Ir-Catalyzed Double Asymmetric Hydrogenation of 3,6-Dialkylidene-2,5-diketopiperazines for Enantioselective Synthesis of Cyclic Dipeptides

Article abstract of DOI:10.1021/jacs.9b02920

An Ir/spiro[4,4]-1,6-nonadiene-based phosphine-oxazoline ligand (SpinPHOX) complex-catalyzed double asymmetric hydrogenation of 3,6-dialkylidene-1,4-dimethylpiperazine-2,5-diones has been developed, providing efficient and practical access to a wide varie

Full text of DOI:10.1021/jacs.9b02920

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Article
Ir-Catalyzed Double Asymmetric Hydrogenation of 3,6-Dialkylidene-2,5-
diketopiperazines for Enantioselective Synthesis of Cyclic Dipeptides
Yao Ge, Zhaobin Han, Zheng Wang, and Kuiling Ding
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b02920 • Publication Date (Web): 12 May 2019
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Ir-Catalyzed Double Asymmetric Hydrogenation of 3,6-Dialkylidene-
2,5-diketopiperazines for Enantioselective Synthesis of Cyclic
Dipeptides
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Yao Ge,†‡ Zhaobin Han,†* Zheng Wang,† and Kuiling Ding†,‡,§*
†State Key Laboratory of Organometallic Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of
Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China
‡ University of Chinese Academy of Sciences, Beijing 100049, China
§ Collaborative Innovation Center of Chemical Science and Engineering, Nankai University, Tianjin 300071, China
ABSTRACT: An Ir/SpinPHOX complex catalyzed double asymmetric hydrogenation of 3,6-dialkylidene-1,4-
dimethylpiperazine-2,5-dione has been developed, providing an efficient and practical access to a wide variety of chiral 3,6-
disubstituted-2,5-diketopiperazines in high yields with exclusive cis-diastereo- and excellent enantioselectivities (>99% de,
up to 98 % ee). The synthetic utilities of the protocol have been demonstrated in a gram scale synthesis of 6a, and efficient
construction of chiral products 8, 14 and 17 as well as a 2-butenyl-bridged bicyclic diketopiperazine 10 and
hydroxydiketopiperazine 11. With an analogous achiral Ir catalyst, the hydrogenation of enantiopure mono-hydrogenated
intermediate 7a gave cis-6a as the only product, indicating that stereochemistry of the second-step hydrogenation of the
titled transformation is a chiral substrate controlled process. Reaction profile study for AH of 5a revealed that the
concentration of the monohydrogenation intermediate 7a remianed at a low level (<8%) during the course of
hydrogenation. The double hydrogenation of 5a to 6a proceeded significantly faster than that of its half-hydrogenated
intermediate (S)-7a, indicating that the double AH reaction involves primarily a processive mechanism, in which a single
catalyst molecule performs consecutive hydrogenation of the two C=C double bonds in substrate 5a without dissociation of
the partially reduced 7a. The present protocol represents a rare example of asymmetric catalytic consecutive
hydrogenation of heterocycles and provides an alternative way for efficient construction of cyclic dipeptides.
Chart 1. Representative bioactive molecules with 3,6-
disubstituted-2,5-diketopiperazine core
INTRODUCTION
Substances containing a conformationally rigid 2,5-
Retosiban
O
R
H
Tryprostatin A
R = OMe
O
diketopiperazine subunit, known as cyclic dipeptides,
represent a large class of biologically interesting molecules
with high stability and protease resistance.1 The features
of the scaffold allow the binding affinity and specificity of
the molecules with biological targets to be enhanced,
which is particularly attractive for drug discovery.2,3 For
examples, retosiban and epelsiban are highly potent
oxytocin antagonists and retosiban has been approved as
O
O
R
R =
N
H
N
N
N
HN
HN
Epelsiban
Tryprostatin B
R = H
O
H
HN
O
R =
O
N
O
H
O
O
N
MeO
N
O
NH
N
N
N
H
N
NH
HN
H
O
HN
O
O
Sch 725418
Fumitremorgin C
an oral drug for treatment of preterm labor.2a,
3a
Cairomycin B
Tryprostatin A and Fumitremorgin C are inhibitors of the
multidrug-resistance protein (BCRP/ABCG2) that mediate
resistance to chemotherapeutics in breast cancer
treatment (Chart 1).3b,c Moreover, some compounds
containing a chiral piperazine motif, which can be obtained
from 2,5-diketopiperazines by carbonyl reduction, display
interesting activity in many biological systems.4 On the
The importance of this type of molecules has stimulated
extensive research on the development of methodologies
for their syntheses.2a,6 Some type of 3,6-disubstituted-2,5-
diketopiperazines have been produced by microorganisms
in nature.1d,f,7 However, the limited productivity hindered
extensive screening of biological activities, and many of
these naturally occurring structures do not have the
expected bioactivity or physicochemical properties. The
other
hand,
some
chiral
3,6-disubstituted-2,5-
diketopiperazine derivatives have also been used in
chemical
synthesis
of
3,6-disubstituted-2,5-
asymmetric synthesis as organocatalysts or auxiliaries.5
diketopiperazines generally involves amide formation via
condensation cyclization of linear dipeptides, which are
derived from protected chiral α-amino acids (Scheme 1a).6
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Despite the versatility of the approach, however,
2,5-diketopiperazines, which would provide a direct access
to the corresponding chiral cyclic dipeptides.
