Asymmetric Synthesis of α-Alkylidene-β-Lactams through Copper Catalysis with a Prolinol-Phosphine Chiral Ligand

Article abstract of DOI:10.1021/acs.orglett.9b00276

A copper/prolinol-phosphine chiral catalyst enabled the one-step synthesis of chiral α-alkylidene-β-lactams. Optimization of the chiral ligand for steric and electronic properties realized the highly enantioselective coupling of nitrones and propargyl alcohol derived alkynes. The resulting chiral α-alkylidene-β-lactams served as a platform for various β-lactams via well-established transformations of α,β-unsaturated carbonyl compounds.

Full text of DOI:10.1021/acs.orglett.9b00276

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Asymmetric Synthesis of α‑Alkylidene-β-Lactams through Copper
Catalysis with a Prolinol-Phosphine Chiral Ligand
Koji Imai,‡ Yurie Takayama,‡ Hiroaki Murayama,‡ Hirohisa Ohmiya,‡,§ Yohei Shimizu,†,‡
and Masaya Sawamura*,†,‡
†Institute for Chemical Reaction Design and Discovery (WPI-ICReDD), Hokkaido University, Kita 21 Nishi 10, Kita-ku, Sapporo,
Hokkaido 001-0021, Japan
‡Department of Chemistry, Faculty of Science, Hokkaido University, Kita 10 Nishi 8, Kita-ku, Sapporo, Hokkaido 060-0810, Japan
S
* Supporting Information
ABSTRACT: A copper/prolinol-phosphine chiral catalyst
enabled the one-step synthesis of chiral α-alkylidene-β-lactams.
Optimization of the chiral ligand for steric and electronic
properties realized the highly enantioselective coupling of
nitrones and propargyl alcohol derived alkynes. The resulting
chiral α-alkylidene-β-lactams served as a platform for various β-
lactams via well-established transformations of α,β-unsaturated
carbonyl compounds.
ince the discovery of penicillin,1 the first antibiotic in the
Scheme 1. Copper-Catalyzed Asymmetric Kinugasa
Reaction with Prolinol-Phosphine Chiral Ligand
Sworld, chiral β-lactams have been recognized as a
privileged structural motif in biologically active compounds.2
The substituent at the α-position of the β-lactam is critically
important for biological activity. Thus, synthetic approaches to
install various α-substituents are in high demand. In this
context, chiral α-alkylidene-β-lactams are attractive linchpin
compounds since the C−C double bond serves as a platform
for numerous transformations such as olefin metathesis,
hydrogenation, Michael addition, etc. In addition, chiral α-
alkylidene-β-lactams exhibit various biologic activities on their
own.3 Although several synthetic methods have been
developed for chiral α-alkylidene-β-lactams,4−6 most of them
require multistep sequences or the use of stoichiometric
amounts of chiral reagents. Thus, catalytic asymmetric
reactions for the one-step synthesis of chiral α-alkylidene-β-
lactams from readily available achiral starting materials remain
unexplored.
The Kinugasa reaction, a coupling reaction between alkynes
and nitrones,7 serves as a straightforward method for the
synthesis of β-lactams.8 We previously developed a copper-
catalyzed asymmetric Kinugasa reaction9 with a prolinol-
phosphine chiral ligand.10 A hydrogen bonding network
including a nonclassical hydrogen bond between a nonpolar
C(sp3)−H bond in the chiral ligand and the oxygen atom of
the nitrone was proposed as an element critical to the catalytic
activity and enantioselectivity (Scheme 1a). Next, we
envisaged that the copper/prolinol-phosphine chiral ligand
system may be utilized for the catalytic asymmetric Kinugasa
reaction to afford chiral α-alkylidene-β-lactams by introducing
a proper leaving group to the alkyne substrate (Scheme 1b).
