Enantioselective organocatalytic synthesis of α- cyclopropylphosphonates through a domino michael addition/intramolecular alkylation reaction

Article abstract of DOI:10.1002/ejoc.201301207

An organocatalytic domino reaction consisting of Michael addition/intramolecular alkylation between α,β-unsaturated aldehydes and bromophosphonoacetates was developed. Highly functionalised cyclopropylphosphonates containing three chiral centres, one of them quaternary, were obtained with good diastereoselectivities of up to 83:17 and very high enantioselectivities of up to 99 %. α-Cyclopropylphosphonates with three stereogenic centres were obtained in good yields and high enantio-and diastereocontrol through a "one-pot" domino process catalysed by a chiral pyrrolidine. The highly functionalised cyclopropanes should be versatile starting materials for biologically important compounds. Copyright

Full text of DOI:10.1002/ejoc.201301207

FULL PAPER
DOI: 10.1002/ejoc.201301207
Enantioselective Organocatalytic Synthesis of α-Cyclopropylphosphonates
through a Domino Michael Addition/Intramolecular Alkylation Reaction
Ana Maria Faísca Phillips*[a] and Maria Teresa Barros*[a]
Keywords: Organocatalysis / Domino reactions / Michael addition / Aldehydes / Cyclopropanes
An organocatalytic domino reaction consisting of Michael
addition/intramolecular alkylation between α,β-unsaturated
aldehydes and bromophosphonoacetates was developed.
Highly functionalised cyclopropylphosphonates containing
three chiral centres, one of them quaternary, were obtained
with good diastereoselectivities of up to 83:17 and very high
enantioselectivities of up to 99%.
large amounts of chiral substance in shorter synthetic
routes, but examples are scarce.[9] The catalytic enantiose-
lective synthesis of chiral cyclopropylphosphonates was re-
ported for the first time in 2003 by Simonneaux and co-
workers,[10] but since then there have been very few exam-
ples.[11] The methods reported were based on the use of
transition-metal-induced carbene transfer in the presence of
chiral ligands from N-diazomethylphosphonates to styrenes
and from aryldiazomethylphosphonates to styrenes, and the
products were obtained with very high enantiomeric excess
in many cases.[10,11] Since electron-donating substituents are
required to stabilise the resulting metal-carbenoids, Fischer
type carbenes with electrophilic character are required, and
the olefinic reaction partner also needs electron-donating
substituents;[9b] the α-CPPs thus produced had the phos-
phoryl group and benzene or other aromatic substituents
as the only substituents, and were therefore poor chiral in-
termediates. In 2013, the first example of the use of a diac-
Introduction
The cyclopropane ring is found in more than 4000 natu-
ral compounds with a diverse range of biological activity,[1]
as for example in chrysanthemic acid, which is present in
the flowers of Chrysanthemum cinerariaefolium, where it
performs a defensive role in the plant. It is also present in
about 100 pharmaceutical products,[2] in many agrochem-
icals,[3] and it is a useful synthetic intermediate.[4] This
structure is used in medicinal chemistry to increase confor-
mational rigidity, which may increase the activity of a drug
or reduce its side effects,[5] and for lead optimisation, to
explore lipophilic binding pockets, hydrophobic interac-
tions and bioactive conformations.[6]
We have been interested in the chemistry of phosphon-
ates for some time and have developed some novel methods
to synthesise chiral phosphonates based on enantioselective
catalysis by metals complexed to chiral ligands or by chiral
organocatalysts.[7] We have now extended our studies and
developed enantioselective methodologies for the synthesis
of chiral α-cyclopropylphosphonates (α-CPPs). These com-
pounds (e.g., A–F, Figure 1) have diverse biological activi-
ties.[8] In phosphonates, the configuration of the chiral cen-
tre is often crucial for biological activity, because they have
to interact with chiral biomolecules. Optically pure α-CPPs
have been synthesised until now mainly by racemic methods
followed by resolution, with chiral auxiliaries, or from chi-
ral reagents.[9] Catalytic enantioselective methods are more
efficient, since a small amount of a chiral catalyst produces
[a] Department of Chemistry, REQUIMTE, CQFB, Faculty of
Sciences and Technology, Universidade Nova de Lisboa,
Campus de Caparica, Quinta da Torre, 2829-516 Caparica,
Portugal
E-mail: amfp@fct.unl.pt
mtb@fct.unl.pt
http://www.docentes.fct.unl.pt/ana-faisca
http://www.dq.fct.unl.pt/pessoas/docentes/
maria-teresa-barros-silva
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201301207.
Figure 1. Potent biologically active α-cyclopropylphosphonates.
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Eur. J. Org. Chem. 2014, 152–163
152

Enantioselective Synthesis of α-Cyclopropylphosphonates
ceptor diazo compound (an α-cyano diazophosphonate rea- as the Michael donor,[17h] and Kanger and co-workers used
gent) was developed by Charette and co-workers,[12] thus it to synthesise spirocyclopropylindoles from 2-chloroox-
broadening the synthetic utility of the catalytic enantiose- indoles and enals.[17i] We chose to use α-bromophos-
lective cyclopropylphosphonylation.
phonoacetates as Michael donors, with the aim of ob-
Organocatalysis could provide an attractive alternative. taining highly substituted cyclopropylphosphonates with
Organocatalysts are environmentally friendly, stable, func- three chiral centres, one of which was quaternary. Since a
tion under mild conditions, and they can usually be handled “one-pot” domino process is involved, eight stereoisomers
in air. More importantly, they have much greater functional may be produced from achiral starting materials, which is
group tolerance, which could imply that additional func- clearly a delicate stereochemical problem to control. One-
tional groups could be initially incorporated in the cyclo- pot processes have, however, the advantage that several
propane ring for further synthetic elaboration into biolo- steps may be carried out in a single synthetic operation,
gically active targets. Enantioselective organocatalytic cy- thus avoiding multiple extraction and purification pro-
clopropane synthesis has attracted the attention of the cedures and minimising time and costs.
chemical community in the last few years. A first example
was developed by Vignola and List,[13] through intramolec-
ular α-alkylation mediated by proline and proline deriva-
tives and, since then, a few methods have been developed.
Results and Discussion
Although a large variety of synthetic strategies have been
used, as well as catalysts with different modes of activation,
most of the methods developed involve Michael initiated
ring closure (MIRC) methodology, consisting of a domino
process of Michael addition/intramolecular alkylation with
electron-poor olefins.[14] Cyclopropanes with a variety of
substituents and one to three chiral centres, have been syn-
thesised from enones,[15] α,β-unsaturated esters,[15a,1] en-
als,[16,17] nitroalkenes,[18] α,β-unsaturated-α-cyanoimides,[19]
β-substituted methylidenemalononitriles,[20] vinylselenon-
es,[21] allylic alcohols,[22] alkylidene oxindoles,[23] 2-arylid-
ene-1,3-indandiones,[24] and 4-nitro-5-styrylisoxazoles,[25]
often with very high diastereomeric ratios (dr) and enantio-
meric excess (ee). However, during this period there was
only one report of an organocatalysed synthesis of cyclo-
The α-bromophosphonoacetates required as substrates
for the envisaged domino reactions were not commercially
available. An obvious route to obtain these compounds is
through direct bromination of the corresponding phos-
phonoacetates, which could themselves be easily obtained
through an Arbuzov reaction between a trialkylphosphite
and an α-bromo ester (Scheme 1).
Scheme 1. Possible route to the α-bromophosphonoacetates.
However, since α-bromophosphonoacetates are more re-
propylphosphonates, in which proline and some of its deriv- active towards bromination than the parent compound,
atives were used to catalyse the cyclopropanation reaction monobromination is difficult to achieve,[27,28] and this has
between α-methylacrolein and α-diazobenzylphosphona- been demonstrated to be so under a large variety of reaction
tes.[26] However, although the products were obtained in conditions by Olpp and Brückner for ethyl bromo(diphenyl-
moderate to good yields, the diastereoselectivity was only phosphono)acetate.[27] Mixtures of unreacted phosphono-
moderate and racemic mixtures were obtained.
acetate can be obtained together with the mono and the
Having in mind the synthetic versatility of the formyl (frequently predominating) dibrominated products, which
group, we decided to attempt the synthesis of α-CPPs based presents a difficult purification challenge. Not only do the
on a methodology previously developed for reactions of mono- and dibrominated phosphonoacetates have very high
α,β-unsaturated aldehydes.[17a] The first organocatalytic cy- boiling points, they are also very difficult to separate by
clopropanation of enals was reported by Cordova and co- column chromatography, due to their very similar Rf values
workers[17a] in 2007 and, shortly after, by Wang and co- under a large variety of conditions, as also observed during
workers.[17b] Iminium-enamine catalysis mediated by chiral the course of this work. Hence, procedures similar to the
pyrrolidines was used effectively to promote the reaction two-step process developed by McKenna and Khawli for
between bromomalonates and enals (the Bingel–Hirch reac- the synthesis of triethyl bromophosphonoacetate were
tion), and also that of 2-bromo 3-keto esters.[17a,17c] Cyclo- used.[29] In this case, α,α-dibrominated phosphonoacetates
propanes with two chiral centres were obtained with high are produced first with freshly prepared sodium hypobrom-
ee and dr values through the application of this domino ite, and then reduced with monohydrated SnCl2 to the de-
protocol. Later, Cordova and co-workers applied this meth- sired monobrominated derivatives. This approach was also
odology to the nitrocyclopropanation of enals.[17d] This re- used by Tago and Kogen to obtain bis(2,2,2-trifuoroeth-
action has since been studied in more detail by Moyano oxy)bromophosphonoacetate, which was needed as a Wit-
and Rios with 2-bromo keto esters,[17e] and by Vicario and tig–Horner reagent.[28] The phosphonoacetates needed for
co-workers, who showed that water could also be used as this work were obtained through the application of Arbu-
solvent.[17f] Campagne and co-workers applied the reaction zov reactions, and modified McKenna and Khawli pro-
to β-unsubstituted-α,β-unsaturated aldehydes,[17g] Ye and cedures were then used for the synthesis of the α-bromo-
co-workers showed that chloroacetophenone could be used phosphonoacetates. The results are shown in Table 1.
Eur. J. Org. Chem. 2014, 152–163
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A. M. Faísca Phillips, M. T. Barros
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Table 1. Synthesis of 3-bromo(dialkylphosphono)acetates 3.