meticulous control of reaction conditions (e.g., pH values)
is obligatory to prevent the racemization and/or
epimerization of chiral carbon centers. Several other
methods8 such as substrate-induced asymmetric alkylation
(3Z, 6Z)-3,6-Dibenzylidene-1,4-dimethylpiperazine-2,5-
dione (5a), a cyclic dehydropeptide, was taken as a model
substrate for catalyst screening and condition optimization
in the asymmetric hydrogenation. The reaction was
typically carried out in CH2Cl2 under 30 atm H2 for 12 h at
room temperature, with 1 mol% SpinPHOX/Ir(I) complex
1a-k as the catalyst (entries 1-14, Table 1). Under these
conditions, the reaction using (R, S)-1a gave the double AH
product (S, S)-6a as a single diastereomer with 92% ee,
albeit in 41% yield along with the co-generation of a small
amount of mono-reduced product (S)-7a (5% yield, 15%
ee) (entry 1). In contrast, the reaction catalyzed by
complex (S, S)-1a, diastereomeric isomer of (R, S)-1a,
afforded (R, R)-6a as the major product in only moderate
enantioselectivity (45% ee), indicating a mismatched
combination of ligand chirality in this case (entry 2).
Further survey of (R, S)-SpinPHOX/Ir(I) catalyst series (R,
S)-1a-k revealed that (R, S)-1k, with a phenyl group on the
oxazoline ring and two 4-methoxyphenyl groups on the P
atom, afforded the optimal reactivity to give (S, S)-6a in
95% yield with 92% ee (entry 13). Elevation of the initial
hydrogen pressure to 40 atm resulted in full conversion of
5a, and (S, S)-6a was obtained in quantitative yield with
94% ee (entry 14). Under otherwise identical conditions,
several types of well-established Ir(I) complexes with
privileged chiral phosphino-oxazoline ligands, including
PHOX ((S)-2a),13 ThrePHOX ((R, R)-3a-b)14 and SIPHOX
((S, S)-4 and (R, S)-4),15 demonstrated no activity or less
satisfactory enantioselectivity (entries 15-19), thus
underscoring the unique performance of SpinPHOX/Ir(I)
catalysts in AH of this type of challenging substrates. The
impact of diketopiperazine N-substituents on the catalysis
has also been examined. While the reaction of 5a with N-
methyl groups delivered the optimal results, similar
diketopiperazines with N-Ac or N-Bn protecting groups, or
with naked N-H moieties demonstrated no hydrogenation
activities under otherwise identical conditions (30 atm H2,
1 mol% (R, S)-1f, CH2Cl2 solvent, rt, 12 h. For details, see
Table S1 in SI). In the case of the diketopiperazine
substrate containing both exocyclic alkylidenyl C=C bonds
and N-allyl groups, 1H NMR indicated that only the
terminal C=C bonds were reduced (see SI). Though the
exact reason for these intriguing reactivity behaviors is
unclear at the present stage, it seems likely that the
of
2,5-diketopiperazines8e-g
or
Pd/C
catalyzed
hydrogenation of enantioenriched dehydrophenylalanine8h
have also been developed. In 1990, Takeuchi and co-
workers reported the synthesis of a piperazine alkaloid via
a Co-catalyzed asymmetric hydrogenation (AH) of 3,6-
dibenzylidene-2,5-diketopiperazine as the key step, albeit
3,6-dibenzyl-2,5-diketopiperazine was obtained with 40%
yield and moderate enantioselectivity (Scheme 1b).9 In the
present work, we report an Ir-catalyzed double
hydrogenation of 3,6-dialkylidene-2,5-diketopiperazines
for asymmetric synthesis of cyclic dipeptides with
excellent stereoselectivity (Scheme 1c). The synthetic
utilities of the protocol in facile construction of biologically
important molecules, and the underlying non-dissociative
pathway involved in the catalysis will also be disclosed.
