Enantio- and diastereocontrolled conversion of chiral epoxides to trans-cyclopropane carboxylates: Application to the synthesis of cascarillic acid, grenadamide and l-(-)-CCG-II

Article abstract of DOI:10.1039/c2ob25622c

An efficient high yielding improved method for the enantio- and diastereoselective cyclopropanation of chiral epoxides using triethylphosphonoacetate and base (Wadsworth-Emmons cyclopropanation) is reported. The utility of this protocol is illustrated by concise and practical synthesis of cascarillic acid, grenadamide and L-(-)-CCG-II, a cyclopropane containing natural products.

Full text of DOI:10.1039/c2ob25622c

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PAPER
Enantio- and diastereocontrolled conversion of chiral epoxides to
trans-cyclopropane carboxylates: application to the synthesis of cascarillic
acid, grenadamide and L-(−)-CCG-II†
Pradeep Kumar,* Abhishek Dubey and Anand Harbindu
Received 26th March 2012, Accepted 3rd July 2012
DOI: 10.1039/c2ob25622c
An efficient high yielding improved method for the enantio- and diastereoselective cyclopropanation of
chiral epoxides using triethylphosphonoacetate and base (Wadsworth–Emmons cyclopropanation) is
reported. The utility of this protocol is illustrated by concise and practical synthesis of cascarillic acid,
grenadamide and L-(−)-CCG-II, a cyclopropane containing natural products.
Introduction
Cyclopropane ring systems are quite ubiquitous in nature and they
constitute the important structural framework of a large number of
natural products, medicinally active compounds, drugs, agrochemi-
cals, foods and fragrances (Fig. 1).1 They also serve as important
synthetic intermediates in cyclopentannulation by a reaction invol-
ving metal-catalyzed ring-opening of cyclopropanes.2 Therefore
methods to access cyclopropanes in a stereocontrolled manner is
of paramount importance. A great deal of effort has been put by
synthetic organic chemists worldwide into the development of
stereoselective methods for cyclopropanes.3 Some of the com-
monly employed methods include the metal-mediated carbene
insertion into alkenes,4 asymmetric variants of the Simmons–
Smith reaction,5 Corey–Chaykovsky reactions,6 Kulinkovich–de
Meijere reactions,7 and Michael-initiated ring closure reactions.8
Besides in recent years there has been a considerable upsurge of
interest in developing enantioselective methods for cyclopropana-
tion that are based on organocatalysis.9 Despite these advances, on
Fig. 1 Structures of some important cyclopropane containing
molecules.
a commercial scale, the wasteful enzymatic resolution still remains
the method of choice for all practical purposes.10
Way back in 1961, Wadsworth and Emmons developed a
method for the direct conversion of epoxides to cyclopropyl
In some of the earlier reports, it was shown that the trans-
esters.11 This reaction is known to provide straightforward access
formation of epoxide to cyclopropane proceeds in an SN2
to a variety of cyclopropanes from readily available enantiopure
fashion with some degree of inversion at the epoxide stereo-
epoxides and phosphonate.12 Very recently Bray et al. have
explored and extended the scope of this method to the stereocon-
trolled synthesis of quaternary cyclopropyl esters13a and trans-
cyclopropyl sulfones from terminal epoxides.13b
centre.12k,l This crucial observation was further revisited by
Armstrong and Scutt12d who demonstrated that (R)-styrene
oxide/(S)-glycidol benzyl ether can be converted into the corre-
sponding cyclopropane derivatives with complete inversion of
configuration in >95% ee albeit in 51% and 63% yields respec-
tively. Subsequently, the scalability of this process was demon-
strated by researchers from Bristol-Myers-Squibb and Eli Lilly
pharmaceutical research institute for substituted styrene
derived epoxides in appreciable yields and with excellent enan-
tioselectivity.12a,e The previous literature reports known to
produce the cyclopropyl esters lack substrate generality and also
Division of Organic Chemistry, National Chemical Laboratory, Pune
411008, India. E-mail: pk.tripathi@ncl.res.in; Tel: +91-20-25902050;
Fax: +91-20-25902629
†Electronic supplementary information (ESI) available: 1H NMR, 13C
NMR spectra of compounds 3a, 7, 8, 9, 3b, 10, 11, 13, 17, 18, 19, 15,
1c, 3c, 20, 15, 21, 14, experimental procedures of compounds 7, 3b, 12,
18, 19, 15. See DOI: 10.1039/c2ob25622c
This journal is © The Royal Society of Chemistry 2012
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Scheme 1 Diastereocontrolled synthesis of cyclopropyl esters (3a–c).
Scheme 2 Mechanistic pathway for the transformation of epoxides to
cyclopropane carboxylates.
suffer either from poor diastereoselectivity or low yields
(20–60%).11,12f,k,m,n Therefore it was considered worthwhile to
develop a general, high yielding stereo- and enantiocontrolled
method for cyclopropanation, with a view to its application for
the total synthesis of biologically active natural products. Herein
we report our successful endeavors towards stereoselective con-
version of epoxide to trans-selective cyclopropyl esters and its
application to the total synthesis of cascarillic acid, grenadamide
and L-(−)-CCG-II.
while 2 equiv. of phosphonate gave only a 60% yield of 3a, a
substantial improvement in the yield (85%) was observed with 4
equiv. of phosphonate. Thus under the optimised conditions
higher optical (95% ee) and chemical yields (85%) of cyclopro-
pyl ester 3a could be obtained using 4 equiv. of phosphonate
and NaH under reflux toluene. Similar results under identical
reaction conditions provided the required cyclopropyl ester 3b in
85% yield and >99% ee from the corresponding chiral epoxide
1b. Likewise, 1c furnished 3c in 75% yield and >99% ee as a
single diastereomer.
