Preparation of enantioenriched γ-substituted lactones via asymmetric transfer hydrogenation of β-azidocyclopropane carboxylates using the ru-TsDPEN complex

Article abstract of DOI:10.1021/ol501895k

The asymmetric transfer hydrogenation of racemic β-azidocyclopropane carboxylates has been explored. Ru-TsDPEN B is found to be a good catalyst for the formation of enantioenriched γ-lactones through a four-step sequence of azide reduction/cyclopropane ri

Full text of DOI:10.1021/ol501895k

Letter
pubs.acs.org/OrgLett
Preparation of Enantioenriched γ‑Substituted Lactones via
Asymmetric Transfer Hydrogenation of β‑Azidocyclopropane
Carboxylates Using the Ru-TsDPEN Complex
Yan Su,†,‡ Yong-Qiang Tu,*,† and Peiming Gu*,‡
†State Key Laboratory of Applied Organic Chemistry, Department of Chemistry, Lanzhou University, Lanzhou 730000, China
‡Key Laboratory of Energy Sources & Engineering, State Key Laboratory Cultivation Base of Natural Gas Conversion and
Department of Chemistry, Ningxia University, Yinchuan 750021, China
S
* Supporting Information
ABSTRACT: The asymmetric transfer hydrogenation of racemic β-
azidocyclopropane carboxylates has been explored. Ru-TsDPEN B is
found to be a good catalyst for the formation of enantioenriched γ-lactones
through a four-step sequence of azide reduction/cyclopropane ring
cleavage/ketone transfer hydrogenation/lactonization, and the enantiomeric
excess of the lactones was up to 94%.
he γ-lactone motif is found to be a very common unit in a
enantiomeric excess was observed with one chiral substrate.4a
Gleason and co-workers have reported the catalytic asymmetric
homoaldol reaction of functionalized cyclopropane and
aldehydes for the construction of enantioenriched γ-lactones;
however, the enantioselectivity was modest (ee up to 72%).4h,i
Following our research on the preparation and conversion of β-
azidocyclopropane carboxylates,5,6 herein we present the
conversion of a range of racemic β-azidocyclopropane
carboxylates to enantioenriched γ-substituted lactones through
an asymmetric transfer hydrogenation process.
T
variety of natural products,1 and it is also a very useful
building block in synthetic chemistry.2 The preparation of these
heterocycles has attracted broad interest from organic
chemists,3 and one method has incorporated the use of
cyclopropanecarboxylates in ring reorganization.4 However, the
synthesis of such enantioenriched γ-lactones from cyclo-
propanes has been quite rare (Scheme 1). Kerr and co-workers
have converted a range of cyclopropane hemimalonates into
racemic γ-substituted lactones, and a slight erosion of
In our research toward the preparation of conformationally
restricted β-amino cyclopropane carboxylic acids (β-ACCs), we
have developed an efficient method to address the cis-β-
azidocyclopropane carboxylates with excellent control of
relative and absolute configuration.5 However, the Staudinger
reduction of the enantioenriched β-azidocyclopropane carbox-
ylates failed to afford the desired β-ACCs, and only the γ-oxo
esters were produced in excellent yield.6 It would be very easy
to understand here that if the racemic cyclopropane
carboxylates were used, the γ-oxo esters would also be
efficiently produced. The asymmetric reduction of the γ-oxo
esters has been reported with some chiral reagents via
stoichiometric processes7 or catalytic processes8 with control
of the stereochemistry. Thus, if a suitable chiral reductant was
applied, further asymmetric reduction of the γ-oxo esters to
enantioenriched γ-hydroxybutyrates might be possible.
Scheme 1. Enantioenriched γ-Lactones from Cyclopropanes
According to the previous research and the above-mentioned
conditions, the preparation of a chiral γ-lactone from a racemic
β-azidocyclopropane carboxylate was designed through the
Received: July 1, 2014
Published: August 1, 2014
© 2014 American Chemical Society
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Organic Letters
Letter
following stages: (1) the reduction of the azido group of the
racemic cyclopropane carboxylate would afford the unstable
donor−acceptor substituted cyclopropane carboxylate I; (2)
ring opening of the cyclopropane carboxylate would afford the
zwitterionic intermediate II,9 and subsequent proton transfer
would give imino ester III, which would be hydrolyzed to the γ-
oxo ester IV; (3) asymmetric hydrogenation10 of the γ-oxo
ester would result in the chiral ethyl γ-hydroxybutyrate V; (4)
lactonization under the acidic conditions would finally deliver
the desired enantioenriched lactone 2 (Scheme 2).
The racemic β-azidocyclopropane carboxylates could be
easily prepared from the cyclopropanation of azido alkenes with
ethyl diazoacetate in the presence of a Rh catalyst.5 The
investigation of the reaction was carried out with the β-
azidocyclopropane carboxylate 1a (Table 1). The initial study
Table 1. Asymmetric Hydrogenation of Ethyl β-
a
Azidocyclopropane Carboxylate 1a
Scheme 2. Designed Conversion of β-Azidocyclopropane
Carboxylates to γ-Butyrolactones
time
(h)
product
(yield)
