polymeric chiral catalyst design and chiral polymer synthesis (itsuno/polymeric chiral catalyst) ||...

CHAPTER 4

PEPTIDE-CATALYZED ASYMMETRICSYNTHESIS

KAZUAKI KUDO and KENGO AKAGAWA

4.1 INTRODUCTION

Our life activity is based on chemical reactions in our body catalyzed by many kinds

of enzymes. Enzymes are naturally occurring, highly sophisticated polymeric chiral

catalysts. They catalyze many kinds of biotransformations with very high efficiency

and selectivity under ambient conditions in water. Another characteristic of enzymes

is their high substrate specificity, which is considered to be a necessary consequence

for them because they work in the body of organism where their substrates are buried

in a mixture of thousands of chemical species. However, when considering the

application of enzymes as synthetic asymmetric catalysts, the substrate specificity,

along with a limited reaction scope, turns into a drawback. Therefore, development

of asymmetric catalysts, of which the efficiency and the selectivity are comparable

with enzymes but are tolerant to kinds of substrates, has long been one of the ultimate

goals for organic chemists.

In the earlier days, it was believed that enzymes were the only species that could

catalyze asymmetric chemical transformation. In fact, some enzymes were used for

the synthesis of optically active compounds. For example, a protease a-chymotryp-

sin was applied to the preparation of chiral a-amino acids by way of kinetic

resolution of the synthetic intermediate [1]. Through the structural analysis of the

enzymes, the chemists tried to elucidate why the enzymes were so excellent as

catalysts. Starting from lysozyme in 1965, the three-dimensional (3D) structure of

several enzyme molecules including a-chymotrypsin [2] was unveiled by X-ray

crystallography in the following years. They consist of polypeptide secondary

structures such as a-helices or b-sheets, just as Pauling et al. had predicted as

early as 1951 [3] (Figure 4.1). Then, a combination of indispensable amino acids for

the action of a-chymotrypsin, Asp, His, and Ser, or a catalytic triad, was clarified.

Polymeric Chiral Catalyst Design and Chiral Polymer Synthesis, First Edition. Edited by Shinichi Itsuno.� 2011 John Wiley & Sons, Inc. Published 2011 by John Wiley & Sons, Inc.

91

FIG

URE4.1.(a)Crystalstructure

ofa-chymotrypsin[4].Only

themainchainofthepolypeptideisshown.Datawereobtained

from

theProtein

Data

Bank[5].(b)a-Helix

and(c)b-turn

foundin

a-chymotrypsin.

92

This finding inspired the chemists to study the mechanism of enzyme-catalyzed

hydrolytic reactions, including the origin of enantioselectivity, in depth and to

construct artificial protease molecules having amino acids included in the catalytic

triad. However, the catalytic efficiency of such molecules was not so high. This fact

made the chemists believe that precise control in the spatial arrangement of specific

amino acids is of key importance to realizing an enzyme-like reaction. Later, this

stream developed in twoways: (1) biomimetic chemistry, or rational design of a long

polypeptide with a controlled 3D structure on the basis of the first principle of the

hierarchical structure of protein molecules, and (2) bioinspired chemistry that only

mimics a small part of the protein structure to realize some functions by artificial

molecules. This chapter mainly concerns the latter.

Nevertheless, at roughly the same time as the beginning of this enzyme-mimicking

research, investigation on asymmetric molecular catalysts, of which the structure is

metal complexes with chiral ligands, started. In 1968, Noyori’s [6] and Knowles’s

groups [7] independently proposed the concept of an asymmetric molecular catalyst.

In the 1970s, because of better catalytic performance and scalability, the research on

asymmetric catalysis began to focus on the homogeneous chiralmetal complexes.As a

result of this research, many chiral metal catalysts were introduced, for example,

Knowles’s rhodium–DiPAMP complex for asymmetric hydrogenation (1975) [8],

Sharpless’s titanium–tatrate ester complex for asymmetric epoxidation (1980) [9],

andNoyori’s ruthenium–BINAP complex for asymmetric hydrogenation (1980) [10].

During this period, progress in asymmetric catalysts mediated by peptide-related

compounds were, in a chronological order, proline-catalyzed asymmetric Robinson

annelation (1971) [11], poly(amino acid)-catalyzed asymmetric conjugate addition

of thiol to enone (1975) [12], cyclic-dipeptide-catalyzed cyanohydrin formation of

aldehydes (1979) [13], enantiomer-differentiating hydrolysis of esters catalyzed by

dipeptide derivatives (1980) [14], asymmetric epoxidation of chalcones in the

presence of poly(amino acid) catalysts (1980) [15], asymmetric electrochemical

oxidation/reduction mediated by poly(amino acid)-coated electrodes (1983) [16],

and again enantiodifferentiating hydrolysis of esters by the Z-Phe-His-Leu-OH

catalyst in the micellar/vesicular system (1984) [17]. Although they are all interest-

ing and unique reactions, development in the peptide-catalyzed reactions was limited

until the latter half of the 1990s. The authors speculate as to the reasons for this delay

as follows: (1) The reactions seemed substrate specific just like the enzyme-

catalyzed ones; (2) in many cases, the reaction was heterogeneous, and for such

reactions, a scientifically appropriate mechanistic consideration was hard to make;

(3) the preparation/purification of peptides was difficult because of the limited

commercial availability of chemicals and the low efficiency of the coupling agents;

and (4) related to the previous reason, peptides were not compatible with trial-and-

error–based improvement, which was routinely used in the field of chiral metal

complex catalysts.

Now, problem 3, and hence problem 4, have been resolved thanks to the progress

of related fields. Then, a question comes to mind. What can peptides do as catalysts ?

To address this question, chemists have to show something unique to peptide

catalysts that cannot be attained by conventional catalysts. Definitely, one answer

INTRODUCTION 93

is that the peptide catalysts have the possibility of adopting secondary structures.

Through the formation of a secondary structure, several parts of the peptide can

cooperatively participate in the catalytic process just like the enzymes do. Therefore,

peptides that take a secondary (or higher) structure might be promising as a novel

catalyst. From this point of view, in this chapter, we will focus on tri- and larger

peptides because it is generally considered that at least a three-amino-acid sequence

is required for the generation of a secondary structure of peptides.

It should be stressed that there is another merit for the peptide catalysts; that is,

they can be prepared by the solid-phase synthesis, and hence, they are compatible

with the combinatorial approach at the optimization stage of the catalysts.

In 2007, Miller and co-workers provided an in-depth, excellent review on the

synthetic peptide-catalyzed asymmetric reactions [18]. Although partial overlap

with their review is inevitable, in this chapter, we intend to introduce the most recent

progress in this field.

4.2 POLY(AMINO ACID) CATALYSTS

Poly(amino acid)s (PAAs) are easily accessible compounds for chemists and maybe

the oldest synthetic polypeptides applied to asymmetric catalysts. Generally, they are

synthesized by amine-initiated, ring-opening polymerization of amino-acid–derived

N-carboxyanhydrides (NCAs).

In 1975, Inoue et al. first reported on an enantioselective reaction catalyzed by

PAAs. Conjugate addition of dodecanethiol to methyl isopropenyl ketone was

performed using poly(g-benzyl-L-glutamate) (PBLG) [12], poly(b-benzyl-L-aspar-tate) [19], and polyalanine [20] as catalysts. The reactions were carried out in either

chloroform or chloroform/EtOH (30/1 to 30/2) with several PAAs having a different

degree of polymerization (DP). The enantioselective process of this reaction was the

protonation to the intermediate enolate, which was formed by the 1,4-addition of

thiolate anion to the substrate unsaturated ketone (Scheme 4.1). The PBLG catalyst

with a DP of 10 and the trialanine catalyst showed significant enantioselectivity in the

presence of ethanol. Inoue et al. explained the experimental results on the basis

of both the secondary structure of PAAs and the amino acid chirality; a decamer of

g-benzyl-L-glutamate adopts the a-helix, whereas trialanine takes the b-form. The

effect of added ethanol was considered to be threefold. First, the ethanol changes the

secondary structure of PAAs. Second, the ethanol molecules strongly interact with

C12H25 SH O+PAA

C12H25 S O

H PAAPAA

C12H25 S O

8 mol% catalyst, 20-68 days, 50 – 98 % conversion, up to 47%ee

SCHEME 4.1. The first synthetic-peptide-catalyzed asymmetric reaction [12,19,20].

