Modular Synthesis of α-Quaternary Chiral β-Lactams by a Synergistic Copper/Palladium-Catalyzed Multicomponent Reaction

Article abstract of DOI:10.1002/anie.202100601

An asymmetric multicomponent, interrupted Kinugasa allylic alkylation (IKAA) reaction has been developed with a synergistic Cu-catalyzed Kinugasa system and a Pd-catalyzed allylic alkylation reaction. This unprecedented reaction provides in high yields and with high stereoselectivity a synthesis of α-quaternary chiral β-lactams, which cannot be produced with existing synthetic methods. Stereoselective coupling of two catalytic amounts of transient organometallic intermediates formed in situ is an important feature of this reaction.

Full text of DOI:10.1002/anie.202100601

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How to cite:
International Edition: doi.org/10.1002/anie.202100601
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Asymmetric Catalysis
Modular Synthesis of a-Quaternary Chiral b-Lactams by a Synergistic
Copper/Palladium-Catalyzed Multicomponent Reaction
Jialin Qi, Fang Wei, Chen-Ho Tung, and Zhenghu Xu*
Abstract: An asymmetric multicomponent, interrupted Kinu-
gasa allylic alkylation (IKAA) reaction has been developed
with a synergistic Cu-catalyzed Kinugasa system and a Pd-
catalyzed allylic alkylation reaction. This unprecedented
reaction provides in high yields and with high stereoselectivity
a synthesis of a-quaternary chiral b-lactams, which cannot be
produced with existing synthetic methods. Stereoselective
coupling of two catalytic amounts of transient organometallic
intermediates formed in situ is an important feature of this
reaction.
stereocenters is still very challenging.[10] The chiral Lewis base
catalyzed asymmetric Staudinger reaction of disubstituted
ketenes with imines can afford this type of structure, but the
preparation and handling of highly reactive ketene inter-
mediates limits their practical use.[7] The Kinugasa reaction,
the copper(I)-catalyzed asymmetric coupling reaction of
alkynes with nitrones, could produce a,b-disubstituted
b-lactams efficiently, but couldnꢀt access a-quaternary
b-lactams.[8] In 2003, Fu et al. reported the only example
using a two-component intramolecular Kinugasa and inter-
molecular allylation cascade with allyl iodide in the presence
of mixed bases (Scheme 1b).[8c] A complete three-component
reaction however has not been realized to date. Very recently,
we developed a copper(I)-catalyzed three-component, inter-
rupted Kinugasa reaction to synthesize a-thiofunctional
chiral b-lactams using a sulfur electrophile to intercept the
key four-membered enolate copper(I) intermediate.[8g]
M
ulticomponent reactions (MCRs) can integrate three or
more simple precursors into complex molecules in a single
process.[1] They have the advantages of bond-formation
efficiency, atom economy, product diversity and complexity,
and avoid the lengthy purification procedures associated with
traditional stepwise syntheses. Despite these advantages and
the tremendous efforts that have been made to develop
efficient MCRs, catalytic asymmetric MCRs to access enan-
tioenriched complex molecules are not highly developed.[1c–h]
Recently, by mimicking enzyme catalysis in biosystems,
multicatalyst combination strategy, especially bimetallic cat-
alysis has been developed as a promising strategy with which
to produce asymmetric MCRs.[2–4] In such systems, various
catalysts activate different reactants and complete the desired
transformation in a highly stereoselective manner. Herein, we
report the assembly of readily available alkynes, nitrones, and
allylic carbonates into a-quaternary chiral b-lactams through
a Cu/Pd-catalyzed IKAA reaction.
The b-lactam is the common core structure of clinically
used drugs such as penicilin, cephalosporin, and also mono-
cyclic antibiotics such as aztrenam.[5] Development of novel
methods to access new b-lactams is important in further
studies of this heterocyclic system, including structure–
activity relationships and discovery of new antibiotics, and is
thus important in global health problems. Although various
syntheic methods have been developed to produce b-lac-
tams,[6–9] synthesis of chiral b-lactams bearing an a-quaternary
[*] J. Qi, F. Wei, Prof. Dr. C.-H. Tung, Prof. Dr. Z. Xu
Department of Chemistry, Shandong University
No. 27 South Shanda Road, Jinan 250100 (China)
E-mail: xuzh@sdu.edu.cn
Prof. Dr. Z. Xu
State Key Laboratory of Organometallic Chemistry, Shanghai Insti-
tute of Organic Chemistry, Chinese Academy of Sciences
Shanghai 200032 (China)
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
https://doi.org/10.1002/anie.202100601.
