The synthesis of single enantiomers of meromycolic acids from mycobacterial wax esters

Article abstract of DOI:10.1016/j.tet.2006.09.019

Three stereoisomers of a wax ester meromycolate have been prepared starting from mannitol. A detailed comparison of their NMR spectra with those reported for a homologous series of natural wax esters allows the relative configurations of the α-methyl grou

Full text of DOI:10.1016/j.tet.2006.09.019

Tetrahedron 62 (2006) 11867–11880
The synthesis of single enantiomers of meromycolic acids from
mycobacterial wax esters
a
b
Juma’a R. Al Dulayymi,a Mark S. Baird,a, Evan Roberts and David E. Minnikin
*
aDepartment of Chemistry, University of Wales, Bangor, Gwynedd LL 57 2 UW, UK
bSchool of Molecular Sciences, University of Birmingham, Birmingham UK
Received 22 May 2006; revised 25 August 2006; accepted 8 September 2006
Available online 27 October 2006
Abstract—Three stereoisomers of a wax ester meromycolate have been prepared starting from mannitol. A detailed comparison of their NMR
spectra with those reported for a homologous series of natural wax esters allows the relative configurations of the a-methyl group and adjacent
trans-cyclopropane to be determined.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
identified as being dibasic.11 A careful analysis11a of the
firmly bound lipids from avian tubercle bacilli (Mycobacte-
rium avium) again yielded long-chain alcohols, with
d-2-eicosanol as main component. These lipid fractions
also produced a long-chain diacid, recognized for the first
time as a mycolic acid and given the title g-mycolic acid
[[a]D +5.3].11a In parallel studies, similar alcohols and acids
were characterized from an organism claimed to be the
causative agent of leprosy.11b It is clear, however, that this
bacterium was not the leprosy bacillus as Mycobacterium
leprae has not been cultivated to date and the mycolic acid
composition of M. leprae is distinct (Scheme 1).11c
Mycobacterial cell walls show unusually low permeability,
a factor which contributes to their resistance to therapeutic
agents, apparently due to an exceptionally thick monolayer
formed by the packing of esters of C60–C90 fatty acids.1
These ‘mycolic acids’, exemplified by structures 1–5, con-
tain various structural features including cis-cyclopropanes
1,2 a-methyl-trans-cyclopropanes, a-methyl-b-methoxy and
a-methyl-b-keto,3–6 cis-alkene, a-methyl-trans-alkene and
a-methyl-trans-epoxy fragments, e.g., 4.7 Each contains
a common b-hydroxy acid group8,9 and they are generally
present as mixtures of various chain lengths. Although the
hydroxy acid grouping is known to be of R,R-configuration
for a number of bacteria,10 little is known about the abso-
lute stereochemistries of the other groups. There is some
evidence that the 1-methyl-2-methoxy unit at the distal
position from the hydroxy acid in mycolic acids 3 is
S,S,10,6 while other reports identify a R-stereochemistry
for the three stereocentres of the a-methyl-trans-epoxy
unit in 4.7
(CH2)b
CH3(CH2)a
(CH2)cCHOHCHCOOH
(1)
a = 15, 17, 18, 19
b = 10,14,16
c = 15, 17, 19, 21
d = 21, 23
CH3(CH2)d
Me
Me
X
Y
(CH2)b
CH3(CH2)a
(CH2)cCHOHCHCOOH
(2) X,Y = CH2
Over 60 years ago, Anderson, in an epic series of papers, ini-
tiated studies on mycobacterial lipids and reported11 that the
isolation of two new optically active long-chain alcohols
from the neutral fraction of the saponified waxes of the so-
called ‘timothy bacillus’, later classified as Mycobacterium
phlei.1 These alcohols were identified as d-2-eicosanol
[[a]D +3.5] and d-2-octadecanol [[a]D +5.7]. It was noted
that the acidic fraction from these saponified waxes con-
tained a high molecular weight component, tentatively
CH3(CH2)d
(3) X = Me, Y = OMe
(4) X,Y = O
H3C
CH3(CH2)a
O
(CH2)b
(CH2)cCHOHCHCOOH
CH3(CH2)d
(5)
Me
O
RO
CH3
(CH2)b
(6) R = CH3(CH2)aCH
(7) R = H
(CH2)cCHOHCHCOOH
CH3(CH2)d
* Corresponding author. Tel.: +44 1248382374; e-mail: chs028@bangor.
ac.uk
Scheme 1.
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.09.019

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J. R. Al Dulayymi et al. / Tetrahedron 62 (2006) 11867–11880
In more recent investigations of mycolic acid structure and
distribution, compounds such as 6 or the corresponding di-
acids 7 were characterized from Mycobacterium paratuber-
culosis12a and Mycobacterium gordonae,12b as a constituent
of trehalose mycolates of M. phlei,13–17 including the iden-
tification of a trehalose monomycolate ester13 and Mycobac-
terium flavescens.17 They are known to be a characteristic
component in the M. avium–Mycobacterium intracellulare
group and other rapidly growing bacteria.17,28 Their pres-
ence in Mycobacterium smegmatis has been implied,19 al-
though not confirmed by a later study.20 Usually they have
been analyzed as the corresponding a-methyl-alkanol and
free acid after hydrolysis.20,21 Some such wax esters do
not appear to contain cyclopropanes, while in other cases
the composition is not clear.22–27 The analysis of the intact
trehalose monomycolate derivatives by MALDI-TOF mass
spectrometry shows ions due to C83, C85 and C87 wax esters
for M. avium–M. intracellulare (the italicized species being
the major one), and C78, C79, C80, C81, C82 and C83 for
M. phlei and M. flavescens.17,18
2. Results and discussion
The meromycolates derived from diacids 7 represent inter-
esting synthetic targets because they contain only one group
of chiral centres, those of the a-methyl-trans-cyclopropane,
and may allow the overall chirality of this part of the mycolic
acid system to be determined. We have already reported
the synthesis of single enantiomers of one example of a di-
cis-cyclopropane containing mycolic acid 1,34 of a corre-
sponding meromycolate,35 and of one enantiomer of the
a-methyl-trans-cyclopropane unit present in 6 and 7.36 We
now report the synthesis of three stereoisomers of the pro-
tected derivative 8b, using a method that can be readily
adapted to produce any appropriate chain length. In each
case, the synthesis involves forming bonds a and b in
Scheme 3 to a central chiral core derived from mannitol.
This was achieved by the use of modified Kocienski–Julia
reactions37 to couple the fragments to produce an E/Z mix-
ture of alkenes, followed by saturation of the alkene.
CH2(CH2)16OCOBut
CH2
O
a
Much is now known about the enzymes controlling the bio-
synthesis of mycolic acids,3,5,7,29 and a number of proposals
have been made as to the relationship between routes to the
different types, e.g., that the cis-cyclopropane unit, the
a-methyl-trans-cyclopropane and the a-methyl-b-alkoxy
unit are formed from a Z-alkene through a common inter-
mediate.30 A consequence of this would be that the three
subunits should have a common absolute stereochemistry
at the carbon bearing the methyl group and C-1 of the cis-
cyclopropane. The number of carbons in the chains of wax
esters closely matches with that of the corresponding keto-
acids, and they have been shown to be related to them, appar-
ently through a Baeyer–Villiger type process.21,31,32
CH2
b
(CH2)13CH2
CH2
MeO
H
(8b)
Me
Scheme 3.
The key 15 carbon unit 11 for the left hand fragment was pre-
pared from methyl 5-bromopentanoate as in Scheme 4.
O
S
N
N
N
(i), (ii)
(CH2)4 COOMe
Br(CH2)4COOMe
N
O
(9)
Ph
(v), (vi)
(iii), (iv)
O
N
N
N
S
(CH2)14 COOMe
A standard method for characterizing mycolic acids is ther-
molysis to fragment the hydroxy acid functionality to pro-
duce a ‘meromycol-aldehyde’ (8).23 This can be oxidized
to the corresponding ‘meromycolic acid’ and then protected
as a derivative such as 8a from 7 (Scheme 2).
Br(CH2)14COOMe
N
O
(11)
(10)
Ph
Scheme 4. (i) 1-Phenyl-1H-tetrazol-5-thiol, K2CO3 (92%); (ii) H2O2,
Mo7O24(NH4)6$4H2O, IMS (81%); (iii) LiHMDS, Br(CH2)9CHO (80%);
(iv) H2, Pd/C (92%); (v) 1-phenyl-1H-tetrazol-5-thiol, K2CO3 (91%);
(vi) H2O2, Mo7O24(NH4)6$4H2O, IMS (91%).
H
H
O
O
O
H
O
In a similar way, the 17 carbon unit 16 for the right hand
fragment was obtained from pentan-1,5-diol (Scheme 5).
+
heat
R
OH
(CH2)nCH3
OH
(CH2)nCH3
R
H
(ii)
(i)
(8)
Br(CH2)5OCOBut
HO(CH2)5OCOBut
HO(CH2)5OH
(13)
(12)
(iii), (iv)
(CH2)zOCOBut
(8a)
O
O
S
N
N
N
N
(v), (vi)
Br(CH2)17OCOBut
OCOBut
(CH2)5
MeO
O
(CH2)yCHMe
(15)
O
(14)
(vii), (viii)
Ph
OH
(CH2)nCH3
O
S
N
N
N
N
OCOBut
(CH2)17
(16)
Scheme 2.
O
Ph
Scheme 5. (i) Pivaloyl chloride, pyridine (84%); (ii) N-bromosuccinimide,
PPh3 (92%); (iii) 1-phenyl-1H-tetrazol-5-thiol, K2CO3 (97%); (iv) H2O2,
Mo7O24(NH4)6$4H2O, IMS (99%); (v) Br(CH2)11CHO, LiHMDS (72%);
(vi) H2, Pd/C (88%); (vii) 1-phenyl-1H-tetrazol-5-thiol, K2CO3 (88%);
(viii) H2O2, Mo7O24(NH4)6$4H2O, IMS (98%).
In this way, Anderson et al. were able to cleave the diacid
([a]D in CHCl3 +6.1) from the hydrolysis of timothy bacillus
(M. phlei) wax ester to produce a mero-compound as a mix-
ture ([a]D in CHCl3 +3.8).33

J. R. Al Dulayymi et al. / Tetrahedron 62 (2006) 11867–11880
11869
In the first approach, it was hoped to create bond a in Scheme 3
first. The alcohol 17, which we have reported earlier,36 was
oxidized to the corresponding aldehyde then treated with
sulfone 11 and a base in a modified Kocienski–Julia reac-
tion,37 followed by saturation of the intermediate alkene to
give ester 18, introducing the acid chain adjacent to the
methyl branch. Cleavage of the acetal gave the cis-aldehyde
19, but this did not give the trans-isomer 20 on attempted
epimerization with base (Scheme 6).
(prepared from methyl 15-bromopentadecanoate) with the
aldehyde 24, again in a modified Julia reaction, led, after sat-
uration of the E/Z-alkene mixture, to the diester 25. The
diester was converted into the corresponding ester alcohol
by hydrolysis with KOH in methanol (95%) followed by
re-esterification of the acid with diazomethane (84%). The
enantiomer of 25 and 33 and one enantiomer of its diastereo-
isomer, 34 were prepared from compound 26, again derived
from mannitol (Scheme 8).38,40
MeOOC
MeOOC
(iv)
Me
TBDPSO
(i) - (iii)
O
MeOOC
(18)
(CH2)16
(i), (ii), (iii)
O
HO
O
H
O
O
Me
H
Me
(iv)
O
(28)
1:1 mixture
O
O
O
(17)
O
O
(26)
(27)
H
(v), (vi)
O
(v)
TBDPSOH2C
1:1 mixture
TBDPSOH2C
Me
Me
(vii) - (ix)
(CH2)16
MeOOC
MeOOC (CH2)16
H
H
Me
H
(19)
Me
(20)
(29)
(CH2)18OCOBut
(x)
(30)
O
Scheme 6. (i) PCC (88%); (ii) LiHMDS, 11 (48%); (iii) KOOCNNCOOK,
AcOH (62%); (iv) HIO4 (80%); (v) NaOMe.
1:1 mixture
O
HOH2C
Me
Me
HOH2C
Me
Given this failure, the other alkyl chain was instead intro-
duced first to create bond b in Scheme 3. The alcohol
17 was protected as a silyl ether and then oxidized to cis-
aldehyde 21, following a route described earlier.38,39 Epime-
rization with NaOMe in MeOH gave the trans-aldehyde
22. Homologation with the sulfone 16 and base by a Julia–
Kocienski reaction,37 and subsequent saturation of the
derived E/Z-alkene mixture using di-imide gave the ester
23 (Scheme 7).
+
(32)
(CH2)18OCOBut
(xi) - (xiii)
(CH2)18OCOBut
(31)
(xi) - (xiii)
MeOOC(CH2)15
MeOOC(CH2)15
Me
(CH2)18OCOBut
(CH2)18OCOBut
(34)
(33)
Scheme 8. (i) Bu4NF, THF (91%); (ii) PCC, CH2Cl2 (91%); (iii)
Ph3P]CHCO2Me, toluene (79%); (iv) MeMgBr, CuBr, THF (70%); (v)
LiAlH4, THF (92%); (vi) ButPh2SiCl, imidizole, DMF (87%); (vii) HIO4
(92%); (viii) LiHMDS, 16 (80%); (ix) KOOCN]NCOOK, AcOH,
MeOH (80%); (x) Bu4NF, THF (88%); (xi) PCC (89%); (xii) LiHMDS,
11 (65%); (xiii) KOOCN]NCOOK, AcOH, MeOH (80%); (xi) PCC (89,
90%) (for 31 and 32, respectively); (xii) LiHMDS, 11 (65, 70%); (xiii)
KOOCN]NCOOK, AcOH, MeOH (80, 80%).
O
Ph
Si
O
(i), (ii)
O
HO
H
H
H
O
Me
(17)
H
Me
Ph
(21)
(iii), (i)
(CH2)18OCOBut
(iv), (v)
O
In this case, the addition of methyl magnesium bromide to
the alkene gave a ca. 1:1 mixture of the two epimers of acetal
28, which could not be separated by column chromato-
graphy. This mixture was therefore reduced to the corre-
sponding mixture of alcohols and protected as the silyl
ethers 29. Chain extension using sulfone 16 and base fol-
lowed by saturation of the double bond, and then removal
of the silyl ether protection gave a mixture of epimeric alco-
hols 31 and 32, which, in this case, could be separated. The
two alcohols were then separately chain extended to give 33
and 34 using the same method as described above for 25.
Ph
Si
Ph
O
H
Me
Si
Ph
O
(23)
H
Me
Ph
(22)
(vi),(vii)
(CH2)18OCOBut
(viii), (ix)
(CH2)18OCOBut
(25)
(24)
O
MeOOC(CH2)14
H
H
Me
Me
Scheme 7. (i) ButPh2SiCl, Et3N, CH2Cl2, DMAP (87%); (ii) HIO4 (96%);
(iii) NaOMe (followed by (i), overall 61%); (iv) LiHMDS, 16 (78%);
(v) KOOCN]NCOOK, AcOH, MeOH (99.5%); (vi) Bu4NF, THF (89%);
(vii) PCC (83%); (viii) LiHMDS, 11 (55%); (ix) KOOCN]NCOOK,
AcOH, MeOH (65%).
The 1H and 13C NMR spectra of 25 and 33 were identical, as
were their other spectra; however, they showed opposite spe-
cific rotations (+3.7 and ꢀ5.1, respectively) as did each of
the single intermediates leading to them. The spectra for
34 were very similar to those for 25 and 33 but significant
differences were seen in the high field regions in each
case. Thus, although the cyclopropane regions of 25 and
Removal of the silyl protecting group from 23, followed by
oxidation gave the aldehyde 24. Reaction of the sulfone 11

