Cyclo[-His-His-] derived C2-symmetric diketopiperazine as chiral ligand for asymmetric diels-alder reactions

Article abstract of DOI:10.3987/COM-08-11604

A cyclic dipeptide based chiral ligand, cyclo[-His(Tr)-His(Tr)-] (Tr = triphenylmethyl), was designed and prepared through bis-(τ)-tritylation of two imidazole rings of cyclo[-His-His-]. The complex prepared in situ by mixing Cu(OTf)₂ with equi

Full text of DOI:10.3987/COM-08-11604

HETEROCYCLES, Vol. 78, No. 5, 2009
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HETEROCYCLES, Vol. 78, No. 5, 2009, pp. 1171 - 1176. © The Japan Institute of Heterocyclic Chemistry
Received, 20th November, 2008, Accepted, 29th December, 2008, Published online, 9th January, 2009
DOI: 10.3987/COM-08-11604
CYCLO[-HIS-HIS-] DERIVED C2-SYMMETRIC DIKETOPIPERAZINE
AS CHIRAL LIGAND FOR ASYMMETRIC DIELS-ALDER REACTIONS
Masahiro Furutani, Seiji Sakamoto, and Kazuaki Kudo*
Institute of Industrial Science, The University of Tokyo, 4-6-1 Komaba,
Meguro-ku, Tokyo 153-8505, Japan. e-mail: kkudo@iis.u-tokyo.ac.jp
Abstract – A cyclic dipeptide based chiral ligand, cyclo[-His(Tr)-His(Tr)-] (Tr =
triphenylmethyl), was designed and prepared through bis-N(τ)-tritylation of two
imidazole rings of cyclo[-His-His-]. The complex prepared in situ by mixing
Cu(OTf)2 with equimolar amount of this ligand successfully catalyzed
asymmetric Diels-Alder reactions in fair to good yields and moderate selectivities.
Peptide derivatives are potential candidates for chiral ligands in homogeneous asymmetric metal-complex
catalysts because they are chiral and can be easily optimized through chemical modification.1 Dipeptide
and tripeptide-derived ligands have been successfully utilized for highly enantioselective
metal-complex-catalyzed chemical transformations such as epoxydation,1 cyanohydrin formation/Strecker
reaction,1-3 conjugate addition,2,4-6 transfer hydrogenation,7,8 allylic alkylation,9 and pinacol coupling.10 In
those examples, the metal coordinating atoms in the ligands is located on the artificial groups introduced
at terminus of the peptides, and the peptide skeleton plays a role to make asymmetric microenvironment
around the metal center. Gilbertson incorporated a non-natural L-diphenylphosphinoalanine into β-turn
peptides, and utilized the peptide side chain as coordinating part of the ligand in chiral Pd catalyst for
asymmetric allylic alkylations.11 Moreover, a side chain of natural amino acid, the sulfide group in
methionine, has been also utilized as a coordination site; Christoffers reported L-methionyl-L-methionine
ethyl ester (H-Met-Met-OEt) ligand for metal-catalyzed Michael reactions, while it gave enantiomeric
excess up to 18% ee.12 We thought that one of the reasons of the low ee’s in their result is due to the
highly flexible nature of the peptide ligand, and that those having a rigid skeleton should show better
performance. Cyclic dipeptides seem to fulfill this requirement because it contains a rigid
diketopiperazine ring and two side chains facing to the same side of the ring.13 We selected
cyclo[-His-His-] 1 having two coordinating imidazole side chains as a candidate for the ligand in

