Catalytic asymmetric synthesis of cyclopropylphosphonates - Catalysts' scope and reactivity

Article abstract of DOI:10.1139/v05-074

The transition metal-catalyzed cyclopropanation of alkenes using α-diazomethylphosphonates leads to cyclopropylphosphonate derivatives in high yields. The reaction proceeds well with copper, rhodium, and ruthenium catalysts. The best catalysts for the ena

Full text of DOI:10.1139/v05-074

533
Catalytic asymmetric synthesis of
cyclopropylphosphonates — Catalysts’ scope and
reactivity1
André B. Charette and Jean-Emmanuel Bouchard
Abstract: The transition metal-catalyzed cyclopropanation of alkenes using α-diazomethylphosphonates leads to
cyclopropylphosphonate derivatives in high yields. The reaction proceeds well with copper, rhodium, and ruthenium
catalysts. The best catalysts for the enantioselective version are either Evans’ Cu·bis(oxazoline) or Nishiyama’s
Ru·pybox.
Key words: cyclopropylphosphonic acids, copper catalysts, ruthenium catalysts, cyclopropanation, diazo reagents.
Résumé : La cyclopropanation d’alcènes impliquant la décomposition de dérivés α-diazométhylphosphonate catalysée
par des métaux de transition conduit aux dérivés cyclopropylphosphonate avec de bons rendements. La réaction
s’effectue efficacement avec des catalyseurs dérivés du cuivre, rhodium et ruthénium. Les meilleurs catalyseurs pour la
version énantiosélective sont le Cu·bis(oxazoline) d’Evans et le Ru·pybox de Nishiyama.
Mots clés : acides cyclopropylphosphoniques, catalyseurs de cuivre, catalyseurs de ruthénium, cyclopropanation, dérivés
diazoïques.
Charette and Bouchard 542
Introduction
precursor is used. Traditionally these compounds have been
prepared by carbene chemistry (6–8), by a Michaëlis–
Arbuzov reaction from a gem-dibromocyclopropane (9), or
by an alkylation – ring closure process (10, 11).
In this paper, we report our study towards the develop-
ment of an efficient synthesis of enantiomerically enriched
cyclopropylphosphonates (12). Various catalysts and phos-
phonate esters were surveyed to optimize both the enantio-
selectivities and the diastereoselectivities. This work
complements Simonneaux and co-workers’ (13–16) recent
reports on the use of ruthenium porphyrin catalysts.
Phosphinic acid derivatives are quite important synthetic
derivatives that have been used to mimic the biological ac-
tivity of phosphates and carboxylic acids (1). They have
found wide applications in medicinal chemistry and agro-
chemical sciences. Unlike the weak phosphorus–oxygen
bond in phosphates, the carbon–phosphorus bond is not eas-
ily hydrolyzed and is, therefore, unsusceptible to the action
of phosphatases. Some important examples are shown in
Fig. 1. Compound 1 possesses antiviral properties (2, 3), 2 is
a nucleoside analog (4), and finally, fosfomycin (3) is a
commonly used antibiotic (5).
One attractive and expedient method for the generation of
enantiomerically pure cyclopropylphosphonate derivatives
would be to generate them from a catalytic asymmetric addi-
tion of a suitably functionalized metal carbene to an alkene
to generate the cyclopropane (Fig. 2). Given the efficiency
of the analogous reaction using an ester functionality in
place of the phosphonate group, one should expect excellent
enantio- and diastereocontrol if the appropriately substituted
Results and discussion
Synthesis of racemic substituted cyclopropylphoshonate
esters
Our first goal was to establish which were the best achiral
catalysts to generate cyclopropylphosphonate derivatives
(Table 1) (17). Although it is well-established that bulkier
esters provide higher diastereocontrol in the cyclopropan-
ation of alkenes using α-diazoacetate derivatives (18) and
that such a trend should also be observed with the analogous
phosphonate reagents, the initial catalyst calibration was
done with the diethylphosphonate derivative 4. Several cata-
lysts were tested and, as expected, the most reactive were
the rhodium-based catalysts (Table 1, entries 2–4). Copper(I)
triflate was also quite effective but in all the examples, the
diastereocontrol was extremely low (Table 1, entry 1). A
ruthenium-based system provided a lesser reactive metal car-
bene, but the diastereoselectivity was much better (Table 1,
entry 5).
Received 16 December 2004. Published on the NRC Research
Press Web site at http://canjchem.nrc.ca on 2 June 2005.
This paper is dedicated to Professor Howard Alper in
recognition of his many contributions to the science of
organometallic chemistry and catalysis.
A.B. Charette2 and J.-E. Bouchard. Département de chimie,
Université de Montréal, P.O. Box 6128, Station Downtown,
Montréal, QC H3C 3J7, Canada.
1This article is part of a Special Issue dedicated to Professor
Howard Alper.
Several alkenes were submitted to these reaction condi-
tions using rhodium(II) pivalate and good to excellent yields
2Corresponding author (e-mail: andre.charette@umontreal.ca).
Can. J. Chem. 83: 533–542 (2005)
doi: 10.1139/V05-074
© 2005 NRC Canada

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Can. J. Chem. Vol. 83, 2005
Fig. 1. Examples of biologically relevant phosphonate derivatives.
NH
2
N
N
N
NH
N
O
N
O
Me
P(OH)
2
N
N
OH
P(OEt)
2
H
H
O
O
O
P
Fosfomycin (3)
2
HO
OH
1
Fig. 2. Synthetic approach to cyclopropylphosphonate derivatives.
O
O
O
OR
OR
OR
OR
1
P
M
N
2
R
P
P
1
+
OR
R
OR
M = Rh, Ru, Cu
Table 1. Cyclopropanation of diethyl α-diazomethylphosphonate.
O
N2
Catalyst
(5 mol%)
O
P(OEt)2
+
P(OEt)2
Ph
Ph
H
P(OEt)2
O
+
Ph
CH2Cl2, 8 h, 20 °C
(3 equiv.)
4
trans-5
cis-5
Entry
Catalyst
Ratio trans-5:cis-5
Yield (%)
1
2
CuOTf
[Rh(OAc)2]
50:50
55:45
77
29
3
4
5
[Rh(octanoate)2]
[Rh(Me3CCO2)2]2
[RuCl2(p-cymene)]2
54:46
55:45
81:19
85
85
40
Cu·bis(oxazoline) 21 catalyzed cyclopropanation of disub-
stituted alkenes with diethyl α-diazomethylphosphonate is
shown in Fig. 4. The general trend is that the diastereo-
control is relatively modest and the enantioselectivities are
lower than those observed for the cyclopropanation of sty-
rene. Furthermore, the cyclopropanation of 1,2-disubstituted
alkenes produced the corresponding cyclopropane in modest
yields and enantioselectivities.
of the corresponding cyclopropane were obtained with
mono-, di- and trisubstituted alkenes (Fig. 3). However,
these reactions produced separable mixtures of the cis- and
trans-cyclopropane isomers.
Enantioselective cyclopropanation — Copper-based
catalysts
Although there is an extensive number of efficient copper-
based catalysts for the cyclopropanation of α-diazoesters, the
bis(oxazoline)-based catalysts were screened because of
their accessibility and their efficiency in the cyclopropanation
of mono- and disubstituted alkenes using α-diazoesters. As
already highlighted by Evans et al. (19) for the cyclopro-
panation of α-diazoesters, the bis(oxazoline) 21 derived from
tert-leucine provided not only the highest enantioselectivities
but also the best diastereocontrol (Table 2). A similar level
of enantiocontrol was also observed with the bis(oxazoline)
22 derived from serine. Increasing the steric bulk of the R
groups of the phosphonate reagent led to a slightly improved
diastereocontrol, but the enantioselectivities were mostly
ligand-dependent. For example, the diisopropyl α-
diazomethylphosphonate and the neopentyl α-diazomethyl-
phosphonate reagents 13 and 14 led to higher
diastereoselectivities, but the enantiomeric excesses of the
products were similar. The scope of the reaction for the
Enantioselective cyclopropanation using ruthenium-
based catalysts
Nishiyama’s ruthenium catalysts (20) are among the most
efficient ones for the cyclopropanation of alkenes with ethyl
diazoacetate. Although the ruthenium carbene is usually less
reactive than the analogous rhodium derivative, the corre-
sponding cyclopropane is obtained with high diastereo- and
enantiocontrol.
