Stereocontrolled synthesis of quaternary cyclopropyl esters

Article abstract of DOI:10.1039/c0cc01333a

Treatment of a variety of enantiopure terminal epoxides with the anion of a range of 2-substituted triethylphosphonoacetates leads to an array of quaternary cyclopropyl esters with high yield and diastereocontrol.

Full text of DOI:10.1039/c0cc01333a

View Online / Journal Homepage / Table of Contents for this issue
COMMUNICATION
www.rsc.org/chemcomm | ChemComm
Stereocontrolled synthesis of quaternary cyclopropyl estersw
Christopher D. Bray* and Fabrizio Minicone
Received 10th May 2010, Accepted 22nd June 2010
DOI: 10.1039/c0cc01333a
Treatment of a variety of enantiopure terminal epoxides with the
anion of a range of 2-substituted triethylphosphonoacetates
leads to an array of quaternary cyclopropyl esters with high
yield and diastereocontrol.
the scaleability of this process has been demonstrated by
Merschaert2a and Singh2e and their respective colleagues
at Bristol-Myers-Squibb and Eli Lilly, who carried out
Wadsworth–Emmons reactions at pilot-plant scale to give up
to 14 kg of cyclopropane product. Thus, the excellent yields
and high trans-selectivities obtained for this process coupled
with the ready availability of enantiopure epoxides7 and
phosphonate esters provide potential access to a range of
enantiopure cyclopropanes in a very straightforward manner.
In spite of this, at present, the reaction is almost exclusively
limited to the synthesis of cyclopropanes from triethyl-
phosphonoacetate,2 little is known of the substrate generality
and the origin of the high trans-selectivity remains a fundamental
unanswered question. More importantly from a synthetic
point of view, there are no reports of the formation of
quaternary cyclopropyl esters from terminal epoxides other
than for oxirane itself2g,h and hence nothing is known of the
diastereoselectivity of such a process.
In 1961, Wadsworth and Emmons described the utility of
phosphonate carbanions in synthesis.1 The olefination method
they described is now a cornerstone reaction in synthetic
chemistry, so it is astonishing that the related conversion of
epoxides to trans-cyclopropyl esters also disclosed in this
seminal paper is seldom employed.2 Cyclopropanes are found
widely in natural products, medicinally active compounds,
drugs, agrochemicals, foods and fragrances (Fig. 1),3 as well
as being highly versatile synthetic intermediates.4 As such,
there exists a substantial number of elegant methods for the
stereocontrolled synthesis of cyclopropanes5 which are now
widely employed in natural product syntheses and medicinal
chemistry.
In the present work, we have sought to investigate the origin
of the diastereocontrol and have explored whether the
Wadsworth–Emmons cyclopropanation provides a feasible
route to quaternary cyclopropyl esters. We began by examining
the reaction between the lithium anion of commercially available
triethyl phosphonopropionate (generated by deprotonation
with n-BuLi (1.05 equiv.)) and (S)-styrene oxide (Scheme 1).
Optimal reaction conditions were found when heating this
anion (2.00 equiv.) with the epoxide at 130 1C in DME for
20 h.8 This gave the known9 cyclopropane 1a in 95% yield and
with a dr of >98 : 2 (GCMS).10
In spite of these advances, the continued prevalence of
routes involving wasteful enzymatic resolution methods at
pilot-plant capacity and above stands as an indictment of
the current methods with respect to scale.6 Alternative
(industrially applicable) methods for the stereocontrolled
preparation of cyclopropanes are therefore still of significant
interest. In light of this, the Wadsworth–Emmons cyclo-
propanation process has received far less interest than it
might merit. The reaction is stereospecific and so levels of
enantiomeric excess in the epoxide starting materials are reliably
translated into the cyclopropane products.2a–e Additionally,
We next sought to determine if this method of generating
trisubstituted cyclopropanes had broad scope (Table 1). Ethyl,
propyl, benzyl and allyl substituted phosphononate esters all
gave excellent yields (86–97%) for the corresponding quaternary
stereocentre containing cyclopropanes 1b–e (entries 2–5). It is
of note that despite the increasing steric bulk of these
substituents, the diastereoselectivity of this process was not
unduly affected. In each case, prior to and following chromato-
graphic purification, the cyclopropane product was obtained
with >98 : 2 dr. In the case of cyclopropane 1e, one could
envisage using the allyl substituent as a synthetic handle either
by way of a metathesis (vide infra) or via an oxidative process
e.g. ozonolysis. We next examined the scope of the epoxide in
Fig. 1 Important cyclopropane containing molecules.
