Amino acid-peptide-catalyzed enantioselective Morita-Baylis-Hillman reactions

Article abstract of DOI:10.1016/j.tet.2006.05.005

Peptide-based catalysts in the presence of proline as co-catalyst have been found to catalyze the enantioselective ketone-based Morita-Baylis-Hillman reaction. The co-catalyst combination has afforded catalysis where enantioselectivities of up to 81% have

Full text of DOI:10.1016/j.tet.2006.05.005

Tetrahedron 62 (2006) 11450–11459
Amino acid-peptide-catalyzed enantioselective
Morita–Baylis–Hillman reactions
*
Melissa M. Vasbinder, Jason E. Imbriglio and Scott J. Miller
Department of Chemistry, Merkert Chemistry Center, Boston College, Chestnut Hill, MA 02467-3860, USA
Received 1 March 2006; revised 2 May 2006; accepted 4 May 2006
Available online 30 May 2006
This article is dedicated to Professor David W. C. MacMillan on the occasion of his receiving the Tetrahedron Young Investigator Award
Abstract—Peptide-based catalysts in the presence of proline as co-catalyst have been found to catalyze the enantioselective ketone-based
Morita–Baylis–Hillman reaction. The co-catalyst combination has afforded catalysis where enantioselectivities of up to 81% have been
obtained.
Ó 2006 Elsevier Ltd. All rights reserved.
O
OH O
O
1
. Introduction
Nucleophile
(Nu)
(
1)
+
R
R
R1
R
R1
H
Our laboratory has been investigating peptide-based nucleo-
philes and bases that enable a number of new enantio-
selective processes, including catalytic asymmetric group
O
O
H
1
2
3
transfers (acylation, phosphorylation, sulfinylation ), azi-
Nu
O
R1
R
4
5
dation, and carbon–carbon bond-forming reactions. Due
to the diversity of function and structure that peptides
provide, we sought to extend the scope of these catalysts
Nu
6
5
d
to the enantioselective Morita–Baylis–Hillman reaction.
The Morita–Baylis–Hillman (MBH) reaction is a powerful
carbon–carbon bond-forming reaction whose multi-step
mechanism allows numerous possibilities for catalyst inter-
2. Results and discussion
7
vention (Eq. 1). There have been many recent contributions
to the enantioselective MBH reaction. Hatakeyama and
8
We embarked upon studying the ketone-based Morita–
Baylis–Hillman reaction by first screening a variety of
substrates, including aldehydes and activated alkenes using
N-methyl imidazole (NMI) as catalyst. In analogy to Shi
and co-workers, we likewise were interested in determining
whether NMI would serve as a catalyst in the MVK-Morita–
Baylis–Hillman reaction. We reasoned if imidazole could
catalyze the MBH reaction in the presence of L-proline,
then NMI should also serve as a catalyst. Indeed, initial
experiments demonstrated that NMI could catalyze the
Morita–Baylis–Hillman reaction of MVK and 4-nitrobenz-
aldehyde (Fig. 1a), although only affording 40% conversion
after 24 h. Using only proline as a catalyst afforded no reac-
co-workers have developed cinchona alkaloid-based chiral
nucleophiles for the acrylate ester-based MBH reaction in
excellent enantioselectivities. In addition, Shi and Jiang
9
have reported the Hatakeyama’s cinchona alkaloid catalyst,
in the presence of proline as a co-catalyst, affords up to 31%
ee for the methyl vinyl ketone (MVK)-based MBH reac-
1
0
tion. In an important control study, Shi and co-workers
had shown that the co-catalyst system of proline and imida-
zole was effective for the production of MBH products,
1
1
albeit with minimal ee.
1
2
tion in the same time frame. However, the combination of
proline and NMI (10 mol % each) led to a near doubling of
rate, yielding 75% conversion to the desired Morita–Baylis–
Hillman product within 24 h (Fig. 1c). Interestingly,
MBH product 1 was generated with <10% ee, implying
that the chirality of L-proline did not lead to substantial ee
in this case.
Abbreviations: Chg, a-cyclohexylglycine; Cha, 3-cyclohexylalanine; Phe,
phenylalanine; Ala, alanine; Leu, leucine; Pro, proline; Trp(Boc), Boc pro-
2
tected tryptophan; HPhe, homophenylalanine; Arg(Boc) , di-Boc protected
arginine; Gln(Trt), trityl protected glutamine; Pip, pipecolinic acid.
*
Corresponding author. Tel.: +1 617 552 3620; fax: +1 617 552 2473;
e-mail: scott.miller.1@bc.edu
0
040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.05.005

M. M. Vasbinder et al. / Tetrahedron 62 (2006) 11450–11459
11451
OH
O
Ph
O
O
O
H
10 mol % Catalyst
Me
O Me
Me
O
O
O
+
Me
b)
H
N
H
N
BOCHN
CHCl3
O N
N
H
N
H
OMe
O N
2
2
24 h
1
Ph
N
N
a)
c)
t-BuO
O
Me
Me
Me
N
CO2H
N
CO H
2
+
2
N
H
N
H
N
N
17% ee
4
0% conv
No Reaction
75% conv <10% ee
BOC
O
N
Figure 1. MBH reaction of 4-nitrobenzaldehyde and MVK in the presence
of (a) NMI as catalyst, (b) Proline (Pro) as catalyst, and (c) co-catalyst
combination of NMI and Pro.
O Me
O
Me
H
N
H
N
BOCHN
N
H
N
H
OMe
O
O
Me
N
N
Optimistic that replacing NMI with p-(methyl)histidine
Pmh)-containing peptides could afford an enantioselective
Me
(
reaction, we set out to screen peptide catalysts in the
MVK-MBH reaction. We began screening libraries of pep-
tides, which were available in our laboratory. These libraries
consisted of tetrapeptides and octapeptides, which were
3
1
7% ee
Ph
O
O Me Me H
O
O
H
N
1
3
BOCHN
N
N
biased toward b-hairpin scaffolds, as well as pentapeptides,
which were unbiased. The pentapeptides consisted of
sequences, which contained Pmh at the i-position and at
the i+4-position either an alanine or phenylalanine. Positions
i+1 through i+3 were random sequences of 16 different
N
H
OMe
H
O
Me
N
N
Me
4
1
4
amino acids.
1
9% ee
A selectivity profile from this initial catalyst screen of 105
peptides revealed a number of interesting trends. Of the
peptide catalysts screened, peptides, which provided up to
Figure 3. Selective pentapeptides which contain similar sequences.
1
5
21% ee for the reaction of 4-nitrobenzaldehyde and MVK
in the presence of proline were identified (Fig. 2).
Boc-Pmh at the i-position and Aib (a-aminoisobutyric
acid) at the i+1-position, followed by the rest of the peptide
sequence (Fig. 3).
1
6
Examining peptide catalysts which afforded 17–21% ee in
the initial peptide screen offered useful comparisons. Three
of the most active peptides screened showed homology
within the peptide framework. Peptides 2–4 contained
Based on the trends apparent within the peptide sequences of
catalysts 2–4, we speculated that the information embedded
within the residues of these peptides would lead to an im-
proved peptide catalyst. Thus, we began exploring the struc-
ture–activity relationship (SAR) of each position of peptides
O
OH
*
O
17
O
3 and 4. Capitalizing on the Boc-Pmh-Aib sequence spe-
H
10 mol % peptide
Me
cificity at the N-terminus of the peptide, we made single
point mutations on the peptide. We immediately discovered
upon synthesizing modified catalysts that different peptide
sequences could lead to higher ee, including 57% ee in the
reaction of 2-nitrobenzaldehyde with MVK in the presence
+
Me
10 mol % L-Proline
O N
2
O N
2
CHCl3
up to 21% ee
16 h
1
8
of proline (Fig. 4). (At this stage, we began a parallel
screen of both the 2- and 4-substituted nitrobenzaldehyde
substrates.) Peptide 6, with Cha at the i+2-position, yields
25
20
15
10
5
0
2
1% ee
21% ee
21% ee
57% ee in the MBH product; peptide 5 resulted in 45% ee.
Stereochemical modifications within the peptide sequence
also proved to have a significant effect on the enantioselec-
tivity. For example, peptide 7, with D-Ala at the i+2-position,
delivers reduced selectivity (23% ee).