Table 3 illustrates the optimization process that led to the
identification of the most efficient ligand and reagent combi-
nation. As previously reported by Nishiyama (20) for the
cyclopropanation of alkenes using α-diazoesters, the ligand
derived from valine was the most effective (Table 3, entry 1
vs. 2 vs. 4). Furthermore, the steric bulk of the phosphonate
reagent was important in providing high diastereocontrol,
© 2005 NRC Canada

Charette and Bouchard
535
Fig. 3. Scope of the rhodium-catalyzed cyclopropanation of alkenes.
R2
N2
R3
R2
R3
[Rh(Me3CCO2)2]2
(0.05 equiv.)
R1
+
H
P(OEt)2
O
R1
P(OEt)2
CH2Cl2, 8 h, 20 °C
(2 to 3 equiv.)
O
4
5-10
O
O
O
Ph
Ph
P(OEt)2
P(OEt)2
P(OEt)2
Ph
Ph
5
6
7
85%
72%
72%
trans:cis
55:45
trans:cis
57:43
O
O
O
P(OEt)2
P(OEt)2
P(OEt)2
O
Ph
8
9
10
69%
trans:cis
64:46
70%
trans:cis
50:50
70%
trans:cis
75:25
Table 2. Copper(I)-catalzyed cyclopropanation of alkenes with α-diazophosphonate reagents.
O
O
N
N
N
O
2
O
+
R'
CuOTf
R'
Ph
P(OR)
P(OR)
Ph
2
2
H
P(OR)
O
2
Styrene (5 equiv.)
trans
cis
CH Cl , 20 °C
2
2
4, 11-14
R' = i-Pr (19), Ph (20), t-Bu (21)
CMe2OMe (22)
5, 15-18
Entry
R
Ligand Yield (%) Product (R)
trans:cis ee (%, trans:cis)
1
2
3
4
5
6
7
8
Me (11)
Me (11)
Me (11)
Et (4)
Et (4)
Et (4)
Et (4)
Bu (12)
i-Pr (13)
19
20
21
19
20
22
21
21
21
72
75
74
72
86
50
65
65
65
67
15 (Me)
15 (Me)
15 (Me)
5 (Et)
5 (Et)
5 (Et)
5 (Et)
16 (Bu)
17 (i-Pr)
81:19
80:20
86:14
80:20
78:22
83:17
84:16
88:12
90:10
76:61
79:83
93:99
75:67
80:74
92:99
92:99
91:nd
92:nd
92:nd
9
10
(CH2C(CH3)3) (14) 21
18 (CH2C(CH3)3) 92:8
Note: nd = not determined.
although even the diethyl derivative provided excellent
diastereoselectivies (Table 3, entry 4).
The scope of the reaction is shown in Table 4. Mono-
substituted alkenes led to the corresponding cyclopropane in
high yield and enantiocontrol (Table 4, entries 1–3, 7). In all
the reactions, the diastereoselectivity was greater than 95:5
favoring the trans isomer. The absolute stereochemistry was
confirmed in one case (compound 31) from the X-ray crystal
structure (Fig. 5). 1,1-Disubstituted alkenes could also be
used but the diastereocontrol was slightly lower (Table 4,
© 2005 NRC Canada

536
Can. J. Chem. Vol. 83, 2005
Fig. 4. Scope of the Cu·bis(oxazoline) 21 catalyzed cyclopropanation of alkenes.
21 (3 mol%)
R
H
2
R
N
2
2
R
O
R
1
1
CuOTf (3 mol%)
P(OEt)
H
2
H
P(OEt)
2
+
R
R'
O
Alkene (5 equiv.)
CH2Cl2, 25 °C
P(OEt)
O
2
trans
cis
4, 13
23-26
O
O
O
Ph
O
P(OEt)
2
P(OEt)
P(OEt)
P(OEt)
2
2
2
Ph
Ph
Ph
23
73%
24
25
50%
26
50%
50%
trans/cis: 64/36
ee trans: 84%
ee: 78%
trans/cis: 85/15
ee trans: 72%
trans/cis: 99/1
ee trans: 37%
Table 3. Optimization of the enantioselective cyclopropanation of alkenes using ruthenium catalysts.
O
O
N
R
R
2
Cl
2
N
N
Ru
N
Cl
2
R
R
1
O
1
O
+
(3 mol%)
27-29
H
P(OR)
2
Ph
P(OR)
Ph
P(OR)
2
2
O
Styrene (5 equiv.)
CH2Cl2, 20 °C
trans
cis
4, 11, 13-14
5, 15-18
Entry
R
R1
R2
Catalyst
Product
Yield (%)
trans:cis
ee (%, trans)
5
5
15
5
17
18
1
2
3
4
5
6
Et (4)
Et (4)
Me (11)
Et (4)
i-Pr (13)
Me
Ph
i-Pr
i-Pr
i-Pr
i-Pr
Ph
H
H
H
H
H
27
28
29
29
29
29
68a
60a
65
65
70
79a
>98:2
78:22
90:10
>98:2
>98:2
>98:2
52
49
76
96
96
96
CH2C(CH3)3 (14)
aThe reaction was heated under reflux.
entry 4). Finally, when a diene was used, the cyclo-
propanation occurred at the least-hindered position (Table 4,
entry 6).
It is also possible to further functionalize the cyclopro-
pylphosphonate and to hydrolyze it to the corresponding
phosphonic (21) acid. It is also possible to convert the styryl
substituent into a primary alcohol through a oxidative cleav-
age – reduction sequence (eq. [1]).
Conclusion
We have shown that the preparation of enantiomerically
enriched cyclopropylphosphonate derivatives can easily be
accomplished using the copper- or ruthenium-catalyzed de-
composition of diethyl or diisopropyl α-diazomethyl-
phosphonate. The products are usually obtained in good
enantiomeric excesses and excellent diastereocontrol.
O
O
1. O3, MeOH, -78
°C
HO
P(Oi-Pr)
P(Oi-Pr)
2
2
Ph
[1]
2. NaBH4, MeOH, -78
°
C
90% ee
88%
36 90% ee
34
© 2005 NRC Canada

Charette and Bouchard
Table 4. Scope of the cyclopropanation of alkenes with Nishiyama’s catalyst (20).
537
N
2
O
+
29 (3 mol%)
Alkene
H
P(Oi-Pr)
O
P(Oi-Pr)
2
2
(5 equiv.)
CH2Cl2, 20 °C
R
13
17, 30-35
Major
Product
ee (%)
:
t c
Entry
Yield (%)
Alkene
:
trans cis
O
96:—
94:—
70
80
>98:2
>98:2
1
2
Ph
P(Oi-Pr)
2
17
Ph
O
P(Oi-Pr)
30
2
p-MeOC H
6
4
MeO
Cl
O
98:—
95:92
91
77
72
>98:2
88:12
3
4
5
P(Oi-Pr)
2
31
p-ClC H
6
4
O
Me
Ph
P(Oi-Pr) 32
2
Ph
O
Ph
Ph
Ph
Ph
39a
P(Oi-Pr) 33
2
O
90a
91a
6
7
P(Oi-Pr)
95:5
90:92
97:—
Ph
34
2
Ph
O
>98:2
P(Oi-Pr)
2
2
-Naphthyl
35
aThe reaction was heated under reflux.
