D-Phg-L-Pro Dipeptide-derived prolinol ligands for highly enantioselective Reformatsky reactions

Article abstract of DOI:10.1016/j.tetlet.2006.01.070

Optically pure N-aminoethyl prolinol derivatives 3a-c have been prepared from the dynamic kinetic resolution of N-(α-bromo-α-phenylacetyl) proline ester 1 in asymmetric nucleophilic substitution and subsequent reduction. The peptide-derived prolinols are

Full text of DOI:10.1016/j.tetlet.2006.01.070

Tetrahedron Letters 47 (2006) 1933–1935
D-Phg-L-Pro Dipeptide-derived prolinol ligands
for highly enantioselective Reformatsky reactions
Eun-kyoung Shin, Hyun Jung Kim, Yongtai Kim, Yangmee Kim and Yong Sun Park*
Department of Chemistry and Bio/Molecular Informatics Center, Konkuk University, Seoul 143-701, Republic of Korea
Received 16 December 2005; revised 12 January 2006; accepted 16 January 2006
Available online 3 February 2006
Abstract—Optically pure N-aminoethyl prolinol derivatives 3a–c have been prepared from the dynamic kinetic resolution of N-(a-
bromo-a-phenylacetyl) proline ester 1 in asymmetric nucleophilic substitution and subsequent reduction. The peptide-derived proli-
nols are tested as chiral ligands in the asymmetric addition of Reformatsky reagent to aromatic aldehydes. Chiral ligand 3c has been
shown to be effective to produce enantioenriched b-hydroxy esters 5a–j with up to 98% ee.
ꢀ 2006 Elsevier Ltd. All rights reserved.
The enantioselective addition of Reformatsky reagents
to carbonyl compounds is one of the most synthetically
useful methods for the asymmetric preparation of b-
hydroxy esters.1,2 Although many existing chiral ligands
can induce useful level of selectivity, it is still desirable
to develop new chiral ligands for highly enantioselective
Reformatsky reaction. Peptides have recently received
much attention as sources of chiral ligands, however,
to the best of our knowledge there is no successful exam-
ple of a peptide-derived chiral ligand for asymmetric
Reformatsky reaction. Herein, as part of our research
on the development of peptide-derived chiral ligands,
we describe an efficient asymmetric synthetic method
for a new class of chiral ligands based on a D-Phg-L-
Pro dipeptide scaffold and their application to highly
enantioselective Reformatsky reactions with aromatic
aldehydes.
The methodology was used for asymmetric preparation
of chiral ligands 3a–c as shown in Scheme 1. The
Ph
Ph
BH3-THF
N
N
Ph
N
Ph
N
CO2Me
O
Ph
HO
Ph
(α
R)-2a (93%, 99:1 dr)
3a (64%, >99:1 dr)
Ph
TBAI
Ph NH
DIEA
Ph
Ph
N
Ph
NH
Ph
N
HO
N
CO2Me
O
Br
Br
TBAI
DIEA
CO2Me
αS)-1
O
OH
(
(
α
R)-2b (69%, 95:5 dr)
BH3-THF
Since a variety of b-amino alcohols derived from proline
have been reported to be effective in the enantioselective
addition of organozinc reagent,2i,3 we initially selected
phenylglycinyl proline-derived prolinol ligand as a pre-
ferred motif. The additional amino group and aromatic
groups could participate in the formation of reactive
intermediate complex and provide attractive and/or
repulsive interaction with aromatic substrates. Recently,
we have reported the dynamic kinetic resolution of
a-halo acetamides in nucleophilic substitution for asym-
metric syntheses of di-, tri- and tetrapeptide analogues.4
Ph
Ph
N
N
N
Ph
CO2Me
αR)-1
O
HO
(
OH
3b (53%, >99:1 dr)
Ph
Ph NH2
TBAI
DIEA
Ph Ph
Ph
Ph
N
BH3-THF
N
Ph
N
H
Ph
N
H
CO2Me
O
HO
3c (68%, >99:1 dr)
(αR)-2c (60%, 94:6 dr)
*
Corresponding author. Tel.: +82 2 450 3377; fax: +82 2 3436 5382;
e-mail: parkyong@konkuk.ac.kr
Scheme 1. Preparation of chiral ligands 3a–c.