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Scheme 1. Asymmetric catalytic synthesis of 3,6-
disubstituted-2,5-diketopiperazines
Previous study
R3
N
O
a)
O
O

PG
OH
R1 R4
O
R1
R1
+
NR4
deprotection
cyclization


condensation
PG
N

N
R3
OR
3N

R
R2
R2
O
O
H
N

R4
Ph
OR
PG = protecting group
R2
b)
O
O
O
O
O
N
Co(dmgH)2/PBu3/QC
Ph
N
Ph
N
N
Ph
H2, 7 days
N
Ph
N
Ph
+
H
O
N
Ph
Me
N
40% yield, 82% ee
58% yield, 79% ee
QC =
O
This work
O
O
R1
R2
O
R2
O
R2
N
N
H
c)
R1
H2
[Ir]
N
/H2
N
R1
N
H
N
H
O
[Ir]
O
a non-dissociative process
[Ir] = SpinPHOX-Ir
>99% d.r.
up to 98% ee
RESULTS AND DISCUSSION
Catalyst optimization for Ir-catalyzed enantioselective
hydrogenation of cyclic dehydropeptides. Although some
chiral catalysts based on iridium, rhodium and ruthenium
have been documented to be effective in asymmetric
hydrogenation of exocyclic α, β-unsaturated lactams,10 the
examples on consecutive AH of two or more C=C double
bonds in a cyclic dehydropeptide are quite rare.11 We
previously reported a class of chiral iridium(I) complexes
with spiro[4,4]-1,6-nonadiene-based phosphine-oxazoline
ligands, SpinPHOX/Ir(I), for AH of ketimines and several
types of α,β-unsaturated carbonyl compounds, including
α,α’-bis-(arylidene)cyclohexanones, cyclic α-alkylidene
carbonyl compounds, and 3-alkylidenephthalides.10f,12
Given the importance of optically active 2,5-
diketopiperazine cyclic dipeptides, we were intrigued by
the feasibility of using SpinPHOX/Ir(I) complexes for the
catalysis of asymmetric hydrogenation of 3,6-dialkylidene-
reluctance to hydrogenation might be
a result of
competitive coordination (N-Ac), steric hindrance (N-Bn),
and/or poor solubility (N-H) of the corresponding
diketopiperazines, which can eventually prevent
coordination of the proximal C=C bond to Ir and hence
inhibit the substrate activation by the catalyst. A variety of
solvents have also been screened in the reaction, and
dichloromethane turns out to be optimal (see Table S2 in
SI).
Table 1. Ir(I)-catalyzed AH of (3Z,6Z)-3,6-
dibenzylidene-1,4-dimethylpiperazine-2,5-dione 5aa
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O
O
O
Moreover, AH of substrates 5o-s, bearing multi-substituted
phenyl rings or naphthyl groups, also worked well to give
the correspongding products (S, S)-6o-s in nearly
quantative yields with 92~98% ee. AH of substrate 5t,
with 2-furanyl groups on the two exocyclic C=C bonds,
afforded 6t in 85% yield with 95% ee under a catalyst
loading of 5 mol%. Substrates with two different
benzylidene substituentents (5u and 5v) were reduced in
excellent yields (97~99%) and enantioselectivities
(96~97% ee). The hydrogenation of aliphatic group
containing substrates 5w-y also proceeded smoothly,
furnishing the corresponding diketopiperazines 6w-y in
quantantive yields with moderate to good ee values.
Ir cat. (1 mol%)
30 atm H2
Ph
N
Ph
N
Ir
Ph
N
+
Ph
N
N
Ph
N
Ph
CH2Cl2, rt, 24 h
O
6a
O
5a
O
7a
1a
R = Bn, Ar = Ph: (S, S)-
R = Ph, Ar = o-Tol: (R, S)-
R = Ph, Ar = m-Xyl: (R, S)-
1a
1b
R = Bn, Ar = Ph: (R, S)-
Ar Ar
P
i
1g
1h
R = Pr, Ar = Ph: (R, S)-
R = sBu, Ar = Ph: (R, S)-
1c
-
BArF
N
R
i
1i
R = Ph, Ar = 4-FC6H4: (R, S)-
1d
1e
R = Bu, Ar = Ph: (R, S)-
t
1j
R = Ph, Ar = 4-MeC6H4: (R, S)-
R = Ph, Ar = 4-MeOC6H4: (R, S)-
R = Bu, Ar = Ph: (R, S)-
O
1k
1f
R = Ph, Ar = Ph: (R, S)-
SpinPHOX-Ir
10
11
12
13
14
15
16
17
18
19
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R
R
(DTB)2
P
Ph
Ph
P
P
O
Ir
Bn
Bn
Ir
Ir
-
-
-
N
BArF
BArF
BArF
tBu
N
Bn
N
O
O
O
3a
3b
R = Cy: (R, R)-
R = Ph: (R, R)-
4
(S, S)- or (
, )-
R S
4
2a
(S)-
Table
2.
AH
of
the
3,6-dialkylidene-2,5-
diketopiperazines (5a-y)a-c
SIPHOX-Ir
ThrePHOX-Ir
PHOX-Ir
O
R'
R
H
O
Ar
Ar
R
N
1k
(R, S)- (x mol% )
N
yield of 6a
ee of 6a
yield of 7a
ee of 7a
Ir
P
+
H2
Entry
Ir cat.