Fig. 5. Chem3D® representation of X-ray structure of cyclo-
propylphosphonate 31.
in dichloromethane (2.0 mL) at room temperature was added
over 3 h via a syringe pump a solution of diethyl α-diazo-
methylphosphonate (4) (22) (80.0 mg, 0.449 mmol, 1 equiv.)
in dichloromethane (2.0 mL). After 8 h of stirring at room
temperature, the reaction mixture was concentrated under re-
duced pressure. The crude residue was purified by flash
chromatography on silica gel using EtOAc as the eluent to
give the desired compound ( )-5 as a colorless oil (100 mg,
85%): Rf 0.40 (80% EtOAc–hexanes). IR (film, cm–1): 2981,
2931, 1244, 1026, 961, 777, 699. 1H NMR (300 MHz,
CDCl3) δ: 7.31–7.10 (m, 5H, C6H5), 4.12 (m, 4H, P-O-CH2-
CH3 (trans)), 3.80 (m, 4H, P-O-CH2-CH3 (cis)), 2.48 (m,
1H, C6H5-CHcycloprop), 1.35 (m, 1H, CH2cycloprop), 1.30 (m,
6H, P-O-CH2-CH3), 1.20 (m, 1H, CH2cycloprop), 1.14 (m, 2H,
CHcycloprop-P). 13C NMR (75 MHz, CDCl3) δ: 140.0, 139.97,
129.4, 129.1, 128.9, 128.5, 128.2, 127.8, 126.6, 126.5,
126.0, 63.6, 63.5, 63.4, 62.0, 61.9, 61.87, 61.8, 21.0, 20.99,
16.5, 16.4, 16.1, 13.5, 12.7, 12.6. 31P NMR (160 MHz,
CDCl3) δ: 29.9 (trans), 28.9 (cis). Anal. calcd. for C13H19O3P:
C 61.41, H 7.53; found: C 61.06, H 7.72.
Experimental
( )-Diethyl 2-phenylcyclopropylphosphonate (( )-5)
(Table 1, entry 4)
To a solution of styrene (0.154 mL, 1.35 mmol, 3 equiv.)
and rhodium(II) pivalate (14.0 mg, 0.0225 mmol, 0.05 equiv.)
© 2005 NRC Canada

538
Can. J. Chem. Vol. 83, 2005
(NMR) by flash chromatography on silica gel to afford ( )-
trans-8 as a colorless oil (44 mg, 44%) and ( )-cis-8
(25 mg, 25%) as a colorless oil. ( )-trans-8: Rf 0.21 (100%
( )-Diethyl 2-methyl-2-phenylcyclopropylphosphonate
(( )-6)
The procedure for the preparation of compound ( )-5 was
followed. Scale: rhodium(II) pivalate (14.0 mg, 0.0225 mmol,
0.05 equiv.), α-methylstyrene (0.117 mL, 0.898 mmol,
2 equiv.); diethyl α-diazomethylphosphonate (4) (80.0 mg,
0.449 mmol, 1 equiv.), CH2Cl2 (4 mL total). 80% EtOAc–
hexanes was used as the eluent for the purification of the
57:43 mixture (NMR) by flash chromatography on silica gel
to afford ( )-trans-6 as a colorless oil (49 mg, 41%) and ( )-
cis-6 (37 mg, 31%) as a colorless oil. ( )-trans-6: Rf 0.37
(EtOAc). IR (film, cm–1): 2981, 1245, 1058, 1027, 960, 889,
1
EtOAc). H NMR (300 MHz, CDCl3) δ: 4.15 (m, 4H, P-O-
CH2-CH3), 3.85 (dt, J = 6.4, 3.1 Hz, 1H, O-CHcycloprop), 3.75
(td, J = 10.7, 3.5 Hz, 1H, O-CH2-CH2-CH2-CHcycloprop), 3.35
(dt, J = 10.6, 2.7 Hz, 1H, O-CH2-CH2-CH2-CHcycloprop), 2.10
(m, 3H, O-CH2-CH2-CH2-CHcycloprop, O-CH2-CH2-CH2-CHcycloprop),
1.45 (m, 1H, O-CH2-CH2-CH2-CHcycloprop), 1.40 (t, J =
7.1 Hz, 1H, P-O-CH2-CH3), 0.80 (m, 1H, CHcycloprop-P). 13C
NMR (75 MHz, CDCl3) δ: 64.7, 61.7, 61.6, 60.9, 60.8, 53.9,
53.8, 27.0, 20.9, 17.4, 16.4, 16.3, 16.2, 15.4, 15.3, 14.8. 31P
NMR (160 MHz, CDCl3) δ: 27.0. IR (film, cm–1): 2979,
2931, 1237, 1056, 1024, 953, 806. HR-MS calcd. for
C10H19O4P (M + H): 235.1099; found: 235.1105. ( )-cis-8:
1
769, 701. H NMR (300 MHz, CDCl3) δ: 7.31–7.26 (m, 5H,
C6H5), 4.16 (m, 1H, P-O-CH2CH3), 1.66 (s, 3H, CH3), 1.38
(m, 8H, P-O-CH2CH3, CH2cycloprop), 1.33 (m, 1H,
CHcyclopropyl-P). 13C NMR (75 MHz, CDCl3) δ: 146.3, 146.28,
128.7, 127.5, 126.7, 61.8, 61.76, 61.7, 27.6, 27.59, 22.1,
22.0, 19.8, 18.9, 18.87, 17.9, 16.8, 16.7, 16.69. 31P NMR
(160 MHz, CDCl3) δ: 30.5. Anal. calcd. for C14H21O3P: C
62.67, H 7.89; found: C 62.73. H 7.77. ( )-cis-6: Rf 0.25
1
Rf 0.13 (100% EtOAc). H NMR (300 MHz, CDCl3) δ: 4.10
(m, 4H, P-O-CH2-CH3), 3.85 (m, 1H, O-CHcycloprop),
3.60 (td, J = 10.9, 3.3 Hz, 1H, O-CH2-CH2-CH2-CHcycloprop),
3.35 (dt, J = 10.7, 3.1 Hz, 1H, O-CH2-CH2-CH2-CHcycloprop),
2.00 (m, 2H, CH2-CH2-CH2-CHcycloprop), 1.60 (m, 1H, O-
CH2-CH2-CH2-CHcycloprop), 1.45 (m, 2H, O-CH2-CH2-CH2-
CHcycloprop), 1.30 (t, J = 7.1 Hz, 1H, P-O-CH2-CH3), 0.90
(m, 1H, CHcycloprop-P). 13C NMR (75 MHz, CDCl3) δ: 64.4,
61.9, 61.8, 61.7, 55.3, 55.2, 21.5, 19.1, 19.0, 18.1, 16.8,
16.7, 16.5, 16.4, 15.7. 31P NMR (160 MHz, CDCl3) δ: 28.2.
IR (film, cm–1): 2979, 2931, 1237, 1056, 1024, 953, 806.
1
(EtOAc). H NMR (300 MHz, CDCl3) δ: 7.17–7.44 (m, 5H,
C6H5), 3.88 (m, 2H, P-O-CH2CH3), 3.70 (m, 1H, P-O-
CH2CH3), 3.33 (m, 1H, P-O-CH2CH3), 1.64 (d, J = 2.4 Hz,
1H, CHcycloprop-P), 1.60 (s, 3H, CH3), 1.17 (m, 5H, P-O-
CH2CH3, CH2cycloprop), 0.96 (t, J = 7.1 Hz, 3H, P-O-CH2CH3).