94 PEPTIDE-CATALYZED ASYMMETRIC SYNTHESIS

the amide groups of PAAs and donate proton to the enolate anion from the same side

of the PAA molecule. Last, ethanol can suppress the racemization of the addition

product through imine formation.

In 1980, Juli�a et al. reported that the polyalanine with a DP of 10 catalyzed

oxidation of chalcone by alkaline hydrogen peroxide in a triphasic system of toluene,

TABLE 4.1. Juli�a–Colonna reaction of chalcone

PAAPh Ph

O

Ph Ph

O

OH2O2, base

Solvent

Ph Ph

OHOO

321

Entry PAAa Conditionsb Yield/% ee/% Ref.

1 poly(L-Ala) triphasic, 24 h 85 (36)c 93 (72)c 21

2 PBLG triphasic, 144 h 12 12 22a

3 poly(L-Leu) triphasic, 28 h 60 84 22a

4 poly(L-Ile) triphasic, 72 h 76 95 22a

5 poly(L-Val) triphasic,168 h 6 10 22a

6 poly(L-Val-ran-L-Leu) triphasic, 96 h 39 88 22a

7 poly(L-Ala)-PSd,e triphasic, 48 h 66 93 23

8 poly(L-Leu)-PSe, f triphasic, 48 h 94 97 23

9 poly(L-Leu)-PSe biphasic, 0.5 h 85 >95 24

10 H(L-Leu)3.9NHCH2CH2(OCH2CH2)71NH(L-Leu) 3.9H

biphasic, 0.5 h 80 98 25

11 H(L-Leu)mNHCH2CH2CH2NH(L-

Leu)nH (mþ n¼ 78)þTBABgtriphasic, 20 h,

100 g scale

77 96 28

12 H(L-Leu)30NHCH2CH2CH2(3-

MeImþ)Cl�hDME:H2O¼ 1:1i,

0.25 h

96 95 29

13

NH

HN

O

NH

O

O

O

H OMe

3

biphasic, 24 h 99 (conv.) 98 30

aDP is 10 unless otherwise noted.btriphasic: toluene/H2O/peptide, H2O2/NaOH, biphasic: THF, urea-H2O2/DBU.cThe values in parenthesis are those obtained by a recycled catalyst.dDP¼ 20.ePS denotes microporous polystyrene resin.fDP¼ 33.gTetrabutylammonium bromide.h3-MeImþ¼ 3-methylimidazolium.iSodium percarbonate was used as an oxidant and a base.

POLY(AMINO ACID) CATALYSTS 95

water, and gel-state polypeptide (Table 4.1) [21]. Conjugate addition of hydroperoxide

anion and the subsequent intramolecular nucleophilic attack of the resulting enolate

anion 2 to the OOH group resulted in epoxide as high as 97%ee. Subsequently, some

other poly(L-amino acid)s were applied for this reaction (Table 4.1). This asymmetric

epoxidation is now widely known as the Juli�a–Colonna reaction, and several

sophisticated reviews have been published [22]. Therefore, here we only briefly

mention this reaction mainly from the viewpoint of advancement in the synthetic

methodology.

In general, the yield and the enantioselectivity were closely related. L-Ala–,

L-Leu–, and L-Ile–derived poly(amino acid)s produced a good result, whereas L-Val–,

L-Phe–, and g-benzyl L-glutamate–derived ones did not (entries 1–5 in Table 4.1).

Concerning random copoly(L-Val-L-Leu), when monomer composition was changed

from L-Val: L-Leu¼ 1:1 to 7:3, the result was worse (14% yield, 39%ee after 192 h)

(cf. entry 6 in Table 4.1).

Although very high enantioselectivity was attained, the first–generation PAA

catalysts have several drawbacks: (1) Because of the presence of the gel phase, the

workup is troublesome; (2) a fairly large amount of catalysts (by wt% basis) is

required; (3) a long reaction time is needed; (4) applicable to a narrow range of

substrates and (5) recycling of the catalyst is of low efficiency.

Afterward, improvement from the synthetic viewpoint was reported. In 1990,

Itsuno et al. prepared immobilized poly(amino acid)s through the polymerization of

NCAs initiated by partially aminomethylated cross-linked microporous polystyrene

(entry 7 in Table 4.1) [23]. When immobilized 33mer polyleucine was used as

a catalyst, 94% yield and 99%ee were attained (entry 8 in Table 4.1). It is noteworthy

that the product of immobilized tetraalanine catalyst showed an enantioselectivity of

88%ee, and this is in sharp contrast to the result with nonsupported pentamer

polyalanine, 11%ee. As the catalyst poly(amino acid)s were bound to insoluble

polymer resins in spatially separated form, interchain interaction of the poly(amino

acid)s was considerably suppressed leading to successful avoidance of gelation.

Other merits of these immobilized catalysts were (1) broader substrate scope and

(2) high recycling ability (94% yield and 95%ee even after the 12th recycle of

immobilized polyleucine).

Using the same type of immobilized peptide catalyst, a nonaqueous variant of

the Juli�a–Colonna reaction was developed by Roberts’s group; they employed an

organosoluble urea–hydrogen peroxide complex as an oxidant and 1,8-diazabicyclo

[5.4.0]undec-7-en (DBU) as a base [24]. The reaction proceeded in a tetrahydrofuran

(THF)/white paste biphasic system with a much higher rate (entry 9 in Table 4.1).

They also developed another type of immobilized PAA on soluble polyethyle-

neglycol (PEG) resin. A 70mer PEG having polyleucine on both ends showed good

catalytic performance even with a shorter length of peptide moiety (entry 10 in

Table 4.1) [25]. Other than polymer-immobilized ones, silica gel adsorbed poly-

leucine [26] and covalently bound polyleucine on aminopropyltriethoxysilane-

treated silica [27] were also reported. Continued improvement of the catalyst and

reaction conditions enabled a large-scale reaction of up to 100 g of substrate (entry 11

in Table 4.1) [28].


Only in the last decade have the mechanistic studies on the Juli�a–Colonnareaction been made. From the accumulated experimental and calculation results,

the consensus mechanism now widely believed is as follows [18, 22]: (1) The

catalyst polyLeu adopts a rigid a-helix conformation; (2) �OOH interacts with

the peptide catalyst first and then the substrate 1 approaches to from a ternary

complex, polyLeu:�OOH:chalcone; (3) a fast, reversible conjugate addition of�OOH to chalcone occurs and then a slow ring closure reaction follows; (4) a

“correct” enantiomer of the �OOH adduct preferentially interacts with the pepetide

catalyst with three N-H groups at the N-terminal of the helix that are not involved in

the helix forming a hydrogen bond; and (5) in such a complex, the conformation

of the intermediate hydroperoxyenolate 2 is fixed to the one in which the overlap

between the enolate p-orbital and the s*-orbital of O-OH bond is maximized to allow

the epoxide formig process to occur.

Recently, Yang and Tang and coworkers demonstrated that polyleucine having

imidazolium salt at the C-terminus is a superior, nonsupported catalyst [29].

Epoxidation of chalcone by sodium percarbonate in 1,2-dimethoxyethane (DME)

using this catalyst afforded the product in 96% yield with 95%ee in 2 h. It is claimed

that the imidazolium moiety serves as a phase-transfer catalyst. This catalyst could

be easily separated from the reaction mixture by rapid filtration and could be reused

at least six times without any loss in both yield and ee. What is interesting is the

reaction rate in the recycled use was much higher (finished in 15min) than that of the

first use. The authors speculated that the catalyst was activated during its first use

(entry 12 in Table 4.1).

Although not a PAA, a helix peptide containing a de novo designed amino acid,

(1S,3S)-1-amino-3-methoxycyclopentanecarboxylic acid (AMC), having a sequence

of -(Leu-Leu-AMC)n- was very recently reported by Tanaka’s group as a good Juli�a–Colonna reaction catalyst [30]. A nonamer was proven to be a highly efficient and

selective catalyst for this reaction (entry 13 in Table 4.1).

Yashima and coworkers prepared helical polyacetylene starting from monomer

R-Ala-Ala-Ala-OH, where R is the (4-ethynyl)benzoyl group [31]. The main-chain

helicity of the polyacetylene was induced by the chirality of the amino acid units.

They applied the polyacetylene having trialanine side chains to the conditions of the

Juli�a–Colonna reaction to obtain the chalcone epoxide with up to 38%ee.