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J. R. Al Dulayymi et al. / Tetrahedron 62 (2006) 11867–11880
had to be dry, e.g., ether, tetrahydrofuran, were dried over
sodium wire. Petrol was of boiling point 40–60 ꢁC. Reactions
carried under inert conditions, were carried out under a slow
stream of nitrogen. Those carried out at low temperatures
were cooled using a bath of methylated spirit with liquid
nitrogen. Silica gel (Merck 7736) and silica plates used for
column and thin layer chromatographies were obtained
from Aldrich. Organic solutions were dried over anhydrous
magnesium sulfate. GLC was carried out on a Perkin–Elmer
Model8410ona capillary column (15 mꢂ0.53 mm). IRspec-
tra were carried out on a Perkin–Elmer 1600 FTIR spectro-
meter as liquid films. NMR spectra were recorded on
a Bruker AC250 or Advance500 spectrometer; for carbon
spectra, +¼CH2, ꢀ¼CH, CH3. [a]D values were recorded in
CHCl3 on a POLAAR 2001 Optical Activity polarimeter.
Mass spectra were recorded on a Bruker Microtof.
0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 -0.1 -0.2 -0.3 -0.4 ppm
Figure 1. Cyclopropane region of 1H NMR of (top to bottom) (i) 34; (ii) 33;
(iii) 25; (iv) a natural sample of the dimethyl ester of an u-carboxy mycolic
acid extracted from M. avium;2 this sample contains mainly trans-cyclopro-
panes accompanied by some cis-cyclopropanes.
3.1.1. 5-(1-Phenyl-1H-tetrazol-5-sulfonyl)pentanoic acid
methyl ester (9). Anhydrous potassium carbonate (50 g,
362 mmol) was added to a stirred solution of methyl 5-
bromovalerate (37.1 g, 190 mmol) and 1-phenyl-1H-tetrazol-
5-thiol (34 g, 190.8 mmol) in acetone (300 ml) at room
temperature. After stirring vigorously at 40 ꢁC for 3 h and
at room temperature for 16 h, the precipitate was filtered
off and washed with acetone, then the filtrate was evaporated
to give a brown oil. This was diluted with dichloromethane
(250 ml) and water (250 ml). The organic layer was sepa-
rated and the aqueous layer was re-extracted with dichloro-
methane (2ꢂ50 ml). The combined organic layers were
washed with water (250 ml), dried and evaporated to give
5-(1-phenyl-1H-tetrazol-5-sulfanyl)pentanoic acid methyl
ester as a brown oil (51 g, 92%) [Found [M+H]+:
293.1070; C13H17N4O2S requires: 293.1067], which showed
dH (500 MHz, CDCl3): 7.59–7.52 (5H, m), 3.65 (3H, s), 3.39
(2H, t, J 7.25 Hz), 2.36 (2H, t, J 7.25 Hz), 1.91–1.84 (2H,
m), 1.8–1.74 (2H, m); dC (125 MHz, CDCl3): 173.4,
154.2, 133.6, 130.1, 129.7, 51.5, 33.2, 32.8, 28.4, 23.7;
nmax: 2950, 1735, 1596, 1500 cmꢀ1. This was used for the
next step without purification; to a vigorously stirred solu-
tion of the ester (27.8 g, 95 mmol) in tetrahydrofuran
(250 ml) and industrial methylated spirits (250 ml) was
added a solution of ammonium heptamolybdate(VI) tetrahy-
drate (18 g, 14.6 mmol) in ice cold 35% w/w hydrogen per-
oxide (50 ml). After three 30 min intervals a similar solution
was added (total 72 g heptamolybdate in hydrogen peroxide
(200 ml) was added). The mixture was stirred for 16 h at
room temperature, diluted with water (2.5 l) and extracted
with dichloromethane (2ꢂ400 ml). The combined organic
layers were washed with water (1000 ml), dried and evapo-
rated to give a thick yellow oil. Chromatography (1:1 petrol/
ethyl acetate) gave 5-(1-phenyl-1H-tetrazol-5-sulfonyl)pen-
tanoic acid methyl ester (9) (24.8 g, 81%) as a white solid,
mp 61–63 ꢁC [Found [M+H]+: 325.0960; C13H17N4O4S
requires: 325.0965], which showed dH (500 MHz, CDCl3):
7.68 (2H, br dd, J 1.25, 7.85 Hz), 7.63–7.57 (3H, m), 3.74
(2H, distorted t, J 7.85 Hz), 3.66 (3H, s), 2.38 (2H, t,
J 7.25 Hz), 2.03–1.97 (2H, m), 1.83 (2H, br pent,
J 7.55 Hz); dC (125 MHz, CDCl3): 172.9, 153.3, 132.9,
33 were visually identical to those reported for mixtures of
wax ester meromycolates, and indeed to the same region
in methoxymethylmycolates containing an a-methyl-trans-
cyclopropane subunit, the same region of 34 was clearly dif-
ferent. Thus, Figure 1 shows the high field region of the 1H
NMR spectra of the three synthetic isomers, together with
the same region for a natural wax ester—in which there is
a mixture of cis- and a-methyl-trans-cyclopropanes. More-
over, there were small but significant differences in the car-
bon spectra between 25/33 and 34; again the published shifts
for either mycolic acids or wax esters containing the a-methyl-
trans-cyclopropane unit were identical to the former. Thus,
the relative stereochemistry of this unit is established. The
close agreement between the rotation obtained for 25 and
that reported by Anderson for a natural mero-wax acid sug-
gests that the natural absolute stereochemistry is that of 25,
though the Anderson product was a mixture obtained well
before modern spectroscopic techniques were available.11
It will be interesting to compare his results with the rotations
of mero-wax acids from other bacteria as these become
available (Table 1).
Table 1. Selected 13C NMR shifts for a-methyl-trans-cyclopropane frag-
ment of natural wax esters and mycolic acids compared to 25/33 and 34
3
2
6
1
5
4
1
2
3
4
Mycobacterium
Ref.
38.35 26.37 18.85 10.72 M. tuberculosis
38.13 26.14 18.62 10.50 M. gordonae
41
12b
38.1
18.6
26.1
10.50 M. avium–M. intracellulare 28
complex
38.11 26.13 18.61 10.48 25 SRS
38.11 26.11 18.60 10.47 33 RSR
38.05 26.11 17.34 11.81 34 SSR
3. Experimental section
131.4, 129.6, 125.0, 55.5, 51.7, 33.0, 23.2, 21.6; nmax
2954, 1734, 1498, 1342, 1153, 766 cmꢀ1
:
3.1. General
.
Chemicals used were obtained from commercial suppliers or
prepared from them by methods described. Solvents, which
3.1.2. 15-Bromopentadecanoic acid methyl ester (10).
Lithium hexamethyldisilazide (49.2 ml, 49.2 mmol, 1 M

J. R. Al Dulayymi et al. / Tetrahedron 62 (2006) 11867–11880
11871
THF) was added dropwise with stirring at ꢀ10 ꢁC to ester
showed dH (500 MHz, CDCl3): 7.72 (2H, br dd, J 1.9,
8.2 Hz), 7.68–7.61 (3H, m), 3.75 (2H, distorted t, J 7.9 Hz),
3.68 (3H, s), 2.32 (2H, t, J 7.5 Hz), 1.97 (2H, br pent,
J 7.55 Hz), 1.64 (2H, br pent, J 7.25 Hz), 1.5 (2H, pent,
J 7.5 Hz), 1.27 (18H, br s); dC (125 MHz, CDCl3): 174.3,
153.5, 133.1, 131.5, 129.7, 125.1, 56.0, 51.4, 34.1, 29.56,
29.54, 29.50, 29.44, 29.40, 29.20, 29.18, 29.1, 28.9, 28.2,
9
(14.5 g, 44.68 mmol) and 10-bromodecanal (10 g,
42.55 mmol) in dry tetrahydrofuran (150 ml) under nitrogen.
The reaction was exothermic and the temperature rose to
ꢀ5 ꢁC. The mixture was then stirred for 16 h at room temper-
ature, when TLC showed no starting material, cooled to 0 ꢁC,
quenched with satd aq ammonium chloride (100 ml) and
extracted with petrol/ether (1:1) (3ꢂ60 ml). The combined
organic layers were washed with brine, dried and evaporated
to give a thick yellow oil; chromatography (10:2 petrol/ether)
gave 15-bromopenta-dec-5-enoic acid methyl ester as a pale
yellow oil (11.33 g, 80%). Palladium on carbon (10%) (1 g)
was added to a stirred solution of the ester (10.5 g,
31.53 mmol) in tetrahydrofuran (75 ml) and methanol
(75 ml) under hydrogen. When no further hydrogen was ab-
sorbed, the products were filtered through Celite, which
was washed with ethyl acetate. The filtrate was evaporated
and the residue was purified by chromatography (5:2 petrol/
ether) giving 15-bromopentadecanoic acid methyl ester (10)
as a white solid (9.7 g, 92%), mp 38–39 ꢁC (lit. 38–39 ꢁC),42
which showed dH (500 MHz, CDCl3): 3.68 (3H, s), 3.42
(2H, t, J 7 Hz), 2.32 (2H, t, J 7.25 Hz), 1.86 (2H, br pent, J
7 Hz), 1.62 (2H, pent, J 7.25 Hz), 1.43 (2H, br pent, J 7 Hz),
1.28 (18H, br s); dC (125 MHz, CDCl3): 174.4, 51.4, 34.1,
34.0, 32.8, 29.58, 29.55, 29.4, 29.2, 29.1, 28.8, 28.2, 24.9.
25.0, 22.0; nmax: 2920, 1731, 1494, 1341, 1151 cmꢀ1
.
3.1.4. 2,2-Dimethylpropionic acid 5-hydroxypentyl ester
(12). Trimethylacetyl chloride (12 g, 95.39 mmol) was
added to a stirred solution of 1,5-pentanediol (20 g,
192 mmol) and pyridine (10 g, 126 mmol) in dichloro-
methane (100 ml) at 10 ꢁC, then allowed to reach room tem-
perature and stirred for 16 h. Awhite precipitate was formed,
and the mixture was diluted with dichloromethane (200 ml)
and washed with dil hydrochloric acid (5%), then the organic
layer was separated and the aqueous layer was re-extracted
with dichloromethane (2ꢂ50 ml). The combined organic
layers were washed with satd aq sodium bicarbonate
(100 ml) and water (100 ml), dried and evaporated to give a
colourless oil. The crude product was columned (5:1 petrol/
ethyl acetate) to give 2,2-dimethylpropionic acid 5-hydroxy-
pentyl ester (12) as a colourless oil (15.1 g, 84%) [Found
[M+Na]+: 211.1302; C10H20O3Na requires: 211.1305],
which showed dH (250 MHz, CDCl3): 4.01 (2H, t,
J 6.4 Hz), 3.58 (2H, t, J 6.4 Hz), 2.37 (1H, br s), 1.67–1.49
(4H, m), 1.44–1.32 (2H, m), 1.14 (9H, s); dC (62.5 MHz,
CDCl3): 178.6, 64.2, 62.3, 38.6, 32.1, 28.3, 27.1, 22.1;
3.1.3. 15-(1-Phenyl-1H-tetrazol-5-sulfonyl)pentadeca-
noic acid methyl ester (11). Anhydrous potassium carbon-
ate (2.76 g, 20 mmol) was added to a stirred solution of ester
10 (2.75 g, 8.2 mmol) and 1-phenyl-1H-tetrazol-5-thiol
(1.6 g, 9.0 mmol) in acetone (50 ml) at room temperature
and stirred vigorously for 16 h. The precipitate was filtered
off and washed with acetone, and the filtrate was evaporated
to give a brown residue. This was diluted with dichloro-
methane (75 ml) and water (50 ml). The aqueous layer was
re-extracted with dichloromethane (2ꢂ25 ml). The com-
bined organic layers were washed with water (50 ml), dried
and evaporated to give a yellow solid. Chromatography (5:1
petrol/ether) gave 15-(1-phenyl-1H-tetrazol-5-sulfanyl)pen-
tadecanoic acid methyl ester (3.25 g, 91%) as a colourless
thick oil, which showed dH (500 MHz, CDCl3): 7.62 (5H,
br s), 3.68 (3H, s), 3.41 (2H, t, J 7.6 Hz), 2.32 (2H, t, J
7.5 Hz), 1.83 (2H, pent, J 7.6 Hz), 1.64 (2H, br pent, J
7.6 Hz), 1.46 (2H, br pent, J 6.65 Hz), 1.27 (18H, br s); dC
(125 MHz, CDCl3): 174.3, 154.5, 133.8, 130.1, 129.8,
123.9, 51.4, 34.1, 33.4, 29.58, 29.55, 29.5, 29.4, 29.3,
nmax: 3379, 2937, 1729 cmꢀ1
.
3.1.5. 2,2-Dimethylpropionic acid 5-bromopentyl ester
(13). N-Bromosuccinimide (15.5 g, 87.2 mmol) was added
in portions over 15 min to a stirred solution of ester
12 (13.1 g, 69.6 mmol) and triphenylphosphine (21 g,
80 mmol) in dichloromethane (240 ml) at 0 ꢁC. After stirring
at room temperature for 1 h, when TLC showed no starting
material, it was quenched with satd aq sodium meta-bisulfate
(200 ml). The aqueous layer was re-extracted with dichloro-
methane (2ꢂ50 ml). The combined organic layers were
washed with water, dried and evaporated to give a residue.
This was treated with 1:1 petrol/ether (100 ml) and refluxed
for 30 min, then the triphenylphosphine oxide was filtered
off and washed with petrol/ether (50 ml). The filtrate was
evaporated and the residue chromatographed (10:2 petrol/
ether) to give 2,2-dimethylpropionic acid 5-bromopentyl
ester (13) (16.04 g, 92%) as a colourless oil [Found [M+Na]+:
273.0449; C10H19O279BrNa requires: 273.0461], which
showed dH (500 MHz, CDCl3): 4.07 (2H, t, J 6.3 Hz), 3.41
(2H, t, J 6.65 Hz), 1.88 (2H, pent, J 6.9 Hz), 1.66 (2H,
pent, J 6.9 Hz), 1.52 (2H, pent, J 6.9 Hz), 1.19 (9H, s); dC
(125 MHz, CDCl3): 178.5, 63.9, 38.7, 33.4, 32.2, 27.7,
29.2, 29.1, 29.0, 28.6, 24.9; nmax: 1732 cmꢀ1
.
To a vigorously stirred solution of the above sulfide (3.2 g,
7.4 mmol) in tetrahydrofuran (45 ml) and industrial methyl-
ated spirits (45 ml) was added a solution of ammonium hep-
tamolybdate(VI) tetrahydrate (4.2 g, 3.4 mmol) in ice cold
35% w/w hydrogen peroxide (13 ml) at 15 ꢁC. After 1.5 h,
a further ice cold solution of heptamolybdate (1.9 g) in
hydrogen peroxide (5 ml) was added. The mixture was
stirred for 16 h at room temperature then diluted with water
(250 ml) and extracted with dichloromethane (2ꢂ50 ml).
The combined organic layers were washed with water
(100 ml), dried and evaporated to give a white solid; chroma-
tography (1:1 petrol/ethyl acetate) gave 15-(1-phenyl-1H-tet-
razol-5-sulfonyl)pentadecanoic acid methyl ester (11) as
a white solid (3.12 g, 91%), mp 78–80 ꢁC [Found [M+Na]+:
487.2343; C23H36N4O4SNa requires: 487.2349], which
27.1, 24.5; nmax: 2959, 2849, 1728, 1480, 1154, 771 cmꢀ1
.
3.1.6. 2,2-Dimethylpropionic acid 5-(1-phenyl-1H-tetra-
zol-5-sulfonyl)pentyl ester (14). Anhydrous potassium car-
bonate (18 g, 130 mmol) was added to a stirred solution of
ester 13 (15 g, 59.7 mmol) and 1-phenyl-1H-tetrazol-5-thiol
(10.7 g, 60 mmol) in acetone (150 ml) at room temperature.
The mixture was stirred vigorously at 40 ꢁC for 3 h, then at
room temperature for 16 h, then worked as above to give
a pale yellow oil, 2,2-dimethylpropionic acid 5-(1-phenyl-
1H-tetrazol-5-sulfanyl)pentyl ester (20.2 g, 97%) [Found