Having optimised the reaction conditions for Wadsworth–
Emmons cyclopropanation, we then turned our attention towards
application of this strategy for the synthesis of cyclopropane con-
taining natural products. Herein we wish to report our successful
endeavours towards the enantioselective synthesis of cascarillic
acid, grenadamide and L-(−)-CCG-II.
Results and discussion
As illustrated in Scheme 1, the enantiopure epoxides (1a–c) were
treated with triethylphosphonoacetate (TEPA) 2 in the presence
of a base to give the trans-selective cyclopropyl esters (3a–c). In
order to examine efficiency and generality of this method, the
reaction with three different substrates (1a–c) was studied using
triethyl phosphonoacetate and NaH as a base. The required
trans-selective14 cyclopropane carboxylates (3a–c) were
obtained in excellent yield and good enantiomeric excess.15 The
reaction mechanism for the formation of trans-selective cyclo-
propyl ester involves ring opening of epoxide 1 with the anion
of phosphonate 2 to give 4 which eventually leads to the cyclic
phosphonate 5. The intermediacy of such an intermediate has
been first proposed by Wadsworth and Emmons for the cyclopro-
panation reaction.11 Subsequent migration of diethyl phosphate
from C to O in the cyclic phosphonate intermediate 5 produces 6
which undergoes stereospecific SN2 intramolecular ring closure
furnishing the corresponding cyclopropyl derivative 3 with com-
plete inversion of configuration at the epoxide centre
(Scheme 2). A clean stereochemical inversion of an aryl epoxide
has been also reported by two groups independently.12d,e
As a part of our research interest aimed at developing new
methodologies16a,b and their application towards the synthesis of
natural products,16c–h we considered developing optimised reac-
tion conditions for stereocontrolled high yielding synthesis of
cyclopropyl esters. Towards this end, we have chosen commer-
cially available (S)-2-hexyloxirane 1a for our study. It is impor-
tant to note that in the Wadsworth–Emmons cyclopropanation
reaction, a better solubility of the TEPA anion in organic solvent
is very important for the efficacy of the reaction. Among the
various solvents screened, toluene and DME (dimethoxyethane)
were found to be the most suitable solvent for this reaction. A
careful monitoring of the reaction revealed that at 80 °C, most of
the epoxide was consumed in ca. 12 h, however, the reaction
mixture contained about 5–10% of intermediates. Once the
epoxide was consumed, the reaction temperature could be raised
to 110 °C to burn off the remaining intermediates. Additionally
Synthesis of cascarillic acid
Cascarillic acid is a cyclopropane containing fatty acid found in
cascarilla essential oil, derived from the bark of the medicinal
shrub Croton eluteria L.17a The oil has been used for many years
to treat the symptoms of cold and influenza as well as respiratory
ailments including bronchitis, via its use as an inhalant. Some
methods reported for the synthesis of the target molecule suffer
either from multisteps, epimerization steps and unwanted protection
and deprotection steps of chiral auxiliary.17 Taking into account the
drawback of reported methods, we considered developing a practi-
cal, concise and high-yielding synthesis of the target molecule
employing the Wadsworth–Emmons cyclopropanation reaction.
The synthetic sequence for the synthesis of cascarillic acid is
shown in Scheme 3. Commercially available (S)-2-hexyloxirane
1a was subjected to optimized Wadsworth–Emmons cyclopropa-
nation to furnish the ester 3a in excellent yield. The ester group
was subjected to reduction with LiAlH4 to furnish alcohol 7 in
80% yield, which was converted into nitrile 8 using a combi-
nation of Me3SiCl–NaCN (1 : 1) and a catalytic amount of NaI
in excellent yield. Finally nitrile 8 was converted into acid 9 by
basic hydrolysis in 75% yield. We thus accomplished the syn-
thesis of cascarillic acid in four steps and 41% overall yield. The
physical and spectroscopic data of 9 were in full agreement with
those reported in the literature.17b
Synthesis of (−)-grenadamide
Grenadamide 13 was isolated from the marine cyanobacterium
Lyngbya majuscula by Sitachitta and Gerwick in 1998.18 The
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Scheme 3 Reagents and conditions: (a) (EtO)2POCH2COOEt, NaH,
toluene, 80 °C (8 h) then 110 °C (6 h), 85%; (b) LiAlH4, THF, −10 °C,
80%; (c) Me3SiCl, NaCN (1 : 1), NaI (cat), DMF–acetonitrile, 65 °C,
80%; (d) 3 N NaOH, MeOH, reflux, 75%.
Scheme 5 Retrosynthetic route to L-CCG-II.