Scheme 1. Synthesis of a-quaternary chiral b-lactams with Kinugasa
reaction.
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However, further application of this strategy in an attempt to
trap this enolate intermediate with allyl electrophiles through
Kinugasa product (K) would dominate; (2) development of
a chiral bimetallic system which could realize the precise
control of chemo-, regio-, diastereo- and enantioselectivity is
difficult. In addition, because two ligands and two metals are
required in the system, the inevitable ligand exchange
between two metals greatly enhances the complexity and
difficulty of this target reaction.
À
C C bond formation and building a,a-disubstituted chiral
b-lactams with an all-carbon quaternary center failed
(Scheme 1a). Changing various allyl electrophiles or modifi-
cation of reaction conditions failed to afford the desired
products (for details, see the Supporting Information). This
À
indicates that formation of this C C bond is very challenging
Because no chiral center is formed on the alkyl side, we
chose a chiral side arm bisoxazoline (SA-BOX) ligand
coordinated with copper(I), and an achiral phosphine ligand
coordinated with palladium to optimize the reaction condi-
tions (for details, see the Supporting Information). The
phosphine ligand plays an important role in the reaction. A
generally used palladium catalyst such as Pd(PPh3)4 or
Pd2(dba)3 together with phosphine ligands such as A or B
formed only protonated Kinugasa product K and failed to
produce any target products (entries 1 and 2, Table 1). When
Xantphos C with a larger bite angle was applied with
palladium, the desired product (4a) was isolated in 42%
yield and 88:12 er (entry 3), and DPEphos (D) further
increased the yield to 69% (entry 4). Application of a chiral
phosphine ligand such as R- or S-BINAP led very low yields
in this copper catalyzed cycle, probably due to the formation
of the sterically hindered all-carbon quaternary center.
The allylic alkylation (AA) reaction, especially the
palladium-catalyzed Tsuji–Trost reaction, is a fundamental
À
C C bond formation reaction and has been widely used in the
synthesis of natural products and in medicinal chemistry.[11]
The general AA is a base-promoted nucleophilic substitution
on the allylic palladium intermediate. Recently such AA
chemistry has been utilized in synergistic catalysis with
a second transition metal to deliver unprecedented and
challenging transformations.[12] Recently, Lee et al. reported
a Rh -catalyzed intramoluecular C H insertion reaction of
a-diazo acetamides, followed by intermolecular AA, provid-
ing a-quaternary chiral b-lactams.[9e] In this context and with
our continuing interests in bimetallic catalysis,[13] we specu-
lated that a Cu/Pd-catalyzed, IKAA achieved by integrating
II
À
Table 1: Optimization of reaction conditions.[a]
À
the two name reactions together could resolve this C C bond
formation problem (Scheme 1c). A plausible catalytic cycle is
proposed in Scheme 2. The cycloaddition of copper(I)
acetylide with nitrones generates the key chiral four-mem-
bered enolate copper(I) intermediate (M1). In the meantime,
palladium catalyst reacts with an allylic electrophile forming
an allylic palladium intermediate (M2). Subsequent stereo-
controlled allylic substitution between M1 and M2 would
produce the target a-quaternary chiral b-lactams, regenerat-
ing both the copper(I) and the palladium (0) catalysts.
However, to realize this ideal synergistic cycle is difficult,
because: (1) the copper(I)-catalyzed Kinugasa cycle and
palladium-catalyzed AA cycle must be synchronized with
each other to deliver the target products, otherwise side
reactions such as protonation of M1 giving a two-component
Entry
PG
L* for Cu
L for Pd
Yield [%][b]
er[c]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15[d]
16[e]
Boc
Boc
Boc
Boc
Boc
Boc
COOMe
Ac
Boc
Boc
Boc
Boc
Boc
Boc
Boc
Boc
L1
L1
L1
L1
L1
L1
L1
L1
L2
L3
L4
L5
L6
L7
L6
L6
A
B
C
D
n.d.
n.d.
42
69
10
n.d.
