Stereoselective cyclopropyl phosphonate formation using (S)-dimethylsulfonium-(p-tolylsulfinyl)methylide. Unusual phosphoryl group migration

Article abstract of DOI:10.1016/j.tetlet.2012.11.002

Methylation of t-butyl-1-dimethylphosphono-2-p-tolylsulfinyl cyclopropanecarboxylic ester occurs with full inversion of the configuration, but the stereochemistry of carbanion formation is structure-dependent. Reaction of cyclopropyl sulfoxide with i-PrMg

Full text of DOI:10.1016/j.tetlet.2012.11.002

Tetrahedron Letters 54 (2013) 223–226
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Stereoselective cyclopropyl phosphonate formation using
(S)-dimethylsulfonium-(p-tolylsulfinyl)methylide. Unusual phosphoryl
group migration
⇑
Wanda H. Midura , Agata Sobczak, Piotr Paluch
Centre of Molecular and Macromolecular Studies, Polish Academy of Sciences, 90-363 Lodz, Sienkiewicza 112, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
Methylation of t-butyl-1-dimethylphosphono-2-p-tolylsulfinyl cyclopropanecarboxylic ester occurs with
full inversion of the configuration, but the stereochemistry of carbanion formation is structure-depen-
dent. Reaction of cyclopropyl sulfoxide with i-PrMgCl leads to unprecedented 1,2 migration of the phos-
phoryl group.
Received 24 September 2012
Revised 11 October 2012
Accepted 1 November 2012
Available online 12 November 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Cyclopropane
Ylide
Phosphonate
1,2-Migration
Cyclopropane-containing compounds exhibit a broad spectrum
of biological properties1 and are present in over 100 therapeutic
agents.2 Cyclopropane rings are found in a variety of natural prod-
ucts and biologically active compounds including terpenes, phero-
mones, fatty acid metabolites, and unusual amino acids. The
synthetic utility and medicinal properties of enantioenriched
cyclopropanes have inspired many investigations on their synthe-
sis.3 New and more efficient methods for the preparation of these
entities in enantiomerically pure form are still evolving, many of
which proceed via Michael addition initiated ring-closure se-
quences (MIRC).4 In cyclopropanation reactions involving conju-
gate addition to an activated olefin, different ylides are used
most often as nucleophiles.5 Stereoselective formation of cyclopro-
panes can be accomplished either by reagent-controlled or sub-
strate-controlled processes.
Continuing our work on the application of optically active sulfi-
nyl compounds in asymmetric synthesis, we have designed a new
type of a chiral sulfur ylide as a single enantiomer, containing a sul-
finyl group bonded to the ylidic carbon atom. Our investigations
proved the utility of sulfinylmethylide in asymmetric syntheses
of the corresponding oxiranes and aziridines.6 High facial stereose-
lectivity was also observed for cyclopropanation, where the stere-
oselectivity depends on the structure of the Michael acceptor.7
Our initial investigations concentrated on cyclopropanation of
vinyl phosphonates, as an approach to the corresponding cyclopro-
panes, which are precursors of constrained phosphonic analogues
of natural and non-natural amino acids of potential, and in some
cases, documented biological and therapeutic activity.8 The
presence of
a chiral sulfinyl substituent on the phosphoryl
cyclopropane structure allows the possibility of additional func-
tionalization under stereochemical control. In particular, cyclo-
propanation of t-butyl 2-dimethoxyphosphoryl acrylate (2) using
(S)-dimethylsulfonium-(p-tolylsulfinyl)methylide (1) and K2CO3
as the base, afforded a separable mixture of three diastereomers
3a–c in a 65:21:14 ratio (Scheme 1A).9 The relative configuration
was determined by 1H NMR spectroscopy, where the coupling con-
3
stant values, JHP provided conclusive evidence for the assignment
of the cis–trans geometry in the substituted cyclopropylphospho-
nates. The absolute stereochemistry of the cyclopropane ring in
3a was assumed to be (1R,2S), based on a preferential approach
to the most stable conformer B of ylide 1 (Fig. 1) as assigned by
DFT calculations.6c
To introduce an additional substituent onto the cyclopropane
ring, at the carbon
a to the sulfinyl substituent, LiHMDS was used
as the base. The carbanion generated from 3 at ꢀ78 °C was
quenched with methyl iodide (as an electrophile). Methylation of
the trans diastereomer of cyclopropyl sulfoxide 3a afforded the
corresponding methylated cyclopropane 4a10 as the only product
(Scheme 1B). The stereochemistry of this process was determined
3
by a NOESY experiment: based on JHP coupling constant values,
the hydrogens bonded to the cyclopropane ring were assigned as
Hcis and Htrans with respect to the phosphorus atom. Since the
methyl group interacted with Htrans (signal enhancement
interaction with Htrans was observed), (Fig. 2) the sulfinyl
⇑
Corresponding author. Tel./fax: +48 42680 3216.
