The synthesis of a single enantiomer of a major α-mycolic acid of M. tuberculosis

Article abstract of DOI:10.1016/j.tet.2005.09.056

We report a synthesis of a single enantiomer of a mycolic acid from Mycobacterium tuberculosis containing a di-cis-cyclopropane. The method can be simply varied to modify the chain lengths or the absolute stereochemistry of either cyclopropane.

Full text of DOI:10.1016/j.tet.2005.09.056

Tetrahedron 61 (2005) 11939–11951
The synthesis of a single enantiomer of a major a-mycolic acid
of M. tuberculosis
*
Juma’a R. Al Dulayymi, Mark S. Baird and Evan Roberts
Department of Chemistry, University of Wales, Bangor, Gwynedd LL57 2UW, UK
Received 29 June 2005; revised 30 August 2005; accepted 15 September 2005
Available online 2 November 2005
Abstract—We report a synthesis of a single enantiomer of a mycolic acid from Mycobacterium tuberculosis containing a di-cis-
cyclopropane. The method can be simply varied to modify the chain lengths or the absolute stereochemistry of either cyclopropane.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
containing trans-cyclopropanes at the position in the chain
closest to the hydroxyacid are reported to have a particular
effect on the cell wall and therefore on the sensitivity of
mycobacterial species to hydrophobic antibiotics.5 Mycolic
acids are present both as bound tetramycolyl penta-
arabinose clusters and as extractable trehalose 6,60-
dimycolates (‘cord factor’).1,6 Cord factors protect mice
against Klebsiella pneumoniae or Listeria monocyogenes,
disrupt mitochondrial and sub-mitochondrial membranes,
are granulomagenic,7 adjuvant active, and a virulence
factor. Lipid fractions from M. bovis show antituberculosis
and antitumour immunogenicity, effects that are directly
dependent on the content of a mycolic acid fraction.
Tuberculosis, caused my Mycobacterium tuberculosis, kills
some 3 m people each year and accounts for about 25% of
preventable deaths. It has been estimated that between a
quarter and a half of the world population is infected with
the organism, though in most cases this does not lead to the
development of the disease.1 A limited number of drugs is
available for treating TB; however, the emergence of multi-
drug-resistant strains of the bacterium with associated
fatality rates of 40–60% is a serious problem. Many other
mycobacteria are either obligate or opportunistic patho-
gens.1 M. leprosae causes leprosy, which afflicts over 12 m
people; other mycobacteria cause opportunistic infections in
immunologically compromised patients, for example, in
AIDS. Mycobacteria are resistant to many common
antibiotics, chemotherapeutic agents and disinfectants.
This resistance is partly because the cell wall, containing
a complex heteropolymer involving a series of esters of very
long chain ‘mycolic acids’, is particularly impermeable. The
barrier is probably caused by a parallel alignment of
mycolic acids in the inner leaflet. The balance of these
structures, which is dependent on the mycobacterial species,
changes membrane permeability and fluidity and hence
resistance to a therapeutic agent. Mycolic acids are highly
complex but include long-chain (R,R)-b-hydroxy-acids
(R0CH(OH)CH(CO2H)R00), commonly containing cis-
cyclopropanes, a-methyl-trans-cyclopropanes, a-methyl-
b-keto- and a-methyl-b-methoxy- groups in the R0-chain
and a simple long-chain alkyl group in the R00 position,2–4
such as compounds 1–4 below (Scheme 1). Mycolic acids
Keywords: Tuberculosis mycolic acid.
*
Corresponding author. Tel.: C44 1 248382374; fax: C44 1 248370528;
e-mail: chs028@bangor.ac.uk
Scheme 1.
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.09.056

11940
J. R. Al Dulayymi et al. / Tetrahedron 61 (2005) 11939–11951
A correlation between lung cancer and pulmonary tubercu-
losis has been discussed.7 ‘Cord factor appears to be one of
the most potent immuno-modulators in the mycobacterial
cell’.7b Thus, the detection of antibodies against cord factor
produced in the serum of patients with pulmonary
tuberculosis is clinically useful in the rapid seriodiagnosis
of the disease;8 similar approaches have been reported
for the seriodiagnosis of Hansen’s disease/leprosy and for
Rhodococcus ruber.9 The need to characterise the molecular
mechanism for such responses is identified. The availability
of unique mycolic acids is seen as key; the availability of the
derived cord factors also offers the potential for improved
ELISA assays for disease.
Scheme 3.
We now report the synthesis of a single enantiomer 8 of the
mycolic acid 5,2 protected at the acid and alcohol positions.†
The stereochemistry of the cyclopropanes A and B is that,
which could have a common biosynthetic precursor with
some S-methyl-branched mycolates.18 The synthetic
method used, which can be varied to allow the synthesis
of either absolute stereochemistry of each cyclopropane,
involved the use of a common precursor for the two chiral
cyclopropane units, C–C bonds being created at the
positions shown below (Scheme 4).
Mycolic acids from Mycobacteria, usually containing
70–90 carbons, are present as complex mixtures with
varying values of a–d above, the exact composition
depending on the species. Structural assignment has often
been based on mass spectra of mixtures of homologues.10 It
is often difficult from the early literature to judge the
certainty with which a structure has been assigned or,
indeed, which actual values of a–d have been determined.
However, recent detailed studies have clarified the situation
considerably.11,1 Moreover, although the hydroxyacid
grouping is known to be of R,R-configuration, the absolute
stereochemistries of the other groups are not known. There
is some evidence that the 1-methyl-2-methoxy unit at the
distal position from the hydroxy acid in mycolic acids (2) is
S,S,12 while other reports identify an R-stereochemistry for
the three stereo-centres of an a-methyl-trans-epoxy unit.13
Much is now known about the enzymes controlling the
biosynthesis of mycolic acids,14 and it has been proposed,
for example, 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 intermediate
(Scheme 2).15 A consequence of this would be that the three
sub-units should have a common absolute stereochemistry
at the carbon bearing the methyl group and C-1 of the
cis-cyclopropane.
Scheme 4.
The (1S,2R)-aldehyde 13 was prepared by a method
described earlier from (1S,2R)-butyryloxymethyl-2-formyl-
cyclopropane 10.19 The first step required the generation of
an ylid from the nonadecyltriphenylphosphonium salt 9.
This was prepared from nonadecanol by conversion into the
bromide by standard methods, followed by reaction with
triphenylphosphine. The nonadecanol was itself prepared
efficiently either by oxidation of eicosene to nonadecanoic
acid,20 and reduction, or by the coupling of heptylmagne-
sium bromide to 12-bromodecanol in the presence of
dilithium tetrachlorocuprate (Scheme 5).
Scheme 2.
Scheme 5. (i) KMnO4, CH3(CH2)15NMe3Br, H2O/HOAc (78%); (ii)
LiAlH4/THF (83%); (iii) Li2CuCl4, THF (91%); (iv) aq HBr, Bu4NCBrK
(99%); (v) PPh3, toluene (85%).
Among the most important of these acids are those
containing two cis-cyclopropanes. The acid 5 (or 1, aZ
19, bZ14, cZ11, dZ23) was reported by Minnikin and
Polgar to be the major mycolic acid of M. tuberculosis var
hominis.2 Syntheses of the ‘mero-mycolic acid’ 6 as a
mixture of four isomeric di-cis-cyclopropanes,16 and of a
single enantiomer of compound 7 have been reported
(Scheme 3).17 The synthesis of single stereoisomers of
individual mycolic acids may lead to a fuller understanding
of their biosynthesis and of the structures of bacterial cell
walls and to cord factor antibodies derived from discrete
mycolic acids characteristic of individual bacteria.
Reaction of (10) with the salt (9) and butyllithium in
tetrahydrofuran led to the ester (11) as a mixture of E and
Z-isomers in ratio 1:6. This was first reduced to the
corresponding alcohols and then the double bond was
saturated using di-imide generated from hydrazine hydrate,
† A preliminary account of these results has already been published (Al
Dulayymi, J. R.; Baird, M. S. and Roberts, E. J. Chem. Soc., Chem.
Comm. 2003, 228–229).

J. R. Al Dulayymi et al. / Tetrahedron 61 (2005) 11939–11951
11941
The remaining major problem was to link the single
enantiomer of the dicyclopropane unit to the hydroxyacid
portion of the target molecule 8. Syntheses of a shorter chain
dialkyl mycolic acid containing no cyclopropane ring as the
R,R-isomer has been reported earlier.22,23 In the present
work, a modified approach for the synthesis of 8 was used.
Ring opening of the epoxide 2024 with a Grignard reagent
prepared from 9-bromononan-1-ol tetrahydropyranyl ether
led to a single enantiomer of the mono-protected diol 21
(as a diastereomeric mixture at the OTHP group) in 86%
yield. This was transformed in four steps into the diol 22
(Scheme 9).
Scheme 6. (i) Me(CH2)18PPh3Br (9), BuLi, THF (81%, 6:1 Z/E),
(ii) LiAlH4, THF (95%), (iii) N2H4, NaIO4, AcOH, CuSO4, i-PrOH (80%);
(iv) PCC, CH2Cl2 (90%).
sodium periodate and copper sulphate in acetic acid and
isopropanol. The derived alcohol 12 was then readily
oxidised to aldehyde (13) (Scheme 6).
The aldehyde 13 was homologated to give 14 by reaction
with 1-carbomethoxy-12-triphenylphosphoniumundecyl
iodide and base, again to give a mixture of E-and Z-alkenes,
followed by the same sequence of reduction to the
corresponding alcohols, hydrogenation of the alkenes
using di-imide, and then oxidation to the aldehyde
(Scheme 7).
Scheme 9. (i) BrMg(CH2)9OTHP, CuI, 2 h, K30 8C (86%); (ii) imidazole,
DMF, ButSiMe2Cl (93%); (iii) H2, Pd/C, MeOH (84%); (iv) NaIO4,
RuCl3$H2O, CH3CN, H2O, CCl4 (69%); (v) MeOH, H2SO4.
1-Iodotetracosane (24) was prepared by coupling dodecyl-
magnesium bromide to 12-bromododecanol to give tetra-
cosan-1-ol (23) (90%), bromination with NBS and
triphenylphosphine (93%) to give 1-bromotetracosane and
then conversion of the bromide into the iodide with sodium
iodide in acetone (86%) (Scheme 10).
Scheme 7. (i) MeO2C(CH2)11PPh3I, MeONa, THF, DMF (70%);
(ii) LiAlH4, THF (92%); (iii) N2H4, NaIO4, AcOH, CuSO4, i-PrOH (85%);
(iv) PCC, CH2Cl2 (93%).
The second cyclopropane unit was prepared by a similar
route, though in this case a Julia reaction was used in place
of Wittig coupling. Ester 1519 was converted into sulphone
16 by reaction with the thiazole 17, triphenylphosphine and
diethyl azodicarboxylate then oxidation of the derived
thioether.21 The sulphone was treated with aldehyde 14 in a
modified Julia reaction,21 to give a 1:1 mixture of E- and
Z-alkenes 18. Reduction to the corresponding alcohols using
lithium aluminium hydride followed by hydrogenation of
the alkene, again using di-imide gave a single enantiomer of
alcohol 19 (Scheme 8).
Scheme 10.
The diol 22 was protected at the primary alcohol group as a
silyl ether and then alkylated,25 using 1-iodotetracosane to
give the hydroxy ester 25 using a method that has been
applied to shorter chain alkyl mycolic acids,23 although the
yield was moderate at best. Protection of the secondary
alcohol in 25 as the acetate, deprotection of the primary
alcohol and oxidation led to the aldehyde 26 (Scheme 11).
Scheme 11. (i) ButPh2SiCl, DMAP, Et3N (84%); (ii) LDA, CH3(CH2)23I,
HMPA (31%); (iii) Ac2O, pyridine (86%); (iv) FK (75%); (v) PCC (95%).
In the final stages of the synthesis, the single enantiomer of
protected aldehyde 26 was coupled to the dicyclopropane
19. Reaction of alcohol 19 with the thiazole 17,
triphenylphosphine and diethyl azodicarboxylate then
oxidation of the derived thioether as before gave the
sulphone 27. Treatment of this with the aldehyde 26 and
base in a Julia reaction led to a mixture of Z- and E- alkenes
28; hydrogenation with di-imide generated from
dipotassium azodicarboxylate and acid gave the saturated
Scheme 8. (i) (17), PPh3, DEAD; (ii) H2O2 or MCPBA, CH2Cl2;
(iii) LiHMDS; (iv) (14) (43% two steps); (v) LiAlH4; (vi) NH2NH2, NaIO4,
CuSO4, AcOH, i-PrOH (77% two steps).

