The first total synthesis of natural grenadamide

Article abstract of DOI:10.1039/b513774h

A concise, high yielding route to the naturally occurring enantiomer of grenadamide utilizing a 3,6-disubstituted 1,2-dioxine starting material is presented. The route allows for ease in synthesizing grenadamide derivatives varying at cyclopropyl carbons

Full text of DOI:10.1039/b513774h

View Article Online / Journal Homepage / Table of Contents for this issue
PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
The first total synthesis of natural grenadamide†
Thomas D. Avery, Julie A. Culbert and Dennis K. Taylor*
Received 28th September 2005, Accepted 4th November 2005
First published as an Advance Article on the web 12th December 2005
DOI: 10.1039/b513774h
A concise, high yielding route to the naturally occurring enantiomer of grenadamide utilizing a
3,6-disubstituted 1,2-dioxine starting material is presented. The route allows for ease in synthesizing
grenadamide derivatives varying at cyclopropyl carbons 2 and 3, with access to both enantiomers.
Evidence for phosphorus-assisted deprotonation of 1,2-dioxines is also discussed.
clopropanation sequence, trisubstituted cyclopropanes exhibiting
the desired stereochemistry can be rapidly generated, Scheme 1.4a,b
Introduction
Grenadamide is a naturally occurring cyclopropyl amide isolated
along with debromogrenadadiene and grenadadiene by Gerwick
and Sitachitta from marine cyanobacterium Lyngbya majuscula.1
Cascarillic acid is another related trans-cyclopropyl fatty acid
isolated from the bark of Croton eluteria Benett, a West Indian
tree-like shrub.2 These natural products are all based on a simple
trans-substituted cyclopropyl fatty acid core, Fig. 1.
Fig. 1 Natural products containing related trans-cyclopropyl fatty acid
cores.
Grenadamide exhibits modest activity in cannabinoid receptor
binding activity assays and brine shrimp toxicity.1 In order
to optimize the biological activity and deduce any structure–
activity relationships, derivatives of grenadamide are required.
Modification of the grenadamide structure at the amide linkage
can be easily achieved through the carboxylic acid, with the more
synthetically challenging motifs being at carbons 2 and 3 of the
cyclopropyl ring.
Non-natural grenadamide has recently been synthesized by
Baird et al. using an enantioselective enzymatic hydrolysis to
generate the required chiral starting material.3 This synthesis
allowed the absolute stereochemistry of natural grenadamide to
be determined.
Scheme 1
Retrosynthetically we could achieve a rapid synthesis of grena-
damide through the Arndt–Eistert homologation/amidation of
carboxylic acid 2 which in turn could be obtained via hydrol-
ysis of ester 3, Scheme 2. Ester 3 could be synthesized by
Baeyer–Villiger oxidation of aromatic ketone 4, which can be
derived from cyclopropane 5a by ester hydrolysis and Barton
decarboxylation. Finally, cyclopropanes of type 5a containing
the required stereochemical relationships can be obtained via
the aforementioned diastereoselective cyclopropanation protocol
from 1,2-dioxine 6a.4a,b This provides us with a route capable of
introducing variation of cyclopropyl substituents at C2 and C3
and provides us with a suitable intermediate carboxylic acid with
which to modify the amide linkage.
Discussed in this paper is the concise synthesis of (+)- and (−)-
grenadamide using the coupling of an intermediate cyclopropyl
carboxylic acid with Evans’ auxiliary as the method by which
the enantiomers were resolved. Utilizing a diastereoselective cy-
Department of Chemistry, University of Adelaide, South Australia, 5005,
Australia. E-mail: dennis.taylor@adelaide.edu.au
† Electronic supplementary information (ESI) available: Variable temper-
ature NMR studies. See DOI: 10.1039/b513774h
In order to accommodate the Baeyer–Villiger reaction in terms
of reaction rate and functional group migration, an electron rich
This journal is
The Royal Society of Chemistry 2006
Org. Biomol. Chem., 2006, 4, 323–330 | 323
©

View Article Online
Table 1 Optimization of cyclopropanation
Isolated yield
(5:9:10:11, %)
Entrya
1,2-Dioxine
Reaction time
1
2
6a
6b
6c
6d
6b
6b
6b
6b
6b
6b
6b
6a
15 days
30 days
4 days
7 days
2 days
30 days
30 days
31 days
32 days
2 days
1 day
55:20:0:0
50:22:0:8
78:0:0:0
3b
4
52:18:0:0
11:5:0:0d
0:0:35:58f
46:24:0:9
15:6:11:24i
24:15:6:13
81:0:0:0
5c
6e
7g
8h
9j
10k
11l
12k
11:11:0:0m
83:0:0:0
2 days
a Reactions were carried out using 1.1 equiv. LiBr and 1.4 equiv.
t
=
Ph3P CHCO2 Bu in DCM at a concentration of 0.06 M with respect
to 1,2-dioxine unless otherwise stated. b Reaction was carried out using
1.2 equiv. Ph3P CHCO2 Bu in DCM at a concentration of 0.2 M with
t
=
respect to 1,2-dioxine. c Reaction carried out in CHCl3 at reflux. d Major
product was corresponding furan from cyclization and dehydration of cis-
c-hydroxy enone intermediate.4a e Reaction carried out in the presence
of 0.1 equiv. LiBr. f Yields adjusted to account for 58% reclaimed
starting material. g Reaction carried out in the absence of light. h Reaction
photolyzed for 5 h each day for the first two days of reaction with a sun
lamp. i Yields adjusted to account for 47% reclaimed starting material.
j Reaction carried out in the presence of 1.1 equiv. of TEMPO. k Reaction
Scheme 2 Retrosynthetic analysis.
aromatic system is required.4b For ease of synthesis and functional
group compatibility, the 4-methoxybenzene system was utilized.
1,2-Dioxines are effectively synthesized through photo-
oxidation of their corresponding 1,3-dienes in the presence
of a photosensitizer. Synthesis of the required 1,3-diene 8a
was achieved in 77% yield via the Wittig coupling of 4-
methoxycinnamaldehyde 7a and octyltriphenylphosphonium io-
dide. Photolysis of 1,3-diene 8a in the presence of oxygen and rose
bengal bis(triethylammonium) salt gave the desired 1,2-dioxine 6a
in 37% yield, Scheme 3. 1,3-Diene 8a was reclaimed as the other
major component of the photolysis and was able to be recycled.
l
carried out in the presence of triethylamine. Reaction carried out in the
presence of 0.1 equiv. of Co(II)-salen. m 24% bis(epoxide)s isolated.5
this alteration in reaction mechanism. This was confirmed by the
synthesis of analogue 6d, which showed formation of cyclopropane
9d when subjected to the reaction conditions, entry 4.
Scheme 4
Scheme 3 a, Octyltriphenylphosphonium iodide (1.45 equiv.), KOtBu
(1.45 equiv.), THF, 0 ◦C → rt, 16 h. b, O2, rose bengal bis(triethyl-
ammonium) salt (cat.), DCM, hm, 5 ◦C, 6 h.
The first step in cyclopropanation is removal of the most
acidic proton adjacent to the O–O linkage of the 1,2-dioxine,
which induces rearrangement to give the cis-c-hydroxy enone 12,
Scheme 5. The cis-c-hydroxy enone undergoes Michael addition
and concomitant P–O bond formation with the stabilized phos-
phorus ylide giving an oxaphospholane intermediate ultimately
leading to cyclopropane 5.4b,c
It is this first step along the reaction pathway that is being
inhibited by the presence of the extended alkyl chain, as we see
no appreciable decomposition of 1,2-dioxine over these extended
reaction times. If the rearrangement to cis-c-hydroxy enone was
occurring rapidly we would expect to see cis-c-hydroxy enone
formation followed by 1,4-diketone formation through its base
Reaction of the tert-butyl ester ylide with 1,2-dioxine 6a gave
expected cyclopropane 5a in 55% yield with isomer 9a making up
the bulk of the remaining isolable reaction products, Table 1, entry
1 (Scheme 4).
