The first syntheses of single enantiomers of the major methoxymycolic acid of Mycobacterium tuberculosis

Article abstract of DOI:10.1016/j.tet.2007.01.007

The synthesis of three stereoisomers of a major homologue of the methoxymycolic acids present in Mycobacterium tuberculosis is described.

Full text of DOI:10.1016/j.tet.2007.01.007

Tetrahedron 63 (2007) 2571–2592
The first syntheses of single enantiomers of the major
methoxymycolic acid of Mycobacterium tuberculosis
a
Juma’a R. Al Dulayymi,a Mark S. Baird,a, Evan Roberts, Madrey Deyselb,y and Jan Verschoorb
*
aSchool of Chemistry, University of Wales, Bangor, Gwynedd LL 57 2 UW, UK
bDepartment of Biochemistry, University of Pretoria, Pretoria, South Africa
Received 18 October 2006; revised 22 December 2006; accepted 4 January 2007
Available online 7 January 2007
Abstract—The synthesis of three stereoisomers of a major homologue of the methoxymycolic acids present in Mycobacterium tuberculosis is
described.
Ó 2007 Elsevier Ltd. All rights reserved.
1, X = Y = CH2
2, X = Me, Y = OMe
X
Y
1. Introduction
CH3(CH2)a
(CH2)cCHOHCHCOOH
(CH2)b
Mycolic acids (Scheme 1) are major constituents of the cell
envelope of Mycobacterium tuberculosis and other myco-
bacteria, some of which are pathogenic to animals and hu-
mans.1,2 Their presence is thought to be linked with the
resistance of these organisms to most current antibiotics
and other chemotherapeutic agents.3 Mycolic acids can be
divided into two parts, meromycolate and mycolic motif
(Scheme 1). The latter is common to each mycobacterial
mycolic acid, except for minor variations in the length of
the chain (d).
a = 15, 17, 18, 19
CH3(CH2)d
b = 10, 14, 16
c = 11, 15, 17, 19, 21
d = 21, 23
CH3
X
Y
(CH2)m
CH3(CH2)l
(CH2)nCHOHCHCOOH
CH3(CH2)p
3, X, Y = CH2
4, X = Me, Y = OMe
H3C
CH3
(CH2)m
O
5
CH3(CH2)l
(CH2)nCHOHCHCOOH
CH3(CH2)p
OH
O
Mycolic acid
[X]
[Y]
α
[X] = Distal position
[Y] = Proximal position
Scheme 2.
OH
β
a
c
b
d
The presence of the hydroxyl group and the relative configu-
ration between it and the alkyl chain have been demonstrated
to be capable of altering the film molecular packing. The
formation of a hydrogen bond between the hydroxyl group
and the carboxylic group has a stabilising effect for the
aligned conformation between the two long chains.11,12
Moreover, the absolute configuration of these two chiral
centres is necessary for efficient recognition by T cells
and the generation of an immune response by the host
organism against pathogenic mycobacteria;13 the same is
also true for the antitumour properties of mycolic acid
derivatives.14
meromycolate
moiety
mycolic
motif
Scheme 1.
The meromycolate moiety, however, is much more variable
(Scheme 2), leading to molecules such as a-mycolic acids 1
and 3, methoxymycolic acids 2 and 4 and ketomycolic acids
5.4,5 The two stereocentres in the a and b-positions relative
to the carboxylic group have been found to be both in the
R-configuration for all the mycolic acids examined, irrespec-
tive of the groups in the meromycolate moiety.6–10
Keywords: Methoxymycolic acids; Mycobacterium tuberculosis.
* Corresponding author. Tel.: +44 1248382374; e-mail: chs028@bangor.
ac.uk
This contribution was carried out in Bangor supported by a grant from the
University of Pretoria.
Mycolic acids are generally present as penta-arabinose tetra-
mycolyl clusters bound to the cell wall or as non-bound spe-
cies such as trehalose dimycolates (TDMs). These species
exert a number of very important immunological effects.15
y
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.01.007