In 1983, Komari and Nonaka realized electrochemical asymmetric oxidation on a

poly(amino acid)-coated electrode surface [32]. He showed that the unsymmetric

sulfides can be enantioselectively oxidized to the corresponding chiral sulfoxides

(Scheme 4.2). The electrode was first covered with electroconducting polypyrrole;

then the whole electrode was dip-coated in the poly(amino acid) solutions. The

electrochemical sulfoxidation of tert-butyl phenyl sulfide on a polyvaline-coated Pt

electrode occurred in 45% yield with 93%ee to produce (R)-sulfoxide. Less effective

were polyleucine (62% yield, 15%ee) and poly(g-benzyl glutamate) (46% yield,

35%ee). The mechanism of asymmetric induction during electrochemical oxidation

is not clear. In the case when the PAA-modified electrode was subjected to reuse, the

first and second reuse of the electrode produced comparable results with that

obtained by a freshly prepared electrode, whereas the enantioselectivity considerably

POLY(AMINO ACID) CATALYSTS 97

decreased after the third reuse. This was explained by the gradual removal of a

noncovalently bound PAA layer, and it was revealed that the retreatment of the

electrode with PAA solution after each run somewhat improved the result.

Nonaka et al. also developed the electrochemical asymmetric reductions. Reduc-

tive debromination of prochiral dibromide 4 on a polyvaline-coated graphite

electrode produced monobromide 5 in 48% yield and 17%ee [33] (Scheme 4.3).

Formal hydrogenation of methylcoumarin 6 resulted in 8% yield with 43%ee [34].

Although the chirality is not derived from amino acid alpha carbon, oligoglycine

having a chiral N-(1-phenylethyl) group showed excellent performance in 2,2,6,6-

tetramethylpiperidine-1-oxyl radical (TEMPO)-catalyzed oxidative kinetic resolu-

tion of racemic 1-phenylethyl alcohol [35] (Scheme 4.4). They carried out a

positional scanning of the TEMPO and found that the reaction did not proceed in

an enantioselective manner when the TEMPOwas on the second or the third nitrogen

to the N-terminal.

PAA-coated electrode

PhS

Bu4N BF4, CH3CN, H2O

electrolysisPh

SO

SCHEME 4.2. Asymmetric electrochemical oxidation promoted by poly(amino acid)-coated

electrode [32].

BrPh

Ph Br

* BrPh

Ph H

O O

*

O O

4

76

HBr

5

poly(L-Val)-coated electrode

poly(L-Val)-coated electrode

2e, 2H+

2e, 2H+

+

SCHEME 4.3. Asymmetric electrochemical reductions promoted by polyvaline-coated

electrode [33,34].

OH1 mol%

NaOCl/KBrCH2Cl2, 0ºC

O OH

+

s-value up to 5.6

N

6NH2

O

O

NH

NO

SCHEME 4.4. Oxidative kinetic resolution of 1-phenylethyl alcohol by TEMPO attached on

chiral peptoid [35].


4.3 TRI- AND TETRAPEPTIDE CATALYSTS

As mentioned in the previous section, trialanine showed ability as an asymmetric

catalyst for the conjugate addition. That might be the first tripeptide-catalyzed

asymmetric reaction. However, in that work, the peptide was made by NCA

polymerization and the polydispersity in DP was inevitable. Inoue’s group was

aware of this point, and later they tried the same reaction with monodisperse

oligoalanines [36]. The result of the catalytic asymmetric conjugated addition using

H-Ala-Ala-Ala-NHPr was proven to be similar to that obtained with the trialanine

derived from NCA polymerization.

Berkessel and coworkers systematically investigated peptide length effect on

the Juli�a–Colonna reaction for TentaGel-supported polyleucines as catalysts. [37]

Di-, tri-, and tetraleucine catalysts produced the chiral epoxide with 15, 65, and

90%ee, respectively. Longer polyleucines up to 20mer constantly resulted in

>95%ee. They emphasized that the a-helical structure of polyleucine is essential

for realizing high enantioselectivity. They also pointed out that the PEG moiety

connected at the C-terminus of polyleucine has a role for the “helix surrogate” of

the polyleucine.

The oldest tripeptide asymmetric catalyst with a nonrepetitive amino acid

sequence might be Z-Phe-His-Leu-OH reported by Ueoka and coworkers for the

enantiomer differentiating hydrolysis of N-acylphenylalanine 4-nitrophenyl

ester in 1984 [17] (Scheme 4.5). This peptide showed surprisingly high selectivity

of kL/kD¼ 71 for the substrate having the N-dodecanoyl group under optimized

micellar/vesicular conditions.

It took 14 more years until the next efficient tripeptide catalyst was reported by

Miller’s group. In 1998, they showed that a tripeptide containing a non-natural amino

acid 3-(1-imidazolyl)-(S)-alanine (Ima) is a good catalyst for the kinetic resolution

in the acetylation of trans-2-(N-acetylamino)cyclohexan-1-ol with acetic anhy-

dride [38] (Scheme 4.6). They intended to use a minimal b-turn peptide so that

the functional groups at two termini cooperatively participated in the catalytic

process. A tripeptide having the sequence of Boc-Ima-Pro-Aib-NH-[(R)-1-pheny-

lethyl], of which the Pro-Aib part adopts a b-turn secondary structure, was claimed to

catalyze efficiently an enantiospecific acetylation through an N-acetylimidazolium

intermediate. The tripeptide was prepared by solution-phase synthesis. The ratio of

the rate constants of the peptide-catalyzed acetylation of two enantiomeric sub-

strates, kfast/kslow or s-value, was up to 12.6. In this reaction, initially, the catalyst 9

Tris buffer (pH 7.6), rt

(C16H33)NMe3 Br

Z-Phe-His-Leu-OH

(C14H29)2NMe2 Br

C11H23CONH CH CCH2

OO

NO2HN CH C

CH2

OHO

C11H23CO HO NO2+

kL/kD = 71

SCHEME 4.5. Tripeptide catalyzed hydrolytic kinetic resolution under micellar/vesicular

conditions [17].

TRI- AND TETRAPEPTIDE CATALYSTS 99

and the substrate 8 were dissolved in chloroform, and then toluene was added to

provide white suspension. The reaction is essentially heterogeneous.

Miller’s group pointed out that the chirality of the 1-phenylethyl group is

important for the efficient kinetic resolution, and when the epimer having a (S)-1-

phenylethylamine unit was used as catalyst, the same product was obtained with

53% ee, or s-value¼ 3.5. They extended this research to the b-turn tetrapeptide

catalyst using p-(methyl)histidine (Pmh) instead of Ima. A sequence Boc-Pmh-

(L or D)-Pro-Aib-Xaa-OMe was optimized for Xaa¼ (L or D)-Phe, (L or D)-Val, and

Gly [39]. Through an analysis of proton nuclear magnetic resonance spectrum they

found that the peptide having D-Pro-Aib moiety has a stronger tendency to adopt a

type II b-turn conformation, and this tendency was reflected on the higher

differentiating ability for the racemic alcohols compared with its analog having

a L-Pro unit. With this catalyst, the ee of unreacted starting alcohol was higher

compared with the corresponding acetate, and the Boc-Pmh-D-Pro-Aib-L-Phe-

OMe–catalyzed reaction produced the intact alcohol with 99%ee and the acetate

with 73%ee, which equals s-value¼ 28, at 58% conversion.

Through the two studies mentioned, they found that when the peptide-catalyzed

reaction is faster, it is also more selective. On the basis of this fact, they proposed a

screening method for the effective peptide catalysts [40]. On the resin beads used for

the preparation of peptides, a 9-(1-piperidinylmethyl)anthracene derivative was

introduced (Figure 4.2). This compound is photochemically inert because of efficient

quenching of the excited state of anthracene by the electron transfer from amino

nitrogen. Once this amino group is protonated, it can no longer participate in the

electron transfer process, resulting in the fluorescence from the excited anthracene.

The peptide library was constructed on the one-bead-one peptide basis. In the

peptide-catalyzed acylation of alcohols with acetic anhydride, one equivalent of

NHAcOH

NHAcOAcpeptide

Ac2O

Toluene,0°C

>90% yield, 84% ee, s-value = 12.6

N

OBocNH

NH

O

HNO

N

N

8 9

SCHEME 4.6. Tripeptide catalyzed kinetic resolution by esterification [38].

peptide

HN

O

Npeptide

HN

O

NH

AcO

Non-fluerescent fluerescent

FIGURE 4.2. Fluorescent sensor for acylation reported by Miller’s group.


acetic acid is released during the progress of the reaction. This acid will protonate the

nearby nitrogen on the piperidine ring, and then the fluorescence is observed. The

usefulness of this selection method was found in the process of seeking penta- and

higher peptides, which will be mentioned later.