E-mail address: whmidura@bilbo.cbmm.lodz.pl (W.H. Midura).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.11.002

224
W. H. Midura et al. / Tetrahedron Letters 54 (2013) 223–226
A
O
S
O
O
O
O
Me
S
CO2But
H
CO2But
CO2But
H
(MeO)2P
CO2But
(MeO)2P
(MeO)2P
(MeO)2P
p-Tol
Me
+
H
S
+
1
S
S
Tol-p
O
O
Tol-p
O
Tol-p
2
3a
3b
δP 20.6
3c
δP 22.3
δP 15.8
δP 22.4
B
O
O
O
CO2But
H
LiHMDS
MeI
CO2But
Me
(MeO)2P
CO2But
Me
(MeO)2P
(MeO)2P
S
SO2Tol-p
S
O
O
4a
δ
P 22.2
Tol-p
Tol-p
3a
5a
δP 22.4
δP 19.8
C
O
O
O
CO2But
CO2But
Me
CO2But
(MeO)2P
(MeO)2P
(MeO)2P
1. LiHMDS
2. MeI
1. LiHMDS
2. MeI
H
H
S
S
S
Tol-p
O
O
O
4b
Tol-p
Tol-p
3b
δP 20.6
3c
δP 20.7
δP 22.3
1. LiHMDS
2. H2O
Scheme 1. Formation of cyclopropyl sulfoxides 3 and their subsequent alkylation.
O
P(OMe)2
BuO2C
.
.
S
.
.
H
1R,2S,
Tol
H
S
H
H
H
Ss
S
O
O
O
B
S
A
Figure 1.
On the other hand, under the same reaction conditions, cis dia-
stereomer 3b gave the product of retention of configuration; the
same product was formed by methylation of the second trans dia-
stereomer 3c (Scheme 1C). Loss of the chirality on sulfur by simple
oxidation of both cyclopropyl sulfoxides 4a and 4b gave only one
sulfone 5a, thus establishing the same relative configuration for
both.
It is generally accepted that the stereochemistry of the reactions
of a-lithiosulfoxides with electrophilic reagents depends upon the
nature of the latter. Thus, electrophiles containing oxygen atoms
(H2O, D2O, and CH2O) react in THF with retention of configuration,
whereas CH3I reacts with inversion.11 Albeit recently, retention of
configuration for both types of electrophiles was found to occur
during cyclopropyl sulfoxide exchange,12 we thus assumed that
the typical steric course of the reaction takes place in the examples
presented here. The different stereochemistry observed for cis iso-
mer 3b results probably via inversion of its corresponding carban-
ion to the more stable trans form. Since subsequent alkylation also
occurs with inversion of configuration, the overall stereochemical
outcome is retention. This assumption was confirmed by an addi-
tional experiment where the carbanion formed from cis isomer 3b
was reacted with H2O affording 3c (Scheme 1C). Similar high syn
selectivity of carbanion formation was observed during sulfoxide/
lithium exchange of bis(p-tolylsulfinyl)cyclopropanes.12b Based
on these observations, the alkylation of 3 was performed without
prior separation of diastereomers, affording 4a and 4b in a 2:1 ra-
tio. Simple recrystallization from diethyl ether gave the major dia-
stereomer 4a in pure form.
Figure 2. NOESY spectrum of 4a. The key NOEs between the methyl group signals
and Htrans with respect to the phosphorus atom are marked with blue circles.
substituent must be on the same side as the phosphoryl group,
which revealed that the alkylation process proceeded with inver-
sion of configuration.