11942
J. R. Al Dulayymi et al. / Tetrahedron 61 (2005) 11939–11951
protected mycolic acid 8,26 [a]D22 C4.2 (c 0.735, CHCl3)
(Scheme 12).
Scheme 12.
The 1H and 13C NMR spectra of 8 were essentially identical
to those of a sample extracted from M. tuberculosis and then
protected ([a]D C3.7),27 which is a mixture of homologues
in which 8 predominates. However, it must be recognised
1
that in such large molecules, identity of H and 13C NMR
spectra is no guarantee that the relative stereochemistries
are identical. The specific rotation of the synthetic material
([a]D C4.2) was also close to that of the natural mixture of
homologues; in this case the rotation is probably dominated
by the chirality of the hydroxy acid part of the molecule and
not indicative of the chirality of the cyclopropanes. The
mass spectrum of 8 measured either using MALDI or
electrospray MS gave a molecular ion pattern (Fig. 2) which
corresponded to the major isomer of the natural sample
(Fig. 1). Studies to further compare the natural and synthetic
samples in order to establish the stereochemistry of the
former are under way.
Figure 2. MALDI MS of synthetic protected a-mycolic acid (8).
2. Experimental
2.1. General
Chemicals used were obtained from commercial suppliers
or prepared from them by methods described. Solvents,
which had to be dry, for example, ether, tetrahydrofuran
were dried over sodium wire. Petroleum was of boiling
point 40–60 8C. Reactions carried under inert conditions,
were carried out under a slow stream of nitrogen. Reactions
carried out at low temperatures were cooled using a bath of
methylated spirit with liquid nitrogen. Silica gel (Merck
7736 silica gel) and silica plates used for thin layer and
column chromatography were obtained from Aldrich.
Organic solutions were dried over anhydrous magnesium
sulphate.
GLC’s were carried out on a Perkin-Elmer Model 8410
using a capillary column (15 m!0.53 mm). IR spectra were
carried out on a Perkin-Elmer 1600 F.T.I.R. spectrometer as
liquid films. NMR spectra were recorded on a Bruker
AC250 or Advance500 spectrometer. [a]D values were
recorded in CHCl3 on a POLAAR 2001 Optical Activity
polarimeter. Mass spectra were recorded on Bruker
Microtof or Maldi tof instruments or by the EPSRC MS
service in Swansea.
Figure 1. MALDI MS of natural mixture of protected a-mycolic acid
homologues.
Variation of the chain lengths in the above sequence or
adjustment of the absolute stereochemistry by using the
enantiomers of either or both of the cyclopropanes 14 and 16
can be used to provide a simple and flexible approach to any
cis-dicyclopropane mycolic acid.19,28
2.1.1. Nonadecanoic acid. Potassium permanganate (80 g,
506 mmol) was added in portions of 1.5 g over 2 h to a
mechanically stirred solution of eicosene (50 g,

J. R. Al Dulayymi et al. / Tetrahedron 61 (2005) 11939–11951
11943
178.57 mmol), water (1000 ml), acetic acid (20 ml),
hexadecyltrimethylammonium bromide (6 g) and sulphuric
acid 1 M (120 ml) in dichloromethane (1000 ml) at 3 8C.
The mixture was stirred for 16 h at room temperature, then
quenched carefully with satd aq sodium metabisulphite until
a clear solution was obtained. The organic layer was
separated and the aqueous layer was extracted with
dichloromethane (2!400 ml). The combined organic layers
were dried, concentrated to 400 ml, decanted from a small
amount of insolubles and then cooled to K10 8C for 12 h.
The solid was filtered, washed with cold dichloromethane
(60 ml) and petroleum (50 ml) and dried to give non-
adecanoic acid as a white solid (41.4 g, 78%) (mp 65–67 8C,
lit.:20 mp 67–68 8C), which showed dH (250 MHz, CDCl3):
2.44 (2H, t, JZ7.0 Hz), 1.65 (2H, pent, JZ6.9 Hz), 1.25
(30H, br s), 0.85 (3H, t, JZ7.1 Hz); dC: 179.8, 34.1, 31.9,
with dichloromethane (2!40 ml), and the combined
organic layers were washed with satd aq sodium bicarbonate
(200 ml), satd aq sodium chloride (200 ml), and dried. The
solvent was evaporated to give a solid; chromatography
eluting with petroleum and ether (10:0.5) gave a white solid,
1-bromononadecane (28.7 g, 99%), mp 35–37 8C (lit.: 30 mp
37 8C), which showed dH (250 MHz, CDCl3): 3.44 (2H, t,
JZ6.7 Hz), 1.86 (2H, pent, JZ6.7 Hz), 1.65–1.22 (32H, br
m), 0.93 (3H, t, JZ6.4 Hz); dC 33.9, 32.9, 31.9, 29.7 (very
broad), 29.6, 29.4, 28.8, 28.2, 22.7, 14.1; nmax: 2960, 1460,
1261, 1215 cmK1
.
2.1.4. Nonadecyltriphenylphosphonium bromide (9).
1-Bromononadecane (29 g, 83.5 mmol) was added to a
stirred solution of triphenylphosphine (33.00 g, 125 mmol)
in toluene (250 ml). The mixture was refluxed for 120 h.
The solvent was evaporated and petroleum (100 ml) was
added and again evaporated. The residue was treated with
diethyl ether (150 ml) and stirred for 1 h; by this time a
slurry of fine crystals had formed. These were filtered,
washed well with ether and dried to give a white solid,
1-nonadecyltriphenylphosphonium bromide (9) (43.5 g,
85%) which showed dH (250 MHz, CDCl3): 7.9–7.45
(15H, m), 3.8–3.72 (2H, m), 1.66–1.51 (4, m), 1.23 (30H,
br s), 0.83 (3H, t, JZ7.0 Hz); dC: 135, 133.7, 133.6, 130.6,
130.4, 119.1, 117.8, 31.9, 30.5, 30.3, 29.7, 29.3, 29.2, 23.2,
22.7, 14.1.
29.7, 29.4, 29.4, 29.2, 29.1, 24.7, 22.7, 20.3, 14.1; nmax
3703 (very broad) cmK1
:
.
2.1.2. 1-Nonadecanol. Method A. Nonadecanoic acid (30 g,
100 mmol) in tetrahydrofuran (500 ml) was added dropwise
over 15 min to a suspension of lithium aluminium hydride
(6 g, 157.9 mmol) in tetrahydrofuran (200 ml) at room
temperature. The mixture was refluxed for 1 h, then
quenched carefully with freshly prepared satd aq sodium
sulphate (40 ml) followed by the addition of anhydrous
magnesium sulphate (10 g). The mixture was stirred
vigorously for 10 min, filtered through a pad of Celite and
washed with tetrahydrofuran (2!50 ml). The filtrate was
evaporated and the residue was recrystallized from
methanol (500 ml) and water (30 ml) at K10 8C for 12 h
then washed with cold methanol (50 ml) to give 1-nona-
decanol as a white solid (23.75 g, 83%) (mp 60–62 8C, lit.: 29
mp 62 8C), which showed dH (250 MHz, CDCl3): 3.65 (2H,
t, JZ7.1 Hz), 1.62 (2H, pent, JZ6.8 Hz), 1.3 (33H, br s),
0.92 (3H, t, JZ7.1 Hz); dC: 63.1, 32.8, 31.9, 29.7, 29.4,
2.1.5. (1S,2R)-(2-Eicosylcyclopropyl)methanol (12). (A)
n-Butyl lithium (24 ml, 34.8 mmol) was added dropwise to
a stirred solution of 1-nonadecyltriphenylphosphonium
bromide (9) (18.0 g, 29.5 mmol) in dry tetrahydrofuran
(180 ml) under nitrogen at K40 8C. The mixture was
allowed to reach room temperature and stirred for 1 h, then
cooled to K50 8C and (1S,2R)-butyryloxy-methyl-2-for-
mylcyclopropane (10)19,28 (4.2 g, 24.6 mmol) in dry
tetrahydrofuran (20 ml) was added. The mixture was stirred
at room temperature overnight. Satd aq ammonium chloride
(150 ml) was added dropwise to quench the reaction,
followed by the addition of petroleum–ether (1/1)
(120 ml). The organic layer was separated and the aqueous
layer was re-extracted with petroleum/ether (2!50 ml).
The combined organic phases were washed with satd aq
sodium chloride, dried and evaporated to give a residue,
which was purified by chromatography eluting with
petroleum–ether (5/2) to give (6:1)-Z,E butyric acid
2-eicos-1-enyl-cyclopropylmethyl ester (11) (7.13 g, 81%)
which showed dH (250 MHz, CDCl3) (major isomer): 5.45
(1H, br td, JZ7.3, 10.7 Hz), 5.05 (1H, br t, JZ10.7 Hz),
4.13 (1H, dd, JZ7.2, 11.7 Hz), 3.96 (1H, dd, JZ8.1,
11.7 Hz), 2.28 (2H, t, JZ7.35 Hz), 2.13 (2H, br q, JZ
6.7 Hz), 1.76–1.68 (1H, m), 1.65 (2H, sext, JZ7.3 Hz),
1.22–1.05 (33H, br m), 1.05 (1H, dt, JZ4.8, 8.3 Hz), 0.94
(3H, t, JZ7.3 Hz), 0.88 (3H, t, JZ6.4 Hz), 0.37 (1H, br q,
JZ5.5 Hz); (minor isomer): 5.58 (1H, td, JZ6.7, 15.2 Hz),
5.25 (1H, br dd, JZ7.64, 15.2 Hz), 2.12–2.01 (2H, br m)
(the remaining signals were obscured by the major isomer);
dC (for two isomers):173.6, 133.5, 127.3, 65.0, 64.9, 36.2,
32.6, 31.9, 29.7, 29.3, 29.2, 27.6, 22.6, 18.5, 16.5, 16.3,
29.4, 25.7, 22.7, 14.1; nmax: 3430 cmK1
.
Method B. 1-Bromoheptane (13.6 g, 76 mmol) was added
dropwise to a suspension of magnesium turnings (1.97 g,
81 mmol) in dry tetrahydrofuran (80 ml) at a rate sufficient to
maintain a steady reflux. Once the exothermic reaction had
subsided, the mixture was heated under reflux for 1 h then
cooled to K10 8C, when 12-bromododecanol (5.3 g,
20 mmol) in tetrahydrofuran (50 ml) was added. The mixture
was cooled to K40 8C followed by the addition of dilithium
tetrachlorocuprate (5 ml), then stirred for 2 h at this
temperature and at room temperature for 12 h. Satd aq
ammonium chloride (100 ml) was added together with ethyl
acetate (100 ml). The organic layer was separated and the
aqueous layer was re-extracted with ethyl acetate (2!50 ml).
The combined organic layers were washed with water, dried
and evaporated to give a residue, which was treated with
petroleum (50 ml). The solution was cooled to K10 8C for
12 h and the solid was filtered off to give 1-nonadecanol
(5.2 g, 91%), which showed identical spectra to those above.
2.1.3. 1-Bromononadecane. 1-Nonadecanol (23.75 g,
83.62 mmol) was added to a stirred solution of hydrobromic
acid (48%, 100 ml) and tetrabutylammonium bromide (1 g).
The mixture was refluxed for 3 h, cooled to room
temperature and diluted with dichloromethane (120 ml)
and water (300 ml). The aqueous layer was re-extracted
14.2, 14.06, 13.6, 12.2, 10.3; nmax: 1737, 1465 cmK1
.
(B) The above mixture of esters (7 g, 0166 mol) in
tetrahydrofuran (20 ml) was added dropwise to a stirred