Cyclopropane 5a was the expected and desired product, how-
ever, cyclopropane 9a was, unusually, the product resulting from
1,2-dioxine ring-opening through removal of the least acidic
proton; that adjacent to the heptyl side-chain. This isomer had
not previously been observed when subjecting 1,2-dioxine 6c to
identical reaction conditions, Table 1, entry 3.4a,b Therefore, it
appears that the presence of the extended alkyl chain is causing
324 | Org. Biomol. Chem., 2006, 4, 323–330
This journal is
The Royal Society of Chemistry 2006
©

View Article Online
Scheme 5
catalyzed decomposition.4 This led us to propose that the extended
alkyl chain is essentially fixing the conformation of the 1,2-dioxine
so that the alkyl chain is pseudo-equatorial5 and that the removal
of the proton adjacent the O–O linkage is greatly assisted by the
phosphorus of the ylide, Scheme 5. Indeed this is potentially the
primary mechanism through which phosphorus stabilised ylides
facilitate the transformation of 1,2-dioxines into cis c-hydroxy
enones. This mechanism allows for charge stabilization of the
ylide, as well as proceeding through a very stable 6-membered
transition state. In the case of 1,2-dioxine 6c, low temperature
NMR spectroscopy has revealed that the Me substituent is
predominantly pseudo-equatorial (69:31) at this temperature.5
partial reversion to the alternate cyclopropanation pathway, entry
8, indicating that exposure of these reactions to light was not causal
in the formation of 9. The addition of TEMPO to the reaction
mixture, entry 9, allowed investigation of possible radical cleavage
of the peroxide linkage, however, the ratio of 5:9 was identical to
that in entry 2, 7:3 respectively. Due to the poor removal of the
most acidic proton by the ylide, addition of triethylamine, which
is known to rapidly ring-open 1,2-dioxines to their corresponding
cis-c-hydroxy enones via removal of the most acidic proton, was
added to the reaction, entry 10. This resulted in only isomer 5
being generated, indicating that cis-c-hydroxy enone 12 is formed
exclusively, giving 81% isolated yield. The rapid timeframe of the
reaction indicates that rearrangement to cis-c-hydroxy enone is the
rate determining step in the reaction.
The Taylor group has investigated the ring-opening of un-
symmetrical 1,2-dioxines using Co(II)-salen catalyst.5 However
utilization of Co(II)-salen to ring-open 1,2-dioxine 6b resulted
in a 1:1 ratio of cyclopropanes 5b and 9b in poor yield, entry
11. This observation further supports Co(II) rearrangement of
cis-c-hydroxy enones is not solely dependent on 1,2-dioxine
conformation.5
1
Variable temperature H NMR carried out on 6b demonstrated
that when R1 is very large then the conformation is essentially
fixed with R1 pseudo-equatorial (9:1), as only a single conformer
was observed at −91 ◦C. This strongly supports the notion that the
conformer with the extended alkyl chain pseudo axial, is present
at a considerably lower percentage of the population than its
pseudo equatorial counterpart at ambient temperature. Due to
the low population the reaction rate through 14 is extended to a
point where the generation of cyclopropane 9a, b and d, through
intermediate 15, competes on the timescale of the reaction. In
concert with this hypothesis is the observation that with increasing
electron density of the aromatic ring and steric bulk (6d→a→b)
we observe an increase in reaction time due to decreased acid-
ity of the proton a to the aromatic ring and as expected a
corresponding increase in the percent yield of cyclopropane 9,
Table 1.
Using the optimized conditions cyclopropane 5a could now be
generated in 83% isolated yield, entry 12, Table 1. With the desired
cyclopropane in hand the tert-butyl ester was hydrolyzed cleanly
in the presence of 99% formic acid to give acid 16,6 in 89% yield,
which was subsequently decarboxylated using the Barton protocol
in 86% yield.7 Baeyer–Villiger oxidation of the resultant ketone 4
using MCPBA proceeded with excellent selectivity to give phenol
ester 3 in 91% yield, Scheme 6.4b
1,2-Dioxine 6b, which was also investigated, showed an identical
product profile to 6a and 6d (Table 1, entries 1 and 4), with the
exception that cyclopropane isomer 11b was observed, Table 1,
entry 2.
We thus chose to investigate the reaction of 6b in order to
optimize formation of cyclopropane 5b. Refluxing in chloroform
resulted in a decreased reaction time but poor yield, entry 5.
Reduction of LiBr to 0.1 equivalents resulted in reversion to the
alternate cyclopropane reaction pathway, entry 6, Table 1, see
Scheme 1.4a To investigate whether light played a part in the ring-
opening, through photo-induced peroxide bond cleavage, to give
cyclopropane isomer 9b, the reaction was carried out in both
the presence and absence of all light. In the absence of light
an essentially identical product profile was observed, compare
entries 7 and 2, Table 1. However on photolyzing the reaction for
5 hours on each of the first two days of the reaction, we observed
Scheme 6 a, 99% Formic acid (excess), rt, 3 h. b, DCC (1 equiv.),
2-mercaptopyridine N-oxide (1 equiv.), DCM, 0 ◦C, 3 h. c, tBuSH
(2 equiv.), benzene, hv, rt, 2 h. d, MCPBA 70% (2 equiv.), DCM, rt,
2 days.
This journal is
The Royal Society of Chemistry 2006
Org. Biomol. Chem., 2006, 4, 323–330 | 325
©

View Article Online
Due to purification difficulties phenol ester 3 was transesterified
to furnish methyl ester 17 in 93% yield, which was subsequently
hydrolyzed to give cyclopropyl fatty acid 2 in 93% yield.4b Arndt–
Eistert homologation/amidation8 of acid 2 proceeded cleanly to
afford racemic grenadamide in 83% yield, through acid chloride9
and diazoketone10 intermediates, Scheme 7.
Experimental
General
Solvents were dried by appropriate methods wherever needed.
Thin-layer chromatography (TLC) used aluminium sheets coated
with silica gel 60 F254 (40 × 80 mm) and visualized under 254 nm
light, or developed in vanillin or permanganate dip. Column
chromatography was conducted using silica gel 60 of particle
1
size 0.040–0.063 mm. Melting points are uncorrected. H NMR
and 13C NMR spectra were recorded in CDCl3 solution at either
300 MHz or 600 MHz with TMS (0 ppm) and CDCl3 (77.0 ppm)
as internal standards. All yields reported refer to isolated material
judged to be homogeneous by TLC and NMR spectroscopy.
Scheme 7 a, MeOH (excess), conc. H2SO4 (cat.) reflux, 16 h. b, 2N KOH
(1.4 equiv.), MeOH–H2O (4:1), rt, 6 h. c, Oxalyl chloride (3 equiv.), DMF
(cat.), DCM, 0 ◦C (2 h) → rt (2 h). d, CH2N2 (1.5 equiv.), triethylamine
(1.5 equiv.), diethyl ether, 0 ◦C, 0.5 h. e, PhCO2Ag (1.1 equiv.), phenethy-
lamine (4 equiv.), THF, triethylamine, −15 ◦C → rt, 16 h.
General procedure for the synthesis of 1,3-dienes 8
To a suspension of octyltriphenylphosphonium iodide (29.2 g,
58.1 mmol) in anhydrous THF (10 ml per g of phosphonium
salt) at ambient temperature and under a nitrogen atmosphere
was added potassium tert-butoxide (1.2 equiv.). After stirring for
15 minutes the orange solution was cooled to 0 ◦C and a solution
of aldehyde 7a,b,d (1 equiv.) in anhydrous THF (10 ml per g of
7) was added dropwise. The solution was stirred for 16 hours at
ambient temperature, diluted with hexanes and filtered through
silica gel. The silica was washed with 1:19 ethyl acetate–hexanes.