We were also curious whether increasing the peptide chain
length would perturb selectivity. To this end, we synthesized
peptides of variable chain length. Hexamers 8 and 9 led to
increased enantioselectivity (Fig. 4, peptide 8, 47% ee and
peptide 9, 49% ee; cf. peptide 5, 45% ee).
1
105
peptides
At this stage, we had observed that both residue identity and
chainlengthweredeterminantsofreactionenantioselectivity.
Figure 2. Initial screen of peptide catalysts in the MVK-MBH reaction.

11452
M. M. Vasbinder et al. / Tetrahedron 62 (2006) 11450–11459
O Me
O
Ri+3
O
Ri+5
NO2 OH
O
Me
O
NO2
O
O
H
N
H
N
BOCHN
OMe
peptide (10 mol %)
L-proline (10 mol %)
toluene/CDCl3
N
H
N
H
N
H
Me
H
+
Me
R
O
R
O
i+2
i+4
N
N
Me
16 h
Peptide
Ri+2
Chg
Ri+3
Phe
Ri+4
Ri+5
-
%ee
Ph
O
R
O
Ri+3
O
R
H
N
H
N
5
D-Phe
45
57
23
BOCHN
N
H
N
H
N
H
CO Me
2
O
R
i+2
O
R
i+4
6
7
Cha
Phe
Phe
D-Phe
D-Phe
-
-
N
N
Me
D-Ala
8
9
Chg
Chg
Phe
Phe
D-Phe
D-Phe
D-Phe
Phe
47
49
Ph
O Me
O
O
Me
O
H
H
BOCHN
N
N
OMe
N
H
N
H
N
Figure 4. Preliminary SAR based on hit pentapeptide sequences.
H
O
O
Ph
N
N
Therefore, we sought a method to rapidly screen the
catalysts. A more combinatorial approach to the synthesis
of new peptides was desired. A 42-membered directed
library of hexapeptides was synthesized based on peptides
and 9. The focused library incorporated 20 unique amino
acids into the i+1 through i+4 positions of the hexamer
Me
10
60% ee
1
9
2
0
8
O
NHTrt
2
1
Ph
O
sequence. The amino acids that were used are listed in
the abbreviations on the first page of the article.
O Me
O
O
Me
O
H
N
H
N
BOCHN
OMe
N
H
N
H
N
H
O
The 42 peptides, which were synthesized in the library were
then screened in the MBH reaction. The peptide selectivities
ranged from 25 to 61% ee in the reaction of 2-nitrobenz-
aldehyde and MVK in the presence of L-proline and peptide
catalyst (10 mol % each) at room temperature. Peptides 10
and 11 indeed provided a boost in enantioselectivity, with
catalyst 10 affording 60% ee and peptide 11 yielding
MBH product in 61% ee (Fig. 5).
Ph
N
N
Me
11
61% ee
Figure 5. Directed library design for the synthesis of 42 new hexapeptides.
Table 1. Catalyst screen for the MVK-MBH reaction with 2-nitrobenzalde-
hyde
a
At this stage, we wondered whether further extension of the
peptide chain would continue to afford more selective cata-
lysts. Because peptide 11 had afforded the highest level of
selectivity in the MBH reaction, we took this sequence and
Entry
Catalyst
%
ee
b
1
2
3
4
5
6
7
Boc-Pmh-OMe (12)
Boc-Pmh-Aib-OMe (13)
Boc-Pmh-Aib-Phe-OMe (14)
Boc-Pmh-Aib-Phe-D-Phe-OMe (15)
Boc-Pmh-Aib-Cha-hPhe-D-Phe-OMe (16)
Boc-Pmh-Aib-Chg-Gln(Trt)-D-Phe-Phe-OMe (11)
Boc-Pmh-Aib-Chg-Gln(Trt)-D-Phe-(Boc)Trp-
Phe-OMe (17)
19
33
33
40
47
61
73
2
2
continued to optimize in an iterative manner. Representa-
tive amino acids were evaluated at the i+5, i+6, and i+7
positions. While aliphatic, aromatic, branched aliphatic,
and other amino acids were inserted at each position, it is
important to note that at no position was a comprehensive
set of residues explored. Thus, we remain uncertain as to
whether the optimum sequence has been discovered. Never-
theless, our observations indicated that heptameric and octa-
meric sequences appeared to increase the enantioselectivity
of the reaction. However, upon reaching the decapeptide
O
NHTrt
Ph
O
O
H
N
O
N
OMe
O Me
O
O
N
H
MeH
N
H
N
BOCHN
8
78
N
H
N
H
O
O
2
3
stage, the enantioselectivity appeared to plateau (Table 1).
Ph
N
N
It is important to underscore further that at no sequence length
was a comprehensive exploration of residues explored. Thus,
although peptide 18 emerged as that exhibiting maximum
enantioselectivity (78% ee), it may be that superior sequences
may be found at shorter chain lengths, or longer sequences.
Efficient methodology for a comprehensive survey of resi-
Me
(18)
9
Boc-Pmh-Aib-Chg-Gln(Trt)-D-Phe-D-Pip-Cha-Phe-
Phe-OMe (19)
Boc-Pmh-Aib-Chg-Gln(Trt)-D-Phe-D-Pip-Cha-Val-(Boc)Trp-
Phe-OMe (20)
75
74
1
0
2
4
dues at a given chain length is, at this time, elusive.
a
ꢀ
All reactions were conducted at 25 C and proceeded to >75% conversion
within 16 h as determined by H NMR.
Determined by chiral HPLC. Reported ee values are the average of at least
two runs.
1
b
With a co-catalyst combination of octapeptide 18-proline
available that afforded MBH product 1 in 78% ee, we wished

M. M. Vasbinder et al. / Tetrahedron 62 (2006) 11450–11459
11453
to determine whether alteration of other reaction parameters
could lead to improved selectivity and overall efficiency.
the MBH reaction with MVK in 69 and 63% ee, respectively
(81% yield, entry 3; 89% yield, entry 7). Another aldehyde
examined was o-trifluoromethylbenzaldehyde, which af-
forded MBH product 23 in 71% ee and 52% yield (entry
4). Furaldehyde participates in the reaction generating
MBH product 25 in 63% ee (entry 6). In addition, 2-fluo-
robenzaldehyde undergoes the MBH reaction under the
optimized reaction conditions in 65% ee with 55% yield
(entry 9). Finally, two aldehydes which provided lower
selectivities under the reaction conditions were 3-nitrobenz-
aldehyde and benzaldehyde, affording selectivities of 45 and
2
5
We also set out to determine whether the optimized reaction
conditions were specific for 2-nitrobenzaldehyde. A variety
of aromatic aldehydes were found to provide acceptable
levels of reactivity in the MVK-based MBH reaction. As
Table 2 illustrates, we observed 81% ee and 88% yield when
2
6
3
(
-methoxy-2-nitrobenzaldehyde was used as a substrate
entry 5). Nitronaphthaldehyde participated in the MBH re-
action affording 22 in up to 73% ee and in 92% yield (entry
). p-Nitrobenzaldehyde and dinitrobenzaldehyde undergo
2
41% ee, respectively (entries 8 and 10).
