Discovery of dipeptide-derived catalysts for the enantioselective addition of dimethylzinc to aldehydes

Article abstract of DOI:10.1002/ejoc.201200063

A new class of modular chiral catalysts derived from various amino acid-L-Pro dipeptides was prepared, and the catalysts were tested for their ability to catalyze the enantioselective addition of dimethylzinc to aromatic aldehydes. Dipeptides derived from L-Asp-L-Pro were identified as effective catalysts for the addition at room temperature with up to 97:3er and 95% yield.

Full text of DOI:10.1002/ejoc.201200063

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201200063
Discovery of Dipeptide-Derived Catalysts for the Enantioselective Addition of
Dimethylzinc to Aldehydes
Seock Yong Kang[a] and Yong Sun Park*[a]
Keywords: Enantioselectivity / Asymmetric catalysis / Chirality / Amino acids / Peptides
A new class of modular chiral catalysts derived from various
amino acid- -Pro dipeptides was prepared, and the catalysts
derived from L-Asp-L-Pro were identified as effective cata-
lysts for the addition at room temperature with up to 97:3er
L
were tested for their ability to catalyze the enantioselective
addition of dimethylzinc to aromatic aldehydes. Dipeptides
and 95% yield.
of dimethylzinc to aromatic aldehydes with amino acid (aa)-
l-Pro dipeptide-based catalysts, whose general structure is
illustrated in Figure 1. Three subunits within the dipeptide
catalyst have been modified to investigate their influence on
the enantioselectivity of the catalyzed reactions: the alkyl
group on the N-terminus (R1), the alkyl group on the C-
terminal ester (R2), and the amino acid side chain (R3).
Introduction
Highly efficient chiral catalysts are often discovered by a
stepwise, iterative process of structural modification. There-
fore, a modular system comprising simple components is
essential for the design of chiral catalysts. An ideal modular
catalyst would be inexpensive and straightforward to syn-
thesize and incorporate several sites of diversity. In this re-
gard, a dipeptide catalyst is particularly attractive, as it can
be prepared on a large scale by a short and simple route
and easily modified by variations in the identity of two α-
amino acid constituents. Dipeptide-based catalysts are
making promising contributions to various asymmetric re-
actions in organometallic chemistry. Notable successes in-
clude cyclopropanation,[1a] alkylation of imines,[1b] vinyl-
ation of aldehydes,[1c] and the Strecker reaction.[1d]
Catalytic asymmetric addition of dialkylzinc to aldehydes
is one of the most important reactions involving carbon–
carbon bond formation. To date, a large number of cata-
lysts has been developed for the preparation of chiral sec-
ondary alcohols with high enantioselectivity.[2] Most of the
effective catalysts are based upon amino alcohol,[3] diol,[4]
and diamine[5] derivatives. To the best of our knowledge,
there have been no successful reports on peptide-based cat-
alysts for the addition of dialkylzinc reagents to alde-
hydes.[6]
Figure 1. General structure of aa-l-Pro dipeptide catalysts.
Results and Discussion
We initiated our studies by examining the ability of the
dipeptide d-Phg-l-Pro to act as a catalyst in the addition
of dimethylzinc to aldehydes. First of all, the effect of N-
alkyl substituents (R1) on the enantioselectivity of the ad-
dition was examined with five d-Phg-l-Pro dipeptides 1–5.
The dipeptides were prepared by using the methodology
which we have developed for the asymmetric synthesis of
peptide derivatives as shown in Scheme 1.[8] Treatment of
two diastereomeric mixtures (1:1) of N-(α-bromo-α-phen-
ylacetyl)-l-proline methyl ester with an amine nucleophile
in the presence of tetrabutylammonium iodide (TBAI) and
diisopropylethylamine (DIEA) gave d-Phg-l-Pro dipeptides
1–5. The stereoselective nucleophilic substitutions with di-
phenylmethylamine, N-methylbenzylamine, piperidine, N-
benzylphenethylamine, and dibenzylamine gave dipeptides
1–5 with diastereomeric ratios of 95:5, 85:15, 91:9, 99:1, and
99:1, respectively. In all cases, the diastereomerically pure
N-alkyl-substituted d-Phg-l-Pro-OMe derivatives 1–5 were
isolated in 91–61% yield by flash column chromatographic
separation. The functional diversity of the amino moiety was
introduced through the use of various amine nucleophiles.