The filtrate was concentrated in vacuo and the resulting residue
purified by column chromatography using 1:99 ethyl acetate–
hexanes as eluent to yield 1,3-dienes 8a,b,d.
To obtain the two enantiomers of grenadamide, cyclopropyl
fatty acid 2 was resolved by coupling it with Evans’ auxiliary
and chromatographically separating the diastereomers 18 and 19
generated, Scheme 8.9 The auxiliary was then cleaved and the
enantiomerically pure fatty acids were subjected to the Arndt–
Eistert protocol to give (−)- and (+)-grenadamide from (−)- and
(+)-2 respectively. Resolution in this manner using carboxylic acid
16 was not feasible due to incompatibility of the ketone moiety
with the conditions required to remove the Evans’ auxiliary.
(1E,3E) and (1E,3Z)-1-(4-Methoxyphenyl)-1,3-undecadiene 8a.
Rf 0.39; (7.99 g, 77%), in a ratio of 95:5, 1E,3E:1E,3Z as a
colourless oil. E,E isomer: dH(300 MHz; CDCl3; Me4Si) 0.85–
0.90 (3H, m, Me), 1.26–1.44 (10H, m, CH2), 2.23–2.32 (2H, m,
=
CH2CH CH), 3.80 (3H, s, OMe), 5.49 (1H, ddd, J 10.8, 6.0 and
=
=
6.0 Hz, CH CH), 6.13 (1H, dd, J 10.8 and 10.8 Hz, CH CH),
=
6.47 (1H, d, J 15.3 Hz, CH CH), 6.82–6.89 (2H, m, Ph), 6.93
(1H, ddd, J 15.3, 10.8 and 0.9 Hz, CH CH), 7.32–7.36 (2H, m,
=
Ph).
Scheme 8 a, Oxalyl chloride (3 equiv.), DMF (cat.), DCM, 0 ◦C (2 h) →
rt (2 h) b, (S)-(−)-4-Benzyl-2-oxazolidinone (1 equiv.), nBuLi (1 equiv.),
THF, −78 ◦C, 4 h. c, Chromatographic separation. d, LiOH (4 equiv.),
H2O2 30% (8 equiv.), H2O, THF, 0 ◦C, 0.5 h.
(1E,3E) and (1E,3Z)-1-(2-Methoxyphenyl)-1,3-undecadiene 8b.
Rf 0.40; (11.45 g, 90%), in a ratio of 85:15, 1E,3E:1E,3Z as a
colourless oil. E,E isomer: dH(300 MHz; CDCl3; Me4Si) 0.86–
0.91 (3H, m, Me), 1.25–1.47 (10H, m, 5 × CH2), 2.28 (2H, q, J
6.6 Hz, CH2), 3.90 (3H, s, OMe), 5.50 (1H, dt, J 10.8 and 7.8 Hz,
Grenadamide synthesized from 19 gave an optical rotation
[a]2D0.5 + 12.0 (CHCl3, c = 0.005) corresponding to that synthesized
by Baird et al. ([a]D22 + 12.6 (CHCl3, c = 0.84))3 with the
grenadamide synthesized from 18 exhibiting an equal and opposite
rotation [a]2D0.5 − 12.0 (CHCl3, c = 0.005) which corresponded to
that of the natural grenadamide isolated by Gerwick and Sitachitta
([a]D − 11.0 (CHCl3, c = 0.1)).1
=
=
CH CH), 6.19 (1H, dd, J 10.8 and 10.8 Hz, CH CH), 6.77–6.89
=
(2H, m, CH CH and Ph), 6.90–6.96 (1H, m, Ph), 7.09 (1H, dd,
=
J 15.6 and 10.8 Hz, CH CH), 7.17–7.23 (1H, m, Ph), 7.48–7.51
(1H, m, Ph).
(1E,3E) and (1E,3Z)-1-Phenyl-1,3-undecadiene 8d. Rf 0.55;
(6.68 g, 67%), in a ratio of 20:1, 1E,3Z:1E,3E as a colourless
oil.11
The route to grenadamide reported herein lends itself to the
easy synthesis of grenadamide derivatives. Variation at carbon 3
of the cyclopropyl ring can be achieved through the use of different
phosphonium salts in the generation of the 1,3-diene for photo-
oxidation. Modification of carbon 2 of the cyclopropyl ring can
be achieved by manipulation of the ester functional group, which
is at this stage redundant in the synthesis of grenadamide. This
synthesis also lends itself to the synthesis of cascarillic acid as
cascarillic acid is only 1 carbon shorter in the alkyl side chain than
cyclopropyl acid 2.
General procedure for the synthesis of 1,2-dioxines 6
A solution of 1,3-dienes 8a,b,d (1 equiv.) in anhydrous dichloro-
methane (25 ml per g of 8) was irradiated with light from 3 ×
500W tungsten–halogen lamps in the presence of rose bengal
bis(triethylammonium) salt (0.01 equiv.) and oxygen bubbled
through the solution for 6 hours. The solution was concentrated
and the resulting residue purified by column chromatography
326 | Org. Biomol. Chem., 2006, 4, 323–330
This journal is
The Royal Society of Chemistry 2006
©

View Article Online
using 1:19 ethyl acetate–hexanes as eluent to yield 1,2-dioxine
6a,b,d.
6.94 (2H, m, Ph), 7.89–7.91 (2H, m, Ph); dC(75 MHz; CDCl3;
Me4Si) 14.0, 22.58, 22.61, 26.3, 26.7, 28.2, 29.1, 29.27, 29.32, 29.5,
31.8, 41.9, 55.4, 80.1, 113.8, 129.8, 130.4, 163.5, 171.4, 197.2; m/z
(EI) 388 (M+, 40%), 332 (33), 330 (36), 314 (100), 272 (38), 186
(7), 149 (7), 134 (55), 56 (29), 41 (18); HRMS (ESI) C24H36O4 +
Na requires 411.2511, found 411.2513. Cyclopropane 9a: Rf 0.36;
(1.76 g, 20%) as a colourless oil mmax(film)/cm−1 1714, 1614, 1515,
1365, 1247; dH(600 MHz; CDCl3; Me4Si) 0.87 (3H, t, J 7.2 Hz,
4-(6-Heptyl-3,6-dihydro-1,2-dioxin-3-yl)phenyl methyl ether 6a.
Rf 0.31; (5.65 g, 37%) as a colourless oil mmax(film)/cm−1 1689, 1681,
1612, 1586, 1513 and 1465; dH(300 MHz; CDCl3; Me4Si) 0.87 (3H,
t, J 6.6 Hz, Me), 1.22–1.54 (10H, m, CH2), 1.56–1.65 (1H, m,
CH2), 1.73–1.80 (1H, m, CH2), 3.80 (3H, s, OMe), 4.49–4.56 (1H,
=
=
m, C7H15CHCH CH), 5.45–5.48 (1H, m, PhCHCH CH), 6.00–
t
Me), 1.17 (9H, s, Bu), 1.22–1.31 (8H, m, 4 × CH2), 1.57–1.62
=
6.13 (2H, m, CH CH), 6.86–6.91 (2H, m, Ph), 7.28–7.33 (2H, m,
(2H, m, CH2), 1.76 (1H, dd, J 9.6 and 5.4 Hz, C(3)H), 2.21 (1H,
dddd, J 8.4, 7.2, 5.4 and 5.4 Hz, C(1)H), 2.29 (1H, dd, J 9.6 and
7.2 Hz, C(2)H), 2.33 (1H, dd, J 16.8 and 8.4 Hz, C(1)HCH2C(O)),
2.42–2.50 (2H, m, CH2C(O)), 2.75 (1H, dd, J 16.8 and 5.4 Hz,
C(1)HCH2C(O)), 3.77 (3H, s, OMe), 6.79–6.81 (2H, m, Ph), 7.23–
7.25 (2H, m, Ph); dC(150 MHz; CDCl3; Me4Si) 14.0, 19.8, 22.6,
23.7, 27.8, 28.8, 29.1, 29.2, 31.6, 31.7, 42.6, 45.9, 55.3, 80.3, 113.4,
128.4, 130.5, 158.4, 169.6, 209.5; m/z (EI) 388 (M+, 15%), 332 (19),
205 (44), 190 (39), 127(20), 67 (100); HRMS (ESI) C24H36O4 + Na
requires 411.2511, found 411.2514.
