Access to β-lactams by enantioselective palladium(0)-catalyzed C(sp3)-H alkylation

Article abstract of DOI:10.1002/anie.201405508

β-Lactams are very important structural motifs because of their broad biological activities as well as their propensity to engage in ring-opening reactions. Transition-metal-catalyzed C-H functionalizations have emerged as strategy enabling yet uncommon h

Full text of DOI:10.1002/anie.201405508

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Angewandte
Communications
DOI: 10.1002/anie.201405508
À
C H Activation
Hot Paper
Access to b-Lactams by Enantioselective Palladium(0)-Catalyzed
3
À
C(sp ) H Alkylation**
Julia Pedroni, Michele Boghi, Tanguy Saget, and Nicolai Cramer*
Abstract: b-Lactams are very important structural motifs
because of their broad biological activities as well as their
propensity to engage in ring-opening reactions. Transition-
inhibitor.[2] Besides these bicyclic b-lactams, monocyclic
congeners such as cholesterol-lowering ezetimibe[3] or the
antibiotic aztreonam[4] are important. Apart from the phar-
macological importance, they are also reactive starting
materials used, for instance, in ring-opening reactions.[5] This
significance is a great stimulus for the development of
methods to access b-lactams.[6] Major synthetic strategies
involve [2+2] cycloadditions like the Staudinger[7] and
Kinugasa[8] reaction, and cyclizations forming either carbon–
À
metal-catalyzed C H functionalizations have emerged as
strategy enabling yet uncommon highly efficient disconnec-
tions. In contrast to the significant progress of Pd0-catalyzed
À
C H functionalization for aryl–aryl couplings, related reac-
3
3
À
tions involving the formation of saturated C(sp ) C(sp ) bonds
À
are elusive. Reported here is an asymmetric C H functional-
ization approach to b-lactams using readily accessible chloro-
nitrogen or acyl–nitrogen bonds. Transition-metal-catalyzed
[9]
À
acetamide substrates. Important aspects of this transformation
C H bond functionalizations could offer complementary
3
3
À
are challenging C(sp ) C(sp ) and strain-building reductive
eliminations to for the four-membered ring. In general, the b-
lactams are formed in excellent yields and enantioselectivities
using a bulky taddol phosphoramidite ligand in combination
with adamantyl carboxylic acid as cocatalyst.
strategies through uncommon disconnections. For instance,
À
asymmetric rhodium(II)-catalyzed C H insertions with diazo
amide precursors have been reported by Hashimoto and co-
workers[10] and Doyle and co-workers.[11] Recently, b-lactams
were obtained through N-directed palladium(II)-catalyzed
À
À
C H functionalizations and formation of the classical C N
S
mall four-membered heterocycles like b-lactones, b-lac-
bond.[12] Given our longstanding interest in enantioselective
[13]
À
tams, b-sultames, and b-sultones are important structural
motifs because of their rich biological activities as well as their
high chemical reactivity. The most important class is b-
lactams which form the backbone of antibiotic weaponry
(Figure 1).[1] Moreover, sulbactam is used as a b-lactamase
C H functionalizations,
we envisioned expanding the
À
scope of asymmetric palladium(0)-catalyzed C H function-
alizations for the synthesis of chiral b-lactams by formation of
3
3
À
the complementary C(sp ) C(sp ) bond. A limiting factor of
palladium(0)-catalyzed[14] asymmetric intramolecular C H
À
functionalization is the ring size of the arising cyclic product
allowing access to five-,[15] six-,[16] and seven-membered
rings.[17] In all cases, the initial C(sp ) Pd species is obtained
2
II
À
by oxidative addition of an aryl/vinyl halide or triflate.
Corresponding C(sp ) Pd intermediates have been very
scarcely used to induce C H activation because of competing
pathways. Hennessy and Buchwald used chloroacetanilides
3
II
À
À
2
À
for the synthesis of oxindoles by achiral aromatic C(sp ) H
functionalization.[18] The achiral construction of benzannu-
lated four-membered rings by reductive elimination has been
shown by Dyker[19] and extended to a practical level by
Baudoin et al.[20] However, neither an asymmetric generation
of four-membered rings, nor the reductive elimination
between two sp3 centers is known by these methods. Specif-
ically, the reductive elimination bears a twofold challenge
Figure 1. Examples of relevant b-lactam drugs.
3
3
À
because of the formation of a C(sp ) C(sp ) bond and the
build-up of ring strain. Herein, we describe the palladium(0)-
catalyzed asymmetric synthesis of b-lactam scaffolds from
readily accessible chloroacetamides.
a-Haloamides are relatively good electrophiles for nucle-
ophilic substitution reactions. This characteristic complicates
[*] J. Pedroni, M. Boghi, Dr. T. Saget, 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
the envisioned C H functionalization in two ways
[**] This work is supported by the European Research Council under the
European Community’s Seventh Framework Program (FP7 2007–
2013)/ERC Grant agreement no. 257891. We thank Dr. R. Scopelliti
for X-ray crystallographic analysis of compound 2n.