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HETEROCYCLES, Vol. 78, No. 5, 2009
asymmetric metal-complex catalysts because bidentate complex between 1 and Cu(II) ion have been
already reported.14 We designed a ligand 2 (cyclo[-His(Tr)-His(Tr)-], Tr = triphenylmethyl) with
expecting the formation of an efficient C2-symmetric chiral microenvironment around the metal center.
O
O
TrCl
triethylamine
N
N
NH
NH
O
NH
N Tr
DMF, 0oC to rt
31%
HN
HN
Tr N
HN
N
N
O
1
2
Scheme 1
Cyclo[-His-His-] 1 was prepared according to a procedure described in the literature (white solid, 24%,
mp >300˚C).15 Ligand 2 was synthesized through conventional tritylation of 1 (light yellow solid, 31%,
mp 118-120˚C, Scheme 1).16 Theoretically, tritylation can be possible at one of the two nitrogen atoms of
His side chain, N(τ) and N(π). In the present case, position of tritylation is considered to be at N(τ)
nitrogen according to the previous study on related compounds.17 Ligand 2 dissolved in relatively less
polar solvents such as CH2Cl2 or CHCl3, while the parent compound 1 dissolved only in highly polar
solvents such as DMSO or DMF. When ligand 2 was added to a dispersion of Cu(OTf)2 in CH2Cl2, the
mixture became homogeneous, dark green solution in a few minutes. This implies the formation of a
soluble complex between Cu(II) ion and ligand 2.
In the UV-VIS spectrum of the above mixture in DMF,18 a peak attributable to ligand-to-metal charge
transfer between imidazole moiety and Cu(II) ion was observed at 322 nm.19 In the case of non cyclic
dipeptide 3 and Cu salt,20 only a weak peak was observed at 334 nm. As Cu(II)-cyclo[-His-His-] 1
mixture gave a peak at 320 nm, the absorbance of Cu(II)-ligand 2 mixture seemed to be specific to
cyclo[-His-His-] skeleton.
In the CD spectrum of Cu(II)-ligand 2 mixture in DMF,18 a negative Cotton effect was observed at 332
nm. A similar negative Cotton effect was observed at 317 nm in the case of cyclo[-His-His-] 1. In contrast,
Cu(II)-ligand 3 mixture gave a weak positive Cotton effect at 365 nm.
These results imply that chemical structure of ligands strongly influences their microenvironment around
Cu(II) ion. Asymmetric microenvironment around Cu(II) center generated by ligand 2 should be similar
with that by parent compound 1, and quite different from those by linear ligand 3.
FAB-MS measurement of the evaporation residue of the Cu(OTf)2/ligand 2 solution showed a main peak
at 821.6, which is corresponding to the sum of one copper atom and one ligand 2 molecule.
O
O
N
Fmoc
NH
NH
NH
O
N Tr
Me
Tr
Tr N
Tr N
HN
NH CO2Me
Fmoc
N
N
N
MeO2C
N
4
3
5

HETEROCYCLES, Vol. 78, No. 5, 2009
1173
Table 1. Asymmetric Diels-Alder reaction of (E)-3-(2-alkenoyl)-2-oxazolidinone with cyclopentadiene
12.5 mol% CuX2
12.5 mol% Ligand
O
O
R
+
O
N
R
+
R
CH2Cl2
COY
COY
endo isomer
COY
O
+
+
COY
Y =
N
O
R
R
exo isomer
Entry
Ligand
X
R
Temperature / ˚C Time / h
Yield / %
Endo/exo
% ee
(endo, config.)
1
2
3
4
5
6
2
3
4
5
2
2
OTf
OTf
OTf
OTf
OTf
H
H
0
0
0
0
rt
rt
2.5
2.5
2.5
2.5
72
76
43
49
67
50
33
12
12
35 (R)
2 (S)
1 (R)
8 (R)
52
H
14
H
10
Me
6.0
4.7
ClO4 Me
72
59
Diels-Alder reactions of 3-(2-alkenoyl)-2-oxazolidinones with cyclopentadiene catalyzed by Cu(II)
complex were performed.21,22 The complex was prepared in situ by mixing Cu(OTf)2 with equimolar
amount of each ligand in CH2Cl2. When the ligand 2 was employed as a ligand, cycloadduct of
acrylamide derivative was obtained in 76% yield and 35% ee (Table 1, entry 1). Lowering the
temperature of this reaction to -40˚C did not improve the result (41% yield, 23% ee). In the case of
ligands 3 and 4,20,23 the enantiomeric excesses were low (Entries 2 and 3). Although the ligand 3 is an
open chain analogue of 2, behavior of these two ligands in the catalytic process was quite different to
each other. This fact coincides with the above mentioned spectroscopic observation and supports our
initial hypothesis that the rigid ligand should bring about better stereoselectivities. Removal of one of the
two tritylated imidazole moieties in 2 resulted in the lowering of enantiomeric excess (Entry 4).24 This
implies that both of the two imidazole side chains cooperatively contributed to the formation of
asymmetric microenvironment for the reaction.
Use of a crotonamide as a dienophile improved the enantiomeric excess at the expense of chemical yields
probably due to the poor reactivity of the dienophile (Entries 5 and 6). Parent compound 1 was also
examined as a chiral ligand, however catalytic performance was quite low (26% yield, 2% ee). This result
demonstrates the importance of the sterically demanding trityl groups in ligand 2.
Concerning the mechanism for stereoselectivity, we performed semiempirical molecular orbital
calculation using MOPAC software with PM6 parameter set.25 As shown in Figure 1, Re-face of the
dienophile is likely to be shielded to give predominantly the (R)-product.