Ph); dC(75 MHz; CDCl3; Me4Si) 14.0, 22.6, 25.5, 29.1, 29.5, 31.7,
33.1, 55.2, 78.4, 79.8, 113.8, 126.5, 128.8, 129.7, 130.1, 160.0; m/z
(EI) 290 (M+, 16%), 272 (53), 258 (100), 187 (9), 173 (24), 134 (22);
HRMS (ESI) C18H26O3 + Na requires 313.1780, found 313.1776.
3-Heptyl-6-(2-methoxyphenyl)-3,6-dihydro-1,2-dioxine 6b. Rf
0.39; (5.98 g, 39%) as a colourless oil mmax(film)/cm−1 1603, 1589,
1493, 1464, 1248, 1030; dH(300 MHz; CDCl3; Me4Si) 0.87 (3H,
t, J 7.2 Hz, Me), 1.22–1.76 (12H, m, 6 × CH2), 3.84 (3H, s,
=
OMe), 4.57–4.63 (1H, m, C7H15CHCH CH), 5.94–5.97 (1H, m,
=
=
PhCHCH CH), 6.01–6.10 (2H, m, CH CH), 6.87–6.97 (2H, m,
Ph), 7.27–7.33 (1H, m, Ph), 7.37–7.40 (1H, m, Ph); dC(75 MHz;
CDCl3; Me4Si) 14.0, 22.6, 25.4, 29.1, 29.5, 31.8, 32.9, 55.5, 74.1,
78.3, 110.6, 120.3, 126.2, 126.4, 128.6, 129.2, 129.7, 157.3; m/z
(EI) 290 (M+, 25%), 272 (31), 258 (91), 187 (79), 173 (37), 159 (40),
135 (100), 121 (67), 105 (16), 77 (61), 60 (67), 43 (62); HRMS (ESI)
C18H26O3 + Na requires 313.1780, found 313.1772.
( )-tert-Butyl [(1R,2R,3R)-2-heptyl-3-[2-(2-methoxyphenyl)-2-
oxoethyl]cyclopropane-1-carboxylate 5b and ( )-tert-butyl [(1R,
2S,3S)-2-heptyl-3-(2-methoxybenzoyl)cyclopropyl]acetate
9b.
Cyclopropane 5b: Rf 0.49; (3.15 g, 50%) as a colourless oil
mmax(film)/cm−1 1716, 1681, 1599, 1583, 1486, 1367, 1246, 1154,
757; dH(600 MHz; CDCl3; Me4Si) 0.87 (3H, t, J 7.2 Hz, Me),
1.04–1.09 (1H, m, C(3)H), 1.20–1.32 (10H, m, 5 × CH2), 1.34–1.50
t
(2H, m, C(2)H and CH2), 1.43 (9H, s, Bu), 1.55–1.62 (2H, m,
3-Heptyl-6-phenyl-3,6-dihydro-1,2-dioxine 6d. Rf 0.38; (2.21 g,
59%) as a colourless oil mmax(film)/cm−1 1682, 1494, 1455, 1067;
dH(200 MHz; CDCl3; Me4Si) 0.88 (3H, t, J 6.8 Hz, Me), 1.20–
C(1)H and CH2), 2.76 (1H, dd, J 16.2 and 7.8 Hz, C(1)HCH2),
3.12 (1H, dd, J 16.2 and 6.0 Hz, C(1)HCH2), 3.88 (3H, s, OMe),
6.94–6.95 (1H, m, Ph), 6.98–7.01 (1H, m, Ph), 7.43–7.45 (1H,
m, Ph), 7.65–7.66 (1H, m, Ph); dC(75 MHz; CDCl3; Me4Si) 14.0,
22.5, 22.6, 26.0, 26.7, 28.1, 29.0, 29.2, 29.3, 29.4, 31.8, 47.2, 55.3,
79.9, 111.3, 120.6, 128.2, 130.2, 133.3, 158.3, 171.5, 201.2; m/z
(EI) 388 (M+, 6%), 359 (1), 331 (16), 287 (2), 273 (18), 247 (2), 219
(2), 175 (2), 150 (5), 135 (100), 92 (4), 57 (15), 42 (9); HRMS (ESI)
C24H36O4 + Na requires 411.2511, found 411.2504. Cyclopropane
9b: Rf 0.41; (1.40 g, 22%) as a colourless oil mmax(film)/cm−1 1718,
1708, 1603, 1585, 1497, 1459, 1365, 1250, 1146; dH(600 MHz;
=
1.80 (12H, m, 6 × CH2), 4.53–4.58 (1H, m, C7H15CHCH CH),
=
=
5.49–5.53 (1H, m, PhCHCH CH), 6.02–6.16 (2H, m, CH CH),
7.33–7.42 (5H, m, Ph); dC(50 MHz; CDCl3; Me4Si) 14.0, 22.6, 25.5,
29.2, 29.5, 31.8, 33.1, 78.5, 80.2, 126.3, 128.5, 128.6, 128.7, 128.9,
137.8; m/z (EI) 260 (M+, 10%), 228 (100), 143 (46), 129 (95), 105
(40); HRMS (ESI) C17H24O2 requires 260.1776, found 260.1765.
Anal. Calcd for C17H24O2 requires C, 78.42; H, 9.29: found C,
78.12; H, 9.34%.
t
CDCl3; Me4Si) 0.87 (3H, t, J 6.6 Hz, Me), 1.11 (9H, s, Bu),
General procedure for the synthesis of cyclopropanes from 6
1.22–1.32 (8H, m, 4 × CH2), 1.57–1.62 (2H, m, CH2), 1.82 (1H,
dd, J 9.6 and 5.4 Hz, C(3)H), 2.19 (1H, dddd, J 8.4, 7.2, 5.4 and
5.4 Hz, C(1)H), 2.24 (1H, dd, J 9.6 and 7.2 Hz, C(2)H), 2.36
(1H, dd, J 16.8 and 8.4 Hz, C(1)HCH2C(O)), 2.42–2.51 (2H, m,
CH2C(O)), 2.76 (1H, dd, J 16.8 and 5.4 Hz, C(1)HCH2C(O)),
6.77–6.79 (1H, m, Ph), 6.89–6.91 (1H, m, Ph), 7.18–7.26 (1H, m,
Ph), 7.36–7.38 (1H, m, Ph); dC(150 MHz; CDCl3; Me4Si) 14.0,
19.9, 22.5, 23.6, 27.6, 28.2, 29.0, 29.1, 31.6, 42.6, 46.0, 55.1, 79.7,
109.4, 120.0, 125.0, 127.8, 130.6, 158.5, 169.9, 209.6; m/z (EI) 388
(M+, 9%), 342 (2), 315 (12), 287 (3), 273 (1), 247 (1), 205 (11), 190
(80), 160 (41), 127 (49), 91 (14), 57 (100), 42 (54); Anal. Calcd for
C20H28O4 requires C, 74.19; H, 9.34: found C, 74.35; H, 9.29%.
To a solution of 1,2-dioxine 6a,b,d (1 equiv.) in anhydrous
dichloromethane (53 ml per g of 6) was added lithium bromide
(1.1 equiv.) and (tert-butoxycarbonylmethylene)triphenylphospho-
rane (1.4 equiv.). The mixture was stirred at ambient temperature
for 15–30 days (Table 1). The solution was concentrated and the
resulting residue purified by column chromatography using 3:17
ethyl acetate–hexanes as eluent to give cyclopropanes 5a,b,d and
9a,b,d.