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.01.070

1934
E. Shin et al. / Tetrahedron Letters 47 (2006) 1933–1935
Table 1. Asymmetric Reformatsky reactions with benzaldehyde
treatment of two diastereomeric mixtures (ca. 50:50) of
N-(a-bromo-a-phenylacetyl)-(L)-proline methyl ester 1
with a nucleophile in the presence of tetrabutylammo-
nium iodide (TBAI) and diisopropylethylamine (DIEA)
in CH2Cl2 at room temperature gave the D-Phg-L-Pro
dipeptide analogues 2a–c in 93–60% yields with 99:1–
94:6 diastereomeric ratios (dr). The epimerization at
the a-position promoted by TBAI and DIEA is suffi-
ciently fast with respect to the rate of substitution and
the (aS)-1 is the faster reacting diastereomer than
(aR)-1.5 In the asymmetric C–N bond formation, the
chiral information of L-proline is transferred to the sub-
stitution at a-bromo carbon center via dynamic kinetic
resolution in the nucleophilic substitution with the
nucleophiles. Functional diversity of N-alkyl group of
the dipeptides can be introduced through the use of var-
ious primary or secondary amine nucleophiles.6 The
subsequent reduction of 2a–c using an excess of BH3–
THF (10 equiv) in THF furnished the expected prolinols
as a mixture of two isomers. In all cases, the optically
pure b-amino alcohols 3a–c were easily isolated in
64%, 53% and 68% yields, respectively, by flash column
chromatographic separation.7 We then explored asym-
metric Reformatsky reactions as a preliminary evalua-
tion of the catalytic properties of three chiral ligands
3a–c, which have different N-alkyl amino groups.
OH
O
O
O
3a-c
THF
+
BrZn
Ph
OR
Ph
H
OR
4
5a-c
Entry
R
Ligand (PhCHO:4:ligand)a Yield (%) % eeb,c
1
2
3
4
5
6
7
8
9
t-Bu 3a (1:4:0.5)
Et 3a (1:4:0.5)
88 (5a)
68 (5b)
85 (5a)
44 (5a)
50 (5a)
38 (5a)
37 (5a)
24 (5b)
25 (5c)
2
14
0
86
98
86
92
95
97
t-Bu 3b (1:4:0.5)
t-Bu 3c (1:4:0.5)
t-Bu 3c (1:8:0.5)
t-Bu 3c (1:8:0.1)
t-Bu 3c (1:8:1.0)
Et
Me
3c (1:8:0.5)
3c (1:8:0.5)
a Molar ratio of benzaldehyde:BrZnCH2CO2R:ligand 3.
b The % ee is determined by CSP-HPLC (Chiralcel OJ-H).
c Absolute configuration of (R)-5 is assigned by the sign of optical
rotation of the isolated product.
the yield by increasing reaction time failed because more
dehydration of 5 took place. Thus the optimal condition
was identified when the reactions were carried out in
refluxing THF for 2 h with t-butyl bromoacetate.
To investigate the scope of the methodology, Reformat-
sky reactions with a variety of aromatic aldehydes were
carried out under the optimal condition, using the
1:8:0.5 molar ratio of benzaldehyde: Reformatsky
reagent 4: chiral ligand 3c, and the results are summa-
rized in Table 2. The reactions of m-methoxybenzalde-
hyde, p-methoxybenzaldehyde, p-phenylbenzaldehyde
and 2-naphthylaldehyde provided the corresponding b-
hydroxy esters 5d–f and 5j with high enantioselectivities.
