Enantioselective C-H Functionalization-Addition Sequence Delivers Densely Substituted 3-Azabicyclo[3.1.0]hexanes

Article abstract of DOI:10.1021/jacs.7b07024

An enantioselective C-H functionalization route to perfluoroalkyl-containing 3-azabicyclo[3.1.0]hexanes is disclosed. A modular and bench-stable diazaphospholane ligand enables highly enantioselective Pd(0)-catalyzed cyclopropane C-H functionalization using trifluoroacetimidoyl chlorides as electrophilic partners. In turn, the resulting cyclic ketimine products react smoothly with a broad variety of nucleophiles in one-pot processes enabling the rapid and modular construction of heavily substituted pyrrolidines.

Full text of DOI:10.1021/jacs.7b07024

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Communication
Enantioselective C-H Functionalization-Addition Sequence
Delivers Densely Substituted 3-Azabicyclo[3.1.0]hexanes
Julia Pedroni, and Nicolai Cramer
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.7b07024 • Publication Date (Web): 23 Aug 2017
Downloaded from http://pubs.acs.org on August 23, 2017
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Enantioselective C-H Functionalization-Addition Sequence Delivers
Densely Substituted 3-Azabicyclo[3.1.0]hexanes
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Julia Pedroni and Nicolai Cramer*
Laboratory of Asymmetric Catalysis and Synthesis, Institute of Chemical Sciences and Engineering, Ecole Polytechnique
Fédérale de Lausanne (EPFL), Lausanne, Switzerland.
Supporting Information Placeholder
16
ABSTRACT: A enantioselective C-H functionalization route to
perfluoroalkyl-containing 3-azabicyclo[3.1.0]hexanes is
disclosed. A modular and bench-stable diazaphospholane ligand
enables highly enantioselective Pd(0)-catalyzed cyclopropane C-
chlorides.
Methodologies introducing fluorine containing
substituents are sought-after in drug discovery, due to their
favorable physico-chemical properties and metabolic stability.
17
18
In this respect, trifluoroacetimidoyl chlorides are highly attractive.
They are stable, readily prepared and in principle competent for
Pd(0)-catalyzed C-H functionalizations.19 We selected this group
to illustrate a concept where the initial C-H functionalization
forges a valuable bond and awakes a unique property on the
intermediate for a further complexity generating transformation,
ideally in a cascade or one-pot manner.
H
functionalization using trifluoroacetimidoyl chlorides as
electrophilic partners. In turn, the resulting cyclic ketimine
products react smoothly with a broad variety of nucleophiles in
one-pot processes enabling the rapid and modular construction
heavily substituted pyrrolidines.
Herein, we disclose an enantioselective access to 3-azabicyclo
[
3.1.0]hexenes 2 using trifluoroacetimidoyl chloride electrophiles
Nitrogen-containing heterocycles are omnipresent in biologically
active molecules and more than half of FDA approved drugs
1 for the Pd(0)-catalyzed C-H cyclization (Scheme 1). The
resulting chiral ketimine displays electrophilic character which
could be exploited for additions of nucleophiles, giving
unprotected secondary pyrrolidines 3. The fused cyclopropane
unit ensures perfect diastereocontrol in subsequent nucleophilic
additions. Overall, our strategy consists of a enantio- and
diastereoselective modular approach for highly substituted
perfluoroalkylated 3-azabicyclo[3.1.0]hexanes.
1
contain a nitrogen heterocycle. Rigid molecules with a higher
3
proportion of sp -hybridized carbon atoms have attracted recently
2
more attention. An intriguing subset of saturated N-heterocyclic
scaffolds that displays diverse biological activities and great
potential for pharmaceutical use are 3-azabicyclo-[3.1.0]hexanes
3
(
Figure 1). This scaffold is commonly accessed by intramolecular
4
C-N bond formation of a cyclopropane-tethered precursor or
cyclopropanation of an unsaturated 5-membered N-heterocycle.
Scheme 1: Merging enantioselective C-H functionalization
with nucleophilic addition for a rapid and modular access
to CF -substituted 3-azabicyclo[3.1.0]hexanes
5,6
Limitations on the decoration of the pyrrolidine moiety remain,
along with the scarcity of enantioselective methods.
3
The envisioned transformation was investigated with substrate 1a
(Table 1). TADDOL-derived P(III)-ligands, previously very
successful for asymmetric C-H functionalizations, failed to
provide good enantioselectivities for 2a (entries 1-4). However,
Figure 1: Selection of biologically active molecules with the 3-
azabicyclo[3.1.0]hexane scaffold.
20
chiral alkoxy diazaphospholidines
were suitable for this
transformation. While the smallest version L5 failed to induce any
selectivity (entry 5), the increased steric bulk of L7 promoted the
reaction to the desired bicyclic imine 2a in high yield and
excellent enantiomeric ratio of 98:2 (entry 7). Increasing the steric
demand further (OiPr instead of OMe in L8) resulted in sluggish
cyclization with loss of selectivity (entry 8). KOAc could be used
instead of CsOAc with very little impact on the reaction outcome
Enantioselective C-H functionalizations have enabled new
synthetic strategies with
complexity, and functionalizations of cyclopropane C-H bonds
made significant progress. asymmetric Pd(0)-catalyzed C-H
a rapid increase in molecular
7,8
9
functionalizations have emerged as complementary processes for
10
stereoselective access to chiral cyclic compounds.