11944
J. R. Al Dulayymi et al. / Tetrahedron 61 (2005) 11939–11951
suspension of lithium aluminium hydride (1 g) in tetra-
hydrofuran (80 ml) at room temperature. The mixture was
refluxed for 1 h when TLC showed no starting material was
left, then worked up as before to give a white solid. This was
purified by chromatography on silica eluting with petro-
leum–ether (5/2) to give 6:1 Z,E-2-eicos-1-enyl-cyclo-
propylmethanol (5.54 g, 95%) [a]2D4 C27.5 (c, 0.24 g in
10 ml CHCl3) (mp 43–45 8C), which showed dH (250 MHz,
CDCl3) (major isomer): 5.45 (1H, br td, JZ7.3, 10.7 Hz),
5.05 (1H, br t, JZ10.7 Hz), 3.69 (1H, dd, JZ6.5, 11.65 Hz),
3.43 (1H, dd, JZ8.7, 11.64 Hz), 2.15–2.07 (2H, br m),
1.70–1.55 (1H, m), 1.45–1.15 (34H, br m), 0.95 (1H, dt, JZ
4.74, 8.23 Hz), 0.83 (3H, t, JZ6.1 Hz), 0.32 (1H, br q, JZ
5.4 Hz); (2nd isomer): dH 5.65–5.52 (1H, td, JZ6.7,
15.2 Hz), 5.25 (1H, br dd, JZ7.64, 15.2 Hz), 1.95 (2H, br
m), 1.53–1.46 (1H, m); the remaining signals were obscured
by the major isomer; dC (for two isomers): 132.3, 132.1,
127.8, 127.6, 63.6, 63.3, 34.8, 32.6, 31.9, 29.9, 29.6, 29.5,
29.3, 27.6, 22.6, 20.65, 20.4, 18.9, 18.1, 14.1, 13.9, 12.3,
bicarbonate (10.75 g, 128 mmol). The mixture was refluxed
for 3 h, when GLC showed no starting material. The solvent
was evaporated and the residue was diluted with water
(100 ml), and dichloromethane (250 ml). The organic layer
was separated and the aqueous layer was re-extracted with
dichloromethane (2!50 ml). The combined organic layers
were washed with satd aq sodium thiosulphate, dried and
evaporated to give a pale yellow oil, which was purified by
chromatography on silica eluting with petroleum–ether (5/
1) to give methyl 12-iodododecanoate31 (26.1 g, 90%) as a
colourless oil, which showed dH (250 MHz, CDCl3): 3.60
(3H, s), 3.12 (2H, br t, JZ7.0 Hz), 2.24 (2H, t, JZ7.4 Hz),
1.75 (2H, br pent, 7 Hz), 1.55–1.45 (2H, m), 1.42–1.17
(14H, m); dC: 176.9, 51.4, 34.1, 33.5, 30.4, 29.4, 29.3, 29.2,
28.5, 24.9, 7.2; nmax: 1730 cmK1
.
(B) The above ester (36 g, 105.8 mmol) was added to a stirred
solution of triphenylphosphine (50 g, 190.6 mmol) in
benzene (150 ml) and refluxed for 42 h. The solvent was
evaporated and ether (200 ml) was added. A very viscous
lower layer separated and this was agitated with the ether
upper layer as well as possible. The ether layer was decanted
off and the procedure was repeated with ether (2!200 ml).
The bottom layer was evaporated under vacuum to leave an
orange/yellow viscous oil, 12-(triphenyl-l5-phosphanyl)
dodecanoic acid methyl ester iodide32 (39.8 g, 62%), which
showed dH (250 MHz, CDCl3): 7.75–7.62 (15H, m), 3.55
(3H, s), 3.54–3.37 (2H, br m), 2.19 (2H, t, JZ7.4 Hz),
1.63–1.45 (6H, m), 1.21–1.45 (12H, m); dP: 23.4 ppm.
10.5; nmax: 3400 cmK1
.
(C) Sodium (meta)periodate (30.55 g, 142.8 mmol) in hot
water (90 ml) was added over 90 min at 70–80 8C to a
stirred solution of the above mixture of alcohols (5 g,
14.28 mmol) in isopropanol (250 ml), acetic acid (2 ml),
satd aq copper sulphate (2 ml) and hydrazine hydrate
(20 ml). The mixture was stirred for 2 h to reach room
temperature and worked up as before to give (1S,2R)-(2-
eicosylcyclopropyl)methanol (12) (4.03 g, 80%) as a white
solid, [a]2D2 K7.5 (c 1.30, CHCl3) (mp 60–62 8C) [Found: C,
81.8; H, 13.7; C24H48O requires: C, 81.74; H, 13.72], which
showed dH (250 MHz, CDCl3): 3.65 (1H, dd, JZ7.1,
11.3 Hz), 3.58 (1H, dd, JZ8, 11.3 Hz), 1.72–1.31 (40H,
m), 1.34–1.14 (1H, m), 0.88 (3H, t, JZ6.4 Hz), 0.71 (1H, dt,
JZ4.5, 8.3 Hz), K0.01 (1H, br q, JZ5.2 Hz); dC: 63.4,
2.1.8. 13-((1S,2R)-2-Eicosylcyclopropyl)tridecan-1-ol.
Sodium methoxide (4.1 g, 75.9 mmol) was added to a
stirred solution of 12-(triphenyl-l5-phosphanyl)dodecanoic
acid methyl ester iodide (46.62 g, 77 mmol) in dry
dimethylformamide (190 ml) under nitrogen at K7 8C.
The mixture was allowed to reach 0 8C for 10 min, then
room temperature for 20 min, then cooled to K2 8C,
followed by the addition of (1S,2R)-2-eicosylcyclopro-
panecarbaldehyde (13) (5.63 g, 16 mmol) in tetrahydrofuran
(20 ml) and dimethylformamide (80 ml). The mixture was
stirred at ambient temperature for 18 h. Satd aq ammonium
chloride (25 ml) was added and the mixture was then diluted
with water (1400 ml) and dichloromethane (160 ml).
The organic phase was separated and the aqueous layer
re-extracted with dichloromethane (3!50 ml). The com-
bined organic phases were washed with a half satd aq
sodium chloride (500 ml), dried and evaporated to yield a
brownish residue. This was stirred with a 1:1 mixture of
ether/petroleum (2!300 ml), filtered through a pad of
silica, then evaporated to give a brown oil. The residue was
purified by chromatography on silica eluting with petro-
leum–ether (10/0.5) to give Z-(1S,2R)-13-(2-eicosyl-cyclo-
propyl)tridec-12-enoic acid methyl ester (6.10 g, 69.5%)
(with a minor amount of the E-isomer). The ester (5.5 g,
10 mmol) in tetrahydrofuran (20 ml) was added to a stirred
suspension of lithium aluminium hydride (1.1 g) in
tetrahydrofuran (120 ml) at room temperature, then refluxed
for 2.5 h. When TLC showed no starting material was left,
satd aq sodium sulphate (5 ml) was added, followed by
anhydrous magnesium sulphate. The solids were filtered off,
washed with tetrahydrofuran and the filtrate was evaporated
to give crude Z-(1S,2R)-13-(2-eicosylcyclopropyl)tridec-
12-en-1-ol (4.8 g, 92%), which was used for next step
31.9, 30.2, 29.7, 29.3, 28.5, 22.7, 18.2, 16.2, 14.1, 9.5; nmax
3400 cmK1
:
.
2.1.6. (1S,2R)-2-Eicosylcyclopropanecarbaldehyde (13).
(1S,2R)-2-(Eicosylcyclopropyl)methanol (6.3 g, 17.86
mmol) in dichloromethane (30 ml) was added to a stirred
suspension of pyridinium chlorochromate (7.95 g,
37 mmol) in dichloromethane (170 ml) at room tempera-
ture. After stirring vigorously for 3 h, TLC showed no
starting material. Diethyl ether (400 ml) was added and the
mixture was filtered through a pad of Celite, then through a
pad of silica, which was washed well with ether and the
filtrate was evaporated to give a solid. Chromatography on
silica eluting with petroleum–ether (5/2) gave (1S,2R)-2-
eicosylcyclopropanecarbaldehyde (13) (5.63 g, 90%) as a
white solid (mp 42–44 8C) [Found: C, 82.1; H, 13.2;
C24H46O requires: C, 82.21; H, 13.22], which showed dH
(250 MHz, CDCl3): 9.34 (1H, d, JZ5.5 Hz), 1.87–1.81 (1H,
m), 1.75–1.04 (41H, m), 0.87 (3H, t, JZ7 Hz); dC: 201.8,
31.9, 29.95, 29.7 (very broad), 29.6, 29.5, 29.3, 29.2,
28.2, 27.8, 24.8, 22.7, 14.7, 14.1; nmax: 1694 cmK1; [a]D22
K3.9 (c 1.22, CHCl3).
2.1.7. 12-(Triphenyl-l5-phosphanyl)dodecanoic acid
methyl ester iodide. (A) Methyl 12-bromododecanoate
(25 g, 85.3 mmol) was added to a stirred solution of sodium
iodide (38.4 g, 256 mmol) in acetone (250 ml) at room
temperature, followed by the addition of sodium

