Synthesis of optically active N-aryl amino acid derivatives through the asymmetric petasis reaction catalyzed by a novel hydroxy-thiourea catalyst

Article abstract of DOI:10.1002/asia.201100453

Thiourea makes peptides: Asymmetric Petasis reactions with vinylboronates and α-iminoamides are effectively catalyzed by the novel hydroxy-thiourea catalyst 1 (up to 86% yield, 93% ee; see scheme). This reaction can be applied not only to the synthesis of

Full text of DOI:10.1002/asia.201100453

COMMUNICATION
DOI: 10.1002/asia.201100453
Synthesis of Optically Active N-Aryl Amino Acid Derivatives through the
Asymmetric Petasis Reaction Catalyzed by a Novel Hydroxy–Thiourea
Catalyst
Tsubasa Inokuma, Yusuke Suzuki, Toshiyuki Sakaeda, and Yoshiji Takemoto*[a]
Optically active nonprotei-
nogenic amino acid derivatives
have received considerable in-
terest due to their biological
activities and ability to serve as
chiral building blocks in asym-
metric synthesis. N-Aryl-substi-
tuted amino acid derivatives
can act as a fibrinogen recep-
tor antagonist,[1] hepatitis C
virus replication inhibitor,[2]
glycine antagonist[3] or an an-
giotensin receptor antagonist[4]
as shown in Figure 1. In addi-
tion, it is known that some
compounds of this class are
protein kinase C (PKC) activa-
tors,[5]
N-methyl-d-aspartate
Figure 1. Examples of N-aryl amino acid derivatives.
(NMDA) receptor antago-
nists,[6] and angiotensin con-
verting enzyme (ACE) inhibitors.[7] Others have been shown
to have anti-ulcer[8] and cyclosporine receptor-binding activi-
ty.[9] Notably, some consist of more than one amino acid
moiety. However, despite the great importance of these
structures, existing methods for their preparation rely heavi-
ly on the copper-catalyzed Ullmann-type N-arylation of
amino acids.[10] For the synthesis of optically active deriva-
tives, it is necessary to prepare the optically active parent a-
amino acids. In addition, suitable aryl donors are limited to
relatively electron-deficient and sparsely substituted aromat-
ic compounds. On the other hand, several groups have re-
ported catalytic asymmetric approaches for the synthesis of
N-aryl amino acid units by using the 1,2-addition of N-aryl-
a-iminoesters with several nucleophiles.[11] We considered
that if a similar process was applied to N-aryl-a-imino
amides instead of esters, it could be a direct and more
useful method for the synthesis of peptides that contain N-
aryl amino acid moieties. Recently, Li et al. reported the
racemic 1,2-addition of N-aryl-a-imino amides and organo-
boronic acids.[12] However, to the best of our knowledge, an
asymmetric version of this reaction has not yet been report-
ed.
The Petasis reaction is a powerful method for the synthe-
sis of a-amino acid derivatives.[13] However, to date, there
have been only two reports on asymmetric catalytic Petasis
reactions.[14,15] We reported the Petasis reaction of quinolini-
um and vinyl boronic acids using a thiourea catalyst that
contains an amino alcohol moiety.[14,16,17] The Schaus re-
search group reported the three-component asymmetric or-
ganocatalytic Petasis reaction of ethyl glyoxylate, an aliphat-
[a] T. Inokuma, Y. Suzuki, Prof. Dr. T. Sakaeda, Prof. Dr. Y. Takemoto
Department of Pharmaceutical Sciences
Kyoto University
Yoshida, Sakyo-ku, Kyoto, 606-8501 (Japan)
Fax : (+81)75-753-4569
E-mail: takemoto@pharm.kyoto-u.ac.jp
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.201100453.
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Chem. Asian J. 2011, 6, 2902 – 2906

ic secondary amine, and vinylboronates.[15] In these reports,
highly reactive iminium species were used as substrates. In
the current project we planned to use N-aryl-a-imino
amides as substrates and considered another methodology
to achieve the asymmetric Petasis reaction. Our hypothesis
is outlined in Scheme 1. When the thiourea and organobor-
Figure 2. Organocatalysts examined in this study.
Table 1. Optimization of the reaction conditions.[a]
Scheme 1. Our mechanistic proposal.
onic acid are combined, the chiral boronic acid–thiourea
species A is formed. We considered that species A is a suita-
ble component for the Petasis reaction with N-aryl-a-imino
amides. It is predicted that the Lewis acidic boron atom of
A would coordinate to the nitrogen atom of the imino group
and the thiourea moiety would form hydrogen bonds with
the amide carbonyl group. The resulting intermediate B
would allow for the quasi-intramolecular attack of the R2
substituent from the boron atom to the imino group owing
to double activation. Herein, we report the first asymmetric
1,2-addition of N-aryl-a-imino amides using the thiourea
catalyst we developed for the synthesis of N-aryl amino acid
derivatives (Figure 2).