Most
(
entry 9). AdCO Cs slightly decreased the enantioselectivity
asymmetric Pd(0)-catalyzed C-H functionalizations rely on aryl
2
11
12
halides or triflates as electrophilic reaction partners. Few
reports showcase the potential of other electrophiles such as vinyl
(entry 10). The reaction was scaled up 60-fold with 2.5 mol% Pd-
catalyst with an at least similar favorable reaction outcome (entry
1
3
14
15
1
1).
bromides and triflates, chloroacetamides and carbamoyl
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a
Table 1: Ligand screening and reaction optimization
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2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
b
Entry
L*
L1
L2
L3
L4
L5
L6
L7
L8
L7
L7
L7
base
yield (%)
er
67:33
72.5:27.5
64:36
74:26
51:49
60:40
98:2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
CsOAc
CsOAc
CsOAc
CsOAc
CsOAc
CsOAc
CsOAc
CsOAc
KOAc
63
75
59
61
66
33
c
d
7
81
e
8
22
71
92:8
9
97:3
1
0
1
AdCO Cs
72
95.5:4.5
98.5:1.5
2
f
d
1
CsOAc
90 [g-scale]
a
a
50 µmol 1a, 2.5 µmol Pd(allyl)Cp, 5.0 µmol L, 60 µmol base,
.1 M in toluene at 110 °C for 1 h; determined by H-NMR with
0.10 mmol 1, 5.0 µmol Pd(allyl)Cp, 10 µmol L7, 0.12 mmol
b
1
b
0
CsOAc, 0.1 M in toluene at 110 °C for 1-6 h, isolated yield;
determined by H NMR with internal standard; 1.5 eq Cs CO
added; with 10 µmol Pd(allyl)Cp and 20 µmol L7.
c
d
e
1
c
internal standard;
0.1 mmol 1a,
isolated yield;
40 %
2
3
f
d
conversion; 3.0 mmol 1a, 75 µmol Pd(allyl)Cp, 150 µmol L, 4.5
mmol CsOAc, 0.2 M in toluene.
The scope of the transformation was investigated with imidoyl
1
2
chlorides 1 bearing different substituents R , R and R (Scheme
F
1
2
). Variations of R include hydrogen, heteroatom-containing
chains (2b), benzyl (2c) and aryl groups (2d-2j). In all cases high
reactivity and enantioselectivities were obtained. Notably, for
aryl-bearing substrates 1d-1j, chiral cyclic imines 2d-2j were
selectively obtained using L7 (for a ligand-promoted reversal of
the selectivity see Table 2). Concerning substituents R , substrates
1 bearing valuable oxetane and azetidine rings delivered
spirocyclic compounds 2j-2l. The cyclization proceeds as well in
high enantioselectivity without substituent R (2n), albeit in
reduced yield. The reaction proceeds with high efficiency and
selectivity irrespective of length of the perfluoroalkyl chain (2o-
The reactivity of the constructed electrophilic ketimine towards
nucleophiles was investigated next (Scheme 3a). The fused
cyclopropane efficiently guides additions from the opposite face
leading to a diastereoselective construction of the CF -substituted
quaternary stereogenic center. For instance, completely
diastereoselective reduction of 2a to pyrrolidine 3aa proceeded
quantitatively under mild conditions with NaBH . Organolithium
species exemplified by 3-lithio-pyridine delivered selectively 3ab.
Moreover, a Friedel-Crafts reaction with N-methyl pyrrole
occurred at C3, giving 3ac. Aminophosphonate 3ad could be
obtained in excellent yield by a Pudovic reaction with diethyl
2
2
1
3
2
4
2
p).
The high fidelity in the cyclopropane C-H enantiodiscrimination
prompted us to explore the potential of a parallel kinetic
22,11c
resolution,
selecting between a cyclopropane Csp3-H and an
phosphonate. Sc(OTf) -catalyzed reaction between 2a and
Danishefsky’s diene furnished indolizidine 3ae in low yield. The
absolute configuration of products 2 was determined by X-ray
3
aryl Csp2-H bond to functionalize (Equation 1). Phenyl-substituted
rac-1q was efficiently resolved yielding constitutional isomers 2q
and 4q in high er. Substrate rac-1r with an electron-rich aryl
moiety had very little effect on the outcome of the parallel kinetic
resolution. Notably, imines 2q and 2r were obtained in excellent
diastereoselectivity.
2
3
crystallography of hemiaminal hydrochloride 3df (Scheme 3b).
The cyclopropane unit of 2d underwent endo-hydrogenolysis with
concomitant reduction of the imine leading to piperidine 5d as the
major product. In contrast, exposure of pyrrolidine 3da to similar
hydrogenation conditions led to complementary exo-
hydrogenolysis of the cyclopropane yielding selectively
pyrrolidine 6d.
a
Scheme 2: Scope for imines 2
Scheme 3: Addition of nucleophiles to chiral imines 2.
