Chiral γ-Lactams by Enantioselective Palladium(0)-Catalyzed Cyclopropane Functionalizations

Article abstract of DOI:10.1002/anie.201505916

Cyclopropanes fused to pyrrolidines are important structural features found in a number of marketed drugs and development candidates. Typically, their synthesis involves the cyclopropanation of a dihydropyrrole precursor. Reported herein is a complementary approach which employs a palladium(0)-catalyzed C-H functionalization of an achiral cyclopropane to close the pyrrolidine ring in an enantioselective manner. In contrast to aryl-aryl couplings, palladium(0)-catalyzed C-H functionalizations involving the formation of C(sp³)-C(sp³) bonds of saturated heterocycles are very scarce. The presented strategy yields cyclopropane-fused γ-lactams from chloroacetamide substrates. A bulky Taddol phosphonite ligand in combination with adamantane-1-carboxylic acid as a cocatalyst provides the γ-lactams in excellent yields and enantioselectivities. Bulk up: An enantioselective C-H functionalization strategy is used to access cyclopropane-fused γ-lactams from readily accessible chloroacetamide substrates. A bulky Taddol phosphonite ligand in combination with adamantane-1-carboxylic acid as a cocatalyst provides the γ-lactams in excellent yields and enantioselectivities.

Full text of DOI:10.1002/anie.201505916

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Angewandte
Communications
International Edition: DOI: 10.1002/anie.201505916
German Edition: DOI: 10.1002/ange.201505916
À
C H Activation
Chiral g-Lactams by Enantioselective Palladium(0)-Catalyzed
Cyclopropane Functionalizations
Julia Pedroni and Nicolai Cramer*
Abstract: Cyclopropanes fused to pyrrolidines are important
structural features found in a number of marketed drugs and
development candidates. Typically, their synthesis involves the
cyclopropanation of a dihydropyrrole precursor. Reported
The relevance of the azabicyclo[3.1.0]hexanes makes
catalytic enantioselective approaches for this scaffold syn-
thetically very valuable. Classical synthetic approaches
involve a cyclopropanation reaction of suitable unsaturated
precursors.[8–10] Complementary to the construction of the
cyclopropane,[11] we aimed for an enantioselective direct
functionalization of an existing achiral cyclopropyl unit.
Besides stoichiometric reactions using strongly basic
herein is
a
complementary approach which employs
À
a palladium(0)-catalyzed C H functionalization of an achiral
cyclopropane to close the pyrrolidine ring in an enantioselec-
tive manner. In contrast to aryl–aryl couplings, palladium(0)-
catalyzed C H functionalizations involving the formation of
reagents,[12] transition-metal-catalyzed C H functionaliza-
À
À
3
3
C(sp ) C(sp ) bonds of saturated heterocycles are very scarce.
The presented strategy yields cyclopropane-fused g-lactams
from chloroacetamide substrates. A bulky Taddol phosphonite
ligand in combination with adamantane-1-carboxylic acid as
a cocatalyst provides the g-lactams in excellent yields and
enantioselectivities.
tions of cyclopropanes have been developed.[13,14] Despite
their utility, enantioselective variants remain rare.[15] In
À
2
2
2
À
À
contrast to the formation of either C(sp ) C(sp ) or C(sp )
C(sp3) bonds,[13c,16] palladium(0)-catalyzed C H functionali-
zations aimed at the construction of C(sp ) C(sp ) bonds are
very scarce.[13b,17,18] Herein, we report a highly enantioselec-
tive synthesis of saxagliptin-type 2-azabicyclo[3.1.0]hexane
À
3
3
À
À
T
he cyclopropane ring is a frequently used design element in
derivatives 2 by an asymmetric C H functionalization
strategy (Scheme 1). The required aminocyclopropane sub-
biologically active compounds with the aim to increase
metabolic stability, as well as rigidity, by a defined three-
dimensional orientation in space.[1] In particular, cyclopro-
panes fused to pyrrolidine units are found as key structural
features in important biologically active agents such as
trovafloxacin,[2] boceprevir,[3] cyproximide,[4] amitifadine,[5]
and bicifadine[6] for the 3-azabicyclo[3.1.0]hexane series and
saxagliptin,[7] as a 2-azabicyclo[3.1.0]hexane (Figure 1).
À
Scheme 1. An enantioselective palladium(0)-catalyzed C H functional-
ization approach to cyclopropane-fused g-lactams (2).
strates 1 are conveniently accessed by Kulinkovich–Szymo-
niak[19] or Kulinkovich–de Meijere reactions.[20] The chloro-
acetamide group of 1 serves as the alkyl electrophile required
to access the alkyl palladium intermediate A. So far, the use
of chloroacetamides as electrophilic components for palla-
Figure 1. Examples of marketed drugs and development candidates
containing a cyclopropane unit fused to a pyrrolidine.
À
dium-catalyzed C H activations remain limited to reports
from the group of Buchwald for the synthesis of oxindoles[21]
and from our group to access b-lactams.[17a] Several selectivity
challenges in the activation step have to be considered. First,
the activation of the hydrogen atoms of A, adjacent to the
nitrogen atom need to be mitigated (Scheme 1). We previ-
[*] J. Pedroni, Prof. Dr. N. Cramer
Laboratory of Asymmetric Catalysis and Synthesis, EPFL SB ISIC
LCSA, BCH 4305
1015 Lausanne (Switzerland)
