Ir-Catalyzed Asymmetric Hydrogenation of α-Alkylidene β-Lactams and Cyclobutanones

Article abstract of DOI:10.1002/cjoc.201800088

Chiral β-lactams and cyclobutanones are present in numerous natural and pharmaceutical products. The stereoselective construction of chiral four-membered cyclic compounds is an ongoing challenge for the chemical community. Herein, we report a highly stere

Full text of DOI:10.1002/cjoc.201800088

Ir-Catalyzed Asymmetric Hydrogenation of α-Alkylidene β-Lactams and
Cyclobutanones
Jingzhao Xia,a Yu Nie,b Guoqiang Yang,b Yangang Liu,a,b Ilya D. Gridnevc and Wanbin Zhanga,b,
*
aShanghai Key Laboratory for Molecular Engineering of Chiral Drugs, School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai
200240, China
bSchool of Chemistry and Chemical Engineering, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China
cDepartment of Chemistry, Graduate School of Science, Tohoku University, Aramaki 3-6, Aoba-ku, Sendai 9808578, Japan
email: wanbin@sjtu.edu.cn
ABSTRACT Chiral β-lactams and cyclobutanones are present in numerous natural and pharmaceutical products. The stereoselective construction of
chiral four-membered cyclic compounds is an ongoing challenge for the chemical community. Herein, we report a highly stereocontrolled construction of
four-membered ring (mini-sized) β-lactams and cyclobutanones via an Ir/In-BiphPHOX-catalyzed asymmetric hydrogenation, providing the corresponding
optically active four-membered ring carbonyl products bearing an α-chiral carbon center with excellent yields (up to 99%) and enantioselectivities (up to
98%) under mild reaction conditions (1.0 - 2.5 bar H2 for 1.0 - 10 h). The reaction presents wide substrate scope. Diverse transformations of the catalyzed
products were also conducted to show the potential utility of this protocol.
KEYWORDS β-lactam, cyclobutanone, iridium, phosphine-oxazoline ligand, asymmetric hydrogenation.
compared to medium- or large-sized cyclic compounds, a more
Introduction
elegant catalyst is needed in terms of the interaction between the
four-membered cyclic substrate and the catalyst.4b,4d,4e Since the
The preparation of chiral cyclic compounds is of great
pioneering work of the Pfaltz group,5 Ir-catalyzed asymmetric
importance in organic synthesis. Four-membered ring compounds,
such as β-lactams and cyclobutanones, are the core scaffolds in
hydrogenation has attracted much attention due to its unique
efficiency for the asymmetric hydrogenation of unfunctionalized
biologically active natural products and pharmaceuticals, as well
as important intermediates in organic synthesis (Figure 1).1,2 The
asymmetric synthesis of these two types of four-membered ring
compounds has remained a long-standing topic of interest.2,3
Compared to other large-sized and medium-sized cyclic
compounds, the construction of small, chiral four-membered
cyclic compounds has not been widely reported.2 Therefore, the
development of a universal and facile method for the preparation
of chiral four-membered ring appears to be more challenging but
desirable.
olefins and olefins bearing weakly coordinating groups.4e,6,7
However, there is still scope to explore new complexes for the
efficient asymmetric hydrogenation of four-membered cyclic
substrates. Previously, our group has developed an unique class of
tropos phosphine-oxazoline biphenyl ligands (BiphPHOX) which
showed excellent performance in several kinds of metal-catalyzed
asymmetric catalysis,8 including Ir-catalyzed asymmetric
hydrogenation.8b-h Bearing this in mind, we herein describe an
Ir/BiphPHOX-catalyzed asymmetric hydrogenation of α-alkylidene
β-lactams and cyclobutanones for the direct preparation of
β-lactams and cyclobutanones bearing an α-substituted
stereocenter.9 Our tropos phosphine-oxazoline biphenyl ligand is
essential for the preparation of the desired products with high
enantioselectivities (Scheme 1).
Scheme
1
Ir/BiphPHOX-catalyzed Asymmetric hydrogenation for
synthesis of chiral four-membered rings
Figure 1 Representative bioactive molecules bearing four-membered
rings
Asymmetric hydrogenation has gained increasing prominence
in both academic and industrial research over the past several
decades due to its excellent atom economy, high levels of
enantioselectivities and simplicity in operation for the
construction of enantioenriched compounds.4 All these features
contribute to the method’s attractiveness for the preparation of
chiral four-membered rings. Unfortunately, a direct preparation of
chiral four-membered rings via metal-catalyzed asymmetric
hydrogenation is not yet to be described. The huge challenges
originate from the control of stereochemistry due to the difficulty
of being able to distinguish between the Re and Si faces when a