Table 2. Substrate screen for the MVK-MBH reaction with co-catalyst
18/Pro
Other aldehydes in addition to those listed in Table 2 were
examined as possible substrates for this reaction. These
included a variety of aliphatic, ‘nonactivated’ aromatic
aldehydes, and unsaturated aldehydes. Unfortunately, no
reaction was observed with the following aldehydes:
propionaldehyde, isobutyraldehyde, trans-cinnamaldehyde,
cyclohexanecarboxaldehyde, 1-naphthaldehyde, hydrocin-
namaldehyde, and o-tolualdehyde. The scope of the ketone
partner was also investigated. Under the optimized reaction
conditions, ethyl vinyl ketone (EVK) participates in the reac-
tion with 2-nitrobenzaldehyde to deliver the product with
a reduced selectivity of 69% ee. Other substituted ketones
we examined afforded no reaction under the optimized con-
ditions. For example, phenyl vinyl ketone, cyclohexyl vinyl
ketone, and tert-butyl vinyl ketone were all screened in this
reaction and exhibited no reactivity. Furthermore, non-
ketone-based a,b-unsaturated compounds such as various
acrylates and acrylonitriles were also unreactive under the
reaction conditions. Clearly, further studies of these systems
are necessary if expansion of substrate scope and reaction
generality is to be achieved.
a
b
Entry
1
Substrate
NO2
BH product
NO OH
% Yield % ee
O
2
O
81
78
73
69
71
81
63
63
45
65
41
H
Me
2
1
NO2
O
NO
2
OH
OH
O
2
3
4
5
Me 92
Me 81
H
H
22
O
O
O N
O N
1
2
2
CF3
O
CF
3
OH
O
52
H
O
Me
23
NO2 OH
O
NO2
MeO
MeO
Me 88
H
To probe the nature of proline–peptide catalyst interaction,
we set out to identify the importance of the proline compo-
nent in these reactions. In the absence of proline, catalyst 18
affords <10% ee, with low conversion. As noted earlier, the
NMI-proline co-catalyst system provided MBH product in
2
4
OH
O
O
O
c
6
O
95
Me
H
25
<
10% ee. Thus, we felt the specific interactions of the pep-
O
NO2 OH
O
tide–proline co-catalyst system could be important. To probe
these effects, we performed parallel co-catalytic reactions
with octapeptide 18 and both enantiomers of proline. Indeed,
double stereodifferentiating effects were observed. Whereas
the combination of L-proline and octapeptide 18 affords (R)-
Morita–Baylis–Hillman product 21 in 78% ee, the catalyst
pair of D-proline and octapeptide 18 yields (S)-21 in a re-
duced 39% ee (Fig. 6). Intriguingly, the opposite enantiomer
is formed when using D-proline in the reaction. The enantio-
divergence occurring in this reaction is of interest because it
suggests that the stereochemistry of proline dictates which
7
8
9
H
Me 89
O N
NO2
O N
26
2
2
O
H
OH
O
O N
O N
2
2
Me 74
2
7
F
O
O
F
OH
OH
O
55
H
H
Me
28
27,28
enantiomer of MBH product is formed.
O
In order to further investigate the role of the amino acid com-
ponent, we screened a number of other amino acids and de-
rivatives as the co-catalyst. As illustrated in Table 3, other
amino acids such as valine, alanine, phenylalanine, histidine,
and tyrosine (entry 1) do not afford appreciable levels of
enantioselectivity in the reaction of 2-nitrobenzaldehyde
and MVK with peptide 18. Protected versions of the amino
acids are also not selective (entry 2). Of interest is sarcosine
(entry 4), in stark contrast to glycine (entry 3), indeed affords
1
0
55
Me
29
a
ꢀ
All reactions were conducted at 25 C and proceeded to >75% conversion
within 16 h as established by H NMR. Isolated yields are after silica gel
chromatography.
1
b
c
Enantioselectivities were determined by chiral HPLC. Reported ee values
are the average of at least two runs.
Reaction with furaldehyde, yield refers to conversion by H NMR; iso-
1
lated yields after catalytic hydrogenation of the olefin are comparable.

11454
M. M. Vasbinder et al. / Tetrahedron 62 (2006) 11450–11459
O
could provide useful information. Thus, a number of N-
methyl amino acids were synthesized and screened; most
N
O
O
of these amino acid derivatives afforded <11% ee for the
MBH reaction (entries 6 and 7). However, as shown in
RHN
Me
29
Peptide
N
Table 3, N-methyl alanine (entry 5) afforded up to 31% ee
in the reaction. From the data, one could conclude that
more sterically hindered N-methyl amino acids begin to
erode selectivity; however, sarcosine and N-methyl alanine
allow for modest levels of enantiodiscrimination.
OH
O
N
Me
Me
Me
NO2
O
(
R)-21
H
7
8% ee
In addition to screening amino acid and amino acid deriva-
tives as co-catalysts for the MBH reaction, we also examined
other proline derivatives to explore the unique role of proline
as a co-catalyst with peptide 18. Simple modifications to the
proline bifunctional nature (i.e., the amine and carboxylic
NO2
OH
O
O
NO2
30
acid termini, as in entries 2–4, 8, and 9; Table 4 ) yield
N
O
(
S
)-21
nonselective reactions with enantioselectivities of <10%
ee. Furthermore, subtle alterations to the proline framework
such as pipecolinic acid and homo-proline (entries 5 and 6)
O
RHN
Me
- 39% ee
Peptide
N
N
Me
a
Table 4. Proline derivatives as catalysts in the MBH reaction with 18
Figure 6. Matched and mismatched pairs of co-catalysts with proline and
peptide 18.
b
Entry
Compound
% ee
CO H
2
1
78
N
H
modest levels of enantioselectivity in the MBH reaction with
peptide 18. Because sarcosine provided appreciable levels
of selectivity (44% ee in the MBH reaction with peptide
CO Me
2
1
8), we felt that screening a variety of N-methyl amino acids
2
3
4
5
6
<10
<10
<10
21
N
H
a
Table 3. Amino acid co-catalysts in the MBH reaction with peptide 18
CO H
2
b
Entry
1
Co-catalyst
% ee
N
BOC
(L)-Val, (L)-Ala, (L)-Phe, (L)-His, (L)-Tyr, (D)-Phe
<10
NH2
O
Me
Me
OH
N
H
2
RHN
<10
O
R = BOC, FMOC
N
CO H
2
H
OH
H N
CO H
2
3
4
2
<10
O
O
35
N
H
H
N
Me
OH
OH
44
R
CO H
2
7
R = O
tBu
39
Me
N
H
R = OH
<10
H
5
6
31
11
N
Me
O
Me
Me
OH
8
9
<10
<10
N
H
H
N
Me
O
CO R
2
R = Li or Na
N
H
OBn
7
<10
H
OH
CO H
N
2
1
0
33–40
N
H
Me
O
R
R = Me, Ph, vinyl
a
ꢀ
a
ꢀ
All reactions were conducted at 25 C.
Determined by chiral HPLC. Reported ee values are the average of at least
two runs.
All reactions were conducted at 25 C.
Determined by chiral HPLC. Reported ee values are the average of at least
two runs.
b
b

M. M. Vasbinder et al. / Tetrahedron 62 (2006) 11450–11459
11455
afforded significantly reduced selectivities (21 and 35% ee,
respectively). The reduced selectivity of pipecolinic acid is
particularly noteworthy in light of our recent observation
that NMI-pipecolinic acid is a particularly effective co-
catalyst system for the intramolecular version of the MBH
obtaining selective peptide catalysts, represents another
important task in our ongoing studies.
1
3
In summary, we have demonstrated success in the catalytic,
asymmetric ketone-based Morita–Baylis–Hillman reaction
using methyl vinyl ketone and a variety of aromatic alde-
hydes. Our catalyst system involves a peptide-based catalyst
in the presence of proline as a co-catalyst. This co-catalyst
system has enabled state-of-the-art enantioselectivities in
the intermolecular MVK-MBH reaction with aldehydes,
affording enantioselectivities in up to 81% ee. We have
uncovered a unique peptide–proline co-catalyst interaction.
Understanding such interactions could enable the discovery
of other selective peptide catalysts and co-catalyst interac-
tions, which could serve as catalysts for other carbon–carbon
bond-forming reactions and group transfers. These explora-
tions are currently underway in our laboratory.
5
a
reaction. Hydroxy-proline derivatives also yield reduced
selectivities (entry 7, 39 and <10% ee, depending on the pro-
tection of the hydroxyl group). In addition, 5-substituted
proline derivatives were also synthesized and examined.
3
1
5
1
-Substituted methyl, phenyl, and vinyl prolinates (entry
0) were tested as co-catalysts in the MBH reaction with
peptide 18. These derivatives also provided lower selectivity
than proline (entry 1) affording 33–40% ee in the MBH
reaction.
3
2
3. Conclusions
The data collected thus far indicate that a specific peptide–
proline co-catalyst interaction may operate to afford an
enantioselective reaction. A cohesive transition state assem-
bly such as 30 could be operative (Fig. 7a). Enamines
derived from proline have been shown to be effective asym-
4
. Experimental
4
4
.1. General
.1.1. General procedures. Proton NMR spectra were re-
3
3
metric scaffolds for enantioselective reactions. Perhaps the
Pmh nucleophilic amine of the peptide catalyst adds to the
proline iminium ion formed between MVK and proline.