α-Bromophosphonoacetates 3 were obtained in moderate
to good overall yields (not optimised) for the two-step se-
quence from phosphonoacetates 1. The identity of the
products was established by NMR and IR spectroscopy,
and by elemental analysis. Monosubstitution at the carbon
atom alpha to the phosphorus was confirmed by the chemi-
cal shift values and signal integration in the 1H NMR spec-
trum and by DEPT-135 experiments, which showed positive
signals for α-CHP carbon atoms, thus confirming mono-
substitution. The bromination reactions were not very re-
producible and, in some cases, the crude product obtained
initially was rebrominated. After monoreduction with tin
chloride, the products were purified by column chromatog-
raphy and were then ready to use in the next step.
We then investigated the possibility of using iminium-
enamine catalysis to promote the formation of the desired
cyclopropanes. To this end, a series of chiral amines was
selected and the reaction was attempted with ethyl bromo-
(diethoxyphosphoryl)acetate (3a) (Table 2). As initial condi-
tions, we tested chloroform as solvent and triethylamine as
a stoichiometric base, which were the conditions found to
be the best in the method initially developed by Córdova
and co-workers for reactions of diethyl bromomalonate.[17a]
In addition to the chiral amine, a stoichiometric amount of
base is usually needed in these reactions, presumably to trap
the hydrobromic acid that is formed.
[a] Overall yield over the two reaction steps.
Table 2. Catalyst screening.[a]
Entry
Cat.
t
[h]
Conv.
[%][b]
Yield
[%][c]
dr
ee (5a)
ee (5b)
(5a/5b)[d]
[%][e]
[%][e]
1
2
3
4
5
6
7
8
I
II
III
IV
V
VI
VII
VIII
23
23
22
2.5
22
48
97
96
78
100
98
67
70
74
49
60
72
49
74
72
78:22
76:24
74:26
70:30
75:25
70:30
77:23
75:25
16
(–)-14
26
98
24
(–)-24
41
(–)-22
11
6
24
Ͼ99
22
50
35
10
3.5
3.5
100
92
[a] Reaction conditions: phosphonate 3a (0.10 mmol), cinnamaldehyde (3.6 equiv.), Et3N (1.1 equiv.), catalyst (0.2 equiv.), CHCl3
(0.30 mL), room temp. [b] Conversion: percentage of 3a that reacted. [c] Yield relative to the amount reacted. Calculated from the 31P
NMR spectra, from the ratio of the signals using tetraethyl methylenediphosphonate as internal standard. [d] From the signal ratios in
31P NMR spectra. [e] Calculated from 31P NMR and 1H NMR spectra from the ratio of the signals of the diastereoisomeric imines
formed through reaction with l-Val-OMe.[30]
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Enantioselective Synthesis of α-Cyclopropylphosphonates
Preliminary experiments showed the formation of two di- immensely, with the products being almost racemic with d-
astereoisomeric cyclopropanes, and three or four minor side proline to practically optically pure with pyrrolidine IV.
products. Other reactions, i.e., simple Michael addition, ep-
oxide formation, or rearrangement, may compete with cy-
clopropane formation, if the reaction conditions are not op-
timum, as previously observed.[17b,17c] When the proportion
of cinnamaldehyde was increased, the formation of other
products was suppressed, and a ratio of cinnamaldehyde to
phosphonate of 3.6:1 was found to be optimal. Hence, the
remaining experiments were conducted with this ratio of
aldehyde to phosphonate.
Cyclopropanes were obtained with all the amines tried,
I–VIII (Table 2). The reactions were found to be slow in
all cases, taking more than a day, except with pyrrolidine
derivative IV (entry 4), and with diamines VII and VIII (en-
tries 7 and 8), which gave full conversion to products in 2.5–
3.5 h. Two diastereomeric cyclopropanes were obtained, as
discussed below, in moderate to good yields and with sim-
ilar moderate diastereoselectivities, which varied from 70:30
to 78:22. On the other hand, the enantioselectivity varied
Hoping to further optimise the chemoselectivity, the
yields and the diastereoselectivity, the reaction was then
tried in different solvents (Table 3), with pyrrolidine IV as
catalyst. The highest yields and diastereoselectivity were ob-
tained in methanol and ethanol (Table 3, entries 6 and 7).
In methanol, the product was obtained in 74% yield, and a
diastereoselectivity of 80:20. The ee of the major dia-
stereoisomer was slightly lower, changing from 99% in
CHCl3 to 96%; however, because the diastereoselectivity in-
creased from 70:30, these were selected as the best condi-
tions for the remaining work. In addition, in this solvent,
only one side product was obtained (δP = 18.93 ppm), mak-
ing up ca. 10% of the crude product. This substance was
not identified. The remaining difference in yield could be
due to some water solubility of the cyclopropanes. For ex-
ample, special precautions have to be used when isolating
diethyl formylmethylphosphonate from reaction mixtures,
due to the very high water solubility of this compound.[31]
The effect of the nature of the stoichiometric base used
was investigated next (Table 4), because this was found by
other groups to have a significant influence on the outcome
of the reaction.[17b,17c] However, the best results were still
those obtained with triethylamine. We did not observe the
rearrangement reported by Wang and co-workers when the
reaction was performed in the presence of NaOAc, but ob-
tained a similar product distribution to that observed when
triethylamine was used.
The possibility of using a lower catalyst load was investi-
gated next (Table 4, entries 9–11). As expected, as the pro-
portion of catalyst was lowered, the reaction took longer.
Although the diastereoselectivity for cyclopropane forma-
tion was not affected, the enantioselectivity of the major
diastereoisomer gradually reduced, becoming only 88%
when the reaction was performed with 1 mol-% catalyst.
However a change from 5 to 1 mol-% caused a sharp de-
crease in the yield, as a result of competition by side prod-
uct formation. When a catalyst load of 0.1 mol-% was used,
some cyclopropane formation was still observed, however,
Table 3. Solvent screening.[a]
Entry Solvent
t
[h]
Conv. Yield
[%][b] [%][c] (5a/5b)
dr[d]
ee (5a) ee (5b)
[%][e]
[%][e]
1
2
3
4
5
6
7
8
CHCl3
MeCN
CH2Cl2
THF
toluene
MeOH
EtOH
EtOH
2.5
2.5
2.5
2.5
2.0
2.0
1.5
2.0
100
100
100
100
100
100
100
100
60
53
51
59
53
74
51
75
70:30
66:33
65:35
60:40
54:46
80:20
76:24
74:26
98
Ͼ99
Ͼ99
97
Ͼ99
96
Ͼ99
Ͼ99
Ͼ99
Ͼ99
Ͼ99
Ͼ99
Ͼ99
n.d.[f]
Ͼ99
n.d.[f]
[a] Reaction conditions: phosphonate 3a (0.10 mmol), cinnamal-
dehyde (3.6 equiv.), Et3N (1.1 equiv.), catalyst IV (0.2 equiv.), sol-
vent (0.30 mL), room temp. [b] Conversion: percentage of 3a that
reacted. [c] Yield relative to the amount reacted. Calculated from
the 31P NMR spectra, from the ratio of the signals using tetraethyl
methylenediphosphonate as internal standard. [d] From the signal
ratios in the 31P NMR spectra. [e] Calculated from 31P NMR and
1H NMR spectra from the ratio of the signals of the diastereoiso-
meric imines formed through reaction with l-Val-OMe.[30] [f] n.d.:
not determined.
Table 4. The effect of the reaction conditions and the proportion of the reagents on the outcome of the reaction.[a]
Entry Base
Catalyst [mol-%]
T [°C]
t [h]
Conv. [%][b] Yield [%][c] dr (5a/5b)[d] ee (5a) [%][e]
ee (5b) [%][e]
1
2
3
4
5
6
7
8
Et3N
DABCO
DBU
DIPEA
NaOAc
pyridine
Et3N
Et3N
Et3N
Et3N
Et3N
20
20
20
20
20
20
20
20
10
5.0
1.0
room temp.
room temp.
room temp.
room temp.
room temp.
room temp.
room temp.
0
2.0
2.25
2.0
2.0
2.0
2.0
2.0
4.0
3.0
4.5
17.0
100
98
100
47
85
38
100
95
100
90
74
63
22
52
57
39
74
80
65
61
29
80:20
81:19
82:18
81:19
78:22
80:20
80:20
83:17
82:18
81:19
83:17
96
96
86
99
95
Ͼ99
96
98
94
92
Ͼ99
Ͼ99
Ͼ99
Ͼ99
Ͼ99
Ͼ99
Ͼ99
Ͼ99
Ͼ99
Ͼ99
Ͼ99
9
10
11
room temp.
room temp.
room temp.
99
88
[a] Reaction conditions (unless otherwise indicated): phosphonate 3a (0.10 mmol), cinnamaldehyde (3.6 equiv.), base (1.1 equiv.), catalyst
IV (0.2 equiv.), MeOH (0.30 mL), room temp. [b] Conversion: percentage of 3a that reacted. [c] Yield relative to the amount reacted.
Calculated from the 31P NMR spectra, from the ratio of the signals using tetraethyl methylenediphosphonate as internal standard.
[d] From the signal ratios in the 31P NMR spectra. [e] Calculated from 31P and 1H NMR spectra from the ratio of the signals of the
diastereoisomeric imines formed through reaction with l-Val-OMe.[30]
Eur. J. Org. Chem. 2014, 152–163
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A. M. Faísca Phillips, M. T. Barros
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after 8 days nearly 20% of the phosphonate remained unre- stereoisomers increased to 80%, and the diastereoselectivity
acted. With a catalyst load of 20 mol-%, the reaction was improved slightly, as did the ee, which improved to 98% for
also tried at lower temperature (ice bath; Table 4, entry 8). the major diastereoisomer.
Under these conditions, the combined yield of both dia-
The structural identity of cyclopropanes 5a and 5b was
established by 1D and 2D NMR techniques, and confirmed
by IR spectroscopy. 2D heteronuclear multiple-bond corre-
lation (HMBC) experiments confirmed the connectivity be-
tween the ring carbon atoms. P–C coupling between the
phosphorus atom and the carbon atom bearing the formyl
group (JP,C = 2.5 Hz) and between the phosphorus atom
and the proton at this ring position (JP,H = 12.2 Hz) also
confirmed the connectivity. The elemental composition was
confirmed by elemental analysis. NOESY experiments were
used to establish the relative stereochemistry of the ring
substituents. Hence, for the major diastereoisomer, cross
peaks between Hb and Hd and He indicate that the formyl
group, the phenyl group, and the phosphoryl ester group
Figure 2. NOEs and coupling constants observed for the major dia-
stereoisomer 5a, which support the relative stereochemistry assign-
ment.