Basak reported a related reaction of a free propargyl alcohol
promoted by a stoichiometric CuI/L-proline system to afford
α-alkylidene-β-lactams with at most 15% ee.6 More recently,
́
Gree extended the method to a catalytic reaction, though the
reaction was only for a racemic system.11 Herein, we report the
first catalytic enantioselective Kinugasa reaction that provides
chiral α-alkylidene-β-lactams in one step.
We initiated our investigation with a C-cyclohexyl-N-
naphthylnitrone 2a to explore the proper activating group for
the propargyl alcohols using the copper/prolinol-phosphine
chiral ligand (L1) catalyst (Table 1). When free propargyl
Received: January 22, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b00276
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
a
Table 1. Optimization of Reaction Conditions
4a
entry
R
ligand
solvent
x (M)
3 yield (%)
yield (%)
ee (%)
1
2
3
4
5
6
7
8
H (1a)
L1
L1
L1
L1
L1
L1
L1
L2
L3
L4
L5
L6
L7
L8
toluene
toluene
toluene
toluene
toluene
toluene
tBuOMe
tBuOMe
tBuOMe
tBuOMe
tBuOMe
tBuOMe
tBuOMe
tBuOMe
0.2
0.2
0.2
0.2
77
52
0
0
0
0
0
0
0
0
0
0
0
22
37
85
75
80
88
quant
quant
94
quant
90
98
99
94
80
91
67
72
66
80
84
83
87
83
2
MOM (1b)
Boc (1c)
Bz (1d)
P(O)(OEt)2 (1e)
Boc (1c)
Boc (1c)
Boc (1c)
Boc (1c)
Boc (1c)
Boc (1c)
Boc (1c)
Boc (1c)
Boc (1c)
0.2
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
9
10
11
12
13
14
80
91
92
0
a
1 (0.2 mmol), 2a (0.2 mmol), Cu(OTf)2 (0.02 mmol), ligand (0.02 mmol), Et2NH (0.2 mmol), 25 °C, 6 h. Yield was determined by 1H NMR
analysis using tetrabromoethane as an internal standard. Enantiomeric excess (ee) was determined by chiral HPLC analysis.
alcohol 1a was the substrate (entry 1), a normal Kinugasa
reaction product 3 was obtained as the major product (77%
yield) and the desired α-methylene-β-lactam 4a was obtained
in 22% yield and 80% ee.12 MOM-protected propargyl alcohol
1b also gave 4a (37% yield, 91% ee) in low yield with 3 (52%
yield) as a major product (entry 2). On the other hand,
substrates with better leaving groups, OBoc (1c), OBz (1d),
and OP(O)(OEt)2 (1e), provided 4a in higher yields, albeit
with moderate enantioselectivities (entries 3−5). The normal
Kinugasa reaction product 3 was not obtained in these cases
while the formation of a small amount of N,N-diethylacryla-
mide (<12% yield) was observed.13 The most reactive 1c was
selected as the substrate for further reaction optimization. As a
result, the yield and enantioselectivity were improved to
quantitative yield and 84% ee by diluting the reaction and
changing the solvent from toluene to tBuOMe (entry 7).
Next, we assessed the effect of each structural motif of the
prolinol-phosphine chiral ligands. The effect of the alcohol
structure was examined first. Sterically less demanding L2 with
a primary alcohol moiety provided 4a with comparable results
(quantitative yield, 83% ee, Table 1, entry 8). A slightly bulkier
CH2SiMe3 substituent (L3) α to the hydroxy group marginally
improved the enantioselectivity (94% yield, 87% ee), while a
much bulkier CH2SiPr3 substituent (L4) did not (quantitative
yield, 83% ee) (entries 9 and 10).14 The enantioselectivity was
nearly lost when the hydroxy group of the ligand was masked
as a methoxy group (L5, entry 11, 90% yield, 2% ee),
indicating that the hydrogen-bonding network was crucial in
this catalytic system. Examination of the substituent effect of
the phosphine moiety revealed that an electron-withdrawing
CF3 group at the para position of the P-phenyl group (L7) had
a significant impact on increasing the enantioselectivity (99%
yield, 91% ee, entry 13). Finally, the enantioselectivity was
slightly improved to 92% ee by a ligand (L8) with a CH2SiMe3
group at the position α to the hydroxy group (entry 14).