Queen Mary University of London, School of Biological and Chemical
Sciences, Mile End Road, London, E1 4NS, UK.
E-mail: c.bray@qmul.ac.uk; Fax: +44 (0)20 7882 7427;
Tel: +44 (0)20 7882 3271
w Electronic supplementary information (ESI) available: Spectro-
scopic data along with 1H and 13C NMR spectra for compounds
1a–l and 2. See DOI: 10.1039/c0cc01333a
Scheme 1 Stereocontrolled synthesis of a quaternary cyclopropyl
ester.
ꢀc
This journal is The Royal Society of Chemistry 2010
Chem. Commun., 2010, 46, 5867–5869 | 5867

View Online
Table 1 Examination of reaction scopea
uneventfully converted to cyclopropane 1h (entry 8), which in
its debenzylated form12 has previously been used in the
synthesis of cyclopropyl carbocyclic nucleosides containing
quaternary stereogenic centres. Epifluorohydrin and (R)-3-
chlorostyrene oxide also gave the expected cyclopropanes
1i13 and 1j (entries 9 and 10) in good yield. The conversion
of (R)-N-(2,3-epoxypropyl)phthalamide to cyclopropylamine
1k (entry 11) is of note since Kennewell et al. have described
how related compounds function as unusual g-aminobutyric
acid analogues with restricted rotation that proved to be
potent in GABA receptor binding studies.14 Epoxides
bearing simply alkyl chains were also effectively converted to
cyclopropanes e.g. 1l (entry 12), which opens up the possibility
of synthesising a range of unusual cyclopropane-containing
fatty acids.
Yieldb
(%)
Entry Epoxide
R0 Cyclopropane
1
Me
1a 95
2
3
4
Et
Pr
Bn
1b 97
1c 93
1d 98
Unequivocal evidence of the syn-relationship between the
alkenyl substituents of cyclopropane 1l was established by
conversion to cycloheptene 2 (Scheme 2) via ring-closing
metathesis with Grubbs 1st generation catalyst (5 mol%).
This process therefore also demonstrates the potential of the
present method for the synthesis of (enantiopure) medium-sized
rings bearing cyclopropanes.
For the reaction of epoxides with the anion of 2-substituted
triethylphoshonoacetates 3, cyclopropane formation would
appear to proceed via SN2-opening of the epoxide ring
(Scheme 3, step 1), transfer of P(O)(OEt)2 to the resultant
alkoxide of 4 to give 5 (step 2), and finally ring-closure with
loss of diethylphosphate (step 3). In reactions involving the
triethylphosphonoacetate anion (3, R0 = H), Wadsworth and
Emmons attributed trans-selectivity to initial formation
of a mixture of cyclopropane ring geometries followed by
equilibration to the thermodynamically more stable trans-
isomer under the reaction conditions.1 Barring the unlikely
possibility that once formed, the cyclopropane ring reversibly
reopens either via an ionic or even a radical process, the
present work does not support this original hypothesis, but
rather, it is consistent with a highly diastereoselective elimination
of diethylphosphate during the reaction pathway i.e. 5 - 1.