The addition product 30 could be stabilized by hydrogen
bonding of the peptide backbone with the carboxylic acid
of proline. However, the possibility of a two-catalyst transi-
tion state involving the peptide and proline-MVK conjugate
addition product 31 is also a possible transition state
corded on a Varian 400 spectrometer. Proton chemical shifts
are reported in parts per million (d) relative to internal tetra-
methylsilane (TMS, d, 0.0 ppm), or with the solvent refer-
ence relative to TMS employed as an internal standard
(CDCl , d, 7.26 ppm). Data are reported as follows: chemical
3
shift (multiplicity [singlet (s), doublet (d), triplet (t), quartet
q), multiplet (m)], coupling constants [hertz], integration).
Carbon NMR spectra were recorded on a Varian 400
100 MHz) or 500 (125 MHz) spectrometers with complete
(
(
Fig. 7b). Not surprisingly, control experiments involving
(
MVK and proline alone show efficient conjugate addition
of the amine to the enone.
proton decoupling. Carbon chemical shifts are reported in
parts per million (d) relative to TMS with the respective sol-
vent resonance as the internal standard (CDCl , d, 77.0 ppm).
3
Exactly, which intermediates and transition states operate,
30 or 31, a combination of both, or even another alternative
transition state, is a matter of current investigation in our lab-
oratory. The possibility to fine-tune these peptide–proline
interactions also presents a possible strategy for asymmetric
catalyst development. Uncovering the identity of the non-
covalent interactions responsible for the high levels of enan-
tioselectivity observed for this reaction remains a challenge.
In addition, understanding the precise role of the helix-
inducing residue Aib, which proved to be important in
All NMR spectra were acquired at ambient temperature.
Analytical thin-layer chromatography (TLC) was performed
˚
using silica gel 60 A F precoated plates (0.25 mm thick-
3
4
254
ness). TLC R values are reported. Visualization was accom-
f
plished by irradiation with a UV lamp and/or staining with
KMnO , cerium ammonium molybdenate (CAM), or ninhy-
drin solutions. Flash column chromatography was performed
4
˚
using silica gel 60 A (32–63 mm). Optical rotations were
recorded on a Rudolph Research Analytical Autopol IV
Automatic polarimeter at the sodium D line (path length
50 mm). High resolution mass spectra were acquired in the
Mass Spectrometry facility at Boston College (Chestnut
Hill, MA) or at the University of Illinois (Urbana-
Champaign, IL). The method of ionization is indicated in
parenthesis.
a)
b)
O
R
N
R
Me
O
HN
O
H
O
Analytical and preparative reverse phase HPLC were per-
formed on a Rainin SD-200 chromatograph equipped with
a single wavelength UV detector (214 or 254 nm). Analyti-
cal normal phase HPLC was performed on a Hewlett–Pack-
ard 1100 Series chromatograph equipped with a diode array
detector (214 and 254 nm). All reactions were carried out
under a nitrogen atmosphere employing oven- and flame-
dried glassware. All solvents were distilled from appropriate
drying agents prior to use. Benzaldehyde and 2-furaldehyde
were freshly distilled while all other aldehydes were used as
received. Methyl vinyl ketone was used as received (Aldrich
N
N
O
O
O
O
Me
Me
RHN
Me
Me
RHN
N
Me
N
H
N
H
O
N
H
N
N
n
n
Me
Me
3
0
31
Figure 7. Possible transition state assemblies involving (a) proline–enamine
intermediates and (b) peptide–proline-MVK conjugate addition product
intermediates.

11456
M. M. Vasbinder et al. / Tetrahedron 62 (2006) 11450–11459
Chemical Company, 99%). HPLC grade chloroform was pu-
rified by the method of Perrin. CDCl was purchased from
(s, 1H), 7.30–7.13 (m, 7H), 6.87 (s, 1H), 6.79 (s, 1H), 5.45
(d, J¼5.3 Hz, 1H), 4.64 (m, 1H), 4.41 (m, 1H), 4.33 (m,
1H), 4.01 (m, 1H), 3.61 (s, 3H), 3.27 (s, 3H), 3.17–3.07
(m, 2H), 3.05 (d, J¼4.4 Hz, 1H), 3.01 (d, J¼4.0 Hz, 1H),
2.81 (dd, J¼16.0 Hz, 9.6 Hz, 2H), 2.68 (m, 2H), 2.40–2.30
3
5
3
Cambridge Isotope Laboratories, Inc., and used as received
in the catalytic reactions. Stereochemical proofs were
conducted as previously reported.
3
6
3
7
(
m, 2H), 2.13–1.90 (m, 4H), 1.80–1.64 (m, 8H), 1.54
4
.1.2. Peptide synthesis. Peptides 11–20 were synthesized
(s, 3H), 1.49 (s, 3H), 1.46 (s, 9H), 1.25–0.94 (m, 4H);
TLC R 0.53 (10% MeOH/CH Cl ); exact mass calcd for
on commercially available Fmoc-Phe-Wang polystyrene
solid support. Couplings were performed with 4 equiv of
amino acid, 4 equiv of HBTU, and 8 equiv H u¨ nig’s base in
DMF, for 3 h. Deprotections were performed in the presence
of 20% piperidine in DMF for 20 min (to minimize diketo-
piperazine formation; dipeptides were deprotected with
f
2
2
+
[C H N O +H] requires m/z 830.4816. Found 830.4817
4
5 63 7 8
+
(FAB ). HPLC retention time 2.6 min on a RP-18 X Terra
(Waters) column eluting with 85% MeOH/water at a flow
rate of 0.2 mL/min.
5
from solid support by using a mixture of MeOH/DMF/
0% piperidine in DMF for 5 min). Peptides were cleaved
4
.1.3.6. Boc-Pmh-Aib-Chg-(trt)Gln-D-Phe-Phe-OMe
1
(
11). H NMR (400 MHz, CDCl ) d 7.52 (d, J¼8.0 Hz,
3
Et N (9:1:1) for 3 days. The peptides were characterized
3
2H), 7.31–7.07 (m, 27H), 7.03–6.91 (m, 2H), 6.84 (s, 1H),
+
by electrospray mass spectrometry (ESI ) and used in reac-
tion screens without further purification.
5
4
.47 (s, 1H), 4.74–4.67 (m, 1H), 4.51–4.45 (m, 1H), 4.41–
.25 (m, 1H), 4.20–4.16 (m, 1H), 4.07–4.05 (m, 1H), 3.50
(
2
2
s, 3H), 3.26–3.21 (m, 1H), 3.18 (s, 3H), 2.99–2.94 (m,
4
.1.3. Data for peptides 11–20.
.1.3.1. Boc-Pmh-OMe (12). H NMR (400 MHz,
H), 2.72–2.66 (m, 2H), 2.36–2.06 (m, 5H), 1.80–1.09 (m,
7H); TLC R 0.43 (8% MeOH/CH Cl ); exact mass calcd
1
4
f
2
2
CDCl ) d 7.39 (s, 1H), 6.78 (s, 1H), 5.22 (br d, J¼7.6 Hz,
+
3
for [C H N O +Na] requires m/z 1194.6004. Found
67 81 9 10
1
18 X Terra (Waters) column eluting with 75% MeOH/water
at a flow rate of 0.2 mL/min.
1
2
H), 4.54 (m, 1H), 3.75 (s, 3H), 3.58 (s, 3H), 3.09 (m,
H), 1.43 (s, 9H); TLC R 0.51 (8% MeOH/CH Cl ); exact
+
194.6016 (ESI ). HPLC retention time 9.7 min on a RP-
f
2
2
+
mass calcd for [C H N O +H] requires m/z 284.1610.
1
3 21 3 4
+
Found 284.1609 (FAB ). HPLC retention time 1.4 min on
a RP-18 X Terra (Waters) column eluting with 75%
MeOH/water at a flow rate of 0.3 mL/min.