J. R. Al Dulayymi et al. / Tetrahedron 61 (2005) 11939–11951
11945
without purification. Sodium (meta)periodate (18.6 g,
86.8 mmol) in hot water (90 ml) was added over 70 min at
70–80 8C, to a stirred solution of the alcohol (4.5 g,
8.7 mmol) in isopropyl alcohol (200 ml), acetic acid
(2 ml), satd aq copper sulphate (2 ml) and hydrazine hydrate
(20 ml). The mixture was stirred for 2 h to reach room
temperature, then diluted with water (300 ml) and dichloro-
methane (450 ml). Because of the low solubility of the
product, the mixture was warmed almost to the boiling point
of dichloromethane to allow separation. The aqueous layer
was re-extracted with warm dichloromethane (3!100 ml).
The combined organic phases were washed with water
(300 ml), dried and evaporated to give a solid, which was
recrystallized from benzene to give a white solid,
13-((1S,2R)-2-eicosylcyclopropyl)tridecan-1-ol (3.84 g,
85%) (mp 74–76 8C) [Found: C, 83.1; H, 14.1; C36H72O
requires: C, 82.99; H, 13.92], which showed dH (250 MHz,
CDCl3): 3.60 (2H, t, JZ6.56 Hz), 1.66–1.12 (63H, m), 0.84
(3H, t, JZ6.4 Hz), 0.6–0.54 (3H, m), K0.36 to K0.39 (1H,
m); dC: 63.1, 32.8, 31.9, 30.2, 29.7, 29.4, 29.2, 28.7, 25.7,
22.67, 15.80, 14.1, 10.9; nmax: 3400 cmK1, [a]D22 K2.04
(c 1.03, CHCl3).
showed dH (250 MHz, CDCl3): 7.83 (1H, dm, JZ
8.04 Hz), 7.72 (1H, dm, JZ8.4 Hz), 7.46–7.33 (1H, m),
7.27–7.22 (1H, m), 4.32 (1H, dd, JZ6.5, 12.1 Hz), 3.98
(1H, dd, JZ8.5, 12 Hz), 3.52 (1H, dd, JZ7.5, 13.27 Hz),
3.34 (1H, dd, JZ7.4, 13.27 Hz), 2.34 (2H, t, JZ7.3 Hz),
1.65 (2H, sext, JZ5.3 Hz), 1.45–1.32 (2H, m), 0.93 (3H, t,
JZ7.3 Hz), 0.95–0.85 (1H, m), 0.37 (1H, br q, JZ5.6 Hz);
dC: 173.7, 166.8, 153.2, 135.2, 126.0, 124.2, 21.4, 121, 64.1,
36.2, 33.9, 18.4, 16.13, 15.7, 13.7, 11.0; nmax: 1733, 1458,
1427, 1180 cmK1; [a]D24 C4.9 (c 2.4, CHCl3).
(B) Method (1). m-Chloroperbenzoic acid (20.2 g,
116.8 mmol) in dichloromethane (100 ml) was added
slowly to a stirred solution of butyric acid (1S,2R)-2-
(benzothiazol-2-ylsulfanylmethyl)cyclopropylmethyl ester
(12.5 g, 38.9 mmol) and sodium bicarbonate (14.72 g,
175.2 mmol) in dichloromethane (100 ml) at 5 8C. The
mixture was stirred for 16 h at room temperature, when TLC
showed no starting material. The solvent was evaporated
and the residue was diluted with ethyl acetate and quenched
slowly with satd aq sodium metabisulphite (25 ml). The
organic layer was separated and the aqueous layer was
extracted with ethyl acetate (2!100 ml). The combined
organic layers were washed with satd aq sodium bicarbonate
(30 ml), water (50 ml), dried, filtered and evaporated to give
a pale yellow oil, which was columned on silica eluting with
petroleum–ether (1/1) to give butyric acid (1S,2R)-2-
(benzothiazole-2-sulfonylmethyl)cyclopropylmethyl ester
(16) (11.3 g, 82.3%) which showed dH (250 MHz,
CDCl3): 8.21–8.15 (1H, m), 7.99–7.95 (1H, m), 7.62–7.45
(2H, m), 4.24 (1H, distorted dd, JZ6, 12 Hz), 3.83–3.72
(2H, m), 3.35 (1H, distorted dd, JZ9.5, 14.7 Hz), 2.22 (2H,
t, JZ7.4 Hz), 1.65 (2H, sext, JZ7.4 Hz), 1.38–1.30 (2H,
m), 0.95–0.8 (4H, m, including t, JZ7.36 Hz), 0.28 (1H, br
q, JZ5.7 Hz); dC: 173.4, 165.8, 152.6, 136.8, 128, 127.6,
2.1.9. 13-((1S,2R)-2-Eicosylcyclopropyl)tridecanal (14).
13-((1S,2R)-2-Eicosylcyclopropyl)tridecan-1-ol (1.3 g,
2.51 mmol) was dissolved in hot dichloromethane
(50 ml) and added to
a refluxing suspension of
pyridinium chlorochromate (1.3 g, 6.03 mmol) in
dichloromethane (50 ml). The mixture was stirred
vigorously under reflux for 1 h. When TLC showed no
starting material, the mixture was allowed to reach room
temperature, diluted with diethyl ether (100 ml) and
filtered through a pad of Celite and then through a pad
of silica. The silica was washed with a 1:1 mixture of
ether/petroleum (60 ml). The combined filtrate was
evaporated to give a residue. Chromatography on silica
eluting with petrol–ether (5/1) gave a white solid, 13-
((1S,2R)-2-eicosylcyclopropyl)tridecanal (14) (1.2 g, 93%)
as a white solid, [a]D K1.69 (c 1.19, CHCl3), mp
64–66 8C, [Found: C, 83.2; H, 13.5; C36H70O requires: C,
82.81; H, 13.59], which showed dH (250 MHz, CDCl3):
9.72 (1H, t, JZ1.8 Hz), 2.38 (2H, dt, JZ1.8, 7.3 Hz),
1.62–1.56 (4H, m), 1.45–1.04 (56H, m), 0.84 (3H, t, JZ
6.4 Hz), 0.64–0.52 (3H, m), K0.37 (1H, q, JZ3.65 Hz);
dC: 203, 43.9, 31.9, 30.2, 29.7, 29.4, 29.3, 29.2, 28.7,
125.4, 122.3, 63.6, 55.1, 4, 18.35, 14.4, 13.6, 9.7, 9.1; nmax
:
1730, 1707, 1470, 762 cmK1, [a]D24 K58.34 (c 1.59,
CHCl3); m/z: MC(353), 266 (MCKC4H7O2), 155 (MCK
C7H4S2O2N).
Method (2). To a stirred solution of butyric acid (1S,2R)-2-
(benzothiazol-2-ylsulfanylmethyl)cyclopropylmethyl ester
(4.0 g, 12.46 mmol) in methylated spirit (100 ml) at 5 8C
was added dropwise a yellow solution of ammonium
molybdate tetrahydrate (1.48 g, 1.17 mmol) in 35% H2O2
(5.44 ml, 56 mmol). The resulting yellow suspension was
stirred for 2 at this temperature and then at room
temperature for 16 h. The solvent was evaporated and the
residue was diluted with water (30 ml) then extracted with
dichloromethane (3!50 ml). The combined organic layers
were washed with brine, dried and evaporated to give a
residue, which was purified by column on silica eluting with
petroleum–ether (1/1) to give butyric acid (1S,2R)-2-
(benzothiazole-2-sulfonylmethyl)cyclopropylmethyl ester
(16) (4.06 g, 92.5%).
22.7, 22.1, 15.76, 14.1, 10.9; nmax: 1720 cmK1
.
2.1.10. Butyric acid (1S,2R)-2-(benzothiazole-2-sulfonyl-
methyl)cyclopropylmethyl ester (16). (A) Diethyl azodi-
carboxylate (11.14 g, 63.9 mmol) in dry tetrahydrofuran
(25 ml) was added to a stirred solution of butyric acid
(1S,2R)-2-hydroxymethylcyclopropylmethyl ester (15)19,28
(10 g, 58.1 mmol), triphenylphosphine (16.77 g,
63.9 mmol) and 2-mercaptobenzthiazole (17) (10.69 g,
63.9 mmol) in tetrahydrofuran (120 ml) at 0 8C. After 18 h
at room temperature, the solvent was evaporated and the
residue was treated with petrol–ether (5/2), filtered and the
filter cake was washed with petrol/ether. The combined
organic layers were evaporated to give a pale yellow oil.
Chromatography on silica eluting with 5:2 petrol/ether gave
butyric acid (1S,2R)-2-(benzothiazol-2-ylsulfanylmethyl)-
cyclopropylmethyl ester (14.4 g, 77%) [Found:
MC321.083; C16H19O2S2N requires: 321.086], which
2.1.11. {(1S,2R)-2-[14-((1S,2R)-2-Eicosylcyclopropyl)tet-
radecyl]cyclopropyl}methanol (19). Lithium hexamethyl-
disilazide (16 ml, 1 M) was added to a stirred solution of
13-((1S,2R)-2-eicosylcyclopropyl)tridecanal (16) (4.3 g,
8.3 mmol) and butyric acid (1S,2R)-2-(benzothiazole-2-
sulfonylmethyl)cyclopropylmethyl ester (4.6 g, 12.6 mmol)
in tetrahydrofuran (100 ml) under nitrogen at K15 8C.