Synthesis of L-(−)-CCG-II
As a pharmacological tool, L-CCG-II 14 has played an important
role for the investigation of the mechanism underlying the gluta-
mate function as well as the design of useful therapeutic drugs of
various neuronal diseases.21 A great deal of attention has been
paid to the modification of these compounds, which has led to
the discovery of several other potent and selective agonists or
antagonists for mGluRsa. Encouraged by our earlier results we
further became interested in extending the scope of optimized
Wadsworth–Emmons cyclopropanation for the total synthesis of
L-CCG-II 14.22 We now wish to report successful application
of our strategy for the synthesis of the target compound from
commercially available cinnamyl alcohol 16 employing Sharp-
less asymmetric dihydroxylation (AD)23 and Wadsworth–
Emmons cyclopropanation as the key steps. Our synthetic
approach for the synthesis of L-CCG-II was envisioned via the
retrosynthetic route as shown in Scheme 5. The compound 14
could be obtained from compound 15 by series of reactions
involving oxidation of the phenyl ring and reduction of azide
into amine. The compound 15 could be derived from 3c by ester
hydrolysis and conversion of alcohol into azide. The compound
3c could be obtained from epoxide 1c by the Wadsworth–
Emmons cyclopropanation reaction. The epoxide 1c in turn
could be easily synthesized by the Sharpless asymmetric dihy-
droxylation (AD) of cinnamyl alcohol 16.
The synthesis of L-CCG-II 14 started from commercially
available cinnamyl alcohol 16 as illustrated in Scheme 6. Cinna-
myl alcohol 16 was subjected to Sharpless asymmetric dihydroxy-
lation using OsO4 and K3Fe(CN)6 as a co-oxidant in the
presence of (DHQ)2PHAL as the ligand to give triol 17 in 84%
yield and 95% ee.24 The regioselective primary monotosyla-
tion25 of triol 17 with tosyl chloride and a catalytic amount of
Bu2SnO furnished the tosyl diol 18 in 89% yield. Base treatment
of compound 18 in the presence of K2CO3 in methanol furnished
epoxy alcohol 19 in 79% yield. The free hydroxy group of 19
was then protected as PMB ether using PMB-bromide to give 1c
in 86% yield. With epoxide 1c in hand, our next aim was to con-
struct the cyclopropane ring.
Scheme 4 Reagents and conditions: (a) (EtO)2POCH2COOEt, NaH,
toluene, 80 °C (8 h) then 110 °C (6 h), 85%; (b) LiCHBr2–(n-BuLi–
tetramethyl piperidine–dibromomethane), −90 °C then n-BuLi, −90 °C
to rt, acidic EtOH, 55%; (c) LiCHBr2–(n-BuLi–tetramethyl piperidine–
dibromomethane), −90 °C then n-BuLi, −90 °C to rt, acidic EtOH,
60%; (d) LiOH, MeOH–H2O (3 : 2), 82%; (e) SOCl2, PhCH2CH2NH2,
4 h, 65%.
structurally unique cyclopropyl fatty acid derived metabolites
were shown to demonstrate cannabinoid receptor binding
activity, as well as cytotoxicity towards cancer cells. Few synth-
eses19 of this molecule have been described, to overcome some
of the drawbacks associated with the reported methods we con-
sidered developing a facile and expeditious synthesis of the
target molecule 13.
The synthesis of (−)-grenadamide started from commercially
available epoxide 1b as illustrated in Scheme 4. The epoxide 1b
was converted into the cyclopropyl ester 3b in 85% yield and
>99% ee.15 The optical purity and stereochemistry was deter-
mined by comparison of the sign of rotation with the literature
values.19d In order to prepare compound 11, we decided to
convert ester 3b into the corresponding aldehyde followed by
the 2-C Wittig reaction, but we observed epimerization of the
chiral center in aldehyde. We then turned our attention towards
sequential homologation of ester. The ester group of compound
3b was double homologated20 to furnish compound 11 in moder-
ate yield over two steps by using a combination of LiCHBr2 and
n-BuLi reagent. The ester hydrolysis under basic conditions
using LiOH furnished acid 12 in 82% yield. Conversion of acid
into acid chloride by using SOCl2 and subsequent coupling with
phenylethylamine furnished grenadamide 13 in 65% yield. The
physical and spectroscopic data of 13 were in full agreement
with those reported.19b
Towards this end, we used the optimized Wadsworth–
Emmons cyclopropanation reaction to furnish 3c as a single dia-
stereomer in 75% yield and >99% ee. In order to introduce an
amino group, PMB-protected hydroxyl was deprotected by DDQ
to furnish the free alcohol 20 in 85% yield. The hydroxyl group
of 20 was converted into O-mesylate, followed by the nucleophi-
lic displacement with NaN3 in dry DMF to afford compound 15
in 85% yield. Compound 15 was then subjected to ester
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After stirring for 10 min, epoxide 1a (5 g, 38.99 mmol) in
20 mL of toluene was added dropwise over 20 min, followed by
heating at 80 °C for 8 h, then raising the temperature up to
110 °C. After completion of the reaction (6 h), the solution was
cooled to room temperature, diluted with EtOAc (100 mL),
then washed with saturated aqueous NH4Cl (100 mL). After
drying over Na2SO4 and concentration in vacuo, the crude
material was purified by flash chromatography using petroleum
ether–EtOAc (98 : 2) as the eluent, to give the desired cyclopro-
pane derivative 3a (6.57 g, 85% yield) as a syrupy colorless oil.
[α]2D5 −58.8 (c 1.2, CHCl3); {lit.:19d [α]D20 +61.9 (c 1.17, CHCl3)
for ent-3a}; IR (neat, cm−1): νmax 2927, 2958, 2856, 1727,
1
1613, 1583, 1452, 1410, 1177, 1097, 757; H NMR (400 MHz,
CDCl3): δ 0.63–0.72 (1H, m), 0.88 (3H, t, J 5.2 Hz), 1.04–1.34
(16H, m), 4.1 (2H, q, J 7.0, 14.2 Hz); 13C NMR (100 MHz,
CDCl3): δ 14.0, 14.2, 15.4, 20.1, 22.5, 22.8, 28.9, 29.0, 31.7,
33.0, 60.2, 174.5; MS(ESI): m/z 221.30 (M + Na)+.