N
R'
(%)b
(%)c
(%)b
(%)c
CH2Cl2, rt, 24 h
H
-
N
N
BArF
Ph
40 atm
O
O
5a-y
1k
(R, S)-
O
6a-y
1
2
(R, S)-1a
(S, S)-1a
(R, S)-1b
(R, S)-1c
(R, S)-1d
(R, S)-1e
(R, S)-1f
(R, S)-1f
(R, S)-1g
(R, S)-1h
(R, S)-1i
(R, S)-1j
(R, S)-1k
(R, S)-1k
(S)-2a
41
37
30
48
40
18
93
94
82
69
85
90
95
>99
41
0
92(S, S)
45(R, R)
94(S, S)
92(S, S)
94(S, S)
97(S, S)
90(S, S)
90(S, S)
96(S, S)
92(S, S)
96(S, S)
92(S, S)
92(S, S)
94(S, S)
79(S, S)
-
5
8
6
4
5
5
3
2
2
3
3
2
2
0
6
0
0
15(S)
7(S)
77(S)
11(S)
26(S)
62(S)
66(R)
67(R)
66(R)
26(R)
26(R)
54(R)
76(R)
-
Ar = 4-MeOC6H4
3
4
5
6
7
8
9
10
11
12
13
14d
15
16
17
7(S)
-
(R, R)-3a
(R, R)-3b
0
-
-
18
19
(R, S)-4
(S, S)-4
0
0
-
-
0
0
-
-
a
Unless otherwise noted, all reactions were conducted in
dichloromethane with [5a] = 0.1 M and Ir cat. = 1.0 mM (1
mol%) under 30 atm of H2 at rt for 12 h (entries 1-7) or 24 h
b
c
(entries 8-19).
Determined by 1H NMR spectroscopy.
d
Determined by HPLC analysis on a chiral stationary phase.
The reaction was conducted under 40 atm of H2.
Substrate Scope of the Catalytic Hydrogenation
Protocol. Having established complex (R, S)-1k as the
optimal catalyst, the substrate scope of this catalytic
protocol was subsequently investigated. As shown in Table
2,
various
symmetric
3,6-dibenzylidene-1,4-
dimethylpiperazine-2,5-diones 5b-n containing different
ortho-, meta-, or para- substituents on the phenyl rings
were smoonthly hydrogenated, affording
corresponding (S, S)-3,6-dibenzyl-1,4-dimethylpipera-
zine-2,5-diones 6b-n in high yields (94~99%), excellent
enantioselectivities (93~98% ee) and complete cis-
diastereoselectivity, irrespective of the position and
electronic nature of the substituents on the phenyl rings.
the
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OMe
MeO
protocol, substrate 5a was hydrogenated on a gram-scale
3
4
5
6
7
8
9
in the presence of catalyst (R, S)-1k (1 mol %) in CH2Cl2
under 50 atm of hydrogen pressure to afford (S, S)-6a in
95% yield with 94% ee (Scheme 2a). The enantiopurity of
6a was readily upgraded to >99% ee by a simple
recrystallization (75% yield). To exemplify the utility of
the hydrogenation products, (S, S)-6a was reduced with
O
O
O
N
N
N
H
H
H
N
N
N
H
H
H
O
O
O
6a
x = 1, >99% (98%), 94% ee
tBu
6b
x = 2, >99% (94%), 94% ee
Cl
6c
x = 1, 94% (94%), 97% ee
tBu
Cl
F
F
O
O
O
N
N
N
LiAlH4
to
afford
(2S,
5S)-2,5-dibenzyl-l,4-
H
H
H
N
N
N
H
H
H
O
O
O
dimethylpiperazine 8, an alkaloid isolated from
Zanthoxylurn arborescens Rose17, in 80% yield without
loss of enantiopurity (Scheme 2b). Moreover, double
allylation of (S, S)-6a with allyl bromide proceeded cleanly
in the presence of NaHMDS as the base, to give 9 in almost
quantitative yield with nearly perfect stereoselectivity
(>99% ee). Such a stereospecificity can be rationalized by
consecutive allylations via stepwise formation of two
distinct chiral sodium enolates, wherein the bulkier Bn
group on the remaining chiral center would effectively
steer the incoming allyl electrophile to the opposite face of
the nearby enolate moiety. Subsequent ring closure olefin
metathesis18 of 9 furnished 2-butenyl-bridged bicyclic
diketopiperazine derivative 10 in >99% ee (Scheme 2c).