As for the tripeptide catalyst, Miller and Guerin had also developed azidation of

a,b-unsaturated imides [41] using peptide catalyst 10 (Scheme 4.7). This reaction

includes controlled formation of hydrazoic acid (HN3) bymixing trimethylsilyl azide

and pivalic acid in the reaction flask and the subsequent amine-catalyzed conjugate

addition of an azide anion in an enantioselective manner.

Another line in peptide-catalyzed asymmetric acylation research has been

reported by Schreiner’s group. They applied tetrapeptide 11 to the kinetic resolution

of cyclic trans-1,2-diols [42] (Scheme 4.8). They had tested racemic 5-, 6-, 7-, and

8-membered substrates and obtained very high efficiency for the enatioseparation

with an s-value> 50 for 6-, 7-, and 8-membered substrates. The enantiomeric excess

of an unreacted substrate was high.

N

O

HNO

ONH

NH

Boc

N

N

Bn

O

N

O

R

O

N

O

R

N3

TMS-N3, tBuCOOHToluene, -10ºC

2.5 mol%

up to 90% yieldup to 92% ee

10

SCHEME 4.7. Tripeptide catalyzed asymmetric conjugate addition of azide anion [41].

HN

NH

NH

HN

OO

OO

O

N N Me

O

O

11

OH

OH

OAc

OH

OH

OHn

n = 1-4

1-2 mol% peptide 11

5.3 equiv Ac2OToluene, -20 to 0ºC n

+

n

SCHEME 4.8. Tetrapeptide catalyzed kinetic resolution of trans-1,2-cycloalkanediols [42].


Sunoj and Shinisha rationalized the mechanism of the kinetic resolution of

cyclohexanediols by peptide 11 through density functional theory (DFT) calculation

of the substrate–catalyst complex [43]. They successfully reasoned for the preferential

isomer of the acylation of trans-1,2-diols and predicted that the desymmetrization of

cis-1,2-cyclohexanediol would also proceed in a highly enantioselective manner by

using the same catalyst 11.

This was experimentally verified again by Schreiner’s group [44]. Although

monoacylated products derived from cyclic cis-1,2-diols easily racemize as a result

of intramolecular transesterification, rapid oxidation of the monoacetate by catalytic

TEMPO and excess m-CPBA was proven to be effective for the suppression of the

racemization (Scheme 4.9).

Miller et al.’s b-turn peptide catalyst was not limited to functional group

manipulation, but it was also applicable to a C-C bond forming reaction. Intramo-

lecular asymmetric C-C bond formation through a Stetter reaction was demonstrated.

For this reaction, thiazole moiety behaves as an activator of the formyl group [45]

(Scheme 4.10).

Miller et al. had also extended their tetrapeptide catalyst to an asymmetric

aza-Baylis–Hillman–like reaction of allenoate ester with imines [46] (Scheme

4.11). Here they introduced the non-natural amino acid, 3-pyridylalanine.

Sophisticated extension of the b-turn tripeptide catalyst with completely different

machinery was reported by Miller et al. They used the tripeptide 12 having Asp

moiety for asymmetric epoxidation of allyl phenylcarbamates through the interme-

diacy of in situ formed percarboxylic acid of the aspartate side chain [47]

Scheme 4.12. The corresponding homoallyl carbamate was not a good substrate

OH

OH

OAc

OH

OAc

O

1 mol% peptide 115.3 equiv Ac2O5.3 equiv DIEA

Toluene, -40ºC, 48 h

81% GC yield88% ee

TEMPOm-CPBABu4NBr

rt, 1 h

70% yield88% ee

SCHEME 4.9. Tetrapeptide catalyzed desymmetrization of cis-1,2-cyclohexanediol [44].

CHO

OOtBu

OR O

O

OtBu

OR

NH

O HN

ONH

S N

Boc

BnO

I

DiisopropylethylamineCH2Cl2, rt, 48 h 39-45% yield

64-76% ee

20 mol%

SCHEME 4.10. b-Turn peptide catalyzed asymmetric Stetter reaction [45].


for the enantioselective reaction. Later they clarified the importance of each part of

the peptide catalyst structure through control experiments with the catalysts in which

the amide bond was isosterically displaced by alkenes [48].

In 2000, List et al. reported that L-proline, a simple amino acid, catalyzes the

direct asymmetric aldol reaction [49]. Although the asymmetric Robinson annelation

including intramolecular asymmetric aldol reaction step was known to be catalyzed

by proline, as mentioned in Section 4.1 [11], its expandability to the intermolecular

version only recently has been investigated. Therefore, their finding opened a new

possibility for proline derivatives including prolyl peptides as asymmetric catalysts.

As a pioneer of the proline catalyst, List and Martin first examined the catalytic

performance of N-terminal prolyl peptides [50]. They tried eight dipeptides and

two tripeptides in the “benchmark” aldol reaction of acetone with 4-nitrobenzalde-

hyde (4NBA). Some gave better yield compared with the proline catalyst; however,

the enantioselectivities were either equal to or less than that of the proline-catalyzed

reaction (entries 2 and 3 in Table 4.2).

After that, many groups tried out this reaction with peptide catalysts. Some

of them, including our group used an immobilized peptide as a catalyst. The results

with such resin-bound peptide catalysts other than ours should be found in the

previous chapter.

N

ONH

NH

O

HNO

NMe2

OBoc

NO

XRN

R1

R2

OO

XRR1

NHO

R2

10 mol%

Toluene+

X = O, S


SCHEME 4.11. Tetrapeptide catalyzed asymmetric aza-Baylis-Hillman-type reaction [46].

N

ONH

NH

O

HNO

HOOC

BocOPhHN

O

OPhHN

O

O

10 mol%

Diisopropylcarbodiimideaq. H2O2, DMAPCH2Cl2/H2O


12

SCHEME 4.12. Asymmetric epoxidation catalyzed by tripeptide through peracid formation

of side chain carboxy group on N-terminal Asp residue [47].


TABLE4.2.Aldolreactionofacetonewith4-nitrobenzaldehidecatalyzedbypeptide

O+

pept

ide

OC

HO

O2N

NO

2

OH

Entry

Catalyst

(mol%

)Prep.a

Conditions

Yield

(%)

ee(abs.config)

Ref.

1H-Pro-O

H(30)

-DMSO,rt,4h

68

76(R)

49

2H-Pro-G

ly-G

ly-O

H(30)

n.m

.DMSO,rt,18h

68

53(R)

50

3H-Pro-H

is-A

la-O

H(30)

n.m

.DMSO,rt,18h

85

56(R)

50

4H-Pro- D-A

la-D-A

sp-N

H2(10)

DAcetone,

rt,24h

73

70(R)

51

5H-Pro-Pro-A

sp-N

H2(1)

DAcetone,

rt,4h

99

80(S)

51

6H-Pro-Pro-A

sn-N

H2(10)

DAcetone,

rt,24h

39

54(S)

52a

7H-Pro-Pro-G

lu-N

H2(1)

DAcetone,

rt,18h

81

64(S)

52a

8H-Pro-Pro- D-A

sp-N

H2(18)

DAcetone,

rt,18h

46

33(S)

52b

9H-Val- D-Pro-G

ly-Leu-O

H(20)þPhCOOH

(40)

NMeO

H,rt,48h

58

95(R)

53

10

H- D-Pro-Tyr-Phe-TentaGel

(20)þZnCl 2(20)

DAcetone/H2O/THF¼1/1/1,0� C

,20h

99

71(S)

57

11

H-Pro-~

-Pro-O

Hb(20)

NAcetone/H2O¼10/1,rt,24h

89

78(R)

55

aPreparationmethodofapeptidecatalyst:D¼solid-phasesynthesis,N¼solution-phasesynthesis,n.m

.¼notmentioned.

bForsymbol~,seeFigure

4.3.

104

The first peptide catalyst that exceeded both the yield and the selectivity of the

proline-catalyzed reaction was the one reported by Wennemers’s group [51]. They

used a combinatorial method for the search of a catalytically active tripeptide along

with their original “substrate-catalyst co-immobilization” approach.

Elements for the tripeptide library H-AA1-AA2-AA3-NHR (R = resin or H) made

by Wennemers’s group are as follows:

AA1, AA3: X, D-Val, L-Ala, L-Leu, D-Phe, L-Tyr, D-Arg, D-Asp, L-Glu, D-Asn, L-Gln

AA2: X, L-Val, D-Ala, D-Leu, L-Phe, D-Tyr, L-Arg, L-Asp, D-Glu, L-Asn, D-Gln.