4.1.3.7. Boc-Pmh-Aib-Chg-(trt)Gln-D-Phe-(Boc)Trp-
Phe-OMe (17). H NMR (400 MHz, CDCl ) d 8.07 (br d,
1
3
J¼7.8 Hz, 1H), 7.58–7.48 (m, 4H), 7.27–7.11 (m, 30H),
1
4.1.3.2. Boc-Pmh-Aib-OMe (13). H NMR (400 MHz,
CDCl ) d 7.40 (s, 1H), 6.87 (s, 1H), 6.61 (s, 1H), 5.17 (s, 1H),
4
7
.00 (s, 1H), 6.83 (s, 1H), 6.69 (br d, J¼8.0 Hz, 1H) 5.54
3
(s, 1H), 4.67–4.55 (m, 2H), 4.10–3.97 (m, 3H), 3.42 (s,
.27 (m, 1H), 3.73 (s, 3H), 3.62 (s, 3H), 3.03 (d, J¼6.4 Hz,
3
2
2
6
H), 3.30–3.20 (m, 2H), 3.18 (s, 3H), 3.13–2.97 (m, 2H),
.92–2.86 (m, 3H), 2.76–2.70 (m, 2H), 2.39–2.29 (m, 3H),
.18–2.10 (m, 5H), 1.85–1.50 (m, 14H), 1.49–1.36 (m,
2H), 1.50 (s, 3H), 1.49 (s, 3H), 1.44 (s, 9H); TLC R 0.40 (8%
MeOH/CH Cl ); exact mass calcd for [C H N O +H] re-
f
+
2
2
17 28 4 5
+
quires m/z 369.2138. Found 369.2138 (FAB ). HPLC reten-
tion time 1.4 min on a RP-18 X Terra (Waters) column
eluting with 75% MeOH/water at a flow rate of 0.3 mL/min.
H), 1.30–1.00 (m, 12H); TLC R 0.48 (8% MeOH/
f
+
CH Cl ); exact mass calcd for [C H N O +H] requires
2
2
83 99 11 13
+
m/z 1458.7502. Found 1458.7506 (FAB ). HPLC retention
time 5.1 min on a RP-18 X Terra (Waters) column eluting
with 90% MeOH/water at a flow rate of 0.2 mL/min.
1
4
.1.3.3. Boc-Pmh-Aib-Phe-OMe (14). H
400 MHz, CDCl ) d 7.39 (s, 1H), 7.30–7.11 (m, 5H), 6.81
NMR
(
3
(
s, 1H), 6.78 (d, J¼7.6 Hz, 1H), 6.73 (s, 1H), 5.25 (d,
4
.1.3.8. Boc-Pmh-Aib-Chg-(trt)Gln-D-Phe-D-Pip-Cha-
J¼6.4 Hz, 1H), 4.82 (dd, J¼13.6 Hz, 6.4 Hz, 1H), 4.19
1
Phe-OMe (18). H NMR (400 MHz, CDCl ) d 8.40 (d,
3
(
m, 1H), 3.72 (s, 3H), 3.59 (s, 3H), 3.06 (m, 4H), 1.45 (s,
H), 1.44 (s, 3H), 1.43 (s, 9H); TLC R 0.43 (8% MeOH/
CH Cl ); exact mass calcd for [C H N O +H] requires
J¼7.6 Hz, 1H), 7.86 (d, J¼8.4 Hz, 1H), 7.60 (d, J¼4.0 Hz,
1H), 7.38–7.06 (m, 24H), 6.90, (s, 1H), 6.78–6.77 (m, 2H),
5.99, (d, J¼4.8 Hz, 1H), 4.60–4.52 (m, 2H), 4.35–4.32
3
f
+
2
2
26 37 5 6
+
m/z 516.2822. Found 516.2823 (FAB ). HPLC retention
time 2.0 min on a RP-18 X Terra (Waters) column eluting
with 85% MeOH/water at a flow rate of 0.2 mL/min.
(
3
2
m, 2H), 4.15–4.10 (m, 3H), 3.54 (s, 3H), 3.27–3.12 (m,
H), 2.97–2.94 (m, 4H), 2.85–2.78 (m, 2H), 2.62–2.57 (m,
H), 2.48–2.41 (m, 2H), 2.25–2.19 (m, 5H), 2.11–2.04
1
(m, 2H), 1.75–1.12 (m, 44H); TLC R 0.47 (8% MeOH/
f
4.1.3.4. Boc-Pmh-Aib-Phe-D-Phe-OMe (15). H NMR
400 MHz, CDCl ) d 7.43 (s, 1H), 7.33–7.15 (m, 10H),
6
+
CH Cl ); exact mass calcd for [C H N O +H] re-
82 105 11 12
(
2
2
3
+
quires m/z 1436.8022. Found 1436.8035 (ESI ). HPLC
retention time 3.4 min on a RP-18 X Terra (Waters) column
eluting with 85% MeOH/water at a flow rate of 0.2 mL/min.
.86 (s, 1H), 6.76 (d, J¼7.6 Hz, 1H), 6.58 (s, 1H), 5.10 (d,
J¼6.0 Hz, 1H), 4.80–4.69 (m, 2H), 4.25–4.20 (m, 1H),
.65 (s, 3H), 3.60 (s, 3H), 3.39 (m, 2H), 3.16–3.04
m, 3H), 2.98–2.88 (m, 2H), 1.44–1.40 (m, 15H); TLC
Rf 0.44 (8% MeOH/CH Cl ); exact mass calcd for
requires m/z 685.3326. Found
85.3322 (ESI ). HPLC retention time 2.5 min on a RP-18
X Terra (Waters) column eluting with 85% MeOH/water at
a flow rate of 0.2 mL/min.
3
(
4.1.3.9. Boc-Pmh-Aib-Chg-(trt)Gln-D-Phe-D-Pip-Cha-
L-Phe-Phe-OMe (19). H NMR (400 MHz, CDCl ) d 8.31
2
2
+
1
[
C H N O +Na]
3
5
46
6
7
3
+
6
(br s, 1H), 7.85 (br s, 1H), 7.59 (br s, 1H), 7.47 (br s, 1H),
7.26–7.08 (m, 27H), 6.99 (br s, 1H), 6.86 (m, 2H), 6.76 (s,
1H), 6.41 (s, 1H), 5.88 (s, 1H), 4.62–4.54 (m, 2H), 4.36–
4
.26 (m, 4H), 4.13 (m, 2H), 3.59 (s, 3H), 3.17 (s, 3H),
1
4.1.3.5. Boc-Pmh-Aib-Cha-hPhe-D-Phe-OMe (16). H
2.98–2.90 (m, 2H), 2.84–2.79 (m, 2H), 2.62–2.54 (m, 2H),
2.48–2.40 (m, 2H), 2.25–2.20 (m, 2H), 2.09–2.03 (m, 2H),
NMR (400 MHz, CDCl ) d 7.60 (d, J¼8.8 Hz, 1H), 7.37
3

M. M. Vasbinder et al. / Tetrahedron 62 (2006) 11450–11459
11457
8
d
1.74–0.87 (m, 51H); TLC R 0.40 (8% MeOH/CH Cl );
exact mass calcd for [C H N O +H] requires m/z
Characterization of (R)-1 has been previously reported.
f
2
2
+
9
1 114 12 13
+
1583.8706. Found 1583.8703 (ESI ). HPLC retention time
6.2 min on a RP-18 X Terra (Waters) column eluting with
85% MeOH/water at a flow rate of 0.2 mL/min.
4.1.4.2. Proof of absolute stereochemistry. The abso-
lute stereochemistry of the major adduct 1 was determined
by comparing the sign of the specific rotation with reported
literature data. The kinetic resolution of the racemic com-
pound 1 by Sharpless epoxidation using L-(+)-diethyl tar-
trate leads to preferentially recovered starting material of
the (S)-configuration. Measurement of the optical rotation
and comparison to the literature showed the sample to be
of the (R)-configuration: [a] ꢁ3.8 (c 0.53, CHCl ); litera-
4
.1.3.10.
Cha-Val-(Boc)Trp-Phe-OMe (20). H NMR (CDCl3,
00 MHz) d 8.74 (br s, 1H), 8.17 (br s, 1H), 7.87 (d,
Boc-Pmh-Aib-Chg-(trt)Gln-D-Phe-D-Pip-
1
4
J¼7.2 Hz, 1H), 7.64 (s, 1H), 7.62 (s, 1H), 7.40–6.91 (m,
3
4
2
0H), 6.75 (s, 2H), 6.71–6.89 (m, 1H), 5.98 (s, 1H),
.74–4.70 (m, 5H), 4.48–4.08 (m, 6H), 3.64 (s, 3H), 3.23–
.84 (m, 15H), 2.25–2.09 (m, 4H), 1.69–0.76 (60H); TLC
D
3
ture for (R)-1: [a] ꢁ12.1 (c 0.53, CHCl ).