small-sized substrate interacts with the catalyst pocket. Thus,
Results and Discussion
Our study began with the asymmetric hydrogenation of
β-lactam 1a as a model substrate (Table 1). Firstly, different
ligands were screened using o-xylene as the solvent (entries 1-7).
Our tropos phosphine-oxazoline biphenyl ligand (BiphPHOX)
bearing an indane-fused chiral oxazoline group gave the desired
product with the highest ee compared to ligands bearing an iPr or
tBu group on the oxazoline ring (entry 3 vs 1 and 2). A bulky Ar2P
group on the BiphPHOX ligand was also evaluated but led to a
reduction in enantioselectivity (entries 4 and 5). Other classic
types of phosphine-oxazoline ligands with different skeletons
a Department, Institution, Address 1
b Department, Institution, Address 2
c Department, Institution, Address 3
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were also tested (entries 6 and 7). The PHOX ligand showed poor
yield and enantioselectivity. The results of the reaction using an
axially-fixed chiral ligand, BinaphPHOX,10 showed that the
position, while the ee was slightly lower for a substrate bearing an
electron-withdrawing group on the benzene ring (2f).
Furthermore, substrates possessing fused-ring aryl and heteroaryl
R2 groups also gave their corresponding products with excellent
yields and enantioselectivities (2j and 2k). The effect of
N-substitution on this asymmetric hydrogenation was also
investigated (2l-2s). Generally, the hydrogenation products for
N-aryl substrates were obtained with slightly lower ees compared
to that of N-Bn substrates. An N-methyl substrate was also
hydrogenated under the standard catalytic conditions, giving the
desired product 2s efficiently, with a similar ee to that of other
substrates. A substrate without protecting group 1t could also be
hydrogenated with full conversion and 96% ee. The absolute
configurations of 2a was determined to be (R) by X-ray
crystallographic analysis.11
presence of
a binaphthyl backbone could decrease the
enantioselectivity compared to chiral ligands bearing a biphenyl
backbone (entry 7 vs 2). Next, the screening of different solvents
showed that o-xylene was the best solvent for this asymmetric
hydrogenation (entry 3 vs 8-10). The influence of hydrogen
pressure and reaction time were also investigated. To our delight,
the enantioselectivity could be improved by reducing the
hydrogen pressure (entries 11 and 12), and the reaction can go to
completion even within 1 h under 2.5 bar H2 pressure (entry 13).
We chose 2.5 bar of H2 as the optimal pressure, in consideration
of both conversion and enantiomeric excess (ee). (entry 13).
Table 1 Screening of Reaction Conditionsa
Scheme 2 Asymmetric hydrogenation of α-alkylidene β-lactams
Entry
1
Solvent
Ligandb
Conv. [%]c
>99
ee [%]d
o-xylene
L1
88
2
3
o-xylene
o-xylene
o-xylene
o-xylene
o-xylene
o-xylene
CH2Cl2
L2
L3
L4
L5
L6
L7
L3
L3
L3
L3
L3
L3
>99
>99
>99
13
87
92
42
27
-6
4
5
6
36
7
>99
>99
>99
>99
>99
68
74
87
85
91
95
96
95
8
9
ClCH2CH2Cl
toluene
Next, α-alkylidene cyclobutanones were also subjected to our
asymmetric hydrogenation conditions. In this case, the optimized
conditions used dichloromethane as solvent and the reaction was
carried out under 1 bar of hydrogen pressure (Scheme 3). The
results show that substrates possessing either electron-donating
or electron-withdrawing substituents on the benzene ring gave
their corresponding products with excellent yields and
enantioselectivities (4a-4g). The hydrogenation of substrate
bearing a para-MeO group gave the desired product with the
highest ee (4b, 98%). Substitution at the ortho position of the
benzene ring had an obvious influence on the enantioselectivity
(4h). Additionally, excellent enantioselectivity was also observed
when the benzene ring was changed to a β-naphthylene ring (4i).
However, a substrate bearing an α-naphthylene ring gave its
reduced product 4j with moderate ee, most likely due to steric
effects similar to those observed for the hydrogenation of 3h.
Substrate 3k bearing a cyclohexyl R group gave its corresponding
product 4k in excellent yield but with low ee.
10
11e
12f
13g
o-xylene
o-xylene
o-xylene
>99
a Reaction conditions: 0.24 mmol scale, ratio of substrate/catalyst (S/C) =
b
100, 2 mL of solvent, 60 bar of H2. When L1~L5 were used, the axial
c
d
chirality of catalysts was (aS). Determined by 1H NMR spectroscopy.
Enantioselectivity was determined by HPLC using a chiral column. e 2.5 bar
of H2. f 1 bar of H2. g 2.5 bar of H2, 1 h.
With the optimized conditions in hand, the α-alkylidene
β-lactam scope was examined, as shown in Scheme 2. The results
showed that α-alkylidene β-lactams bearing either electron-rich
or electron-deficient aryl groups as R2 gave the corresponding