X¼ {Gly, D-Pro, L-Pro, D-His, L-His}

They successfully picked up two tripeptides from a 153¼ 3375–sized library (entries

4 and 5 in Table 4.2). One of them, H-Pro-Pro-Asp-NH2, was found to be effective,

and the reaction was completed within 4 h in the presence of only 1 mol% of catalyst.

When the reaction was performed at a lowered temperature, the aldol product was

obtained in 98% yield and 90%ee. It is very interesting that this peptide produced

(S)-aldol as a major product, whereas the reactions catalyzed by other peptides

having L-proline atN-terminal proceeded in an (R)-selectivemanner. This means that

the stereochemistry of the aldol reaction catalyzed by H-Pro-Pro-Asp-NH2 was

controlled by the 3D structure of the whole peptide rather than by the point chirality

of the proline at the N-terminal. Computational calculation of this molecule showed

that the Pro-Pro has a turned conformation. Related peptides having an N-terminal

Pro-Pro sequence, including those containing D-proline, were thoroughly surveyed

byWennemers’s group, but a catalyst with better performance was not found (entries

6 to 8 in Table 4.2) [52].

Da et al. demonstrated that tetrapeptides having a b-turn structure are also

enantioselective catalysts for the aldol reaction (entry 11 in Table 4.2) [53]. When

cocatalyzed with benzoic acid, H-Val-D-Pro-Gly-Leu-OH produced the product with

95%ee, although the yield was moderate. When the benzoic acid is absent, the

enantioselectivity reduces to 66%ee.

In our body, enzymes catalyze many kinds of reactions in water. As the enzymes

are polypeptides in their chemical structure, it is expected that the peptide can also

catalyze the reaction under aqueous conditions. However, the addition of water to the

proline-catalyzed aldol reaction of acetone with 4NBA brings about lowering of the

enantioselectivity [54]. For example, the proline-catalyzed aldol reaction in acetone/

H2O¼ 10/1 (v/v) proceeds with entirely no enantioselectivity [55].

Development of a water-tolerable version of a proline-related asymmetric catalyst

would open a new horizon to organic synthesis. Great progress in this field has been

achieved mainly by prolinol-derived catalysts [56]. However, it would be desirable

that such a catalytic reaction can also be realized by peptides because the peptide

catalyst can be optimized for a variety of substrates through “fine-tuning” of its

sequence.

Kudo and coworkers have developed the prolyl peptide catalyst from this

viewpoint by employing a tripeptide D-Pro-Tyr-Phe covalently immobilized on


amphiphilic polyethyleneglycol-polystyrene (PEG-PS) resin, or TentaGel, as a

catalyst (entry 10 in Table 4.2) [57]. Nearly quantitative yield and good enantios-

electivity was attained for the reaction in the solvent system of acetone/H2O/

THF¼ 1/1/1.

The same reaction in the presence of water was also reported by Reiser’s

group [55]. They designed 2c,3t-2-amino-3-methoxycarbonylcycropropanecar-

boxylic acid (b-ACC) as a turn-inducing element (Figure 4.3). Both antipodes of

this chiral b-amino acid were prepared and incorporated into the peptide sequence

to find the optimal catalyst, which is shown in Table 4.2, entry 11. The presence of

10 vol% of water was essential for high enantioselectivity.

Kudo’s group extended their research to a one-pot sequential reaction including

the enantioselective process [58]. In general, acid catalysts are not compatible

with base, and vice versa. If the acidic and basic sites are spatially separated, they

might independently work without perturbing each other [59]. In the presence of an

acidic ion-exchange resin Amberlite and the resin-supported D-Pro-Tyr-Phe peptide,

the deprotection of acetal 13 and the subsequent asymmetric aldol reaction of

generated aldehyde 14with acetone occurred successively in one pot (Scheme 4.13).

The mixture of these two kinds of resin-supported catalysts could be reused six times

without significant loss in catalytic activity.

Another synthetically useful sequential reaction, an oxidation of primary alcohols

to aldehydes followed by the asymmetric aldol reaction, was found by the same

group (Scheme 4.14). The oxidation was performed by a combination of TEMPO

and a copper salt using air as an oxidant [60]. Resin-supported TEMPO was used to

avoid possible amine-mediated C-O bond formation between acetone and TEM-

PO [61]. The triglycyl peptide between TEMPO and the resin was proven to absorb

the Cu complex, leading to the enhancement of the oxidation process [62].

H2N COOH

O O

(+)-cis-β-ACC,

H2N COOH

O O

(-)-cis-β-ACC,

FIGURE 4.3. Structure of Reiser’s amino acids having a cyclopropane skeleton.

OCH3

H3CO

O2N

OHO

O2N+

OHC

O2N

HO3S

514131

D-Pro Tyr Phe

13 : 14 : 15 = 10 : 1 : 89ee of 15 = 73%

H2O/Acetone/THF = 1/1/1rt, 24 h

Amberlite

20 mol%

SCHEME 4.13. One pot sequential deacetalization-asymmetric aldol reaction catalyzed by

an acidic Amberlite resin and a basic resin-supported tripeptide [58].


In 2005, Cordova and coworkers showed that several nonproline amino acids,

such as alanine, valine, and aspartate, catalyze the aldol reaction of cyclohexanone

with 4NBA in a highly diastereoselective (anti/syn up to 37/1) and exceptionally

enantioselective manner of 99%ee or higher [63]. This finding can be regarded as

another breakthrough in the amino acid organocatalysis, and it is also significant

from the viewpoint of an industrial application.

Then, just as many chemists did after the finding of the proline catalyst, the

catalytic ability of the related peptides was investigated by Cordova’s group [64].

Although several dipeptides including H-Ala-Ala-OH showed a comparable result

with amino acid catalysts, a tripeptide H-Ala-Ala-Ala-OH was proven to be less

efficient (entries 2–4 in Table 4.3).

It is noteworthy that N-terminal prolyl peptides are a good catalyst for the

asymmetric aldol reaction of acetone but not so for the reaction of cyclohexanone,

and vise versa, although some exceptions to the consensus were introduced recently.

A peptide-catalyzed aldol reaction of hydroxyacetone with aryl aldehydes was

reported by Gong and coworkers in 2004 [65] (Scheme 4.15). When the reaction was

performed in aqueous media, the C-C bond formation occurred preferentially at the

3-position of hydroxyacetone. The reaction took days to obtain affordable yield, and

the stereoselectivity was high. They had synthesized the peptide catalysts in gram

scale by liquid-phase reaction and had purified theN-protected precursor of the target

peptide through recrystallization from ethanol. What is interesting is that their

catalyst 17 was not only stereoselective but regioselective as well.

When chemists discover a certain good catalyst, they will try to use that catalyst

for another reaction. That is true for peptide catalysts. Peptide catalysts for aldol

reaction have been widely examined as catalysts for Michael addition, which is

another important C-C bond forming reaction.

Cordova and coworkers had extended their simple di- and tripeptide catalysts to

asymmetric Michael addition, and they found that the reaction of a 6-membered

ketone with b-nitrostyrene (BNS) proceed in a highly enantioselective manner [66]

(Scheme 4.16). Catalytic efficiency was in the order of H-Ala-Ala-OH>H-Ala-Ala-

Ala-OH > H-Ala-OH, whereas enantioselectivity was close to each other. It is

interesting to add that, for the reaction, H-L-Ala-D-Ala-OH was more potent

compared with the parent H-L-Ala-L-Ala-OH. As shown in the aldol reaction, the

reaction of the acyclic ketone did not produce a good result.

HO

O2N

OHO

O2N

+OHC

O2N

(Gly)3TEMPOO

D-Pro Tyr( tBu) Phe

16 14 15

air, DMF, rt, 24 h

Cu-complex adsorbed on

buffer (pH 7.8) 0°C, 24 h

16 : 14 : 15 = 0 : 13 : 87ee of 15 = 85%

20 mol%

20 mol%

SCHEME 4.14. Sequential primary alcohol oxidation and asymmetric aldol reaction of the

resulting aldehyde catalyzed by a copper ion/immobilized TEMPO couple and a resin-

supported tripeptide [62].