2
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Table 2: Ligand-controlled chemoselectivity switch
a
1
2
3
4
5
6
7
8
9
between aryl Csp2-H vs cyclopropyl Csp3-H
b
c
Entry
1
L
ratio 2:7
1:14
6:1
major product, yield (%)
1
1d
1d
1e
1e
1f
1f
1g
1g
1h
1h
1i
PPh3
L7
7d, 82
2d, 73
7e, 87
2e, 77
7f, 89
2f, 88
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
2
3
PPh3
1:15
4:1
4
L7
5
PPh3
L7
1:11
6:1
6
d
7
PPh3
1:13
2:1
7g, 74
8
L7
2g, 63
e
9
PPh3
L7
1: >99
2:1
7h, 87
10
2h, 59
7i, 73
2i, 78
7j, 74
2j, 70
1
1
1
1
2
3
4
PPh3
L7
1:11
8:1
1i
1j
1j
PPh3
L7
1:10
9:1
1
The pyrrolidines 3 can be directly accessed from 1 via a
convenient one-pot process, without any change in the er (Scheme
a
0
.1 mmol 1, 5.0 µmol Pd(allyl)Cp, 10 µmol L, 0.12 mmol
b
4
). For instance, a C-H functionalization / reduction sequence
CsOAc, 0.1 M in toluene at 110 °C (1 h with L7, 6 h with PPh );
determined by H-NMR; isolated yield; o/p=1.1:1; o/p=8:1.
3
1
c
d
e
(
3ca) was performed by the addition of LiAlH to the reaction
4
mixture after completion of the Pd-catalyzed C-H
functionalization. Suitable nucleophiles for the one-pot process
encompass a broad range of Grignard and organo-lithium
organometallics. Aminonitrile 3cl was obtained in 84 % yield by
In conclusion, we reported modular and bench-stable
diazaphospholane ligands enabling highly enantioselective Pd(0)-
catalyzed
cyclopropane
C-H
functionalization
with
.
trifluoroacetimidoyl chloride electrophiles. The cyclic CF3-
the addition of TMSCN and BF OEt .
3
2
ketimines products are versatile intermediates and react smoothly
a
Scheme 4: One-pot synthesis of pyrrolidines 3
with a broad variety of nucleophiles providing access to important
building blocks. The native bis-electrophilic nature of the
trifluoroacetimidoyl chlorides was directly exploited in one-pot
processes enabling the rapid and modular construction of heavily
substituted pyrrolidines. Additionally, we have investigated the
selectivity between cyclopropane and aryl C-H bonds leading to
the development of parallel kinetic resolutions. Moreover, we
discovered
a
ligand-controlled
chemoselective
C-H
functionalization allowing efficient access to two different
scaffolds from the same starting materials.
ASSOCIATED CONTENT
Supporting Information
Synthetic procedures, characterization data for all new
compounds and HPLC traces of the chiral products. This material
is available free of charge via the Internet at http://pubs.acs.org.
a
1
) 0.10 mmol 1, 5.0 µmol Pd(allyl)Cp, 10 µmol L7, 0.15 mmobl
CsOAc, 0.1 M in toluene; isolated yields; 98:2 er for 2c
Nu=LiAlH ;
BF OEt .
c
d
e
Nu= allylMgBr;
Nu=RLi;
Nu=TMSCN,
4
.
AUTHOR INFORMATION
3
2
The chemoselectivity of the C-H bond activation (cyclopropyl vs.
aryl C-H) can be modulated by the phosphine ligand. Under
otherwise
functionalization is observed with L7 (see Scheme 2). However,
using PPh3 reverses the selectivity and leads aryl Csp -H
functionalization generating spirocyclic trifluoromethylated
dihydroisoquinolines 7 (Table 2). No reaction occurred in the
absence of palladium, excluding a Bischler-Napieralsky pathway.
Corresponding Author
nicolai.cramer@epfl.ch
identical
conditions,
selective
cyclopropane
2
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
3
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This work is supported by the Swiss National Science Foundation
Wasa, M.; Engle, K. M.; Lin, D. W.; Yoo, E. J.; Yu, J.-Q. J. Am. Chem.
o
Soc. 2011, 133, 19598; (d) Gao, D.-W.; Shi, Y.-C.; Gu, Q.; Zhao, Z.-L.;
You, S.-L. J. Am. Chem. Soc. 2013, 135, 86; (e) Chu, L.; Wang, X.-C.;
Moore, C. E.; Rheingold, A. L.; Yu, J.-Q. J. Am. Chem. Soc. 2013, 135,
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(N 157741). We thank Dr. R. Scopelliti and Dr. F. Fadaei Tirani
.
for X-ray analysis of 3df HCl.
1
6344; (f) Du, Z.-J.; Guan, J.; Wu, G.-J.; Xu, P.; Gao, L.-X.; Han, F.-S. J.
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