D
3
1
Rf 0.33 (8% MeOH/CH Cl ); exact mass calcd for
2
Compound 23: H NMR (CDCl , 400 MHz) d 7.72 (d,
3
2
+
[
C103H132N O +Na] requires m/z 1843.9843. Found
14
J¼7.7 Hz, 1H), 7.66 (d, J¼7.7 Hz, 1H), 7.59 (m, 1H), 7.42
16
+
1
843.9840 (ESI ). HPLC retention time 45.4 min on a RP-
8 X Terra (Waters) column eluting with 55% MeOH/water
at a flow rate of 0.2 mL/min.
(t, J¼7.7 Hz, 1H), 6.19 (s, 1H), 6.06 (br s, 1H), 5.54 (s,
1
3
1
1H), 3.42 (d, J¼3.7 Hz, 1H), 2.39 (s, 3H); C NMR
(CDCl , 100 MHz) d 199.9, 149.7, 139.2, 131.9, 127.7,
3
127.6, 127.3, 125.7, 122.6, 119.9, 67.3, 26.4; IR (film,
cm ) 3420, 1678, 1312, 771; TLC R 0.48 (30% ethyl
ꢁ1
4.1.4. General procedure for the Morita–Baylis–Hillman
reaction.
f
acetate/hexane); [a] ꢁ31 (c 0.83, CHCl ); exact mass calcd
D
3
+
4
.1.4.1. Enantioselective Morita–Baylis–Hillman re-
for [C H O F +Na] requires m/z 267.0609. Found
12 11 2 3
+
action employing catalyst 18 with product isolation. To
a 10 mL round bottom flask, flame-dried and equipped with
a stir bar, were added peptide 18 (0.0015 mmol), dissolved
267.0605 (ESI ). Assay of enantiomeric purity: enantiomers
of product were separated by chiral HPLC employing a
Chiralcel AD column (Diacel). Conditions: hexane/2-propo-
nal 95:5; flow rate 0.75 mL/min; 13.2 min (minor ent),
15.5 min (major ent).
in CHCl /THF (1:2, 0.5 M), L-proline (0.0015 mmol), 2-
3
nitrobenzaldehyde (0.015 mmol), and methyl vinyl ketone
(
0.029 mmol). The resulting mixture was stirred until com-
1
plete loss of starting material was observed by TLC (2:1
hexane/ethyl acetate). The reaction mixture was diluted
with chloroform and purification via silica gel chromato-
graphy (SiO , CHCl ) afforded 2.7 mg (81%) of 21 as a
Compound 24: H NMR (CDCl , 400 MHz) d 7.43 (t,
3
J¼8.1 Hz, 1H), 7.14 (d, J¼7.7 Hz, 1H), 6.99 (d, J¼8.4 Hz,
1H), 6.24 (s, 1H), 5.96 (s, 1H), 5.66 (d, J¼5.5 Hz, 1H),
1
3
3.89 (s, 3H), 3.46 (d, J¼5.5 Hz, 1H), 2.34 (s, 3H);
C
2
3
pale yellow oil.
NMR (CDCl , 100 MHz) d 199.7, 150.9, 147.8, 140.2,
3
134.7, 131.4, 128.1, 119.6, 112.4, 68.1, 56.8, 26.5; IR
(film, cm ) 3414, 1674, 1531; TLC R 0.30 (30% ethyl ace-
1
ꢁ1
Compound 21: H NMR (CDCl , 400 MHz) d 7.98 (d,
3
f
J¼8.4 Hz, 1H), 7.78 (d, J¼7.7 Hz, 1H), 7.66 (t, J¼7.6 Hz,
tate/hexane); [a] ꢁ112 (c 1.0, CHCl ); exact mass calcd for
D
3
+
1
H), 7.47 (t, J¼7.2 Hz, 1H), 6.22 (s, 1H), 6.17 (s, 1H),
[C H N O +Na] requires m/z 274.0691. Found 274.0699
12 10 4 4
1
3
+
5
.79 (s, 1H), 3.49 (br s, 1H), 2.37 (s, 3H); C NMR
(ESI ). Assay of enantiomeric purity: enantiomers of prod-
uct were separated by chiral HPLC employing a Chiralcel
AD column (Diacel). Conditions: hexane/2-proponal
90:10; flow rate 0.75 mL/min; 30.7 min (minor ent),
33.7 min (major ent).
(
1
3
CDCl , 100 MHz) d 199.5, 149.0, 147.8, 136.7, 133.5,
3
ꢁ
1
28.8, 128.5, 126.6, 124.5, 67.1, 26.2; IR (film, cm
414, 1675, 1525, 1351; TLC R 0.52 (40% ethyl acetate/
)
f
hexane); [a] ꢁ114 (c 1.0, CHCl ); exact mass calcd for
D
3
+
[
(
C H NO +Na] requires m/z 244.0586. Found 244.0585
11 11 4
ESI ). Assay of enantiomeric purity: Enantiomers of product
+
1
Compound 25: H NMR (CDCl , 400 MHz) d 7.36 (s, 1H),
3
were separated by chiral HPLC employing a Chiralcel AD
column (Diacel). Conditions: hexane/2-proponal 95:5; flow
rate0.75 mL/min;29.8 min(minorent), 32.5 min(majorent).
6.34–6.32 (m, 1H), 6.25–6.24 (m, 2H), 6.1 (s, 1H), 5.63 (d,
J¼5.8 Hz, 1H), 3.26 (br s, 1H), 2.38 (s, 3H); C NMR
1
3
(CDCl , 100 MHz) d 199.2, 154.2, 147.2, 141.6, 126.4,
3
ꢁ1
109.9, 106.6, 65.2, 25.7; IR (film, cm ) 3320, 2957,
2923, 2852, 1714, 1667, 1510, 1462, 1376; TLC R 0.56
1
Compound 22: H NMR (CDCl , 400 MHz) d 7.99 (d,
3
f
J¼8.8 Hz, 1H), 7.91 (d, J¼7.3 Hz, 1H), 7.77 (d, J¼8.1 Hz,
(30% ethyl acetate/hexane); [a] ꢁ6.5 (c 0.31, CHCl ); ex-
D
3
+
1
H), 7.66–7.58 (m, 3H), 6.29 (s, 1H), 6.00 (s, 1H), 5.89 (d,
act mass calcd for [C H O +Na] requires m/z 189.0528.
9 10 3
+
J¼4.4 Hz, 1H), 3.51 (d, J¼4.7 Hz, 1H), 2.36 (s, 3H);
Found 189.0526 (ESI ). Assay of enantiomeric purity: enan-
tiomers of product were separated by chiral HPLC employ-
ing a Chiralcel AD column (Diacel). Conditions: hexane/
ethanol 95:5; flow rate 0.75 mL/min; 29.0 min (major ent),
37.0 min (minor ent).
1
3
C NMR (CDCl , 100 MHz) d 199.3, 147.5, 146.2,
3
1
1
2
32.9, 130.8, 130.6, 128.5, 127.8, 127.7, 127.3,
24.0, 123.9, 121.5, 67.9, 26.2; IR (film, cm ) 3414,
363, 2332, 1675, 1527, 1361; TLC R 0.45 (40% ethyl
f
ꢁ1
acetate/hexane); [a] ꢁ196 (c 1.0, CHCl ); exact mass calcd
D
3
+
1
for [C H N O +Na] requires m/z 294.0742. Found
1
Compound 26: H NMR (CDCl , 400 MHz) d 8.80 (d,
3
5
13
1
4
+
2
94.0741 (ESI ). Assay of enantiomeric purity: enantiomers
J¼2.2 Hz, 1H), 8.48 (dd, J¼8.4, 2.2 Hz, 1H), 8.05 (d,
of product were separated by chiral HPLC employing a
Chiralcel AD column (Diacel). Conditions: hexane/2-propa-
nol 93:7; flow rate 0.75 mL/min; 34.1 min (minor ent),
J¼8.8 Hz, 1H), 6.30 (s, 1H), 6.23 (s, 1H), 5.85 (s, 1H),
1
3
3.55 (br s, 1H), 2.38 (s, 3H); C NMR (CDCl , 100 MHz)
3
d 199.5, 148.1, 147.9, 147.2, 143.2, 130.6, 127.3,
127.1, 120.1, 67.4, 25.9; IR (film, cm ) 3408, 3106,
ꢁ1
3
8.1 min (major ent).

