π-Facial selectivity in polyaniline supported cobalt catalysed aerobic epoxidation of N-cinnamoyl proline derivatives

Article abstract of DOI:10.1016/S0040-4039(00)01949-3

Polyaniline supported cobalt salen catalyses the facially selective aerobic epoxidation (oxygen/2-methylpropanal) of N-cinnamoyl proline derived peptides. A high diastereoselectivity is observed for peptides which are able to adopt a γ- or β-turn due to intramolecular hydrogen bonding.

Full text of DOI:10.1016/S0040-4039(00)01949-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 333–337
p-Facial selectivity in polyaniline supported cobalt catalysed
aerobic epoxidation of N-cinnamoyl proline derivatives
E. N. Prabhakaran, Jyoti Prokash Nandy, Shalini Shukla and Javed Iqbal*,†
Department of Chemistry, Indian Institute of Technology, Kanpur 208 016, India
Received 4 August 2000; revised 23 October 2000; accepted 2 November 2000
Abstract—Polyaniline supported cobalt salen catalyses the facially selective aerobic epoxidation (oxygen/2-methylpropanal) of
N-cinnamoyl proline derived peptides. A high diastereoselectivity is observed for peptides which are able to adopt a g- or b-turn
due to intramolecular hydrogen bonding. © 2000 Elsevier Science Ltd. All rights reserved.
We have recently shown1 that N-cinnamoyl amides 1
dissolved in dichloromethane and washed successively
with a saturated solution of sodium bicarbonate and
water. Drying and evaporation of the solvent gave a
residue which was chromatographed over silica gel to
afford the corresponding epoxides in high purity. The
purities of these epoxides were determined by chiral
HPLC to be ꢀ85–90%. The results for these epoxida-
tions are compiled in Tables 1 and 2. It is noteworthy
that these reactions are chemospecific as only the cin-
namoyl double bond is epoxidized under these conditions.
The results in Table 1 indicate that the epoxidation of
can be converted to the corresponding b-phenylisoser-
ine derivatives 3 via a tandem polyaniline supported
cobalt(II) salen catalysed aerobic epoxidation and ami-
nation protocol (Scheme 1). The intermediate cin-
namoyl epoxides 2 underwent a stereoselective SN2 type
of opening with several aromatic amines leading to a
highly selective synthesis of the anti diastereomer of the
b-phenylisoserine derivatives. In order to achieve a
chiral synthesis of these derivatives, we have attempted
a diastereoselective aerobic epoxidation of N-cin-
N-cinnamoyl
L
-proline methyl ester 1a exhibits very
namoyl L-proline derivatives and our findings are de-
poor diastereoselectivity (2a) during these epoxidations,
however, the corresponding allylic amide 1b showed
better selectivity (2b) than the former. Interestingly, the
diastereoselectivity increases for substrates having an
additional C-terminal amino acid residue in 1a. Thus
the polyaniline supported cobalt(II) salen catalysed aer-
obic epoxidation of dipeptides 1c–1e afforded the cor-
responding epoxides 2c–2e, respectively, with higher
diastereoselectivities. The ratio in favour of the major
scribed below.
Typically, N-cinnamoyl -proline containing peptides 1
L
(5 mmol) were dissolved in acetonitrile (10 mL) and the
solution was stirred in the presence of polyaniline sup-
ported cobalt(II) salen (catalyst) and 2-methylpropanal
(4 equiv.) under an oxygen balloon at ambient condi-
tions for 15–20 h. The cobalt catalyst was filtered off
and the solvent removed to give a residue, which was
Scheme 1.
* Corresponding author.
† Present address: Dr. Reddy’s Research Foundation, Bollaram Road, Miyapur, Hyderabad 500 050, India.
0040-4039/01/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01949-3

334
E. N. Prabhakaran et al. / Tetrahedron Letters 42 (2001) 333–337
Table 1. Polyaniline supported cobalt(II) salen catalysed aerobic epoxidation of N-cinnamoyl
L
-proline peptidesa
Table 2. Polyaniline supported cobalt(II) salen catalysed enantioselective aerobic epoxidation of N-cinnamoyl L-proline
containing tripeptidesa