Hydroxylation of (S, S)-6a with oxygen as the oxidant
afforded enantiomeric pure C-hydroxydiketopiperazine
11, an analog of Thaxtomin A (a potential pesticides) 19, in
65% yield (Scheme 2d). Finally, AH of 12 and 15 using (R,
S)-1k as the catalyst provides key chiral precursors for the
synthesis of calpain inhibitor (S, S)-1420 and Sch725418
1721, respectively, in high yields with excellent ee values
(Scheme 2e-f).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
6d
6e
6f
x = 1, >99% (96%), 96% ee
x = 2, 94% (93%), 94% ee
x = 2, >99% (98%), 98% ee
OAc
AcO
OMe
MeO
O
N
O
N
O
N
H
H
H
N
H
N
H
N
H
O
O
O
6g
6h
6i
x = 2, >99% (99%), 93% ee
OMe
x = 5, >99% (>99%), 94% ee
x = 2, >99% (>99%), 96% ee
MeO
Br
Br
O
O
N
O
N
N
H
H
H
N
N
N
H
H
H
O
O
O
6j
6k
x = 2, >99% (>99%), 94% ee
6l
x = 5, >99% (99%), 94% ee[d]
x = 2, >99% (>99%), 94% ee
OMe
MeO
Cl
OAc
Br
Cl
AcO
Br
O
O
O
N
N
N
H
H
H
N
N
N
H
H
H
O
O
O
6n
6m
6o
x = 1, >99% (98%), 97% ee
x = 5, >99% (99%), 96% ee[d]
x = 2, >99% (96%), 98% ee
O
N
O
N
O
N
H
H
H
N
N
N
H
H
H
O
O
O
6r
6p
6q
x = 5, >99% (99%), 92% ee
x = 2, 96% (95%), 96% ee
x = 5, >99% (>99%), 97% ee[d]
OMe
MeO
MeO
OMe MeO
OMe
MeO
O
O
O
N
O
O
N
N
H
H
H
N
N
N
H
H
H
O
O
O
O
N
6t
x = 5, >99% (85%), 95% ee[d]
6s
6u
x = 2, >99% (94%), 96% ee
x = 2, >99% (97%), 97% ee
F
H
MeO
N
H
O
6a
O
O
(S, S)-
O
N
Et
O
N
N
nPr
H
Et
N
Et
H
N
H
H
N
H
N
H
O
H
N
6v
O
H
O
O
6w
6x
6y
x = 5, >99% (95%),
64% ee
x = 2, >99% (99%)
96% ee
x = 5, >99% (99%)
86% ee
x = 5, >99% (99%)
70% ee
O
a Unless otherwise noted, all reactions were performed with 5
(0.04-0.2 mmol) in CH2Cl2 (2.0 mL) in the presence of (R, S)-
1k (0.002 mmol) under hydrogen atmosphere (40 atm) at 25
N
H
N
Ph
O
°C for 24 h. The conversions of 5 were determined by 1H
b
7a
()-
NMR spectroscopy. Data in the parentheses are the yields for
isolated products 6a-y. The ee values were determined by
HPLC analysis on a chiral stationary phase.
hydrogen pressure of 80 atm.
c
Figure 1. Molecular structure of double and mono-
hydrogenated cyclic dipeptides (S, S)-6a and ()-7a.
d
Under a
Scheme 2. Gram-scale AH of 5a and Utilities of the
Hydrogenation Products in the Synthesis of
Biologically Interesting Molecules
Synthetic Application of the Protocol for Efficient
Construction of Biologically Interesting Molecules. As
shown in Figure 1, in the molecular structure of product (S,
S)-6a the two benzyl moeities are orientated cis to each
other at the same side of the quasi-planar six-membered
dipeptide ring. Such a structural feature of the prepared
cyclic dipeptides would provide an interesting molecular
platform for the design of chiral organocatalysts5a,b and as
useful intermediates for the synthesis of biologically
important molecules.16 To showcase the practicality of this
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O
(40%), along with mono-hydrogenated 7a as the major
N
1 mol% (R, S)-1k
O
H2
(58%) and meso-isomer in trace amount (1% yield)
(Scheme 1b),9 implying that in this case the hydrogenation
of second C=C double bond in the substrate is somehow
slower than AH of first C=C double bond. In sharp contrast,
AH of 5a using SpinPHOX/Ir(I)-type catalysts (1a-k)
generally gave the double-hydrogenated 6a as the major
product with exclusive cis-configuration (entries 1-13,
Table 1), and mono-hydrogenated intermediate 7a was
only detected as a minor product in less than 8% yield
irrespective of the conversion of substrate 5a. A close
examination of reaction profile for AH of 5a (Figure 2) [1
mol% of (R, S)-1k] revealed that (S, S)-6a remains the
major product throughout the whole reaction course with
7a being kept at a consistently low level (<8%), further
verifying the observation in Table 1. It is also noteworthy
that over the reaction course no meso-isomer of 6a was
detected, indicating the complete cis-selectivity for the
relative stereochemistry in the tandem AH process. During
the reaction course, the ee values of the double-
hydrogenation product (S, S)-6a decreased slightly from
the initial >99% at 5 min to a final 94% at 12 h.
Concomitantly, the ee value of 7a also gradually
diminished, and eventually shifted its absolute
configuration from S to R. This intriguing behavior might
be caused by the kinetic resolution in the AH of
enantioenriched 7a by (R, S)-1k-derived Ir catalyst, which
by chiral discrimination led to preferential AH of (S)-7a
and a gradual enrichment of (R)-7a in the reaction mixture
(vide infra).