11872
J. R. Al Dulayymi et al. / Tetrahedron 62 (2006) 11867–11880
[M+H]+: 349.1675; C17H25N4O2S requires: 349.1693],
which showed dH (500 MHz, CDCl3): 7.58–7.51 (5H, m),
4.04 (2H, t, J 6.65 Hz), 3.39 (2H, t, J 7.6 Hz), 1.86 (2H,
pent, J 7.55 Hz), 1.67 (2H, pent, J 6.6 Hz), 1.51 (2H, pent,
J 6.97 Hz), 1.17 (9H, s); dC (125 MHz, CDCl3): 178.5,
154.3, 133.7, 130.0, 129.8, 123.8, 63.8, 38.7, 33.0, 28.7,
2,2-dimethylpropionic acid 17-(1-phenyl-1H-tetrazol-5-yl-
sulfanyl)heptadecyl ester (10.07 g, 88%) as a colourless oil
[Found [M+H]+: 517.3563; C29H49O2N4S requires:
517.3571], which showed dH (500 MHz, CDCl3): 7.59–
7.51 (5H, m), 4.04 (2H, t, J 6.65 Hz), 3.39 (2H, t,
J 7.25 Hz), 1.81 (2H, pent, J 7.55 Hz), 1.61 (2H, pent,
J 6.65 Hz), 1.43 (2H, pent, J 6.6 Hz), 1.37–1.23 (24H, m),
1.19 (9H, s); dC (125 MHz, CDCl3): 178.6, 154.5, 133.7,
130.0, 129.7, 123.8, 64.4, 38.7, 33.3, 29.61, 29.59, 29.58,
29.7, 29.51, 29.49, 29.46, 29.4, 29.2, 29.04, 28.98, 28.6,
28.0, 27.1, 24.9; nmax: 2971, 1725, 1156, 762, 694 cmꢀ1
.
This was used for next step without purification. To a
vigorously stirred solution of the above ester (32.5 g,
93.27 mmol) in tetrahydrofuran (220 ml) and industrial
methylated spirits (270 ml) was added a solution of ammo-
nium heptamolybdate(VI) tetrahydrate (18 g, 14.56 mmol)
in ice cold 35% w/w hydrogen peroxide (50 ml). A similar
solution was added three times at 0.5 h intervals (total 72 g
of heptamolybdate in hydrogen peroxide (200 ml) was
added). The mixture was stirred for 16 h at room temperature
then worked up as above to give a yellow oil. Chromato-
graphy (1:1 petrol/ethyl acetate) gave 2,2-dimethylpropionic
acid 5-(1-phenyl-1H-tetrazol-5-sulfonyl)pentyl ester (14) as
a thick pale yellow oil (35 g, 99%) [Found [M+H]+:
381.1590; C17H25N4O4S requires: 381.1591], which showed
dH (500 MHz, CDCl3): 7.69–7.67 (2H, m), 7.64–7.57 (3H,
m), 4.06 (2H, t, J 6.3 Hz), 3.74 (2H, distorted t, J 7.9 Hz),
2.03–1.97 (2H, m), 1.7 (2H, pent, J 6.3 Hz), 1.58 (2H,
pent, J 6.95 Hz), 1.18 (9H, s); dC (125 MHz, CDCl3):
178.4, 153.4, 132.9, 131.4, 129.7, 125.0, 63.5, 55.8, 38.7,
28.0, 27.1, 24.7, 21.7; nmax: 2968, 1723, 1497, 1343, 1156,
28.6, 27.2, 25.9; nmax: 2920, 2851, 1727, 1500, 1159 cmꢀ1
.
To a vigorously stirred solution of the above sulfide (9.7 g,
18.77 mmol) in tetrahydrofuran (110 ml) and industrial
methylated spirits (110 ml) was added a solution of ammo-
nium heptamolybdate(VI) tetrahydrate (8.5 g, 6.88 mmol)
in ice cold 35% w/w hydrogen peroxide (25 ml) at 15 ꢁC.
After 1.5 h, further ice cold heptamolybdate (8.5 g) in
hydrogen peroxide (25 ml) was added. The mixture was
stirred for 16 h at room temperature, diluted with water
(250 ml) and worked up as above to give a white solid. Chro-
matography (1:1 petrol/ethyl acetate) gave 2,2-dimethylpro-
pionic acid 17-(1-phenyl-1H-tetrazol-5-sulfonyl)heptadecyl
ester (16) as a white solid (10.1 g, 98%) [Found [M+Na]+:
571.3271; C29H48N4O4SNa requires: 571.32885], mp 51–
53 ꢁC, which showed dH (500 MHz, CDCl3): 7.71–7.69
(2H, m), 7.65–7.58 (3H, m), 4.04 (2H, t, J 6.65 Hz), 3.73
(2H, distorted t, J 8.2 Hz), 1.98–1.92 (2H, m), 1.62 (2H,
pent, J 6.6 Hz), 1.49 (2H, pent, J 6.9 Hz), 1.39–1.24 (24H,
m), 1.20 (9H, s); dC (125 MHz, CDCl3): 178.6, 153.5, 133.1,
131.4, 129.7, 125.1, 64.5, 56.0, 38.7, 29.63, 29.61, 29.53,
29.49, 29.4, 29.20, 29.16, 28.9, 28.6, 28.1, 27.2, 25.9, 21.9;
764 cmꢀ1
.
3.1.7. 2,2-Dimethylpropionic acid 17-bromohepta-
decyl ester (15). Lithium hexamethyldisilazide (38 ml,
40.2 mmol, 1.06 M THF) was added dropwise to a stirred so-
lution of ester 14 (14.1 g, 37 mmol) and 12-bromododecanal
(9.58 g, 36.5 mmol) in dry tetrahydrofuran (150 ml) under
nitrogen at ꢀ10 ꢁC. The reaction was exothermic and the
temperature rose to ꢀ5 ꢁC. The mixture was allowed to
reach room temperature and stirred for 16 h when TLC
showed no starting material. Work up as above gave a thick
yellow oil; chromatography (10:1 petrol/ether) gave E/Z-
2,2-dimethylpropionic acid 17-bromoheptadec-5-enyl ester
in ratio 2.7:1 as a colourless oil (10.9 g, 72%). Palladium
on carbon (10%) (0.8 g) was added to a stirred solution of
the ester (10.9 g, 26.11 mmol) in ethyl acetate (45 ml) and
methanol (110 ml) under hydrogen. When no further hydro-
gen was absorbed, the reaction mixture was worked up as
above. Chromatography(5:2petrol/ether) gave2,2-dimethyl-
propionic acid 17-bromoheptadecyl ester (15) as a white solid
(9.68 g, 88%), mp 36–38 ꢁC [Found [M+Na]+: 441.2321;
C22H4379BrO2Na requires: 441.2339], which showed dH
(500 MHz, CDCl3): 4.05 (2H, t, J 6.65 Hz), 3.41 (2H, t,
J 6.65 Hz), 1.85 (2H, pent, J 7.25 Hz), 1.62 (2H, pent,
J 6.6 Hz), 1.42 (2H, pent, J 7.25 Hz), 1.38–1.22 (24H, m),
1.2 (9H, s); dC (125 MHz, CDCl3): 178.7, 64.5, 38.7, 34.0,
32.8, 29.64, 29.60, 29.55, 29.53, 29.51, 29.4, 29.2, 28.8,
nmax: 2922, 1727, 1497, 1463, 1341, 1284, 1153, 762 cmꢀ1
.
3.1.9. (S)-3-[(1R,2R)-2-((S)-2,2-Dimethyl[1,3]dioxolan-4-
yl)cyclopropyl]butyraldehyde. (S)-3-[(1R,2R)-2-((S)-2,2-
Dimethyl[1,3]dioxolan-4-yl)cyclopropyl]butanol 17 (1.6 g,
7.47 mmol) in dichloromethane (10 ml) was added to
a stirred suspension of pyridinium chlorochromate (4.03 g,
18.7 mmol) in dichloromethane (75 ml) at room temperature
and stirred vigorously for 3 h, when TLC showed no starting
material, then poured into ether (200 ml), filtered through
silica and washed well with ether. The filtrate was evapo-
rated to give an oil; chromatography (5:2 petrol/ether)
gave (S)-3-[(1R,2R)-2-((S)-2,2-dimethyl[1,3]dioxolan-4-yl)-
cyclopropyl]butyraldehyde (1.4 g, 88%), [a]2D2 +10.14 (c
1.45, CHCl3), which showed dH (500 MHz, CDCl3): 9.77
(1H, t, J 1.9 Hz), 4.07 (1H, dd, J 6, 7.85 Hz), 3.87 (1H, br
dt, J 6.3, 7.85 Hz), 3.67 (1H, t, J 7.55 Hz), 2.41–2.39 (2H,
m), 1.74–1.67 (1H, m), 1.44 (3H, s), 1.35 (3H, s), 1.1 (3H,
d, J 6.6 Hz), 0.97 (1H, br dq, J 5.65, 8.2 Hz), 0.88 (1H, br
dt, J 4.75, 8.8 Hz), 0.82–0.75 (1H, m), 0.36 (1H, br q, J
5.35 Hz); dC (125 MHz, CDCl3): 201.8 (+), 108.6 (+), 76.7
(+), 70.0 (ꢀ), 51.3 (ꢀ), 28.6 (+), 26.8 (ꢀ), 25.7 (+), 23.2
28.6, 28.2, 27.2, 25.9; nmax: 1719 cmꢀ1
.
(+), 20.8 (+), 19.2 (+), 8.8 (ꢀ); nmax: 1724 cmꢀ1
.
3.1.8. 2,2-Dimethylpropionic acid 17-(1-phenyl-1H-tetra-
zol-5-sulfonyl)heptadecyl ester (16). Anhydrous potassium
carbonate (5 g, 36.2 mmol) was added to a stirred solution of
ester 15 (9.28 g, 22.12 mmol) and 1-phenyl-1H-tetrazol-5-
thiol (4 g, 22.4 mmol) in acetone (100 ml) at room tempera-
ture. After stirring vigorously for 16 h, work up as above
gave a brown oil. Chromatography (5:1 petrol/ether) gave
3.1.10. (S)-18-[(1R,2R)-2-((S)-2,2-Dimethyl[1,3]dioxolan-
4-yl)cyclopropyl]nonadecanoic acid methyl ester (18).
Lithium hexamethyldisilazide (10.12 ml, 10.1 mmol, 1 M
THF) was added dropwise to a stirred solution of 15-(1-
phenyl-1H-tetrazol-5-sulfonyl)pentadecanoic methyl ester
(2.74 g, 6.74 mmol) and (S)-3-[(1R,2R)-2-((S)-2,2-di-
methyl[1,3]dioxolan-4-yl)cyclopropyl]butyraldehyde (1.3 g,