11946
J. R. Al Dulayymi et al. / Tetrahedron 61 (2005) 11939–11951
The mixture was allowed to reach room temperature and
stirred for 24 h, then quenched with satd aq ammonium
chloride (50 ml) followed by the addition of dichloro-
methane (200 ml). The organic layer was separated and
the aqueous layer was re-extracted with dichloromethane
(2!50 ml). The combined organic layers were washed with
50% brine solution (200 ml), dried and evaporated to give a
thick dark brown residue. The residue was purified by
chromatography on silica eluting with petroleum–ether
(5/1) to give a 1:1 mixture E/Z of butyric acid (1S,2S)-2-
[14-((1S,2R)-2-eicosylcyclopropyl)tetradec-1-enyl]cyclo-
propylmethyl esters (18) (2.34 g, 43%). The product (2.3 g)
was dissolved in tetrahydrofuran (20 ml), added to a
stirred suspension of lithium aluminium hydride (1 g) in
tetrahydrofuran (100 ml) and refluxed for 2 h, when TLC
showed no starting material. The mixture was quenched
with satd aq sodium sulphate (3 ml) and worked up as
before to give a white solid, E/Z-{(1S,2S)-2-[14-((1S,2R)-2-
eicosylcyclopropyl)tetradec-1-enyl]cyclopropyl}methanol
(1.8 g, 86%). The crude product (1.8 g) was dissolved in
propan-2-ol (150 ml) and mixed with hydrazine hydrate
(15 ml), acetic acid (1.5 ml) and satd aq copper sulphate
(1.5 ml). The mixture was stirred and heated to 75 8C, then
sodium (meta)periodate (15 g) in warm water (60 ml) was
added in portions maintaining the temperature below 85 8C.
The mixture was allowed to cool to room temperature
and worked up as before to give a solid, which was
purified by recrystallisation from petroleum–ether (10/1) to
(1H, m), 1.75 (2H, pent, JZ6.1 Hz), 1.65–1.25 (24H, br m);
dC: 137.9, 128.4, 127.7, 127.6, 98.8, 73.3, 71.45, 69.3, 67.7,
62.3, 37.4, 36.4, 30.8, 29.7, 29.7, 29.6, 29.55, 29.5, 29.5,
26.2, 25.7, 25.6, 25.5, 19.7; nmax: 3455 cmK1; [a]D20 C7.77
(c 1.62, CHCl3).
2.1.13. (R)-(C)-1-Benzyloxy-3-acetoxy-13-tetrahydro-
pyranyloxytridecane. 1-Benzyloxy-3-hydroxy-13-tetra-
hydropyranyloxytridecane (3 g, 0.0074 mol) was mixed
with acetic anhydride (15 ml) and anhydrous pyridine
(15 ml) at room temperature. The mixture was stirred for
16 h then toluene (20 ml) was added and the solvent was
evaporated to give an oil. The residue was purified by
chromatography on silica eluting with petroleum–ethyl
acetate (5/0.5) to give (R)-1-benzyloxy-3-acetoxy-13-
tetrahydropyranyloxytridecane (2.97 g, 90%) as a colour-
less oil (Found: C, 72.2; H, 9.9; C27H44O5: required: C,
72.28; H, 9.88), which showed dH (250 MHz, CDCl3): 7.28
(5H, br s), 5.00 (1H, br p, JZ4.3 Hz), 4.57 (1H, t, JZ
3.9 Hz), 4.43 (2H, s), 3.95–3.85 (1H, m), 3.74 (1H, dt, JZ7,
9.4 Hz), 3.52–3.41 (3H, m), 3.87 (1H, dt, JZ6.7, 9.75 Hz),
1.96 (3H, s), 1.85–1.83 (2H, br m), 1.6–1.4 (8H, m), 1.35–
1.25 (16H, br m); dC: 170.7, 138.3, 128.3, 127.7, 127.5,
98.8, 73.0, 71.9, 67.65, 66.8, 62.3, 34.4, 34.3, 30.8, 29.7,
29.5, 29.5, 26.2, 25.5, 25.2, 21.2, 19.7; nmax: 1737 cmK1
[a]2D0 K12.1 (c 1.3, CHCl3).
;
2.1.14. (R)-1-Hydroxy-3-acetoxy-13-tetrahydropranyl-
oxytridecane. (R)-1-Benzyloxy-3-acetoxy-13-tetrahydro-
pyranyloxytri-decane (6.5 g, 0.014 mol) in methanol
(350 ml) was stirred with Pd/C (10%) under a hydrogen
atmosphere for 30 h. TLC showed no starting material; the
mixture was filtered through Celite and evaporated to give
an oil. This was purified by chromatography on silica
eluting with petroleum–ethyl acetate (5/1) to give (R)-1-
hydroxy-3-acetoxy-13-tetrahydropyranyloxytridecane as a
colourless oil (4.71 g; 91.5%), (Found: C, 66.8; H, 10.6;
C20H38O5 requires: C, 67.00; H, 10.68) which showed dH
(250 MHz, CDCl3): 5.52–4.82 (1H, m), 4.56 (1H, br t, JZ
4.3 Hz), 3.92–3.81 (1H, m), 3.75–3.68 (1H, m), 3.65–3.55
(1H, m), 3.54–3.45 (2H, m), 3.42–3.35 (1H, m), 2.34 (1H, br
s), 2.10 (3H, s), 1.80 (2H, s), 1.7–1.4 (10H, m), 1.25 (16H,
br s); dC:171.9, 98.8, 71.6, 67.6, 62.3, 58.5, 37.4, 34.5, 30.7,
give
{(1S,2R)-2-[14-((1S,2R)-2-eicosylcyclopropyl)-
tetradecyl]cyclopropyl}methanol (19) (16 g, 89%) (Found:
C, 83.9; H, 13.8. C41H80O requires: C, 83.60; H, 13.68)
which showed dH (250 MHz, CDCl3): 3.69–3.53 (2H, m),
1.84–1.21 (67H, br m), 1.15–1.05 (1H, m), 0.95–0.85 (5H,
m, including a triplet with coupling constant 6.8 Hz), 0.75–
0.5 (3H, m), K0.04 (1H, br q, JZ5.5 Hz), K0.33 (1H, br q,
JZ5.5 Hz), dc: 63.6, 31.9, 30.2, 29.7 (very broad), 29.3,
28.7, 28.5, 22.7, 18.1, 16.1, 15.7, 14.1, 10.9, 9.5, nmax
3300 cmK1, [a]2D2 K4.55 (c 1.17, CHCl3).
:
2.1.12. (R)-(C)-1-Benzyloxy-3-hydroxy-13-tetrahydro-
pyranyl-oxytridecane (21). 1-Bromo-9-tetrahydropyranyl-
oxynonane37 (12.93 g, 0.042 mol) in tetrahydrofuran
(15 ml) was added dropwise to magnesium turnings
(1.31 g, 0.054 mol) in tetrahydrofuran (20 ml) under
nitrogen. The mixture was refluxed for 2 h, then cooled to
room temperature and added dropwise to a stirred solution
of purified copper iodide (0.53 g, 0.0028 mol)39 in dry
tetrahydrofuran (30 ml) at K30 8C. After 10 min a solution
of (S)(K)-(2-benzyloxyethyl)oxirane (20)36 (5 g,
0.028 mol) in tetrahydrofuran (10 ml) was added dropwise.
The mixture was stirred for 3 h at K30 8C, when TLC
showed no starting material, quenched with satd aq
ammonium chloride (10 ml) and allowed to reach room
temperature. The product was extracted with ethyl acetate
(3!50 ml); the combined organic layers were washed with
water (30 ml), dried and evaporated to give a colourless oil;
chromatography on silica eluting with petroleum–ethyl
acetate (5/2) gave (R)-(C)-1-benzyloxy-3-hydroxy-13-
tetrahydropyranyloxytridecane (21) (9.8 g, 86%) (Found:
C, 73.4; H, 10.1; C25H42O4 requires: C, 73.84; H, 10.41)
which showed dH (250 MHz, CDCl3): 7.32 (5H, br s), 4.57
(1H, br t, JZ4.25 Hz), 4.13 (2H, s), 3.77–3.66 (5H, m),
3.52–3.41 (1H, m), 3.35 (1H, dt, JZ6.9, 9.8 Hz), 1.96–1.81
29.7, 29.5, 29.4, 29.3, 26.2, 25.5, 25.4, 21.1, 19.6; nmax
3453, 1736 cmK1; [a]D20 K12.2 (c 1.45, CHCl3).
:
2.1.15. (R)-(C)-1-Benzyloxy-3-t-butyldimethylsilyloxy-
13-tetrahydropyranyloxytridecane. (i) Method A.
Triethylamine (4.11 g, 0.04 mol) was added to a stirred
solution of (R)-(C)-1-benzyloxy-3-hydroxy-13-tetrahydro-
pyranyloxytridecane (6.6 g, 0.016 mol) in dry dichloro-
methane (20 ml) under nitrogen. The mixture was stirred
for 10 min then t-butyldimethylsilylchloride (2.94 g,
0.019 mol) in dry dichloromethane (5 ml) was added,
followed by dimethylaminopyridine (300 mg) in dichloro-
methane (3 ml). The mixture was stirred for 48 h, then
quenched with water (10 ml). The organic layer was
separated and the aqueous layer re-extracted with
dichloromethane (2!50 ml). The combined organic
layers were dried and evaporated to give an oil; chromato-
graphy on silica eluting with petroleum–ether (5/1) gave
(R)-(C)-1-benzyloxy-3-t-butyldimethylsilyloxy-13-tetra-
hydropyranyloxytridecane (5.3 g, 62.7%) (Found: C, 71.2;

J. R. Al Dulayymi et al. / Tetrahedron 61 (2005) 11939–11951
11947
H 10.7; C31H56O4S requires: C, 71.48; H, 10.84) which
showed dH (250 MHz, CDCl3): 7.32 (5H, br s), 4.60 (1H, br
m), 4.53 (1H, d, JZ11.6 Hz), 4.46 (1H, d, JZ11.6 Hz),
3.95–3.7 (3H, m), 3.62–3.45 (3H, m, including a triplet with
JZ6.7 Hz), 3.42–3.34 (1H, m), 1.93–1.71 (2H, m), 1.65–
1.50 (6H, m), 1.45–1.22 (18H, br m), 0.88 (9H, s), 0.054
(3H, s), 0.045 (3H, s); dC: 138.6, 128.3, 127.6, 127.5, 98.8,
72.9, 69.5, 67.7, 67.3, 62.3, 37.6, 36.9, 30.77, 29.8, 29.8,
29.6, 29.6, 29.5, 29.5, 26.2, 25.9, 25.5, 25.0, 19.7, 18.1,
temperature and the solvent evaporated. The residue was
dissolved in dichloromethane (50 ml) and washed with satd
aq sodium bicarbonate (10 ml) and water (15 ml). The
aqueous layer was re-extracted with dichloromethane (2!
30 ml). The combined organic layers were dried and
evaporated to give a brown precipitate. Chromatography
eluting with petroleum/ethyl acetate (1:1) (RfZ0.24) gave
methyl (R)-3,10-dihydroxytridecanoate (22) as a white solid
(1.2 g; 69%), (mp 55–57 8C) (Found: C, 64.7; H, 10.8;
C14H28O4 requires: C, 64.58; H, 10.83), which showed dH
(250 MHz, CDCl3): 4.00–3.91 (1H, m), 3.65 (3H, s), 3.57
(2H, t, JZ6.7 Hz), 2.46 (1H, dd, JZ3.6, 16.4 Hz), 2.32 (1H,
dd, JZ7.75, 16.4 Hz), 2.15 (2H, br s), 1.66–1.53 (2H, br m),
1.48–1.25 (16H, br m); dC:173.5, 67.97, 62.96, 51.7, 41.1,
36.5, 32.7, 29.5, 29.5, 29.4, 29.3, 25.7, 25.4; nmax: 3300,
1737 cmK1; [a]2D4 K15.6 (c 1.035, CHCl3).
K4.4, K4.6; nmax: 2926, 2854, 1119, 1034 cmK1
.
(ii) Method B. (R)-(C)-1-Benzyloxy-3-hydroxy-13-tetra-
hydropyranyloxytridecane (10 g, 0.025 mol) in dry DMF
(10 ml) was added to a stirred solution of imidazole (4.36 g,
0.064 mol) in dry DMF (40 ml) at 5 8C, followed by the
addition of t-butyldimethylsilylchloride (4.83 g, 0.032 mol).
The mixture was allowed to reach room temperature and
stirred for 4 h. When TLC showed no starting material, the
reaction was quenched with water (200 ml) and the product
was extracted with dichloromethane (3!100 ml). The
combined organic layers were washed with water (2!
100 ml), dried and evaporated to give an oil; chromatog-
raphy on silica eluting with petroleum and ethyl acetate (5:
0.5) gave (R)-(C)-1-benzyloxy-3-t-butyl-dimethylsilyloxy-
13-tetrahydropyranyloxytridecane (11.9 g, 93%) which
showed identical spectra to those obtained above.
2.1.18. Tetracosan-1-ol (23). 1-Bromododecane (45.14 g,
0.118 mol) in tetrahydrofuran (50 ml) was added to
magnesium turnings (5.2 g, 0.217 mol) in dry tetrahydro-
furan (150 ml) at a rate sufficient to maintain a steady
reflux. Once the exothermic reaction had subsided, the
mixture was heated under reflux for 3 h. When GLC
showed no starting material was left, the Grignard reagent
was cooled (0 to K5 8C) then 12-bromododecanol (15 g,
0.0566 mol) in tetrahydrofuran (120 ml) was added. The
reaction was cooled again to K50 8C followed by the
addition of dilithium tetrachlorocuprate (13 ml, 0.1 M
solution). The mixture was stirred for 2 h at this
temperature and at room temperature for 12 h, then satd
aq ammonium chloride (150 ml) and dilute hydrochloric
acid (60 ml, 8 M solution) were added. The mixture was
extracted with hot ethyl acetate (2!300 ml). The
combined organic layers were washed with brine, dried
and evaporated to give crude product; recrystallisation
from ethyl acetate gave tetracosanol (23) as a white solid
(17.96 g, 90%). An analytical sample was further purified
by column on silica eluting with petroleum–ethyl acetate
(5/1) (mp 74–76 8C, lit.: 33,29 mp 75.5 8C) (Found: C, 81.5;
H, 14.2; C24H50O requires: C, 81.28; H, 14.21) which
showed dH (250 MHz, CDCl3): 3.60 (2H, t, JZ6.4 Hz),
1.55–1.45 (4H, m), 1.26 (41H, br s), 0.88 (3H, t, JZ
6.7 Hz); dC: 63.1, 32.8, 31.9, 29.7, 29.6, 29.6, 29.4, 29.35,
2.1.16. (R)-1-Hydroxy-3-t-butyldimethylsilyloxy-13-
tetrahydropyranyloxytridecane. A solution of (R)-1-
benzyloxy-3-t-butyldimethyl-silyloxy-13-tetrahydropyra-
nyloxytridecane (7 g; 0.0134 mol) in methanol (350 ml)
was stirred with Pd/C (1.5 g; 10%) under a hydrogen
atmosphere for 30 h. When the TLC showed no starting
material, the mixture was filtered through Celite and
evaporated to give an oil. Chromatography on silica eluting
with 5:1 petroleum/ethyl acetate gave (R)-1-hydroxy-3-t-
butyldimethyl-silyloxy-13-tetrahydropyranyloxytridecane
(4.86 g; 84%), (Found: C, 67.0; H, 11.7; C24H50O4Si
requires: C, 66.92; H, 11.70) which showed dH (250 MHz,
CDCl3): 4.53 (1H, br t, JZ4.3 Hz), 3.92–3.75 (3H, m),
3.71–3.63 (2H, m), 3.54–3.42 (1H, m), 3.35 (1H, dt, JZ6.9,
9.4 Hz), 1.85–1.72 (2H, m), 1.68–1.44 (10H, m), 1.23 (15H,
br s), 0.84 (9H, s), 0.04 (3H, s), 0.03 (3H, s); dC: 98.8, 72.0,
67.7, 62.3, 60.35, 37.65, 36.8, 30.75, 29.7, 29.5, 29.5, 26.2,
25.8, 25.5, 25.3, 21.0, 19.67, 17.94, 14.16, K4.4, K4.7;
nmax: 3445, 2928, 1077 cmK1; [a]D20 K7.3 (c 1.2, CHCl3).
25.7, 22.6, 14.1; nmax: 3300 cmK1
.
2.1.19. 1-Bromotetracosane. Triphenylphosphine (8.53 g,
0.032 mol) was added to a stirred suspension of tetracosan-
1-ol (9.6 g, 0.027 mol) in dry dichloromethane (250 ml),
followed by N-bromosuccinimide (6.27 g, 0.035 mol) at
w25 8C. The exothermic reaction was controlled using a
water bath. The mixture was stirred at room temperature for
5 h when TLC showed no starting material, then quenched
with water (200 ml) and the organic layer separated. The
aqueous layer was extracted with dichloromethane (2!
100 ml). The combined organic layers were dried and
evaporated to give a solid, which was refluxed with
petroleum (500 ml) and ethyl acetate (20 ml) then filtered.
The filtrate was evaporated to give a white solid;
chromatography eluting with petroleum–ethyl acetate
2.1.17. Methyl (R)-3,10-dihydroxytridecanoate (22).
(R)-1-Hydroxy-3-t-butyldimethylsilyloxy-13-tetrahydro-
pyranyloxytridecane (2.9 g; 0.0067 mol) in carbon tetra-
chloride (15 ml) was added over 4 h at 20 8C with stirring to
a solution of sodium (meta)periodate (4.33 g; 0.02 mol) and
ruthenium(III)chloride hydrate (56 mg; 0.0003 mol) in
acetonitrile (30 ml), carbon tetrachloride (15 ml) and
water (40 ml). The mixture was stirred for an additional
16 h, then diluted with dichloromethane (50 ml). The
aqueous layer was re-extracted with dichloromethane (2!
50 ml). The combined organic layers were dried and
evaporated to give a thick black oil, which was dissolved
in ether (100 ml) and filtered through a pad of Celite; the
solvent was evaporated and the residue was dissolved in
methanol (50 ml) and concentrated sulphuric acid (2 ml).
The mixture was refluxed for 6 h, then cooled to room
(5/1) gave a white solid, 1-bromotetracosane (10.5 g,
34
93%) (mp 49–51 8C, lit.:
69.3; H, 11.7; C24H49Br requires: C, 69.04; H, 11.83) which
mp 51–52.5 8C) (Found: C,
showed dH (250 MHz, CDCl3): 3.36 (2H, t, JZ6.7 Hz), 1.82