(Scheme 1). First, the essential carboxylate ligand engaging
in the enantiodiscriminating concerted metalation–deproto-
nation (CMD) step[21] can serve as a nucleophile. This
undesired substitution pathway not only forms the ester side
product 3, but also depletes the carboxylate stock, thus
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201405508.
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For instance dibenzyl bromoacetamide (1a’) is not suitable
because of a more favored nucleophilic substitution pathway
(entry 1). Adamantyl carboxylic acid (AdCO2H) and pivalic
acid proved to be superior to acetic acid in terms of
enantioselectivity (entries 2–4). The evaluation of different
taddol phosphoramidites revealed that increasing the bulk of
the aryl groups (3,5-xylyl, 3,5-C6H3, 3,5-tBu-4-MeO-C6H2) of
the ligand improves both the yield and the selectivity of the
process (entries 5–10). L5, having the DTBM-group and
pyrrolidino substituent on the phosphorous atom, is the best
performer (entry 9). The amount of AdCO2H could be
reduced to 10 mol% (entry 10). While the enantioselective
transformation could be established with L5, the execution of
an achiral reaction required further screening. Simple PPh3
provides 2a, however in modest yield (entry 12). Diphenyl
SPhos (L7) was a useful ligand (entry 13), whereas a more-
electron-rich variant such as Ruphos (L8) was not suitable
(entry 14).
À
Scheme 1. b-Lactam formation by C H functionalization and the
undesired SN2 pathway.
causing the reaction to stall once it is all consumed. Moreover,
the utilized phosphine ligand should not display too high
a nucleophilicity so as to avoid the formation of the
phosphonium 4.
We initially examined the reaction parameters with N,N-
dibenzyl chloroacetamide (1a) as a model substrate (Table 1).
The scope for the b-lactam formation was subsequently
evaluated with the aforementioned optimized reaction con-
ditions. The reaction efficiency, but not the selectivity, proved
to be dependent on the nature of the substituent R1. While
a methyl group is not suitable (Table 2, entry 1), the reaction
works well with either an ethyl or cyclopropyl methyl group
(entries 2 and 3). Bulkier and branched substituents are also
tolerated. Specifically a tert-butyl group gives rise to excellent
yields, presumably because of conformational preorganiza-
tion which facilitates activation/cyclization (entry 5). The
catalyst loading can be lowered without affecting the reaction
performance on both a 0.1 mmol (2.5 mol% Pd; entry 5) and
1.0 mmol scale (5 mol% Pd; entry 6). The steric and elec-
tronic parameters of the benzyl group can be modulated over
a wide range, thus maintaining the characteristics of the
process (entries 6–14). Interestingly, for electron-rich five-
À
The anticipated reactivity increase of benzylic C H groups is
2
À
traded for competing C(sp ) H activations, thus leading to
the dihydroisoquinolone 5a, which was only detected in small
amounts. There is a highly critical balance between the
substrates ability to engage in nucleophilic substitution with
the employed carboxylate ligand and its propensity to
undergo oxidative additions with the palladium(0) catalyst.
Table 1: Optimization of the Pd-catalyzed Cyclization.[a]
membered heterocycles such as a furyl or indolyl group, the
2
À
formation of a d-lactam by competing C(sp ) H functional-
ization becomes dominant (entries 14 and 15). The absolute
configuration of the b-lactam products was unambiguously
established by X-ray crystallographic analysis of 2n to be S.[22]
With substrates possessing a pre-existing stereogenic
center in the form of a classical a-methyl benzylamine
group [(R)-1q and (S)-1q], we investigated the degree of
Entry L*
Acid
Conv.
[%][b]
3
5a
2a
e.r.[d]
[%][b] [%][b]
[%][c]
1[e]
2
3
4
5
6
7
8
L5
L5
L5
L5
L1
L2
L3
L4
L5
L5
L6
AdCO2H 40 (1a’) 10
–
PivOH
AcOH
AdCO2H 47
AdCO2H 100
AdCO2H 100
AdCO2H 100
AdCO2H 100
AdCO2H 100
AdCO2H 100
0
<2
18
5
n. d. 12
n. d. 70
8
4
0
7
0
0
8
76
55
–
À
ligand control in the C H activation step (Scheme 2). Indeed,
50
100
84
0
3
n. d.
98:2
92.5:7.5
n. d.
86.5:13.5
96:4
98:2
98.5:1.5
97:3
96:4
–
for both enantiomers of 1q, very high levels of diastereose-
lectivity [> 95:5, 74% for (R)-1q and 94:6, 50% for (S)-1q]
were observed, thus showing excellent catalyst control.