( )-tert-Butyl [(1S,2R,3R)-2-heptyl-3-[2-(4-methoxyphenyl)-2-
oxoethyl]cyclopropane-1-carboxylate 5a and ( )-tert-butyl [(1R,
2S,3S)-2-heptyl-3-(4-methoxybenzoyl)cyclopropyl]acetate 9a. Cy-
clopropane 5a: Rf 0.43; (4.83 g, 55%) as
a
colourless
( )-tert-Butyl [(1R,2R,3R)-2-heptyl-3-(2-phenyl-2-oxoethyl)-
cyclopropane-1-carboxylate 5d and ( )-tert-butyl [(1R,2S,3S)-
2-heptyl-3-benzoylcyclopropyl]acetate 9d. Cyclopropane 5d: Rf
0.43; (3.07 g, 52%) as a colourless oil mmax(film)/cm−1 1718, 1690,
1598, 1581, 1449, 1366, 1212, 1153; dH(600 MHz; CDCl3; Me4Si)
0.87 (3H, t, J 7.2 Hz, Me), 1.11 (1H, dddd, J 9.0, 7.8, 6.6 and
oil mmax(film)/cm−1 1722, 1715, 1682, 1602, 1576 and 1511;
dH(600 MHz; CDCl3; Me4Si) 0.86 (3H, t, J 6.6 Hz, Me), 1.09–1.14
(1H, m, C(3)H), 1.23–1.34 (10H, m, CH2), 1.44 (9H, s, tBu), 1.50
(1H, dd, J 9.0 and 4.8 Hz, C(2)H), 1.53–1.67 (3H, m, CH2C(3)H
and C(1)H), 2.65 (1H, dd, J 16.2 and 8.4 Hz, C(1)HCH2), 3.14
(1H, dd, J 16.2 and 6.0 Hz, C(1)HCH2), 3.87 (3H, s, OMe), 6.92–
t
6.6 Hz, C(3)H), 1.20–1.33 (10H, m, 5 × CH2), 1,45 (9H, s, Bu),
This journal is
The Royal Society of Chemistry 2006
Org. Biomol. Chem., 2006, 4, 323–330 | 327
©

View Article Online
1.46–1.52 (2H, m, C(2)H and CH2), 1.59–1.68 (2H, m, C(1)H
and CH2), 2.72 (1H, dd, J 16.2 and 7.8 Hz, CH2C(O)Ph), 3.18
(1H, dd, J 16.2 and 5.4 Hz, CH2C(O)Ph), 7.44–7.47 (2H, m,
Ph), 7.54–7.57 (1H, m, Ph), 7.91–7.93 (2H, m, Ph); dC(150 MHz;
CDCl3; Me4Si) 14.1, 22.3, 22.6, 26.3, 26.7, 28.2, 29.1, 29.26,
29.32, 29.5, 31.8, 42.2, 80.2, 128.1, 128.6, 133.0, 136.7, 171.3,
198.7; m/z (EI) 359 [(M + H)+, 4%], 285 (8), 120 (23), 105 (100),
57 (32); HRMS (ESI) C23H34O3 + Na requires 381.2406, found
381.2400. Cyclopropane 9d: Rf 0.36; (1.06 g, 18%) as a colourless
oil mmax(film)/cm−1 1723, 1714, 1605, 1367, 1146; dH(600 MHz;
Optimized procedure for the synthesis of 5a and 5b
To a solution of 1,2-dioxine 6a or 6b (1 equiv.) in anhydrous
dichloromethane (53 ml per g of 6) was added lithium bromide
(1.1equiv.), (tert-butoxycarbonylmethylene)triphenylphosphorane
(1.4 equiv.) followed by triethylamine (2 drops for every 50 mg
of 6). The mixture was stirred at ambient temperature for 2 days
(Table 1). The solution was concentrated and the resulting
residue purified by column chromatography using 3:17 ethyl
acetate–hexanes as eluent to give cyclopropanes 5a or 5b.
t
CDCl3; Me4Si) 0.87 (3H, t, J 7.2 Hz, Me), 1.13 (9H, s, Bu),
( )-(1S,2R,3R)-2-Heptyl-3-[2-(4-methoxyphenyl)-2-
oxoethyl]cyclopropane-1-carboxylic acid 16
1.23–1.31 (8H, m, 4 × CH2), 1.58–1.62 (2H, m, CH2), 1.81 (1H,
dd, J 9.6 and 4.8 Hz, C(3)H), 2.27 (1H, dddd, J 8.4, 6.6, 5.4 and
4.8 Hz, C(1)H), 2.33–2.37 (2H, m, C(2)H and C(2)HCH2C(O)),
2.45–2.48 (2H, m, CH2C(O)CH2C(2)H), 2.76 (1H, dd, J 16.8
and 5.4 Hz, C(2)HCH2C(O)), 7.17–7.20 (1H, m, Ph), 7.24–7.27
(2H, m, Ph), 7.32–7.34 (2H, m, Ph); dC(150 MHz; CDCl3; Me4Si)
14.0, 19.6, 22.6, 23.7, 27.7, 28.9, 29.0, 29.2, 31.6, 32.3, 42.6, 45.9,
80.3, 126.6, 127.9, 129.5, 136.3, 169.5, 209.4; m/z (EI) 358 (M+ <
1%), 302 (63), 284 (34), 257 (12), 57 (100), 41 (45); HRMS (ESI)
C23H34O3 + Na requires 381. 2406, found 381.2396.
99% Formic acid (2 ml) was added to cyclopropyl ester 5a (400 mg,
1.03 mmol) and the solution stirred for 3 hours. The formic
acid was then removed in vacuo, the resulting crude acid 16 was
dissolved in ethyl acetate and washed with 6% NaHCO3 solution.
The organics were then dried (MgSO4), filtered and the volatiles
removed in vacuo to yield cyclopropyl acid 16 (304 mg, 89%)
as a colourless crystalline solid. Mp 116–117 ◦C (diethyl ether);
mmax(film)/cm−1 2601, 1688, 1682, 1668, 1602, 1574, 1171, 1027,
925; dH(600 MHz; CDCl3; Me4Si) 0.87 (3H, t, J 6.6 Hz, Me),
1.21–1.29 (12H, m), 1.54–1.67 (3H, m), 1.75–1.79 (1H, m), 2.79
(1H, dd, J 16.2 and 7.2 Hz, CH2), 3.09 (1H, dd, J 16.2 and 6.6 Hz,
CH2), 3.87 (3H, s, OMe), 6.93–6.94 (2H, m, Ph), 7.90–7.91 (2H,
m, Ph); dC(75 MHz; CDCl3; Me4Si) 14.1, 22.6, 24.1, 24.9, 26.6,
29.17, 29.22, 29.3, 30.4, 31.8, 41.8, 55.5, 113.8, 129.7, 130.4, 163.6,
178.3, 196.8; m/z (EI) 332 (M+, 16%), 315 (65), 273 (45), 247 (4),
219 (21), 187 (11), 150 (31), 135 (100), 121 (12), 92 (19), 77 (24),
55 (17), 41 (41); HRMS (ESI) C20H28O4 + Na requires 355.1885,
found 355.1879.