Having the optimized conditions in hand, the substrate
scope was examined (Scheme 2). Both alkyl and aryl C-
substituents (R2) of the nitrones were competent. The reaction
smoothly proceeded in 1 mmol scale with comparable results
(4a, 100% yield, 93% ee). An isopropyl substituent gave both a
B
DOI: 10.1021/acs.orglett.9b00276
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a
the N-phenyl moiety of the C-cyclohexyl-N-phenylnitrone (4l,
58% yield, 87% ee).
Scheme 2. Substrate Scope
The secondary propargylic alcohol derivative with a methyl
group at the propargylic position reacted smoothly to afford
4m in 95% yield with high enantioselectivity (cis/trans 44:56,
cis: 90% ee, trans: 85% ee). Although the influence of
elongating the alkyl chain of the alkyne was marginal (4n,
62% yield, cis/trans 42:58, cis: 66% ee, trans: 80% ee), a branch
at the homopropargylic position resulted in a significant
decrease in the enantioselectivity (4o, 46% yield, cis/trans
46:54, cis: 46% ee, trans: 28% ee). An O-Boc-activated tertiary
propargylic alcohol did not participate in the reaction.
To gain information on how the elimination of the Boc-
activated hydroxy group occurs, we conducted the following
two experiments (eqs 1 and 2). A β-lactam 5 containing the
OBoc group at the position β to the carbonyl group was
subjected to the conditions of the Kinugasa reaction. This
resulted in no reaction with complete recovery of 5 (eq 1),
strongly suggesting that the elimination of the OBoc group
occurs prior to β-lactam formation. If the elimination occurs
before the coupling of the alkyne and the nitrone, a copper−
allenylidene complex is a probable intermediate. If this is the
case, the copper complex should give the corresponding
propargylic methyl ether 7 upon trapping with MeOH.15
Having this in mind, alkyne 6 was treated with the copper/
prolinol-phosphine catalyst in the presence of MeOH in
CD2Cl2 and the reaction progress was monitored by 1H NMR
1
spectroscopy. The H NMR spectra did not show any change
during the reaction and no sign of propargyl methyl ether 7
was detected, ruling out the formation of the copper−
allenylidene complex. These experimental results strongly
suggest that the elimination of the OBoc group occurs during
the coupling of the two compounds.
a
1 (0.2 mmol), 2 (0.2 mmol), Cu(OTf)2 (0.02 mmol), L8 (0.02
mmol), Et2NH (0.2 mmol), 25 °C, 6 h. Isolated yields are shown.
Enantiomeric excess (ee) was determined by chiral HPLC analysis.
b
The reaction was conducted in 1 mmol scale.
high yield and high enantioselectivity (4b, 93% yield, 89% ee).
However, a nitrone with a bulkier substituent, a tert-butyl
group, was unreactive. High enantioselectivity was retained
with a phenyl substituent while the yield was moderate (4c,
69% yield, 93% ee). Substituents at the para- or meta-position
on the aryl group provided the products in high enantiose-
lectivities (4d, 4e). On the other hand, ortho substituent
diminished the enantioselectivity (4f, 88% yield, 56% ee). Both
electron-donating (4g) and -withdrawing (4h) substituents
were competent to afford high enantioselectivities.
Higher enantioselectivity was observed when the N-
substituent of the nitrone (R3) was changed to a phenyl
group (4i, 57% yield, 98% ee). The N-phenyl-C-[N-(tert-
butoxycarbonyl)piperazine-4-yl]nitrone was tolerated under
the same conditions (4j, 63% yield, 97% ee). Introduction of a
4-MeO group to the N-phenyl moiety of the C-cyclohexyl-N-
phenylnitrone resulted in even higher enantioselectivity (4k,
48% yield, 99% ee). On the other hand, the enantioselectivity
was slightly decreased when a 4-CF3 group was introduced to
Based on the results shown above and the knowledge from
our previous work,9 we tentatively propose the following
catalytic cycle (Figure 1). A copper−alkyne complex forms a
hydrogen-bonding network via Et2NH A, and deprotonation of
the terminal proton of the alkyne produces a copper acetylide.