Table 5. The scope of the cyclopropanation reaction.[a]
[a] Reaction conditions: phosphonates 3 (0.10 mmol), cinnamaldehyde (3.6 equiv.), base (1.1 equiv.), catalyst IV (0.2 equiv.), MeOH
(0.30 mL). [b] Calculated from the 31P NMR spectra, from the ratio of the signals using tetraethyl methylenediphosphonate as internal
standard. n.d. = Not determined. [c] Yield of product isolated after chromatography. n.d. = Not determined. [d] From the signal ratios
1
in 31P NMR spectra. [e] Calculated from 31P NMR and H NMR spectra from the ratio of the signals of the diastereoisomeric imines
formed through reaction with l-Val-OMe.[30]
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Enantioselective Synthesis of α-Cyclopropylphosphonates
are on the same side of the ring (Figure 2). The fact that perature were slower, as expected, but the yields were
the phenyl group and the phosphoryl ester group are in a higher, varying from moderate to good. The diastereoselec-
cis relationship may also be indicated by the chemical shift tivity did not vary much with a change in the substitution
1
of the phosphoryl methylene ester groups. In the H NMR pattern of the reagents, except when the carboxyl ester
spectrum they appear as multiplets at 3.55–3.69 and 3.76– group was tert-butyl. It seems that the steric bulk of this
3.93 ppm, which is very much upfield from the typical group and that of the phosphonyl group become less dif-
chemical shift range of 4.0–4.2 ppm that is observed for ferent in this case and the preference for the formation of
many straight-chain phosphonates. This fact suggests that one diastereoisomer over the other decreases. The enantio-
they are located in the shielding region of the aromatic ring. selectivities were very high, varying from 89 to Ͼ99%. In
Although the cyclopropane ring has itself a considerable this case, the presence of bulkier ester substituents at either
anisotropic effect, this difference in chemical shift has not the carboxyl group or the phosphonyl group favoured enan-
been reported in other cyclopropylphosphonates that have tioselection. The structural identity of the products was
a phenyl ring and a diethyl phosphonyl group with a trans confirmed by 1D and 2D NMR spectroscopy techniques
relationship.[32] NOE difference experiments also confirmed and by IR spectroscopy and elemental analysis as before.
this relative stereochemistry, as discussed below.
To confirm the stereochemical assignments obtained from
The NOESY spectrum of the minor diastereoisomer also NOESY experiments, NOE difference spectra were ob-
showed cross peaks indicating a trans relationship between tained. For cyclopropane 8a, particularly strong NOE sig-
the formyl and the phenyl groups, and a cross peak between nals were observed between the nine protons of the tert-
the proton geminal to the formyl group and the carboxyl butyl ester group and the formyl group, the ring proton
ester methylene protons. The NOESY spectrum of the geminal to the phenyl group and the phosphoryl ester sub-
minor diastereoisomer also showed cross peaks indicating stituents. In some of the compounds this connectivity could
a trans relationship between the formyl and the phenyl not be observed, although a similar stereochemistry is as-
groups. The relationship between the other two groups sumed, since the reaction mechanism is the same in all
could not be established from this spectrum, however, by
virtue of their diastereomeric relationship, their relative po-
sitions must be the inverse of those in the major dia-
stereoisomer.
Using the optimised conditions, the synthesis of cyclop-
ropylphosphonates with different substitution patterns was
then undertaken to investigate the scope of the reaction.
The structure of the phosphoryl ester groups as well as that
of the carboxyl ester group was varied. The results obtained
are shown in Table 5. Reactions performed at lower tem- Figure 3. Chemical shifts of the major diastereoisomer 8a in ppm.
Figure 4. NOE difference spectra of 8a recorded in CDCl3. The arrows indicate the signals irradiated in each spectrum.
Eur. J. Org. Chem. 2014, 152–163
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A. M. Faísca Phillips, M. T. Barros
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Figure 5. The mechanism proposed for the domino process leading to α-cyclopropylphosphonates.
cases. These experiments, summarised in Figure 3 and Fig-
ure 4, prove that the phenyl and the formyl group have a
trans relationship, and that the tert-butyl carboxyl ester
group is cis to the formyl group.
The mechanism proposed for the reaction is shown in
Figure 5. Reaction of the chiral pyrrolidine with cinnamal-
dehyde gives rise to an iminium ion. Enantioselective
Michael addition of the α-bromophosphono acetate to one
of the enantiotopic faces results in the formation of a chiral
enamine, which, through intramolecular nucleophilic sub-
stitution, expels bromide ion generating the cyclopropane
ring. Upon iminium hydrolysis, the product is released as
well as the catalyst, ready for another reaction cycle.
The mechanism of cyclopropanation reactions of
cinnamaldehyde catalysed by (S)-(–)-α,α-diphenyl-2-pyrrol-
idinemethanol trimethylsilyl ether was studied in detail and
documented by Córdova and co-workers[17a,17c] and by
Wang and co-workers,[17b] as well as the configuration of
the products obtained. From their reports and others pub-
lished more recently,[17] it is known that the Si face of the
chiral iminium intermediate is shielded by the bulky aryl
Figure 6. Determination of the absolute configuration of the prod-
ucts.
Conclusions
We have developed a novel method with which to synthe-
groups of the catalyst. As a result, conjugate addition is sise highly substituted chiral α-cyclopropylphosphonates
stereoselective and takes place on the Re face, thus estab- with three chiral centres including a quaternary centre. The
lishing the configuration of the first chiral centre. A similar method involves a “one-pot” domino Michael addition re-
process would take place with the bromo(phosphono)acet- action/intramolecular alkylation between α,β-unsaturated
ates. The enamine intermediate undergoes an intramolecu- aldehydes and bromophosphonoacetates that proceeds with
lar 3-exo-tet nucleophilic attack to form the cyclopropane a high degree of stereocontrol. Only two diastereoisomers
ring, according to Baldwin’s rules for ring closure. This im- are obtained, with good diastereoselectivities of up to 73:17
plies that an angle of 180° is required for Walden inversion, and very high enantioselectivities of more than 99%. Cata-
and reaction as shown in I (Figure 6) will give the prod- lyst loads as low as 5 mol-% still give products in satisfac-
uct.[35] Although there are two possibilities for enolate ap- tory yields, albeit with a drop in ee to 92%. This method
proach to the reacting enamine, G or H, only reaction as produces cyclopropanes with a variety of substituents on
shown in H will give a major diastereoisomer with the the ring, which allows for further synthetic manipulation
phenyl and the phosphoryl groups with a cis relationship, and conversion into more elaborate biologically active tar-
and the formyl group trans, as observed for the major dia- gets if so wished. Most of the compounds have not been
stereoisomer, i.e. a (1R,2S,3S)-α-CPP.
described previously.
158
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© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Enantioselective Synthesis of α-Cyclopropylphosphonates
1131, 1096, 1049, 1025, 978, 865, 793, 755, 710, 665, 633 cm–1. The
NMR spectroscopic data were consistent with reported data.[29]
Experimental Section
General Information: All reactions were performed under an atmo-
sphere of argon. The reagents were obtained from commercial sup-
pliers and used without further purification. The solvents were
purified by standard methods and distilled before use. For column
chromatography, Merck silica gel 60 (230–400 mesh) was used, and
for thin-layer chromatography, silica gel plates Merck 60 F254 were
used. Optical rotations were measured with an AA-1000 Polarime-
ter from Optical Activity Ltd. with 1-mL, 0.5-dm cells. NMR spec-
tra were obtained with a Bruker AR X400 NMR spectrometer or
with a Bruker Avance 400 MHz spectrometer (1H: 400 MHz, 13C:
100 MHz, 31P: 162 MHz). Chemical shifts are reported relative to
TMS. 31P NMR chemical shifts are reported relative to phosphoric
acid, used as external standard. The assignment of signals in the
13C NMR spectra was determined by DEPT experiments. NOE
difference spectra were also obtained for the determination of the
relative stereochemistry of the compounds. 2D spectra (COSY 45,
HMQC, HMBC, NOESY) were used to help with structural deter-
minations whenever necessary. For yield determination by NMR
spectroscopy, the signal ratios obtained in a 31P NMR spectrum
relative to tetraethyl methylenediphosphonate, used as internal
standard, were used. For the determination of the enantiomeric
excesses, derivatisation with l-VAL-OMe was used. The values
were calculated from the ratios of the signals observed in 31P and
1H NMR spectra of the diastereoisomeric imines formed through
reaction with l-Val-OMe.[30] IR spectra were obtained with a Per-
kin–Elmer Spectrum BX FTIR spectrophotometer. Elemental
analyses were performed with a Thermo Finnigan Elemental Ana-
lyzer 1112 series, by the Laboratory for External Services of CQFB-
Lab Associado/REQUIMTE, of the Department of Chemistry,
FCT, UNL. Trialkyl phosphonoacetates were either purchased
from commercial sources or were prepared from the corresponding
trialkyl phosphites and α-bromoacetates through an Arbuzov reac-
tion.[33]
Ethyl Bromo(diisopropylphosphono)acetate (3b): Prepared from
ethyl (diisopropylphosphono)acetate according to the general pro-
cedure. The crude product was purified by column chromatography
(silica gel; ethyl acetate/hexane, 1:1 then ethyl acetate only) as a
1
colourless oil, yield 0.338 g (26%). H NMR (CDCl3): δ = 1.30 (t,
J = 7.1 Hz, 3 H, CH3, EtO), 1.32–1.40 (m, 12 H, 4ϫ CH3 of iPr),
4.26 (q, J = 7.1 Hz, 2 H, CH2 of EtO), 4.29 (d, J = 14.0 Hz, 1 H,
CHP), 4.76–4.89 (m, 2 H, 2ϫ CH of iPr) ppm. 13C NMR (CDCl3):
δ = 13.88 (s, CH3, COCCH3), 23.56 (d, JC,P = 4.2 Hz, iPr-CH3),
23.62 (d, JC,P = 4.0 Hz, iPr-CH3), 24.05 (d, JC,P = 3.5 Hz, iPr-CH3),
24.13 (d, JC,P = 3.3 Hz, CH3 of iPr-CH3), 36.53 (d, JC,P = 146.6 Hz,
CHP), 62.87 (CH2), 73.47 (d, JC,P = 5.5 Hz, POCH), 73.53 (d, JC,P
= 5.2 Hz, POCH), 165.2 (C=O) ppm; 31P NMR (CDCl3): δ =
10.51 ppm. IR (neat): ν = 2981, 2935, 2914, 1737, 1650, 1467, 1453,
˜
1386, 1378, 1265, 1178, 1149, 1124, 1102, 1008, 1000, 938, 902, 890,
833, 832, 755, 722, 666, 615 cm–1. C10H20BrO5P (331.143): calcd. C
36.27, H 6.09; found C 35.00, H 6.05.