E-mail: nicolai.cramer@epfl.ch
Homepage: http://isic.epfl.ch/lcsa
À
ously reported functionalizations of such C H bonds for an
enantioselective b-lactam synthesis.[17a] Instead, the formation
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201505916.
À
of 2 would require a selective C H activation of one of the
11826
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Angewandte
Chemie
Table 1: Optimization of the enantioselective g-lactam formation.[a]
of cesium carbonate (entries 13 and 14). For instance,
potassium carbonate gave 2a with only slightly reduced
À
enantioselectivity (entry 13). Remarkably, for this type of C
H activation, the reaction temperature could be lowered to
708C, thus further increasing the enantioselectivity to 95.5:4.5
e.r. while maintaining full conversion and high yields
(entry 15).
The scope for the g-lactam formation was subsequently
evaluated with the aforementioned optimized reaction con-
ditions (Table 1, entry 15). Several benzyl derivatives and
alkyl groups are tolerated on the nitrogen atom (R2; Table 2,
entries 1–5). However, a tertiary amide is required as
secondary ones do not cyclize and lead mainly to recovery
of starting material (entry 6). Besides a hydrogen atom, R1
accommodates a wide range of alkyl, benzyl, and aryl
substituents. In addition, common and versatile functional
groups including adjacent esters and nitriles work well
(entries 7–14). The transformation furnishes, on a gram
scale, the cyclized product in equally high yield and selectivity
(entry 8). Concerning spirocyclic substrates, the success of the
enantioselective activation is dependent on the ring size. For
instance, the pyrrolidine 1n did not provide the pyrrolizidine
2n (entry 15). In contrast, the larger piperidine 1o gave the
indolizidine scaffold 2o in excellent yield and enantioselec-
tivity (entry 16). Remarkably, the reaction proceeds at
reaction temperatures as low as 358C (entry 17). Moreover,
the substrate 1q, featuring a tetrasubstituted cyclopropane
Entry
L*
Acid
T [8C]
Yield [%][b]
e.r.[c]
1
2
3
4
5
6
7
8
L1
L2
L3
L4
L5
L6
L7
L8
L9
L9
L9
L9
L9
L9
L9
AdCO2H
AdCO2H
AdCO2H
AdCO2H
AdCO2H
AdCO2H
AdCO2H
AdCO2H
110
110
110
110
110
110
110
110
110
110
110
110
110
110
70
16
76
88
95
73
93
68
29
93
89
82
96
52:48
68.5:31.5
83.5:16.5
84:16
85.5:14.5
92.5:7:5
95:5
95.5:4.5
93.5:6.5
89:11
94:6
92.5:7.5
92:8
93:7
95.5:4.5
9
AdCO2H
AcOH
10
11
12
13
14
15[d]
Xanth-CO2H
PivOH
AdCO2H (K2CO3)
AdCO2H (Rb2CO3)
AdCO2H (5 mol%)
96
94
99 (89)[e]
À
having only methine C H bonds, is selectively functionalized
[a] Reaction conditions: 0.05 mmol 1a, 2.5 mmol [Pd(dba)2], 5.0 mmol L*,
5.0 mmol acid, 1.5 equiv Cs2CO3, 0.1m in toluene, 12 h at the indicated
temperature. [b] Determined by 1H NMR spectroscopy using an internal
standard. [c] Determined by HPLC analysis using a chiral stationary
phase. [d] 0.1 mmol scale, 24 h. [e] Yield of isolated product. dba=di-
benzylideneacetone, Piv=pivaloyl.
to provide the tricyclic lactam 2q (entry 19). The absolute
configuration of the g-lactams was unambiguously established
to be (R,R) by X-ray crystallographic analysis of 2j.[23]
As g-lactams with a free NH could not be directly
accessed, the 2,4,6-trimethoxybenzyl group of 2d was cleaved
under acidic conditions, thus providing 2 f in good yield
(Scheme 2a). Exemplarily for compound 2i, the cyclopro-
À
two enantiotopic C H bonds of the cyclopropane ring during
the concerted metalation–deprotonation (CMD) step,[22] via
B, to give the six-membered palladacycle C. Subsequent
reductive elimination would yield the cyclopropane-fused g-
lactam 2.
The initial reaction parameters were evaluated using
chloroacetamide 1a as a model substrate (Table 1). A brief
screen of different Taddol phosphoramidite ligands showed
that an increased bulk of the flanking aryl groups of the ligand
À
(L1–L4) improved the yield as well as the selectivity of the C
H functionalization (entries 1–4), thus giving 2a in 95% and
84:16 e.r. when using L4. Exchange of the dimethylamino
substituent for a pyrrolidine (L5) had little effect (entry 5),
whereas the installation of an aromatic pyrrole group (L6)
increased the selectivity to 92.5:7.5 (entry 6). Changing the
bulk of the pyrrole by replacing it with either an indole (L7;
entry 7) or a carbazole (L8; entry 8) further increased the
selectivity for 2a, but drastically reduced the yield. Exchange
of the 1-pyrrole substituent by a simple phenyl group (L9)
resulted in excellent reactivity while maintaining the high
selectivity (93.5:6.5) of the pyrrole-type ligands (entry 9).
Among a small range of carboxylic acid additives tested
(entries 9–12), adamantyl carboxylic acid provided the high-
est selectivities. Other carbonate bases could be used instead
Scheme 2. Selected modifications of the g-lactams 2. TFA=trifluoro-
acetic acid.
pane unit is shown to serve as a latent methyl group
(Scheme 2b). Hydrogenation under heterogeneous condi-
tions with Pd/C selectively yielded the trans g-lactam 3
without a loss of optical purity.
The enantioselective g-lactam formation is not limited to
À
the use of cyclopropanes as source of activatable C H bonds.
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www.angewandte.org 11827