( )-tert-Butyl 2-[(1S,2R,3S)-2-heptyl-3-(2-methoxybenzoyl)cyclo-
propyl]acetate 10b and ( )-tert-butyl 2-[(1S,2R,3R)-2-heptyl-3-
(2-methoxybenzoyl)cyclopropyl]acetate 11b
To a solution of 1,2-dioxine 6b (1 equiv.) in anhydrous
dichloromethane (53 ml per g of 6b) was added lithium bro-
mide (0.1 equiv.) and (tert-butoxycarbonylmethylene)triphenyl-
phosphorane (1.4 equiv.). The mixture was stirred at ambient
temperature for 30 days. The solution was concentrated and the
resulting residue purified by column chromatography using 3:17
ethyl acetate–hexanes as eluent to give cyclopropane 10b: Rf 0.57;
(47 mg, 35% based on 117 mg recovered starting material) as a
colourless oil mmax(film)/cm−1 1732, 1726, 1667, 1660, 1598, 1485,
1463, 1435, 1392, 1367, 1282, 1246, 1152; dH(300 MHz; CDCl3;
Me4Si) 0.86 (3H, t, J 7.2 Hz, Me), 1.25–1.53 (21H, m), 1.64–
1.68 (2H, m), 1.85 (1H, pentet, J 7.8 Hz), 2.78–2.81 (2H, m,
( )-2-[(1R,2S)-2-Heptylcyclopropyl]-1-(4-methoxyphenyl)-1-
ethanone 4
To a solution of cyclopropane acid 16 (384 mg, 1.15 mmol) in
anhydrous dichloromethane (30 ml) at 0 ◦C under a nitrogen atmo-
sphere and protected from light was added 2-mercaptopyridine N-
oxide (147 mg, 1.15 mmol) followed by DCC (238 mg, 1.15 mmol).
The reaction mixture was then stirred for 3 hours under the stated
conditions. After this time the precipitate was filtered off and
washed with cold dichloromethane. The volatiles were removed in
vacuo and the crude oil reconstituted in anhydrous benzene (45 ml).
The solution was then degassed and tert-butyl thiol (0.26 ml,
2.31 mmol) added; irradiation of the solution was preformed with
1 sun lamp (at a distance of 30 cm from the reaction vessel) under a
nitrogen atmosphere for 2 hours. The volatiles were then removed
in vacuo and the crude oil purified by column chromatography
using 3:1 dichloromethane–hexanes as eluent to give cyclopropane
4. Rf 0.50; (287 mg, 86%) as a colourless oil. mmax(film)/cm−1 1681,
1602, 1577, 1510, 1259, 1170, 1033; dH(300 MHz; CDCl3; Me4Si)
0.31–0.36 (2H, m, CH2), 0.51–0.62 (1H, m, CH), 0.82–0.90 (4H, m,
Me and CH), 1.19–1.39 (12H, m, 6 × CH2), 2.82 (2H, d, J 6.9 Hz,
CH2C(O)), 3.86 (3H, s, OMe), 6.91–6.94 (2H, m, Ph), 7.91–7.94
(2H, m, Ph); dC(75 MHz; CDCl3; Me4Si) 11.9, 14.1, 14.5, 18.9,
22.6, 29.3, 29.36, 29.39, 31.8, 34.0, 43.1, 55.4, 113.7, 130.2, 130.4,
163.3, 198.6; m/z (EI) 288 (M+, 51%), 273 (79), 175 (12), 135 (65),
92 (12), 77 (11), 64 (11), 55 (13), 41 (100); HRMS (ESI) C19H28O2 +
Na requires 311.1987, found 311.1984.
t
CH2CO2 Bu), 3.87 (3H, s, OMe), 6.92–6.99 (2H, m, PH), 7.38–
7.46 (2H, m, Ph); dC(75 MHz; CDCl3; Me4Si) 14.1, 22.0, 22.6,
24.1, 28.1, 28.7, 29.1, 29.2, 29.3, 29.4, 29.7, 31.9, 55.5, 80.0, 111.4,
120.5, 129.3, 132.0, 132.2, 157.7, 172.9, 202.2; m/z (EI) 389 [(M +
H)+, 10%], 333 (97), 273 (33), 135 (100), 57 (12); HRMS (ESI)
C24H36O4 + H requires 389.2692, found 389.2690 and 11b: Rf 0.46;
(65 mg, 58% based on recovered starting material) as a colourless
oil mmax(film)/cm−1 1732, 1727, 1660, 1651, 1598, 1485, 1463, 1438,
1367, 1283, 1246, 1154; dH(600 MHz; CDCl3; Me4Si) 0.87 (3H, t, J
7.2 Hz, Me), 1.21–1.34 (10H, m, 5 × CH2), 1.37–1.51 (11H, m, CH2
t
and Bu), 1.79 (1H, dddd, J 9.0, 7.2, 7.2 and 4.2 Hz, CHC7H15),
t
2.04 (1H, dddd, J 9.0, 7.2, 7.2 and 4.2 Hz, CHCH2CO2 Bu), 2.30
(1H, t, J 4.2 Hz, CHC(O)), 2.37 (1H, dd, J 15.0 and 7.2 Hz,
t
t
CH2CO2 Bu), 2.38 (1H, dd, J 15.0 and 7.2 Hz, CH2CO2 Bu), 6.95–
7.00 (2H, m, Ph), 7.41–7.44 (1H, m, Ph), 7.55–7.57 (1H, m, Ph);
dC(150 MHz; CDCl3; Me4Si) 14.0, 22.6, 27.3, 27.9, 28.0, 29.2,
29.4, 31.2, 31.8, 34.6, 36.2, 55.5, 80.4, 111.5, 120.5, 129.7, 129.8,
132.8, 158.2, 171.6, 201.9; m/z (EI) 389 [(M + H)+, 13%], 333 (41),
273 (39), 135 (100), 57 (29); HRMS (ESI) C24H36O4 + H requires
389.2692, found 389.2691.
328 | Org. Biomol. Chem., 2006, 4, 323–330
This journal is
The Royal Society of Chemistry 2006
©

View Article Online
( )-4-Methoxyphenyl 2-[(1R,2S)-2-heptylcyclopropyl]acetate 3
29.35, 29.4, 31.9, 33.8, 38.8, 179.2; m/z (EI) 199 ([M + H]+, 100%),
181 (64), 163 (20), 151 (6), 138 (63), 123 (17), 112 (34), 97 (63), 83
(98), 82 (53), 69 (45), 55 (36), 41 (53); HRMS (ESI) C12H22O2 − H
requires 197.1542, found 197.1540.
To a solution of cyclopropane 4 (986 mg, 3.42 mmol) in
dichloromethane (10 ml) was added 70% MCPBA (1.685 g,
6.83 mmol) and the mixture was stirred for 2 days. Dichloro-
methane (20 ml) was then added and the solution extracted with
saturated Na2S2O3 followed by saturated NaHCO3. The organic
layers were combined, dried (MgSO4), filtered and the volatiles
removed in vacuo to yield 947 mg, 91% of cyclopropyl ester 3 as a
colourless oil. mmax(film)/cm−1 1760, 1608, 1598, 1506, 1249, 1196,
1036; dH(300 MHz; CDCl3; Me4Si) 0.39–0.47 (2H, m, CH2), 0.63–
0.74 (1H, m, CH), 0.88–0.98 (4H, m, Me and CH), 1.23–1.50 (12H,
m, 6 × CH2), 2.43 (1H, dd, J 15.3 and 7.5 Hz, CH2C(O)), 2.53
(1H, dd, J 15.3 and 6.6 Hz, CH2C(O)), 3.84 (3H, s, OMe), 6.90–
7.00 (2H, m, Ph), 7.03–7.08 (2H, m, Ph); dC(75 MHz; CDCl3;
Me4Si) 11.7, 14.1, 14.3, 18.8, 22.7, 29.3, 29.4, (masked carbon),
31.9, 33.9, 39.1, 55.6, 114.4, 122.3, 144.4, 157.2, 172.0; m/z (EI)
304 (M+, 51%), 273 (7), 203 (7), 175 (31), 163 (5), 135 (17), 124
(100), 109 (9), 82 (10), 55 (14), 41 (15); HRMS (ESI) C19H28O3 +
Na requires 327.1936, found 327.1936.