Trimethyl Bromophosphonoacetate (3c): Prepared from trimethyl
phosphonoacetate according to the general procedure. The crude
product was purified by column chromatography (silica gel; ethyl
acetate/hexane, 2:1) as a colourless oil, yield 2.11 g (33%). 1H
NMR (CDCl3): δ = 3.84 (s, 3 H, CH3, COOMe), 3.89 (d, J =
4.4 Hz, 3 H, POCH3), 3.91 (d, J = 4.4 Hz, 3 H, POCH3), 4.40 (d,
J = 14.2 Hz, 1 H, CHP) ppm. 13C NMR (CDCl3): δ = 34.63 (d,
JC,P = 147.6 Hz, CHP), 53.95 (s, CH3, COOCH3), 54.88–55.07 (2ϫ
d, 2ϫ POCH3), 165.4 (s, C=O) ppm. 31P NMR (CDCl3): δ =
14.93 ppm. IR (neat): ν = 3007, 2957, 2855, 1884, 1745, 1643, 1540,
˜
1436, 1262, 1186, 1154, 1042, 900, 869, 830, 762, 779, 715,
632 cm–1. C5H10BrO5P·H2O (279.093): calcd. C 21.88, H 4.33;
found C 22.03, H 4.06.
tert-Butyl Bromo(dimethylphosphono)acetate (3d): Prepared from
tert-butyl (dimethylphosphono)acetate according to the general
procedure. The crude product was purified by column chromatog-
raphy (silica gel; diethyl ether/ethyl acetate/hexane, 1:1:1) as a
General Procedure for the Synthesis of Bromophosphonoacetates 3a–
e: Dialkyl dibromophosphonoacetates were prepared from the re-
spective trialkyl phosphonoacetate, bromine and sodium hydroxide
according to the method described by McKenna and Khawli for
the synthesis of triethyl dibromophosphonoacetate.[29] It was found
that the extent of dibromination varied between reactions and when
mixtures of unreacted material, mono- and dibrominated phospho-
noacetate were obtained, the dibromination was repeated on the
crude product mixture. Alternatively, sodium hydride and bromine
were used, as described for the synthesis of α-brominated diethyl
diphenylphosphonoacetates by Olpp and Brückner.[27] In both
cases, the crude products were then reduced to trialkyl mono-
bromophosphonoacetates by SnCl2·2H2O in H2O/EtOH as de-
scribed by McKenna and Khawli for triethyl dibromophosphono-
acetate.[29]
1
colourless oil, yield 0.337 g (27%). H NMR (CDCl3): δ = 1.53 (s,
9 H, 3ϫ CH3 of tBu), 3.90 (d, J = 11.0 Hz, 3 H, 2ϫ OCH3), 4.31
(d, J = 13.6 Hz, 1 H, CHP) ppm. 13C NMR (CDCl3): δ = 27.65 (s,
3ϫ CH3, tBu-CH3), 36.59 (d, JC,P = 146.2 Hz, CHP), 54.80 (appar-
ent t, JC,P = 6.50 Hz, 2ϫ OCH3), 84.29 (s, Cq, tBu-C), 163.7 (s,
Cq, C=O) ppm. 31P NMR (CDCl ): δ = 15.69 ppm. IR (neat): ν =
˜
3
2978, 2940, 2892, 2709, 1754, 1739, 1734, 1724, 1369, 1261, 1179,
1153, 1124, 1055, 1031, 830 cm–1. C8H16BrO5P (302.98): calcd. C
31.71, H 5.32; found C 31.44, H 5.42.
Ethyl Bromo(dimethylphosphono)acetate (3e):[34] Prepared from
ethyl (dimethylphosphono)acetate according to the general pro-
cedure.[29] The crude product was purified by column chromatog-
raphy (silica gel; ethyl acetate/hexane, 2:1) as a colourless oil, yield
0.631 g (79%). 1H NMR (CDCl3): δ = 1.28 (t, J = 7.1 Hz, 3 H,
CH3 of EtO), 3.85 (d, J = 3.9 Hz, 3 H, OCH3), 3.88 (d, J = 3.9 Hz,
3 H, OCH3), 4.25 (q, J = 7.1 Hz, 2 H, CH2 of EtO), 4.36 (d, J =
14.0 Hz, 1 H, CHP) ppm. 13C NMR (CDCl3): δ = 13.75 (s, CH3,
OCCH3), 34.92 (d, JC,P = 147.3 Hz, CHP), 54.89–54.73 (2ϫ d, 2ϫ
POCH3), 63.11 (s, CH2), 164.7 (s, C=O) ppm. 31P NMR (CDCl3):
Triethyl Bromophosphonoacetate (3a):[29] Prepared from triethyl
phosphonoacetate according to the general procedure.[29] The crude
product was purified by column chromatography (silica gel; ethyl
acetate–hexane, 2:1) as a colourless oil, yield 2.97 g (52%). 1H
NMR (CDCl3): δ = 1.32 (t, J = 7.1 Hz, 3 H, CH3, COCCH3), 1.38
(t, J = 7.0 Hz, 6 H, 2ϫ CH3, POCCH3), 4.23–4.33 (m, 6 H, 3ϫ
CH2, COCH2, 2ϫ POCH2), 4.35 (overlapped t, JH,P = 14.0 Hz,
CHP) ppm. 13C NMR (CDCl3): δ = 13.85 (s, CH3, OCCH3), 16.27
(d, J = 6.0 Hz, CH3, POCCH3), 35.72 (d, JC,P = 145.9 Hz, CHP),
δ = 15.14 ppm. IR (neat): ν = 2955, 2922, 2853, 1753, 1741, 1734,
˜
1723, 1464, 1458, 1452, 1387, 1368, 1263, 1178, 1139, 1045, 1031,
948, 872, 830, 783, 766, 666 cm–1. C6H12BrO5P (275.035): calcd. C
26.20, H 4.40; found C 26.07, H 4.20.
63.04 (s, COCH2), 64.59 (d, J = 6.6 Hz, POCH2), 165.0 (d, JC,P
=
1.0 Hz, C=O) ppm. 31P NMR (CDCl3): δ = 13.32 ppm. IR (neat):
General Procedure for the Domino Michael Addition/Intramolecular
ν = 2982, 2937, 2910, 2871, 1755, 1740, 1734, 1654, 1648, 1636, Alkylation Reaction: The phosphonate (0.10 mmol) was weighed
˜
1559, 1540, 1522, 1507, 1475, 1469, 1444, 1392, 1368, 1262, 1161,
into a reaction vessel, covered with a rubber septum and the cata-
Eur. J. Org. Chem. 2014, 152–163
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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159

A. M. Faísca Phillips, M. T. Barros
FULL PAPER
lyst (0.020 mmol) dissolved in anhydrous methanol (0.30 mL) was
added. The resulting solution was stirred under an atmosphere of
argon, while cinnamaldehyde (0.36 mmol) was added dropwise. Fi-
nally, triethylamine (0.10 mmol) was added. The rubber septum
was changed for a plastic stopper under an atmosphere of argon,
and the reaction vessel was covered with aluminium foil for protec-
tion from light. The resulting solution was then stirred for the
periods indicated in the tables. For low temperature reactions, the
solution was cooled in an ice bath once the phosphonate and the
catalyst were mixed and the reaction mixture was kept at this tem-
perature thereafter. Once the reaction was complete, hydrochloric
acid (1 m) was added, and the product was extracted four times
into chloroform. The combined chloroform extracts were washed
once with water, and the organic phase was separated and filtered
through anhydrous sodium sulfate. The solvent was removed in a
rotary evaporator to give the crude product, which was sub-
sequently purified by plate or column chromatography as indicated
for each compound.
3058, 3022, 2982, 2932, 2906, 2870, 1732, 1718, 1706, 1654, 1647,
1636, 1603, 1583, 1560, 1542, 1498, 1474, 1448, 1424, 1390, 1367,
1262, 1232, 1181, 1163, 1123, 1097, 1052, 1022, 975, 917, 863, 798,
767, 721, 697, 665, 615, 594, 559 cm–1. C17H23O6P·1.5H2O
(372.354): calcd. C 54.84, H 6.77; found C 54.64, H 6.73.
(1S,2S,3S)-(+)-5b (Minor Diastereoisomer): 1H NMR (CDCl3): δ =
0.81 (t, J = 7.1 Hz, 3 H, COCCH3), 1.26 (t, J = 7.0 Hz, 3 H,
POCCH3), 1.38 (t, J = 7.1 Hz, 3 H, POCCH3), 3.20 (ddd, JH,H
=
5.4, 7.6, JH,P = 10.4 Hz, 1 H, CHCHO), 3.73 (dd, JH,H = 7.6, JH,P
= 17.1 Hz, 1 H, CHPh), 3.80 (q, J = 7.1 Hz, 2 H, COCH2), 4.08
(m, 2 H, POCH2), 4.20–4.34 (m, 2 H, POCH2), 7.10–7.29 (m, 5 H,
Ph), 9.66 (d, J = 5.4 Hz, 1 H, CHO) ppm. 13C NMR (CDCl3): δ =
13.57 (s, CH3, COCCH3), 16.26 (d, JC,P = 6.0 Hz, CH3, POCCH3),
16.44 (d, JC,P = 6.4 Hz, CH3, POCCH3), 34.23 (d, JC,P = 2.6 Hz,
CH, CHPh), 37.49 (d, JC,P = 184.3 Hz, Cq, CP), 38.17 (d, JC,P
1.5 Hz, CH, CHCHO), 61.95 (s, CH2, COCH2), 63.23 (d, JC,P
=
=
6.2 Hz, CH2, POCH2), 63.46 (d, JC,P = 6.2 Hz, CH2, POCH2),
128.0 (s, CH, pC-Ph), 128.5 (s, 4ϫ CH, oC-Ph, mC-Ph), 132.6 (d,
JC,P = 2.2 Hz, Cq, iC-Ph), 164.7 (d, JC,P = 6.3 Hz, Cq, COO), 198.3
(d, JC,P = 3.3 Hz, Cq, CHO) ppm. 31P NMR (CDCl3): δ =
18.92 ppm.