J. R. Al Dulayymi et al. / Tetrahedron 62 (2006) 11867–11880
11873
6.13 mmol) in dry tetrahydrofuran (30 ml) under nitrogen at
ꢀ25 ꢁC. The reaction was exothermic and the temperature
rose to 0 ꢁC resulting in a yellow solution. The mixture
was allowed to reach room temperature and stirred for 1 h
when TLC showed no starting material, then cooled to 0 ꢁC
and quenched with satd aq ammonium chloride (10 ml). The
product was extracted with petrol/ether (1:1) (3ꢂ40 ml). The
combined organic layers were washed with brine, dried and
evaporated to give a thick oil; chromatography (10:1 petrol/
ether) gave a pale yellow oil, (S)-18-[(1R,2R)-2-((S)-2,2-di-
methyl[1,3]dioxolan-4-yl)cyclopropyl]nonadec-15-enoic acid
methyl ester (1.2 g, 48%). Dipotassium azodicarboxylate
(2.15 g, 11.1 mmol) was added to a stirred solution of the
above ester (1 g, 2.22 mmol) in dry THF (15 ml) and meth-
anol (7 ml) at 10 ꢁC under nitrogen, resulting in a yellow
suspension. Glacial acetic acid (3 ml) in dry THF (4 ml)
was added dropwise over 48 h, after which a white precipi-
tate had formed. The mixture was cooled to 0 ꢁC and
quenched slowly with satd aq ammonium chloride (5 ml),
then extracted with petrol/ether (1:1) (2ꢂ50 ml). The com-
bined organic layers were washed with water (20 ml), dried
and evaporated to give a thick oil, which solidified slowly;
(30 ml) and tetrahydrofuran (10 ml). This was refluxed for
56 h, cooled to room temperature and quenched with satd
aq ammonium chloride (20 ml), and extracted with ether
(3ꢂ50 ml). The combined organic layers were dried, evapo-
rated and no product was obtained (gave a white gel, which
was not soluble in CDCl3).
3.1.13. tert-Butyl-{(S)-3-[(1R,2R)-2-((S)-2,2-dimethyl-
[1,3]dioxolan-4-yl)cyclopropyl]butoxy}diphenylsilane.
Triethylamine (5.66 g, 56.1 mmol) was added to a stirred
solution of alcohol 17 (6 g, 28.03 mmol) in dry dichloro-
methane (150 ml). After 10 min, tert-butyldiphenylsilyl chlo-
ride (10 g, 36.4 mmol) in dichloromethane (20 ml) was
added, followed by dimethylaminopyridine (0.5 g) in dry
dichloromethane (5 ml). The mixture was stirred for 4 h,
when TLC showed no starting material, quenched with water
(50 ml) and extracted with dichloromethane (3ꢂ100 ml).
The combined organic layers were washed with brine and
water, and dried to give a residue. This was purified by
chromatography (5:1 petrol/ether) to give a colourless oil
tert-butyl-{(S)-3-[(1R,2R)-2-((S)-2,2-dimethyl[1,3]-dioxolan-
4-yl)cyclopropyl]butoxy}diphenylsilane (11.02 g, 87%)
[Found M+: 452.2747; C28H40O3Si requires: 452.2747],
[a]2D2 ꢀ7.8 (c 1.54, CHCl3); dH (500 MHz, CDCl3): 7.69–
7.67 (4H, m), 7.47–7.39 (6H, m), 4.19 (1H, dd, J 6, 8 Hz),
3.79–3.63 (4H, m), 1.76–1.7 (1H, m), 1.48 (3H, s), 1.41–
1.35 (1H, m), 1.35 (3H, s), 1.07 (9H, s), 0.97 (3H, d,
J 6.3 Hz), 0.96–0.915 (1H, m), 0.91–0.85 (2H, m), 0.74–
0.68 (1H, m), 0.29 (1H, br q, J 5.1 Hz); dC (125 MHz,
CDCl3): 135.6, 135.5, 133.80, 133.78, 129.64, 129.62,
127.68, 127.66, 108.3, 77.8, 70.1, 61.5, 40, 29.7, 26.8,
25.7, 23.9, 19.6, 19.3, 19.2, 9.3; nmax: 2930, 2858, 1111,
1
however, the H NMR spectra showed that there was still
starting material left. The procedure was repeated for
another 16 h and the residue was purified by chromatography
(10:1 petrol/ethyl acetate) to give (S)-18-[(1R,2R)-2-((S)-
2,2-dimethyl[1,3]dioxolan-4-yl)cyclopropyl]nonadecanoic
acid methyl ester (18) as a colourless oil, which solidified
later (0.62 g, 62%) [Found [M+Na]+: 475.3759;
C28H52O4Na requires: 475.3758], [a]2D2 ꢀ11.75 (c 1.07,
CHCl3), which showed dH (500 MHz, CDCl3): 4.13–4.09
(1H, m), 3.74–3.71 (2H, m), 3.68 (3H, s), 2.32 (2H, t, J
7.55 Hz), 1.63 (2H, br pent, J 7.25 Hz), 1.46 (3H, s), 1.37
(3H, s), 1.35–1.2 (28H, m), 1.01 (4H, br s), 0.92 (1H, br
dq, J 5.3, 8.8 Hz), 0.84 (1H, dt, J 4.75, 8.85 Hz), 0.71–0.66
(1H, m), 0.24 (1H, br q, J 5.35 Hz); dC (125 MHz, CDCl3):
174.4, 108.3, 77.9 (ꢀ), 70.0 (+), 51.4 (ꢀ), 37.4 (+), 34.1
(+), 33.3 (ꢀ), 30 (+), 29.7 (+), 29.6 (+), 29.5 (+), 29.3 (+),
29.2 (+), 27.2 (+), 26.9 (ꢀ), 25.8 (ꢀ), 25.0 (+), 23.9 (ꢀ),
1062 cmꢀ1
.
3.1.14. cis-(1R,2R)-2-[(S)-3-(tert-Butyldiphenylsilanyl-
oxy)-1-methylpropyl]cyclopropanecarbaldehyde (21).
Periodic acid (12.6 g, 55.3 mmol) was added to a stirred
solution of tert-butyl-{(S)-3-[(1R,2R)-2-((S)-2,2-dimethyl-
[1,3]dioxolan-4-yl)cyclopropyl]butoxy}diphenylsilane (10 g,
22.12 mmol) in dry ether (150 ml) under nitrogen at room
temperature. The mixture was stirred for 16 h when TLC
showed no starting material. The precipitate was filtered then
washedwithetherandthesolventwasevaporatedtogiveares-
idue; chromatography (10:2 petrol/ether) gave cis-(1R,2R)-2-
[(S)-3-(tert-butyldiphenylsilanyloxy)-1-methylpropyl]cyclo-
propanecarbaldehyde (21) (8 g, 96%) [Found: C 75.5, H 8.6;
C24H32O2Si requires: C 75.74, H 8.47], [a]2D2 +3.66 (c 1.64,
CHCl3); dH (500 MHz, CDCl3): 9.32 (1H, d, J 6 Hz), 7.69–
7.66 (4H, m), 7.47–7.40 (6H, m), 3.73–3.64 (2H, m),
1.91–1.86 (1H, m), 1.72–1.63 (2H, m), 1.5–1.45 (1H, m),
1.33–1.17 (3H, m), 1.07 (9H, s), 1.06 (3H, d, J 6.3 Hz); dC
(125 MHz, CDCl3): 201.5, 135.6, 133.9, 133.8, 129.6,
127.6, 61.4, 39.8, 31.7, 29.3, 28.6, 26.9, 19.9, 19.1, 13.8;
20.0 (ꢀ), 19.2 (ꢀ), 9.1 (+); nmax: 1730 cmꢀ1
.
3.1.11. cis-(S)-18-((1R,2R)-2-Formylcyclopropyl)nona-
decanoic acid methyl ester (19). Periodic acid (0.9 g,
3.98 mmol) was added to a stirred solution of ester 18
(0.6 g, 1.33 mmol) in dry ether (40 ml) under nitrogen at
room temperature. After 16 h, TLC showed no starting ma-
terial. The precipitate was filtered, washed with ether and the
solvent was evaporated. Chromatography (10:1 petrol/ethyl
acetate) gave cis-(S)-18-((1R,2R)-2-formylcyclopropyl)-
nonadecanoic acid methyl ester (19) (0.4 g, 80%) [Found
[M+Na]+: 403.3202; C24H44O3Na requires: 403.3183],
[a]2D2 +1.98 (c 1.19, CHCl3); dH (500 MHz, CDCl3): 9.33
(1H, d, J 5.65 Hz), 3.67 (3H, s), 2.3 (2H, t, J 7.85 Hz),
1.93–1.87 (1H, m), 1.61 (2H, br pent, J 7.2 Hz), 1.44–1.15
(32H, m), 1.05 (3H, d, J 6.6 Hz); dC (125 MHz, CDCl3):
201.8 (ꢀ), 174.3, 51.4 (ꢀ), 37.4 (+), 34.1 (+), 32.3 (ꢀ),
32.0 (ꢀ), 29.9 (+), 29.7 (+), 29.64 (+), 29.60 (+), 29.5 (+),
29.3 (+), 29.2 (+), 28.7 (ꢀ), 26.8 (+), 24.9 (+), 20.1 (ꢀ),
nmax: 1703 cmꢀ1
.
3.1.15. trans-(1S,2R)-2-[(S)-3-(tert-Butyldiphenylsilanyl-
oxy)-1-methylpropyl]cyclopropanecarbaldehyde (22).
Sodium methoxide (0.937 g, 17.36 mmol) was added to a
stirred solution of cis-aldehyde 21 (6 g, 15.78 mmol) in
methanol (250 ml) and refluxed for 56 h.43 The mixture
was cooled to room temperature and quenched with satd aq
ammonium chloride (100 ml), and the product was extracted
with ether (3ꢂ150 ml). The combined organic layers were
13.6 (+); nmax: 1740, 1706 cmꢀ1
.
3.1.12. Attempted epimerization43 of aldehyde (19). So-
dium methoxide (0.13 g, 2.43 mmol) was added to a stirred
solution of cis-aldehyde 18 (0.37 g, 0.97 mmol) in methanol

11874
J. R. Al Dulayymi et al. / Tetrahedron 62 (2006) 11867–11880
dried and evaporated to give a thick oil, which solidified later.
Chromatography (5:2 petrol/ether) gave trans-(1S,2R)-2-
[(S)-3-(tert-butyldiphenylsilanyloxy)-1-methylpropyl]cyclo-
propanecarbaldehyde (22) (1.16 g, 19%) [Found [M+Na]+:
403.2075; C24H32O2NaSi requires: 403.2064], [a]2D2 +22.9
(c 1.28, CHCl3); dH (500 MHz, CDCl3): 9.00 (1H, d, J
5.35 Hz), 7.71–7.67 (4H, m), 7.47–7.39 (6H, m), 3.77 (1H,
br dt, J 6.3, 10.4 Hz), 3.71 (1H, dt, J 6.65, 10.4 Hz), 1.76–
1.71 (1H, m), 1.7–1.67 (1H, m), 1.56–1.5 (1H, m),
1.32–1.24 (3H, m), 1.07 (9H, s), 0.99 (3H, d, J 6.3 Hz),
0.96–0.93 (1H, m); dC (125 MHz, CDCl3): 200.9, 135.6,
135.5, 135.2, 134.8, 133.9, 133.8, 129.6, 127.73, 127.69,
127.66, 61.4, 39.3, 33.3, 30.1, 29.2, 26.9, 26.6, 19.3, 19.2,
19.0, 13.6; nmax: 1707 cmꢀ1. The second fraction (1:1 petrol/
ethyl acetate) was (1S,2R)-2-((S)-3-hydroxy-1-methyl-
propyl)cyclopropanecarbaldehyde (1.16 g, 52%), which
showed dH (500 MHz, CDCl3): 8.97 (1H, d, J 5.65 Hz),
3.73–3.63 (2H, m), 2.15 (1H, br s), 1.76–1.73 (1H, m),
1.71–1.65 (1H, m), 1.59–1.53 (1H, m), 1.35–1.30 (1H, m),
1.29–1.25 (1H, m), 1.21–1.13 (1H, m), 1.03 (3H, d,
J 7 Hz), 0.95 (1H, m); dC (125 MHz, CDCl3): 201.1 (ꢀ),
60.2 (+), 39.4 (+), 33.5 (ꢀ), 30.3 (ꢀ), 28.9 (ꢀ), 19.6 (ꢀ),
13.3 (+); nmax: 3414 cmꢀ1. The alcohol was protected as be-
fore to give the title compound in 81% yield. There was less
than 5% of the cis-isomer.
dropwise over 48 h, after which a white precipitate had
formed. The mixture was cooled to 0 ꢁC, quenched slowly
with satd aq ammonium chloride (5 ml) and extracted with
1:1 petrol/ether (2ꢂ100 ml). The combined organic layers
were washed with water (20 ml), dried and evaporated to
1
give a thick oil, which solidified slowly; H NMR showed
that there was still starting material left. The procedure
was repeated twice for 16 h and the residue was chromato-
graphed (10:1 petrol/ether) to give 2,2-dimethylpropionic
acid 18-{(1S,2R)-2-[(S)-3-(tert-butyldiphenylsilanyloxy)-1-
methylpropyl]cyclopropyl}octadecyl ester (23) as a white
solid (4.5 g, 99.5%) [Found [M+Na]+: 727.5477;
C46H76O3NaSi requires: 727.5456], [a]2D2 +5.7 (c 1.93,
CHCl3); dH (500 MHz, CDCl3): 7.69–7.66 (4H, m), 7.43–
7.36 (6H, m), 4.07 (2H, t, J 6.6 Hz), 3.80–3.72 (2H, m),
1.74–1.68 (1H, m), 1.65–1.59 (2H, br pent, J 6.5 Hz),
1.56–1.49 (1H, m), 1.36–1.23 (31H, br s), 1.20 (9H, s),
1.17–1.12 (1H, m), 1.05 (9H, s), 0.94–0.84 (4H, including
br s, d 0.88), 0.46–0.40 (1H, m), 0.18–0.137 (2H, m),
0.12–0.09 (1H, m); dC (125 MHz, CDCl3): 178.6, 135.6
(+), 134.2, 129.5 (+), 127.5 (+), 64.46 (ꢀ), 62.35 (ꢀ),
40.21 (ꢀ), 38.72, 34.77 (+), 34.34 (ꢀ), 29.7 (ꢀ), 29.63
(ꢀ), 29.58 (ꢀ), 29.56 (ꢀ), 29.5 (ꢀ), 29.2 (ꢀ), 28.6 (ꢀ),
27.2 (+), 26.9 (+), 25.9 (ꢀ), 19.8 (+), 19.2, 18.6 (+),
10 (ꢀ); nmax: 2920, 2850, 1730 cmꢀ1
.
3.1.16. 2,2-Dimethylpropionic acid 18-{(1S,2R)-2-[(S)-3-
(tert-butyldiphenylsilanyloxy)-1-methylpropyl]cyclopro-
pyl}octadecyl ester (23). Lithium hexamethyldisilazide
(14.1 ml, 14.1 mmol, 1 M THF) was added dropwise to a
stirred solution of sulfone (16) (5.15 g, 9.4 mmol) and alde-
hyde 22 (3.25 g, 8.55 mmol) in dry tetrahydrofuran (50 ml)
under nitrogen at ꢀ20 ꢁC. The reaction was exothermic and
the temperature rose to ꢀ10 ꢁC, resulting in a yellow solu-
tion. The mixture was allowed to reach room temperature,
stirred for 2 h when TLC showed no starting material, then
cooled to 0 ꢁC and quenched with satd aq ammonium chlo-
ride (10 ml). The product was extracted with 1:1 petrol/ether
(3ꢂ50 ml). The combined organic layers were washed with
brine, dried and evaporated to give a thick oil. Chromatography
(10:1 petrol/ether) gave a pale yellow oil, 2,2-dimethyl-
propionic acid 18-{(1R,2R)-2-[(S)-3-(tert-butyldiphenylsi-
lanyloxy)-1-methylpropyl]cyclopropyl}octadec-17-enyl ester
(4.5 g, 78%), as a 2.7:1 mixture of two isomers [Found
[M+Na]+: 725.5303; C46H74O3NaSi requires: 725.5299]; dH
(500 MHz, CDCl3) (major isomer): 7.70–7.68 (4H, m),
7.46–7.37 (6H, m), 5.38 (1H, br dt, J 6.6, 15 Hz), 4.94 (1H,
br dd, J 8.5, 15 Hz), 4.1 (2H, t, J 6.6 Hz), 3.85–3.74 (2H,
m), 1.94 (2H, br q, J 6.3 Hz), 1.67–1.58 (4H, m), 1.4–1.26
(25H, br s), 1.23 (9H, s), 1.17–1.12 (1H, m), 1.07 (9H, s),
1.04–0.97 (1H, m), 0.93 (3H, d, J 6.6 Hz), 0.89–0.87 (1H,
m), 0.47–0.41 (3H, m); dH (500 MHz, CDCl3) (minor iso-
mer): 5.26 (1H, br dt, J 7.25, 10.8 Hz), 4.73 (1H, br t,
J 10.8 Hz), 2.13 (1H, m). The remaining signals were
obscured by the major isomer.
Method B: triisopropylbenzenesulfonyl hydrazide (0.63 g,
2.13 mmol) was added to the above ester (0.5 g,
0.712 mmol) in tetrahydrofuran (20 ml) at room temperature
and stirred for 24 h at 45–50 ꢁC, followed by the addition of
another mol. equivalent of triisopropylbenzenesulfonyl
hydrazide then stirring for 24 h. After diluting with petrol/
ether (1:1) (100 ml) and quenching with aq sodium hydrox-
ide (2%, 20 ml), the organic layer was separated and
the aqueous layer was re-extracted with petrol/ether
(2ꢂ25 ml). The combined organic layers were washed
with brine, dried and evaporated. Chromatography on silica
eluting with 10:1 petrol/ether gave 23 (0.42 g, 85%), which
showed identical spectra to those above.
3.1.17. 2,2-Dimethylpropionic acid 18-[(1S,2R)-2-((S)-1-
methyl-3-hydroxypropyl)cyclopropyl]octadecyl ester.
Tetra-n-butylammonium fluoride (9.6 ml, 9.6 mmol, 1 M
solution) was added with stirring to ester 23 (4.5 g,
6.4 mmol) in dry tetrahydrofuran (50 ml) at 5 ꢁC. The mix-
ture was stirred for 16 h at room temperature, when TLC
showed no starting material, then evaporated, quenched
with water (30 ml) and extracted with dichloromethane
(3ꢂ50 ml). The combined organic layers were dried and
evaporated to give a thick oil. Chromatography (5:0.5 petrol/
ethyl acetate) gave 2,2-dimethylpropionic acid 18-[(1S,2R)-
2-((S)-1-methyl-3-hydroxypropyl)cyclopropyl]octadecyl ester
(2.63 g, 89%) [Found [M+Na]+: 489.4300; C30H58O3Na
requires: 489.4278], [a]2D2 +11.02 (c 1.27, CHCl3); dH
(500 MHz, CDCl3): 4.04 (2H, t, J 6.6 Hz), 3.77–3.68 (2H,
br m), 1.75–1.68 (1H, sext, J 6.65 Hz), 1.65–1.60 (2H, m),
1.58–1.51 (1H, m), 1.35–1.24 (32H, br m), 1.19 (9H, s),
1.17–1.11 (1H, m), 0.95 (3H, d, J 6.65 Hz), 0.90–0.81
(1H, m), 0.51–0.45 (1H, m), 0.25–0.13 (3H, m); dC
(125 MHz, CDCl3): 178.6, 64.5 (+), 61.4 (+), 40.4 (+),
38.7, 35.0 (ꢀ), 34.3 (+), 29.7 (+), 29.62 (+), 29.58 (+),
29.54 (+), 29.51 (+), 29.2 (+), 28.6 (+), 27.2 (ꢀ), 25.9 (+),
Method A: dipotassium azodicarboxylate (3.3 g,
17.1 mmol) was added to a stirred solution of 2,2-dimethyl-
propionic acid 18-{(1R,2R)-2-[(S)-3-(tert-butyldiphenyl-
silanyloxy)-1-methylpropyl]cyclopropyl}octadec-17-enyl
ester (4.5 g, 6.4 mmol) in dry THF (30 ml) and methanol
(15 ml) at 10 ꢁC under nitrogen, giving a yellow suspension.
Glacial acetic acid (4 ml) in dry THF (4 ml) was added
19.8 (ꢀ), 18.7 (ꢀ), 10.6 (+); nmax: 3397, 1731 cmꢀ1
.