E. N. Prabhakaran et al. / Tetrahedron Letters 42 (2001) 333–337
335
Scheme 2.
Figure 1.
pared with the peptides 1b–e as they underwent highly
selective aerobic epoxidation, leading to the corre-
sponding epoxides 2f–h in high yields (Table 2). The
ratio in favour of the major diastereomer was found to
be >85:<15 (HPLC) and they were separated by
column chromatography to afford epoxides whose pu-
rity was ꢀ90% (Chiral HPLC). The absolute stereo-
chemistry for the major diastereomer was assigned to
be 2R,3S by converting 2c (obtained by aerobic epoxi-
dation) to 2f–g using the procedure5 described earlier
and comparing these compounds. The high facial selec-
tivity in epoxidation of 1b–h may be explained by
invoking the possibility of these reactions taking place
on organized structures resulting from intramolecular
hydrogen bonding and such structures,6 known as g-
and b-turns, are invariably responsible for the sec-
ondary structures in peptides and proteins. Interest-
ingly, the tripeptides 1b–e can adopt a seven-membered
g-turn thereby forcing the cinnamoyl group to exist
with the trans, s-cis geometry (Fig. 1, 1c), as the
corresponding trans, s-trans geometry will be disfa-
voured due to non-bonding interactions. This seven-
membered g-turn will render only one face of the
cinnamoyl double bond exposed and thus epoxidation
via such organized structures will be facially selective. A
similar explanation can be offered for the high enan-
ꢀ90%. The absolute stereochemistry for the major
enantiomer of epoxides 2a–e were assigned as 2R,3S
which was established by following a correlation with
the epoxide obtained by Sharpless epoxidation.2 Thus
cinnamoyl alcohol was subjected to Sharpless’ epoxida-
tion using (+)-DET to give the enantiomerically pure
epoxide 4 which was converted to the corresponding
carboxylic acid 5 by ruthenium catalysed oxidation3 of
the primary alcohol group. The carboxylic acid 5 was
subsequently transformed to the corresponding peptide
2c by mixed anhydride coupling with the methyl ester
of L-proline-L-leucine dipeptide (Scheme 2).
The specific rotation of 2c prepared by the Sharpless
procedure (hD= −191) and by polyaniline supported
cobalt(II) salen catalysed epoxidation of 1c (hD=
−183) were similar in sign and magnitude. Also, the
proton NMR of the epoxide 2c obtained by both routes
(i.e. the Sharpless procedure and the cobalt catalysed
aerobic protocol) were identical. Thus based on this
correlation, the absolute stereochemistry of the epoxide
2c is assigned 2R,3S. A similar correlation was also
carried out for epoxides 2d and 2e.
It is noteworthy that the epoxidation of tripeptides
1f–h were found to be highly diastereoselective4 com-

336
E. N. Prabhakaran et al. / Tetrahedron Letters 42 (2001) 333–337
Scheme 3.
Scheme 4.
tioselectivity during the epoxidation of 1f–h which will
take place on well-organized b-turn conformations
(Fig. 1, 1f), which will render such epoxidations facially
selective (Fig. 1, 2f). The presence of intramolecular
hydrogen bonding7 in 1c–h has been observed by using
proton NMR studies in a mixture of CDCl3 and
DMSO-d6. The role of a g- or b-turn in promoting high
diastereoselectivity is evident from the fact that the
peptide 6 undergoes a non-diastereoselective oxidation
of the cinnamoyl double bond to afford a 1:1 mixture
of the corresponding monoepoxide 6a (Scheme 3) ow-
ing to the absence of the intramolecular hydrogen
bonding features responsible for a g- or b-turn. That
the high enantioselectivity is dictated by the b-turn is
seen during the epoxidation of the N-cinnamoyl pep-
tides 7 and 8 which,8 are constrained to have an in-
tramolecular 10-membered hydrogen bond. The
constraint present due to the aziridine and dehy-
drophenylalanine residues in 7 and 8, respectively, is
responsible for coaxing the carbonyl groups of the
cinnamoyl and the amino groups of the leucine residue
to adopt a geometry which encourages the intramolecu-
lar hydrogen bond whose presence is established7 by
proton NMR studies (Scheme 4). This intramolecular
hydrogen bonding preorganizes the cinnamoyl group to
undergo facially selective aerobic epoxidation under the
conditions described above to give predominantly one
diastereomer 7a and 8a, respectively, (95:5) as indicated
by the chiral HPLC. The absolute configuration for 7a
and 8a is assigned as 2R,3S by analogy with the epox-
ides 2f–h.
In conclusion, polyaniline supported cobalt(II) salen
catalysed reaction of N-cinnamoyl
L-proline derived
peptides in the presence of oxygen and 2-methyl-
propanal leads to a highly diastereoselective epoxida-
tion of the cinnamoyl double bond. The high facial
selectivity for these epoxidations may be explained by
assuming that the reactions are taking place on well-
organized g- or b-turns formed by the substrates.
Acknowledgements
We thank DST, New Delhi for the financial support to
this work.
References
1. For the synthesis and reaction of this catalyst, see: (a) Das,
B. C.; Iqbal, J. Tetrahedron Lett. 1997, 38, 2903. (b)
Punniyamurthy, T.; Iqbal, J. Tetrahedron Lett. 1997, 38,
4463. (c) De, A.; Basak, P.; Iqbal, J. Tetrahedron Lett.
1997, 38, 8383.