Next, capturing the nitrone oxyanion by two-point-hydrogen-
bonding, in which the copper-bound OH group and the
C(sp3)−H of the pyrrolidine moiety work as hydrogen bond
donors, leads to assembly of the two reactants for the copper
catalysis (B).16 Since the oxyanion of the nitrone is hydrogen-
bonded, subsequent C−C bond and C−O bond formations
proceed in a stepwise fashion (C → D → E). The positive
charge in the alkyne-derived moiety would hamper elimination
of the BocO− leaving group from C or D. Rearrangement of E
produces a copper enolate of the β-lactam (F), and elimination
of BocO−, which may be assisted by protonation with the
hydrogen-bonded Et2NH, affords a copper-coordinated β-
lactam (G). Dissociation of the β-lactam (4) from G and
recoordination of the alkyne (1) complete the catalytic cycle.
C
DOI: 10.1021/acs.orglett.9b00276
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Letter
in no reaction. On the other hand, β-(pinacolato)boryl
derivative 9, which has the potential for further derivatization,
was obtained through copper-catalyzed boron conjugate
addition.17 An intriguing spiro compound (10) involving a
three-membered ring was synthesized in 49% yield through
cyclopropanation with trimethylsilyldiazomethane. Elongation
of the carbon skeleton was possible by alkene cross-metathesis
with heptene using the second generation Grubbs catalyst to
afford 11 in 63% yield with moderate cis/trans selectivity.18
Subsequent hydrogenation of the double bond produced 3,4-
cis-dialkyl product 12 exclusively in 85% yield. Epimerization
of 12 at the position α to the carbonyl group was feasible with
15 mol % of KOtBu at room temperature to afford the 3,4-
trans-dialkyl product selectively (13, 86% yield).
In summary, the one-step asymmetric synthesis of chiral α-
alkylidene-β-lactams has been achieved through the catalytic
enantioselective Kinugasa reaction between O-Boc-activated
propargylic alcohols and nitrones. Both C-aryl and C-alkyl
nitrones are suitable substrates for the reaction with high
enantioselectivity. Further studies on the transformative
reactivities of the chiral α-alkylidene-β-lactams for the
synthesis of various β-lactams and related compounds are
underway.
ASSOCIATED CONTENT
* Supporting Information
■
S
Figure 1. Proposed catalytic cycle.
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b00276.
Next, we assessed the potential of the α-methylene-β-lactam
4a as a linchpin for various β-lactams (Scheme 3). Hydro-
genation of the double bond occurred with high diaster-
eoselectivity (dr 98:2) to give the 3,4-cis-dialkyl β-lactam 8.
Attempts at conjugate addition of alkyl groups with conven-
tional Gilman reagents or higher-order cyanocuprates resulted
Detailed experimental procedures, additional condition
screening table, characterization data, HPLC charts,
NMR spectra (PDF)
AUTHOR INFORMATION
■
Scheme 3. Representative Transformations
Corresponding Author
*E-mail: sawamura@sci.hokudai.ac.jp.
ORCID
Hirohisa Ohmiya: 0000-0002-1374-1137
Masaya Sawamura: 0000-0002-8770-2982
Present Address
§Division of Pharmaceutical Sciences, Graduate School of
Medical Sciences, Kanazawa University, Kakuma-machi,
Kanazawa 920-1192
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Institute for Chemical Reaction Design and Discovery
(ICReDD) was established by World Premier International
Research Initiative (WPI), MEXT, Japan. This work was
supported by JST ACT-C Grant Number JPMJCR12YN and
JSPS KAKENHI Grant Number JP18H03906 in Grant-in-Aid
for Scientific Research (A) to M.S. Y.T. thanks JSPS for
scholarship support.
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■
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