Scheme 6 Reagents and conditions: (a) (DHQ)2PHAL (1 mol%),
0.1 M OsO4 (0.4 mol%), CH3SO2NH2, K2CO3, K3Fe(CN)6, t-BuOH–
H2O (1 : 1), 30 h, 84%; (b) TsCl, Et3N, CH2Cl2, Bu2SnO, 0 °C, 6 h,
89%; (c) K2CO3, MeOH, 15 min, 79%; (d) PMBBr, NaH, THF, 0 °C,
6 h, 86%; (e) (EtO)2POCH2COOEt, NaH, toluene, 80 °C to 110 °C,
14 h, 75%; (f) DDQ, CH2Cl2–H2O (18 : 1), 3 h, 85%; (g) (i) MsCl,
Et3N, DMAP, CH2Cl2, 1 h; (ii) NaN3, DMF, 60 °C, 8 h, 85%; (h) LiOH,
MeOH–H2O (3 : 2), 5 h, 82%; (i) [i] RuCl3, NaIO4, 70 °C, 15 min; [ii]
Pd(OH)2, H2, MeOH, 2 h, for two steps 72%.
2-((1S,2R)-2-Hexylcyclopropyl)acetonitrile (8)
A solution of the alcohol 7 (2.0 g, 12.10 mmol), NaCN (1.25 g,
25.59 mmol), NaI (5–10 mg) in CH3CN (20 mL) and DMF
(10 mL) was deaerated, under an argon atmosphere, and
Me3SiC1 (3.24 mL, 25.29 mmol) was added at room tempera-
ture. The mixture was then placed in a preheated (60–65 °C) oil
bath and heated with stirring for 6 h. After consumption of the
starting material, the mixture was poured into H2O (100 mL) and
the mixture extracted with Et2O (100 mL). The organic phase
was washed with H2O (5 × 50 mL) and with brine (50 mL),
dried (Na2SO4), and concentrated in vacuo. Silica gel column
chromatography of the crude product using petroleum ether–
EtOAc (95 : 5) as the eluent gave 8 (1.69 g, 80% yield) as a pale
yellow color syrupy liquid; [α]2D5 −17.9 (c 1.0, CHCl3); IR (neat,
hydrolysis by using LiOH to furnish the acid 21 in 82% yield.
Compound 21 was subjected to phenyl group oxidation26 by
using a combination of RuCl3·3H2O and NaIO4 to furnish the
diacid 22, which unfortunately underwent decomposition
during work-up and purification. We then decided to directly
proceed to the next step of reduction of azide into amine by
using Pd(OH)2 without column purification of diacid 22 furnish-
ing L-CCG-II 14 in 72% yield (over two steps). The physical and
spectroscopic data were identical with those reported.22c The
overall yield of the target compound 14 was found to be 16%
from nine steps.
1
cm−1): νmax 2927, 2251, 1460, 1215, 668; H NMR (200 MHz,
CDCl3): δ 0.37–0.51 (2H, m), 0.60–0.81 (2H, m), 0.89 (3H, t,
J 6.6 Hz), 1.15–1.5 (10H, m), 2.36 (2H, dd, J 2.3, 6.6 Hz);
13C NMR (50 MHz, CDCl3): δ 11.9, 13.9, 14.0, 18.9,
21.5, 22.5, 29.0, 29.2, 31.7, 33.3, 118.8; MS (ESI): m/z 188.16
(M + Na)+. Elemental analysis (%) calcd for (C11H19N): C,
79.94; H, 11.59; N, 8.47%; Found: C, 79.75; H, 11.70; N,
8.23%.
Conclusion
In summary, we have developed a facile and practical enantio-
selective synthesis of cascarillic acid, grenadamide and L-CCG-II.
The key step involves an improved high yielding direct trans-
formation of epoxide to enantiopure cyclopropane carboxylate.
The synthetic strategy is flexible and would permit maximum
variability in product structure with regard to stereochemical
diversity which is particularly important for making various
synthetic analogues required for the screening of biological
activity.
2-((1S,2R)-2-Hexylcyclopropyl)acetic acid (9)
A solution of nitrile 8 (1.0 g, 6.05 mmol) and 20 mL of 3 N
NaOH in 58 mL of methanol was refluxed for 6 h. Then the
reaction mixture was cooled to 0 °C, acidified to pH 5 with 1 M
aqueous hydrochloric acid, and partitioned between EtOAc and
brine. The organic phase was washed with H2O (1 × 50 mL) and
brine (50 mL), dried (Na2SO4), and concentrated in vacuo. Silica
gel column chromatography of the crude product using pet-
roleum ether–EtOAc (8 : 2) as the eluent gave 9 (0.84 g, 75%
yield) as a pale yellow color syrupy liquid. [α]2D5 −9.8 (c 0.50,
CHCl3); {lit.:17b [α]D25 −10.5 (c 0.553, CHCl3)}; IR (neat,
Experimental section
(1R,2R)-Ethyl 2-hexylcyclopropanecarboxylate (3a)
cm−1): νmax 3420, 2855, 1711, 1458, 1216, 759, 668; H NMR
1
To a suspension of sodium hydride (4.67 g, 116.97 mmol, 60%
in mineral oil) in toluene (100 mL) at 0 °C was added triethyl-
phosphonoacetate (31 mL, 155.99 mmol) dropwise over 30 min.