E. N. Prabhakaran et al. / Tetrahedron Letters 42 (2001) 333–337
337
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5. The absolute stereochemistry for 2d–h was correlated ac-
cording to the following protocol. The key intermediate 2c
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respective epoxypeptides by base hydrolysis and mixed
anhydride coupling with the corresponding amines/esters
of amino acids.
L
-leucinate 2c: Ru(III)Cl3·H2O (7.5 mg, 33 mM) was added
to a stirring biphasic mixture of epoxy alcohol 4 (150 mg,
1 mmol), sodium periodate (643 mg, 3 mmol) and sodium
bicarbonate (420 mg, 5 mmol) in CCl4 (2 mL), acetonitrile
(2 mL) and water (3 mL). After 42 h of stirring, additional
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h to complete the reaction. Then dichloromethane (8 mL)
was added followed by a small amount of water (until
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peated until the pH remained constant. The combined
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reaction vessel was cooled to −5°C. Isobutyl chlorofor-
mate (0.13 mL, 1 mmol) was added and stirred for 0.5
6. For b-turns see: (a) Ball, J. B.; Hughes, R. A.; Alewood, P.
L.; Andrews, P. R. Tetrahedron 1993, 49, 3467 and refer-
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Tetrahedron Lett. 1999, 40, 7987.
7. The presence of intramolecular hydrogen bonds was
proved by the standard protocol mentioned in References
6c and 6e by FT-IR and by recording the proton NMR
spectrum of 1, 7 and 8 dissolved in various concentrations
of DMSO-d6 in the CDCl3. The amide protons are gener-
ally characterized by the appearance of signal between 6
and 9 ppm. The chemical shift of the amide proton did not
change appreciably with increasing concentration of
DMSO-d6 thereby indicating the presence of an in-
tramolecular hydrogen bond in 1, 7 and 8.
min. A solution of methyl L-proline-L-leucinate hydrochlo-
ride (0.418 mg, 1.5 mmol) in DMSO (0.5 mL) was added
and the mixture stirred vigorously for 3–4 h. Removal of
solvent under vacuum yielded a residue which was taken
up in EtOAc and washed with a saturated aqueous solu-
tion of NaHCO3, water and brine. The resulting organic
layer was dried and concentrated to give a residue which
was subjected to column chromatography to yield the
required product 2c as a solid in moderate yields (31%,
mp=105–107°C). [h]2D5= −191 (CH2Cl2, c 0.002). 1H
NMR (400 MHz, CDCl3): 7.36–7.26 (m, 5H), 4.66 (m,
1H), 4.49 (m, 1H), 4.09 (s, 1H), 3.73 (s, 3H), 3.61 (s, 1H),
3.56 (m, 2H), 2.39–2.11 (m, 4H), 1.98–1.88 (m, 3H), 0.96
(m, 6H). FT-IR (CH2Cl2): 3286.2, 3063.3, 2965.3, 2872.6,
1743.5, 1648.5, 1541.7, 1449.9. Mass (m/z): 389 (M+1)+
8. The manuscript describing the synthesis and reverse turn
properties of 6, 7 and 8 will be submitted for the publica-
tion in J. Org. Chem.
.