Reaction times were determined on the basis of 31P NMR spectro-
scopic analysis. For ee determinations, one drop of l-Val-OMe was
added to an NMR tube containing the product, and a few minutes
later the spectra were run. Imine formation was almost immediate.
The chemical shifts in 31P and 1H NMR spectra were assigned
based on those of racemic samples prepared by using equal
amounts of d- and l-proline as catalyst.
Ethyl
1-(2-Formyl-1-diisopropoxyphosphoryl-3-phenyl)cycloprop-
anecarboxylate (6): Prepared from ethyl bromo(diisopropoxyphos-
phoryl)acetate and cinnamaldehyde, according to the general pro-
cedure. It was obtained as a 83:17 mixture of diastereoisomers as
Ethyl
1-(1-Diethoxyphosphoryl-2-formyl-3-phenyl)cyclopropane- determined by 31P NMR spectroscopic analysis. Preparative thin-
carboxylate (5): Compound 5 was prepared from ethyl bromo(di-
ethoxyphosphoryl)acetate and cinnamaldehyde, according to the
general procedure. It was obtained as an 83:17 mixture of dia-
stereoisomers, as determined by 31P NMR spectroscopic analysis.
After preparative thin-layer plate chromatography purification on
silica gel, the pure diastereoisomers (69 mg, 65%) were obtained as
a colourless oil. The enantiomeric excess was determined by 1H
and 31P NMR spectroscopic analysis of the diastereoisomeric
imines formed after in situ reaction with l-Val-OMe in CD3CN.[30]
For a racemic sample prepared in a similar way with equal amounts
of d-proline plus l-proline as catalysts: 1H NMR (400 MHz,
layer plate chromatography purification carried out twice in each
case (silica gel; acetone/CHCl3, 1:4 or acetone/CHCl3, 1:6) pro-
vided the two diastereoisomers as separate compounds. After pre-
parative thin-layer plate chromatography purification on silica gel,
the pure diastereoisomers (34 mg, 89%) were obtained as a colour-
1
less oil. The enantiomeric excess was determined by H NMR and
31P NMR spectroscopic analysis of the diastereoisomeric imines
formed after in situ reaction with l-Val-OMe in CD3CN.[30] For a
racemic sample prepared in a similar way with equal amounts of d-
proline plus l-proline as catalysts: 1H NMR (400 MHz, CD3CN): δ
= 7.50 (d, J = 7.0 Hz, major), 7.56 (d, J = 6.8 Hz, major), 7.85 (d,
CD3CN): δ = 7.51 (d, J = 6.8 Hz, major), 7.56 (d, J = 6.8 Hz, J = 7.4 Hz, minor), 7.87 (d, J = 7.4 Hz, minor) ppm. 31P NMR
major), 7.79 (d, J = 2.8 Hz, minor), 7.81 (d, J = 2.8 Hz, (162 MHz, CD3CN): δ = 15.02 (major), 15.02 (major), 16.90
minor) ppm. 31P NMR (162 MHz, CD3CN): δ = 16.47 (major),
16.57 (major), 19.04 (minor), 19.10 (minor) ppm. Preparative thin-
layer plate chromatography purification carried out twice in either
case on the crude product (silica gel; acetone/CHCl3, 1:4 or acet-
one/CHCl3, 1:4, followed by acetone/CHCl3, 1:6) provided the two
diastereoisomers as separate compounds.
(minor), 17.01 (minor) ppm.
(1R,2S,3S)-(+)-6a (Major Diastereoisomer): [α]1D6 = +27.0 (c = 0.54,
CHCl3). 1H NMR (CDCl3): δ = 1.01 (d, J = 6.2 Hz, 3 H, iPr-CH3),
1.08 (d, J = 6.2 Hz, 3 H, iPr-CH3), 1.10 (d, J = 6.3 Hz, 3 H, iPr-
CH3), 1.18 (d, J = 6.2 Hz, 3 H, iPr-CH3), 1.30 (t, J = 7.2 Hz, 3 H,
COCCH3), 3.22 (ddd, JH,H = 4.8, 7.4, JH,P = 12.3 Hz, 1 H,
CHCHO), 3.63 (dd, JH,H = 7.4, JH,P = 14.0 Hz, 1 H, CHPh), 4.15–
(1R,2S,3S)-(+)-5a (Major Diastereoisomer): [α]1D6 = +21.0 (c = 1.10,
1
CHCl3). H NMR (CDCl3): δ = 1.08 (overlapped t, J = 7.0 Hz, 3 4.34 (m, 3 H, COOCH2, POCH), 4.48–4.61 (m, 1 H, POCH), 7.18–
H, POCCH3), 1.11 (overlapped t, J = 7.1 Hz, 3 H, POCCH3), 1.34
(t, J = 7.1 Hz, 3 H, COCCH3), 3.23 (ddd, JH,H = 4.8, 7.4, JH,P
7.3 (m, 3 H, Ph-H), 7.33 (d, J = 7.0 Hz, 2 H, Ph-H), 9.51 (dd, J =
0.8, 4.8 Hz, 1 H, CCHO) ppm. 13C NMR (CDCl3): δ = 13.99 (s,
CH3, COCCH3), 23.43 (d, JC,P = 5.1 Hz, iPr-CH3), 23.50 (d, JC,P
= 5.9 Hz, iPr-CH3), 23.71 (d, JC,P = 3.5 Hz, iPr-CH3), 23.96 (d,
JC,P = 4.0 Hz, iPr-H3), 35.48 (d, JC,P = 3.7 Hz, CH, CHPh), 37.28
=
12.2 Hz, 1 H, CHCHO), 3.55–3.69 (m, 1 H, POCHH), 3.73 (over-
lapped dd, JH,H = 7.4, JH,P = 14.0 Hz, 1 H, CHPh), 3.76–3.93
(overlapped m, 3 H, 2ϫ POCH2), 4.24–4.36 (m, 2 H, COCH2),
7.28–7.38 (m, 5 H, Ph), 9.56 (d, J = 4.7 Hz, 1 H, CHO) ppm. 13C (d, JC,P = 1.9 Hz, CH, CHCHO), 38.59 (d, JC,P = 183.7 Hz, Cq,
NMR (CDCl3): δ = 14.00 (s, CH3, COCCH3), 16.05 (d, JC,P
=
CP), 62.47 (s, CH2, COCH2), 71.46 (d, JC,P = 6.8 Hz, POCH),
6.1 Hz, CH3, POCCH3), 16.14 (d, JC,P = 6.3 Hz, CH3, POCCH3), 71.75 (d, JC,P = 6.2 Hz, POCH), 127.7 (s, CH, pC-Ph), 127.9 (s,
35.32 (d, JC,P = 3.4 Hz, CH, CHPh), 37.47 (d, JC,P = 2.5 Hz, CH,
2ϫ CH, mC-Ph), 129.6 (s, 2ϫ CH, oC-Ph), 132.7 (d, JC,P = 5.3 Hz,
Cq, iC-Ph), 167.3 (d, JC,P = 5.6 Hz, Cq, COO), 197.2 (s, Cq,
CHCHO), 37.84 (d, JC,P = 184.2 Hz, Cq, CP), 62.44 (d, JC,P
6.1 Hz, CH2, POCH2), 62.67 (s, CH2, COCH2), 62.85 (d, JC,P
=
=
CHO) ppm. 31P NMR (CDCl ): δ = 13.61 ppm. IR: ν = 3021, 3004,
˜
3
6.7 Hz, CH2, POCH2), 127.8 (s, CH, pC-Ph), 128.1 (s, 2ϫ CH, mC-
Ph), 129.4 (s, 2ϫ CH, oC-Ph), 132.8 (d, JC,P = 5.3 Hz, Cq, iC-Ph),
152.1 (d, JC,P = 6.3 Hz, Cq, COO), 197.0 (d, JC,P = 1.7 Hz, Cq,
2980, 2935, 2927, 1738, 1730, 1714, 1605, 1560, 1541, 1499, 1465,
1453, 1386, 1375, 1257, 1234, 1178, 1142, 1103, 1010, 993, 950, 913,
900, 867, 845, 771, 697, 666, 615, 594, 564 cm–1. C19H27O6P·H2O
(400.408): calcd. C 56.99, H 7.30; found C 56.73, H 6.25.
CHO) ppm. 31P NMR (CDCl ): δ = 15.47 ppm. IR (neat): ν =
˜
3
160
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Enantioselective Synthesis of α-Cyclopropylphosphonates
(1S,2S,3S)-(+)-6b (Minor Diastereoisomer): 1H NMR (CDCl3): δ = 2ϫ CH, mC-Ph), 128.6 (s, 2ϫ CH, oC-Ph), 132.3 (s, Cq, iC-Ph),
0.84 (t, J = 7.1 Hz, 3 H, COCCH3), 1.23 (d, J = 6.1 Hz, 3 H, iPr- 156.1 (d, JC,P = 6.4 Hz, Cq, COO), 197.9 (s, Cq, CHO) ppm. 31P
CH3), 1.26 (d, J = 6.1 Hz, 3 H, iPr-CH3), 1.38 (app. t, J = 7.7 Hz,
6 H, 2ϫ iPr-CH3), 3.14–3.25 (m, 1 H, CHCHO), 3.70 (dd, JH,H
NMR (CDCl3): δ = 21.73 ppm.