J. R. Al Dulayymi et al. / Tetrahedron 62 (2006) 11867–11880
11875
3.1.18. 2,2-Dimethylpropionic acid 18-[(1S,2R)-2-((S)-
1-methyl-3-oxopropyl)cyclopropyl]octadecyl ester
(24). 2,2-Dimethylpropionic acid 18-[(1S,2R)-2-((S)-1-
methyl-3-hydroxypropyl)cyclopropyl]octadecyl ester (2.5 g,
5.5 mmol) in dichloromethane (20 ml) was added to a sus-
pension of pyridinium chlorochromate (2.96 g, 13.7 mmol)
in dichloromethane (100 ml). The mixture was stirred vigor-
ously at room temperature for 3 h, when TLC showed no
starting material, then diluted with ether (250 ml) and fil-
tered through a pad of Celite and then a pad of silica. The
silica was washed with ether. The combined filtrate was
evaporated to give a residue, which was purified by chroma-
tography (5:0.5 petrol/ethyl acetate) to give a colourless oil,
2,2-dimethylpropionic acid 18-[(1S,2R)-2-((S)-1-methyl-3-
oxopropyl)cyclopropyl]octadecyl ester (24) (2.07 g, 83%)
[Found [M+Na]+: 487.4100; C30H56O3Na requires:
487.4122], [a]2D2 +17.1 (c 1.82, CHCl3); dH (500 MHz,
CDCl3): 9.8 (1H, t, J 2.5 Hz), 4.06 (2H, t, J 6.6 Hz), 2.52
(1H, ddd, J 2.5, 6.0, 15.75 Hz), 2.39 (1H, ddd, J 2.5, 7.55,
15.75 Hz), 1.63 (2H, pent, 6.6 Hz), 1.4–1.24 (32H, m), 1.2
(9H, s), 1.20–1.14 (1H, m), 1.03 (3H, d, J 6.6 Hz), 0.54–
0.47 (1H, m), 0.36–0.23 (3H, m); dC (125 MHz, CDCl3):
202.8, 178.6, 64.4 (ꢀ), 51.4 (ꢀ), 38.7, 34.1 (ꢀ), 33.9 (+),
29.7 (ꢀ), 29.64 (ꢀ), 29.62 (ꢀ), 29.58 (ꢀ), 29.55 (ꢀ), 29.5
(ꢀ), 29.2 (ꢀ), 28.6 (ꢀ), 27.2 (+), 25.9 (ꢀ), 25.6 (+), 19.9
1.71 mmol) in dry THF (15 ml) and methanol (7 ml) at
10 ꢁC under nitrogen, giving a yellow suspension. Glacial
acetic acid (2 ml) in dry THF (4 ml) was added dropwise
over 48 h, after which a white precipitate had formed. The
mixture was cooled to 0 ꢁC, quenched slowly with satd aq
ammonium chloride (5 ml) and extracted with 1:1 petrol/
ether (2ꢂ50 ml). The combined organic layers were washed
with water (20 ml), dried and evaporated to give a thick oil,
which solidified slowly; the 1H NMR spectrum showed that
there was still starting material left. The procedure was
repeated for another 16 h and the residue was purified by
chromatography (10:1 petrol/ether) to give a white solid, (S)-
18-{(1R,2S)-2-[18-(2,2-dimethylpropionyloxy)octadecyl]-
cyclopropyl}nonadecanoic acid methyl ester (25) (0.78 g,
65%) [Found [M+Na]+: 727.6560; C46H88O4Na requires:
727.6575], [a]D22 +3.7 (c 1.03, CHCl3), mp 47–49 ꢁC; dH
(500 MHz, CDCl3): 4.06 (2H, t, J 6.6 Hz), 3.68 (3H, s),
2.32 (2H, t, J 7.6 Hz), 1.64 (4H, m), 1.4–1.24 (60H, br m),
1.2 (9H, s), 0.91 (3H, d, J 6.6 Hz), 0.69–0.63 (1H, m),
0.48–0.41 (1H, m), 0.21–0.08 (3H, m); dC (125 MHz,
CDCl3): 178.62, 174.31, 64.45 (+), 51.39 (ꢀ), 38.71, 38.11
(ꢀ), 37.41 (+), 34.47 (+), 34.11 (+), 30.06 (+), 29.70 (+),
29.64 (+), 29.56 (+), 29.51 (+), 29.45 (+), 29.25 (+), 29.22
(+), 29.15 (+), 28.61 (+), 27.25 (+), 27.19 (ꢀ), 26.13 (ꢀ),
25.90 (+), 24.95 (+), 19.67 (ꢀ), 18.61 (ꢀ), 10.48 (+); nmax
2918, 1733 cmꢀ1
:
(+), 18.8 (+), 11.4 (ꢀ); nmax: 2922, 2853, 1729 cmꢀ1
.
.
3.1.19. (S)-18-{(1R,2S)-2-[18-(2,2-Dimethylpropionyloxy)-
octadecyl]cyclopropyl}nonadecanoic acid methyl ester
(25). Lithium hexamethyldisilazide (6.4 ml, 6.4 mmol, 1 M
THF) was added dropwise to a stirred solution of 15-(1-
phenyl-1H-tetrazol-5-sulfonyl)-pentadecanoic methyl ester
11 (1.73 g, 4.26 mmol) and ester 24 (1.8 g, 3.87 mmol) in
dry tetrahydrofuran (30 ml) under nitrogen at ꢀ30 ꢁC. The
reaction was exothermic and the temperature rose to 0 ꢁC re-
sulting in a yellow solution. The mixture was allowed to
reach roomtemperature and stirred for 1 hwhenTLC showed
no starting material, then cooled to 0 ꢁC and quenched with
satd aq ammonium chloride (10 ml). The product was ex-
tracted with petrol/ether (1:1) (3ꢂ30 ml). The combined or-
ganic layers were washed with brine, dried and evaporated to
give a thick yellow oil. Chromatography (10:1 petrol/ether)
gave a pale yellow oil, (S)-18-{(1R,2S)-2-[18-(2,2-dimethyl-
propionyloxy)octadecyl]cyclopropyl}nonadec-15-enoic acid
methyl ester (1.5 g, 55%) as a mixture of two isomers in ratio
2.2:1 [Found [M+Na]+: 725.6446; C46H86O4Na requires:
725.6418]; dH (500 MHz, CDCl3) (major isomer): 5.47–
5.37 (2H, m), 4.06 (2H, t, J 6.65 Hz), 3.68 (3H, s), 2.3
(2H, t, J 7.5 Hz), 2.17–2.12 (1H, m), 2.06–1.92 (3H, m),
1.67–1.61 (5H, m), 1.38–1.25 (51H, m), 1.27 (9H, s), 0.91
(3H, d, J 6.6 Hz), 0.78–0.73 (1H, m), 0.50–0.45 (1H, m),
0.30–0.12 (3H, m); dC (125 MHz, CDCl3): 178.6, 174.3,
131.4, 128.8, 64.5, 51.4, 34.4, 34.1, 32.7, 29.72, 29.70,
29.68, 29.65, 29.63, 29.60, 29.57, 29.55, 29.53, 29.47,
29.27, 29.24, 29.22, 29.17, 28.6, 27.2, 25.9, 25.7, 25.0,
19.2, 18.6, 10.8; nmax: 2921, 1731, 1479 cmꢀ1; dH
(500 MHz, CDCl3) (minor isomer): 1.12–1.18 (1H, m),
0.88–0.85 (3H, d, J 6.6 Hz), 0.86 (1H, m); dC (125 MHz,
CDCl3): 130.4, 128.4, 34.7, 34.4, 29.4, 29.1, 27.3, 25.8,
22.65, 22.62, 22.3, 19.4, 15.3, 14.3, 14.1, 14.0, 11.4, 10.7.
The remaining signals were obscured by the major isomer.
Dipotassium azodicarboxylate (3.3 g, 17.1 mmol) was
added to a stirred solution of the above ester (1.2 g,
3.1.20. (S)-18-[(1R,2S)-2-(18-Hydroxyoctadecyl)cyclo-
propyl]-nonadecanoic acid methyl ester. (S)-18-{(1R,2S)-
2-[18-(2,2-Dimethylpropionyloxy)octadecyl]cyclopropyl}-
nonadecanoic acid methyl ester (0.27 g, 0.383 mmol) in
tetrahydrofuran (5 ml) was added to a stirred solution of
potassium hydroxide (0.31 g, 5.59 mmol) in methanol
(10 ml), tetrahydrofuran (10 ml) and water (1.5 ml) at
room temperature. The mixture was stirred and refluxed at
70 ꢁC for 4 h, when TLC showed no starting material, then
cooled to 5 ꢁC, when a white precipitate formed, filtered
on a sinter, then washed with ether (2ꢂ20 ml). The precipi-
tate was dissolved in hot water and acidified with H2SO4
(10%) and the product was extracted with hot petrol/ether
(1:1). The organic layer was dried and evaporated to give
a white solid, (S)-18-[(1R,2S)-2-(18-hydroxyoctadecyl)-
cyclopropyl]nonadecanoic acid (0.22 g, 95%). This was
treated with excess diazomethane solution in ether and left
to stand for 24 h at room temperature, then the solvent
was evaporated to give a solid, which was recrystallized
from petrol/ether to give a white solid, (S)-18-[(1R,2S)-
2-(18-hydroxyoctadecyl)cyclopropyl]nonadecanoic acid
methyl ester (0.19 g, 84%) [Found [M+Na]+: 643.35991;
C41H80O3Na requires: 643.6000], [a]2D2 +5.12 (c 1.21,
CHCl3), mp 65–67 ꢁC; dH (500 MHz, CDCl3): 3.67 (3H,
s, OCH3), 3.64 (2H, t, J 6.65 Hz, CH2OH), 2.3 (2H,
t, J 7.55 Hz, CH2CO), 1.63–1.54 (6H, m, satd alkane),
1.45–1.21 (57H, m, satd alkane), 1.2–1.15 (2H, br dq,
J 3.15, 7.2 Hz, satd alkane), 0.9 (3H, d, J 6.6 Hz, a-Me),
0.71–0.63 (1H, m, CHCH3), 0.48–0.42 (1H, m, CH-trans-
cyclopropane), 0.21–0.09 (3H, m, CH and CH2-trans-cyclo-
propane); dC (125 MHz, CDCl3): 174.36, 63.1 (+), 51.42
(ꢀ), 38.12 (ꢀ), 37.42 (+), 34.47 (+), 34.12 (+), 32.81 (+),
30.06 (+), 29.71 (+), 29.66 (+), 29.60 (+), 29.46 (+), 29.43
(+), 29.26 (+), 29.15 (+), 27.25 (+), 26.14 (ꢀ), 25.73 (+),
24.96 (+), 19.69 (ꢀ), 18.62 (ꢀ), 10.49 (+); nmax: 3340,
1733 cmꢀ1
.