TABLE4.3.Peptide-catalyzedaldolreactionofcyclohexanonewith4NBA

O

+pe

ptid

eO

OH

C

NO

2N

O2

OH

O

NO

2

OH

+

anti

syn

ee(%

)

Entry

PeptideCatalyst(m

ol%

)a

Conditions

Yield

(%)

anti/syn

anti

syn

Ref.

1H-A

la-O

H(30)

DMSO,10eq.H2O,rt,3days

95

15/1

99

-63

2H-A

la-A

la-O

H(30)

DMSO,10eq.H2O,rt,48h

73

8/1

91

-64a

3H-A

la-A

la-A

la-O

H(30)

DMSO,10eq.H2O,rt,48h

90

1/2

81

-64a

4H-A

la-A

la-A

la-O

H(30)

H2O,SDS(1

eq),rt,120h

42

2/1

75

-64b

5H-Val- D-Pro-G

ly-Leu-O

H

(20)þPhCOOH

(40)

MeO

H,rt,76h

87

36/64

95

51

53

6H-Pro-~

-Pro-O

H(20)

Ketone/H2O¼10/1,rt,24h

75

6/1

95

99

55

aAllpeptides

wereprepared

bysolution-phasesynthesis.

108

The Michael addition of the same combination of substrates was also repoted by

Tsogoeva’s group. The reaction was carried out “on water,” which means that the

substrate is not water soluble and the reaction occurs at the oil/water interface [67].

The result of the Michael addition of cyclohexanone to BNS with dipeptide catalyst

H-Pro-Phe-OH was better (99% yield, syn/anti¼ 95/5, 68%ee) compared with the

tripeptide catalyst H-Pro-Phe-Phe-OH (70% yield, syn/anti¼ 96/4, 56%ee).

Wennemers’s group had also succeeded in finding a good catalyst for Michael

additions. In the previous study on the structure-activity relationship of the peptide

catalyst for an asymmetric aldol reaction, her group had tried a several of tripeptides

that are structurally related to the parent catalyst H-Pro-Pro-Asp-NH2. They had

surveyed that tripeptide library for the Michael addition shown in Scheme 4.17 and

had found that H-D-Pro-Pro-Asp-NH2, a diastereomer of the parent compound, was a

good catalyst for the Michael addition of aldehydes to b-substituted nitroolefins [68].They explained the high performance of the catalyst by the “double activation”

mechanism, namely, enamine formation by proline and nitro group activation by a

carboxylate of Asp side chain in a fixed turn conformation. After additional

RCHO

OOH

NH

NH

O HN

NH

O

O

O

O

OOH

R

OH

R

OH O

OH

+

20 mol%

THF/H2O, 0ºC


+

minor

17

SCHEME 4.15. Tetrapeptide-catalyzed regioselective asymmetric aldol reaction of hydro-

xyacetone [65].

R1 R2

O

+ ArNO2

30 mol%

H2N

HN

OH

O

O

10 equiv H2ODMSO/NMP

R1

O

R2

Ar

NO2

or

45 mol%

H2N

HN

OH

O

O

up to 95% yieldup to 36:1 drup to 98% ee

SCHEME 4.16. Peptide-catalyzed diastereo- and enantioselective conjugate addition of

ketones to b-nitrostyrenes [66].


screening, they found that H-D-Pro-Pro-Glu-NH2 is an even better catalyst [69], and

they applied this Michael reaction to the production of g2-amino acids [70]. Through

kinetic study of this reaction, they found that the catalyst loading can be decreased to

as low as 0.1 mol% when dried solvents, substrates, and glassware were used [71].

4.4 LONGER PEPTIDES WITH A SECONDARY STRUCTURE

Longer peptide catalysts, provided that they have an ideal 3D structure, will interact

with substratesmore efficiently comparedwith shorter ones; hence, the higher activity/

selectivity is expected for them. However, the challenge of finding a longer peptide

catalyst is associatedwith an increased risk because chemists have towiden the field of

search and that takes more time and money with no guarantee of hitting any target.

In the combinatorial approach, the number of possible sequences increases in the

manner of geometric progression with an increase in the peptide length. If the

elements were limited only to the proteinogenic 20 L-amino acids, the number of

combinations is 3.2� 106, 6.4� 107, 1.3� 109, and 2.6� 1010 for penta-, hexa-,

hepta-, and octapeptides, respectively. As has been shown in the previous section, it is

effective to add D-amino acids to the elements for the library. In that case, even

pentapeptide has 9.0� 107 possible combinations. In addition, chemists sometimes

want to try a couple of other non-natural amino acids. This situation makes it

impossible to apply an orthodox combinatorial approach. Instead, a biased library

containing an affordable number of members (maybe at most 106 order) that consist

of only selected amino acids might be of practical use.

Moreover, it should be mentioned that the larger peptide catalyst had lower

versatility because of the limitation in the production of peptide. This situation requires

the longer peptide catalyst at least one of the following: (1) the catalytic reaction is so

unique and cannot be achieved by any other catalysts, (2) the catalytic ability of the

peptide is exceptionally high, (3) the catalyst can be recycled and used repeatedly.

Since 2001, efforts toward finding good penta- and longer peptide catalysts have

been made by Miller and coworkers. They first applied their combinatorial

approach to the peptide catalyst optimization for a kinetic resolution of secondary

N

OO

HN

NH

O

NH20.1-0.4 mol%

0.1-0.4 mol% NMMCHCl3/iPrOH, rt, 48 h

OHC

R1

+ R2 NO2 OHC

R1

R2

NO2

COOH

up to 98% yieldup to 98:2 drup to 98% ee

SCHEME 4.17. Peptide-catalyzed diastereo- and enantioselective conjugate addition of

aldehydes to b-nitrostyrenes [69].


alcohols [72a]. Unlike the substrate 8 used in the tri- or tetrapeptide-mediated

kinetic resolution, simple chiral secondary alcohols having no functional

groups other than hydroxyl group, 1-phenylethanol, for example, are obviously

more difficult to differentiate. The peptide catalyst with a longer chain will be

required to realize efficient recognition of the substrates. Accordingly, they began

a quest in the octapeptide space. N- and C-termini of the peptide were fixed to be

Pmh and L-Ala, respectively, and the rest of hexapeptide region was screened using

14 kinds of amino acids, D-Val, D-Phe, D-Pro, L-Ile, L-Tyr(tBu), L-Gln(Trt), L-Ala,

L-Asn(Trt), Gly, Aib, L-Asp(tBu), L-Trp(Boc), L-His(Trt), and D-Glu(tBu) (Aib

¼ 2-aminoisobutyric acid). After screening the library with the size of 146¼ 7.5

� 106 for the acetylation of (�)-1-phenylethanol in toluene at room temperature,

they picked up one peptide, Pmh-L-Asn(Trt)-D-Val-L-His(Trt)-D-Phe-D-Val-D-Val-

L-Ala (18), with an s-value of 8.2. Then they made a second-generation library

that is directed to the peptide 18. The directed library is a library that is designed so

that the peptide sequence of the member is similar to the parent peptide 18. Then

they selected eight new peptide catalyst candidates, and subjected them to the

solution-phase assay. Although “on resin” and “in solution” results was not

identical, they could find the most effective octapeptide, Pmh-L-Tyr(tBu)-D-Val-

L-His(Trt)-D-Phe-D-Val-L-Tyr(tBu)-L-Ile (19), which showed an s-value of 20.

The scope of this peptide for the kinetic resolution of secondary alcohols was

checked with nine substrates. For all the substrates, the catalyst 19 was proven to

be effective. Two of them, 1-(1-naphthyl)ethanol and trans-2-phenylcycloheanol,

produced an s-value of >50. Even 2-butanol could be resolved with an s-value

of 4.0.

Their method was successfully applied to the development of a substrate-specific

peptide catalyst for a synthetic intermediate of mitosane 22 [72b] (Scheme 4.18).

They screened a 152-membered b-turn peptide library and concluded that penta-

peptide 20 was the best catalyst. The optical resolution was achieved starting from

0.25 g of racemate using 13mg of the peptide catalyst to produce 0.12 g of the

recovered alcohol with 90%ee. Single recrystallization resulted in an enantiomeri-

cally pure compound with the total yield of >40%.

The same strategy was applied for the phosphorylation of myo-inositol to seek

the kinase analog from the peptide library [73] (Scheme 4.19). The targeted reaction

was desymmetrization, that is, site-selective phosphorylation ofmeso-triol, 2,4,6-tri-

O-benzyl-myo-inositol. It should be noted that both the 1-position selective catalyst

23 and the 3-position selective catalyst 24 were successfully found after intense

screening. For the selection of the latter catalysts, screening was carried out three

times in a gradually focusing manner. They had also succeeded in fishing out a good

acylating peptide catalyst for desymmetrization of a linear substrate, 2-protected

glycerol [74]. Later, they showed that the desymmetrization reactions of meso-diols

can also be achieved through the sulfonylation with 4-nitrophenylsulfonyl chloride.