(400 MHz, CDCl3): δ 0.30–0.37 (2H, m), 0.48–0.64 (1H, m),
0.70–0.91 (4H, m), 1.11–1.47 (10H, m), 2.26 (2H, d, J 7.2 Hz),
9.61 (1H, brs); 13C NMR (100 MHz, CDCl3): δ 12.0, 13.9, 14.1,
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18.9, 22.6, 29.1, 29.3, 32.0, 33.8, 38.9, 179.9; MS (ESI): m/z
CDCl3): δ 0.26–0.28 (2H, m), 0.49–0.53 (1H, m), 0.71–0.85
(1H, m), 0.85 (3H, t, J 6.3 Hz), 1.22–1.49 (15H, m), 1.56–1.66
207.31 (M + Na)+.
(2H, m), 2.28 (2H, t, J 7.3 Hz), 4.13 (2H, q, J 7.0, 14.2 Hz); 13
C
NMR (100 MHz, CDCl3): δ 11.7, 14.1, 14.2, 18.1, 18.8, 22.7,
26.9, 29.3, 29.6, 29.9, 31.9, 32.5, 34.7, 60.1, 173.9; MS (ESI):
m/z 241.33 (M + H)+.
Ethyl-2-((1S,2R)-2-heptylcyclopropyl)acetate (10)
To an ice cooled solution of 2,2,6,6-tetramethylpiperidine
(5.76 g, 33.9 mmol) in 40 mL of THF, n-butyllithium (19.4 mL,
1.6 M in hexane, 31.08 mmol) was added dropwise. This
mixture was added dropwise to a stirred solution of dibromo-
methane (2.17 mL, 31.06 mmol) in 40 mL of THF, cooled with
a −90 °C bath (dry ice–diethyl ether). After 5 min, a solution of
ethyl ester 3b (3 g, 14.12 mmol) in 30 mL of THF was added
dropwise over 15 min, and 10 min later a solution of n-butyl-
lithium (44.15 mL, 1.6 M in hexane, 70.64 mmol) was added
dropwise. The −90 °C cooling bath was replaced with a 30 °C
water bath, and then stirred for 15 min. The reaction mixture
was added via a cannula to a rapidly stirred, ice-cooled solution
of acidic ethanol (prepared from 5 mL of acetyl chloride in
25 mL of absolute ethanol). The mixture was diluted with
200 mL of ether, washed with 10% sulfuric acid, 5% aqueous
sodium bicarbonate, and saturated brine, dried over Na2SO4 and
concentrated under reduced pressure to give a crude product
which was purified by chromatography on silica eluting with pet-
roleum ether–EtOAc (98 : 2) to give homologated ester 10
(1.75 g, 55% yield) as a pale yellow liquid. [α]2D5 −13.99 (c 1.0,
CHCl3); IR (neat, cm−1): νmax 2933, 2874, 1736; 1H NMR
(500 MHz, CDCl3): δ 0.29–0.31 (2H, m), 0.47–0.54 (1H, m),
0.75–0.82 (1H, m), 0.88 (3H, t, J 6.1 Hz), 1.19–1.35 (15H, m),
2.15–2.25 (2H, m), 4.13 (2H, q, J 7.1, 14.1 Hz); 13C NMR
(125 MHz, CDCl3): δ 11.6, 14.1, 14.2, 14.3, 18.6, 22.7, 29.4,
29.6, 31.9, 33.9, 39.2, 60.2, 173.3. Elemental analysis (%) calcd
for C14H26O2: C, 74.29; H, 11.58%; Found: C, 74.33; H,
11.49%.
3-((1R,2R)-2-Heptylcyclopropyl)-N-phenethylpropanamide (13)
3-((1R,2R)-2-Heptylcycloprop-1-yl)propionic acid 12 (100 mg,
0.47 mmol) was treated with thionyl chloride (3 mL) and
refluxed for 2 h. The excess of thionyl chloride was distilled off
to give a residue of 3-((1R,2R)-2-heptylcyclopropyl)propionyl
chloride. The residue was cooled to 5 °C and treated with phenyl-
ethyl amine (0.285 g, 2.35 mmol) under a nitrogen atmosphere.
A white precipitate was formed and the reaction was stirred for
2 h. The mixture was diluted with H2O and the product was
extracted with ether (2 × 20 mL). The combined organic
layers were washed with brine, dried over Na2SO4 and concen-
trated to give a crude product which was purified by chromato-
graphy on silica eluting with petroleum ether–EtOAc (1 : 1) to
give 3-((1R,2R)-2-heptylcyclopropyl)-N-phenethylpropionamide
13 (96 mg, 65% yield) as a pale yellow solid. M.p. 48–49 °C
lit.:19b 46–47 °C; [α]D25 −11.8 (c 1.0, CHCl3); {lit.:19b [α]2D5
−11.0 (c 1.0, CHCl3)}; IR (neat, cm−1): νmax 3320, 2935, 1678,
1560, 1216, 759; 1H NMR (400 MHz, CDCl3): δ 0.28–0.32
(2H, m), 0.51–0.54 (1H, m), 0.75–0.79 (1H, m), 0.86 (3H,
t, J 6.7 Hz), 1.09–1.12 (2H, m), 1.13–1.48 (10H, m), 1.54–1.62
(2H, m), 2.12 (2H, t, J 7.3 Hz), 2.83 (2H, t, J 7.0 Hz), 3.53
(2H, q, J 6.7, 13.0 Hz), 5.43 (1H, brs), 7.19–7.43 (5H, m);
13C NMR (100 MHz, CDCl3): δ 11.4, 14.1, 18.2, 19.5,
22.6, 27.0, 29.3, 29.6, 29.9, 31.9, 32.6, 35.7, 36.9, 40.5,
126.5, 128.7, 138.9, 173.1; MS (ESI): m/z 338.49 (M + Na)+.