11876
J. R. Al Dulayymi et al. / Tetrahedron 62 (2006) 11867–11880
3.1.21. [(1R,2R)-2-((S)-2,2-Dimethyl[1,3]dioxolan-4-yl)-
cyclopropyl]methanol. Tetra-n-butylammonium fluoride
(79.2 ml, 79.2 mmol) was added to a stirred solution of
tert-butyl-[(1R,2R)-2-((S)-2,2-dimethyl[1,3]dioxolan-4-yl)-
cyclopropylmethyl]diphenylsilane (25 g, 60.9 mmol) in dry
tetrahydrofuran (150 ml), at 0 ꢁC under nitrogen. The mix-
ture was allowed to reach room temperature, stirred for
16 h when TLC showed no starting material, cooled to 5 ꢁC
and quenched with satd aq ammonium chloride (50 ml) and
extracted with ethyl acetate (3ꢂ200 ml). The combined or-
ganic layers were washed with brine (100 ml) and water
(100 ml), dried and evaporated to give an oil. Chromato-
graphy (1:1 petrol/ethyl acetate) gave [(1R,2R)-2-((S)-2,2-
dimethyl[1,3]dioxolan-4-yl)cyclopropyl]methanol (9.54 g,
91%) [Found [M+NH4]+: 190.1442; C9H20O3N requires:
190.1443], [a]2D2 ꢀ16.2 (c 0.995, CHCl3), which showed dH
(500 MHz, CDCl3): 3.99 (1H, dd, J 2.12, 7.6 Hz), 3.6 (1H,
br t, J 7.3 Hz), 3.52 (1H, dt, J 5.5, 7.3 Hz), 3.4 (1H, dd, J
6.7, 11.3 Hz), 3.32 (1H, dd, J 7, 11.3 Hz), 2.8 (1H, br s),
1.34 (3H, s), 1.25 (3H, s), 1.00–0.86 (1H, m), 0.84–0.74
(1H, m), 0.57 (1H, dt, J 4.9, 8.55 Hz), 0.46 (1H, dt, J 5.17,
8.55 Hz); dC (125 MHz, CDCl3): 108.7, 78.9, 68.9, 65.4,
(1H, d, J 15.5 Hz), 4.05 (1H, dd, J 5.2, 7.3 Hz), 3.76–3.62
(5H, m, including s at d 3.68), 1.58–1.47 (1H, m), 1.4 (3H,
s), 1.32 (3H, s), 1.22–1.15 (1H, m), 1.07 (1H, dt, J 5.2,
8.55 Hz), 0.89 (1H, dt, J 5, 8.55 Hz); dC (125 MHz,
CDCl3): 166.8, 151.7, 118.5, 109.1, 77.5, 69.0, 51.3, 26.6,
25.5, 24.4, 18.4, 12.8; nmax: 1720, 1647 cmꢀ1. There was
less than 5% of the cis-isomer.
3.1.24. Addition of methyl magnesium bromide to (E)-3-
[(1S,2R)-2-((S)-2,2-dimethyl[1,3]dioxolan-4-yl)cyclopro-
pyl]acrylic acid methyl ester (27). Methyl magnesium bro-
mide (35.4 ml, 106.2 mmol) was added dropwise to a stirred
suspension of copper bromide (7.6 g, 53.1 mmol) in dry tetra-
hydrofuran (250 ml) at ꢀ40 ꢁC under nitrogen. The mixture
was stirred for 30 min then (E)-3-[(1S,2R)-2-((S)-2,2-di-
methyl[1,3]dioxolan-4-yl)-cyclopropyl]acrylic acid methyl
ester (8 g, 35.4 mmol) in dry tetrahydrofuran (50 ml) was
added dropwise at ꢀ30 ꢁC. The mixturewas allowed to reach
ꢀ5 ꢁC over 2 h, when GLC showed no starting material, then
quenched slowly with satd aq ammonium chloride (50 ml)
at ꢀ30 ꢁC. The product was extracted with ethyl acetate
(3ꢂ250 ml). The combined organic layers were washed with
brine (100 ml), dried and evaporated to give a brown oil.
Chromatography (5:2 petrol/ethyl acetate) gave a mixture
of (R)-3-[(1S,2R)-2-((S)-2,2-dimethyl[1,3]dioxolan-4-yl)-
cyclopropyl]butyric acid methyl ester and (S)-3-[(1S,2R)-2-
((S)-2,2-dimethyl[1,3]dioxolan-4-yl)cyclopropyl]butyric acid
methyl ester in ratio 1:1 (28) (6 g, 70%) [Found [M+Na]+:
265.1414; C13H22O4Na requires: 265.1410], [a]2D2 ꢀ12.3 (c
1.14, CHCl3). The mixture showed dH (500 MHz, CDCl3):
4.05 (1H, dd, J 6.3, 7.6 Hz), 4.02 (1H, dd, J 6, 12 Hz), 3.67
(3H, s), 3.667 (1H, t, J 7.9 Hz), 3.66 (3H, s), 3.62 (1H, t,
J 7.9 Hz), 3.94 (1H, br dd, J 3.45, 7.9 Hz), 3.45 (1H, br dd,
J 3.15, 7.9 Hz), 2.4 (1H, br dd, J 6.3, 15 Hz), 2.35 (1H,
br dd, J 6.3, 15 Hz), 2.26 (2H, br dd, J 7.85, 14.8 Hz), 1.43
(3H, s), 1.42 (3H, s), 1.36–1.30 (2H, m), 1.33 (3H, s), 1.32
(3H, s), 1.03 (3H, d, J 6 Hz), 1.02 (3H, d, J 6.5 Hz), 0.82–
0.77 (1H, m), 0.76–0.71 (1H, m), 0.61–0.55 (2H, m), 0.54–
0.50 (3H, m), 0.49–0.44 (1H, m); dH (500 MHz, C6D6):
3.87 (1H, dd, J 6, 7.9 Hz), 3.81 (1H, dd, J 6, 7.9 Hz), 3.54
(1H, t, J 7.6 Hz), 3.5 (1H, t, J 7.6 Hz), 3.36 (1H, dt, J 6.3,
7.6 Hz), 3.35 (6H, s), 3.33 (1H, dt, J 6, 7.3 Hz), 2.21 (1H,
dd, J 6.3, 14.8 Hz), 2.15 (1H, dd, J 6.3, 14.8 Hz), 2.06 (1H,
dd, J 7.85, 14.8 Hz), 2.02 (1H, dd, J 7.55, 14.8 Hz), 1.54
(6H, s), 1.44 (3H, s), 1.43 (3H, s), 1.32–1.24 (2H, m), 1.00
(3H, d, J 6.6 Hz), 0.93 (3H, d, J 6.9 Hz), 0.77–0.72 (1H,
m), 0.64–0.58 (1H, m), 0.57–0.52 (2H, m), 0.42–0.34 (3H,
m), 0.28 (1H, dt, J 4.7, 8.2 Hz); dC (125 MHz, CDCl3):
173.2, 173.1, 108.9, 108.8, 79.9, 79.8, 69.3, 69.2, 51.43,
51.41, 41.5, 41.4, 34.9, 34.8, 26.8, 25.75, 25.71, 25.69,
26.6, 25.4, 18.8, 17.5, 7.8; nmax: 3436, 2984, 2934 cmꢀ1
.
3.1.22. (1R,2R)-2-((S)-2,2-Dimethyl[1,3]dioxolan-4-yl)-
cyclopropanecarbaldehyde. [(1R,2R)-2-((S)-2,2-Dimethyl-
[1,3]dioxolan-4-yl)cyclopropyl]methanol (9 g, 52.32 mmol)
in dichloromethane (50 ml) was added to a suspension of pyri-
dinium chlorochromate (23.7 g, 109.8 mmol) in dichloro-
methane (400 ml) and stirred vigorously. After 2 h, when
TLC showed no starting material, it was cooled to room
temperature, poured into ether (500 ml), then the precipitate
was filtered through silica and washed with ether. The filtrate
was evaporated to give a yellow oil; chromatography (1:1
petrol/ethyl acetate) gave (1R,2R)-2-((S)-2,2-dimethyl[1,3]-
dioxolan-4-yl)cyclopropanecarbaldehyde (8.1 g, 91%)
[Found [M+H]+: 171.1023; C9H15O3 requires: 171.1021],
[a]2D2 ꢀ66 (c 1.33, CHCl3), which showed dH (500 MHz,
CDCl3): 9.08 (1H, d, J 4.9 Hz), 4.1 (1H, dd, J 5.9, 7.7 Hz),
3.78 (1H, br q, J 6.7 Hz), 3.65 (1H, br t, J 6.9 Hz), 1.89–
1.81 (1H, m), 1.73–1.63 (1H, m), 1.45 (3H, s), 1.37–1.29
(1H, m), 1.33 (3H, s), 1.26–1.16 (1H, m); dC (125 MHz,
CDCl3): 199.9, 109.4, 76.4, 69.0, 26.52, 26.49, 25.5, 23.7,
11.7; nmax: 1709 cmꢀ1
.
3.1.23. (E)-3-[(1S,2R)-2-((S)-2,2-Dimethyl[1,3]dioxolan-
4-yl)cyclopropyl]acrylic acid methyl ester (27). Methyl-
(triphenylphosphoranylidene)acetate (19.1 g, 47 mmol) was
added in portions to a stirred solution of (1R,2R)-2-((S)-2,2-
dimethyl[1,3]dioxolan-4-yl)cyclopropanecarbaldehyde (8 g,
47 mmol) in toluene (100 ml) at 10 ꢁC. The mixture was
allowed to reach room temperature and stirred for 24 h
when GLC showed no starting material. The solvent was
evaporated and the residue was treated with petrol/ether
(1:1) (200 ml) and refluxed for 10 min. The precipitate
was filtered off and washed with petrol/ether (100 ml). The
solvent was evaporated and the residue was purified by
chromatography eluting with petrol/ethyl acetate (5:2) to
give (E)-3-[(1S,2R)-2-((S)-2,2-dimethyl[1,3]dioxolan-4-yl)-
cyclopropyl]acrylic acid methyl ester (27) (8.4 g, 79%)
[Found [M+Na]+: 249.1095; C12H18O4Na requires:
249.1097], [a]2D2 ꢀ75 (c 1.16, CHCl3), which showed dH
(500 MHz, CDCl3): 6.43 (1H, dd, J 10.1, 15.5 Hz), 5.85
22.2, 22.1, 20.3, 20.00, 19.8, 19.7, 9.7, 9.2; nmax: 1738 cmꢀ1
.
3.1.25. Reduction of (R)-3-[(1S,2R)-2-((S)-2,2-di-
methyl[1,3]-dioxolan-4-yl)cyclopropyl]butyric acid
methyl ester and (S)-3-[(1S,2R)-2-((S)-2,2-dimethyl[1,3]-
dioxolan-4-yl)-cyclopropyl]butyric acid methyl ester.
The mixture of (R)-3-[(1S,2R)-2-((S)-2,2-dimethyl[1,3]-
dioxolan-4-yl)cyclopropyl]butyric acid methyl ester and
(S)-3-[(1S,2R)-2-((S)-2,2-dimethyl[1,3]dioxolan-4-yl)-cyclo-
propyl]butyric acid methyl ester (5.5 g, 22.7 mmol) in dry
tetrahydrofuran (30 ml) was added dropwise to a stirred sus-
pension of lithium aluminium hydride (1.73 g, 45.4 mmol)
in tetrahydrofuran (150 ml) at room temperature under