However, the reactions of p-methylbenzaldehyde, p-
chlorobenzaldehyde and 1-naphthylaldehyde resulted
in slightly decreased enantioselectivities, which indicate
that the enantioselectivity depends on the substituent
of the aldehyde. At present rational explanation about
the variation of enantioselectivity with the aldehydes is
not possible due to the uncertainty on the structures of
Reformatsky reagent and transition state.
We initially used the reaction of benzaldehyde with
BrZnCH2CO2R (4) in refluxing THF as a standard con-
dition to test the effects of changing chiral ligands. The
mixture of benzaldehyde, bromoacetate and a chiral
ligand was added to previously activated zinc metal with
trimethylchlorosilane8,2d and subsequent stirring for 2 h
at reflux provided b-hydroxy esters 5a–c.9 In this preli-
minary screen of the chiral ligands 3a–c, the chiral
ligand 3c gave a promising result to give (R)-b-hydroxy
ester 5a in 44% yield and 86% ee, while the N,N-dibenz-
ylated prolinol derivative 3a and bis-amino alcohol 3b
failed to induce noticeable enantioselectivities (entries
1–4).
In order to obtain the optimized condition for the reac-
tion with chiral ligand 3c, we have examined some
experimental parameters such as solvent, molar ratio
of reactants and reaction temperature. Among the sol-
vents examined, THF was found to be the best for chiral
ligand 3c. The results in entries 5–7 suggested that the
molar ratio of benzaldehyde: Reformatsky reagent (4):
chiral ligand (3c) was important. When a 1:8:0.5 ratio,
rather than a 1:4:0.5 ratio was used, the enantioselectiv-
ity was improved (98% ee, entry 5). As shown in entries
6 and 7, the use of 0.1 and 1.0 equiv of chiral ligand
resulted in a decrease in the enantioselectivity (86% ee
and 92% ee, respectively). Utilization of ethyl bromo-
acetate and methyl bromoacetate instead of t-butyl
bromoacetate gave 5b and 5c in lower yields with com-
parable enantioselectivities (entries 8 and 9). Lowering
the reaction temperature to 45 ꢁC abated enantioselec-
tivity and the reactions below 30 ꢁC did not produce
b-hydroxy esters 5. It should be noted that in most reac-
tions with chiral ligand 3c shown in Table 1, the reaction
in THF at reflux caused dehydration of 5 to form cinna-
mates in 10–30% isolated yields. Attempts to improve
Table 2. Asymmetric Reformatsky reactions with various aldehydes
OH
O
O
O
3c
+
BrZn
Ar
Ot-Bu
Ot-Bu
Ar
H
THF
5d-j
Entrya
Ar
Yield (%)
% eeb
1
2
3
4
5
6
7
m-MeO–Ph
p-MeO–Ph
p-Ph–Ph
p-CH3–Ph
p-Cl–Ph
55 (5d)
32 (5e)
45 (5f)
70 (5g)
32 (5h)
41 (5i)
49 (5j)
96
98
98
80
81
89
96
1-Naphthyl
2-Naphthyl
a All reactions were carried out in refluxing THF for 2 h with a 1:8:0.5
molar ratio of benzaldehyde:BrZnCH2CO2R:ligand.
b The % ee is determined by CSP-HPLC (Chiralcel OJ-H).

E. Shin et al. / Tetrahedron Letters 47 (2006) 1933–1935
1935
(d) Nam, J.; Chang, J.-y.; Hahm, K.-S.; Park, Y. S.
Tetrahedron Lett. 2003, 44, 7727.
In summary, we have developed dipeptide-derived chiral
ligand 3c which is effective in asymmetric Reformatsky
reaction with various aromatic aldehydes.10 Some of
the enantioselectivities are, to the best of our knowledge,
higher than the best record which has been attained.1,2
Importantly, after the reaction was completed, the chiral
ligand could be easily separated from the adduct by sim-
ple extractive work-up and silicagel chromatography.
While the effective chiral ligand was found in this work,
the structures of the zinc complex and transition state
are still unclear. Further studies to clarify them as well
as to use them in other asymmetric catalytic reactions
are currently in progress in our laboratory.