products in excellent yields and with good to excellent
enantioselectivities (2a-2i). The best ee was observed with
substrate 1b bearing an electron-donating MeO group at the para
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Scheme 3 Asymmetric hydrogenation of α-alkylidene cyclobutanones
yield and with good diastereoselectivity via the CBS reduction of
the carbonyl group of 4a (Scheme 5, b). A Wittig reaction
successfully introduced a C=C double bond at the carbonyl
position with no loss in ee (Scheme 5, c). The Baeyer-Villiger
oxidation of 4a gave a chiral γ-lactone in 87% yield with no
reduction in ee (Scheme 5, d). Finally, the protecting group PMP
could be removed using CAN, giving compound 2t in good yield
and with the same ee as compound 2l (Scheme 5, e).
Conclusions
In summary, we have developed a highly efficient asymmetric
hydrogenation of α-alkylidene β-lactams and cyclobutanones
using the Ir complex of our axially-unfixed biphenyl
phosphine-oxazoline ligand as
a catalyst. A relatively wide
substrate scope of these two classes of substrates are compatible
with our reaction conditions. Chiral α-substituted β-lactams,
cyclobutanones and benzo-fused cyclobutanones could be
prepared with excellent enantioselectivities (up to 98% ee) using
our catalyst systems. Several transformations of these
hydrogenation products were also conducted showing the
potential utility of this protocol.
Three α-alkylidene benzo-fused cyclobutanones were also
tested as substrates (Scheme 4). Under the newly optimized
conditions, chiral α-substituted benzo-fused cyclobutanones
could be prepared in excellent yields and with good ees.
Experimental
The catalyst (4.0 mg, 0.0024 mmol, 0.01 equiv.) and substrate
1a (0.24 mmol, 1.0 equiv.) were placed in a 5-mL tube equipped
with a magnetic stirrer bar. This tube was then placed into a
nitrogen-filled autoclave. Solvent (2.0 mL) was added to the
mixture under nitrogen atmosphere. The autoclave was then
closed, purged three times with hydrogen (less than the pressure
needed), and finally pressurized to 2.5 bar. The reaction mixture
was stirred at r.t. for 1.0 h, and the hydrogen gas was slowly
released. The conversion of the product was determined by 1H
NMR spectroscopic analysis of the crude reaction mixture and the
product was isolated by chromatography. The ee was determined
by chiral HPLC. (R)-1,3-Dibenzylazetidin-2-one (2a). White solid,
Scheme
4
Asymmetric hydrogenation of α-alkylidene benzo-fused
cyclobutanones
1
m.p. = 30.2 – 31.4 °C. 98% yield. H NMR (400 MHz, CDCl3) δ 7.33
– 7.17 (m, 8H), 7.04 – 6.97 (m, 2H), 4.44 (d, J = 15.2 Hz, 1H), 4.19
(d, J = 15.2 Hz, 1H), 3.53 – 3.48 (m, 1H), 3.19 – 3.16 (m, 1H), 3.10
(dd, J = 14.4, 4.8 Hz, 1H), 2.98 – 2.93 (m, 1H), 2.89 (dd, J = 5.6, 2.4
Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 169.7, 138.0, 135.4, 129.0,
128.7, 128.6, 128.0, 127.5, 126.6, 50.7, 45.8, 44.0, 34.2. HRMS
(ESI) calcd for C17H18NO (M+H)+: 252.1388; found: 252.1381. HPLC
[DAICEL CHIRALPAK AD-H, hexane/iPrOH = 95/5, 210 nm, 1.0
mL/min, 25 oC. tR1 = 18.7 min (major), tR2 = 17.4 min (minor)]; ee =
95%. [α]25D = –54.65 (c = 0.63, CHCl3).
Scheme
products
5
High S/C reaction and transformations of hydrogenated
Supporting Information
The supporting information for this article is available on the
WWW under https://doi.org/10.1002/cjoc.2018xxxxx.
Acknowledgement
We thank the Shanghai Municipal Education Commission (No.
201701070002E00030), Science and Technology Commission of
Shanghai Municipality (No. 15JC1402200), and National Natural
Science Foundation of China (Nos. 21472123, 21572131,
21620102003) for financial support.
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1998, 39, 4343.
(The following will be filled in by the editorial staff)
Manuscript received: XXXX, 2017
Revised manuscript received: XXXX, 2017
Accepted manuscript online: XXXX, 2017
Version of record online: XXXX, 2017
[11] CCDC [1559211] for (R)-2a, CCDC [1559212] for (R)-2r, which contain
the supplementary crystallographic data for this paper. Data are
provided free of charge by The Cambridge Crystallographic Data
Centre.
This article is protected by copyright. All rights reserved.

Entry for the Table of Contents
Page No.
Ir-Catalyzed Asymmetric Hydrogenation of
α-Alkylidene
β-Lactams
and
Cyclobutanones
An asymmetric hydrogenation of α-alkylidene β-lactams and cyclobutanones was developed using
the Ir complex of an axially-unfixed biphenyl phosphine-oxazoline ligand as a catalyst. The desired
optically active four-membered ring carbonyl compounds were obtained with excellent
enantioselectivities.
Jingzhao Xia, Yu Nie, Guoqiang Yang,
Yangang Liu, Ilya D. Gridnev, Wanbin
Zhang*
This article is protected by copyright. All rights reserved.