+
a
N
N
CH2Cl2, 30 °C, 24 h
50 atm
H
N
H
O
5a
O
6a
>99% conv. 95% yield, 94% ee
75% yield, > 99% ee
after recrystallization
1 g
10 eq. LiAlH4,
THF
b
N
0 °C - r.t. - reflux
H
N
H
80% yield. > 99% ee
8
natural product
O
N
0.25 eq. Grubbs Catalyst
2nd Generation
allyl bromide
NaHMDS
O
O
H
N
H
N
N
O
6a
> 99% ee
c
THF, -78 °C ~ r.t.
N
N
PhCH3, 60 °C
O
O
99% yield, >99%ee
9
10
92% yield, >99% ee
O2 ,NaHMDS
O
d
N
THF, -78 °C ~ r.t.
65% yield, >99% ee
H
N
HO
O
11
OBn
BnO
O
5 mol% (R, S)-1k,
40 atm H2,
e
OBn
N
N
CH2Cl2, rt, 24 h
O
BnO
N
O
> 99% conv. 99% yield, 96% ee
OH
H
N
12
H
O
HO
13
50% Pd/C, 20 atm H2,
O
N
CH3OH : CHCl3 = 1 : 1,
r.t., 16 h
H
N
H
91% yield, 94% ee
O
14
natural product
O
N
5 mol% (R, S)-1k
BocN
N
Boc
NBoc
O
70 atm H2
N
27
f
N
N
Boc
O
CH2Cl2, 50 oC , 24 h
H
28
29
30
31
32
33
34
35
N
H
O
> 99% conv. 97% yield, 95% ee
HN
15
16
NH
O
TMSOTf, DBU
N
CH2Cl2, 0 oC ~ rt,
92% yield, 94% ee
H
N
H
O
17
Sch 725418
Reaction Pathway Study. While some mechanistic
details remain controversial, the reaction pathways for Ir-
catalyzed asymmetric hydrogenation of monoenes have
been intensively studied both experimentally and
theoretically in recent years.22 On the other hand, Ir-
mediated AH of dienes remains much less explored so far,
and the mechanism relevant informations are scarce. In
this context, Burgess and coworkers reported elegant
studies on Ir-carbene-oxazoline catalyzed AH of
conjugated dienes, whereby the reduction was suggested
to occur in mechanistically different phases.23 Andersson
et al recently described an efficient regio- and
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 2. Reaction profile of hydrogenation of 5a in the
presence of (R, S)-1k under the optimized reaction conditions:
1 mol % of (R, S)-1k, 40 atm of H2 in CH2Cl2 with an initial [5a]
= 0.1 M.
enantioselective
monohydrogenation
of
1,4-
cyclohexadienes, arguably a type of isolated dienes, using
an iridium catalyst with a chiral N,P-ligand.24 However, no
mechanistic information was available in this report. Given
the excellent performance of SpinPHOX/Ir catalyst (R, S)-
1k in the AH of the 3,6-dialkylidene-2,5-diketopiperazines,
we were intrigued by the mechanistic events in the
hydrogenation of this particular type of functionalized
dienes.
In order to provide further illuminating insights into the
stereochemistry and the kinetic behavior in the titled reaction,
control experiments on the AH of mono-hydrogenated
intermediate enantiopure (S)-7a, (R)-7a, and racemic (±)-7a,
respectively, were performed with 1 mol% of (R, S)-1k under
standard reaction conditions (Scheme 3). The hydogenation of
(S)-7a (Scheme 3a) is obviously much faster than that of (R)-
As discussed in the introduction, Co catalyzed AH of
cyclic dehydropeptide 5a reported previously by Takeuchi
afforded the double-hydrogenated cis-6a as minor product
7a (Scheme 3b), suggesting
a strong catalyst–substrate
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recognition in the reaction. Either (S, S)-6a or (R, R)-6a (both
for double allylation of (S, S)-6a (vide supra for discussion
>99% ee) was obtained in >99% diastereoselectivity but with
an opposite asymmetric induction depending on the absolute
configuration of 7a, implying a substrate-control of the
relative stereochemistry in the process. Such a distinction in
reaction rate between (S)-7a and (R)-7a with the same chiral
catalyst [(R, S)-1k] is consistent with the presence of a kinetic
resolution process of 7a in its hydrogenation. Indeed, the AH
of (±)-7a to half conversion in the presence of 1 mol% of (R,
S)-1k afforded (S, S)-6a with 80% ee, along with an almost
equal amount of the remaining (R)-7a with 77% ee, without
detection of any meso-isomer (Scheme 3c).