13C NMR (75 MHz, CDCl3) δ: 141.96, 141.9, 129.5, 128.2,
126.9, 61.5, 61.4, 61.35, 61.35, 61.3, 29.64, 29.6, 28.24,
28.2, 21.1, 19.1, 17.4, 17.3, 16.5, 16.46, 16.4, 16.3. 31P
NMR (160 MHz, CDCl3) δ: 27.9. HR-MS calcd. for
C14H2O3P (M + H): 268.1228; found: 228.1228.
( )-Diethyl 2-butylcyclopropylphosphonate (( )-9)
The procedure for the preparation of compound ( )-5 was
followed. Scale: rhodium(II) pivalate (14.0 mg, 0.0225 mmol,
0.05 equiv.), 1-hexene (0.116 mL, 0.898 mmol, 2 equiv.), di-
ethyl α-diazomethylphosphonate (4) (80.0 mg, 0.449 mmol,
1 equiv.), CH2Cl2 (4 mL total). The purification of the 50:50
mixture (NMR) by flash chromatography on silica gel (80%
EtOAc–hexanes) afforded ( )-trans-9 as a colorless oil
(42 mg, 35%) and ( )-cis-9 (42 mg, 35%) as a colorless oil.
( )-Diethyl 2,2-diphenylcyclopropylphosphonate (( )-7)
The procedure for the preparation of compound ( )-5 was
followed. Scale: rhodium(II) pivalate (7.40 mg, 0.0121 mmol,
0.05 equiv.), 1.1-diphenylethylene (0.134 mL, 0.898 mmol,
3 equiv.), diethyl α-diazomethylphosphonate (4) (50.0 mg,
0.243 mmol, 1 equiv.), CH2Cl2 (4 mL total). Purification by
flash chromatography on silica gel (80% EtOAc–hexanes)
afforded ( )-7 as a colorless oil (63 mg, 72%). Rf 0.34 (80%
EtOAc–hexanes). IR (film, cm–1): 2980, 1599, 1495, 1446,
1248, 1227, 1020, 953, 772, 695. 1H NMR (300 MHz,
CDCl3) δ: 7.51–7.16 (m, 10H, C6H5), 3.95 (m, 2H,
P-O-CH2-CH3), 3.76 (m, 1H, P-O-CH2-CH3), 3.50 (m, 1H,
P-O-CH2-CH3), 2.03 (m, 1H, CH2cycloprop), 1.83 (m, 1H,
CH2cycloprop), 1.57 (m, 1H, CHcycloprop-P), 1.22 (t, J = 7.1 Hz,
3H, P-O-CH2-CH3), 1.05 (t, J = 7.1 Hz, 3H, P-O-CH2-CH3).
13C NMR (75 MHz, CDCl3) δ: 145.4, 145.3, 140.3, 140.26,
130.1, 128.4, 128.0, 127.91, 127.90, 126.9, 126.6, 63.6,
61.5, 61.4, 61.35, 36.7, 36.63, 21.3, 18.7, 17.9, 17.8, 16.3,
16.24, 16.2, 16.1. 31P NMR (160 MHz, CDCl3) δ: 27.1. HR-
MS calcd. for C19H23O3P (M + H): 331.1463; found:
331.1457.
1
( )-trans-9: Rf 0.36 (EtOAc). H NMR (300 MHz, CDCl3)
δ
: 4.10 (m, 2H, P-O-CH -CH ), 1.30 (m, 13H, CH -CH -
2
3
3
2
CH2-CH2-CHcycloprop, P-O-CH2-CH3), 1.00 (m, 1H, CH2cycloprop),
0.85 (t, J = 7.0 Hz, 3H, CH3-CH2-CH2-CH2-CHcycloprop),
0.60 (m, 2H, CHcycloprop-P, CH2cycloprop). 13C NMR (75 MHz,
CDCl3) δ: 61.7, 61.6, 33.3, 33.27, 31.3, 22.3, 17.4, 17.3,
16.5, 16.4, 14.0, 11.9, 10.4, 10.37, 9.3. 31P NMR (160 MHz,
CDCl3) δ: 32.3. HR-MS calcd. for C11H23O3P (M + H):
235.1463; found: 235.1453. ( )-cis-9: Rf 0.44 (EtOAc). IR
(film, cm–1): 2957, 2928, 1458, 1245, 1059, 1030, 957, 732.
1H NMR (300 MHz, CDCl3) δ: 4.10 (m, 2H, P-O-CH2-CH3),
1.70 (m, 1H, CHcycloprop), 1.50 (m, 11H, CH3-CH2-CH2-CH2-
CHcycloprop, P-O-CH2-CH3), 1.10 (m, 2H, CH2cycloprop), 0.90
(t, J = 7.0 Hz, 3H, CH3-CH2-CH2-CH2-CHcycloprop), 0.85 (q,
J = 7.0 Hz, 2H, CH3-CH2-CH2-CH2-CHcycloprop). 13C NMR
(75 MHz, CDCl3) δ: 61.4, 61.35, 61.3, 31.9, 28.5, 28.4,
22.4, 17.9, 16.5, 16.4, 16.4, 14.1, 10.9, 10.5, 10.47, 10.4,
7.9. 31P NMR (160 MHz, CDCl3) δ: 32.5.
( )-Diethyl 2-oxa-bicyclo[4.1.0]hept-7-ylphosphonate
(( )-8)
The procedure for the preparation of compound ( )-5 was
followed. Scale: rhodium(II) pivalate (14.0 mg, 0.0225 mmol,
0.05 equiv.), 3,4-dihydro-2H-pyran (0.082 mL, 0.898 mmol,
2 equiv.), diethyl α-diazomethylphosphonate (4) (80.0 mg,
0.449 mmol, 1 equiv.), CH2Cl2 (4 mL total). EtOAc was
used as the eluent for the purification of the 64:46 mixture
( )-Diethyl 2-methyl-3-phenylcyclopropylphosphonate
(( )-10)
The procedure for the preparation of compound ( )-5 was
followed. Scale: rhodium(II) pivalate (14.0 mg, 0.0225 mmol,
0.05 equiv.), trans-β-methylstyrene (0.116 mL, 0.898 mmol,
2 equiv.), diethyl α-diazomethylphosphonate (4) (80.0 mg,
© 2005 NRC Canada

Charette and Bouchard
539
0.449 mmol, 1 equiv.), CH2Cl2 (4 mL total). The purifica-
tion of the 50:50 mixture (NMR) by flash chromatography
on silica gel (80% EtOAc–hexanes) afforded ( )-trans-10 as
a colorless oil (63 mg, 53%) and ( )-cis-10 (21 mg, 17%) as a
colorless oil. ( )-trans-10: Rf 0.42 (EtOAc). IR (film, cm–1):
was stirred for an additional 12 h at room temperature and
was then concentrated under reduced pressure. The diaster-
eomeric ratio (64:36) was determined by 31P NMR of the
crude reaction mixture (δ major: 30.5 and δ minor: 27.9).
The crude mixture was then purified by flash chromatogra-
phy on silica gel (80% EtOAc–hexanes) to give trans-23
(46 mg, 47%) and cis-23 (26 mg, 26%). The enantiomeric
excesses (85%) were determined by SFC on a chiral station-
ary phase (Chiralcel OD, 1% MeOH, 1.2 mL/min: tr (major)
19.9 min, tr (minor), 18.1 min). trans-23: Rf 0.37 (EtOAc).
IR (film, cm–1): 2981, 1245, 1058, 1027, 960, 889, 769, 701.