( )-2-[(1S,2R)-2-Heptylcyclopropyl]ethanoyl chloride 20
To a solution of cyclopropyl acid 2 (413 mg, 2.08 mmol) and
DMF (1 drop) in anhydrous dichloromethane (15 ml) at 0 ◦C
under a nitrogen atmosphere was added oxalyl chloride (0.55 ml,
6.25 mmol) as a solution in anhydrous dichloromethane (15 ml).
The solution was then stirred for 2 hours at 0 ◦C then allowed to
attain ambient temperature and stirred for a further 2 hours. The
volatiles were then removed in vacuo to give crude acid chloride 20,
which was used without further purification. dH(300 MHz; CDCl3;
Me4Si) 0.37–0.45 (2H, m, CH2), 0.59–0.65 (1H, m, CH), 0.82–0.91
(4H, m, Me and CH), 1.21–1.38 (12H, m, 6 × CH2), 2.75 (1H, dd,
J 16.8 and 7.1 Hz, CH2C(O)Cl), 2.80 (1H, dd, J 16.8 and 6.8 Hz,
CH2C(O)Cl).
( )-Methyl 2-[(1S,2R)-2-heptylcyclopropyl]acetate 17
To a solution of cyclopropyl ester 3 (1.031 g, 3.39 mmol) in
anhydrous methanol (20 ml) was added concentrated H2SO4
(1 drop) and the solution refluxed for 16 hours under a nitrogen
atmosphere. NaHCO3 (50 mg, 0.6 mmol) was then added and the
volatiles removed in vacuo until approximately 5 ml remained.
Dichloromethane (20 ml) was then added and the solution
extracted with saturated NaHCO3, dried (MgSO4), filtered and
the volatiles removed in vacuo. Column chromatography of the
crude residue using 7:3 dichloromethane–hexanes as eluent gave
cyclopropyl ester 17, Rf 0.63; (670 mg, 93%), as a colourless oil.
mmax(film)/cm−1 1746, 1436, 1256, 1171, 1020; dH(600 MHz; CDCl3;
Me4Si) 0.28–0.32 (2H, m, CH2), 0.50–0.55 (1H, m, CH), 0.74–
0.79 (1H, m, CH), 0.88 (3H, t, J 6.6 Hz, Me), 1.16–1.23 (1H,
m), 1.23–1.31 (9H, m), 1.34–1.39 (2H, m, CH2), 2.21 (1H, dd, J
15.6 and 7.2 Hz, CH2CO2Me), 2.23 (1H, dd, J 15.6 and 7.2 Hz,
CH2CO2Me), 3.68 (3H, s, OMe); dC(75 MHz; CDCl3; Me4Si) 11.6,
14.1, 14.2, 18.6, 22.7, 29.3, 29.4, (masked carbon), 31.9, 33.9, 38.9,
51.5, 173.8; m/z (EI) 213 ([M + H]+, 13%), 197 (7), 183 (8), 180
(66), 169 (14), 152 (3), 138 (50), 128 (13), 110 (16), 101 (61), 83
(57), 74 (94), 59 (85), 55 (87), 41 (100); HRMS (ESI) C19H24O3
requires 212.1776, found 212.1771.
(4S)-4-Benzyl-3-2-[(1S,2R)-2-heptylcyclopropyl]acetyl-1,3-
oxazolan-2-one 18 and (4S)-4-benzyl-3-2-[(1R,2S)-2-heptyl-
cyclopropyl]acetyl-1,3-oxazolan-2-one 19
To a solution of (S)-(−)-4-benzyl-2-oxazolidinone (369 mg,
2.08 mmol) in anhydrous THF (20 ml) at −78 ◦C under a nitrogen
atmosphere was added nBuLi (1.1 ml, 1.88 M) and the solution
stirred for 0.5 hours. After this time the solution of acid chloride
20 (synthesized from 413 mg, 2.08 mmol of acid 2) in anhydrous
THF (15 ml) was added dropwise and the solution stirred at
−78 ◦C for 4 hours. The reaction was then quenched with saturated
NH4Cl, diluted with water and extracted with dichloromethane.
The organics were dried (MgSO4), filtered and concentrated in
vacuo to give crude oxazolidinones. Oxazolidinones 18 and 19
were purified by column chromatography to give a combined
yield of 789 mg, 59%. The oxazolidinones were resolved by suc-
cessive column chromatography using 1:4 ethyl acetate–hexanes
as eluent. Oxazolidinone 18 (1st eluted): Rf 0.44; mp 45–46 ◦C;
mmax(nujol)/cm−1 1790, 1691, 1225, 1151, 758; dH(300 MHz; CDCl3;
Me4Si) 0.33–0.41 (2H, m, CH2), 0.54–0.65 (1H, m, CH), 0.83–0.94
(4H, m, Me and CH), 1.18–1.44 (12H, m, 6 × CH2), 2.78 (1H, dd,
J 13.2 and 9.6 Hz, CH2Ph), 2.81 (1H, dd, J 17.1 and 7.2 Hz,
CH2C(O)), 2.92 (1H, dd, J 17.1 and 6.9 Hz, CH2C(O)), 3.33 (1H,
dd, J 13.2 and 3.0 Hz, CH2Ph), 4.16 (1H, dd, J 9.0 and 3.6 Hz,
CH2O), 4.20 (1H, dd, J 9.0 and 7.2 Hz, CH2O), 4.69 (1H, dddd, J
9.6, 7.2, 3.6 and 3.0 Hz, NCH), 7.20–7.37 (5H, m, Ph); dC(75 MHz;
CDCl3; Me4Si) 11.6, 13.7, 14.1, 18.5, 22.7, 29.3, 29.4, (masked
carbon), 29.5, 31.9, 34.0, 38.0, 40.3, 55.2, 66.2, 127.3, 128.9, 129.4,
135.3, 153.5, 173.0; m/z (EI) 357 (M+, 37%), 342 (5), 272 (7), 244
(19), 219 (9), 178 (43), 152 (6), 134 (20), 117 (48), 91 (83), 55 (69),
41 (100); Anal. Calcd for C22H31NO3 requires C, 73.92; H, 8.74;
N, 3.92: found C, 74.04; H, 8.67; N, 3.99%. Oxazolidinone 19 (2nd
eluted): Rf 0.38; mp 46–48 ◦C; mmax(nujol)/cm−1 1786, 1696, 1222,
1118, 998; dH(300 MHz; CDCl3; Me4Si) 0.33–0.39 (2H, m, CH2),
0.56–0.66 (1H, m, CH), 0.83–0.94 (4H, m, Me and CH), 1.22–1.44
(12H, m, 6 × CH2), 2.76 (1H, dd, J 17.1 and 7.2 Hz, CH2C(O)),
( )-2-[(1R,2S)-2-Heptylcyclopropyl]acetic acid 2
To a solution of cyclopropyl ester 17 (1.209 g, 5.69 mmol) in water
and methanol (15 ml, 1:4 v/v) was added aqueous KOH (4 ml, 2M)
and the solution stirred for 6 hours. After this time, water (10 ml)
was added and the solution was acidified (conc. HCl) to pH 1.