J. R. Al Dulayymi et al. / Tetrahedron 62 (2006) 11867–11880
11877
nitrogen. The mixturewas refluxed for 1 h when TLC showed
no starting material, then cooled to 0 ꢁC and quenched with
satd aq sodium sulfate (40 ml) until a white solid was formed.
The precipitate was filtered off and washed with tetrahydro-
furan (2ꢂ50 ml). The filtrate was evaporated to give a crude
product which was purified by chromatography (1:1 petrol/
ethyl acetate) to give a mixture of (R)-3-[(1S,2R)-2-((S)-
2,2-dimethyl[1,3]dioxolan-4-yl)cyclopropyl]butan-1-ol and
(S)-3-[(1S,2R)-2-((S)-2,2-dimethyl[1,3]dioxolan-4-yl)cyclo-
propyl]butan-1-ol (4.47 g, 92%) [Found [M+Na]+: 237.1454;
C12H22O3Na requires: 237.1461], [a]2D2 ꢀ13.9 (c 1.69,
CHCl3), which showed dH (mixture, C6D6, 500 MHz): 3.84
(1H, dd, J 5.35, 6 Hz), 3.85 (1H, dd, J 5.1, 6 Hz), 3.55 (1H,
t, J 7.85 Hz), 3.54 (1H, t, J 7.6 Hz), 3.48–3.32 (6H, m),
1.49–1.40 (8H, including two s at d 1.44 and 1.42 (each
3H)), 1.35–1.23 (8H, including two s at d 1.33 and 1.32
(each 3H)), 0.97 (2H, br s), 0.84 (3H, d, J 6.95 Hz), 0.77
(3H, d, J 6.3 Hz), 0.74–0.67 (2H, m), 0.66–0.61 (1H, m),
0.53–0.43 (3H, m), 0.33–0.24 (2H, m), 0.21–0.13 (2H, m);
dC (mixture, C6D6, 125 MHz): 109.5, 109.4, 80.5, 79.9,
70.1, 69.9, 61.3, 61.2, 40.9, 40.8, 35.2, 35.0, 27.8, 27.7,
(3H, s), 1.32 (3H, s), 1.17 (18H, s), 0.86–0.82 (5H, br m),
0.76 (3H, d, J 6.6 Hz), 0.63–0.58 (1H, m), 0.54–0.5 (1H,
m), 0.49–0.44 (2H, m), 0.36–0.33 (1H, dt, J 5.05, 8.2 Hz),
0.35–0.25 (1H, m), 0.21–0.14 (2H, m); dC (125 MHz,
CDCl3): 135.5, 134.1, 133.9, 129.6, 129.5, 127.60, 127.58,
127.56, 108.8, 108.6, 80.5, 80.0, 69.3, 69.2, 62.0, 61.8,
39.8, 39.7, 34.1, 34.0, 30.9, 26.9, 26.8, 26.5, 25.8, 25.7,
23.5, 22.8, 22.5, 20.2, 19.8, 19.5, 19.4, 19.2, 10.2, 8.8; dC
(125 MHz, C6D6): 136.6, 135.10, 135.05, 130.60, 130.55,
80.5, 79.8, 70.2, 70.1, 63.1, 62.9, 40.9, 40.8, 35.2, 34.9,
27.8, 27.7, 26.74, 26.72, 23.4, 23.22, 21.4, 20.6, 20.5, 20.4,
20.1, 20.0, 10.7, 9.2; nmax: 2932, 2858, 1111, 1062 cmꢀ1
.
3.1.27. (1R,2S)-2-[(R)-3-(tert-Butyldiphenylsilanyloxy)-1-
methylpropyl]cyclopropanecarbaldehyde and (1R,2S)-2-
[(S)-3-(tert-butyldiphenylsilanyloxy)-1-methylpropyl] cy-
clopropanecarbaldehyde. Periodic acid (6.3 g, 27.6 mmol)
was added to a stirred mixture of tert-butyl-{(R)-3-[(1S,2R)-
2-((S)-2,2-dimethyl[1,3]dioxolan-4-yl)cyclopropyl]butoxy}-
diphenylsilane and tert-butyl-{(S)-3-[(1S,2R)-2-((S)-2,2-
dimethyl[1,3]dioxo-lan-4-yl)cyclopropyl]butoxy}diphenyl-
silane (5 g, 11.1 mmol) in dry ether (100 ml) under nitrogen
at room temperature. After stirring for 16 h, TLC showed no
starting material. The precipitate was filtered, washed with
ether and the solvent was evaporated to give a residue.
Chromatography (10:2 petrol/ethyl acetate) gave a mixture
of (1R,2S)-2-[(R)-3-(tert-butyldiphenylsilanyloxy)-1-methyl-
propyl]cyclopropanecarbaldehyde and (1R,2S)-2-[(S)-3-
(tert-butyldiphenylsilanyloxy)-1-methylpropyl]cyclopropane-
carbaldehyde (3.86 g, 92%) [Found [M+Na]+: 403.2048;
C24H32O2SiNa requires: 403.2064], [a]2D2 ꢀ17.85 (c 1.26,
CHCl3). The mixture showed dH (500 MHz, CDCl3): 8.98
(2H, d, J 5.65 Hz), 7.68–7.65 (8H, m), 7.45–7.37 (12H,
m), 3.82–3.66 (4H, m), 1.74–1.47 (7H, m), 1.35–1.18 (7H,
m), 1.06 (18H, s), 0.97 (3H, d, J 6.6 Hz), 0.95 (3H, d, J
6.65 Hz); dH (500 MHz, C6D6): 8.74 (1H, d, J 3.15 Hz),
8.73 (1H, d, J 2.85 Hz), 7.78–7.73 (8H, m), 7.28–7.19
(12H, m), 3.67–3.57 (4H, m), 1.5–1.39 (3H, m), 1.38–1.29
(2H, m), 1.28–1.22 (1H, m), 1.15 (9H, s), 1.14 (9H, s),
0.87–0.76 (6H, m), 0.71 (3H, d, J 6.3 Hz), 0.67 (3H, d, J
6.3 Hz), 0.49–0.45 (1H, m), 0.35–0.31 (1H, br ddd, J 4.4,
6.0, 10.1 Hz); dC (125 MHz, CDCl3): 200.9, 200.8, 135.5,
134.8, 133.9, 133.8, 129.6, 127.64, 127.61, 61.5, 61.4,
39.4, 39.3, 33.5, 33.3, 30.1, 29.3, 29.25, 29.19, 26.8, 26.5,
19.5, 19.3, 19.2, 14.6, 13.5; dC (125 MHz, C6D6): 199.6,
199.5, 136.6, 136.5, 135.8, 134.91, 134.90, 134.8, 130.64,
130.63, 62.6, 62.5, 40.3, 40.26, 34.2, 34.1, 30.6, 29.6, 29.3,
26.7, 26.6, 23.3, 23.2, 21.3, 20.7, 20.4, 10.8, 9.3; nmax
3410 cmꢀ1
:
.
3.1.26. tert-Butyl-{(R)-3-[(1S,2R)-2-((S)-2,2-dimethyl[1,3]-
dioxolan-4-yl)cyclopropyl]butoxy}diphenylsilane and
tert-butyl-{(S)-3-[(1S,2R)-2-((S)-2,2-dimethyl[1,3]dioxo-
lan-4-yl)cyclopropyl]butoxy}diphenylsilane (29). The
mixture of (R)-3-[(1S,2R)-2-((S)-2,2-dimethyl[1,3]-dioxo-
lan-4-yl)cyclopropyl]butan-1-ol and (S)-3-[(1S,2R)-2-((S)-
2,2-dimethyl[1,3]dioxolan-4-yl)cyclopropyl]butan-1-ol (3 g,
14 mmol) in dry DMF (15 ml) was added to a stirred solution
of imidazole (1.43 g, 21 mmol) in dry DMF (40 ml) at 5 ꢁC
under nitrogen. The mixture was stirred for 20 min then tert-
butyldiphenylsilylchloride (4.62 g, 16.8 mmol) was added,
then allowed to reach room temperature and stirred for 4 h
when TLC showed no starting material. The solvent was
evaporated under high vacuum and the residue was diluted
with dichloromethane (100 ml) and water (50 ml). The
organic layer was separated and the aqueous layer was re-
extracted with dichloromethane (2ꢂ50 ml). The combined
organic layers were washed with water and brine, dried and
evaporated to give a residue, which was purified by chroma-
tography on silica eluting with 5:1 petrol and ethyl acetate to
giveamixtureof tert-butyl-{(R)-3-[(1S,2R)-2-((S)-2,2-dime-
thyl[1,3]dioxolan-4-yl)cyclopropyl]butoxy}diphenylsilane
and tert-butyl-{(S)-3-[(1S,2R)-2-((S)-2,2-dimethyl[1,3]di-
oxolan-4-yl)cyclopropyl]butoxy}diphenylsilane (29) (5.5 g,
87%) [Found [M+Na]+: 475.2628; C28H40O3SiNa requires:
475.2639], [a]2D2 ꢀ6.8 (c 137, CHCl3). The mixture showed
dH (500 MHz, CDCl3): 7.70–7.65 (8H, m), 7.45–7.38 (12H,
m), 4.05 (1H, dd, J 6, 8.2 Hz), 3.96 (1H, dd, J 6, 8 Hz),
3.79–3.64 (5H, m), 3.57 (1H, t, J 8 Hz), 3.46–3.40 (2H, m),
1.70–1.63 (2H, sext, J 6.5 Hz), 1.56–1.48 (2H, m), 1.45
(3H, s), 1.43 (3H, s), 1.35 (3H, s), 1.34 (3H, s), 1.30–1.25
(2H, m), 1.06 (9H, s), 1.05 (9H, s), 0.91 (3H, d, J 6.3 Hz),
0.907 (3H, d, J 6.6 Hz), 0.72–0.63 (2H, m), 0.56–0.47 (3H,
m), 0.46–0.34 (3H, m); dH (500 MHz, C6D6): 7.79–7.76
(8H, m), 7.25–7.22 (12H, m), 3.83 (1H, dd, J 6, 7.85 Hz),
3.78 (1H, dd, J 6, 7.6 Hz), 3.76–3.67 (4H, m), 3.54 (1H, t, J
7.85 Hz), 3.5 (1H, t, J 7.6 Hz), 3.42–3.38 (1H, br q, J
7.25 Hz), 3.37–3.33 (1H, br dt, J 6.3, 7.55 Hz), 1.67–1.60
(2H, m), 1.50–1.44 (2H, m), 1.44 (3H, s), 1.42 (3H, s), 1.33
29.0, 27.7, 27.4, 20.1, 20.0, 14.7, 13.3; nmax: 1703 cmꢀ1
.
3.1.28. 2,2-Dimethylpropionic acid 18-{(1R,2S)-2-[(R)-3-
(tert-butyldiphenylsilanyloxy)-1-methylpropyl]cyclo-
propyl}octadecyl ester and 2,2-dimethylpropionic acid
18-{(1R,2S)-2-[(S)-3-(tert-butyldiphenylsilanyloxy)-1-
methylpropyl]cyclopropyl}octadecyl ester (30). Lithium
hexamethyldisilazide (16.6 ml, 16.6 mmol, 1 M THF) was
added dropwise to a stirred solution of 2,2-dimethylpro-
pionic acid 17-(1-phenyl-1H-tetrazol-5-sulfonyl)heptadecyl
ester 16 (6.06 g, 11.1 mmol) and a mixture of (1R,2S)-2-
[(R)-3-(tert-butyldiphenylsilanyloxy)-1-methylpropyl]cyclo-
propanecarbaldehyde and (1R,2S)-2-[(S)-3-(tert-butyldiphe-
nylsilanyloxy)-1-methylpropyl]cyclopropanecarbaldehyde
(3.5 g, 9.21 mmol) in dry tetrahydrofuran (50 ml) under
nitrogen at ꢀ15 ꢁC. The reaction was exothermic and the

11878
J. R. Al Dulayymi et al. / Tetrahedron 62 (2006) 11867–11880
temperature rose to ꢀ5 ꢁC giving in a yellow solution. The
mixture was allowed to reach room temperature and stirred
for 2 h when TLC showed no starting material, cooled to
0 ꢁC and quenched with satd aq ammonium chloride (10 ml).
The product was extracted with 1:1 petrol/ether (3ꢂ50 ml).
The combined organic layers were washed with brine, dried
and evaporated to give a thick yellow oil. Chromatography
(10:1 petrol/ether) gave a pale yellow oil, (E/Z)-2,2-di-
methylpropionic acid 18-{(1S,2S)-2-[(R)-3-(tert-butyldi-
phenylsilanyloxy)-1-methylpropyl]cyclopropyl}octadec-17-
enyl ester and 2,2-dimethylpropionic acid 18-{(1S,2S)-2-
[(S)-3-(tert-butyldiphenylpropylsilanyloxy)-1-methylpropyl]
cyclopropyl}octadec-17-enyl ester (5.17 g, 80%). Dipotas-
sium azodicarboxylate (3.9 g, 20.1 mmol) was added to
a stirred solution of the above mixture (4.7 g, 6.69 mmol)
in dry THF (30 ml) and methanol (15 ml) at 10 ꢁC under
nitrogen, resulting in a yellow suspension. Freshly distilled
glacial acetic acid (4 ml) in dry THF (4 ml) was added drop-
wise over 48 h, after which a white precipitate had formed.
The mixture was cooled to 0 ꢁC and quenched slowly with
satd aq ammonium chloride (5 ml). The product was ex-
tracted with petrol/ether (1:1) (2ꢂ100 ml). The combined
organic layers were washed with water (20 ml), dried and
evaporated to give a thick oil, which solidified slowly; how-
ever, the 1H NMR spectrum showed that there was still start-
ing material left. The procedure was repeated twice for 16 h
and the residue was purified by chromatography (10:1 petrol/
ether) to give 2,2-dimethylpropionic acid 18-{(1R,2S)-2-
[(R)-3-(tert-butyldiphenylsilanyloxy)-1-methylpropyl]cyclo-
propyl}octadecyl ester and 2,2-dimethylpropionic acid
18-{(1R,2S)-2-[(S)-3-(tert-butyldiphenylpropylsilanyloxy)-
1-methylpropyl]cyclopropyl}octadecyl ester (30) as a white
solid (3.77 g, 80%) [Found [M+Na]+: 727.5470; C46H76O3SiNa
requires: 727.5456], [a]2D2 ꢀ6.1 (c 1.23, CHCl3). The mix-
ture showed dH (500 MHz, CDCl3): 7.68–7.67 (8H, m),
7.43–7.37 (12H, m), 4.06 (4H, t, J 6.65 Hz), 3.79–3.7 (4H,
m), 1.74–1.68 (2H, m), 1.65–1.6 (4H, m), 1.57–1.47 (2H,
m), 1.38–1.24 (64H, m), 1.21 (18H, s), 1.18–1.13 (2H, m),
1.06 (9H, s), 1.05 (9H, s), 0.86 (3H, br s), 0.84 (3H, br s),
0.42–0.31 (2H, m), 0.19–0.04 (6H, m); dC (125 MHz,
CDCl3): 178.6, 135.6, 134.2, 129.4, 127.5, 67.9, 64.5,
62.3, 62.2, 40.2, 40.0, 38.7, 34.8, 34.7, 34.4, 34.35, 29.7,
29.63, 29.56, 29.5, 29.4, 29.2, 28.6, 27.2, 26.9, 25.9,
give an oil. Chromatography (5:1 petrol/ethyl acetate) gave
as the first fraction 2,2-dimethylpropionic acid 18-{(1R,2S)-
2-((R)-3-hydroxy-1-methylpropyl)cyclopropyl]octadecyl
ester (31) as a white solid (1.1 g, 48%) [Found [M+Na]+:
489.4290; C30H58O3Na requires: 489.4278], [a]2D2 ꢀ11.29
(c 1.08, CHCl3), mp 34–36 ꢁC, which showed dH
(500 MHz, CDCl3): 4.04 (2H, t, J 6.6 Hz), 3.76–3.67 (2H,
m), 1.74–1.68 (1H, br sext., J 6.65 Hz), 1.64–1.58 (2H,
pent, J 6.65 Hz), 1.57–1.51 (1H, m), 1.49 (1H, br s), 1.35–
1.23 (31H, br m), 1.19 (9H, s), 1.13 (1H, m), 0.95 (3H, d, J
6.65 Hz), 0.88–0.82 (1H, m), 0.51–0.44 (1H, m), 0.25–0.13
(3H, m); dC (125 MHz, CDCl3): 178.6, 64.4 (+), 61.3 (+),
40.4 (+), 38.7, 34.9 (ꢀ), 34.3 (+), 29.7 (+), 29.6 (+), 29.57
(+), 29.5 (+), 29.48 (+), 29.2 (+), 28.6 (+), 27.2 (ꢀ), 25.9
(+), 19.8 (ꢀ), 18.7 (ꢀ), 10.6 (+); nmax: 3396, 1730 cmꢀ1
.
The second fraction was 2,2-dimethylpropionic acid 18-
{(1R,2S)-2-((S)-3-hydroxy-1-methylpropyl)cyclopropyl]-
octadecyl ester (32), a white solid (0.92 g, 40%) [Found
[M+Na]+: 489.4288; C30H58O3Na requires: 489.4278],
[a]2D2 ꢀ4.03 (c 1.29, CHCl3), mp 44–46 ꢁC, which showed
dH (500 MHz, CDCl3): 4.04 (2H, t, J 6.65 Hz), 3.76 (1H, br
dd, J 6.3, 10.5 Hz), 3.71 (1H, br dd, J 6.9, 10.5 Hz), 1.72–
1.65 (1H, br sext., J 6.95 Hz), 1.64–1.59 (2H, br pent, J
6.6 Hz), 1.56–1.51 (1H, m), 1.46 (1H, br s), 1.36–1.26
(31H, br m), 1.29 (9H, s), 1.09–1.02 (1H, m), 0.99 (3H, d, J
6.6 Hz), 0.90–0.82 (1H, m), 0.46–0.39 (1H, m), 0.29–2.00
(3H, m); dC (125 MHz, CDCl3): 178.6, 64.5 (+), 61.4 (+),
40.3 (+), 38.7, 35.2 (ꢀ), 34.3 (+), 29.7 (+), 29.6 (+), 29.54
(+), 29.50 (+), 29.2 (+), 28.6 (+), 27.2 (ꢀ), 25.9 (+), 25.8
(ꢀ), 20.3 (ꢀ), 17.6 (ꢀ), 11.9 (+); nmax: 3396, 1730 cmꢀ1
.
3.1.30. 2,2-Dimethylpropionic acid 18-[(1R,2S)-2-((R)-1-
methyl-3-oxopropyl)cyclopropyl]octadecyl ester. 2,2-Di-
methylpropionicacid18-{(1R,2S)-2-((R)-3-hydroxy-1-meth-
ylpropyl)cyclopropyl]octadecyl ester (0.7 g, 1.5 mmol) was
dissolved in dichloromethane (10 ml) and added to a suspen-
sion of pyridinium chlorochromate (0.8 g, 3.75 mmol) in di-
chloromethane (50 ml). The mixture was stirred vigorously
at room temperature for 3 h when TLC showed no starting
material was left, diluted with diethyl ether (150 ml) and fil-
tered through a pad of Celite and then through a pad of silica.
The silica was washed with ether. The combined filtrate was
evaporated to give a residue, which was purified by chromato-
graphy (5:0.5 petrol/ethyl acetate) to give a colourless oil,
2,2-dimethylpropionic acid 18-[(1R,2S)-2-((R)-1-methyl-3-
oxopropyl)cyclopropyl]octadecyl ester, which solidified later
(0.62 g, 89%) [Found [M+Na]+: 487.4122; C30H56O3Na re-
quires: 487.4122], [a]2D2 ꢀ16.4 (c 1.82, CHCl3), mp 28–
30 ꢁC; dH (500 MHz, CDCl3): 9.78 (1H, t, J 2.5 Hz), 4.05
(2H, t, J 6.6 Hz), 2.50 (1H, ddd, J 2.5, 6.0, 15.75 Hz), 2.38
(1H, ddd, J 2.5, 7.6, 15.75 Hz), 1.62 (2H, br pent, J 6.6 Hz),
1.36–1.25 (32H, m), 1.2 (9H, s), 1.16–1.02 (4H, including
d, J 6.6 Hz, d 1.03), 0.53–0.46 (1H, m), 0.35–0.22 (3H, m);
dC (125 MHz, CDCl3): 202.8 (+), 178.6, 64.4 (ꢀ), 51.4 (ꢀ),
38.7, 34.1 (ꢀ), 33.9 (+), 29.7 (ꢀ), 29.63 (ꢀ), 29.61 (ꢀ),
29.58 (ꢀ), 29.5 (ꢀ), 29.49 (ꢀ), 29.2 (ꢀ), 28.6 (ꢀ), 27.2 (+),
25.9 (ꢀ), 25.6 (+), 19.9 (+), 18.8 (+), 11.4 (ꢀ); nmax: 2920,
25.88, 25.6, 20.0, 19.8, 19.2, 18.6, 17.5, 11.8, 10.6; nmax
2920, 2850, 1732 cmꢀ1
:
.
3.1.29. 2,2-Dimethylpropionic acid 18-{(1R,2S)-2-((R)-3-
hydroxy-1-methylpropyl)cyclopropyl]octadecyl ester
(31) and 2,2-dimethylpropionic acid 18-{(1R,2S)-2-((S)-
3-hydroxy-1-methylpropyl)cyclopropyl]octadecyl ester
(32).
Tetra-n-butylammonium
fluoride
(7.45 ml,
7.45 mmol) was added to a stirred solution of 2,2-dimethyl-
propionic acid 18-{(1R,2S)-2-[(R)-3-(tert-butyldiphenylsila-
nyloxy)-1-methylpropyl]cyclopropyl}octadecyl ester and
2,2-dimethylpropionic acid 18-{(1R,2S)-2-[(S)-3-(tert-butyl-
diphenylsilanyloxy)-1-methylpropyl]cyclopropyl}octadecyl
ester (3.5 g, 4.97 mmol) in dry tetrahydrofuran (50 ml) at
0 ꢁC under nitrogen. The mixture was stirred at room temper-
ature for 16 h when TLC showed no starting material, cooled
to 5 ꢁC and quenched with satd aq ammonium chloride
(50 ml) and the product extracted with ethyl acetate
(3ꢂ50 ml). The combined organic layers were washed with
brine (50 ml) and water (50 ml), dried and evaporated to
2850, 1728 cmꢀ1
.
3.1.31. 2,2-Dimethylpropionic acid 18-[(1R,2S)-2-((S)-
1-methyl-3-oxopropyl)cyclopropyl]octadecyl ester.
2,2-Dimethylpropionic acid 18-{(1R,2S)-2-((S)-3-hydroxy-1-
methylpropyl)cyclopropyl]octadecyl ester (0.7 g, 1.5 mmol)