Enantioselective addition of dimethylzinc to aldehydes
has attracted much less attention than diethylzinc additions
because of its lower reactivity.[7] However, the development
of an efficient method for the asymmetric addition of di-
methylzinc is still a highly desirable goal in asymmetric syn-
thesis. In this paper, we disclose enantioselective additions
[a] Department of Chemistry, Konkuk University
1 Hwayangdong, Seoul 143-701, South Korea
Fax: +82-2-3436-5382
E-mail: parkyong@konkuk.ac.kr
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201200063.
Eur. J. Org. Chem. 2012, 1703–1706
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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S. Y. Kang, Y. S. Park
SHORT COMMUNICATION
Table 1. Effects of the R1 and R2 groups.[a]
Scheme 1. Preparation of dipeptide catalysts 1–5.
Entry R1
R2
Catalyst Yield
er[b]
(S/R)[c]
We then explored the asymmetric addition of dimeth-
ylzinc to 4-chlorobenzaldehyde as a preliminary evaluation
of the catalytic properties of N-alkyl-substituted dipeptides
1–5 as shown in Table 1. Reactions were performed with
4 equiv. of dimethylzinc in toluene and 10 mol-% of the cat-
alyst at room temperature for 48 h. When 4-chlorobenzalde-
hyde was added to the mixture of dimethylzinc and dipept-
ide 1, 1-(4-chlorophenyl)-1-ethanol was obtained with poor
selectivity and yield. (Table 1, Entry 1) Also, the reaction of
N-benzyl-N-methyl-substituted tertiary amine catalyst 2 did
not provide the improved enantioselectivity (Table 1, En-
try 2). However, initial investigations with tertiary amine
catalyst 2 proved promising, as the aldehyde was completely
consumed, and after workup, the product was isolated in a
satisfactory yield despite the low reactivity of dimethylzinc.
In the reaction with cyclic amine catalyst 3, an enantiomeric
ratio of 71:29 was observed to provide (R)-enantiomer as a
[%]
1
2
3
Ph2CH, H
PhCH2, CH3
–(CH2)5–
Me
Me
Me
1
2
35
85
81
84
85
80
77
88
85
85
10
90
53:47
47:53
29:71
69:31
88:12
88:12
88:12
81:19
74:26
44:56
74:26
82:18
3
4
5
6
7
8
9
10
11[d]
12[e]
PhCH2, PhCH2CH2 Me
4
PhCH2, PhCH2
PhCH2, PhCH2
PhCH2, PhCH2
PhCH2, PhCH2
PhCH2, PhCH2
PhCH2, PhCH2
PhCH2, PhCH2
PhCH2, PhCH2
Me
Et
Bn
nPr
iPr
tBu
Me
Me
5
6
7
8
9
10
5
5
[a] Reactions run for 48 h. [b] Determined by CSP-HPLC (Chi-
ralcel OB-H). [c] Absolute configuration assigned by comparison
with known elution order according to ref.[7] [d] Reaction carried
out at 0 °C. [e] Reaction carried out at 40 °C.
major product. (Table 1, Entry 3) When N-benzyl-N-phen- Increasing the temperature to 40 °C resulted in a modest
ethyl-substituted catalyst 4 was subjected to the same reac- decrease in enantioselectivity with a slightly higher yield
tion conditions, a curious result was obtained. Catalyst 4 (Table 1, Entry 12).
led to a reversal in the configuration of the product to af-
In the next stage of catalyst optimization, we examined
ford the (S)-enantiomer as a major product with an how the amino acid side chain (R3) of the dipeptide affected
enantioselectivity of 69:31er (Table 1, Entry 4). Pleasingly, the stereoselectivity of the addition reaction while the R1
N,N-dibenzylated catalyst 5 was found to be more effective and R2 groups were held constant as dibenzyl and methyl,
to give the (S)-enantiomer in 85% yield with 88:12er respectively[9] (Table 2). When d-Phg of 5 was changed into
(Table 1, Entry 5). The brief survey of N-substituents (R1) d-Phe or d-Ala, lower selectivities were observed in both
indicates that subtle N-alkyl group modifications can lead reactions with catalysts 11 and 12 (Table 2, Entries 1 and
to substantial variations in enantioselection. The N,N-di- 2). We then examined Gly-l-Pro catalyst 13 to investigate
benzylamino group appears to function cooperatively with the effect of the chiral center at the α-position of the N-
the catalytic core structure of d-Phg-l-Pro and appears to terminal amino acid. Interestingly, no stereoselectivity was
be appropriate for high enantioselectivity.