11948
J. R. Al Dulayymi et al. / Tetrahedron 61 (2005) 11939–11951
(2H, pent, JZ6.7 Hz), 1.62–1.15 (42H, br s), 0.84 (3H, t,
JZ6.2 Hz); dC: 34.0, 32.8, 31.9, 29.7 (very broad), 29.6,
29.5, 29.4, 29.35, 28.8, 28.2, 22.7, 14.1; nmax: 2960, 1463,
(2!20 ml), dried and evaporated to give a residue.
Chromatography on silica eluting with petrol–ethyl acetate
(5/0.5) gave methyl (2R,3R)-3-hydroxy-2-tetracosanyl-13-t-
butyldiphenylsilyloxytridecanoate (25) (1.05 g; 31%), as a
white solid, mp 46–48 8C (Found: C, 77.4; H, 11.0;
C54H94O4Si requires: C, 77.63; H, 11.34), which showed
dH (250 MHz, CDCl3): 7.71–7.67 (4H, m), 7.44–7.22 (6H,
m), 3.73 (3H, s), 3.70 (1H, m), 3.67 (2H, t, JZ6.4 Hz), 2.45
(1H, br dt, JZ5.8, 9.0 Hz; integration showed two protons,
which reduced to one after shaking with D2O), 1.85–1.21
(64H, br m), 1.07 (9H, s), 0.90 (3H, t, JZ6.4 Hz); dC: 176.2,
135.56, 134.2, 129.4, 127.5, 72.3, 64.0, 51.45, 50.8, 35.7,
32.6, 31.9, 29.7, 29.55, 29.4, 29.35, 27.4, 26.9, 25.8, 22.7,
19.2, 14.1; nmax: 3358, 1713 cmK1; [a]D22 C4.46 (c 1.03,
CHCl3).
1261, 1215 cmK1
.
2.1.20. 1-Iodotetracosane (24). Sodium iodide (11.33 g,
0.075 mol) was added to a stirred solution of 1-bromo-
tetracosane (10.5 g, 0.025 mol) in acetone (400 ml). Sodium
bicarbonate (2.3 g, 0.0277 ml) was added and the mixture
was refluxed for 5 h then cooled and evaporated. Water
(100 ml) was added and the mixture was extracted with hot
dichloromethane (3!100 ml). The combined organic layers
were dried, and evaporated to give a solid; chromatography
on silica eluting with petroleum–ethyl acetate (5/1) gave
1-iodotetracosane (24)38 (10.0 g, 86%) as a creamy white
35
solid (mp 52–54 8C, lit.: mp 52–53 8C) (Found: C, 61.9;
H, 10.6; C24H49I requires: C, 62.05; H, 10.63) which
showed dH (250 MHz, CDCl3): 3.14 (2H, t, JZ6.97 Hz),
1.75 (2H, pent, JZ6.7 Hz), 1.50–1.20 (42H, br s), 0.83 (3H,
t, JZ6.5 Hz); dC: 33.55, 31.9, 30.5, 29.7, 29.6, 29.5, 29.4,
2.1.23. (2R,3R)-3-Acetoxy-2-tetracosanyl-13-hydroxytri-
decanoate. (A) A mixture of acetic anhydride (10 ml) and
anhydrous pyridine (10 ml) was added to a stirred solution
of methyl (2R,3R)-3-hydroxy-2-tetracosanyl-13-t-butyl-
diphenylsilyloxytridecanoate (25) (0.89 g; 0.96 mmol) in
dry toluene (7 ml). The mixture was stirred for 16 h at room
temperature then diluted with toluene (10 ml); the solvent
was evaporated under reduced pressure to give an oil.
Chromatography on silica eluting with petrol–ethyl acetate
(5/0.5) gave methyl (2R,3R)-3-acetoxy-2-tetracosanyl-13-t-
butyldiphenylsilyloxytridecanoate (0.73 g, 86%) as a thick
oil (Found: C, 77.1; H, 11.2; C56H96O5Si requires: C, 76.65;
H, 11.03) which showed dH: 7.72–7.67 (4H, m), 7.55–7.36
(6H, m) 5.15–5.11 (1H, m), 3.70 (3H, s), 3.67 (2H, t, JZ
6.7 Hz), 2.64 (1H, ddd, JZ4.25, 6.7, 10.67 Hz), 2.04 (3H,
s), 1.62–1.52 (6H, m), 1.30 (58H, br s), 1.07 (9H, s), 0.90
(3H, t, JZ6.1 Hz); nmax: 1742 cmK1, [a]D22 C6.9 (c 1.39,
CHCl3).
28.5, 22.7, 14.1, 9.1, 7.4; nmax: 2950, 1462, 1165, 719 cmK1
.
2.1.21. Methyl (R)-3-hydroxy-13-t-butyldiphenylsilyloxy-
tridecanoate. Triethylamine (1.77 g; 0.0175 mol) was
added to a stirred solution of methyl (R)-3,10-dihydroxy-
tridecanoate (1.3 g; 0.005 mol) in dry dichloromethane
(15 ml). After 10 min, t-butyldiphenylsilyl chloride
(1.78 g, 0.0065 mol) in dichloromethane (3 ml) was
added, followed by dimethylaminopyridine (61 mg) in
dichloromethane (3 ml). The mixture was stirred for 4 h,
when TLC showed no starting material, then quenched with
water (10 ml) and worked-up as before to give an oil.
Chromatography on silica eluting with 5:1 petrol/ethyl
acetate gave a colourless oil, methyl (R)-3-hydroxy-13-t-
butyldiphenylsilyloxytridecanoate (2.1 g; 84%). (Found: C,
72.0; H, 9.2; C30H46O4Si requires: C, 72.24; H, 9.30), which
showed dH (250 MHz, CDCl3): 7.77–7.40 (4H, m), 7.46–
7.73 (6H, m), 4.08–4.00 (1H, m), 3.73 (3H, s), 3.66 (2H, t,
JZ6.1 Hz), 2.87 (1H, br d, JZ4.27 Hz), 2.54 (1H, dd, JZ
3.6, 16.4 Hz), 2.38 (1H, dd, JZ8.5, 16.4 Hz), 1.66–1.52
(2H, m), 1.45–1.22 (16H, br m) 1.09 (9H, s); dC: 173.6,
135.6, 134.8, 134.2, 129.6, 129.4, 127.7, 127.5, 67.9, 64.0,
51.7, 41.0, 36.4, 32.6, 29.6, 29.5, 29.4, 26.9, 26.5, 25.8,
25.5, 19.2; nmax: 3455, 1738 cmK1; [a]D24 K10.6 (c 0.97,
CHCl3).
(B) Tetra-n-butylammonium fluoride (1.8 ml, 1 M solution,
1.8 mmol) was added with stirring to methyl (2R,3R)-3-
acetoxy-2-tetracosanyl-13-t-butyldiphenylsilyloxytride-
canoate (0.62 g; 0.71 mmol) in dry tetrahydrofuran (10 ml)
at ca. 5 8C. The mixture was stirred for 16 h at room
temperature when TLC showed no starting material; the
solution was evaporated, the residue quenched with water
(10 ml) and the product extracted with dichloromethane
(3!30 ml). The combined organic layers were dried and
evaporated to give a thick oil. Chromatography on silica,
eluting with petrol–ethyl acetate (5/1.5) gave methyl (2R,
3R)-3-acetoxy-2-tetracosanyl-13-hydroxytridecanoate as a
white solid (0.32 g, 74%) (mp 52–54 8C) (Found: C, 75.4;
H, 12.2; C40H78O5 requires: C, 75.18; H, 12.3) which
showed dH (250 MHz, CDCl3): 5.08 (1H, ddd, JZ4.2, 7,
11.3 Hz), 3.67 (3H, s), 3.63 (2H, t, JZ6.4 Hz), 2.61 (1H,
ddd, JZ4.2, 6.7, 10.7 Hz), 2.03 (3H, s), 1.65–1.55 (6H, m),
1.25 (59H, br s), 0.88 (3H, t, JZ7 Hz); dC: 173.6, 170.3,
74.1, 63, 51.5, 49.6, 32.75, 31.9, 31.7, 29.6, 29.6, 29.5, 29.5,
29.4, 29.4, 28.1, 27.4, 25.7, 24.96, 22.6, 20.9; nmax: 3415,
1731 cmK1; [a]2D2 C10.14 (c 1.015, CHCl3).
2.1.22. Methyl (2R,3R)-3-hydroxy-2-tetracosanyl-13-t-
butydiphenylsilyloxytridecanoate (25). Butyllithium
(6.8 ml; 0.01 mol, 1.5 M in hexane) was added to a stirred
solution of diisopropylamine (1.02 g; 0.01 mol) in dry
tetrahydrofuran (10 ml) at K10 8C, allowed to reach room
temperature for 15 min, then the solution of lithium
diisopropylamide was cooled to K50 8C and methyl
(R)-3-hydroxy-13-tert-butyldiphenylsilyloxytridecanoate
(2.03 g; 0.00407 mol) in dry tetrahydrofuran (8 ml) was
added dropwise at below K40 8C. The reaction was allowed
to reach K10 8C, when a mixture of 1-iodo-tetracosane
(2.83 g; 0.006 mol), and hexamethylphosphoramide (1.5 g;
0.008 mol) in tetrahydrofuran (10 ml) was added. The
mixture was slowly allowed to reach 10 8C, stirred for
22 h, then quenched with satd aq ammonium chloride
(15 ml) and extracted with ethyl acetate (3!50 ml).
The combined organic layers were washed with water
2.1.24. ((1R, 2R)-1-Acetoxy-11-oxoundecyl)hexacosanoic
acid methyl ester (26). Methyl (2R,3R)-3-acetoxy-2-
tetracosanyl-13-hydroxytridecanoate (0.2 g, 0.0031 mol) in
dichloromethane (3 ml) was added to a suspension of
pyridinium chlorochromate (0.17 g, 0.0078 mol) in
dichloromethane (10 ml) at room temperature. A black