J. R. Al Dulayymi et al. / Tetrahedron 62 (2006) 11867–11880
11879
was dissolved in dichloromethane (10 ml) and added to a sus-
pension of pyridinium chlorochromate (0.8 g, 3.75 mmol) in
dichloromethane (50 ml). The mixture was stirred vigorously
at room temperature for 3 h when TLC showed no starting ma-
terial, diluted with diethyl ether (150 ml) and worked up as
above to give 2,2-dimethylpropionic acid 18-[(1R,2S)-2-((S)-
1-methyl-3-oxopropyl)cyclopropyl]octadecyl ester (0.63 g,
90%), [Found [M+Na]+: 487.4106; C30H56O3Na requires:
487.4122], [a]2D2 ꢀ0.011 (c 1.23, CHCl3), mp 31–32 ꢁC; dH
(500 MHz, CDCl3): 9.78 (1H, t, J 2.5 Hz), 4.05 (2H, t,
J 6.6 Hz), 2.49 (1H, ddd, J 2.2, 6.0, 15.45 Hz), 2.35 (1H,
ddd, J 2.5, 7.6, 15.45 Hz), 1.61 (2H, br pent, J 6.6 Hz), 1.38–
1.24 (32H, m), 1.19 (9H, s), 1.09–1.02 (4H, including d,
J 6.65 Hz, d 1.05), 0.54–0.48 (1H, m), 0.34–0.29 (1H, m),
0.27–0.21 (2H, m); dC (125 MHz, CDCl3): 202.9 (+), 178.6,
64.4 (ꢀ), 51.3 (ꢀ), 38.7, 34.2 (ꢀ), 34.0 (+), 29.7 (ꢀ), 29.6
(ꢀ), 29.54 (ꢀ), 29.51 (ꢀ), 29.2 (ꢀ), 28.6 (ꢀ), 27.2 (+), 25.9
(ꢀ), 25.6 (+), 20.3 (+), 18.5 (+), 11.9 (ꢀ); nmax: 2920, 2850,
0.48–0.43 (1H, m, CH-trans-cyclopropane), 0.216–0.087
(3H, m, CH and CH2-trans-cyclopropane); dC (125 MHz,
CDCl3): 178.56, 174.25, 64.42 (+), 51.35 (ꢀ), 38.68,
38.11 (ꢀ), 37.41 (+), 34.46 (+), 34.07 (+), 30.05 (+), 29.69
(+), 29.63 (+), 29.588 (+), 29.55 (+), 29.51 (+), 29.44 (+),
29.24 (+), 29.21 (+), 29.13 (+), 28.59 (+), 27.24 (+), 27.17
(ꢀ), 26.11 (ꢀ), 25.88 (+), 24.93 (+), 19.677 (ꢀ), 18.60
(ꢀ), 10.47 (+); nmax: 2918, 1733 cmꢀ1
.
3.1.33. Methyl (S)-18-{(1S,2R)-2-[18-(2,2-dimethylpro-
pionyloxy)octadecyl]cyclopropyl}nonadecanoate (34).
Lithium hexamethyldisilazide (1.6 ml, 1.6 mmol, 1 M) was
added dropwise to a stirred solution of 15-(1-phenyl-1H-tet-
razol-5-sulfonyl)pentadecanoic methyl ester 11 (0.48 g,
1.375 mmol) and 2,2-dimethylpropionic acid 18-[(1R,2S)-
2-((S)-1-methyl-3-oxopropyl)cyclopropyl]octadecyl ester
(0.50 g, 1.07 mmol) in dry tetrahydrofuran (20 ml) under
nitrogen at ꢀ15 ꢁC. The reaction was exothermic and the
temperature rose to 0 ꢁC resulting in a yellow solution.
This was allowed to reach room temperature and stirred for
1 h when TLC showed no starting material, then worked up
as above. Chromatography gave (E/Z)-(S)-18-{(1S,2R)-2-
[18-(2,2-dimethylpropionyloxy)octadecyl]cyclopropyl}nona-
dec-15-enoic acid methyl ester (0.52 g, 70%). Hydrogena-
tion and purification as above gave methyl (S)-18-{(1S,2R)-
2-[18-(2,2-dimethylpropionyloxy)octadecyl]cyclopropyl]-
nonadecanoate (34) as a white solid (0.4 g, 80%) [Found
[M+Na]+: 727.6552; C46H88O4Na requires: 727.6575],
[a]2D2 ꢀ3.87 (c 1.16, CHCl3), mp 60–62 ꢁC; dH (500 MHz,
CDCl3): 4.05 (2H, t, J 6.65 Hz, CH2OCO), 3.67 (3H, s,
OCH3), 2.30 (2H, t, J 7.25 Hz, CH2CO), 1.62 (4H, br pent,
J 6.3 Hz, CH2CH2CH2CO), 1.43–1.23 (59H, br m, satd
alkane), 1.2 (9H, s, COC(CH3)3), 1.07–1.01 (1H, m, satd
alkane), 0.93 (3H, d, J 6.65 Hz, a-Me), 0.69–0.64 (1H, m,
CHCH3), 0.41–0.35 (1H, m, CH-trans-cyclopropane),
0.23–0.21 (1H, m, CH-trans-cyclopropane), 0.197–0.14
(2H, m, CH2-trans-cyclopropane); dC (125 MHz, CDCl3):
178.61, 174.30, 64.45 (+), 51.38 (ꢀ), 38.71, 38.05 (ꢀ),
37.34 (+), 34.48 (+), 34.1 (+), 30.08 (+), 29.69 (+), 29.63
(+), 29.588 (+), 29.55 (+), 29.51 (+), 29.44 (+), 29.24 (+),
29.21 (+), 29.13 (+), 28.59 (+), 27.24 (+), 27.17 (ꢀ), 26.11
(ꢀ), 25.90 (+), 24.95 (+), 19.90 (ꢀ), 17.34 (ꢀ), 11.81 (+);
1728 cmꢀ1
.
3.1.32. Methyl (R)-18-{(1S,2R)-2-[18-(2,2-dimethylpro-
pionyloxy)octadecyl]cyclopropyl}nonadecanoate (33).
Lithium hexamethyldisilazide (1.87 ml, 1.87 mmol, 1 M
THF) was added dropwise to a stirred solution of 15-(1-
phenyl-1H-tetrazol-5-sulfonyl)pentadecanoic methyl ester
(0.558 g, 1.375 mmol) and 2,2-dimethylpropionic acid 18-
[(1R,2S)-2-((R)-1-methyl-3-oxopropyl)cyclopropyl]octa-
decyl ester 11 (0.58 g, 1.25 mmol) in dry tetrahydrofuran
(20 ml) under nitrogen at ꢀ15 ꢁC. The reaction was exother-
mic and the temperature rose to 0 ꢁC resulting in a yellow
solution. This was stirred at room temperature for 1 h when
TLC showed no starting material, then cooled to 0 ꢁC,
quenched with satd aq ammonium chloride (10 ml) and ex-
tracted with 1:1 petrol/ether (3ꢂ30 ml). The combined or-
ganic layers were washed with brine, dried and evaporated
to give a thick yellow oil; chromatography (10:1 petrol/
ether) gave a pale yellow oil, (E/Z)-(R)-18-{(1S,2R)-2-[18-
(2,2-dimethylpropionyloxy)octadecyl]cyclopropyl}nonadec-
15-enoic acid methyl ester (0.57 g, 65%) as a 2.2:1 mixture
of isomers. Dipotassium azodicarboxylate (1.38 g,
7.12 mmol) was added to a stirred solution of the ester
(0.5 g, 0.712 mmol) in dry THF (15 ml) and methanol
(7 ml) at 10 ꢁC under nitrogen, resulting in a yellow suspen-
sion. Glacial acetic acid (2 ml) in dry THF (4 ml) was added
dropwise over 48 h, after which a white precipitate had
formed. The mixture was cooled to 0 ꢁC, quenched slowly
with satd aq ammonium chloride (5 ml), then extracted
with petrol/ether (1:1) (2ꢂ50 ml). The combined organic
layers were washed with water (20 ml), dried and evaporated
to give a thick oil, which solidified slowly; however, the
1H NMR spectrum showed that there was still starting mate-
rial left. The procedure was repeated twice for 24 h and the
residue was purified by chromatography (10:1 petrol/ether)
to give (R)-18-{(1S,2R)-2-[18-(2,2-dimethylpropionyloxy)-
octadecyl]cyclopropyl}nonadecanoic acid methyl ester
(33) as a white solid (0.4 g, 80%), mp 47–49 ꢁC, [Found
[M+Na]+: 727.6579; C46H88O4Na requires: 727.6575],
[a]2D2 ꢀ5.08 (c 1.16, CHCl3); dH (500 MHz, CDCl3): 4.05
(2H, t, J 6.65 Hz, CH2OCO), 3.67 (3H, s, OCH3), 2.30
(2H, t, J 7.27 Hz, CH2CO), 1.62 (4H, br pent, J 7 Hz,
CH2CH2CH2CO), 1.4–1.22 (59H, br m, satd alkane), 1.2
(9H, s, COC(CH3)3), 1.18–1.15 (1H, m, satd alkane), 0.90
(3H, d, J 6.9 Hz, a-CH3), 0.693–0.637 (1H, m, CHCH3),
nmax: 2918, 1733 cmꢀ1
.
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