1
1458
M. M. Vasbinder et al. / Tetrahedron 62 (2006) 11450–11459
357, 1673, 1606, 1536, 1347; TLC R 0.43 (40% ethyl
2. (a) Sculimbrene, B. R.; Xu, Yingju; Miller, S. J. J. Am. Chem.
f
2
acetate/hexane); [a] ꢁ135 (c 1.0, CHCl ); exact mass calcd
Soc. 2004, 126, 13182–13183; (b) Sculimbrene, B. R.; Morgan,
A. J.; Miller, S. J. J. Am. Chem. Soc. 2002, 124, 11653–11656;
(c) Sculimbrene, B. R.; Miller, S. J. J. Am. Chem. Soc. 2001,
123, 10125–10126.
D
3
+
for [C H N O +Na] requires m/z 289.0437. Found
1
1 10 2 6
+
2
89.0430 (ESI ). Assay of enantiomeric purity: enantiomers
of product were separated by chiral HPLC employing a
Chiralcel OJ column (Diacel). Conditions: hexane/ethanol
3. Evans, J. W.; Fierman, M. B.; Miller, S. J.; Ellman, J. A. J. Am.
Chem. Soc. 2004, 126, 8134–8135.
4. (a) Guerin, D. J.; Miller, S. J. J. Am. Chem. Soc. 2002, 124,
9
6
0:10; flow rate 0.75 mL/min; 54.3 min (major ent),
3.1 min (minor ent).
2134–2136; (b) Horstmann, T. E.; Guerin, D. J.; Miller, S. J.
Angew. Chem., Int. Ed. 2000, 39, 3635–3638.
1
Compound 27: H NMR (CDCl , 400 MHz) d 8.22 (s, 1H),
3
8
1
1
1
7
.13 (m, 1H), 7.74 (d, J¼7.7 Hz, 1H), 7.52 (t, J¼7.7 Hz,
5. (a) Aroyan, C. E.; Vasbinder, M. M.; Miller, S. J. Org. Lett.
2005, 7, 3849–3851; (b) Mennen, S. M.; Gipson, J. D.; Kim,
Y. R.; Miller, S. J. J. Am. Chem. Soc. 2005, 127, 1654–1655;
(c) Mennen, S. M.; Blank, J. T.; Tran-Dube, M. B.; Imbriglio,
J. E.; Miller, S. J. Chem. Commun. 2005, 195–197; (d)
Imbriglio, J. E.; Vasbinder, M. M.; Miller, S. J. Org. Lett.
2003, 5, 3741–3743.
6. Kuntz, K. W.; Snapper, M. L.; Hoveyda, A. H. Curr. Opin.
Chem. Biol. 1999, 3, 313–319.
7. (a) Basavaiah, D.; Rao, A. J.; Satyanarayana, T. Chem. Rev.
2003, 103, 811–891 and references therein; (b) Langer, P.
Angew. Chem., Int. Ed. 2000, 39, 3049–3052.
H), 6.29 (s, 1H), 6.09 (s, 1H), 5.67 (s, 1H), 3.36 (br s,
H), 2.37 (s, 3H); C NMR (CDCl , 100 MHz) d 200.1,
1
3
3
49.1, 148.4, 144.1, 132.9, 129.5, 127.9, 122.8, 121.6,
2.4, 26.8; IR (film, cm ) 3439, 1671, 1529, 1349; TLC
ꢁ
1
Rf 0.44 (30% ethyl acetate/hexane); [a]D ꢁ14 (c 1.0,
+
CHCl ); exact mass calcd for [C H NO +Na] requires
3
11 11
4
+
m/z 244.0586. Found 244.0589 (ESI ). Assay of enantio-
meric purity: enantiomers of product were separated by
chiral HPLC employing a Chiralcel AD column (Diacel).
Conditions: hexane/ethanol 90:10; flow rate 0.75 mL/min;
1
9.9 min (minor ent), 35.3 min (major ent).
8
. For recent ketone-based enantioselective MBH reactions, see:
(a) Hayashi, Y.; Tamura, T.; Shoji, M. Adv. Synth. Catal.
2004, 346, 1106–1110; (b) Krishna, P. R.; Kannan, V.;
Reddy, P. V. N. Adv. Synth. Catal. 2004, 346, 603–606; (c)
McDougal, N. T.; Schaus, S. E. J. Am. Chem. Soc. 2003, 125,
12094–12095; (d) Shi, M.; Jiang, J.-K. Tetrahedron: Asymme-
try 2002, 13, 1941–1947; (e) Barrett, A. G. M.; Cook, A. S.;
Kamimura, A. Chem. Commun. 1998, 2533–2534; (f) Mark o´ ,
I. E.; Giles, P. R.; Hindley, N. J. Tetrahedron 1997, 53, 1015–
1024; (g) Oishi, T.; Oguri, H.; Hirama, M. Tetrahedron:
Asymmetry 1995, 6, 1241–1244.
1
Compound 28: H NMR (CDCl , 400 MHz) d 7.50 (m, 1H),
3
7
.28 (m, 1H), 7.17 (m, 1H), 7.03 (m, 1H), 6.19 (s, 1H), 5.89
(
3
1
br d, 1H), 5.87 (s, 1H), 3.44 (br d, J¼5.1 Hz, 1H), 2.38 (s,
1
3
H); C NMR (CDCl , 100 MHz) d 200.0, 160.6, 158.2,
3
48.4, 128.8, 127.7, 126.5, 123.7, 114.9, 65.9, 26.1; IR (film,
cm ) 3416, 1675, 1490; TLC R 0.48 (30% ethyl acetate/
f
hexane); [a]D +20 (c 0.68, CHCl ); exact mass calcd for
3
C H O F+Na] requires m/z 217.0641. Found 217.0643
1
ꢁ1
+
[
(
1 11 2
+
ESI ). Assay of enantiomeric purity: enantiomers of prod-
uct were separated by chiral HPLC employing a Chiralcel
AD column (Diacel). Conditions: hexane/ethanol 98:2;
flow rate 0.75 mL/min; 34.2 min (minor ent), 39.8 min
9. Iwabuchi, Y.; Nakatani, M.; Yokoyama, N.; Hatakeyama, S.
J. Am. Chem. Soc. 1999, 121, 10219–10220.
10. Shi, M.; Jiang, J.-K. Tetrahedron: Asymmetry 2002, 13, 1941–
(
major ent).
1
947.
1
Compound 29: H NMR (CDCl , 400 MHz) d 7.33–7.22 (m,
3
11. The Shi laboratory reported imidazole in the presence of pro-
line as a co-catalyst (30 mol % each), which afforded enhanced
reactivity in the MVK-MBH reaction. Yields of up to 90% were
obtained for a variety of activated aldehydes. See: Shi, M.;
Jiang, J.-K.; Li, C.-Q. Tetrahedron Lett. 2002, 43, 127–130.
12. Proline has been shown to be an efficient and selective catalyst
for a number of transformations. For reviews covering this
chemistry, see the following and references therein: (a) List,
B. Chem. Commun. 2006, 819–824; (b) List, B. Synlett 2001,
1675–1686; (c) List, B. Tetrahedron 2002, 58, 5573–5590;
(d) Movassaghi, M.; Jacobsen, E. N. Science 2002, 298,
1904–1905; (e) List, B. Acc. Chem. Res. 2004, 37, 548–557.