1H NMR (300 MHz, CDCl3) δ: 7.31–7.26 (m, 5H, C6H5),
4.16 (m, 1H, P-O-CH2CH3), 1.66 (s, 3H, CH3), 1.38 (m, 8H,
1
2981, 2905, 1240, 1055, 1029, 963. H NMR (300 MHz,
CDCl3) δ: 7.07–7.30 (m, 5H, C6H5), 4.10 (m, 4H, P-O-CH2-
CH3), 2.35 (m, 1H, C6H5-CHcycloprop), 1.85 (d, 3H, CH3
(cis)) 1.57 (m, 1H, CHcycloprop-P), 1.46 (d, J = 6.4 Hz, 3H,
CH3 (trans)), 1.36 (m, 6H, P-O-CH2-CH3), 1.20 (m, 2H,
CH2cycloprop). 13C NMR (75 MHz, CDCl3) δ: 140.6, 140.58,
128.5, 126.3, 125.9, 62.8, 62.7, 61.6, 61.56, 61.51, 61.4,
29.5, 29.4, 22.4, 22.3, 22.0, 19.5, 16.5, 16.46, 16.4, 16.38,
14.0, 13.9. 31P NMR (160 MHz, CDCl3) δ: 29.3. HR-MS
calcd. for C14H21O3P (M + H): 268.1228; found: 268.1230.
P-O-CH2CH3, CH2cycloprop), 1.33 (m, 1H, CHcyclopropyl-P). 13
C
NMR (75 MHz, CDCl3) δ: 146.3, 146.28, 128.7, 127.5,
126.7, 61.8, 61.76, 61.7, 27.6, 27.59, 22.1, 22.0, 19.8, 18.9,
18.87, 17.9, 16.8, 16.7, 16.69. 31P NMR (160 MHz, CDCl3)
δ: 30.5. Anal. calcd. for C14H21O3P: C 62.67, H 7.89; found:
C 62.73, H 7.77. cis-23: Rf 0.25 (EtOAc). 1H NMR
(300 MHz, CDCl3) δ: 7.17–7.44 (m, 5H, C6H5), 3.88 (m,
2H, P-O-CH2CH3), 3.70 (m, 1H, P-O-CH2CH3), 3.33 (m,
1H, P-O-CH2CH3), 1.64 (d, J = 2.4 Hz, 1H, CHcycloprop-P),
1.60 (s, 3H, CH3), 1.17 (m, 5H, P-O-CH2CH3, CH2cycloprop),
0.96 (t, J = 7.1 Hz, 3H, P-O-CH2CH3). 13C NMR (75 MHz,
CDCl3) δ: 141.96, 141.9, 129.5, 128.2, 126.9, 61.5, 61.4,
61.35, 61.35, 61.3, 29.64, 29.6, 28.24, 28.2, 21.1, 19.1, 17.4,
17.3, 16.5, 16.46, 16.4, 16.3. 31P NMR (160 MHz, CDCl3)
δ: 27.9. HR-MS calcd. for C14H2O3P (M + H): 268.1228;
found: 228.1228.
Dineopentyl diazomethylphosphonate (14)
To a solution of dineopentyl methylphosphonate (23)
(3.00 g, 12.7 mmol, 1 equiv.) in THF (125 mL) at –78 °C
was added dropwise 2.5 mol/L of n-BuLi in hexanes
(2.50 mL, 1.5 equiv.). The mixture was stirred at –78 °C for
30 min and 2,2,2-trifluoroethyltrifluoroacetate (1.90 mL,
13.9 mmol, 1.1 equiv.) was added in one portion. The reac-
tion was stirred at –78 °C for 25 min and then warmed to
room temperaure. A 10% aqueous solution of HCl (5 mL)
was added and the aqueous layer was extracted with two
portions of EtOAc. The combined organic layers were
washed with satd. aq. NaHCO3, satd. aq. NaCl, dried over
Na2SO4, and concentrated under reduced pressure. The
residue was dissolved in acetonitrile (125 mL) and p-
acetamidobenzenesulfonyl azide (3.05 g, 12.7 mmol,
1 equiv.) was added followed by triethylamine (1.80 mL,
12.7 mmol, 1 equiv.). The reaction mixture was stirred for
12 h at room temperature and satd. aq. NH4Cl was added.
The layers were separated and the aqueous layer was washed
with EtOAc. The combined organic layers were washed with
satd. aq. NaHCO3, satd. aq. NaCl, dried over Na2SO4, and
concentrated under reduced pressure. The residue was dis-
solved in CHCl3 (30 mL) and the mixture was filtered
through Celite®. The filtrate was concentrated under reduced
pressure and the residue was purified by flash chromatogra-
phy on silica gel (30% EtOAc–hexanes) to give the desired
diazo reagent 14 as a yellow oil (1.10 g, 33%). Rf 0.50 (30%
EtOAc–hexanes). IR (film, cm–1): 2958, 2873, 2101, 1659,
1479, 1245, 999, 874, 850, 584. 1H NMR (300 MHz,
CDCl3) δ: 3.77 (d, J = 11.1 Hz, 1H, CH=N2), 3.75 (m, 4H,
P-O-CH2), 0.96 (s, 18H, C(CH3)3). 13C NMR (75 MHz,
CDCl3) δ: 75.75, 75.66, 32.2, 32.1, 32.06, 32.02, 26.0. 31P
NMR (160 MHz, CDCl3) δ: 20.2. HR-MS calcd. for
C11H23N2O3P (M + H): 263.1511; found: 263.1513.
Diethyl (1R)-2,2-diphenylcyclopropylphosphonate (24)
The general procedure described for the preparation of
cyclopropane 23 was used on a 0.411 mmol scale. The puri-
fication was accomplished by flash chromatography on silica
gel (80% EtOAc–hexanes) to give the desired cyclopropane
24 as a colorless oil (185 mg, 50%). The enantiomeric ex-
cesses (78%) was determined by SFC on a chiral stationary
phase (Chiralcel OD, 1.5% MeOH, 1.0 mL/min: tr (major)
23.9 min, tr (minor) 18.4 min). Rf 0.34 (80% EtOAc–
hexanes). IR (film, cm–1): 2980, 1599, 1495, 1446, 1248,
1
1227, 1020, 953, 772, 695. H NMR (300 MHz, CDCl3) δ:
7.51–7.16 (m, 10H, C6H5), 3.95 (m, 2H, P-O-CH2-CH3),
3.76 (m, 1H, P-O-CH2-CH3), 3.50 (m, 1H, P-O-CH2-CH3),
2.03 (m, 1H, CH2cycloprop), 1.83 (m, 1H, CH2cycloprop), 1.57
(m, 1H, CHcycloprop-P), 1.22 (t, J = 7.1 Hz, 3H, P-O-CH2-
CH3), 1.05 (t, J = 7.1 Hz, 3H, P-O-CH2-CH3). 13C NMR
(75 MHz, CDCl3) δ: 145.4, 145.3, 140.3, 140.26, 130.1,
128.4, 128.0, 127.91, 127.90, 126.9, 126.6, 63.6, 61.5, 61.4,
61.35, 36.7, 36.63, 21.3, 18.7, 17.9, 17.8, 16.3, 16.24, 16.2,
16.1. 31P NMR (160 MHz, CDCl3) δ: 27.1. HR-MS calcd.
for C19H23O3P (M + H): 331.1463; found: 331.1457.
General procedure for the Cu·bis(oxazoline) 21
catalyzed cyclopropanation — Diethyl (1R,2S)-2-methyl-
2-phenylcyclopropylphosphonate (23)
Diethyl (1R,2S)-2-methyl-3-phenylcyclopropylphos-
phonate (25)
A solution of bis(oxazoline) 21 (3.70 mg, 0.0126 mmol,
0.031 equiv.) and copper(I) triflate (3.20 mg, 0.0124 mmol,
0.03 equiv.) in CH2Cl2 (2 mL) was stirred at room tempera-
ture for 3 h and α-methylstyrene (0.260 mL, 2.00 mmol,
5 equiv.) was added. A solution of diethyl α-diazomethyl-
phosphonate (4) (73.2 mg, 0.411 mmol, 1 equiv.) in CH2Cl2
(2 mL) was added over 8 h via a syringe pump. The reaction
The general procedure described for the preparation of
cyclopropane 23 was used on a 0.411 mmol scale. The
diastereomeric ratio (85:15) was determined by 31P NMR of
the crude reaction mixture (δ major: 29.3 and δ minor: 28.2).