36
44
60
73
65
62
77
50
75
19
–
–
88:12
88:12
88:12
–
88:12
88:12
87.5:12.5
90:10
90.5:9.5
85.5:14.5
94:6
R-BINAP
S-BINAP
D
D
D
D
D
D
D
D
D
D
87:13
96:4
95:5
[a] Reaction conditions: a mixture of 1a (0.2 mmol), 2a (0.3 mmol), 3
(0.3 mmol), Cu(CH3CN)4PF6 (10 mol%), ligand L* for Cu (11 mol%),
Pd2dba3·CHCl3 (5 mol%), phosphine ligand for Pd (10 mol%), K2CO3
(0.3 mmol), CH3CN (1 mL), RT, 30 h. [b] Isolated yields. [c] Determined
by HPLC using a chiral stationary phase. [d] 08C. [e] À108C. PMP=
4-MeOC6H4; BINAP=2,2’-bis(diphenylphosphino)-1,1’-binaphthalene.
Scheme 2. Proposed catalytic cycle of Cu/Pd-catalyzed IKAA.
2
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Table 2: Substrate scope of allyl Boc carbonates.[a]
(entries 5 and 6), and varying the leaving group failed to give
better results (entries 7 and 8). Next, the chiral SA-BOX
ligands on a copper(I) catalyst were optimized (entries 9–14).
Substituents with different steric and electronic effects were
introduced into the two benzyl rings of chiral SA-BOX
ligands, and the ligand (L6) with six methoxyl groups afforded
the highest yield (77%) with an er of 94:6 (entry 13). Ligand
L7 bearing two t-butyl groups and one methoxy group gave
a lower yield and enantioselectivity (entry 14). Lowering the
reaction temperature to 08C led to the highest er (96:4) and
a 75% yield (entry 15) and these conditions were determined
to be optimal. Further decreasing the reaction temperature to
À108C greatly inhibited the reaction (entry 16).
The side arm groups play an important role in improving
the reactivity and selectivity in asymmetric catalysis.[14] To
further understand the substituent effects in SA-BOX ligands,
a single crystal of L6/CuBr2 was obtained and analyzed by
X-ray crystallography (for details, see the Supporting Infor-
mation).[15] It has a C2 symmetric structure in which the two
pendant aromatic rings bend towards the metal center,
affecting the shape of catalyst. The whole complex forms
a chiral cage-like complex. The six methoxy groups on the two
benzyl rings tune the electronic properties and extend the
chiral space, thus giving the highest stereoselectivity. Such
a strategy of introducing multiple methoxy groups onto chiral
ligands could be utilized in further chiral catalyst design.
After establishing the optimal conditions for the asym-
metric IKAA reaction, the scope of substrates was further
investigated. First, the reactivities of various allylic electro-
phile precursors were examined (Table 2). Besides the linear
cinnamic carbonates (l-3a), the branched carbonates (b-3a)
were found to react equally efficiently with 1a and 2a, giving
the same linear product (4a) in similar yield and with similar
enantioselectivity, indicating formation of the same allylic
palladium intermediate. Only one diastereoisomer with two
cis aromatic rings was observed in all these reactions, and the
absolute configuration of 4a was established as (3S,4R) by
X-ray crystallography (Table 2).[15] A series of substituted
cinnamic carbonates bearing various electron-withdrawing or
electron-donating functional groups at the ortho-, meta- or
para-position of the phenyl ring reacted smoothly with 2a,
giving the corresponding a-quaternary b-lactams (4b–4m) in
good yields with high enantioselectivity. Functional groups
such as halogens, methoxy, trifluoromethyl and nitro are all
well tolerated. It is noteworthy that branched allylic carbo-
nates from various medicinally important heterocycles includ-
ing indole (4o), furan (4p), and thiophene (4q), all react well
in this dual catalytic system. Pyridine-functionalized allylic
carbonate is amenable to this reaction, giving a b-lactam (4r)
in 52% yield with 89:11 er. Simple allyl carbonates and
2-phenyl allylic carbonates give the corresponding products in
good yields with good enantioselectivity (4s–4u). More
challenging crotyl carbonates failed to react under these
conditions.
[a] Standard conditions were employed. Isolated yields are shown. [b] b-3
was used.
desired product (4ac) in 80% yield. Reaction of a chiral
tyrosine-functionalized alkyne under this dual catalytic
system produced the corresponding lactam (4ad) in 87%
yield with 95:5 dr. Cyclohexenyl alkyne reacted well with
slightly decreased enantioselectivity, providing a lactam (4ae)
which was isolated in 50% yield. Various nitrones with
different electron-donating groups or electron-withdrawing
groups on the aromatic ring are all amenable to this trans-
formation, giving the corresponding products (4af–4aj)
smoothly.
b-Lactams are very important synthetic building blocks in
organic synthesis. To demonstrate the synthetic utility of this
Cu/Pd-catalyzed IKAA reaction, the b-lactam (4a) was
synthesized on a gram scale in 67% yield with 96:4 er, and
several subsequent transformations were carried out. As
shown in Scheme 3, reduction of 4a with LiAlH4 produced an
amino alcohol (5), which has adjacent quaternary and tertiary
chiral centers. Upon treatment of 4a with Lewis acid (AlCl3)
and LiAlH4 or LiAlD4, a chiral azetidine (7) or the
corresponding deuterated azetidine (7-D) were isolated in
91% yield without loss of enantiomeric purity. Wacker
oxidation of the allyl group of lactam (4u) produced
a chiral b-lactam with an attached acetone (6).