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Angewandte
Communications
Table 2: Scope for the synthesis of the g-lactams 2.[a]
Entry
1
1
2
Yield [%][b] e.r.[c]
1a
2a
R2 =PMB, R1 =H
89
95.5:4.5
2
3
4
1b
1c
1d
2b
2c
2d
99
96:4
93:7
98:2
Scheme 3. The g-lactams 5 from the functionalization of enantiotopic
methyl groups. Mes=2,4,6-trimethylphenyl.
propanes, it is remarkable that the reaction allows a selection
99
78
between a methyl and an ethyl group (5b).
À
In summary, we disclosed an enantioselective C H
functionalization approach for the synthesis of valuable
azabicyclo[3.1.0]hexane scaffolds using readily accessible
chloroacetamides. This palladium(0)-catalyzed transforma-
tion yields cyclized products in excellent enantioselectivities
by using a bulky Taddol phosphonite ligand and 1-adaman-
tane carboxylic acid as a cocatalyst. A salient aspect of this
transformation is its broad tolerance for substituents on the
cyclopropane, thus enabling access to versatile molecular
building blocks.
5
6
7
8
1e
1 f
1g
1g
1h
1i
1j
1k
1l
2e
2 f
2g
2g
2h
2i
2j
2k
2l
R2 =iPr, R1 =(CH2)3Ph
R2 =H, R1 =(CH2)3Ph
R2 =PMB, R1 =(CH2)3Ph
gram scale (2.69 mmol)
R2 =PMB, R1 =Bn
94
0
98:2
–
96.5:3.5
97.5:2.5
95.5:4.5
98:2
92
93
98
99
68
99
90
9
10
11[d]
12
13
14
R2 =PMB, R1 =Ph
R2 =PMB, R1 =p-ClC6H4
R2 =PMB, R1 =CN
95:5
Acknowledgements
92.5:7.5
91.5:8.5
96.5:3.5
R2 =PMB, R1 =CO2Et
This work is supported by the European Research Council
under the European Communityꢀs Seventh Framework Pro-
gram (FP7 2007–2013)/ERC Grant agreement no 257891 and
the Swiss National Science Foundation (no 155967). We thank
Dr. R. Scopelliti for X-ray crystallographic analysis of
compound 2j.
1m 2m R2 =PMB, R1 =CH2OTIPS 95
15
1n
2n
0
–
À
Keywords: asymmetric catalysis · C H activation · lactams ·
palladium · small-ring compounds
16
1o
1o
1p
2o
2o
2p
99
65
76
95:5
17[e]
18
at 358C
98:2
How to cite: Angew. Chem. Int. Ed. 2015, 54, 11826–11829
Angew. Chem. 2015, 127, 11992–11995
97.5:2.5
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Received: June 27, 2015
Published online: August 12, 2015
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