of Scheme 2c). In this case, 7a bears a chiral center that is
in proximity to its C=C bond. As shown in the molecular
structure of 7a (Figure 1), the reduced benzyl moiety on
the chiral carbon center of 7a can be expected to
effectively block one of the prochiral alkene faces, thus
preventing the access of Ir catalyst species to the same side
of diketopiperazine face. As a result, the catalyst would
bind to the C=C bond of 7a on the opposite side of its Bn
group, leading to the formation of cis-6a via ensuing
hydrogenation. Accordingly, it can be deduced that for (R,
S)-1k mediated AH of cyclic dehydropeptide 5a, the
enantioselectivity of the whole hydrogenation process is
completely determined by the asymmetric induction of the
first-step hydrogenation, if intermediate 7a is completely
consumed at the end of reaction.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 3. Hydrogenation of Mono-Hydrogenated
Intermediate 7a in the Presence of (R, S)-1k and
Achiral Ir Catalyst 2b
Ph
O
Ph
Ph
O
N
1k
(R, S)- (1 mol%)
N
+
+
a)
H2
A notable pattern in both the data of Table 1 and Figure
2 can be found, in that the half-reduced intermediate 7a
was always detected in minor or negligible amount (< 8%)
over the course of 5a hydrogenation. Although this
observation might suggest that hydrogenation of 7a could
be somehow faster than that of 5a, there is an alternative
possibility that the hydrogenation of the two C=C bonds in
cyclic dehydropeptide 5a occurs processively. In the latter
case, after reduction of the first C=C bond in 5a the
resulting intermediate (S)-7a can remain bound to the
catalyst without dissociation, which can undergo an
intramolecular re-organization for the second step of
hydrogenation. Such an intramolecular process is expected
to be entropically more favorable than the one involving
dissociation-reassociation of 7a from/to the catalyst, thus
leading to faster reaction. To shed some light on this
mechanistic ambiguity, the initial rate for the
hydrogenation of 5a was compared with that of (S)-7a by
1H NMR analysis of the reaction mixture. As shown in
Scheme 4a, the hydrogenation of 5a and (S)-7a (a matched
isomer of intermediates) were carried out under otherwise
identical reaction conditions (1 mol% of (R, S)-1k, 5 min).
It was notable that both the conversion of cyclic
dehydropeptide 5a and yield of (S, S)-6a in the
hydrogenation of 5a are significantly higher than those
observed in the hydrogenation of (S)-7a (Scheme 4a). This
indicates for generation of 6a, the double hydrogenation of
two C=C bonds in 5a is even faster than the hydrogenation
of single C=C bond in half-hydrogenated (S)-7a. Based on
H
CH2Cl2, rt, 24 h
N
H
Ph
N
H
40 atm
O
80% conv., 80% yield
O
7a
(S)- ( >99% ee)
6a
(S, S)- (>99% ee)
O
O
H
N
H
N
H
1k
(R, S)- (1 mol%)
H2
b)
N
N
Ph
CH2Cl2, rt, 24 h
<5% yield
O
Ph
O
Ph
40 atm
Ph
7a
6a
(R, R)- (>99% ee)
(R)- ( >99% ee)
Ph
Ph
O
N
O
H
N
H
O
Ph
N
1k
(R, S)- (1 mol%)
6a
(S, S)- (80% ee)
+
H2
c)
N
Ph
CH2Cl2, rt, 24 h
50% conv.
O
40 atm
H
N
O
7a
rac-
N
Ph
O
Ph
7a
(R)- (77% ee)
Ph
O
Ph
Ph
O
N
2b
(5 mol%)
N
+
H2
d)
e)
H
N
CH2Cl2, rt, 24 h
97% conv.
Ph
H
40 atm
N
H
O
O
7a
(S)- (>99% ee)
6a
O
(S, S)- (>99% ee)
O
H
N
H
N
H
2b
(5 mol%)
+
N
H2
Ph
N
O
CH2Cl2, rt, 24 h
96% conv.
Ph
O
Ph
40 atm
Ph
6a
7a
(R)- ( >99% ee)
(R, R)- (>99% ee)
Ph
Ph
Ar Ar
P
Ir
Ir
P
Ar = 4-MeOC6H4
2b
-
-
BArF
BArF
N
(R, S)-1k
N
Ph
O
O
The substrate control of the diastereoselectivity has
been further demonstrated by the stereochemical
outcomes in the hydrogenation of enantiomers of 7a with
an achiral Pfaltz-type Ir catalyst 2b, which was used to
exclude the otherwise matched or mis-matched catalyst–
substrate recognition in the case of a chiral Ir catalyst such
as (R, S)-1k. As shown in Schemes 3d-e, the
hydrogenations of (S)-7a or (R)-7a in the presence of the
achiral Ir catalyst 2b (5 mol%) gave (S, S)-6a or (R, R)-6a,
respectively, with >99% ee without the co-production of
any meso-isomer. These results also clearly confirmed that
the stereoselectivity for hydrogenation of 7a is completely
controlled by the chirality of the substrate, irrespective of
the Ir catalysts used thereof. The complete cis-selectivity
for the relative stereochemistry in Scheme 3d and 3e can
be rationalized in a way analogous to that discussed above
these results, we tentatively propose
a processive
mechanism as the major pathway for Ir-catalyzed double
hydrogenation of 3,6-dialkylidene-2,5-diketopiperazines.