W. H. Midura et al. / Tetrahedron Letters 54 (2013) 223–226
225
nions. Although a variety of bases was used for this purpose,13,14
due to the presence of other reactive centers in cyclopropyl sulfox-
ide 4, isopropylmagnesium chloride was used as the reagent of
choice in our preliminary investigations.
O
CO2But
Me
(MeO)2P
In the reaction of 4a with isopropylmagnesium chloride per-
formed at ꢀ10 °C in diethyl ether for 20 min the expected isopro-
pyl p-tolyl sulfoxide was formed. Although 31P and 1H NMR
spectra revealed the presence of two compounds in a 2:5 ratio,
now lacking a sulfur substituent, these spectroscopic data were
inconsistent with the expected product structure 6. Large coupling
constants (hydrogen–phosphorus with the methyl group),
12.45 Hz and 11.0 Hz, suggested a close proximity between the
phosphoryl and methyl substituents. The new products were iden-
tified as cis and trans diastereomers of t-butyl-2-methyl-2-dimeth-
ylphosphonocyclopropanecarboxylates cis-7a15 and trans-7b
(Scheme 2). The reaction, repeated under the same conditions, of
the mixture of diastereomers 4a/4b occurred in a similar manner
affording a mixture of cis/trans diastereomers 7 in the same ratio
5:2.
The formation of cyclopropanes 7 can be explained via 1,2-
migration of a phosphoryl group. Taking into account that 7a and
7b are optically active, this process seems to occur in a concerted
manner (Scheme 3). Predominant formation of 7a, where the two
bulky (phosphoryl and carbobutoxy) groups are in a cis relation-
ship, suggests preferential protonation of the enolate from the less
hindered face.
6
O
CO2But
Me
CO2But
Me
iPrMgCl
CO2But
Me
(MeO)2P
+
P(OMe)2
P(OMe)2
S
O
O
O
5 : 2
Tol-p
4a
δP 22.2
7a
δP 30.6
7b
δP 32.2
Scheme 2. Sulfinyl exchange.
CO2But
P(OMe)2
OMgCl
OBut
ClMgO
O
CO2But
C
(MeO)2P
Me
or
Me
P(OMe)2
O
MgCl
Me
OMe
OMe
tBuO2C
P
O
MgCl
Me
We investigated further whether the phosphoryl group 1,2-
migration was general and would occur for cyclopropanecarbox-
ylic ester 3. Initial experiments were performed on trans isomers
of 3. The application of various conditions (Table 1) showed that
this reaction was temperature dependent. At low temperature
(ꢀ50 °C) desulfinylated cyclopropane 8 was observed as the only
product (entries 1–3), whereas increasing the temperature and
extending the reaction time caused the formation of regioisomer
9. However, increasing the time to 2 h did not improve the 9/8 ra-
tio, but resulted in partial decomposition (entry 8). There was no
significant difference between diethyl ether and CH2Cl2, but more
polar THF inhibited the rearrangement (entry 7). According to
the plausible mechanism presented in Scheme 3, to accomplish
phosphoryl group 1,2-migration, the magnesium-bearing carbon
CO2But
Me
P(OMe)2
O
CO2But
+
Me
P(OMe)2
O
7b
7a
Scheme 3. 1,2-Migration of a phosphoryl group.
For further functionalization, mono-methylated cyclopropanes
4 were subjected to sulfoxide/metal exchange, a reaction that has
been widely applied to the synthesis of enantiomerically pure sulf-
oxides, and also as a method to generate the corresponding carba-
Table 1
Reaction of 3 with iPrMgCl
O
O
CO2But
CO2But
CO2But
(MeO)2P
iPrMgCl
(MeO)2P
+
P(OMe)2
STol-p
O
9
O
8
3a
δP 22.2
δP 27.2
δP 29.4
Entry
Cyclopro pane
Reaction conditions
Solvent
Regioisomer ratioa
i-PrMgCl
Temp/time
8
9
1
2
3
4
5
6
7
8
9
3a/3c
3a/3c
3a
3a/3c
3a
3a
3a
3a
3b
1.5 equiv
3 equiv
3 equiv
3 equiv
3 equiv
3 equiv
3 equiv
3 equiv
3 equiv
3 equiv
CH2Cl2
CH2Cl2
Et2O
CH2Cl2
Et2O
Et2O
THF
Et2O
Et2O
ꢀ50 °C/10 min
ꢀ50 °C/10 min
ꢀ50 °C/10 min
ꢀ10 °C/20 min
ꢀ10 °C/20 min
0 °C—rt/30 min
0 °C/30 min
>99%b
>99%
>99%
40%
62%
32%
90%
30%
75%
30%
—
—
—
60%
38%c
68%
10%
70%
25%c
70%
d
rt/2 h
ꢀ10 °C/30 min
10
3b
Et2O
0 °C/1 h
a
b
c
Product ratios measured by 31P and 1H NMR spectroscopy.