Given that the steric requirements for an ethyl ester and R0 in
5 are not vastly different, this selectivity would not appear to
5
Allyl
1e 86
6
7
8
Bn
Bn
Me
1f 75
1g 76
1h 78
9
Bn
Et
1i 75
1j 73
10
11
Et
1k 57
1l 86
Scheme 2 Formation of a [5.1.0]-bicyclic ester.
12
Allyl
a
Reactions carried out with phosphonate (2 equiv.) at 130 1C in DME
for 20 h. Percentage isolated yield following column chromatography.
b
this process. Owing to their volatility, substrates such as
(R)-propylene oxide and (S)-1,2-epoxybutane were potentially
challenging, however these were successfully converted to the
corresponding a-benzylcyclopropyl esters 1f and 1g (entries 6
and 7) albeit in slightly diminished yields to those obtained
when using (S)-styrene oxide.11 (R)-Benzyl glycidyl ether was
Scheme 3 Reaction pathway for cyclopropane formation.
ꢀc
This journal is The Royal Society of Chemistry 2010
5868 | Chem. Commun., 2010, 46, 5867–5869

View Online
be solely due to steric interactions but rather, it would imply a
more deep seated stereoelectronic effect.15 We are endeavouring
to obtain experimental as well as computational evidence for
the origin of this diastereocontrol, including the possible
existence of chelated intermediates during the reaction process
such as those suggested by Merschaert and Krawczyk.16,17
In conclusion, we have demonstrated that quaternary
cyclopropyl esters can be formed in high yield using the
Wadsworth–Emmons cyclopropanation from readily available
epoxides and 2-substituted phosphonoacetates. The stereo-
chemistry of the epoxide is transferred into the newly formed
all carbon stereocentre with high diastereocontrol. This
control likely arises due to an electronically governed
diastereoselective ring-closure rather than an equilibration of
the products as was originally suggested by Wadsworth and
Emmons. The present method proceeds without the need for
hazardous precursors (e.g. diazo compounds) or any costly
metals or ligands and since the process is under substrate
control, laborious optimisation of conditions is not required
for each reaction. The Wadsworth–Emmons cyclopropanation
might now be considered as one of simplest methods for the
synthesis of an all carbon stereocentre.
6 For a recent example, see: P. L. Beaulieu, J. Gillard, M. Bailey,
C. Boucher, J. S. Duceppe, B. Simoneau, X. J. Wang, L. Zhang,
K. Grozinger, I. Houpis, V. Farina, H. Heimroth, T. Krueger and
J. Schnaubelt, J. Org. Chem., 2005, 70, 5869.
7 (a) M. Amatore, T. D. Beeson, S. P. Brown and D. W.
C. MacMillan, Angew. Chem., Int. Ed., 2009, 48, 5121;
(b) O. A. Wong and Y. Shi, Chem. Rev., 2008, 108, 3958;
(c) S. E. Schaus, B. D. Brandes, J. F. Larrow, M. Tokunaga,
K. B. Hansen, A. E. Gould, M. E. Furrow and E. N. Jacobsen,
J. Am. Chem. Soc., 2002, 124, 1307.
8 (1R,2S)-Ethyl 1-methyl-2-phenyl-cyclopropanecarboxylate 1a: to a
solution of triethyl 2-phosphonopropionate (0.42 cm3, 2.00 mmol)
in DME (4.0 cm3) at 25 1C was added n-butyllithium (2.5 M,
0.82 cm3, 2.05 mmol) dropwise over 5 min. (S)-Styrene oxide
(114 ml, 1.00 mmol) was added in one portion. The reaction was
heated to 130 1C for 20 h. The reaction was cooled before sat. aq.
NH4Cl (8 cm3) was added. The reaction was extracted three times
with Et2O (3 ꢁ 20 cm3). The organic layers were combined, dried
over MgSO4 and filtered before the solvent was removed in vacuo.