The crude mixture was then purified by flash chromatogra-
phy on silica gel (60% EtOAc–hexanes) to give trans-25
(128 mg, 43%) and cis-25 (22 mg, 7%) as colorless oils. The
© 2005 NRC Canada

540
Can. J. Chem. Vol. 83, 2005
enantiomeric excesses (85%) were determined by SFC on a
chiral stationary phase (Chiralcel OD, 0.8% MeOH,
1.5 mL/min: tr (major) 24.3 min, tr (minor) 26.9 min). trans-
25: Rf 0.42 (EtOAc). IR (film, cm–1): 2981, 2905, 1240,
2.0% MeOH, 1.6 mL/min: tr (major) 6.7 min, tr (minor)
5.9 min). Rf 0.43 (50% EtOAc–hexanes). IR (film, cm–1):
2957, 2871, 1246, 1062, 1008, 921, 870. 1H NMR
(300 MHz, CDCl3) δ: 7.20 (m, 5H, C6H5), 3.70 (m, 4H,
CH2C(CH3)3), 2.50 (m, 1H, C6H5-CHcycloprop), 1.55 (m, 1H,
CH2cycloprop), 1.25 (m, 1H, CHcycloprop-P), 1.15 (m, 1H,
CH2cycloprop), 0.95 (d, J = 14.8 Hz, 18H, CH2C(CH3)3). 13C
NMR (75 MHz, CDCl3) δ: 140.1, 128.5, 126.5, 126.2, 75.3,
75.2, 75.1, 32.2, 32.1, 26.1, 26.0, 20.9, 15.8, 13.3, 12.4. 31P
NMR (160 MHz, CDCl3) δ: 29.5. Anal. calcd. for
C19H31O3P: C 67.43, H 9.23; found: C 67.79, H 9.93.
1
1055, 1029, 963. H NMR (300 MHz, CDCl3) δ: 7.07–7.30
(m, 5H, C6H5), 4.10 (m, 4H, P-O-CH2-CH3), 2.35 (m, 1H,
C6H5-CHcycloprop), 1.85 (d, 3H, CH3 (cis)) 1.57 (m, 1H,
CHcycloprop-P), 1.46 (d, J = 6.4 Hz, 3H, CH3 (trans)), 1.36
(m, 6H, P-O-CH2-CH3), 1.20 (m, 2H, CH2cycloprop). 13C
NMR (75 MHz, CDCl3) δ: 140.6, 140.58, 128.5, 126.3,
125.9, 62.8, 62.7, 61.6, 61.56, 61.51, 61.4, 29.5, 29.4, 22.4,
22.3, 22.0, 19.5, 16.5, 16.46, 16.4, 16.38. 14.0, 13.9. 31P
NMR (160 MHz, CDCl3) δ: 29.3. HR-MS calcd. for
C14H21O3P (M + H): 268.1228; found: 268.1230.
Diisopropyl (1R,2S)-2-(4-methoxyphenyl)cyclopropyl-
phosphonate (30)
The general procedure reported for compound 17 was fol-
lowed using: trans-RuCl2((S,S)-i-Pr-pybox)(ethylene) (29)
(5.8 mg, 0.0116 mmol, 0.03 equiv.), 4-methoxystyrene
(0.258 mL, 1.94 mmol, 5 equiv.), diisopropyl diazomethyl-
phosphonate (13) (80.0 mg, 0.388 mmol, 1 equiv.). The
diastereomeric ratio (>98:2) was determined by 31P NMR of
the crude reaction product (δ major: 28.0, δ minor: 27.9).
The crude residue was then purified by flash chromatogra-
phy on silica gel (80% EtOAc–hexanes) to afford the desired
cyclopropylphosphonate 30 as a colorless oil (97 mg, 80%).
The enantiomeric excess (94%) was determined by SFC on
chiral stationary phase (Chiralcel OD, 1.0% MeOH,
1.3 mL/min: tr (major) 23.7 min, tr (minor) 26.1 min). Rf
0.40 (EtOAc). [α]D20 –10.2 (c 1.65, CH2Cl2). IR (film, cm–1):
2978, 2935, 1754, 1715, 1516, 1243, 979, 924, 826. 1H
NMR (300 MHz, CDCl3) δ: 6.90 (m, 4H, C6H5), 4.70 (m,
2H, P-O-CH(CH3)2), 3.77 (s, 3H, C6H5OCH3), 2.43 (m, 1H,
C6H5-CHcycloprop), 1.44 (m, 1H, CH2cycloprop), 1.33 (m, 12H,
P-O-CH(CH3)2), 1.20 (m, 1H, CH2cycloprop), 1.14 (m, 2H,
CHcycloprop-P). 13C NMR (75 MHz, CDCl3) δ: 158.1, 132.2,
127.2, 113.9, 70.4, 70.3, 70.2, 70.1, 55.2, 24.1, 24.09, 24.0,
20.7, 20.6, 17.0, 14.5, 12.7, 12.6. 31P NMR (160 MHz,
CDCl3) δ: 28.0. Anal. calcd. for C16H25O4P: C 61.53, H
8.07; found: C 61.01, H 8.45.
General procedure for the Ru-pybox 29 catalyzed
cyclopropanation — Diisopropyl (1R,2S)-2-
phenylcyclopropylphosphonate (17)
To a solution of trans-RuCl2((S,S)-i-Pr-pybox)(ethylene)
(29) (5.1 mg, 0.0102 mmol, 0.03 equiv.) and styrene
(0.194 mL, 1.70 mmol, 5 equiv.) in CH2Cl2 (2 mL) was
added a solution of diisopropyl α-diazomethylphosphonate
(13) (24) (70.0 mg, 0.340 mmol, 1 equiv.) in CH2Cl2 over
5 h via a syringe pump. After stirring for an additional 10 h
at room temperature, the reaction mixture was concentrated
under reduced pressure. The diastereomeric ratio (>98:2)
was determined by 31P NMR of the crude reaction product
(δ major: 27.6, δ minor: 26.9). The crude residue was then
purified by flash chromatography on silica gel (80% EtOAc–
hexanes) to afford the desired cyclopropylphosphonate 17 as
a colorless oil (67 mg, 70%). The enantiomeric excess
(96%) was determined by SFC on chiral stationary phase
(Chiralcel OD, 1.5% MeOH, 1.5 mL/min: tr (major) 9.9 min,
tr (minor) 8.1 min). Rf 0.38 (EtOAc). [α]2D0 –80.0 (c 0.35,
CH2Cl2). IR (film, cm–1): 2978, 2933, 1732, 1385, 1243,
1
982, 918. H NMR (300 MHz, CDCl3) δ: 7.10–7.30 (m, 5H,
C6H5), 4.71 (m, 2H, P-O-CH(CH3)2), 2.43 (m, 2H, C6H5-
CHcycloprop), 1.46 (m, 1H, CH2cycloprop), 1.33 (m, 12H, P-O-
CH(CH3)2), 1.20 (m, 1H, CH2cycloprop), 1.17 (m, 1H,
CHcycloprop-P). 13C NMR (75 MHz, CDCl3) δ: 140.34,
140.31, 128.5, 126.4, 126.1, 70.4, 70.4, 70.38, 70.33, 24.1,
24.08, 24.04, 21.3, 21.2, 17.2, 15.2, 13.0, 12.9. 31P NMR
(160 MHz, CDCl3) δ: 27.6. Anal. calcd. for C15H23O3P: C
63.82, H 8.21; found: C 63.73, H 8.55.