50% Conversion.
A trace of cis-9 was detected.
d
10% of by-products were formed.

226
W. H. Midura et al. / Tetrahedron Letters 54 (2013) 223–226
6. (a) Midura, W. H. Synlett 2006, 733; (b) Midura, W. H. Tetrahedron Lett. 2007,
48, 3907; (c) Midura, W. H.; Cypryk, M. Tetrahedron: Asymmetry 2010, 21, 177.
7. Midura, W. H., Sieron´ , L. unpublished results.
8. (a) Amori, L.; Serpi, M.; Marinozzi, M.; Constantino, G.; Diaz, M. G.; Hermit, M.
B.; Thomsen, C.; Pelliciari, R. Bioorg. Med. Chem. Lett. 2006, 16, 196–199; (b)
Hercouet, A.; Le Corre, M. Tetrahedron Lett. 2000, 41, 197; (c) Midura, W. H.;
Mikołajczyk, M. Tetrahedron Lett. 2002, 43, 3061.
9. Procedure for cyclopropanation: to a round-bottomed flask equipped with a
magnetic stir bar were added 2 mmol (0.47 g) of t-butyl-1-
dimethylphosphonoacrylate and 2 mmol (0.6 g) of (S)-dimethyl sulfonium-(p-
tolylsulfinyl) methyl tetrafluoroborate in 10 mL of CH2Cl2. To this suspension
was added 0.3 g of K2CO3 and the mixture stirred vigorously overnight.
Filtration and evaporation of the solvent afforded a crude residue, which was
purified by chromatography. Separation of the diastereomers was achieved by
chromatography on silica (hexane/acetone 2:1).
atom should be in the appropriate configuration. Surprisingly,
although the required relationship should be easily accessible from
cis-3b, we did not observe a significant increase in the amount of
regioisomer 9 (entries 9 and 10). In the absence of an anion-stabi-
lizing group the magnesium derivative is quite unstable. Therefore,
the only possibility of its stabilization is by coordination with the
phosphoryl group which is, however, accessible only from one side.
This probably reduces the barrier of inversion for the trans-magne-
sium derivative and similar reactivity for both isomers was ob-
served. The crucial element of the structure under investigations
is the presence of two electron-withdrawing substituents on car-
bon 2, which makes the 1,2 migration of the phosphoryl group
possible.
10. (+)-(1R,2R,Ss)-t-Butyl-1-dimethylphosphono-2-p-tolylsulfinyl-2-methylcyclo-
propane-carboxylate (4a): ½a D20 + 28.8 (c 3.9, acetone); mp 133–135 °C; 31P
ꢁ
NMR (81 MHz, CDCl3) d: 22.2; 1H NMR (500 MHz, CDCl3) d: 1.17 (s, 3H, CH3–
C(SO)), 1.45 (s, 9H, COC(CH3)3), 1.63 (dd, 1H, JHH = 6.2, JPH = 9.1 Hz), 1.93 (dd,
1H, JHH = 6.2, JPH = 16.6 Hz), 2.39 (s, 3H, C6H4CH3), 3.84 (d, 3H, POCH3,
JPH = 11.2 Hz), 3.96 (d, 3H, POCH3, JPH = 11.4 Hz), 7.29 and 7.50 (A2B2, 4H,
C6H4CH3); 13C NMR (125 MHz, CDCl3): 9.15 (d, JCP = 1.4 Hz), 20.1 (d,
JCP = 3.0 Hz), 21.3, 27.7, 35.7 (d, JCP = 179.7 Hz), 47.8 (d, JCP = 4.4 Hz), 53.4 (d,
JCP = 5.9 Hz), 53.8 (d, JCP = 6.4 Hz), 83.2, 124.7, 129.6, 138.5, 141.6, 165.2 (d,
JCP = 4.3 Hz); MS (CI) m/z 403 [M+H]+. Anal. Calcd. for C18H27O6PS: C, 53.72, H,
6.76. Found: C, 53.84, H, 6.87.
The migration product 9 was formed as the trans isomer, only
traces of the cis isomer16 were detected in two cases (entries 5
and 9). Evidently, in the case of cyclopropane 3 only a thermody-
namically controlled product could be obtained.