The residue was dry loaded onto silica (5 cm3) and purified by flash
column chromatography (4% EtOAc/petrol) to give the title
compound 1a (195 mg, 95%) as colourless oil: [a]D ꢂ142.0
(c 1.7, Me2CO); nmax/cmꢂ1 1714, 1603, 1499, 1454, 1381, 1311,
1240, 1206, 1151, 1112, 1078, 1060, 1026; dH (400 MHz, CDCl3)
7.26–7.08 (5H, m, Ph), 4.10 (2H, q, J 7.1, OCH2), 2.73 (1H, dd,
J 9.2 and 7.0, CH), 1.61 (1H, dd, J 9.2 and 4.5, CH(H)), 1.21 (3H, t,
J 7.1, CH2Me), 1.08 (1H, dd, J 7.0 and 4.5, CH(H)), 0.91 (3H, s,
Me); dC (100 MHz, CDCl3) 175.6, 137.0, 129.3, 128.1, 126.6, 60.7,
31.6, 25.1, 19.9, 14.5, 14.2; m/z 205.1223 (M + H+. C13H17O2
requires 205.1223).
9 P. Panne, A. DeAngelis and J. M. Fox, Org. Lett., 2008, 10, 2987.
10 The assignment of the syn-relationship between the phenyl ring
and the methyl group of 1a was based on 1H NMR spectroscopy
where the methylene hydrogens of the ester functionality resonated
with a highly diagnostic chemical shift of 4.10 ppm. The corres-
ponding methylene protons of the epimer display a diagnostic
upfield shift to 3.74 ppm due to the proximity of the phenyl group.
For a detailed explanation of how this, and further diagnostic
differences, can be used to distinguish cis and trans-cyclopropyl
esters, see the ESI of ref. 9.
11 We believe that the lower yields are on account of the volatility of
the products, which possessed fruity odours.
´
12 E. Muray, J. Rife, V. Branchadell and R. M. Ortuno, J. Org.
Chem., 2002, 67, 4520.
13 Cyclopropanes bearing 18F-fluorine have been synthesised as medicinal
building blocks for use in positron emission tomography (PET), see:
Notes and references
1 W. S. Wadsworth and W. D. Emmons, J. Am. Chem. Soc., 1961,
83, 1733.
2 Examples of Wadsworth–Emmons cyclopropanation are:
(a) L. Delhaye, A. Merschaert, P. Delbeke and W. Brione, Org.
Process Res. Dev., 2007, 11, 689; (b) M. Khurram, N. Qureshi and
M. D. Smith, Chem. Commun., 2006, 5006; (c) A. Armstrong and
J. N. Scutt, Chem. Commun., 2004, 510; (d) A. Armstrong and
J. N. Scutt, Org. Lett., 2003, 5, 2331; (e) A. K. Singh, M. N. Rao,
J. H. Simpson, W. S. Li, J. E. Thornton, D. E. Kuehner and
D. J. Kacsur, Org. Process Res. Dev., 2002, 6, 618; (f) T. E. Jacks,
H. Nibbe and D. F. Wiemer, J. Org. Chem., 1993, 58, 4584;
(g) R. C. Petter, S. Banerjee and S. Englard, J. Org. Chem.,
1990, 55, 3088; (h) R. C. Petter, Tetrahedron Lett., 1989, 30, 399;
(i) B. J. Fitzsimmons and B. Fraser-Reid, Tetrahedron, 1984, 40,
1279; (j) R. G. Ghirardelli, J. Am. Chem. Soc., 1973, 95, 4987;