J. R. Al Dulayymi et al. / Tetrahedron 61 (2005) 11939–11951
11949
colour appeared after 10 min; after 2 h, TLC showed no
starting material, and the reaction was diluted with ether
(50 ml) and filtered through a pad of silica. The solvent was
evaporated to give a solid. Chromatography eluting with
petrol and ethyl acetate (5:1) gave a white solid, ((1R, 2R)-
1-acetoxy-11-oxoundecyl)hexacosanoic acid methyl ester
(26) (0.19 g, 95%) (Found: C, 75.8; H, 11.8; C40H76O5
requires: C, 75.42; H, 12.02) which showed dH (250 MHz,
CDCl3): 9.73 (1H, t, JZ1.8 Hz), 5.03 (1H, ddd, JZ4.2, 7,
11.3 Hz), 3.64 (3H, s), 2.57 (1H, ddd, JZ4.2, 6.7, 10.7 Hz),
2.38 (2H, dt, JZ1.8, 7.2 Hz), 2.03 (3H, s), 1.95–1.08 (62H,
br s), 0.88 (3H, t, JZ7 Hz); dC: 202.9, 173.6, 170.3, 74.1,
51.5, 49.6, 43.9, 31.9, 31.7, 29.7 (very broad), 29.3, 29.1,
28.1, 27.5, 25.0, 22.6, 22.0, 21.0, 14.1; nmax: 2917, 2849,
1741 cmK1; [a]2D2 C9.8 (c 1.06, CHCl3).
127.9, 127.6, 125.4, 122.3, 55.7, 31.9, 30.2, 29.7 (very
broad), 29.3, 29.0, 28.7, 22.7, 15.8, 15.8, 14.1, 11.3, 10.9,
8.8; nmax: 2922, 1707, 1468 cmK1, [a]D22 C14.8 (c 0.81,
CHCl3).
2.1.26. (R)-2-((R)-1-Acetoxy-12-{(1S,2R)-2-[14-((1S,2R)-
2-eicosylcyclopropyl)tetradecyl]cyclopropyl}dodec-11-
enyl)hexacosanoic acid methyl ester. Lithium hexa-
methyldisilazide (0.5 ml, 0.49 mmol) was added dropwise
to a stirred solution of (26) (0.19 g, 0.3 mmol) and (27)
(0.253 g, 0.33 mmol) in dry THF (15 ml) under nitrogen at
K5 8C. The reaction was exothermic and the temperature
rose to 5 8C resulting in a dark orange solution. It was
allowed to reach room temperature and stirred for 24 h, then
cooled to 0 8C and quenched with satd aq ammonium
chloride (5 ml). The product was extracted with ethyl
acetate (2!20 ml), dried and evaporated to give a thick oil,
which was purified by chromatography on silica eluting
with petroleum–ether (10/0.5) to give ca. 1.7:1 E:Z (R)-2-
((R)-1-acetoxy-12-{(1S,2R)-2-[14-((1S,2R)-2-eicosylcyclo-
propyl)tetradecyl]cyclopropyl}dodec-11-enyl)hexacosa-
noic acid methyl ester (28) (0.13 g, 37%) which showed dH
(250 MHz, CDCl3) (major isomer): 5.53 (1H, br dt, JZ6.6,
15.1 Hz), 5.18 (1H, br dd, JZ8.5, 15.1 Hz), 5.11 (1H, m),
3.68 (3H, s), 2.62 (1H, ddd, JZ4.2, 6.7, 10.7 Hz), 2.18–2.12
(1H, m), 2.03 (3H, s), 2.00–1.95 (2H, m) 1.75–1.48 (14H, br
m), 1.45–1.12 (113H, m), 0.97–0.82 (9H, including a triplet,
JZ7 Hz), 0.72–0.62 (2H, m), 0.58 (1H, dt, JZ4.1, 8 Hz),
0.12 (1H, br q, JZ5.35 Hz), K0.31 (1H, br q, JZ5.3 Hz);
dH (minor isomer): 5.43 (1H, br t, JZ11.0 Hz), 5.05 (1H, br
t, JZ11.0 Hz), the remaining signals were obscured by
those of the major isomer, dC: 173.6, 170.3, 130.4, 130.13,
129.5, 74.1, 51.5, 49.6, 32.7, 31.9, 31.7, 30.2, 29.7 (very
broad), 29.5, 29.5, 29.3, 29.1, 28.7, 28.1, 27.45, 25.0, 22.6,
21, 18.4, 18.24, 15.75, 14.1, 13.9, 12.3, 10.9; nmax: 2917,
2849, 1745, 1467, 1234, 1021 cmK1; mass spectra: FAB,
m/z: 1214 (MCNa)C for C81H154O4 (1191.1847), NOBA
matrix showed: 121/894/1046/1132/1214.
2.1.25. 2-{(1S,2R)-2-[14-((1S,2R)-2-Eicosylcyclopropyl)
tetradecyl]cyclopropylmethanesulfonyl}benzothiazole
(27). (A) Diethyl azodicarboxylate (1.06 g, 6.1 mmol) in dry
tetrahydrofuran (10 ml) was added to a stirred solution of
{(1S,2R)-2-[14-((1S,2R)-2-eicosylcyclopropyl)tetradecyl]-
cyclopropyl}methanol (2.5 g, 4.23 mmol), triphenylphos-
phine (1.57 g, 6.0 mmol) and 2-mercaptobenzthiazole
(0.88 g, 5.28 mmol) in dry tetrahydrofuran (25 ml) at 0 8C.
The mixture was allowed to reach room temperature and
stirred for 48 h. The solvent was evaporated and the residue
was dissolved in ether (50 ml) and petroleum (50 ml), then
filtered through a pad of silica and evaporated to give a pale
yellow oil. Chromatography on silica eluting with 10:0.5
petrol/ether gave 2-{(1S,2R)-2-[14-((1S,2R)-2-eicosylcyclo-
propyl)tetradecyl]cyclopropylmethylsulfanyl}benzothia-
zole (2.1 g, 66%) which showed dH (250 MHz, CDCl3):
7.88 (1H, br dd, JZ0.6, 8.25 Hz), 7.76 (1H, br dd, JZ6,
8 Hz), 7.44 (1H, br dt, JZ1.5, 8.5 Hz), 7.30 (1H, dt, JZ
1.22, 8 Hz), 3.48 (1H, dd, JZ7.6, 15.5 Hz), 3.39 (1H, dd,
JZ7.9, 12.5 Hz), 1.65–1.22 (66H, br m), 0.92–0.83 (6H,
m), 0.68–0.59 (3H, m), 0.09–0.05 (1H, m), K0.30 to K0.35
(1H, m); dc: 167.4, 153.3, 135.2, 125.9, 124.0, 121.4, 120.9,
34.8, 31.9, 30.2, 30.0, 29.7 (very broad), 29.6, 29.3, 28.7,
28.5, 22.7, 17.7, 15.8, 14.9, 14.1, 12.3, 10.9; nmax: 2923,
1455, 1426 cmK1, [a]D22 K6.38 (c 1.36, CHCl3).
2.1.27. (R)-2-((R)-1-Acetoxy-12-{(1S,2R)-2-[14-((1S,2R)-
2-eicosylcyclopropyl)tetradecyl]cyclopropyl}dodecyl)-
hexacosanoic acid methyl ester (8). Dipotassium azo-
dicarboxylate (1.5 g, 7.73 mmol) was added to a stirred
solution of (28) (0.05 g, 0.042 mmol) in dry THF (7 ml) at
10 8C under nitrogen resulting in a yellow suspension.
A solution of glacial acetic acid (2 ml) in dry THF (4 ml)
was added dropwise over 16 h, after which a white
precipitate had formed. The mixture was cooled to 0 8C
and quenched slowly with satd aq ammonium chloride
(5 ml). The product was extracted with ethyl acetate (2!
25 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 spectra
showed that there was still starting material left. The
procedure was repeated for another 16 h and the residue was
purified by chromatography on silica eluting with petro-
leum–ether (10/0.5) to give (R)-2-((R)-1-acetoxy-12-
{(1S,2R)-2-[14-((1S,2R)-2-eicosylcyclopropyl)tetradecyl]-
cyclopropyl}dodecyl)hexacosanoic acid methyl ester (8) as
a semi-solid (0.03 g, 60%) (Found: C, 81.5; H, 12.9;
C81H156O4 requires: C, 81.47; H, 13.17); which showed dH
(500 MHz): 5.11–5.07 (1H, ddd, JZ4.2, 7, 11.3 Hz,
CHOCOCH3), 3.68 (3H, s, OCH3), 2.64–2.60 (1H, ddd,
(B) m-Chloroperbenzoic acid (3 g) in dichloromethane
(25 ml) was added slowly to a stirred solution of 2-
{(1S,2R)-2-[14-((1S,2R)-2-eicosylcyclopropyl)tetradecyl]-
cyclopropylmethyl sulfanyl}benzothiazole (2 g, 2.8 mmol)
and sodium bicarbonate (1.7 g, 20 mmol) in dichloro-
methane (30 ml) at 5 8C. The mixture was stirred for 48 h
at room temperature, when TLC showed no starting
material. Work up as before gave a yellow solid, which
was purified by chromatography on silica eluting with 5:2
petroleum/diethyl ether to give 2-{(1S,2R)-2-[14-((1S,2R)-2-
eicosylcyclopropyl)tetradecyl]cyclopropylmethanesulfon-
yl}benzothiazole (27) (1.36 g, 62%) [Found: C, 74.4; H,
10.6; N, 2.0; C48H83O2S2N requires: C,74.84; H, 10.86; N,
1.82] [Found MC: 770.5927, C48H83O2S2N requires:
770.5943] which showed dH (250 MHz, CDCl3): 8.24 (1H,
br d, JZ8 Hz), 8.03 (1H, dd, JZ1.2, 8 Hz), 7.68–7.57 (2H,
m), 3.74 (1H, dd, JZ5.2, 14.3 Hz), 3.34 (1H, dd, JZ9.45,
14.3 Hz), 1.95–1.12 (66H, br m), 0.99–0.89 (5H, m,
including a triplet with a coupling constant JZ6.4 Hz),
0.81–0.72 (1H, m), 0.71–0.52 (3H, m), 0.01 (1H, br q, JZ
5.5 Hz), K0.31 (1H, q, JZ5.5 Hz), dc: 166.1, 152.6, 136.8,