However, the stereogenic center of the substrate has an
influence on the reaction performance. The S-configured
substrate 1q is the mismatching enantiomer causing reduced
yields. With the achiral ligand L7, we observed a low intrinsic
substrate control of 55:45 and moderate yield of 44–47%.
To gain further insights into the regioselectivity drivers of
the reaction, the substrate 1r, featuring an electron-rich
(PMB) and an electron-poor (p-cyanobenzyl) benzyl group,
13
20
20
14
17
19
10
20
20
13
18
63
76
81
80
67
9
10[f]
11
12
13
14
PPh3 AdCO2H 100
L7
L8
n. d. 58
<2
<2
AdCO2H 100
AdCO2H 71
83
30
–
–
À
was subjected to the asymmetric C H functionalization
[a] Reaction conditions: 0.10 mmol 1a, 10 mmol [Pd(dba)2], 20 mmol L*,
20 mmol acid, 1.5 equiv Cs2CO3, 0.1m in toluene, 1108C, 12–16 h.
[b] Determined by 1H NMR spectroscopy. [c] Yield of isolated 2a.
[d] Determined by HPLC using a chiral stationary phase. [e] With
bromoacetamide. [f] With 10 mol% AdCO2H.
(Scheme 3). The experiment showed a clear bias of 4.8:1 for
3
À
the activation of the more acidic benzylic C(sp ) H bonds.
These findings are in agreement with the CMD mechanism
À
governed by kinetic C H bond acidity.
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Table 2: Scope for the synthesis of b-lactams 2.[a]
Entry
1
2
Yield
[%][b]
e.r.[c]
1
1b
1c
2b
2c
20
74
n. d.
98:2
2[d]
Scheme 2. Influence of a pre-existing stereogenic center on the diaste-
reoselectivity.
3[d]
1d
2d
94
95
97.5:2.5
97:3
4
1e
1 f
1g
1h
1i
2e
2 f
2g
2h
2i
93
98.5:1.5
5
99[e]
98.5:1.5[e]
99
99.5:0.5
6
96[f]
98.5:0.5[f]
Scheme 3. Electronic influence on the selectivity for the b-lactam
formation.
7
94
98
81
76
95
97
96
98:2
8
95.5:4.5
98:2
9
1j
2j
10
11
12
13
1k
1l
2k
2l
97.5:2.5
99:1
Scheme 4. Asymmetric ring closure of a glycine ester derivative.
1m
1n
2m
2n
99:1
When exposing the glycine ester 1s to the reaction
conditions, the b-lactam 2s was obtained in 70% yield with
an enantiomeric ratio of 91:9 (Scheme 4). No benzylic
activation was observed, presumably because of the hindered
nature of the mesityl group. Although a small uncatalyzed
background substitution reaction is observed in a palladium-
99.5:0.5
40
60 (3o)
14
15
1o
1p
2o
2p
98:2
98:2
À
free control experiment, this result suggests that the C H
activation pathway is operative and highly selective, taking
the racemic background reaction into account.[23]
À
In summary, we reported an asymmetric C H function-
39
59 (3p)
alization strategy for the synthesis of valuable b-lactams from
readily accessible chloroacetamides. The palladium(0)-cata-
lyzed process provides excellent enantioselectivities with
a bulky taddol phosphoramidite ligand in combination with
adamantyl carboxylic acid as a cocatalyst. Another salient
[a] Reaction conditions: 0.10 mmol 1, 10 mmol [Pd(dba)2], 20 mmol L4,
10 mmol AdCO2H, 1.5 equiv Cs2CO3, 0.1m in toluene, 1108C, 12 h.
[b] Yield of isolated product. [c] Determined by HPLC using a chiral
stationary phase. [d] An additional 10 mmol of AdCO2H added after 6 h.
[e] 2.5 mol% [Pd(dba)2], 5 mol% L4, 5 mol% AdCO2H. [f] 1.00 mmol 1,
5 mol% [Pd(dba)2] 10 mol% L4, 10 mol% AdCO2H.
3
3
À
feature of this reaction is a challenging C(sp ) C(sp ) and
strain-building reductive elimination forming the four-mem-
bered lactam. Further work focuses on expanding the scope
for the formation of higher substituted b-lactams with
biological activities.
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e) X. Wu, Y. Zhao, G. Zhang, H. Ge, Angew. Chem. 2014, 126,
Received: May 22, 2014
Published online: July 1, 2014
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Kuninobu, M. Kanai, Angew. Chem. 2014, 126, 3564; Angew.
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À
Keywords: asymmetric catalysis · C H activation ·
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cross coupling · lactams · palladium
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À
Lett. 2014, 16, 480; for an example of C N bond formation of
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Am. Chem. Soc. 2012, 134, 3; for examples with Cu catalysis, see:
Angew. Chem. Int. Ed. 2014, 53, 9064 –9067
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