For the catalyst, 24-related tetrapeptide in which the C-terminal Try(tBu)-Phe-OMe

is changed to Leu-OMe was used [75].

Then, they tried how far they can go. Desymmetrization of a prochiral bisphenol 25,of which the two hydroxy groups are separated by nearly 1 nm, was challenged [76]

LONGER PEPTIDES WITH A SECONDARY STRUCTURE 111

(Scheme 4.20). A hexapeptide library having N-terminal Pmh was designed to have

efficient interaction with the substrate. Starting from 138 peptides, repetitive screen-

ing, truncation, and final C-terminal modification of the peptide produced the best

catalyst 26.

N

OHOO

BocN

OAcOO

BocN

OHOO

Boc

N

O

NH

O

Toluene

2 mol% peptide 20Ac2O

+

6 steps, 27% yield

21

21

22

N

ONH

NH

O

HNO

Boc

N

N

Me

NHO

OO20

SCHEME4.18. Application of peptide-catalyzed kinetic resolution toward the total synthesis

of mitosane [72b].

N

ONH

NH

O

HNO

Boc

N

N

Me

NHO

OO

O

O

OBnHO OH

OHBnO OBn

OBnHO O

OHBnO OBn

P(OPh)2

O

OBnOHO

OHOBnBnO

(PhO)2PO

24

HN

ONH

Boc

N

N

Me

O

HN

NH

O

Trt

N

N

BnO

HNO

ONH

OO

O

23

2 mol% peptide 23

13

1

65% yield>98% ee

2.5 mol% peptide 24

Cl-P=O(OPh)2, Et3NToluene, 0ºC

3

56% yield>98% ee

SCHEME 4.19. Controlled phosphorylative desymmetrization of myo-inositol-derived

meso-diol by peptide catalysts [73].


Then, they extended their chemistry to site-selective acylation of an unsymmetrical

polyol compound.By using erythromycin 27 as a substrate, theydemonstrated that the

peptide catalyst can override the inherent reactivity order of the hydroxy groups [77].

When acylation was performed using N-methylimidazole as a catalyst, site a

acetylated product and site b acetylated product were obtained in a ratio of a:b¼ 4:1,

whereas the value was 1:5 for the reaction catalyzed by peptide 28, which was

screened out of 137 candidates (Figure 4.4). Such a site-selective acylation is useful

for the study of the structure-activity relationship of bioactive compounds [78].

This methodology was extended to site-selective deoxygenation of diols through

a thionocarbonate intermediate (Scheme 4.21). The peptide 31 preferentially pro-

duced compound 29 with the ratio of 29:30¼ 11.7:1, whereas that of the reaction

mediated by the peptide 32 in the presence of FeCl3 cocatalyst was 1:6.6. Both

products were successfully deoxygenated by the action of tin hydride [79].

Peptide-catalyzed kinetic resolution is also applicable to racemic amines [80]

(Scheme 4.22). Boc protection of the amide nitrogen of thioformamide of

chiral 1-phenylethyl amine. Without using the library approach, they could obtain

O

O

O O

OH

O

OH

OH

OOH

OHO

OMe

NMe2

a

b

27

N

ONH

NH

O

HNO

Boc

N

N

Me

NHO

OO

NBoc28

FIGURE 4.4. Structure of erythromycin and its acylation site.

HO OH HO OAc

2.5 mol% peptideAc2O

CHCl3, -30ºC

25

HN

NH

BocNH

HN

XO

O

O

O

NN

Me

OHN

Trt

O

HN

HN

OMeO

O

Bn

iBu

HNHN

PhPh

Ts

X =

X = 80% yield, 95% ee

68% yield, 72% ee

(26)

SCHEME 4.20. Desymmetrization of prochiral bisphenol by peptide catalyst [76].


significantly an enantiospecific peptide catalyst 33. The Boc-protected thioforma-

mide was easily converted to the corresponding Boc-protected amines.

Other than for functional group transformation, Miller’s group tried to find a

peptide catalyst for C-C bond forming reactions. An asymmetric Baylis–Hillman

reaction of electron-deficient aryl aldehydes with methyl vinyl ketone in the presence

of cocatalyst L-Pro [81] (Scheme 4.23). Starting from 19%ee for a single amino acid,

Boc-NH-Pmh-OMe, they went as far as the octapeptide 34 shown in Scheme 4.23 to

achieve the ee of 78%. The precise method for the screening was not shown;

however, they claimed that rough optimization could lead to acceptable enantios-

OO OPh

HOHOOMe

Cl OPh

S N

OO OPh

OHOOMe

S OPh

29

OO OPh

HOOOMe

OPhS

30

catalyst

(2 equiv)(1.5 equiv)

CH2Cl2, rt, 1 h

+

N

ONH

NH

O

HNO

Boc

N

N

Me

NHO

OOPh

NBoc

HN

NH

BocNH

HN

NH

HN

NH

HN

OO

O

O

O

O

O

O

O

NN

Me

O

N

N

Trt

O

3132

SCHEME 4.21. Controlled site-selective thionocarbonate formation by peptide catalysts. [79].

N

ONH

NH

O

HNO

Ac

N

N

Me

NHO

OO

R2 NH

R1

H

S

R2 N

R1

H

S

BocR2 N

H

R1

H

S

5 mol%

Boc2O (0.6 equiv)CHCl3, 25ºC, 24 h

+

~50% conversions-value up to 43.7

33

SCHEME 4.22. Kinetic resolution of thioformamides by peptide-catalyst [80].


electivity. It should be noted that the combinatorial approach that has been used in the

acylation chemistry is not applicable to this reaction.

That is also the case for conjugate addition of highly enolizable alpha-nitro ketone

to enones. Instead of a combinatorial approach, they carried out a mechanism-driven

catalyst design to find the best peptide 35 [82] (Scheme 4.24).When the phenyl group

of the Michael donor is replaced by the cyclohexyl group, the enantioselectivity

reduces to 0%.

Kudo and coworkers took a totally different approach. Again they targeted the

asymmetric reactions under aqueous conditions. They used amphiphilic resin-

supported 30mer peptides that are “chimeras” of PAA and the b-turn peptide [83–85].

RCHO +

O 10 mol% peptide10 mol% proline

CHCl3/THF, 25ºC

O

R

OH


NH

OHN

HN

ONH

OHN

OBoc

NN

Me

HNO

Trt

N

OO

HN

O

NH

O

O

34

SCHEME 4.23. Octapeptide-catalyzed asymmetric Baylis-Hillman reaction [81].

N

ONH

NH

O

HNO

NHO

OO

N N BnO

NH

N

NH2

SO O

O

R3

O

R1

ONO2

R2

R1 R3

OO

R2 NO2


+Toluene, 4ºC

2 mol% peptide

35

SCHEME 4.24. Asymmetric conjugate addition of a-nitroketones to enones catalyzed by

rationally designed peptide [82].


The catalyst 36 consists of the N-terminal pentapeptide Pro-D-Pro-Aib-Trp-Trp,

which adopts the b-turn structure, and the a-helical polyleucine chain. This highlyhydrophobic peptide is attached to the amphiphilic PEG-PS resin (Figure 4.5). In

the molecular design, the polyLeu moiety was expected to behave as a hydrophobic

sink for organic compounds in aqueous media, which enhances the reaction by

raising the local concentration of substrates around the reaction center. The catalyst

was prepared through the polymerization of Leu-NCA initiated by the amino

residues on the TentaGel resin and the subsequent orthodox Fmoc solid-phase

peptide synthesis.

Catalyst 36 promotes the asymmetric transfer hydrogenation [83], the asymmetric

Friedel–Crafts-type alkylation [84], and the asymmetric a-oxyamination [85] effi-

ciently and enantioselectively in aqueous media (Scheme 4.25). The former two

reactions proceed through the iminium ion formation, whereas the mechanism of the

last reaction involves an enamine intermediate. It is worth noting that a single peptide

catalyst was effective in mechanistically different reactions.

(Leu)25.4D-ProPro Aib Trp Trp

catalytically active site hydrophobic chain

(36)

FIGURE 4.5. Structure of “chimeric” peptide catalyst by Kudo’s group.

