Highly stereoselective synthesis of cyclopropylphosphonates catalyzed by chiral Ru(II)-pheox complex

Article abstract of DOI:10.1021/ol501135p

Ru(II)-Pheox-catalyzed asymmetric cyclopropanation of diethyl diazomethylphosphonate with alkenes, including α,β-unsaturated carbonyl compounds, afforded the corresponding optically active cyclopropylphosphonates in high yields and with excellent diastereoselectivity (up to 99:1) and enantioselectivity (up to 99% ee).

Full text of DOI:10.1021/ol501135p

Letter
pubs.acs.org/OrgLett
Highly Stereoselective Synthesis of Cyclopropylphosphonates
Catalyzed by Chiral Ru(II)-Pheox Complex
Soda Chanthamath, Seiya Ozaki, Kazutaka Shibatomi, and Seiji Iwasa*
Department of Environmental and Life Sciences, Toyohashi University of Technology, 1-1 Hibarigaoka, Tempaku-cho, Toyohashi
441-8580, Japan
*
S Supporting Information
ABSTRACT: Ru(II)-Pheox-catalyzed asymmetric cyclopropa-
nation of diethyl diazomethylphosphonate with alkenes,
including α,β-unsaturated carbonyl compounds, afforded the
corresponding optically active cyclopropylphosphonates in
high yields and with excellent diastereoselectivity (up to 99:1)
and enantioselectivity (up to 99% ee).
ptically active cyclopropylphosphonate derivatives are
important units and found in useful biologically active
to be an important factor in providing high diastereocontrol,
and the cyclopropanation of diazomethylphosphonate with
electron-deficient alkenes such as α,β-unsaturated carbonyl
compounds has not been reported yet. Herein, we report a
highly stereoselective synthesis of cyclopropylphosphonates by
the catalytic asymmetric cyclopropanation of simple diethyl
diazomethylphosphonate with various alkenes, including α,β-
unsaturated carbonyl compounds, catalyzed by a Ru(II)-Pheox
complex.
O
natural products or pharmacologically interesting compounds
1
such as an analogue of nucleotide 1, an intermediate for HCV
2
3
NS3 protease inhibitor 2, an analogue of L-Glu 3, and an
4
analogue of fosmidomycin 4 (Figure 1). Moreover, cyclo-
propylphosphonates are also convenient intermediates for the
synthesis of alkylidenecyclopropane derivatives by the Wads-
5
worth−Emmons reaction.
Recently, we reported that the complex, Ru(II)-Pheox, is
extremely efficient in carbene transfer reactions, particularly
10
cyclopropanation and N−H insertion reactions. Therefore,
we attempted the cyclopropanation of styrene 5a with diethyl
diazomethylphosphonate 6 in the presence of the Ru(II)-Pheox
catalyst and first optimized the reaction conditions (Table 1).
The cyclopropanation reaction of the simple diethyl
diazomethylphosphonate 6 proceeded smoothly at room
temperature in various solvents to afford the corresponding
cyclopropylphosphonate 7 in an excellent trans/cis ratio (99:1
in most cases) and with high enantioselectivity (94−98% ee)
(
Table 1, entries 1−6). The cyclopropanation in toluene and
CH OH afforded low yields of the desired product due to the
3
Figure 1. Examples of biologically relevant cyclopropylphosphonate
derivatives.
formation of the dimer from the diazo compound and an O−H
insertion compound as the byproducts, respectively (Table 1,
entries 2 and 5). Conducting the reaction at a lower
temperature afforded lower yields and diastereoselectivity
Among the few methods developed for the synthesis of
1
−4,6
optically active cyclopropylphosphonate derivatives,
the
(
Table 1, entries 6−8). The catalyst loading could be decreased
catalytic asymmetric cyclopropanation of alkenes with diazo-
methylphosphonates is the most efficient method from a
stereoselective synthesis perspective. Over the past decade,
efficient catalytic systems have been developed using chiral
to 1 mol %; however, the yield of 7 slightly decreased (Table 1,
entry 9).
With the optimal reaction conditions in hand, we further
studied the generality of the asymmetric cyclopropanation of
7
8
9
Cu(I), Rh(II), and Ru(II) catalysts to afford the
corresponding cyclopropylphosphonates in good yields and
with high diastereo- and enantioselectivity. However, the
bulkiness of the diazomethylphosphonate moiety was found
Received: April 19, 2014
©
XXXX American Chemical Society
A
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Organic Letters
Letter
a
Table 1. Optimization of Reaction Conditions
could also be easily cyclopropanated to afford the desired
cyclopropane products in high yields and with high diastereo-
and enantioselectivity (Table 2, entries 2−4). Moreover, the
cyclopropanation of styrene derivatives bearing an electron-
withdrawing group such as chloro and nitro was also
investigated (Table 2, entries 5 and 6). Interestingly, the
enantioselectivity could be increased to 99% ee, while the
diastereoselectivity decreased slightly to 98:2 dr. The cyclo-
propanation of α-methylstyrene smoothly afforded the
corresponding cyclopropylphosphonate in a high yield and
with high enantioselectivity (Table 2, entry 7). However, the
diastereoselectivity was lower compared to that of the styrene
without a substituent at the α-position. Vinylamine derivatives
could also be cyclopropanated under the same reaction
conditions to afford the corresponding 2-amino cyclopropyl-
phosphonates in high yields and with high diastereo- and