Initially, the asymmetric Petasis reaction of imino amide
4a, which was readily prepared from 2a[18] and 3a, with
trans-2-phenylvinylboronic acid diisopropyl ester 5a was ex-
amined in the presence of 10 mol% of different catalysts 1
(Table 1). When amino alcohol-type thiourea 1a, which we
had previously reported as the best catalyst for the Petasis
reaction of quinolines and vinylboronic acids,[14] was used,
the desired adduct 6a was obtained in poor yield and almost
racemic form (Table 1, entry 1). Similarly, iminophenol-type
catalyst 1b[19] also did not give a good result (Table 1,
entry 2). We anticipated that the basic amino or imino
groups in catalysts 1a and 1b might prevent the boronates
from coordinating to the nitrogen atom of 4a. Therefore, we
screened other hydroxy-type thioureas that did not contain
basic sites. In the case of 1c, while the enantiomeric excess
was improved compared to those of 1a and 1b, the chemical
yield remained low (Table 1, entry 3). Next, we tested the
Entry
R1
R2
R3
1
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
Me
Me
Me
Me
Me
Me
Me
Me
Ph
Ph
Ph
Ph
Ph
Me (2a)
Me (2a)
Me (2a)
Me (2a)
Me (2a)
Me (2a)
Me (2a)
Me (2a)
Me (2b)
Et (2c)
Et (2c)
Et (2c)
Et (2c)
Et (2c)
Et (2c)
Et (2c)
iPr (5a)
iPr (5a)
iPr (5a)
iPr (5a)
iPr (5a)
iPr (5a)
iPr (5a)
iPr (5a)
iPr (5a)
iPr (5a)
H (5b)
Me (5c)
Et (5d)
iPr (5a)
iPr (5a)
iPr (5a)
1a
1b
1c
1d
1e
1 f
1g
1h
1g
1g
1g
1g
1g
1g
1g
1g
21 (6a)
22 (6a)
18 (6a)
27 (6a)
29 (6a)
51 (6a)
47 (6a)
27 (6a)
75 (6b)
74 (6c)
72 (6c)
69 (6c)
70 (6c)
71 (6c)
8 (6c)
1
30
50
12
0
46
74
1
86
90
77
88
88
62
59
92
9
10
11
12
13
14[d]
15[e]
16[f]
Ph
Ph
Ph
74 (6c)
[a] Unless otherwise noted, the reactions were conducted with
2
(1.0 equiv), 3a (1.0 equiv), 5 (1.2 equiv), 1 (10 mol%), and 3 ꢁ MS
(100 mg/1 mmol of 2) in toluene at room temperature for 24 h. [b] Yield
of isolated product for the two-step process based on 2. [c] Determined
by chiral HPLC analysis. [d] CH2Cl2 was used as the solvent. [e] Tetrahy-
drofuran (THF) was used as the solvent. [f] Cyclohexane was used as the
solvent.
homologated thioureas 1d–f. Although the enantioselectivi-
ties decreased with 1d and 1e, the chemical yields improved
slightly by using catalysts with a linker between the chiral
scaffolds and the hydroxy group. A pronounced increase in
yield was observed with the three-carbon linker of thiourea
1 f (Table 1, entries 4–6). We assumed that the introduction
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Y. Takemoto et al.
COMMUNICATION
of another weak Lewis basic site into the carbon linker of
the catalyst should result in the effective formation of a
complex between the organoboronic acid and the catalyst.
When we employed thiourea 1g, which contained an ether
moiety, we observed an improved result (Table 1, entry 7).
Based on the results of the reaction catalyzed by the corre-
sponding amide 1h, it became clear that the thiourea moiety
was necessary for the catalytic activity (Table 1, entry 8).
Both the yield and enantioselectivity were further improved
when we used the N-phenyl-N-methyl amide 4b, and N-
phenyl-N-ethyl amide 4c was found to be the optimal sub-
strate (Table 1, entries 9 and 10). With regard to the sub-
stituents of the boronic acid ester moieties, boronic acid 5b
gave a diminished enantioselectivity and other aliphatic bor-
onates such as 5c and 5d gave results similar to those with
5a (Table 1, entries 11–13). Next, we screened several sol-
vents and found that less-polar solvents were desirable in
this reaction, similar to that of other thiourea-catalyzed
asymmetric reactions (Table 1, entries 14–16). The best
result was obtained when we used cyclohexane as the sol-
vent.[20]
(Table 2, entries 4 and 5). Heteroaromatic boronic acid ester
5j gave the corresponding adduct 6i in high stereoselectivity
(Table 2, entry 6). In the case of the aliphatic vinyl boronic
acid ester 5k, although the reactivity was somewhat low, the
enantioselectivity was maintained at a high level (Table 2,
entry 7). With regard to the aromatic rings at the imine ni-
trogen atom, electron-rich substrates were preferred, in con-
trast to copper-catalyzed N-arylation reactions[10] (Table 2,
entries 8–12). In addition, derivatives that contained hydrox-
ymethyl or amino groups were also accessible (Table 2, en-
tries 13 and 14).