Ethyl 3-((1R,2R)-2-heptylcyclopropyl)propanoate (11)
(1S,2S)-1-Phenylpropane-1,2,3-triol (17)
To an ice cooled solution of 2,2,6,6-tetramethylpiperidine (2.7 g,
15.88 mmol) in 40 mL of THF, n-butyllithium (9.1 mL, 1.6 M
in hexane, 14.56 mmol) was added dropwise. This mixture was
added dropwise to a stirred solution of dibromomethane (1 mL,
14.56 mmol) in 40 mL of THF, cooled with a −90 °C bath (dry
ice–diethyl ether). After 5 min, a solution of ethyl ester 10
(1.5 g, 6.62 mmol) in 30 mL of THF was added dropwise over
15 min, and 10 min later a solution of n-butyllithium (20.7 mL,
1.6 M in hexane, 33.1 mmol) was added dropwise. The −90 °C
cooling bath was replaced with a 30 °C water bath, and
then stirred for 15 min. The reaction mixture was added via a
cannula to a rapidly stirred, ice-cooled solution of acidic
ethanol (prepared from 5 mL of acetyl chloride in 25 mL of
absolute ethanol). The mixture was diluted with 200 mL of
ether, washed with 10% sulfuric acid, 5% aqueous sodium bicar-
bonate, and saturated brine, dried over Na2SO4 and concentrated
under reduced pressure to give a crude product which was
purified by silica gel column chromatography with petroleum
ether–EtOAc (96 : 4) to give homologated ester 11 (955 mg,
60% yield) as a colorless syrupy liquid. [α]2D5 −13.00 (c 1,
CHCl3); {lit.:19a [α]D25 +12.5 (c 0.69, CHCl3) for ent-11}; IR
(neat, cm−1): νmax 2938, 2871, 1734; 1H NMR (400 MHz,
To a mixture of K3Fe(CN)6 (73.61 g, 223 mmol), K2CO3
(30.9 g, 223 mmol) and (DHQ)2PHAL (580.55 mg, 1 mol%)
in t-BuOH–H2O (1 : 1, 745.36 mL, 5 mL mmol−1) cooled at
0 °C was added OsO4 (2.98 mL, 0.1 M sol in toluene, 0.4 mol
%) followed by methane sulfonamide (7.08 g, 74 mmol).
After stirring for 5 min at 0 °C, the olefin 16 (10 g, 74 mmol)
was added in one portion. The reaction mixture was stirred at
0 °C for 30 h and then quenched with solid sodium sulfite
(10 g). The stirring was continued for 45 min and the solution
was extracted with EtOAc (5 × 200 mL). The combined organic
phases were washed (10% KOH, then brine), dried (Na2SO4)
and concentrated. Silica gel column chromatography of the
crude product using petroleum ether–EtOAc (3 : 7) as the
eluent gave the triol 17 (10.52 g, 85% yield) as a thick syrupy
liquid. [α]2D5 +20.8 (c 3.5, CHCl3); {lit.:24 [α]2D5 +20.92 (c 3.68,
CHCl3)}; IR (neat, cm−1): 3369, 2932, 1447, 1215, 1008,
770, 702, 668; 1H NMR (400 MHz, CDCl3): δ 3.26–3.36
(2H, m), 3.64–3.69 (1H, m), 4.3 (3H, brs), 4.54 (1H, d,
J 7.1 Hz), 7.23–7.27 (5H, m); 13C NMR (100 MHz, CDCl3): δ
63.0, 74.6, 76.0, 126.7, 127.9, 128.4, 140.5; MS (EI) m/z (%):
191 (M + Na)+.
This journal is © The Royal Society of Chemistry 2012
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(S)-2-((S)-(4-Methoxybenzyloxy)(phenyl)methyl)oxirane (1c)
The resulting mixture was stirred for 3 h at 0 °C. The mixture
was poured into saturated aqueous NaHCO3 and further diluted
with CH2Cl2. The layers were separated and the aqueous layer
was extracted with CH2Cl2 (2 × 20 mL). The combined organic
layers were dried over Na2SO4, filtered, and concentrated. The
solvents were removed under reduced pressure to give the crude
product mixture as a yellow oil. Silica gel column chromato-
graphy of the crude product using petroleum ether–EtOAc (8 : 2)
as the eluent gave 20 (1.09 g, 85% yield) as a colorless solid.