(k) R. A. Izydore and R. G. Ghiradelli, J. Org. Chem., 1973, 38,
P. J. Riss and F. Rosch, Org. Biomol. Chem., 2008, 6, 4567.
¨
14 P. D. Kennewell, S. S. Matharu, J. B. Taylor, R. Westwood and
P. G. Sammes, J. Chem. Soc., Perkin Trans. 1, 1982, 2563.
15 On the assumption that initial epoxide ring-opening by the
phosphonate anion is not entirely diastereoselective, then these
results are consistent with those of Krawczyk and co-workers who
demonstrated that a mixture of diastereomers of a range of
lactones, such as 6, converged to give cyclopropanes e.g. (ꢃ)-1d
in which the alkyl/aryl substituents are cis-oriented, presumably
proceeding via 4d on treatment with NaOEt, see ref. 2q
1790; (l) I. Tomoskozi, Tetrahedron, 1966, 22, 179. For the
¨
¨
¨
analogous, but less facile use of phosphoranylidenes, see:
(m) D. B. Denney, J. J. Vill and M. J. Boskin, J. Am. Chem.
Soc., 1962, 84, 3944. For related approaches, see: ; (n) C. Clarke,
D. J. Fox, D. S. Pedersen and S. Warren, Org. Biomol. Chem.,
2009, 7, 1329; (o) C. Clarke, S. Foussat, D. J. Fox, D. S. Pedersen
and S. Warren, Org. Biomol. Chem., 2009, 7, 1323;
(p) H. Krawczyk, K. Wa˛sek and J. Ke˛dzia, Synthesis, 2009,
1473; (q) H. Krawczyk, K. Wa˛sek, J. Ke˛dzia, J. Wojciechowski
and W. M. Wolf, Org. Biomol. Chem., 2008, 6, 308; (r) D. J. Fox,
S. Parris, D. J. Pedersen, C. R. Tyzack and S. Warren, Org.
Biomol. Chem., 2006, 4, 3108.
3 (a) F. Brackmann and A. de Meijere, Chem. Rev., 2007, 107, 4493;
(b) L. A. Wessjohann, W. Brandt and T. Thiemann, Chem. Rev.,
2003, 103, 1625; (c) W. A. Donaldson, Tetrahedron, 2001, 57, 8589.
4 (a) C. A. Carson and M. A. Kerr, Chem. Soc. Rev., 2009, 38, 3051;
(b) M. Rubin, M. Rubina and V. Gevorgyan, Chem. Rev., 2007,
107, 3117.
5 (a) S. R. Goudreau and A. B. Charette, Angew. Chem., Int. Ed.,
2010, 49, 486; (b) H. Pellissier, Tetrahedron, 2008, 64, 7041;
(c) E. M. McGarrigle, E. L. Myers, O. Illa, M. A. Shaw,
S. L. Riches and V. K. Aggarwal, Chem. Rev., 2007, 107, 5841;
(d) G. Maas, Chem. Soc. Rev., 2004, 33, 183; (e) H. Lebel,
J. F. Marcoux, C. Molinaro and A. B. Charette, Chem. Rev.,
2003, 103, 977; (f) Catalytic Asymmetric Synthesis, ed. I. Ojima,
Wiley-VCH Inc, New York, 2nd edn, 2000, p. 864; (g) M. P. Doyle
and D. C. Forbes, Chem. Rev., 1998, 98, 911.
16 A 7-membered chelate intermediate has been proposed by
Merschaert et al. to explain the high diastereoselectivities
(>98 : 2) obtained in the synthesis of (R,R)-2-methylcyclo-
propanecarboxylic acid where only moderate steric effects are
involved, see ref. 2a. A closely related 9-membered ring chelate
has also been used to explain the high levels of trans-stereochemical
control seen when cyclopropyl esters are formed when independently
prepared analogues of 4 are generated with base, see: ref. 2q.
17 There are two examples of 1-(benzotriazol-1-yl)alkyldiphenyl
phosphine oxide anions reacting with styrene oxide. This also gave
a single diastereomer of the cyclopropane product in which the
aryl/alkyl groups are cis-oriented, see: A. R. Katrizky, H. Wu,
L. Xie and J. Jiang, J. Heterocycl. Chem., 1995, 32, 595.
ꢀc
This journal is The Royal Society of Chemistry 2010
Chem. Commun., 2010, 46, 5867–5869 | 5869