We then investigated the interconversion of the obtained
N-aryl amino acid derivatives into pharmacologically impor-
tant heterocyclic structures, as shown in Scheme 2. The
Next, we explored the scope of this reaction. The results
are shown in Table 2. As expected, electron-rich vinyl boro-
nates such as 5e and 5 f gave good results with excellent
enantiomeric excess (Table 2, entries 1 and 2). In addition,
electron-poor 5g could also be used and the enantioselectiv-
ity remained high (Table 2, entry 3). The position of the sub-
stituents in the aromatic ring did not influence the results
Scheme 2. Synthesis of heterocycle 9. Reaction conditions: a) LiBHEt3,
THF, À788C to RT, 30 min (71%); b) 1,1-carbonyldiimidazole, toluene,
808C, 3 h (91%); c) BTMA·ICl2, ZnCl2, AcOH, RT, 1 h (65%).
Table 2. Scope of boronates and anilines.[a]
amide moiety of 6m could be reduced into amino alcohol 7
by using LiBHEt3,[21] and subsequently converted into the
corresponding oxazolidinone 8. When 8 was treated with
benzyltrimethylammonium dichloroiodate (BTMA·ICl2) and
[22]
ZnCl2,
an intramolecular iodoarylation occurred to give
the tricyclic dihydroquinoline derivative 9, which could be a
valuable pharmacophore, as a single diastereoisomer.[23] The
diastereoselectivity of this reaction could be explained as
Entry
R1
R2
Yield [%][b]
ee [%][c]
follows. When the olefin moiety of
8 reacts with
1
2
3
4
5
6
7
2,4-(MeO)2 (4c)
2,4-(MeO)2 (4c)
2,4-(MeO)2 (4c)
2,4-(MeO)2 (4c)
2,4-(MeO)2 (4c)
2,4-(MeO)2 (4c)
2,4-(MeO)2 (4c)
4-MeO (4d)
2-MeO (4e)
4-Me (4 f)
H (4g)
2,3-Me2 (4h)
4-MeOC6H
G
77 (6d)
76 (6e)
65 (6 f)
69 (6g)
86 (6h)
77 (6i)
53 (6j)
62 (6k)
77 (6l)
78 (6m)
58 (6n)
56 (6o)
63 (6p)
54 (6q)
87
90
90
89
93
89
80
82
86
87
84
90
82
90
4-MeC6H
4-ClC6H4A(5g)
3-MeOC6H4A(5h)
2-MeC6H4A(5i)
3-thienyl(5j)
Cy(5k)
4ACHTUNGERTN(NUNG 5 f)
BTMA·ICl2, two possible diastereomers of the iodinium in-
termediates are produced. However, this step would be re-
versible and in only one of the diastereomers the phenyl
ring is in the proper position to attack the iodonium, there-
by producing the single diastereomer 9 under kinetic con-
trol.
Next, we applied this reaction to the modification of pep-
tide compounds (Table 3).[24] The reaction of 11a with 5a
proceeded to give the Gly-(styryl glycine) compound 12a in
82% enantiomeric excess. Substrate 11b containing a 4-bro-
mophenyl group on the amide nitrogen atom could also be
converted into the corresponding adduct 12b, which can be
used for further elaboration of the chemical structure by
manipulation of the bromine atom (Table 3, entry 2). Next,
we examined the synthesis of tripeptides. When we used
11c, we obtained the desired tripeptide 12c in good diaste-
reoselectivity (Table 3, entry 3). The use of the enantiomeric
CHTUNGTRENNUNG
CHTUNGTRENNUNG
ACHTUNGTRENNUNG
G
8[d]
9[d]
10[d]
11[d]
12[d]
13[e]
14[e]
Ph (5a)
Ph (5a)
Ph (5a)
Ph (5a)
Ph (5a)
Ph (5a)
Ph (5a)
2-TBSOCH2 (4i)
3-NHBoc (4j)
[a] Unless otherwise noted, the reactions were conducted with 2a
(1.0 equiv), 3 (1.0 equiv), 1g (10 mol%), 5 (1.2 equiv), and 3 ꢁ MS
(100 mg/1 mmol of 2) in cyclohexane at room temperature. [b] Yield of
isolated product for the two-step process based on 2. [c] Determined by
chiral HPLC analysis. [d] Petasis reaction was performed for 48 h. [e] Pe-
tasis reaction was performed for 72 h. TBS=tert-butyldimethylsilyl;
Boc=tert-butoxycarbonyl.