5
H), 7.78 (d, J¼7.7 Hz, 1H), 6.15 (s, 1H), 5.98 (s, 1H), 5.56
3
1
3
(
s, 1H), 3.55 (br s, 1H), 2.28 (s, 3H); C NMR (CDCl ,
1
1
00 MHz) d 200.0, 149.9, 141.5, 128.1, 127.4, 126.4,
26.2, 72.2, 26.2; IR (film, cm ) 3414, 1673, 1369; TLC
ꢁ
1
Rf 0.47 (30% ethyl acetate/hexane); [a]D ꢁ19 (c 0.23,
+
CHCl ); exact mass calcd for [C H O +Na] requires
11 12 2
3
+
m/z 199.0735. Found 199.0732 (ESI ). Assay of enantio-
meric purity: enantiomers of product were separated by
chiral HPLC employing a Chiralcel AD column (Diacel).
Conditions: hexane/ethanol 97:3; flow rate 0.75 mL/min;
3
1.1 min (minor ent), 35.7 min (major ent).
1
3. Venkatraman, J.; Shankaramma, S. C.; Balaram, P. Chem. Rev.
001, 101, 3131–3152 and references therein.
2
Acknowledgements
14. The sequences for the unbiased peptide libraries were defined
randomly by assigning a numerical descriptor (1–16) to each
of 16 unique amino acids. These 16 labels were then random-
ized at ‘www.randomizer.org’ using a random sequence gener-
ator. The random pentapeptide libraries were initially
synthesized for the kinetic resolution of tertiary alcohols and
previously characterized by MS and reported elsewhere. See:
Jarvo, E. R.; Evans, C. A.; Copeland, G. T.; Miller, S. J.
J. Org. Chem. 2001, 66, 5522–5527.
This research is supported by the National Science Founda-
tion (CHE-0550458).
References and notes
1
. (a) Lewis, C. A.; Sculimbrene, B. R.; Xu, Y.; Miller, S. J. Org.
Lett. 2005, 7, 3021–3023; (b) Fierman, M. B.; O’Leary, D. J.;
Steinmetz, W. E.; Miller, S. J. J. Am. Chem. Soc. 2004, 126,
15. The initial screening was performed by adding to test tubes the
peptide catalyst and L-proline (10 mol % each), 4-nitrobenz-
6967–6971.
3
aldehyde, MVK, and CHCl . The reactions were stirred at room

M. M. Vasbinder et al. / Tetrahedron 62 (2006) 11450–11459
11459
temperature for 16 h followed by purification and screening for
enantioselectivity by chiral HPLC.
6. For studies that describe the conformational biasing prowess of
Aib, see: (a) Ref. 13; (b) Toniolo, C.; Crisma, M.; Formaggio,
F.; Peggion, C. Biopolymers 2001, 60, 396–419.
7. Because peptides 3 and 4 exhibited identical sequences at the
positions i through i+2, we chose these peptides to begin
SAR studies.
27. For a review addressing the reversal of stereochemistry in
enantioselective reactions, see: Sibi, M. P.; Liu, M. Curr.
Org. Chem. 2001, 5, 719–755.
28. We note that the nonadditivity of the single components of the
co-catalysts system suggests that the cooperativity among chi-
ral species is nonclassical in the sense of double stereodifferen-
tiation. See: Masamune, S.; Choy, W.; Petersen, J. S.; Sita, L. R.
Angew. Chem., Int. Ed. Engl. 1985, 97, 1–31.
1
1
1
8. We began using 2-nitrobenzaldehyde as the aldehyde compo-
nent because it was discovered to afford slightly higher enan-
tioselectivities in the MBH reaction with MVK. In addition,
29. N-Methyl amino acids were synthesized according to the
following procedure. See: (a) McDermott, J. R.; Benoiton,
N. L. Can. J. Chem. 1971, 51, 1915–1919; (b) Cheung, S. T.;
Benoiton, N. L. Can. J. Chem. 1977, 55, 906–910.
30. The Li and Na-salts were prepared by mixing proline with
either LiOH or NaOH in methanol for 10 min as reported in:
Yamaguchi, M.; Yokota, N.; Minami, T. J. Chem. Soc.,
Chem. Commun. 1991, 1088–1089.
31. For the preparation of 5-substituted proline derivatives, see: (a)
Silverman, R. B.; Levy, M. J. Org. Chem. 1980, 45, 815–818;
(b) Collado, I.; Ezquerra, J.; Pedregal, C. J. Org. Chem. 1995,
60, 5011–5015.
3
we uncovered ethanol-free chloroform (or CDCl ) as solvent
provided enhanced enantioselectivity.
1
9. For reviews on combinatorial catalyst screening, see the
following papers and references therein: (a) Fonseca, M.;
List, B. Curr. Opin. Chem. Biol. 2004, 8, 319–326; (b)
Gennari, C.; Piarulli, U. Chem. Rev. 2003, 103, 3071–3100;
(c) Berkessel, A. Curr. Opin. Chem. Biol. 2003, 7, 409–419;
(d) Reetz, M. T. Angew. Chem., Int. Ed. 2001, 40, 284–310;
(e) Hoveyda, A. H. Chem. Biol. 1998, 5, R187–R191.
2
2
2
0. Previous studies in our laboratory have demonstrated that
focused libraries based on initial hit peptide structures can
lead to more selective peptide sequences. See Ref. 2b.
1. The synthesis of each peptide sequence was confirmed by MS
analysis and crude peptides were then screened in the MBH
reaction.
2. We recognize that this decision assumes the peptide sequence
thus far is optimal at each amino acid position, and therefore,
this decision does not take into account cooperativity of the
different amino acids.
32. Proline has been shown to serve as a catalyst for a variety of
catalytic asymmetric reactions. See Ref. 12.
33. (a) Cheong, P.; Houk, K. N. Synthesis 2005, 9, 1533–1537; (b)
List, B.; Hoang, L.; Martin, H. J. Proc. Natl. Acad. Sci. 2004,
101, 5839–5842; (c) Hoang, L.; Bahmanyar, S.; Houk, K. N.;
List, B. J. Am. Chem. Soc. 2003, 125, 16–17; (d) Bahmanyar,
S.; Houk, K. N.; Martin, H. J.; List, B. J. Am. Chem. Soc.
2003, 125, 2475–2479.
34. For some important recent work on the mechanism of acrylate-
based variants of the MBH reaction, see: (a) Price, K. E.;
Broadwater, S. J.; Walker, B. J.; McQuade, D. T. J. Org.
Chem. 2005, 70, 3980–3987; (b) Aggarwal, V. K.; Fulford,
S. Y.; Lloyd-Jones, G. C. Angew. Chem., Int. Ed. 2005, 44,
1706–1708; (c) Raheem, I. T.; Jacobsen, E. N. Adv. Synth.
Catal. 2005, 347, 1701–1708; (d) For an earlier report, see:
Fort, Y.; Berthe, M. C.; Caubere, P. Tetrahedron 1992, 48,
6371–6384.
2
3. We also synthesized peptides of shorter length, catalysts
1
2–15, to determine if the length-selectivity trend would be
apparent with smaller peptides. Shorter peptide lengths such
as dipeptide 13, tripeptide 14, and tetrapeptide 15 did appear
to follow this trend with the limited number of cases examined.
4. A brief study of the peptide/proline ratio revealed that 1:1
stoichiometry is optimal in the cases we explored.
2
2
5. In addition to solvent screens, temperature was also examined.
35. Chloroform was washed with concentrated sulfuric acid
(5ꢂ5 mL) followed by washing with water (5ꢂ5 mL), dried
over potassium carbonate, and distilled under nitrogen. See:
Armarego, W. L. F.; Perrin, D. D. Purification of Laboratory
Chemicals, 4th ed.; Butterworth and Heinemann: Oxford,
1997; p 143.
ꢀ
ꢀ
A variety of ranges (ꢁ20 C/50 C) were screened, all of
which afforded either low conversions to MBH product or sig-
nificantly reduced enantioselectivities. Solvent screens with 21
different solvent combinations were examined. Mixtures (2:1)
3 3
of either THF/CHCl or toluene/CHCl yielded similar selec-
tivities of 78% ee in the MBH reaction of 2-nitrobenzaldehyde
with peptide 18.
6. For the furaldehyde reaction, higher enantioselectivities are
36. CDCl was used in order to monitor reaction progression by
3
1
H NMR.
37. Oishi, T.; Oguri, H.; Hirama, M. Tetrahedron: Asymmetry
1995, 6, 1241–1244.
2
observed in toluene/CHCl (2:1) solvent mixtures.
3