Diisopropyl (1R,2S)-2-(4-chlorophenyl)cyclopropylphos-
phonate (31)
The general procedure reported for compound 17 was
followed using: trans-RuCl2((S,S)-i-Pr-pybox)(ethylene) (29)
(5.8 mg, 0.0116 mmol, 0.03 equiv.), 4-chlorostyrene
(0.233 mL, 1.94 mmol, 5 equiv.), diisopropyl diazomethyl-
phosphonate (13) (80.0 mg, 0.388 mmol, 1 equiv.). The
diastereomeric ratio (>98:2) was determined by 31P NMR of
the crude reaction product (δ major: 27.1, δ minor: 26.5).
The crude residue was then purified by flash chromatogra-
phy on silica gel (50% EtOAc–hexanes) to afford the desired
cyclopropylphosphonate 31 as a white solid (97 mg, 80%).
The enantiomeric excess (98%) was determined by SFC on
chiral stationary phase (Chiralcel OD, 1.0% MeOH,
1.0 mL/min: tr (major) 21.7 min, tr (minor) 24.4 min); mp
58 °C. Rf 0.30 (EtOAc). [α]2D0 –88.3 (c 0.40, CH2Cl2). IR
(film, cm–1): 2979, 2935, 1496, 1374, 1238, 1105, 980, 923,
Dineopentyl (1R,2R)-2-phenylcyclopropylphosphonate (18)
To a solution of trans-RuCl2((S,S)-i-Pr-pybox)(ethylene)
(29) (4.6 mg, 0.0915 mmol, 0.03 equiv.) and styrene
(0.175 mL, 1.53 mmol, 5 equiv.) in CH2Cl2 (2 mL) under
reflux was added a solution of dineopentyl α-diazomethyl-
phosphonate (14) (80.0 mg, 0.305 mmol, 1 equiv.) in
CH2Cl2 over 5 h via a syringe pump. After stirring for an ad-
ditional 13 h under reflux, the reaction mixture was cooled
to room temperaure and was concentrated under reduced
pressure. The diastereomeric ratio (>98:2) was determined
by 31P NMR of the crude reaction product (δ major: 29.5, δ
minor: 28.9). The crude residue was then purified by flash
chromatography on silica gel (50% EtOAc–hexanes) to af-
ford the desired cyclopropylphosphonate 18 as a colorless
oil (81 mg, 79%). The enantiomeric excess (96%) was deter-
mined by SFC on chiral stationary phase (Chiralcel OD,
1
729. H NMR (300 MHz, CDCl3) δ: 7.10 (m, 4H, C6H5),
4.69 (m, 2H, P-O-CH(CH3)2), 2.43 (m, 2H, C6H5-CHcycloprop),
1.46 (m, 1H, CH2cycloprop), 1.33 (m, 12H, P-O-CH(CH3)2),
1.20 (m, 1H, CH2cycloprop), 1.15 (m, 1H, CHcycloprop-P). 13C
NMR (75 MHz, CDCl3) δ: 138.9, 138.85, 132.0, 128.6,
© 2005 NRC Canada

Charette and Bouchard
541
127.4, 70.6, 70.4, 70.3, 24.1, 24.07, 24.02, 20.8, 20.7, 17.7,
15.1, 13.1, 13.0. 31P NMR (160 MHz, CDCl3) δ: 27.6. Anal.
calcd. for C15H22ClO3P: C 56.88, H 7.00; found: C 56.57, H
7.34.
2H, P-O-CH(CH3)2), 2.00 (m, 1H, CH2cycloprop), 1.75 (m, 1H,
CH2cycloprop), 1.60 (m, 1H, CHcycloprop-P), 1.35 (m, 1H, P-O-
CH(CH3)2), 1.20 (m, 8H, P-O-CH(CH3)2), 1.00 (d, 3H, P-O-
CH(CH3)2). 13C NMR (75 MHz, CDCl3) δ: 145.7, 145.6,
140.4, 140.3, 136.5, 130.3, 127.9, 126.8, 126.5, 70.1, 69.9,
69.8, 36.9, 36.8, 24.1, 24.02, 24.00, 23.9, 23.9, 23.8, 23.6,
23.5, 22.3, 19.7, 17.9, 17.8. 31P NMR (160 MHz, CDCl3) δ:
25.2. HR-MS calcd. for C21H23O3P (M + H): 358.1698;
found: 358.1684.
Diisopropyl (1R,2S)-2-methyl-2-phenylcyclopropyl-
phosphonate (32)
The general procedure reported for compound 17 was fol-
lowed using: trans-RuCl2((S,S)-i-Pr-pybox)(ethylene) (29)
(5.1 mg, 0.0102 mmol, 0.03 equiv.), α-methylstyrene
(0.221 mL, 1.70 mmol, 5 equiv.), diisopropyl diazomethyl-
phosphonate (13) (70.0 mg, 0.340 mmol, 1 equiv.). The
diastereomeric ratio (88:12) was determined by 31P NMR of
the crude reaction product (δ major: 27.6, δ minor: 26.0).
The crude residue was then purified by flash chromatogra-
phy on silica gel (80% EtOAc–hexanes) to afford the desired
cyclopropylphosphonate trans-32 (63 mg, 63%) and cis-32
(9 mg, 9%) as colorless oils. The enantiomeric excesses
(95% and 92%) were determined by HPLC on a chiral sta-
tionary phase. trans-32: Chiralcel AD, 98.8% hexane–
isopropanol, 0.3 mL/min (tr (major) 30.0 min, tr (minor)
32.1 min). cis-32: Chiralcel AD, 98.8% hexane–isopropanol,
0.5 mL/min (tr (major) 34.1 min, tr (minor) 30.1 min). trans-
32: Rf 0.45 (50% EtOAc–hexanes). [α]2D2 –59.2 (c 0.30,
CH2Cl2). IR (film, cm–1): 2977, 2931, 1385, 1374, 1244,
Diisopropyl (1R,2S)-2-[(E)-2-phenylvinyl]cyclopropyl-
phosphonate (34)
The general procedure reported for compound 18 was fol-
lowed using: trans-RuCl2((S,S)-i-Pr-pybox)(ethylene) (29)
(5.8 mg, 0.0116 mmol, 0.03 equiv.), (E)-1-phenyl-1,3-
butadiene (0.253 g, 1.94 mmol, 5 equiv.), diisopropyl diazo-
methylphosphonate (13) (80.0 mg, 0.388 mmol, 1 equiv.).
The diastereomeric ratio (95:5) was determined by 31P NMR
of the crude reaction product (δ major: 27.8, δ minor: 28.3).