noted for the addition with Gly-derived catalyst 13 (Table 2,
In addition, the alkyl group (R2) of the ester was varied Entry 3). Also, we replaced the N-terminal amino acid with
while the R1 position was held constant as N-benzyl substit- the amino acid of opposite chirality. Both catalysts 14 and
uents (Table 1, Entries 6–10). No substantial difference was 15 derived from l-Phe or l-Ala gave the major product of
found in the reactions of ethyl ester 6 and benzyl ester 7, same absolute configuration (S) as in the reactions with d-
whereas lower enantioselectivities were noted for the reac- aa-l-Pro catalysts (Table 2, Entries 4 and 5). The results
tions of propyl esters 8 and 9 (Table 1, Entries 6–9). Some- tend to indicate that the presence of the chiral center at the
what surprisingly, the larger steric bulk of tBu ester 10 re- α-position of the N-terminal amino acid is essential for high
sulted in much lower enantioselectivity (Table 1, Entry 10). asymmetric induction, but the absolute configuration of the
The observations suggest that the steric bulk of the C-ter- product is mainly dominated by l-Pro, the C-terminal
minal ester is an important factor in determining enantio- amino acid. Notably, better enantioselectivities were ob-
selectivity. It is worth mentioning that N,N-dialkylated cata- served in the reactions with both l-aa-l-Pro catalysts 14
lysts 2–10 do not have an O–H or N–H bond, which is and 15 compared with d-aa-l-Pro catalysts 11 and 12
known to be critical for the efficient chelation of zinc in the (Table 2, Entries 4 and 5).
highly enantioselective reactions with amino alcohol, diol,
Encouraged by the high enantioselectivity with l-Ala-l-
and diamine based chiral catalysts.[2–4] Also, the reactivity Pro catalyst 15, we carried out a series of reactions with
and stereoselectivity were sensitive to temperature. Lower- several different l-aa-l-Pro catalysts. With dipeptide cata-
ing the temperature of the reaction with catalyst 5 from lysts 16–20 derived from l-Trp, l-Cys(SBn), l-Glu(OBn), l-
room temperature to 0 °C resulted in a significant decrease Leu, and l-Ser(OBn) amino acids, the reactions showed
in both reactivity and enantioselectivity (Table 1, Entry 11). lower stereoselectivities compared to the reaction with l-
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Dipeptide-Derived Catalysts for the Addition of Dimethylzinc to Aldehydes
Table 2. Effect of the R3 group.[a]
Table 3. Reactions of various aldehydes with l-Asp-l-Pro dipept-
ides.[a]
Entry R3
Catalyst
Yield
[%]
er[b]
(S/R)[c]
1
2
3
4
5
6
7
8
CH2Ph (R)
CH3 (R)
H
CH2Ph (S)
CH3 (S)
CH2(3-indole) 16 (l-Trp-l-Pro)
CH2SBn
CH2CH2CO2Bn 18 [l-Glu(OBn)-l-Pro]
CH2CH(CH3)2 19 (l-Leu-l-Pro)
CH2OBn
11 (d-Phe-l-Pro)
12 (d-Ala-l-Pro)
13 (Gly-l-Pro)
14 (l-Phe-l-Pro)
15 (l-Ala-l-Pro)
79
81
82
70
72
3
81:19
80:20
51:49
83:17
92:8
56:44
74:26
82:18
86:14
90:10
94:6
17 [l-Cys(SBn)-l-Pro]
8
89
73
95
90
95
9
10
11
12
20 [l-Ser(OBn)-l-Pro]
21 [l-Asp(OBn)-l-Pro]
22 [l-Asp(OMe)-l-Pro]
CH2CO2Bn
CH2CO2Me
94:6
[a] Reactions run for 48 h. [b] Determined by CSP-HPLC (Chi-
ralcel OB-H). [c] Absolute configuration assigned by comparison
with known elution order according to ref.[7]
Ala-l-Pro catalyst 15 (Table 2, Entries 6–10). Particularly,
much lower stereoselectivity and reactivity were observed
with l-Trp-l-Pro catalyst 16 and l-Cys-l-Pro catalyst 17
(Table 2, Entries 6 and 7). In this series of catalysts, the ste-
ric factors of the side chain do not appear to play a domi-
nant role in determining enantioselectivity. We were very
pleased to observe that l-Asp(OBn)-l-Pro catalyst 21 and
l-Asp(OMe)-l-Pro catalyst 22 gave the best result to pro-
duce (S)-ethanol with 94:6er (Table 2, Entries 11 and 12).