[α]2D5 +11.9 (c 1.0, CHCl3); IR (CHCl3, cm−1): νmax 3343, 3012,
To a solution of epoxy alcohol 19 (2.03 g, 13.51 mmol) in dry
THF (20 mL) was added sodium hydride (60%, 0.810 g,
20.57 mmol) at 0 °C. The reaction mixture was then stirred at
room temperature for 30 min after which it was again cooled to
0 °C. To this was added slowly p-methoxybenzyl bromide
(1.84 mL, 14.86 mmol) and tetra n-butylammonium iodide
(0.50 g, 1.35 mmol) with further stirring for 6 h at room temp-
erature. The reaction mixture was quenched with addition of
cold water at 0 °C. The two phases were separated and the
aqueous phase was extracted with EtOAc (3 × 100 mL). The
combined organic layer was washed with water (3 × 100 mL),
brine, dried (Na2SO4) and concentrated. Silica gel column
chromatography of the crude product using petroleum ether–
EtOAc (93 : 7) as the eluent furnished the PMB protected
epoxide 1c (3.14 g, 86% yield) as a colorless oil. [α]2D5 +41.3 (c
1.8, CHCl3); IR (CHCl3, cm−1): νmax 3031, 2836, 1612, 1513,
1
1612, 1514, 1465, 1249, 1035; H NMR (200 MHz, CDCl3): δ
1.13–1.20 (1H, m), 1.22–1.29 (4H, m), 1.68–2.05 (3H, m), 4.09
(2H, q, J 6.5 Hz), 4.51 (1H, d, J 6.5 Hz), 7.33–7.40 (5H, m);
13C NMR (50 MHz, CDCl3): δ 12.2, 14.1, 17.7, 28.4, 60.5,
73.9, 126, 127.8, 142.8, 173.8; HRMS (EI/DIP) for (M+): calcd
220.10705, Found: 220.10574.
1
1454, 1248, 1173, 1086, 1035, 821, 754; H NMR (400 MHz,
(1R,2R)-2-((S)-Azido(phenyl)methyl)cyclopropanecarboxylic
CDCl3): δ 2.60 (1H, dd, J 2.6, 4.8 Hz), 2.72–2.77 (1H, m),
3.23–3.29 (1H, m), 3.82 (3H, m), 4.10 (1H, d, J = 6.5 Hz),
4.43–4.59 (2H, m), 6.89 (2H, d, J 8.7 Hz), 7.29 (2H, d, J 8.7
Hz), 7.38–7.41 (5H, m); 13C NMR (100 MHz, CDCl3): δ 44.1,
55.1, 55.2, 70.3, 82.1, 113.7, 127.1, 128.2, 128.5, 129.3, 130.0,
138.1, 159.1. Elemental analysis (%) calcd for C17H18O3: C,
75.53; H, 6.71%; Found: C, 75.68; H, 6.84%.
acid (21)
To the ester 15 (400 mg, 1.63 mmol) dissolved in MeOH
(10 mL) and H2O (6.67 mL) was added LiOH·H2O (205 mg,
4.89 mmol) and stirred at 0 °C to room temperature for 5 h. The
reaction mixture was further diluted with H2O (5 mL) and stirred
for 30 min, then concentrated by a rotary evaporator to a quarter
of its volume. The mixture was acidified with 1 M HCl (pH 3)
and the reaction mixture was extracted with EtOAc (3 × 10 mL).
The combined organic layer was washed with brine (2 × 10 mL)
and dried over anhydrous Na2SO4, filtered, evaporated and the
crude product was purified by column chromatography using
petroleum ether–EtOAc (7 : 3) as the eluent to give 21 (255 mg,
82% yield) as a pale yellow color syrupy liquid. [α]2D5 −13.2
(c 0.36, CHCl3); IR (neat, cm−1): νmax 3032, 2862, 2100, 1700,
(1R,2R)-Ethyl-2-((R)-(4-methoxybenzyloxy)(phenyl)methyl)-
cyclopropanecarboxylate (3c)
To a suspension of sodium hydride (1.33 g, 33.29 mmol, 60% in
mineral oil) in toluene (30 mL) was added triethylphosphono-
acetate (8.8 mL, 44.36 mmol) dropwise over 15 min. After stir-
ring at room temperature, epoxide 1c (3 g, 11.09 mmol) in
20 mL of toluene was added dropwise over 10 min, followed by
heating at 80 °C for 8 h and then temperature was raised up to
110 °C for 6 h. The solution was cooled to room temperature,
diluted with ethyl acetate (50 mL), then washed with saturated
aqueous ammonium chloride (50 mL). After drying over
Na2SO4 and concentration in vacuo, the crude material was
purified by flash chromatography using petroleum ether–EtOAc
(96 : 4), to yield the desired cyclopropane carboxylate 3c
(2.83 g, 75% yield) as a thick colorless oil. [α]2D5 +9.3 (c 1.0,
CHCl3); IR (CHCl3, cm−1): νmax 2927, 2957, 2855, 1729, 1624,
1456, 1375, 1215, 1027, 759, 669; 1H NMR (400 MHz,
CDCl3): δ 1.10–1.27 (5H, m), 1.69–1.85 (2H, m), 3.82 (3H, s),
4.08 (2H, q, J 2.1, 7.2 Hz), 4.2 (2H, ABq, J 11.2 Hz), 4.46
(1H, d, J 4.2 Hz), 6.7 (2H, d, J 8.2 Hz), 7.22–7.40 (7H, m);
13C NMR (100 MHz, CDCl3): δ 12.6, 14.2, 17.5, 27.9, 55.2,
60.4, 69.8, 71.4, 76.4, 77.6, 79.7, 113.7, 127.0, 128.5,
129.2, 129.4, 130.2, 140.8, 159.1, 173.9; MS(ESI): m/z 363.30
(M + Na)+; HRMS (EI/DIP) for (M+): calcd 340.14909, Found:
340.1437.
