylated pyrrolidine 4 in 7% ee (15% yield) by cleavage
of the C-C bond. The major enantiomer of 4 had the same stereoconfiguration as the major enantiomer
derived from N-o-phenylbenzoylated L-proline, albeit with low enantiomeric excess.
β
α
N
R
N
-2e
CH2OH
OMe
Pt electrodes
O
O
NaOMe (1.2 equiv)
in MeOH, at -30oC
Ph
Ph
7% ee
15% yield
4
5a
Scheme 4. Electrochemical oxidation of prolinol derivative 5a
To deduce the absolute configuration of 4, racemic N-o-phenylbenzoyl-cis-3-methylproline (6) was
prepared.6 The amino acid 6 was used instead of its β-amino alcohol since the oxidation products from
both the proline 2 and the prolinols 5 were the same. The electrochemical oxidation of 6 afforded cis-77 as

HETEROCYCLES, Vol. 79, 2009
341
a major product and trans-8 as a minor product in 44% de (Scheme 5).
Me
Me
Me
NaOMe
MeOH
2.3 F/mol
0οC
CO2H
OMe
OMe
N
N
N
+
O
O
O
Ph
Ph
cis-7 (major)
44% de, 72% yield
Ph
6
trans-8 (minor)
Scheme 5. Memory of chirality in the electrochemical oxidation of cis-3-methylproline 6
Epimerization of cis-7 (44% de) in methanol with catalytic amount of sulfuric acid afforded a mixture of
cis-7 (minor isomer) and trans-8 (major isomer) in 17% de (Scheme 6). This implied that the initially
formed cis-7 was thermodynamically less stable and its formation was most likely achieved via memory
of chirality.8 It is on this basis of the results shown in Schemes 5 and 6 that the R-configuration of 4 was
deduced.
H+/MeOH
cis-7
trans-8
rt, 4 h
17% de
44% de
Scheme 6. Epimerization of cis-7 to trans-8 in acidic methanol
Next we synthesized and investigated α,α-dimethylprolinol 5b (Scheme 7). Electrolysis of 5b under
similar reaction conditions furnished α-methoxylated product 4 in 28% yield. The enantiomeric excess
(12% ee) albeit low was relatively better than that of 5a (7% ee) and the stereoconfiguration for the major
enantiomer was the same as that of the products derived from 5a.
-2e
OH
N
Pt electrodes
Me
Me
4
O
NaOMe (1.2 equiv)
in MeOH, at -30oC
12% ee
28% yield
Ph
5b
Scheme 7. Electrochemical oxidation of dimethylprolinol 5b
The slight improvement in the enantiomeric excess (from 7% to 12%) was ascribed to the presence of two
methyl groups, which are more bulkier than the protons for the prolinol. Furthermore, the improvement in
yield (from 14% to 28%) was attributed to the faster chemical step for the dialkylated compound 5b than
for the primary prolinol 5a due to relatively greater stability of the cationic side-product species.

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HETEROCYCLES, Vol. 79, 2009
Phenyl group are known to stabilize carbocations due to increased resonance of the cationic species. It
was envisaged that the use of compounds with aryl substituents would increase the rate of the chemical
bond fission step and thus improve the degree of enantioselectivity. In this perspective, we synthesized
N-o-phenylbenzoyl-α,α-diphenylprolinol (5c) and electrolyzed it in methanol (Scheme 8).9
-2e
Pt electrodes
N
4
+
OH
NaOMe (1.2 equiv)
in MeOH, at -30oC
O
50% ee
37% yield
O
43% yield
5c
Ph
Scheme 8. Electrochemical oxidation of N-o-phenylbenzoyl-α,α-diphenylprolinol (5c)
C-C bond fission occurred with subsequent formation of the α-methoxylated compound 4 in 37% yield
and benzophenone as the side-product in 43% yield. The enantioselectivity of 4 (50% ee) was much better
than that from prolinol derivatives 5a and 5b (7% and 12% ee, respectively, Schemes 4 and 7). The large
improvement in the enantioselectivity could be ascribed to two factors; firstly, the enhanced stability of
the [Ph2COH]+ intermediate ion, which could have improved the rate of C-C bond cleavage. Secondly,
the bulkiness of the phenyl groups could have had a significant contribution to the conformational
arrangement of the starting material especially the location of the o-phenyl group. These hypotheses were
investigated by use of para- and/or ortho-substituted derivatives.11
To test which of the above-hypothesized factors contributed more to the memory of chirality, we
investigated the effect of para- and/or ortho-substituents in the phenyl group on the ee. The results along
with temperature effect are summarized in Table 1.
Electrolysis of all these compounds 5c-i at -30 oC resulted into the cleavage of the C-C bond on the side
chain and the formation of α-methoxylated product 4 in 28-44% yield. The enantiomeric excesses
(34-42% ee) obtained for all 4 derived from the derivatives bearing substituents at the para-position
(Entries 2-4) were smaller than that of the unsubstituted compound 5c (50% ee) (Entry 1). However, the
electron donating groups (OMe, Me), which are known to stabilize carbocation, afforded slightly lower
enantioselectivities than the derivative with electron withdrawing group (CF3). This was contrary to our
expectations. We deduced from these results that the stability of the intermediate [Ar2COH]+ did not have
a direct correlation with the observed ee. To investigate the effect of ortho-substitutents on the ee,
compounds 5g-i were electrochemically oxidized to afford 4 in 56-73% ee. The o-methyl substituted
compound 5g afforded 4 in 56% ee (Entry 5), the o-methoxyl substituted derivative 5h afforded 4 in 73%
ee (Entry 6), whereas the ortho, para di-substituted compound 5i afforded 4 in 66% ee (Entry 11). These
enantiomeric excesses from ortho-substituted compounds 5g-i were higher than those from either the