11950
J. R. Al Dulayymi et al. / Tetrahedron 61 (2005) 11939–11951
201–204. Maekura, R.; Nakagawa, M.; Nakamura, Y.; Higara,
T.; Yamamura, Y.; Ito, M.; Ueda, E.; Yano, S.; He, H.; Oka, S.;
Kashima, K.; Yano, I. Am. Rev. Respir. Dis. 1993, 148,
997–1001.
JZ4.2, 6.7, 10.7 Hz, CHCO), 2.03 (3H, s, COCH3) 1.61–
1.15 (134H, br m, CH satd), 0.88 (6H, t, JZ6.45 Hz, 2!
terminal CH3), 0.68–0.62 (4H, m, 4!CH cyclopropane),
0.58–0.53 (2H, dt, JZ4, 8 Hz, 2!HCH, of the cyclopro-
pane), K0.31 to K0.34 (2H, br q, JZ5.5 Hz, 2!HCH of
cyclopropane); dC: 173.6, 170.3, 74.1 (K), 51.5 (K),
49.6 (K), 31.9 (C), 31.7 (C), 30.2(C), 29.7 (very broad,
C), 29.5 (C), 29.4 (C), 29.3(C), 28.7 (C), 28.1(C),
27.5(C), 24.96(C), 22.6(C), 21(K), 15.8(K), 14.1(K),
10.9(C)[CveZCH2, KveZCH, CH3]; nmax: 2921, 2849,
1736 cmK1; [a]2D2 C4.22 (c 0.735, CHCl3).
9. Wang, L.; Izumi, S.; He, H.; Fujiwara, N.; Saita, N.; Yano, I.;
Kobayashi, K.; Tatsumi, N. Jpn. J. Lepr. 1999, 68, 165–174.
Fujiwara, N.; Oka, S.; Ide, M.; Kashima, K.; Honda, T.; Yano,
I. Microbiol. Immunol. 1999, 43, 785–793.
10. See, for example, Gensler, W. J.; Marshall, J. P. Chem. Phys.
Lipids 1977, 19, 128–143.
11. For the analysis of mycolic acids see, for example, Watanabe,
M.; Aoyagi, Y.; Mitome, H.; Fujita, T.; Naoki, H.; Ridell, M.;
Minnikin, D. E. Microbiology 2002, 148, 1881. Watanabe, M.;
Aoyagi, Y.; Ridell, M.; Minnikin, D. E. Microbiology 2001,
147, 1825. Minnikin, D. E.; Kremer, L.; Dover, L. G.; Besra,
G. S. Chem. Biol. 2002, 9, 545.
Acknowledgements
We thank Professor D. E. Minnikin for valuable discussions.
Thanks are also due to the EPSRC MS Service in Swansea
and to Dr. B. Grail of the School of Biological Sciences,
Bangor, for obtaining the mass spectra of 8.
´
´
12. Lacave, C.; Laneelle, M.-A.; Daffe, M.; Montrozier, H.; Rols,
M.-P.; Asselineau, C. Eur. J. Biochem. 1987, 163, 369.
Asselineau, C.; Asselineau, J.; Tocanne, G. Bull. Soc. Chim.
Fr. 1966, 1992.
´
13. Daffe, M.; Laneelle, M. A.; Lacave, C. Res. Microbiol. 1991,
´
´
142, 397–403. Dubnau, E.; Laneelle, M.-A.; Soares, S.;
´
Benichou, A.; Vaz, T.; Prome, D.; Prome, J. C.; Daffe, M.;
Quemard, A. Mol. Microbiol. 1997, 23, 313.
References and notes
14. See, for example, Lee, R. E.; Armour, J. W.; Takayama, K.;
Brennan, P. J.; Besra, G. S. Biochim. Biophys. Acta 1997,
1346, 275–284. Grogan, D. W.; Cronan, J. E. Microbiol. Mol.
Biol. Rev. 1997, 61, 429–441. Asselineau, C.; Asselineau, J.;
1. (a) Brennan, P. J.; Nikaido, H. Annu. Rev. Biochem. 1995, 64,
29–63. (b) Qureshi, N.; Takayama, K.; Jordi, H. C.; Schnoes,
H. K. J. Biol. Chem. 1978, 253, 5411–5417. (c) Minnikin,
D. E.; Daffe, M.; Draper, P. Adv. Microbial Phys. 1998, 39,
131–203. (d) Minnikin, D. E.; Kremer, L.; Dover, L. G.; Besra,
G. S. Chem. Biol. 2002, 9, 545.
´
´
Laneelle, G.; Laneelle, M.-A. Prog. Lipid Res. 2002, 41, 501.
Kremer, L.; Baulard, A. R.; Besra, G. S. In Molecular Genetics
of Mycobacteria; Hatfull, G. F., Jacobs, W. R., Eds.; American
Society for Microbiology: Washington, DC, 2000;
pp 173–190.
2. Minnikin, D. E.; Polgar, N. J. Chem. Soc., Chem. Commun.
1967, 312–314, 916–918. (See also pp 1172–1174).
3. Yuan, Y.; Crane, D. C.; Musser, J. M.; Sreevatsan, S.; Barry,
C. E. J. Biol. Chem. 1997, 272, 10041–10049. George, K. M.;
Yuan, Y.; Sherman, D. S.; Barry, C. E. J. Biol. Chem. 1995,
272, 27292–27298.
15. Yuan, Y.; Mead, D.; Schroeder, B. G.; Zhu, Y. Q.; Barry, C. E.
J. Biol. Chem. 1998, 273, 21282–21290. Yuan, Y.; Barry, C. E.
Proc. Nat. Acad. Sci. U.S.A. 1996, 93, 12828–12833.
16. Gensler, W. J.; Marshall, J. P.; Langone, J. J.; Chen, J. C.
J. Org. Chem. 1977, 42, 118–125.
4. Dobson, G.; Minnikin, D. E.; Minnikin, S. M.; Parlett, J. H.;
Goodfellow, M.; Ridell, M.; Magnusson, M. In Chemical
Methods in Bacterial Systematics; Minnikin, D. E., Good-
fellow, M., Eds.; Academic: London, 1985; p 237.
17. Baird, M. S.; Al Dulayymi, J. R.; Roberts, E. Tetrahedron Lett.
2000, 41, 7107–7110.
18. Dubneau, E.; Laneelle, M.-A.; Soares, S.; Benichou, A.; Vaz,
T.; Prome, D.; Prome, J.-C.; Daffe, M.; Quemard, A. Mol.
Microbiol. 1997, 23, 313–322.
5. Glickman, M. S.; Cahill, S. M.; Jacobs, W. R. J. Biol. Chem.
2001, 276, 2228–2233.
19. Grandjean, D.; Pale, P.; Cuche, J. Tetrahedron 1991, 47, 1215.
20. Krapcho, A. P.; Larson, J. R.; Eldridge, J. M. J. Org. Chem.
1977, 42, 3749–3753.
6. Toubiana, R.; Desh, B. C.; Defaye, J.; Mompon, G.; Toubiana,
M.-J. Carbohydr. Res. 1975, 44, 308–312. Prome, J.-C.;
Lacave, C.; Ahibo-Coffy, A.; Savagnac, A. Eur. J. Biochem.
1976, 63, 543–552. Baer, H. H.; Wu, X. Carbohydr. Res. 1993,
245, 347.
21. Baudin, J. B.; Hareau, G.; Julia, S. A.; Ruel, O. Tetrahedron
Lett. 1991, 32, 1175–1178. Blakemore, J. R.; Kocienski, P. J.;
Marzcak, S.; Wicha, J. Synthesis 1999, 1209–1215. Smith,
N. D.; Kocienski, P. J.; Street, S. D. A. Synthesis 1996,
652–666.
7. See, for example, Matsunaga, I.; Oka, S.; Fujiwara, N.; Yano,
I. J. Biochem. 1996, 120, 663–670. Parant, M.; Audibert, F.;
Parant, F.; Chelid, L.; Soler, E.; Polonsky, J.; Lederer, E.
Infect. Immunol. 1978, 20, 12–19. Tanaka, A.; Sugiwara, K.;
Azuma, I.; Yamamura, Y.; Kato, M.; Goren, M. B. Infect.
Immun. 1976, 13, 776–781. Sueoka, E.; Nishiwaki, S.; Okabe,
S.; Iida, N.; Suganuma, M.; Yano, I.; Aoki, K.; Fujiki, H.
Jpn. J. Cancer Res. 1995, 86, 749–755. Yano, I. Kekkaku
1998, 73, 37–42.
22. Kitano, Y.; Kobayashi, Y.; Sato, F. J. Chem. Soc., Chem.
Commun. 1985, 498–499.
23. Utaka, M.; Higashi, H.; Takeda, A. J. Chem. Soc., Chem.
Commun. 1987, 1368–1369.
24. Prepared from (R)-aspartic acid based on, Frick, J. A.; Klassen,
J. B.; Bathe, A.; Abramson, J. M.; Rappoport, H. Synthesis
1992, 621.
8. See, for example, Pan, J.; Fujiwara, N.; Oka, S.; Maekura, R.;
Ogura, T.; Yano, I. Microbiol. Immunol. 1999, 43, 863–869.
Fujiwara, N.; Pan, J.; Enomoto, K.; Terano, Y.; Honda, T.;
Yano, I. FEMS Immunol. Med. Microbiol. 1999, 24, 141–149.
He, H.; Oka, S.; Han, Y.; Yamamura, Y.; Kusunose, E.;
Kusunose, M.; Yano, I. Microbiol. Immunol. 1991, 76,
25. Fujisawa, T.; Fujimura, A.; Sato, F. Bull. Chem. Soc. Jpn.
1988, 61, 1273–1279.
26. Jorgensen, W. J. Am. Chem. Soc. 1969, 91, 6430–6443.
27. We thank Prof. D. E. Minnikin for providing a sample of
natural a-mycolic acid.2

J. R. Al Dulayymi et al. / Tetrahedron 61 (2005) 11939–11951
11951
28. Coxon, G. D.; Knobl, S.; Roberts, E.; Baird, M. S.; Al
Dulayymi, J. R.; Minnikin, D. E. Tetrahedron: Asymmetry
2003, 14, 1211–1222.
23, 497, 500) or PBr3 (Lukes, C. Collect. Czech. Chem.
Commun., 1958, 23, 1100, 1102, 1107) or by coupling of
octadecylmagnesium bromide to 1,6-dibromohexane in the
presence of Li CuCl4.35
29. Watanabe, A. Bull. Chem. Soc. Jpn. 1963, 36, 336–340.
30. Delpeuch, J.-J. Bull. Soc. Chim. Fr. 1966, 1631.
35. Gensler, W.; Alam, I.; Prasad, R. S.; Radhakrishnan, A. I.;
Laudhun, A. P. C. Tetrahedron 1979, 35, 2595–2600.
36. Frick, J. A.; Klassen, J. B.; Bathe, A.; Abramson, J. M.;
Rapoport, H. Synthesis 1992, 621–623.
31. Bricard, L.; Kunesch, G. Synth. Commun. 1993, 23 18, 2547.
32. Bai, D.; Bo, Y.; Zhou, Q. Tetrahedron Lett. 1990, 2161–2164.
33. This has previously been prepared by reduction of the
corresponding acid or its esters (Watanabe, A Bull. Chem.
Soc. Jpn., 1961, 34, 398–402), from the corresponding alkene
or alkyne by hydroboration (Brown, H. C.; Iyer, R. R.; Bhat, N.
G. Racherla, U. S.; Brown, C. A. Tetrahedron, 1992, 48,
9187), or from tetracos-10-yn-1-ol (Menger, F. M.; Yamasaki,
Y. J. Am. Chem. Soc. 1993, 115, 3840).
37. Sharma, A.; Chattopadhyay, S. J. Org. Chem. 1998, 63, 6128.
Wolfgang, M.; Clemensk, H.; Juergen, S.; Gladysz, J. A.
Synthesis 2003, 8, 1279.
38. The iodide has previously been prepared either by this method
or direct from the alcohol by reaction with iodine and
phosphorus.35
34. This has previously been prepared from the alcohol by reaction
with HBr (Lukes, C. Collect. Czech. Chem. Commun., 1958,
39. Linstrumelle, G.; Krieger, J. K.; Whiteside, G. M. Org. Synth.
1976, 55, 103–113.