To the best of our knowledge, the migration of a phosphoryl
group on a cyclopropane ring, as described above, has not been
previously reported. It can be compared to [1,2]anionic rearrange-
ment in N-Boc and N-phosphonate terminal aziridines providing
an access to the corresponding aziridinyl esters and aziridinyl
phosphonates.17 Relevant base-induced migrations of a phosphoryl
group between a heteroatom and carbon have been the subject of
investigations in different laboratories.18 In the case presented
here, rearrangement takes place between carbon atoms in different
electronic environments, being electron deficient due to the pres-
ence of electron-withdrawing substituents and a carbanion. Fur-
ther studies of this reactivity pattern are currently underway in
our laboratory.
11. (a) Nishihata, K.; Nishio, M. Tetrahedron Lett. 1976, 17, 1695; (b) Biellmann, J.
F.; Vicens, J. J. Tetrahedron Lett. 1974, 15, 2915; (c) Durst, T.; Molin, M.
Tetrahedron Lett. 1975, 16, 63; (d) Chassaing, G.; Lett, R.; Marquet, A.
Tetrahedron Lett. 1978, 19, 471; (d) Chassaing, G.; Lett, R.; Marquet, A.
Tetrahedron Lett. 1978, 19, 471.
12. (a) Koppe, F.; Sklute, G.; Polborn, K.; Marek, I.; Knochel, P. Org. Lett. 2005, 7,
3789; (b) Abramovitch, A.; Fensterbank, L.; Malacria, M.; Marek, I. Angew.
Chem., Int. Ed. 2008, 47, 6865.
13. (a) Satoh, T.; Kondo, A.; Musashi, J. Tetrahedron Lett. 2004, 45, 5453; (b)
Hoffmann, R. W.; Nell, P. G. Angew. Chem., Int. Ed. 1999, 38, 338; (c) Hoffmann,
R. W. Chem. Soc. Rev. 2003, 32, 225.
14. Midura, W. H.; Krysiak, J. A.; Mikołajczyk, M. Tetrahedron: Asymmetry 2003, 14,
1245.
15. (+)-(1S,2R)-t-Butyl-2-methyl-2-dimethylphosphonocyclopropanecarboxylate
7a: ½a 2D0
ꢁ
+ 19.4 (c 1.2, acetone) 31P NMR (81 MHz, CDCl3) d: 30.7; 1H NMR
Acknowledgement
(500 MHz, CDCl3) d: 0.94 (ddd, 1H, J = 4.5, 7.75, JPH = 9.37 Hz), 1.30 (d, 3H
JPH = 12.45 Hz, CH3–CP), 1.47 (s, 9H, COC(CH3)3), 1.67 (ddd, 1H, JHH = 4.5, 6.6,
JPH = 16.75 Hz)⁄, 1.72 (ddd, 1H, JHH = 6.6, 7.75, JPH = 9.33 Hz)⁄, 3.74 (d, 3H,
POCH3, J = 10.7 Hz), 3.76 (d, 3H, POCH3, JPH = 10.7 Hz); 13C NMR (125 MHz,
CDCl3): 18.3 (CH2C), 19.0 (d, JCP = 194.0 Hz, CP), 21.8 (d, JCP = 4.7 Hz), 27.9
(COC(CH3)3), 29.4 (d, JCP = 2.9 Hz), 52.5 (d, JCP = 6.3 Hz), 52.9 (d, JCP = 6.2 Hz,
POCH3), 81.0 (COC(CH3)3), 168.4 (d, JCP = 7.1 Hz); MS (CI) m/z 265 [M+H]+;
HRMS (FAB) m/z Calcd for C11H22O5P [M+H]+ 265.1205 Found 265.1211.
16. Cis-9 (dP 28.8 ppm), was not separated in pure form.
We gratefully acknowledge financial support from the Ministry
of Science and Higher Education nr. 2579/B/H03//2010/38.
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