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Chem. Asian J. 2011, 6, 2902 – 2906

Synthesis of Optically Active N-Aryl Amino Acid Derivatives
Table 3. Application in the peptide modification.[a]
dinates to the nitrogen atom of the imine moiety, and the
thiourea moiety forms a hydrogen bond with the amide car-
bonyl oxygen. We assume that the higher enantioselectivity
of 1g is a result of the additional dipole moment introduced
by the oxygen in the alcohol chain. The dipole moments of
the carbon–oxygen bonds in the ROCH2CH2OH subunit
might align themselves so that the overall dipole moment is
minimized. This limits the number of possible conformations
of the transition state as compared to, for example, catalyst
1 f. Further studies are currently underway to clarify the pre-
cise mechanism of this reaction.
In summary, we have developed a bifunctional hydroxy
thiourea-catalyzed asymmetric Petasis reaction of N-aryl-a-
imino amides and vinyl boronates. This process can be used
not only for the asymmetric synthesis of unnatural amino
acid derivatives but also for the stereoselective synthesis of
modified dipeptides and tripeptides. Further studies are cur-
rently underway to reveal the reaction mechanism.
Entry
R
X
Yield [%][b]
ee [%][c]
d.r.[d]
1
2
3
4
-OMe
-OMe
-(l)-Ala-OMe
-(d)-Ala-OMe
OMe (10a)
Br (10b)
OMe (10c)
OMe
67 (12a)
71 (12b)
58 (12c)
57 (12d)
82
92
–
–
–
85:15
89:11
–
AHCTUNGTRENNUNG
5
-(l)-Phe-OMe
60 (12e)
–
88:12
[a] The reactions were conducted with 10 (1.0 equiv), 3 (1.0 equiv), 5a
(1.2 equiv), 1g (10 mol%), and 3 ꢁ MS (100 mg/1 mmol of 10) in toluene
at room temperature. [b] Yield of isolated product for the two-step pro-
cess based on 10. [c] Determined by chiral HPLC analysis. [d] Deter-
Experimental Section
1
mined by H NMR analysis.
A mixture of N-ethyl-N-phenyl glyoxylamide 2c (84.1 mg, 0.475 mmol),
2,4-dimethoxyaniline 3a (72.7 mg, 0.475 mmol), and Na2SO4 (67.5 mg,
0.475 mmol) in toluene (2.0 mL) was stirred at room temperature for 1 h.
After that, the mixture was filtered and the filtrate was evaporated in
vacuo to afford the imine 4c, which was used without further purifica-
tion. A mixture of 4c, 5a (132 mg, 0.570 mmol), 3 ꢁ molecular sieves
(47.5 mg), and thiourea catalyst 1g (20.4 mg, 0.0475 mmol) in cyclohex-
ane (9.5 mL) was stirred under an argon atmosphere at room tempera-
ture. After 24 h, the reaction mixture was directly purified by silica-gel
column chromatography (eluent hexane/EtOAc 2:1) to obtain the desired
product 4c (146 mg, 74% over 2 steps, 92% ee).
substrate ent-11c gave the other diastereoisomer of 12c as a
major product (Table 3, entry 4). Therefore, the stereoselec-
tivity of this process is controlled by the catalyst. In addi-
tion, 11d, which contains a more bulky amino acid unit than
that of 11c, could be converted to the corresponding tripep-
tide 12e (Table 3, entry 5).
Finally, we have performed spectroscopic experiments to
obtain insight into the reaction mechanism.[25] When a 10:1
mixture of 5d and 1g was analyzed in toluene by ESI-MS,[26]
the mass of the 1:1 complex of 5d and 1g was observed. In
1
Acknowledgements
addition, H NMR studies revealed that the boronate 5d im-
mediately exchanged an ethoxy group for the hydroxy thio-
urea at room temperature, thus liberating ethanol. An equi-
librium between 1g, 5d, and the complex was quickly
reached (<5 min), and the composition of the mixture did
not change over time. Similar results were seen with 1g and
1 f. Therefore, we conclude that the ether moiety of 1g does
not serve to accelerate the formation of the thiourea–boro-
nate complex.
This work was supported in part by a Grant-in-Aid for Scientific Re-
search (B) (Y.T.), Grant-in-Aid for Young Scientists (start-up)
(21890112) (T.I.), the “Targeted Proteins Research Program” and the
“Service Innovation Program” from the Ministry of Education, Culture,
Sports, Science, and Technology in Japan.
Keywords: amino acids
·
asymmetric synthesis
·
organocatalysis · Petasis reaction · thiourea
One possible reaction intermediate is shown in Scheme 3.
As shown in our proposal (Scheme 1), the boron atom coor-
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Scheme 3. Possible reaction pathway.
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Y. Takemoto et al.
COMMUNICATION
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Published online: August 3, 2011
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