=
tert-Butyl 1-(2-Formyl-1-dimethoxyphosphoryl-3-phenyl)cycloprop-
anecarboxylate (8): Prepared from tert-butyl bromo(dimethoxy-
phosphoryl)acetate and cinnamaldehyde, according to the general
procedure. It was obtained as a 68:32 mixture of diastereoisomers,
as determined by 31P NMR spectroscopic analysis. After prepara-
tive thin-layer plate chromatography purification on silica gel, the
pure diastereoisomers (48 mg, 47%) were obtained as a colourless
7.5, JH,P = 17.2 Hz, 1 H, CHPh), 3.81 (q, J = 7.1 Hz, 3 H, CO-
OCH2), 4.54–4.70 (m, 1 H, POCH), 4.75–4.90 (m, 1 H, POCH),
7.14 (d, J = 6.6 Hz, 2 H, Ph-H), 7.15–7.30 (m, 3 H, Ph-H), 9.69
(d, J = 5.3 Hz, 1 H, CCHO) ppm. 13C NMR (CDCl3): δ = 13.65
(s, CH3, COCCH3), 23.78 (d, JC,P = 4.6 Hz, iPr-CH3), 23.91 (d,
JC,P = 4.1 Hz, iPr-CH3), 24.04 (d, JC,P = 4.3 Hz, iPr-CH3), 24.10
(d, JC,P = 4.9 Hz, iPr-H3), 34.20 (d, JC,P = 2.5 Hz, CH, CHPh),
38.38 (s, CH, CHCHO), 38.55 (d, JC,P = 185.7 Hz, Cq, CP), 61.81
(s, CH2, COCH2), 72.07 (d, JC,P = 6.3 Hz, POCH), 72.47 (d, JC,P
= 6.7 Hz, POCH), 128.0 (s, CH, pC-Ph), 128.4 (s, 2ϫ CH, mC-
Ph), 128.5 (s, 2ϫ CH, oC-Ph), 132.8 (s, Cq, iC-Ph), 164.9 (s Cq,
COO), 198.7 (d, JC,P = 3.2 Hz, Cq, CHO) ppm. 31P NMR (CDCl3):
δ = 16.71 ppm.
oil. The enantiomeric excess was determined by H and 31P NMR
1
spectroscopic analysis of the diastereoisomeric imines formed after
in situ reaction with l-Val-OMe in CD3CN.[30] For a racemic sam-
ple prepared in a similar way with equal amounts of d-proline plus
1
l-proline as catalysts: H NMR (400 MHz, CD3CN): δ = 7.44 (d,
J = 7.1 Hz, major), 7.46 (d, J = 7.2 Hz, major), 7.75 (d, J = 5.0 Hz,
minor), 7.76 (d, J = 4.9 Hz, minor) ppm. 31P NMR (162 MHz,
CD3CN): δ = 19.74 (major), 19.77 (major), 22.57 (minor), 22.72
(minor) ppm. Preparative thin-layer plate chromatography purifica-
tion carried out twice in either case on the crude product (silica gel,
acetone/CHCl3, 1:4 or acetone/CHCl3, 1:4, followed by acetone/
CHCl3, 1:6) provided the two diastereoisomers as separate com-
pounds.
Methyl
1-(2-Formyl-1-dimethoxyphosphoryl-3-phenyl)cycloprop-
anecarboxylate (7): Prepared from methyl bromo(dimethoxyphos-
phoryl)acetate and cinnamaldehyde, according to the general pro-
cedure. It was obtained as a 82:18 mixture of diastereoisomers, as
determined by 31P NMR spectroscopic analysis. After preparative
thin-layer plate chromatography purification on silica gel, the pure
diastereoisomers (63 mg, 60%) were obtained as a colourless oil.
The enantiomeric excess was determined by 1H and 31P NMR spec-
troscopic analysis of the diastereoisomeric imines formed after in
situ reaction with l-Val-OMe in CD3CN.[30] For a racemic sample
prepared in a similar way with equal amounts of d-proline plus l-
(1R,2S,3S)-(+)-8a (Major Diastereoisomer): [α]2D5 = –11.6 (c = 1.78,
CHCl3). 1H NMR (CDCl3): δ = 1.34 [s, 9 H, COC(CH3)3], 3.20
(ddd, JH,H = 4.7, 7.2, JH,P = 12.0 Hz, 1 H, CHCHO), 3.42 (app. t,
JH,P = 11.5 Hz, 6 H, 2ϫ POCH3), 3.66 (dd, JH,H = 7.3, JH,P
=
14.6 Hz, 1 H, CHPh), 7.25–7.41 (m, 5 H, Ph), 9.53 (dd, J = 4.6 Hz,
1 H, CHO) ppm. 13C NMR (CDCl3): δ = 27.83 (s, 3ϫ OCCH3),
34.51 (d, JC,P = 3.3 Hz, CH, CHPh), 36.99 (d, JC,P = 2.5 Hz, CH,
1
proline as catalysts: H NMR (400 MHz, CD3CN): δ = 7.55 (d, J
= 6.5 Hz, major), 7.60 (d, J = 6.4 Hz, major), 7.77 (app. t, J =
6.6 Hz, minor) ppm. 31P NMR (162 MHz, CD3CN): δ = 19.22
(major), 19.32 (major), 21.76 (minor), 21.84 (minor) ppm. Prepara-
tive thin-layer plate chromatography purification carried out twice
in each case (silica gel, ethyl acetate only or acetone/CHCl3, 1:6)
provided the two diastereoisomers as separate compounds.
CHCHO), 38.89 (d, JC,P = 183.8 Hz, Cq, CP), 52.79 (d, JC,P
=
6.0 Hz, POCH3), 53.18 (d, JC,P = 6.6 Hz, POCH3), 83.85 [s,
COC(CH3)3], 127.8 (s, CH, pC-Ph), 128.2 (s, 2ϫ CH, mC-Ph),
129.3 (s, 2ϫ CH, oC-Ph), 132.9 (d, JC,P = 5.5 Hz, Cq, iC-Ph), 165.6
(d, JC,P = 5.9 Hz, Cq, COO), 196.6 (d, JC,P = 1.9 Hz, Cq,
CHO) ppm. 31P NMR (CDCl ): δ = 18.82 ppm. IR (neat): ν =
(1R,2S,3S)-(+)-7a (Major Diastereoisomer): [α]1D6 = +19.2 (c = 0.51,
˜
3
2980, 2956, 2928, 2852, 1715, 1647, 1654, 1636, 1560, 1542, 1508,
1498, 1457, 1451, 1420, 1394, 1369, 1285, 1257, 1192, 1156, 1120,
1052, 1034, 942, 912, 836, 806, 775, 733, 697, 664 cm–1. C17H23O6P
(354.339): calcd. C 57.63, H 6.54; found C 57.55, H 6.66.
1
CHCl3). H NMR (CDCl3): δ = 3.23 (ddd, JH,H = 4.6, 7.5, JH,P
=
12.1 Hz, 1 H, CHCHO), 3.32 (d, JH,P = 11.1 Hz, 3 H, POCH3),
3.45 (d, JH,P = 11.3 Hz, 3 H, POCH3), 3.75 (dd, JH,H = 7.5, JH,P
= 14.1 Hz, 1 H, CHPh), 3.85 (s, 3 H, COOCH3), 7.25–7.40 (m, 5
H, Ph), 9.59 (dd, J = 0.8, 4.6 Hz, 1 H, CHO) ppm. 13C NMR
(1S,2S,3S)-(+)-8b (Minor Diastereoisomer): 1H NMR (CDCl3): δ =
1.01 [s, 9 H, COC(CH3)3], 3.10–3.20 (m, 1 H, CHCHO), 3.66–3.75
(overlapped m, 1 H, CHPh), 3.72 (overlapped d, JH,P = 11.3 Hz, 3
H, POCH3), 3.91 (d, JH,P = 11.2 Hz, 3 H, POCH3), 7.15–7.35 (m,
5 H, Ph), 9.63 (d, JH,H = 5.4 Hz, 1 H, CHO) ppm. 13C NMR
(CDCl3): δ = 27.28 (s, 3ϫ OCCH3), 33.86 (d, JC,P = 2.6 Hz, CH,
CHPh), 37.40 (d, JC,P = 184.5 Hz, Cq, CP), 37.58 (d, JC,P = 1.3 Hz,
(CDCl3): δ = 35.45 (d, JC,P = 3.2 Hz, CH, CHPh), 37.34 (d, JC,P
=
186.6 Hz, Cq, CP), 37.41 (d, JC,P = 2.7 Hz, CH, CHCHO), 52.79
(d, JC,P = 6.1 Hz, POCH3), 53.42 (d, JC,P = 6.6 Hz, POCH3), 53.56
(s, COOCH3), 127.9 (s, CH, pC-Ph), 128.2 (s, 2ϫ CH, mC-Ph),
129.3 (s, 2ϫ CH, oC-Ph), 132.7 (d, JC,P = 5.3 Hz, Cq, iC-Ph), 167.5
(d, JC,P = 6.6 Hz, Cq, COO), 196.7 (s, Cq, CHO) ppm. 31P NMR
(CDCl ): δ = 18.13 ppm. IR (neat): ν = 3060, 3028, 2956, 2853,
˜
3
CH, CHCHO), 53.37 (d, JC,P = 6.2 Hz, POCH3), 53.68 (d, JC,P =
1767, 1729, 1657, 1648, 1639, 1627, 1588, 1559, 1540, 1498, 1448,
1436, 1385, 1355, 1262, 1232, 1196, 1184, 1154, 1124, 1094, 1034,
992, 924, 870, 836, 788, 775, 730, 698, 665, 646, 614, 589, 559 cm–1.
C14H17O6P (312.258): calcd. C 53.85, H 5.49; found C 53.52, H
5.08.
6.1 Hz, POCH3), 83.05 [s, COC(CH3)3], 128.0 (s, CH, pC-Ph),
128.4 (s, 2ϫ CH, mC-Ph), 128.8 (s, 2ϫ CH, oC-Ph), 132.4 (d, JC,P
= 2.2 Hz, Cq, iC-Ph), 163.1 (d, JC,P = 6.3 Hz, Cq, COO), 198.3 (d,
JC,P = 3.3 Hz, Cq, CHO) ppm. 31P NMR (CDCl3): δ = 22.63 ppm.
Ethyl 1-(2-Formyl-1-dimethoxyphosphoryl-3-phenyl)cyclopropane-
(1S,2S,3S)-(+)-7b (Minor Diastereoisomer): 1H NMR (CDCl3): δ = carboxylate (9): Prepared from ethyl bromo(dimethoxyphosphor-
3.29 (ddd, JH,H = 5.3, 7.6, JH,P = 10.6 Hz, 1 H, CHCHO), 3.43 (s,
yl)acetate and cinnamaldehyde, according to the general procedure.