Following acidification the solution was extracted with ether, the
organics were dried (MgSO4), filtered and the volatiles removed
in vacuo to give cyclopropyl acid 2 (1.05, 93%) as a colourless oil.
mmax(film)/cm−1 2673, 1714, 1416, 1304, 1223, 940; dH(600 MHz;
CDCl3; Me4Si) 0.31–0.35 (2H, m, CH2), 0.53–0.58 (1H, m, CH),
0.75–0.80 (1H, m, CH), 0.88 (3H, t, J 7.2 Hz, Me), 1.21–1.31 (10H,
m, 5 × CH2), 1.35–1.40 (2H, m, CH2), 2.25 (1H, dd, J 16.2 and
6.7 Hz, CH2CO2H), 2.27 (1H, dd, J 16.2 and 7.7 Hz, CH2CO2H);
dC(75 MHz; CDCl3; Me4Si) 11.6, 14.0, 14.1, 18.7, 22.7, 29.32,
This journal is
The Royal Society of Chemistry 2006
Org. Biomol. Chem., 2006, 4, 323–330 | 329
©

View Article Online
2.78 (1H, dd, J 13.5 and 9.6 Hz, CH2Ph), 2.98 (1H, dd, J 17.1 and
6.6 Hz, CH2C(O)), 3.32 (1H, dd, J 13.5 and 3.3 Hz, CH2Ph), 4.16
(1H, dd, J 9.0 and 3.6 Hz, CH2O), 4.20 (1H, dd, J 9.0 and 7.2 Hz,
CH2O), 4.69 (1H, dddd, J = 9.6, 7.2, 3.6 and 3.3 Hz, NCH), 7.20–
7.37 (5H, m, Ph); dC(75 MHz; CDCl3; Me4Si) 11.5, 13.7, 14.1, 18.7,
22.7, 29.3, 29.4, (masked carbon), 31.9, 33.9, 38.0, 40.2, 55.2, 66.2,
127.3, 128.9, 129.4, 135.3, 153.5, 173.0; m/z (EI) 357 (M+, 23%),
342 (3), 272 (8), 244 (19), 219 (11), 181 (40), 134 (20), 117 (39),
91 (80), 55 (58), 41 (100); HRMS (ESI) C22H31NO3 + Na requires
380.2202, found 380.2199.
cooled to −15 ◦C, to this solution was added phenethylamine
(0.63 ml, 5.04 mmol). The reaction was then protected from
light and a solution of silver benzoate (317 mg, 1.39 mmol.)
in triethylamine (5.4 ml) was added. On complete addition of
the silver benzoate solution the mixture was allowed to attain
ambient temperature and was stirred for 16 hours. The volatiles
were removed in vacuo and the residue purified by column
chromatography using 1:1 ethyl acetate–hexanes as eluent to give
racemic grenadamide, Rf 0.66; (329 mg, 83%), as a colourless solid,
mp 54–56 ◦C; mmax(nujol)/cm−1 3312, 1636, 1549, 1194, 1024, 747;
dH(300 MHz; CDCl3; Me4Si) 0.12–0.21 (2H, m, CH2), 0.32–0.47
(2H, 2 × CH), 0.88 (3H, t, J 6.9 Hz, Me), 1.05–1.38 (12H, m, 6 ×
CH2), 1.44–1.57 (2H, m, CH2), 2.21 (2H, t, J 7.5 Hz, CH2C(O)),
2.82 (2H, t, J 6.9 Hz, CH2Ph), 3.52 (2H, q, J 6.9 Hz, NCH2), 5.78
(1H, br s, NH), 7.18–7.33 (5H, m, Ph); dC(75 MHz; CDCl3; Me4Si)
11.7, 14.1, 18.1, 18.8, 22.6, 29.3, 29.4, 29.6, 30.4, 31.8, 34.1, 35.6,
36.7, 40.5, 126.4, 128.6, 128.7, 138.8, 173.2; m/z (EI) 315.3 (M+,
16%), 286.3 (8), 267.4 (6), 244.2 (8), 230.1 (18), 217.3 (8), 182.2
(20), 163.1 (33), 132.1 (12), 115.1 (20), 140.1 (100), 72.1 (71), 55.1
(87), 43.1 (73); Anal. Calcd for C21H33NO requires C, 79.95; H,
10.54; N, 4.44: found C, 79.98; H, 10.68; N, 4.50%.
(−)-2-[(1S,2R)-2-Heptylcyclopropyl]acetic acid (−)-2
To a solution of oxazolidinone 18 (516 mg, 1.44 mmol) in THF
and water (10 ml, 3:1 v/v) at 0 ◦C was added 30% hydrogen
peroxide (1.31 ml, 11.6 mmol) and LiOH (138 mg, 5.76 mmol),
and the solution was then stirred for 0.5 hours. After this time
the reaction was quenched with 1.5 M Na2SO3 and extracted with
dichloromethane, the addition of brine was necessary to break up
the emulsions formed. The aqueous layer was then acidified (conc.
HCl) to pH 1 and extracted with dichloromethane. The organics
were dried (MgSO4), filtered and concentrated in vacuo to give
cyclopropyl acid (−)-2 (254 mg, 89%) as a colourless oil. [a]D20.5
−14.0◦ (CHCl3, c = 0.01).
(−)-(R,R)-Grenadamide (−)-1
Procedure as for ( )-grenadamide synthesis from (−)-2 (296 mg,
80%) as a colourless solid. [a]2D0.5 −12.0◦ (CHCl3, c = 0.005); mp
54–56 ◦C.
(+)-2-[(1R,2S)-2-Heptylcyclopropyl]acetic acid (+)-2
Procedure as for acid (−)-2 synthesis from oxazolidinone 19
(275 mg, 86%) as a colourless oil. [a]2D0.5 +14.0◦ (CHCl3, c = 0.01).
(+)-(S,S)-Grenadamide (+)-1
Procedure as for ( )-grenadamide synthesis from (+)-2 (308 mg,
83%) as a colourless solid. [a]2D0.5 +12.0◦ (CHCl3, c = 0.005); mp
55–57 ◦C.
References
1 N. Sitachitta and W. Gerwick, J. Nat. Prod., 1998, 61, 681.
2 O. Motl, M. Amin and P. Sedmera, Phytochemistry, 1972, 11, 407; S.
Wilson and K. Prodan, Tetrahedron Lett., 1976, 47, 4231.
3 J. Al Dulayymi, M. Baird and K. Jones, Tetrahedron, 2004, 60, 341.
4 (a) T. Avery, B. Greatrex, D. Taylor and E. Tiekink, J. Chem. Soc.,
Perkin Trans. 1, 2000, 1319; (b) T. Avery, G. Fallon, B. Greatrex, S.
Pyke, D. Taylor and E. Tiekink, J. Org. Chem., 2001, 66, 7955; (c) T.
Avery, D. Taylor and E. Tiekink, J. Org. Chem., 2000, 65, 5531.
5 B. Greatrex and D. Taylor, J. Org. Chem., 2005, 70, 470.
6 S. Chandrasekaran, A. Kluge and J. Edwards, J. Org. Chem., 1977, 42,
3972.
7 D. Barton, D. Crich and W. Motherwell, Tetrahedron, 1985, 41, 3901.
8 C. Guibourdenche, J. Podlech and D. Seebach, Liebigs Ann., 1996,
1121.
9 S. Neset, H. Hope and K. Undheim, Tetrahedron, 1997, 53, 10459.
10 V. Lee and M. Newman, Org. Synth., Coll Vol. VI, 1988, 613.
11 M. Arisawa and M. Yamaguchi, J. Am. Chem. Soc., 2000, 122, 2387.
12 T. de Boer and H. Backer, Org. Synth., Coll Vol. IV, 1963, 250.
( )-Grenadamide 1
A solution of acid chloride 20 (synthesized from 250 mg,
1.26 mmol of acid 2) in anhydrous ether (8 ml) was added to a
stirred solution of diazomethane12 (∼80 mg, 1.9 mmol) in ether
(∼60 ml) and triethylamine (0.2 ml, 1.43 mmol) at 0 ◦C. The
mixture was stirred for 0.5 hours, after which time half the
volume of ether was evaporated under a stream of nitrogen. The
precipitated NEt3·HCl was then filtered off and washed with
cold ether. The volatiles were removed in vacuo to give crude
diazoketone 21. Rf 0.67 (1:9 ether–dichloromethane). Diazoketone
21 was reconstituted in anhydrous, degassed THF (4 ml) and
330 | Org. Biomol. Chem., 2006, 4, 323–330
This journal is
The Royal Society of Chemistry 2006
©