The scope of terminal alkynes and nitrones was next
examined (Table 3). All aromatic alkynes that were tested
reacted smoothly, affording the corresponding b-lactams in
good yields with high enantioselectivity (4v–4ad). An alkyne
derived from clofibrate also reacted efficiently, providing the
Further control experiments were conducted to under-
stand the reaction mechanism [Eq. (1)]. The reaction of the
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Table 3: Substrate scope with alkynes and nitrones.[a]
Scheme 3. Synthetic applications of chiral b-lactams.
chemistry and also provides new insights for further develop-
ment of other challenging asymmetric transformations.
Acknowledgements
We are grateful for financial support from the Natural Science
Foundation of China and Shandong Province (no.21971149,
ZR2019BB060, ZR2019ZD45) and the Fundamental
Research Funds of Shandong University.
Conflict of interest
[a] Standard conditions were employed. Isolated yields are shown.
[b] Determined by 1H NMR analysis of the products.
The authors declare no conflict of interest.
Keywords: allylic alkylation ·
asymmetric multicomponent reaction · Kinugasa ·
synergistic reactions · b-lactam
Kinugasa product (K) with 3 in a Pd0-catalyzed diastereo-
selective intermolecular AA under standard condition failed
to produce any products and 95% K was recovered. It
indicates that K is not the reaction intermediate and thus
interception of the enolate copper intermediate (M1) is viable
in this reaction.
In summary, by conducting a Cu-catalyzed Kinugasa
reaction and a Pd-catalyzed AA in one pot, we have
successfully developed a strategically novel IKAA reaction,
which allows a step-economic and modular synthesis of
enantioenriched a-quaternary b-lactams from three readily
available precursors. This strategy is distinguished by a well-
programmed reaction sequence, highly efficient formation of
multiple bonds in asymmetric MCRs, construction of medi-
cally important a-quaternary chiral b-lactams, and a key
stereoselective coupling of two in situ formed catalytic
amounts of transient intermediates. We anticipate that this
Cu/Pd-catalyzed IKAA strategy will be useful in medicinal
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2018, 130, 11151; g) J. Qi, F. Wei, S. Huang, C.-H. Tung, Z. Xu,
Angew. Chem. Int. Ed. 2021, 60, 4561; Angew. Chem. 2021, 133,
4611.
[15] Deposition Numbers 2007755 (for L6/CuBr2), 2007754 (for 4a)
contain the supplementary crystallographic data for this paper.
These data are provided free of charge by the joint Cambridge
Crystallographic Data Centre and Fachinformationszentrum
Karlsruhe Access Structures service www.ccdc.cam.ac.uk/
structures.
Manuscript received: January 13, 2021
Revised manuscript received: April 1, 2021
Accepted manuscript online: April 4, 2021
Version of record online: && &&, &&&&
Angew. Chem. Int. Ed. 2021, 60, 1 – 6
ꢀ 2021 Wiley-VCH GmbH
www.angewandte.org
5
These are not the final page numbers!

Angewandte
Communications
Chemie
Communications
Asymmetric Catalysis
J. Qi, F. Wei, C.-H. Tung,
Z. Xu*
&&&& — &&&&
Modular Synthesis of a-Quaternary Chiral
b-Lactams by a Synergistic Copper/
Palladium-Catalyzed Multicomponent
Reaction
An asymmetric multicomponent inter-
rupted Kinugasa allylic alkylation (IKAA)
reaction has been developed with a syn-
ergistic Cu-catalyzed Kinugasa and Pd-
catalyzed allylic alkylation system. This
strategy provides a high yield and highly
selective synthesis of a-quaternary chiral
b-lactams, which are not easily produced
by other methods. Stereoselective cou-
pling of two transient organometallic
intermediates formed in situ is the most
important feature of this reaction.
6
www.angewandte.org
ꢀ 2021 Wiley-VCH GmbH
Angew. Chem. Int. Ed. 2021, 60, 1 – 6
These are not the final page numbers!