3 H, COOCH3), 3.79 (overlapped d, JH,P = 8.4 Hz, 3 H, POCH3), It was obtained as a 82:18 mixture of diastereoisomers, as deter-
3.78–3.85 (overlapped m, 1 H, CHPh), 3.97 (d, JH,P = 11.3 Hz, 3 mined by 31P NMR spectroscopic analysis. After preparative thin-
H, POCH3), 7.19–7.35 (m, 5 H, Ph), 9.71 (dd, J = 5.0 Hz, 1 H,
CHO) ppm. 13C NMR (CDCl3): δ = 34.31 (d, JC,P = 2.6 Hz, CH,
layer plate chromatography purification on silica gel, the pure dia-
stereoisomers (32 mg, 56%) were obtained as a colourless oil. The
1
CHPh), 36.64 (d, JC,P = 186.0 Hz, Cq, CP), 38.24 (s, CH, enantiomeric excess was determined by H and 31P NMR spectro-
CHCHO), 52.90 (s, COOCH3), 53.60 (d, JC,P = 6.3 Hz, POCH3), scopic analysis of the diastereoisomeric imines formed after in situ
53.94 (d, JC,P = 6.2 Hz, POCH3), 128.2 (s, CH, pC-Ph), 128.4 (s,
reaction with l-Val-OMe in CD3CN.[30] For a racemic sample pre-
161
Eur. J. Org. Chem. 2014, 152–163
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org

A. M. Faísca Phillips, M. T. Barros
FULL PAPER
[5]
[6]
[7]
G. L. Patrick, An Introduction to Medicinal Chemistry, 4th ed.,
Oxford University Press, Oxford, UK, 2009, p. 234–235.
A. Gagnon, M. Duplessis, L. Fader, Org. Prep. Proced. Int.
2010, 42, 1–69.
pared in a similar way with equal amounts of d-proline plus l-
proline as catalysts: H NMR (400 MHz, CD3CN): δ = 7.53 (d, J
1
= 6.6 Hz, major), 7.56 (d, J = 6.6 Hz, major), 7.77 (app. t, J =
6.7 Hz, minor) ppm. 31P NMR (162 MHz, CD3CN): δ = 19.28
(major), 19.36 (major), 21.89 (minor), 21.97 (minor) ppm. Prepara-
tive thin-layer plate chromatography purification carried out twice
(silica gel; acetone/CHCl3, 1:4) provided the major diastereoiso-
a) M. T. Barros, A. M. Faísca Phillips, Eur. J. Org. Chem. 2008,
2525–2529; b) M. T. Barros, A. M. Faísca Phillips, Tetrahedron:
Asymmetry 2010, 21, 2746–2752; c) M. T. Barros, A. M. Faí-
sca Phillips, Eur. J. Org. Chem. 2011, 4028–4036 (Special Issue:
Women in Chemistry); d) A. M. Faísca Phillips, M. T. Barros,
Org. Biomol. Chem. 2012, 10, 404–412; for recent reviews on
organocatalytic enantioselective synthesis of phosphonates, see
e) A. M. Faísca Phillips, Mini-Rev. Org. Chem., accepted for
publication; f) for organocatalytic asymmetric synthesis of or-
ganophosphorus compounds, see: Ł. Albrecht, A. Albrecht, H.
Krawczyk, K. A. Jorgensen, Chem. Eur. J. 2010, 16, 28–48.
a) J. R. Reid, R. S. Marmor, J. Org. Chem. 1978, 43, 999–1001;
b) M. Marinozzi, M. Serpi, L. Amori, M. G. Diaz, G. Con-
stantino, U. Meyer, P. J. Flor, F. Gasparini, R. Heckendorn, R.
Kuhn, G. Giorgi, M. B. Hermit, C. Thomsen, R. Pellicciari,
Bioorg. Med. Chem. 2007, 15, 3161–3170; c) M. D. Erion, C. T.
Walsh, Biochemistry 1987, 26, 3417–3425; d) V. Devreux, J.
Wiesner, J. L. Goeman, J. Van der Eycken, H. Jomaa, S.
van Calenbergh, J. Med. Chem. 2006, 49, 2656–2660; e) Z. Yan,
S. Zhou, E. R. Kern, J. Zemlicka, Tetrahedron 2006, 62, 2608–
2615; f) X. C. Sheng, H.-J. Pyun, K. Choudhary, J. Wang, E.
Doerffler, M. Fleury, D. McMurtrie, X. Chen, W. E. De-
laney IV, C. U. Kim, Bioorg. Med. Chem. Lett. 2009, 19, 3453–
3457.
mers as
a separate compound. Preparative thin-layer plate
chromatography purification carried out twice (silica gel; acetone/
CHCl3, 1:4, then EtOAc only) provided the minor diastereoisomer
as a separate compound (plus Ͻ 10% major diastereoisomer).
(1R,2S,3S)-(+)-9a (Major Diastereoisomer): [α]2D1 = +20.0 (c = 0.94,
CHCl3). 1H NMR (CDCl3): δ = 1.34 (t, J = 7.2 Hz, 3 H,
COCCH3), 3.23 (ddd, JH,H = 4.6, 7.5, JH,P = 12.1 Hz, 1 H,
[8]
CHCHO), 3.34 (d, JH,P = 11.0 Hz, 3 H, POCH3), 3.47 (d, JH,P
=
11.3 Hz, 3 H, POCH3), 3.75 (dd, JH,H = 7.4, JH,P = 14.1 Hz, 1 H,
CHPh), 4.28–4.33 (m, 2 H, OCH2), 7.25–7.40 (m, 5 H, Ph), 9.57
(dd, J = 4.6 Hz, 1 H, CHO) ppm. 13C NMR (CDCl3): δ = 13.99
(s, COCCH3), 35.21 (d, JC,P = 3.3 Hz, CH, CHPh), 37.37 (d, JC,P
= 2.7 Hz, CH, CHCHO), 37.56 (d, JC,P = 186.1 Hz, Cq, CP), 52.78
(d, JC,P = 6.1 Hz, POCH3), 53.38 (d, JC,P = 6.7 Hz, POCH3), 62.79
(s, COOCH3), 127.9 (s, CH, pC-Ph), 128.2 (s, 2ϫ CH, mC-Ph),
129.4 (s, 2ϫ CH, oC-Ph), 132.8 (d, JC,P = 5.3 Hz, Cq, iC-Ph), 166.9
(d, JC,P = 6.5 Hz, Cq, COO), 196.7 (s, Cq, CHO) ppm. 31P NMR
(CDCl ): δ = 18.27 ppm. IR (neat): ν = 3059, 3048, 2981, 2957,
˜
3
[9]
For selected reviews see: a) H. Lebel, J.-F. Marcoux, C. Molin-
aro, A. B. Charette, Chem. Rev. 2003, 103, 977–1050; b) A. A.
Al Quntar, V. M. Dembitsky, M. Srebnik, Org. Prep. Proced.
Int. 2008, 40, 505–542; also ref.[2]
2852, 2800, 2743, 1730, 1713, 1643, 1603, 1499, 1469, 1448, 1422,
1391, 1367, 1263, 1211, 1181, 1153, 1100, 1033, 943, 916, 862, 835,
801, 776, 698, 665, 624, 614, 594, 559 cm–1. C15H19O6P·1.25 H2O
(348.814): calcd. C 51.65, H 6.21; found C 51.67, H 5.94.
[10]
[11]
C. Paul-Roth, F. De Montigny, G. Rethore, G. Simonneaux,
M. Gulea, S. Masson, J. Mol. Catal. A 2003, 201, 79–91.
a) H. M. L. Davies, G. H. Lee, Org. Lett. 2004, 6, 2117–2120;
b) H. M. L. Davies, A. M. Walji, T. J. Nagashima, J. Am.
Chem. Soc. 2004, 126, 4271–4280; c) Y. Ferrand, P. Le Maux,
G. Simonneaux, Org. Lett. 2004, 6, 3211–3214; d) A. B. Cha-
rette, J.-E. Bouchard, Can. J. Chem. 2005, 83, 533–542; e) P.
Le Maux, I. Abrunhosa, M. Berchel, G. Simonneaux, M. Gu-
lea, S. Masson, Tetrahedron: Asymmetry 2004, 15, 2569–2573;
f) R. P. Reddy, G. H. Lee, H. M. L. Davies, Org. Lett. 2006, 8,
3437–3440.
N. G. Vincent, N. G. Lindsay, D. Fiset, P. J. Gritsch, S. Azzi,
A. B. Charette, J. Am. Chem. Soc. 2013, 135, 1463–1470.
N. Vignola, B. List, J. Am. Chem. Soc. 2004, 126, 450–451.
For selected reviews on organocatalytic domino reactions or
organocatalytic cyclization reactions, see: a) D. Enders, C.
Grondal, M. R. M. Huttl, Angew. Chem. 2007, 119, 1590; An-
gew. Chem. Int. Ed. 2007, 46, 1570–1581; b) X. Yu, W. Wang,
Org. Biomol. Chem. 2008, 6, 2037–2046; c) A. N. Alba, X.
Companyo, M. Viciano, R. Rios, Curr. Org. Chem. 2009, 13,
1432–1474; d) C. Grondal, M. Jeanty, D. Enders, Nat. Chem.
2010, 2, 167–178; e) A. Moyano, R. Rios, Chem. Rev. 2011,
111, 4703–4832.
For intramolecular cyclopropane synthesis from enones, see a)
N. Bremeyer, S. C. Smith, S. V. Ley, M. J. Gaunt, Angew. Chem.
2004, 116, 2735; Angew. Chem. Int. Ed. 2004, 43, 2681–2684;
b) C. D. Papageorgiou, M. A. Cubillo de Dios, S. V. Ley, M. J.
Gaunt, Angew. Chem. 2004, 116, 4741; Angew. Chem. Int. Ed.
2004, 43, 4641–4644; c) C. C. C. Johansson, N. Bremeyer, S. V.
Ley, D. R. Owen, S. C. Smith, M. J. Gaunt, Angew. Chem.
2006, 118, 6170; Angew. Chem. Int. Ed. 2006, 45, 6024–6028;
for intermolecular cyclopropane synthesis from enones, see: d)
J. Lv, J. Zhang, Z. Lin, Y. Wang, Chem. Eur. J. 2009, 15, 972–
979; e) H. M. Hansen, D. A. Longbottom, S. V. Ley, Chem.