e
entry
1
catalyst
conditions
ee
A
30 atm of H2, MeOH,
25 °C
30 atm of H2, MeOH,
60 °C
18
40
40
24
24
24
−
−
b
2
3
4
5
6
(S,S)-B
3 (trace)
3 (trace)
−
b
(R,R)-C 30 atm of H2, MeOH,
60 °C
(S,S)-B
−
c
HCO2H/Et3N (5:2),
60 °C
2 (69),
93,
d
2 (55)
94
c
f
(R,R)-C HCO2H/Et3N (5:2),
60 °C
(R,R)-D HCO2H/Et3N (5:2),
60 °C
2 (62)
−65
c
f
2 (35)
−88
a
Reaction of cyclopropane 1a (40.0 mg, 0.17 mmol) with a Ru catalyst
b
(0.085 mmol) under the conditions mentioned above. Only trace γ-
oxo ester 3 formed. Isolated yield after acidic workup. Transfer
hydrogneation of 180.0 mg of cyclopropane 1a. Determined by chiral
HPLC. Opposite enantioselectivity of the product was observed.
c
d
e
f
For the designed process to be successful, the key issue is to
find a good asymmetric reduction system, which must be
comparable with the following requirements: (1) reduction of
the azido group should be efficiently addressed; (2) the
reactivity of the chiral reducing agent should be retained during
the cyclopropane ring opening, as NH3 released from the
rearrangement could deactivate some metal catalysts; (3) the
enantioselectivity of the hydrogenation must be well controlled.
The designed reaction features two reduction processes, so at
least 2 equiv of a chiral reductant must be used if a
stoichiometric asymmetric reduction was employed. Thus, the
catalytic asymmetric hydrogenation seemed to be more
suitable. We decided to explore the following two types of
commercially available Ru catalysts, Ru-BINAP complex A and
Ru-TsDPEN catalysts B−D (Figure 1), which had been widely
applied in the asymmetric hydrogenation or the related
asymmetric transfer hydrogenation.
of the asymmetric hydrogenation with the Ru-BINAP complex
A was found to be invalid (Table 1, entry 1). It was thought
that the Ru-BINAP complex A might be deactivated by the
potential Staudinger reaction of the azido group with the
BINAP ligand.6 Thus, we switched to exploring the Ru(II)
complexes containing TsDPEN ligands B−D. Hydrogenation
of the β-azidocyclopropane carboxylate 1a with Ru-TsDPEN
catalysts B and C at 30 atm of H2 and 60 °C for 40 h produced
only trace γ-oxo ester 3, and none of the desired ethyl γ-
hydroxybutyrate or γ-lactone 2a could be observed. To our
delight, under the asymmetric transfer hydrogenation con-
ditions with the wet HCO2H/Et3N azeotrope, a mixture of γ-
hydroxybutyrates and γ-lactones was observed in the presence
of all of the three Ru-TsDPEN catalysts. Treatment of the
mixture with TFA afforded the lactone 2a as the ultimate
product. The best enantioselecitivity of the transformation was
achieved with catalyst B containing the (S,S)-TsDPEN ligand.
The absolute configuration of 2a was assigned by comparison
of the rotation data ([α]D −22.3) with that of the previous
reports.11
The lactone 2a was obtained with excellent enantioselectivity
from the transfer hydrogenation of the β-azidocyclopropane
carboxylate 1a with Ru-TsDPEN catalyst (S,S)-B followed by
lactonization, but the yield was slightly reduced when the
amount of 1a was improved from 40.0 mg to 180.0 mg (Table
1, entry 4). For comparison, the transfer hydrogenation of γ-
oxo ester 3 (32 mg) under similar conditions followed by TFA
had been explored, and the resulting lactone 2a was obtained in
better yield (93%) but with slightly poor enantioselectivity
(86% ee). The difference between the yields (69% vs 93%) of
the two experiments could be easily understood, as the γ-oxo
ester 3 was supposed to be the intermediate of the designed
process. However, it was very interesting that the enantiose-
Figure 1. Ru-complex for asymmetric hydrogenation of the β-
azidocyclopropane ester 1a.
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Organic Letters
Letter
lectivity of hydrogenation of 1a was better than that of the γ-
oxo ester 3. The γ-oxo ester seemed to be simpler than the β-
azidocyclopropane carboxylate. But it should be noted here that
the general method toward γ-oxo ester was the Stetter reaction
of an aldehyde with an α,β-unsaturated compound, which was
catalyzed by a highly toxic metal cyanide or a complex
thiazolium salt.
lactones, and most lactones were obtained in good to excellent
enantioselectivities.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures and spectroscopic data and copies of
NMR spectra for all the β-azidocyclopropane carboxylates and
γ-lactones. This material is available free of charge via the
Internet at http://pubs.acs.org.
With the above results, we next explored the scope of the
substrates with Ru-TsDPEN catalyst (S,S)-B (Scheme 3). The
a
Scheme 3. Scope of Conversion
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: tuyq@lzu.edu.cn.
*E-mail: gupm@nxu.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the National Natural Science
Foundation of China (No. 21262024), the Program for New
Century Excellent Talents in University (NCET-13-0874), and
the Scientific Research Foundation for Returned Scholars
(Ministry of Education of China).
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