1
1601, 1455, 1431, 1290, 1229, 1161, 1074, 738, 700; H NMR
(400 MHz, CDCl3): δ 1.06–1.41 (2H, m), 1.68–2.03 (2H, m),
4.31 (1H, d, J 6.5 Hz), 7.13–7.47 (5H, m), 10.05 (1H, brs); 13C
NMR (100 MHz, CDCl3): δ 13.1, 13.8, 26.9, 66.1, 126.9, 128.7,
128.9, 138.1, 179.6. Elemental analysis (%) calcd for
C11H11N3O2: C, 75.75; H, 12.71; N, 7.62%; Found: C, 75.87;
H, 12.48; N, 7.91%.
(1R,2R)-2-((S)-Amino(carboxy)methyl)cyclopropanecarboxylic
acid (14)
Compound 21 (100 mg, 0.460 mmol) was dissolved in a mixture
of CCl4 (4 mL), CH3CN (4 mL) and distilled H2O (8 mL). The
vigorously stirred mixture was heated to reflux temperature. Sub-
sequently NaIO4 (2.95 g, 13.8 mmol) and fresh RuCl3 hydrate
(14 mg, 0.069 mmol) were added. The colour changed from
black via orange to yellow within 2 min, after which the hetero-
geneous mixture was poured into a mixture of DCM and ice
water (1 : 1). After stirring for 30 min, the pH of the mixture was
adjusted to 10 with aq. NaOH (3 M) and the mixture was
extracted with DCM. The aq. layer was acidified with conc. HCl
(pH < 3) and extracted with EtOAc (10 × 5 mL). The combined
organic extracts were dried (Na2SO4) and concentrated to diacid
22 as a brown color syrupy liquid. This was directly used for the
next step.
(1R,2R)-Ethyl 2-((R)-hydroxy(phenyl)methyl)cyclopropane-
carboxylate (20)
To a stirring solution of PMB ether 3c (2 g, 5.87 mmol) in
CH2Cl2–H2O (20 : 1) was added DDQ (2.66 g, 11.75 mmol).
6992 | Org. Biomol. Chem., 2012, 10, 6987–6994
This journal is © The Royal Society of Chemistry 2012

View Online
S. V. Ley and M. J. Gaunt, Angew. Chem., Int. Ed., 2004, 43, 4641;
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10 For a recent example, see: P. L. Beaulieu, J. Gillard, M. D. 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.
To a solution of 22 (60 mg, 0.324 mmol) in methanol (4 mL)
was added in portions 10% Pd(OH)2 (10 mg, 0.0810 mmol), and
the mixture was hydrogenated under H2 and at room temperature
for 2–2.5 h. The reaction mixture was filtered through a pad of
Celite and concentrated under reduced pressure. The residue was
11 W. S. Wadsworth and W. D. Emmons, J. Am. Chem. Soc., 1961, 83,
1733.
+
dissolved in water and purified on Amberlite CG-50 resin (NH4
form), eluting with 1.5% aq. NH4OH to furnish 14 (52 mg, 72%
yield) as a colorless crystalline solid. M.p. 255–256 °C; [lit.22c
M.p. 255–258 °C], [α]2D5 −19.7 (c 0.51, H2O), {lit.:22c [α]2D5
12 (a) L. Delhaye, A. Merschaert, P. Delbeke and W. Brione, Org. Process
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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, 1790;
(l) I. Tömösközi, Tetrahedron, 1966, 22, 179; (m) D. B. Denney, J. J. Vill
and M. J. Boskin, J. Am. Chem. Soc., 1962, 84, 3944; (n) T. Meul,
P. Weinhold and A. G. Lonza, Eur. Pat., 491330, 1992; (o) D. L. J. Clive
and S. Daigneault, J. Chem. Soc., Chem. Commun., 1989, 332;
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(b) C. D. Bray and G. D. Faveri, J. Org. Chem., 2010, 75, 4652.
14 The assignment of the trans relationship between the R-group and ester
of 3a and 3b was based on 1H NMR spectroscopy where the methylene
hydrogen of ester functionality resonated with a highly diagnostic
downfield chemical shift of >4 ppm. According to the literature report,
the methylene proton of the cis compound is known to exhibit an upfield
shift to 3.74; for a detailed explanation to distinguish cis and trans-cyclo-
propyl ester, see the ESI† of: P. Panne, A. DeAnglesi and J. M. Fox, Org.
Lett., 2008, 10, 2987.
1
−20.2 (c 0.51, H2O)}; H NMR (500 MHz, D2O): δ 1.22 (1H,
ddd, J 5.0, 6.3, 8.9 Hz), 1.36 (1H, ddd, J 5.0, 4.9, 8.9 Hz) 1.84
(1H, dddd, J 4.1, 6.3, 8.9, 8.9 Hz), 2.01 (1H, ddd, J 5.0, 4.9, 8.9
Hz), 3.55 (1H, d, J 9.8 Hz); 13C NMR (125 MHz, D2O): δ 13.5,
19.5, 21.9, 56.8, 172.4, 177.3.
Acknowledgements
A. D. thanks CSIR New Delhi and A. H. thanks UGC New
Delhi for senior research fellowships. Financial support from
DST, New Delhi (grant no. SR/S1/OC-44/2009) is gratefully
acknowledged. We would like to thank Mrs S. S. Kunte for
HPLC analysis.
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This journal is © The Royal Society of Chemistry 2012