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Figure 1 Optimized structure of the substrate-catalyst complex. The phenyl group relevant to
the enantiotopic face differentiation is shown with CPK model. All other hydrogens are
omitted for clarity.
Diels-Alder reaction using another type of dienophile, (E)-2-(3-phenylpropenoyl)pyridines were also
examined with Cu2+ and ligand 2 complex (Table 2).21,26 Good yields and modest enantioselectivities
were observed. In some cases, lowering of the reaction temperature improved enantioselectivity.
Table 2. Asymmetric Diels-Alder reaction of (E)-2-(3-phenylpropenoyl)pyridine with cyclopentadiene
O
12.5 mol% Cu(OTf)2
12.5 mol% 2
R
N
R
+
+
CH2Cl2, 0oC, 1 h
R
COY
COY
endo isomer
COY
N
+
+
COY
Y =
R
R
exo isomer
Entry
R
Yield / %a
89 (70)
Endo/exoa
6.3 (9.0)
10 (18)
% eea,b
40 (60)
39 (45)
29 (26)
1
2
3
NO2
H
89 (79)
OMe
82 (19)
14 (56)
aValues in parentheses were results at -40˚C. Reaction time was 5 to 9 h.
bFor endo isomers.
ACKNOWLEDGEMENTS
MF is grateful for the Global Core of Excellent Committee, The University of Tokyo for research
assistantship.

HETEROCYCLES, Vol. 78, No. 5, 2009
1175
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6.67 (s, 2H), 4.21 (dd, 2H), 3.32 (dd, 2H), 2.76 (dd, 2H); 13C NMR (400 MHz, CDCl3) δ 167.3,
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1489, 1443, 1317, 755, 698 cm-1; FAB-MS: m/z 759.7 MH+; [α]2D8 -60.7 deg (c 0.3, CHCl3).

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HETEROCYCLES, Vol. 78, No. 5, 2009
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ligand (0.01 mmol) in CH2Cl2 was added dienophile (0.08 mmol) at rt under argon atmosphere.
After the mixture was stirred for 30 min, it was cooled to the predetermined temperature.
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13
1H), 4.26 (dd, 1H), 4.08 (q, 1H), 3.32 (dd, 1H), 2.80 (dd, 1H), 1.47 (d, 3H); C NMR (400 MHz,
CDCl3): δ 168.2, 168.1, 142.1, 138.8, 136.6, 129.6, 128.1, 128.0, 119.2, 75.4, 55.1, 50.6, 30.6, 19.3;
FT-IR (KBr) 3443, 3276, 3171, 1679, 1650, 1491, 1453, 1316, 766, 749, 707 cm-1; FAB-MS: m/z
451.3 MH+; [α]2D3 -78.7 (c 0.3, CHCl3).
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