5. It has been proposed by several examples that the
epimerization can be promoted by a base via keto-enol
tautomerization and/or a halide ion via nucleophilic
displacement. For a review, see: (a) Kim, H. J.; Shin,
E.-k.; Chang, J.-y.; Kim, Y.; Park, Y. S. Tetrahedron Lett.
2005, 46, 4115; (b) Valenrod, Y.; Myung, J.; Ben, R. N.
Tetrahedron Lett. 2004, 45, 2545; (c) Nam, J.; Lee, S.-k.;
Park, Y. S. Tetrahedron 2003, 59, 2397; (d) Nam, J.; Lee,
S.-k.; Kim, K. Y.; Park, Y. S. Tetrahedron Lett. 2002, 43,
8253; (e) Lee, S.-k.; Nam, J.; Park, Y. S. Synlett 2002, 790;
(f) Caddick, S.; Afonso, C. A. M.; Candeias, S. X.;
Hitchcock, P. B.; Jenkins, K.; Murtagh, L.; Pardoe, D.;
Santos, A. G.; Treweeke, N. R.; Weaving, R. Tetrahedron
2001, 57, 6589; (g) Lee, S.-k.; Lee, S. Y.; Park, Y. S.
Synlett 2001, 1941; (h) Ben, R. N.; Durst, T. J. Org. Chem.
1999, 64, 7700; (i) Kubo, A.; Kubota, H.; Takahashi, M.;
Nunami, K. J. Org. Chem. 1997, 62, 5830; (j) Ward, R. S.;
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Acknowledgements
This paper was supported by a Grant from Molecular &
Cellular BioDiscovery Research Program (M1-0311-13-
0003) from the Ministry of Science and Technology,
Korea and Korea Research Foundation (KRF-2004-
F00019).
6. Reactions of 1 with cyclic secondary amines such as
pyrrolidine, piperidine, morpholine and 1,2,3,4-tetra-
hydroisoquinoline gave the substituted products with
low selectivities (74:26–67:33 dr). Unpublished results.
1
7. Optical purities of 3a–c were evaluated by H NMR and
References and notes
confirmed by CSP-HPLC. Absolute configurations of
a-position of 3a and 3c were assigned to be (R) by
comparison to the 1H NMR of authentic epimers prepared
from reduction of N-diphenylmethylene-D-Phg-L-Pro ester
and N,N-dibenzyl D-Phg-L-Pro ester, respectively. That
of 3b was assigned by analogy to the formation of 3a and
3c.
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¨
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9. General procedure for asymmetric Reformatsky reactions:
Trimethylchloro-silane (0.1 equiv) was added to a suspen-
sion of zinc metal (8.0 equiv) in anhydrous THF (2 ml).
After the mixture was refluxed for 30 min, the heating was
stopped, and a solution of ligand (0.5 equiv), t-butyl
bromoacetate (8.0 equiv) and aromatic aldehyde
(0.5 mmol, 1.0 equiv) in THF (2 ml) was slowly added.
The mixture was stirred at reflux for 2 h and then
quenched at 0 ꢁC with 10% HCl solution. The resulting
mixture was extracted with methylene chloride (3 · 5 ml)
and the combined extracts were washed with saturated
aqueous sodium bicarbonate solution and brine. The
solvents were removed under reduced pressure and the
residue purified by flash column chromatography to give 5
(32–70% yield) and 3c (50–75% recovery). The enantiose-
lectivities of 5b–j were determined by HPLC using
Chiralcel OJ-H column (0.5 ml/min, 2% 2-propanol/hex-
ane). For better chromatographic separation in CSP-
HPLC analysis, t-butyl ester 5a was converted to methyl
ester 5c.
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10. By employing the L-Phg-L-Pro dipeptide-derived diaste-
reomeric prolinol ligand of 3c, the product (R)-5a was
formed with 68% ee. Also, reactions of some aliphatic
aldehydes in the presence of 3c gave lower selectivities and
yields under the same reaction condition.
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