As shown in Scheme 4b, due to the conformational rigidity
of the piperazine-2,5-dione core, the two C=C bonds in
diene 5a are located too far from each other to
simultaneously bind to a single Ir center (distance between
diene internal carbons: 2.7533(27) Å. for the X-ray
structure of 5a, see Figure S1). After one of C=C bonds in
dehydropeptide 5a is reduced, the mono-hydrogenated
(S)-7a remains bound to the catalyst, and by way of an
intramolecular movement is ready for consecutive
hydrogenation of second C=C bond. Such a processive
double hydrogenation pathway can account for the fact
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that no distinct accumulation of mono-hydrogenated
imtermediate 7a is observed (Table 1 and Figure 2), and is
Supporting Information
The Supporting Information is available free of charge
on the ACS Publications website at xxxxxx.
consistent with the observation that double-AH of 5a to 6a
is conspicuously faster than mono-AH of 7a under
otherwise identical reaction conditions, as well as the
essentially exclusive cis-stereochemistry in the formation
of two chiral centers. It is noteworthy that such a pathway
features a “walking” model, which is reminiscent of work
by Sigman, Ma, and others.25
Detailed
synthetic,
crystallographic,
and
characterization data (PDF)
Crystallographic data for 5a (CIF)
Crystallographic data for (S, S)-6a (CIF)
Crystallographic data for ()-7a (CIF)
Crystallographic data ()-11 (CIF)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 4. a) Comparison of the reactivity in (R, S)-1k
catalyzed hydrogenation of 5a and (S)-7a, and b)
Schematic Illustration of the Major Pathway for the
Asymmetric Hydrogenation of 5a
AUTHOR INFORMATION
Corresponding Author
*kding@mail.sioc.ac.cn
ORCID
O
a)
Ph
Ph
Ph
O
O
Ph
N
N
N
1k
(R, S)- (1 mol%)
Kuiling Ding: 0000-0003-4074-1981
+
H2
40 atm
+
N
Ph
H
H
CH2Cl2, rt, 5 min
33% conv.
N
N
H
Ph
O
O
O
5a
Notes
6a
7a
(S)-
8% yield
68% ee
(S, S)-
25% yield
>99% ee
The authors declare no competing financial interest.
Ph
Crystallographic data (CIF files) for 5a (CCDC 1877956), (S，
S)-6a (CCDC 1877960), ()-7a (CCDC 1877959), ()-11 (CCDC
1893145) have been deposited at the Cambridge
Crystallographic Data Center
O
Ph
Ph
O
N
1k
(R, S)- (1 mol%)
N
+
H2
H
CH2Cl2, rt, 5 min
N
H
Ph
N
H
N
40 atm
O
14% conv.
O
6a
7a
(S)- ( >99% ee)
(S, S)-
14% yield
>99% ee
b)
ACKNOWLEDGMENT
O
Ph
+ H2
Ph
O
Ph
O
N
Ph
Ph
Ph
[Ir]
N
+ H2
6a
(S,S)-
N
This work was financially supported by Ministry of Science
and Technology of China (2016YFA0202900), the National
Natural Science Foundation of China (21790333,
21872167), CAS (QYZDY-SSW-SLH012, XDB20000000).
N
H
N
H
[Ir]
O
[Ir]
O
O
CONCLUSION
In summary, a highly enantioselective hydrogenation
reaction of 3,6-dialkylidene-1,4-dimethylpiperazine-2,5-
dione has been developed using a SpinPHOX/Ir(I) complex
as the catalyst, providing a wide variety of chiral cis, cis-
3,6-disubstituted-2,5-diketopiperazines in high yields with
excellent optical purities (up to 98% ee). The perfect
diasteroselectivity arised from a very effective chiral
substrate controled process. Synthetic utilities of the
protocol were demonstrated in the asymmetric synthesis
of natural products 8, 14 and 17 as well as a 2-butenyl-
bridged bicyclic diketopiperazine derivative 10 and
hydroxyl substituted diketopiperazine derivative 11.
Mechanistic investigation revealed that a partly processive
catalysis pathway is present in the reaction course,
wherein the two carbon carbon double bonds of the
substrate are hydrogenated successively on a single
iridium center via the formation of an undissociated mono-
reduced intermediate. Such kind of processivity is essential
in nature,26 and the present catalytic system represents
rare example of artificial catalyst in asymmetric processive
hydrogenation of heterocycles.11 The present protocol
might inspire further studies and applications of
asymmetric hydrogenation for the synthesis of chiral 2,5-
diketopiperazines and their derivatives with biological and
medicinal interests.
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R2
H
O
O
Ar2
P
Ph
O
R2
N
N
N
Ir
(cod)
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H
N
R1
N
-
H2
BArF
O
R1
O
R2
O
 processive hydrogenation
 27 examples
 exclusive cis selectivity
 up to 98% ee
R1
N
N
H
O
[Ir]
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