Commun. 2006, 4838–4840; f) V. Wascholowski, H. M. Hansen,
D. A. Longbottom, S. V. Ley, Synthesis 2008, 1269–1275; g) Q.-
S. Du, L.-T. Dong, J.-J. Wang, R.-J. Lu, M. Yan, ARKIVOC
2009, (xiv), 191–199; h) L.-T. Dong, Q.-S. Du, C.-L. Lou, J.-
(1S,2S,3S)-(+)-9b (Minor Diastereoisomer): 1H NMR (CDCl3): δ =
0.86 (t, J = 7.1 Hz, 3 H, COCCH3), 3.22–3.36 (m, 1 H, CHCHO),
3.79 (overlapped d, JH,P = 11.0 Hz, 3 H, POCH3), 3.72–3.92 (over-
lapped m, 3 H, CHPh, COCH2), 3.97 (d, JH,P = 11.1 Hz, 3 H,
POCH3), 7.15–7.35 (m, 5 H, Ph), 9.71 (d, JH,H = 5.2 Hz, 1 H,
CHO) ppm. 13C NMR (CDCl3): δ = 13.54 (s, COCCH3), 34.23 (s,
CH, CHPh), 36.61 (d, JC,P = 186.0 Hz, Cq, CP), 38.03 (s, CH,
CHCHO), 53.56 (d, JC,P = 6.3 Hz, POCH3), 53.76 (d, JC,P
6.2 Hz, POCH3), 62.09 (s, COOCH3), 128.2 (s, CH, pC-Ph), 128.52
(s, 2ϫ CH, mC-Ph), 128.53 (s, 2ϫ CH, oC-Ph), 132.3 (d, JC,P
=
[12]
=
2.1 Hz, Cq, iC-Ph), 164.6 (s, Cq, COO), 198.0 (d, JC,P = 3.5 Hz,
Cq, CHO) ppm. 31P NMR (CDCl3): δ = 21.88 ppm.
[13]
[14]
Supporting Information (see footnote on the first page of this arti-
cle): 1H and 13C NMR spectra of all compounds synthesised, as
well as examples of 31P and 1H NMR spectra of racemic imine
standards and those of the chiral compounds used to determine
enantiomeric excess values.
Acknowledgments
[15]
Financial support from the Fundação para a Ciência e a Tecnolo-
gia (FCT) and the Ministério da Educação e Ciência to A. M. F. P.
is gratefully acknowledged. The NMR spectrometers are part of
The National NMR Facility, supported by FCT (RECI/BBB-BQB/
0230/2012).
[1] J. Salaün, Top. Curr. Chem. 2000, 207, 69–88.
[2] J. H. Pellissier, Tetrahedron 2008, 64, 7041–7095.
[3] J. Salaün, Top. Curr. Chem. 2000, 207, 1–67.
[4] B. Rozsondai, Cyclopropyl Group, in: Patai’s Chemistry of Func-
tional Groups (Ed.: Z. Rappport), Wiley, Chichester, UK, 2004,
vol. 2, p. 1–83.
162
www.eurjoc.org
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 152–163

Enantioselective Synthesis of α-Cyclopropylphosphonates
M. Zhang, R.-J. Lu, M. Yan, Synlett 2010, 266–270; for cyclo-
propane synthesis from β,γ-unsaturated α-keto esters, see: Y.
Cheng, J. An, L.-Q. Lu, L. Luo, Z.-Y. Wang, J.-R. Chen, W.-J.
Xiao, J. Org. Chem. 2011, 76, 281–284.
[21]
[22]
F. Marini, S. Sternativo, F. Del Verme, L. Testaferri, M. Tiec-
coa, Adv. Synth. Catal. 2009, 351, 1801–1806.
For cyclopropane synthesis from allylic alcohols in combina-
tion with oxidation, see: a) M. Rueping, H. Sundén, E. Su-
giono, Chem. Eur. J. 2012, 18, 3649–3653; b) M. Rueping, H.
Sundén, L. Hubener, E. Sugiono, Chem. Commun. 2012, 48,
2201–2203.
a) F. Pesciaioli, P. Righi, A. Mazzanti, G. Bartoli, G. Benciv-
enni, Chem. Eur. J. 2011, 17, 2842–2845; b) A. Noole, N. S.
Sucman, M. A. Kabeshov, T. Kanger, F. Z. Macaev, A. V. Mal-
kov, Chem. Eur. J. 2012, 18, 14929–14933.
[16] For cyclopropane synthesis from α,γ-unsaturated aldehydes
and sulfur ylides, see: a) R. K. Kunz, D. W. C. MacMillan, J.
Am. Chem. Soc. 2005, 127, 3240–3241; b) A. Hartikka, P. I.
Arvidsson, J. Org. Chem. 2007, 72, 5874–5877; for synthesis
from α,γ-unsaturated aldehydes and arsonium-ylides, see: c) Y.-
H. Zhao, G. Zhao, W.-G. Cao, Tetrahedron: Asymmetry 2007,
18, 2462–2467.
[23]
[17] For cyclopropane synthesis from α,γ-unsaturated aldehydes
mediated by secondary amines, see: a) R. Rios, H. Sundén, J.
Vesely, G.-L. Zhao, P. Dziedzic, A. Córdova, Adv. Synth. Catal.
2007, 349, 1028–1032; b) H. Xie, L. Zu, H. Li, J. Wang, W.
Wang, J. Am. Chem. Soc. 2007, 129, 10886–10894; c) I. Ib-
rahem, G.-L. Zhao, R. Rios, J. Vesely, H. Sundén, P. Dziedzic,
A. Córdova, Chem. Eur. J. 2008, 14, 7867–7879; d) J. Vesely,
G.-L. Zhao, A. Bartoszewicz, A. Córdova, Tetrahedron Lett.
2008, 49, 4209–4212; e) X. Company, A.-N. Alba, F. Cardenas,
A. Moyano, R. Rios, Eur. J. Org. Chem. 2009, 3075–3080; f)
U. Uria, J. L. Vicario, D. Badia, L. Carrillo, E. Reyes, A. Pes-
quera, Synthesis 2010, 701–713; g) V. Terrasson, A.
van der Lee, R. M. de Figueiredo, J. M. Campagne, Chem. Eur.
J. 2010, 16, 7875–7880; h) W. Li, X. Li, T. Ye, W. Wu, X. Liang,
J. Ye, Tetrahedron Lett. 2011, 52, 2715–2718; i) A. Noole, M.
Osˇeka, T. Pehk, M. Öeren, I. Järving, M. R. J. Elsegood, A. V.
Malkov, M. Lopp, T. Kanger, Adv. Synth. Catal. 2013, 355,
829–835; j) for cyclopropanation through oxidative N-hetero-
cyclic carbene catalysis, see A. Biswas, S. De Sarkar, L. Tebben,
A. Studer, Chem. Commun. 2012, 48, 5190–5192.
[24]
[25]
a) A. Russo, S. Meninno, C. Tedesco, A. Lattanzi, Eur. J. Org.
Chem. 2011, 5096–5103; b) U. Das, Y.-L. Tsai, W. Lin, Org.
Biomol. Chem. 2013, 11, 44–47.
C. D. Fiandra, L. Piras, F. Fini, P. Disetti, M. Moccia, M. F. A.
Adamo, Chem. Commun. 2012, 48, 3863–3865.
A. El-Gokha, G. Maas, Tetrahedron 2011, 67, 2849–2857.
T. Olpp, R. Brückner, Synthesis 2004, 2135–2152.
K. Tago, H. Kogen, Tetrahedron 2000, 56, 8825–8831.
[26]
[27]
[28]
[29] C. E. McKenna, L. A. Khawli, J. Org. Chem. 1986, 51, 5467.
[30] a) Y. C. Timothy, J. Peelen, S. H. Gellman, Org. Lett. 2005, 7,
3469–3472; b) M. T. Barros, A. M. Faísca Phillips, Eur. J. Org.
Chem. 2008, 2525–2529; c) for a recent review on the determi-
nation of enantiomeric excesses by NMR spectroscopy, see:
T. J. Wenzel, J. D. Wilcox, Chirality 2003, 15, 3469–3472.
[31] W. Nagata, T. Wakabayashi, Y. Hayase, Organic Syntheses,
Coll. Vol. 1988, 6, 448–451.
[32] See for example: M. Marinozzi, M. Serpi, L. Amori, M. G.
Diaz, G. Costantino, U. Meyer, P. J. Flor, F. Gasparini, R.
Heckendorn, R. Kuhn, G. Giorgi, M. B. Hermit, C. Thom-
send, R. Pellicciaria, Bioorg. Med. Chem. 2007, 15, 3161–3170.
[33] A. van der Klei, R. L. P. de Jong, J. Lugtenburg, A. G. M. Tie-
lens, Eur. J. Org. Chem. 2002, 3015–3023.
[18] a) S. H. MacCooey, T. MacCabe, S. J. Connon, J. Org. Chem.
2006, 71, 7494–7497; b) Y.-N. Xuan, S.-Z. Nie, L.-T. Dong, J.-
M. Zhang, M. Yan, Org. Lett. 2009, 11, 1583–1586; c) A.
Russo, A. Lattanzi, Tetrahedron: Asymmetry 2010, 21, 1155–
1157; d) X. Dou, Y. Lu, Chem. Eur. J. 2012, 18, 8315–8319; e)
R. Fan, Y. Ye, W. Li, L. Wang, Adv. Synth. Catal. 2008, 350,
2488–2492.
[34] This compound has been described previously, see: G. V. Gri-
nev, G. I. Chervenyuk, A. V. Dombrovskii, J. Gen. Chem.
USSR (Engl. Transl.) 1969, 39, 1223–1225.
[35] Similar arguments were used by Rios and co-workers[17e] to
explain the configurational assignments of the products in re-
lated cyclopropanations reactions.
[19] T. Inokuma, S. Sakamoto, Y. Takemoto, Synlett 2009, 1627–
1630.
[20] S. Kojima, M. Suzuki, A. Watanabea, K. Ohkata, Tetrahedron
Lett. 2006, 47, 9061–9065.
Received: August 9, 2013
Published Online: November 25, 2013
Eur. J. Org. Chem. 2014, 152–163
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