The crude residue was then purified by flash chromatogra-
phy on silica gel (50% EtOAc–hexanes) to afford the desired
cyclopropylphosphonate trans-34 (103 mg, 86%) and cis-34
(5 mg, 4%) as colorless oils. The enantiomeric excesses
(90% and 92%) were determined by HPLC on a chiral sta-
tionary phase for trans-34: Chiralcel OD, 98% hexanes–
isopropanol, 0.9 mL/min: tr (major) 9.8 min, tr (minor)
14.7 min) and by SFC on a chiral stationary phase for cis-
34: Chiralcel OD, 2.0% MeOH, 1.6 mL/min: tr (major)
10.7 min, tr (minor) 9.9 min). trans-34: Rf 0.17 (50%
EtOAc–hexanes). [α]D20 –14.3 (c 1.60, CH2Cl2). IR (film, cm–1):
1
1006, 981, 891. H NMR (300 MHz, CDCl3) δ: 7.19–7.30
(m, 5H, C6H5), 4.75 (m, 1H, P-O-CH(CH3)2), 1.67 (s, 3H,
CH3), 1.37 (m, 14H, P-O-CH(CH3)2, CH2cycloprop), 1.16 (m,
1H, CHcyclopropyl-P). 13C NMR (75 MHz, CDCl3) δ: 146.4,
146.35, 128.4, 127.28, 127.27, 126.4, 69.94, 69.86, 27.5,
27.46, 27.4, 24.3, 24.2, 24.1, 24.09, 24.08, 24.0, 21.7, 21.6,
20.9, 18.9, 18.5, 18.49. 31P NMR (160 MHz, CDCl3) δ:
27.6. Anal. calcd. for C16H25O3P: C 64.85, H 8.50; found: C
64.85, H 8.50. cis-32: Rf 0.39 (EtOAc). IR (film, cm–1):
2978, 2933, 1732, 1385, 1243, 982, 918. 1H NMR
(300 MHz, CDCl3) δ: 7.18–7.48 (m, 5H, C6H5), 4.47 (m, 1H, P-
O-CH(CH3)2), 4.30 (m, 2H, P-O-CH(CH3)2), 1.63 (m, 1H,
CH2cycloprop), 1.30 (d, J = 2.4 Hz, 3H, CH3), 1.17 (m, 9H, P-
O-CH(CH3)), 0.90 (d, J = 6.2 Hz, 3H, P-O-CH(CH3)). 13C
NMR (75 MHz, CDCl3) δ: 140.34, 140.31, 128.5, 126.4,
126.1, 70.4, 70.4, 70.38, 70.33, 24.1, 24.08, 24.0, 21.3, 21.2,
17.2, 15.2, 13.0, 12.9. 31P NMR (160 MHz, CDCl3) δ: 26.0.
HR-MS calcd. for C16H25O3P (M + H): 297.1620; found:
297.1613.
1
2978, 2934, 1385, 1374, 1238, 1106, 978, 886, 746, 694. H
NMR (300 MHz, CDCl3) δ: 7.16–7.35 (m, 5H, C6H5), 6.55
(d, J = 15.7 Hz, 1H, C6H5-CH=CH), 5.73 (dd, J = 15.7,
8.7 Hz, 1H, C6H5-CH=CH), 4.70 (m, 2H, P-O-CH(CH3)2),
2.15 (m, 1H, C=CH-CHcyclopropyl), 1.34 (m, 13H, P-O-
CH(CH3)2, CH2cyclopropyl), 1.00 (m, 2H, CH2cycloprop
,
CHcycloprop). 13C NMR (75 MHz, CDCl3) δ: 137.0, 130.6,
130.57, 130.0, 128.5, 127.2, 125.8, 70.5, 70.4, 70.3, 70.2,
24.1, 24.05, 20.6, 12.9, 11.8, 11.7. 31P NMR (160 MHz,
CDCl3) δ: 27.8. Anal. calcd. for C17H25O3P: C 66.22, H
8.17; found: C 66.78, H 8.62. cis-34: Rf 0.28 (50% EtOAc–
1
hexanes). H NMR (300 MHz, CDCl3) δ: 7.15–7.37 (m, 5H,
C6H5), 6.55 (d, J = 15.9 Hz, 1H, C6H5-CH=CH), 6.45 (dd,
J = 15.9, 9.6 Hz, 1H, C6H5-CH=CH), 4.70 (m, 2H, P-O-
CH(CH3)2), 2.05 (m, C=CH-CHcyclopropyl), 1.30 (m, 15H, P-
O-CH(CH3)2, CH2cycloprop). 13C NMR (75 MHz, CDCl3) δ:
137.4, 130.5, 129.5, 129.47, 128.5, 126.8, 125.9, 70.1,
70.09, 70.05, 70.0, 24.1, 24.05, 23.9, 23.88, 21.3, 21.28,
14.9, 12.3, 12.0, 11.9. 31P NMR (160 MHz, CDCl3) δ: 28.3.
HR-MS calcd. for C17H25O3P: 308.1541; found: 308.1549.
Diisopropyl (1R)-2,2-diphenylcyclopropylphosphonate
(33)
The general procedure reported for compound 18 was fol-
lowed using: trans-RuCl2((S,S)-i-Pr-pybox)(ethylene) (29)
(5.1 mg, 0.0102 mmol, 0.03 equiv.), 1,1-diphenylethylene
(0.300 mL, 1.70 mmol, 5 equiv.), diisopropyl diazomethyl-
phosphonate (13) (70.0 mg, 0.340 mmol, 1 equiv.). The
crude residue was then purified by flash chromatography on
silica gel (50% EtOAc–hexanes) to afford the desired cyclo-
propylphosphonate 33 as a colorless oil (47 mg, 39%). The
enantiomeric excess (91%) was determined by SFC on a
chiral stationary phase (Chiralcel OD, 2.0% MeOH,
1.5 mL/min: tr (major) 11.1 min, tr (minor) 12.3 min). Rf
0.46 (80% EtOAc–hexanes). [α]2D2 –30.3 (c 0.37, CH2Cl2).
IR (film, cm–1): 2977, 1600, 1249, 980, 704. 1H NMR
(300 MHz, CDCl3) δ: 7.15–7.52 (m, 10H, C6H5), 4.50 (m,
Diisopropyl (1R,2S)-2-(2-
naphtyl)cyclopropylphosphonate (35)
The general procedure reported for compound 18 was fol-
lowed using: trans-RuCl2((S,S)-i-Pr-pybox)(ethylene) (29)
(5.8 mg, 0.0116 mmol, 0.03 equiv.), 2-vinylnaphthalene
(0.299 g, 1.94 mmol, 5 equiv.), diisopropyl diazomethyl-
phosphonate (13) (70.0 mg, 0.340 mmol, 1 equiv.). The
diastereomeric ratio (>98:2) was determined by 31P NMR of
the crude reaction product (δ major: 27.6, δ minor: 27.1).
The crude residue was then purified by flash chromatogra-
© 2005 NRC Canada

542
Can. J. Chem. Vol. 83, 2005
phy on silica gel (50% EtOAc–hexanes) to afford the desired
cyclopropylphosphonate 35 (116 mg, 91%) as a white solid.
The enantiomeric excesses (97%) were determined by SFC
on a chiral stationary phase: Chiralcel OD, 1.2% MeOH,
1.5 mL/min: tr (major) 41.7 min, tr (minor) 45.6 min); mp
65 °C. Rf 0.18 (50% EtOAc–hexanes). [α]2D0 –82.1 (c 1.00,
CH2Cl2). IR (film, cm–1): 2977, 2933, 1633, 1601, 1509,
1384, 1374, 1234, 1104, 976, 745, 729. 1H NMR (300 MHz,
CDCl3) δ: 7.80–7.20 (m, 7H, CH (Napth)), 4.75 (m, 1H, P-
O-CH(CH3)2), 2.65 (m, 1H, Napth-CHcycloprop), 1.65 (m, 1H,
CH2), 1.35 (m, 14H, P-O-CH(CH3)2, CH2cycloprop, CHcycloprop).
13C NMR (75 MHz, CDCl3) δ: 137.7, 137.6, 133.3, 132.2,
128.2, 127.6, 127.3, 127.0, 126.2, 125.4, 124.9, 124.6,
124.3, 70.5, 70.5, 70.45, 70.41, 70.32, 69.7, 25.3, 24.4, 24.1,
24.0, 23.9, 23.7, 23.2, 22.8, 21.5, 17.4, 14.9, 13.0, 12.9. 31P
NMR (160 MHz, CDCl3) δ: 27.6. HR-MS calcd. for
C19H25O3P: 332.1541; found: 332.1534.
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This work was supported by the Natural Sciences and En-
gineering Research Council of Canada (NSERC) and the
Université de Montréal.
© 2005 NRC Canada