N,N-Dibenzyl-l-Asp(OBn)-l-Pro catalyst 21, which gave
the highest stereoselectivity for the addition of dimethylzinc
to 4-chlorobenzaldehyde was then used to explore the scope
of the addition reaction with aromatic aldehydes, and the
results are summarized in Table 3. Among the reactions of
4-substituted benzaldehydes, high stereoselectivities were
observed in the reactions with 4-fluoro-, 4-bromo-, and 4-
cyano-substituted benzaldehydes, whereas mild drops in
stereoselectivity were seen with 4-trifluoromethyl-, 4-nitro-,
and 4-methyl-substituted benzaldehydes (Table 3, Entries 1–
6). Also, the reactions of 1-naphthaldehyde, 2-naphth-
aldehyde, and 3-bromobenzaldehyde gave comparable enan-
tiomeric ratios of 94:6 and 92:8 with a lower level of reactiv-
ity (Table 3, Entries 7–9).
In an effort to improve asymmetric induction, we have
attempted to modify the catalytic properties of 21 by intro-
ducing 3,5-substituents into the phenyl ring of the N-benzyl
group (Table 3, Entries 10–29). Catalysts 23–25 with sub-
stituents such as methyl, methoxy, and tert-butyl generally
gave higher enantioselectivities when compared to those ob-
tained with catalyst 21, regardless of the electronic charac-
[a] Reactions run for 48 h. [b] Determined by CSP-HPLC (Chi-
ralcel OB-H or Chiralcel OJ-H). [c] Absolute configuration as-
signed by comparison with known elution order according to ref.[7]
[d] A catalyst loading of 5 mol-% was used.
ter of the aldehydes. The highest enantioselectivity was ob- tries 16 and 22). It was also found that the catalyst loading
served in the reactions of 4-bromobenzaldehyde with cata- could be decreased to 5 mol-% while still maintaining the
lyst 24 and 4-chlorobenzaldehyde with catalyst 25 to give asymmetric induction in the products with good yields
the corresponding (S)-alcohols with 97:3er (Table 3, En- (Table 3, Entries 11, 15, 16, and 24).
Eur. J. Org. Chem. 2012, 1703–1706
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S. Y. Kang, Y. S. Park
SHORT COMMUNICATION
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Conclusions
We have developed a new class of dipeptide catalysts for
the enantioselective addition of dimethylzinc to aromatic
aldehydes. Three subunits within aa-l-Pro dipeptide were
varied to increase the enantioselectivity and the optimiza-
tion led us to identify l-Asp-l-Pro dipeptides 21–25 as ef-
fective catalysts for the addition. The simple modular struc-
ture in combination with the ready availability of l-amino
acids renders the dipeptide catalysts highly attractive. This
work paves the way for the synthesis and evaluation of
larger libraries of dipeptide catalysts for reactions involving
alkylzinc, as well as other organometallic reagents. Further
studies on the improvement of enantioselectivity and on the
structure of the zinc–dipeptide complex are now in progress.
[4]
[5]
Experimental Section
General Procedure: Dimethylzinc (2 m in toluene, 4.0 equiv.) was
added to a solution of the dipeptide catalyst (0.1 or 0.05 equiv.)
and aldehyde (1.0 equiv.) in toluene at 0 °C. The homogeneous
solution was stirred at room temperature for 48 h. The reaction was
quenched by the addition of 1 m HCl, and the solution was ex-
tracted with CHCl3. The combined organic extracts were dried with
anhydrous MgSO4, filtered, and concentrated in vacuo. Chromato-
graphic separation on silica gel (hexane/EtOAc) afforded the en-
antioenriched ethanols in 95–93% yield, and the enantioselectivity
of the products was measured by HPLC with chiral columns by
using racemic material as a standard.
[6]
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including copies of the H NMR and 13C NMR spectra.
1
Acknowledgments
This work was supported by a grant from the Korea Research
Foundation (2009–0089650) and the Seoul R&BD Program
(WR090671).
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[9] Catalysts 11–25 shown in Tables 2 and 3 were prepared by the
coupling of N-Boc-aa-OH and l-Pro-OMe and following N,N-
dibenzylation with the corresponding benzyl bromide. See the
Supporting Information for details.
Received: January 18, 2012
Published Online: Februars 21, 2012
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Eur. J. Org. Chem. 2012, 1703–1706