b
c
d
entry
solvent
temp [°C] yield [%] trans/cis
ee [%] trans
1
2
3
4
5
6
7
8
THF
rt
81
43
79
81
36
93
93
78
67
96:4
99:1
99:1
99:1
99:1
99:1
98:2
98:2
99:1
97
94
98
97
97
97
97
97
97
toluene
acetone
dioxane
rt
rt
rt
CH OH
rt
3
CH Cl
rt
0
2
2
2
2
2
CH Cl2
CH Cl2
−10
rt
e
10b,e
9
CH Cl2
enantioselectivity (Table 2, entries 8 and 9).
We also
a
Reaction conditions: styrene (1 mmol) and diethyl diazomethyl-
phosphonate (0.2 mmol) in the presence of Ru(II)-Pheox (3 mol %)
examined the cyclopropanation of inner alkenes such as trans-2-
hexene and cis-2-hexene; however, no cyclopropane products
were observed due to the formation of a dimer from the diazo
compound.
b
c
d
under Ar. Isolated yield. Determined by NMR. Determined by
e
chiral HPLC analysis. With 1 mol % of catalyst.
Encouraged by the results obtained with the styrene and
vinylamine derivatives, we next turned our attention to the
cyclopropanation of diethyl diazomethylphosphonate with
electron-deficient alkenes such as α,β-unsaturated esters,
ketones, and amides (Table 3). Surprisingly, the reaction with
various styrene derivatives in the presence of the chiral Ru(II)-
Pheox catalyst. As summarized in Table 2, styrene derivatives
bearing an electron-donating group such as methyl or methoxy
Table 2. Ru(II)-Pheox Catalyzed Asymmetric
Cyclopropanation of Various Alkenes with Diethyl
Diazomethylphosphonate
Table 3. Ru(II)-Pheox Catalyzed Asymmetric
Cyclopropanation of Various α,β-Unsaturated Carbonyl
Compounds with Diethyl Diazomethylphosphonate
a
a
a
Reaction conditions: alkenes 5 (1 mmol) and diethyl diazomethyl-
phosphonate 6 (0.2 mmol) in the presence of catalyst (3 mol %)
b
c
d
under Ar. Isolated yield. Determined by NMR. Determined by
chiral HPLC analysis. Bn = benzyl.
phenyl acrylate afforded cyclopropane product 7j in 65% yield
and with an excellent trans/cis ratio (99/1) and enantiose-
lectivity (98% ee). Moreover, 1-phenylprop-2-en-1-one and N-
phenylacrylamide could also be cyclopropanated to afford the
corresponding products, 7k and 7l, in high yields and with high
diastereo- and enantioselectivity (Table 3, entries 2 and 3).
Although the reaction was sensitive to the N-substituents of
acrylamides in terms of the yield (Table 3, entries 4 and 5), to
a
Reaction conditions: alkenes 5 (1 mmol) and diethyl diazomethyl-
phosphonate 6 (0.2 mmol) in the presence of catalyst (3 mol %)
under Ar. Isolated yield. Determined by NMR. Determined by
chiral HPLC analysis.
b
c
d
B
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Organic Letters
Letter
the best of our knowledge, this is the first example of the
catalytic asymmetric cyclopropanation of diazomethylphos-
phonate with electron-deficient alkenes.
To determine the absolute configuration of cyclopropyl-
phosphonates obtained using this catalytic system, we decided
to synthesize a known compound, diethyl-2-(butyl)cyclo-
propylphosphonate 7o, by carrying out the Ru(II)-Pheox-
catalyzed cyclopropanation of diethyl diazomethylphosphonate
with hex-1-ene 5o (Scheme 1). The (1R,2R) configuration was
and the diastereo- and enantioselectivity efficiency reported
until now.
1
,3,14
In conclusion, we developed the highly stereoselective
cyclopropanation of alkenes with diethyl diazomethylphos-
phonate by using the Ru(II)-Pheox complex as the catalyst.
Moreover, the cyclopropanation of electron-deficient alkenes
such as α,β-unsaturated ester, ketone, and amides could be
carried out smoothly under mild reaction conditions to afford
the corresponding cyclopropylphosphonate products in high
yields and with excellent diastereo- and enantioselectivity.
Furthermore, this method confirms the synthetic value of
(−)-diethyl-2-(hydroxymethyl) cyclopropylphosphonate 8, a
key intermediate in the synthesis of the analogue of nucleotide
Scheme 1. Determination of Absolute Configuration of
Diethyl-2-(butyl)cyclopropylphosphonate 7o
1
and L-Glu 3. This efficient procedure can contribute to the
progress of synthetic organic chemistry.
ASSOCIATED CONTENT
Supporting Information
■
*
S
Experimental procedures and characterization data of all the
new compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
confirmed by a comparison of the optical rotation value
11
reported in the literature. Interestingly, although a normal
alkene 5o was used as the substrate, highly stereoselective
cyclopropanation could also be achieved (trans/cis = 99:1).
Finally, to demonstrate the utility of our highly stereo-
selective cyclopropylphosphonate synthesis, we prepared a key
intermediate in the reported synthesis of the analogue of
nucleotide 1 and L-Glu 3 (Scheme 2). The optically active
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: iwasa@ens.tut.ac.jp.
Notes
The authors declare no competing financial interest.
Scheme 2. Preparation of (−)-Diethyl-2-
ACKNOWLEDGMENTS
■
(
hydroxymethyl)cyclopropylphosphonate 8, a Key
This work was supported by a Grant-in-Aid for Scientific
Research (C) (No. 23550179) from the Japan Society for the
Promotion of Science.
Intermediate in the Synthesis of Analogue of Nucleotide 1
and L-Glu 3
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D
dx.doi.org/10.1021/ol501135p | Org. Lett. XXXX, XXX, XXX−XXX