HETEROCYCLES, Vol. 79, 2009
343
para-substituted compounds 5d-f or the unsubstituted compound 5c. It was deduced from those results
that the ortho substituents enhanced the enantiomeric excesses possibly due to increased bulkiness of the
o
starting material. Effect of temperature is shown in Entries 6-10. -30 C was the optimum temperature
affording the best ee value.
Table 1. Effect of para- and/or ortho-substituents and temperature on ee of 4a
R2
R1
R1
-2e
Pt electrodes
N
4
NaOMe (1.2 equiv)
in MeOH
OH
R2
O
5c-i
Ph
α-Methoxypyrrolidine 4
% ee
Reaction
temp (oC)
Entry
Substrate
R1
R2
H
Me
OMe
CF3
H
H
H
H
H
yield (%)b
1
2
3
4
5
6
7
8
5c
5d
5e
5f
5g
5h
5h
5h
5h
5h
5i
H
H
H
H
-30
-30
-30
-30
-30
-30
-40
-20
0
50
34
37
42
56
73
68
67
64
54
66
37
35
34
44
35
32
28
35
40
42
28
Me
OMe
OMe
OMe
OMe
OMe
OMe
9
10
11
H
Me
+15
-30
a 2 F/mol of electricity was passed. b Isolated yield.
For the purpose of gaining a better understanding on this C-C bond cleavage, the role of the hydroxyl
group was investigated. This was achieved by synthesis of compound 9 that did not have the hydroxyl
group and subjecting it to the same electrolysis process as discussed above. The electrochemical oxidation
of 9 in methanol cleaved the C-C bond of the side chain in a similar fashion as for the carbinols to afford
α-methoxylated product 4 (Scheme 9). Surprisingly, the enantiomeric excess, 55% ee obtained was
relatively better than that from diphenylprolinol 5c.
-2e
Ph
Ph
Pt electrodes
N
4
NaOMe (1.2 equiv)
in MeOH, at -30oC
O
55% ee
36% yield
9
Ph
Scheme 9. Electrochemical oxidation of diphenylpyrrolidine derivative 9

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HETEROCYCLES, Vol. 79, 2009
This indicated that the electrochemical oxidation of 9 proceeded via retention mechanism. That is, the
methoxyl group was introduced predominantly from the same side of the carboxyl group for the
non-Kolbe reaction of 2.3,4 Similarly, it can be deduced that the methoxylation of the prolinols 5a-i and
diphenylmethylated pyrrolidines 9 proceeded via retention mechanism to afford (R)-4 as the main product
(Scheme 10).
OMe
MeOH
N
O
syn
Ph
Ph
OH
(R)-4
75%
-2e 2 F/mol
NaOMe
N
N
O
O
Pt electrodes
MeOH, -30ºC
5c
N
O
anti
-Ph2CO
OMe
MeOH
Chiral iminium ion
(S)-4
25%
Scheme 10. Reaction mechanism for electrochemical oxidation of 5c
In conclusion, the electrochemical oxidation of N-o-phenylbenzoylated prolinols proceeded with C-C
bond cleavage to generate iminium ions that were trapped with methanol to furnish optically active
N,O-acetals. The α,α-diarylated prolinols afforded α-methoxylated product with better enantiomeric
excess (up to 73% ee). In the prolinol derivatives, the C-C bond fission and the methoxylation steps
occurred via retention mechanism as deduced from the derivatization reactions.
REFERENCES AND NOTES
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4. Y. Matsumura, T. Tanaka, G. N. Wanyoike, T. Maki, and O. Onomura, J. Electroanal. Chem., 2001,
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and J. F. Normant, J. Org. Chem., 1998, 63, 2442.
7. Strong NOESY peaks illustrated in Figure 1 were observed between 3-methyl protons and the
2-methoxyl protons. No cross peaks were observed between the methoxyl protons and the proton at
3-carbon. On the basis of this result, the stereochemistry of the major diastereomer was deduced to
be a cis configuration.
Me
H
3
H
2
OMe
N
O
cis-7
Ph
Figure 1. NOESY for major oxidation product derived from 6
8. It can not be overruled that the repulsion of 3-methyl group and N-o-phenylbenzoyl group in iminium
ion intermediate generated from 6 partially contributed the cis-methoxylation.
9. Electrochemical oxidation of 5c: A solution of serine derivative 5c (0.5 mmol) and NaOMe (0.6
mmol) in MeOH (10 mL) was put into an undivided cell equipped with platinum plate electrodes (1
cm x 2 cm), and then the solution was subjected to constant current (50 mA) electrolysis at –30°C.
After 2 F/mol of electricity was passed,10 the solvent was removed. The residue was subjected to
silica gel chromatography to give 4 (37% yield, 50% ee) as a colorless oil and benzophenone (40 %
yield). The optical purity of 4 was determined by HPLC analysis using Daicel Chiralcel OD (0.46
cmφ x 25 cm). Condition: n-hexane : 2-propanol=9 : 1; wavelength, 254 nm; flow rate 1.0 mL/min;
retention time, 6.6 min for (R)-4, 8.7 min for (S)-4.
10. Excess amount of electricity (2.5 or 3.0 F/mol) did not improve the yield and % ee of 4.
11. N-o-Phenylbenzoyl-α,α-diarylprolinol 5c-i were prepared by the Grignard reaction of N-o-phenyl-
benzoyl-L-proline methyl ester with 2.2 equiv of the corresponding arylmagnesium bromide in THF
(over 70% yields).