+ N

O

RCHO

R

Ar

OH

RCHO

NH

OEtEtO

OO

RCHO

Ar-HNaBH4

R CHON

OR OH

NaBH4

THF/H2O = 1/2rt, 1 h


α-Oxyamination

Friedel–Crafts-type alkylation

+THF/H2O =1/2 (or H2O), rt



THF/H2O = 1/2, rt

20 mol% TFA • 36,

Transfer hydrogenation

20 mol% 3630 mol% FeCl2 • 4H2O30 mol% NaNO2, air

TEMPO

20 mol% TFA • 36

SCHEME 4.25. Catalytic asymmetric reactions of aldehydes by a common resin-immobi-

lized chimera peptide 36 [83–85].


As expected, the hydrophobic polyLeu moiety significantly enhanced the reac-

tion. More interestingly, the polyLeu part considerably affected the enantioselec-

tivity for the reactions. The case of asymmetric a-oxyamination is illustrated in

Scheme 4.26. When peptide 37 without a hydrophobic segment was used as a

catalyst, the reaction hardly proceeded and the enantioselectivity dramatically

decreased. The reaction catalyzed by the peptides having hydrophobic, but non–

a-helical, polyisoleucine or polyvaline moieties were slow, and low enantioselec-

tivities were observed. Replacing the part of the terminal five residues with their

antipode (catalyst 40) also resulted in a poor reaction rate and selectivity.

A brief molecular mechanical study showed that one enantiotopic face of the

reaction intermediate, regardless ofwhether it is iminium ion or enamine, is effectively

shielded by the peptide chain; hence, the enantioselectivity was attained. Infrared

spectroscopic observation revealed that the polyLeu moiety assists the formation of a

b-turn structure at the N-terminus even in the highly polar reaction media [83].

As mentioned in the previous section, if the chiral-amine–catalyzed organoca-

talytic reactions of aldehydes can be coupled by preceding in situ oxidation of the

precursor primary alcohol, it would be synthetically useful. Catalyst 36 could be

applied to the one-pot sequential reaction including the oxidation of alcohols to

aldehydes by the TEMPO/Cu system and the following peptide-catalyzed asymmet-

ric a-oxyamination (Scheme 4.27) [86]. This one-pot reaction was unique to peptide

catalysis in aqueous media, and it could not be attained by a homogeneous catalyst.

It was also demonstrated that the resin-supported peptide had high reusability,

affording the product without significant loss in yield and enantioselectivity even

after repeated use.

Finally, the same group has recently found an asymmetric epoxidation catalyzed

by the immobilized peptide. After screening the peptide sequence starting from the

lead catalyst 36 (73%ee for the reaction in Scheme 4.28) through to elongation/

TrpD-ProPro Aib Trp (Leu)25.4

CHO+ N

O

NO

OH

NaBH4

TrpD-ProPro Aib Trp

TrpD-ProPro Aib Trp (Ile)26.5

TrpD-ProPro Aib Trp (Val)26.3

D-TrpProD-Pro Aib D-Trp (Leu)26.5

(36)

THF/H2O = 1/2rt, 3 h

20 mol% catalystFeCl3 (1 equiv)

8 39

57 89

yield (%) ee (%)catalyst

20 13

21 14

14 -23(40)

(38)

(39)

(37)

SCHEME 4.26. Asymmetric a-oxyamination of aldehyde catalyzed by immobilized

peptides [82].


truncation of the amino acids and displacement of targeted positions, they found that

peptide catalyst 41 was the best [87]. Catalyst 41 contains hydrophobic and bulky

pyrenylalanines. These amino acids should effectively shield the one face of the

intermediate iminium ion from the attack of the small nuclephile, �OOH.

4.5 OTHERS

Although we focused on peptide catalysts consisting of more than three amino acid

residues, it should be noted that there are excellent dipeptide asymmetric catalysts.

Besides the ones hitherto mentioned, cyclo-Phe-(S)-a-amino-g-guanidinobutyryl foran asymmetric Strecker reaction [88], and H-Pro-Phe-OH [89], H-Pro-Trp-OH [90],

H-Ala-Phe-OH, H-Val-Phe-OH, H-Val-Val-OH, and H-Val-Ala-OH [65] for an

asymmetric aldol reaction are notable. Dipeptide H-Pro-Val-OC12H25 having a long

alkyl chain was reported to form hydrogel at a lower temperature [91]. The aldol

reaction of cyclohexanone with 4NBA catalyzed by this peptide hydrogel was

considerably improved (18%ee to 88%ee) by changing the temperature from 25�Cto 5�C. It is interesting that this small difference in the temperature brought about

considerable increase in the enantioselectivity.

(Ala(1-Pyn))3 (Leu)28.6AchD-Pro

NaBH4

H2N COOH

CHO

O2NH2O2

OOH

O2N

H2N COOH(41)

THF/H2O = 1/2, 0°C, 24 h

Ach

+1.5 equiv

20 mol% 41

78% yieldtrans/cis = 98/291% ee (trans)

Ala(1-Pyn)

SCHEME 4.28. Asymmetric epoxidation of enal by hydrogen peroxide in the presence of

immobilized peptide catalyst [87].

+ N

O

ROH N

OR OH

NaBH4

O2, THF/H2O = 1/2rt, 36 h

yield: up to 85%ee: up to 93%

20 mol% 3630 mol% CuCl

30 mol% 2,2'-bipyridine

TEMPO

SCHEME 4.27. One-pot sequential aerobic primary alcohol oxidation and aldehyde a-oxyamination catalyzed by a copper complex and an immobilized peptide in the presence of

TEMPO [86].


Several groups concentrated on the development of an asymmetric metal catalyst

having a peptide as a chiral ligand. This kind of catalyst is of interest in relation to

naturally occurring metalloenzymes. Gilbertson’s group prepared non-natural amino

acids having metal-coordinating units and applied them to peptide ligands having a

secondary structure [92]. Hoveyda’s group developed two kinds of tripeptide ligands

having the metal-binding site at the N-terminal. Both the Cu-catalyzed asymmetric

conjugate addition of dialkylzinc [93] and the Al-catalyzed asymmetric TMSCN

addition to ketones [94] underwent with very high ee. Meldal and coworkers made

immobilized peptidyl P-N and P-S ligands and applied them to Pd-catalyzed

asymmetric allylic substitution [95]. Chiral surface modification of a heterogeneous

catalyst Pt/Al2O3 by Trp-Gly-Gly was reported by Baiker et al. and used for

asymmetric hydrogenation [96].

4.6 CONCLUSIONS AND OUTLOOKS

The last decade seems to have been a “renaissance” in the peptide catalyst:

Miller et al.’s histidine derivatives, N-terminal prolyl peptides, mentioned in this

and other chapters; Cordova et al.’s nonhistidyl/nonprolyl simple peptides; and so on.

New knowledge is accumulating at a pace never seen before. This situation is

expected to lead to the creation of a database of a peptide catalysts, and to “in silico”

optimization of the peptide catalyst in the future. However, now we are still in the

stage of collecting more experimental facts. The combinatorial approach is promis-

ing for the exploration of a good peptide catalyst. Obviously, a “full-scale” library is

not realistic, and appropriate design of a library with selected “correct” components

is the key to success. As observed in the result of both Miller’s and Wennemers’s

group, incorporation of both D- and L-isomers seems important. Needless to say,

development of an efficient assay method is of critical importance.

So what will be the future of peptide catalysts? As shown by Miller’s group for

site-selective acylation, the peptide catalyst has expandability to hitherto unrealized

differentiation of functional groups. The goal toward this direction might be the

usage of a peptide catalyst in the key reaction of multistep synthesis of a target

compound with a highly complex structure, such as highly bioactive natural

products. Even a complete peptide-catalyzed multistep synthesis without using any

protective group can be expected. Furthermore, development of a good peptide

catalyst for large-scale production of chiral compounds such as a synthetic interme-

diate of drugs is also expected. Thus, a major breakthrough in peptide preparation

method is coming.

Another aspect of the peptide catalyst is its relevance to the biological system.

It sounds exciting that simple peptides, or even amino acids, can catalyze the aldol

reaction, which is related to the formation of sugar molecules [97]. The progress of

research toward this direction is scientifically interesting. We believe that peptide

catalysts can be a tool in the chemical biology field. The possibility of the large-scale

production of catalytic peptides based on biological machinery is yet another

probability.

CONCLUSIONS AND OUTLOOKS 119

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