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Juma’a. R. Al Dulayymi et al. / Tetrahedron 63 (2007) 2571–2592
OMe
(CH2)16
Recent studies have indicated that antisera against either M.
tuberculosis or Mycobacterium avium cord factor raised in
rabbits preferentially recognise TDM from the species
used as antigen source, suggesting that the underlying IgG
antibodies were directed at the specific mycolic acids rather
than the common sugar backbone.16,17 Moreover, in a key
paper, it was reported that the reactivity of human antisera
to various mycolic acid subclasses is different, anti-cord
factor IgG antibody recognising methoxymycolic acids
more strongly than keto- or a-mycolic acids.18,16 Moreover,
a-mycolates stimulate DN1/JRT3 cells at least 100 times
less than methoxy or ketomycolates.19 The biosynthesis
of keto- and methoxymycolates is closely linked through
a common hydroxymycolate precursor, that is, the product
of the MMAS-4 enzyme.2,20–22 Structural variations in the
meromycolate chain may be of crucial biological impor-
tance because mutants without some groups profoundly
alter membrane permeability and affect virulence.21–24
Mycobacterium marinum is an established model for dis-
covering genes involved in mycobacterial infection; kasB
mutants synthesise mycolic acids, which, among other
changes, show a significant reduction in ketomycolate
content and a small increase in a- and methoxymycolates.
These show markedly different cell wall permeability
and a marked increase in susceptibility to lipophilic anti-
biotics.25 These results suggest that methoxymycolic
acids may play a particular role in the pathogenesis of
M. tuberculosis.
OH
OH
OH
O
(CH2)17
(CH2)17
(CH2)17
(CH2)17
OH
6
Me
(CH2)23Me
OMe
O
(CH2)17
OH
(CH2)16
7
Me
(CH2)23Me
OMe
(CH2)16
O
(CH2)17
Me
OH
8
(CH2)23Me
Scheme 3.
2. Results and discussion
The a-methyl-b-methoxy unit was first prepared from man-
nitol by a known sequence leading to the aldehyde 11.35,36
In a similar way, the enantiomer 16 was prepared from
L-gulono-1,4-lactone (12), derived by hydrogenation of as-
corbic acid.37 In a modification of the literature procedure,38
the lactone was protected as the acetal with 2-methoxypro-
pene, oxidatively cleaved with sodium periodate and then
reacted with methyl diisopropoxyphosphinyl acetate and
potassium carbonate to give the ester 13 in 34% overall yield
in a one-pot process.37,38 This gave the E-alkene rather than
an E/Z mixture as described earlier. The ester was treated
with methyllithium as in the preparation of the enantiomer
9 to give 14; this was in turn converted into the enantiomeric
aldehyde 16 (Scheme 4).
In one strain of M. tuberculosis, the methyl and methoxy
fragments have been shown to be of S,S-configuration on
the basis of the additivity of optical rotations.7,20,6 The
methyl branch of wax esters apparently derived by enzy-
matic oxidation of ketomycolic acids is also of S-stereo-
chemistry.43 Other reports identify a R-stereochemistry for
the three stereocentres of the a-methyl-trans-epoxy unit in
related mycolic acids.8 Little is known about the absolute
stereochemistry of the cis-cyclopropane. Interestingly,
however, a recent computational study of the binding of
a model methoxymycolic acid glucose ester to the human
MHC class I like molecule CD1b using a R,R-configuration
for the a-methyl-b-methoxy unit shows a close fit to the
shape of a non-functional natural mycolate.26 The same
paper reports a similar good fit for a model a-mycolic acid
having a distal cyclopropane with an S,R-configuration.
Other crystal structures give indications of the nature and
geometry of the active site in related enzymes,27–29 with
no modelling of bound mycolates. A further study30 is re-
ported to show the fit of a putative a-mycolate containing
a distal a-methyl-trans-cyclopropane and a proximal cis-
cyclopropane to the CD1 receptor, but the actual fit
appears to be with a structure having the methyl group
one carbon removed from the trans-cyclopropane and
with the second cyclopropane having trans-geometry. We
have reported the synthesis of single enantiomers of the
major a-mycolic acid of M. tuberculosis,31 of related mer-
omycolates32 and of wax esters containing an a-methyl-
trans-cyclopropane fragment.33,34 We now report the first
syntheses of three stereoisomers of a complete methoxy-
mycolic acid (Scheme 3) corresponding to the major com-
ponent of this type isolated from M. tuberculosis,4,6 in
order that the role of these acids and of their stereoisomers
may be determined.
O
O
O
HO
(i)
O
EtO
10
O
9
(ii)
OH
OH
O
O
HO
OH
O
O
O
O
12
11
(iii)
O
-(v)
O
O
O
O
O
O
(vi)
O
14
13
(vii)
O
O
(viii)
O
O
HO
16
15
Scheme 4. (i) LiAlH4, THF (96%); (ii) PCC (80%); (iii) pyridinium p-tol-
uene sulfonate, 2-methoxypropene, DMF; (iv) NaIO4; (v) methyl diisopro-
poxyphosphinyl acetate, K2CO3 (34%, three steps); (vi) MeLi, ꢀ78 ꢁC
(82%); (vii) LiAlH4, THF (80%); (viii) PCC (81%).
The aldehydes were each then homologated to 19 and 20,
respectively, by reaction with the sulfone 18 and base in
a modified Julia–Kocienski reaction, followed by hydrogena-
tion of the E/Z mixtures of alkenes produced. Sulfone 18 was
in turn prepared by reaction of 1-phenyl-1H-tetrazole-5-thiol
with 1-bromohexadecane to give 17, followed by oxidation
(Scheme 5).

Juma’a. R. Al Dulayymi et al. / Tetrahedron 63 (2007) 2571–2592
2573
The esters 32 and 33 were deprotected to the primary
alcohols 34 and 35, converted into the bromides and hence,
via the corresponding sulfides, to sulfones 36 and 37
(Scheme 9).
O
N
N
N
CH3(CH2)15
S
CH3(CH2)17
O
(ii) (90 %)
(iii) (97 %)
N
17
19
(i)
Ph
O
O
S
N
N
N
CH3(CH2)17
O
CH3(CH2)15
N
(ii) (93 %)
O
20
18
(iii) (88 %)
Ph
OMe
OMe
(CH2)15OH
O
S
N
N
CH3(CH2)17
(i) (86%)
CH3(CH2)17
(CH2)15
Scheme 5. (i) H2O2, Mo7O24(NH4)6$4H2O, IMS (93%); (ii) LiHMDS, 16
(for 20) or 11 (for 19); (iii) H2, Pd/C.
N
(ii) (91%)
(iii) (82%)
N
Me
Me
O
36
34
Me
Me
Ph
Each acetal was deprotected to the corresponding diol, e.g.,
21, which was in turn converted into the epoxide 22 via
the monotosylate. The epoxide was opened to form alcohol
23 by reaction with the Grignard reagent prepared from
6-bromotetrahydropyranyloxyhexane (Scheme 6).
OMe
(CH2)15
OMe
(CH2)15OH
O
S
N
N
CH3(CH2)17
(i) (76%)
CH3(CH2)17
N
(ii) (99%)
(iii) (91%)
N
37
O
35
Ph
Scheme 9. (i) N-Bromosuccinimide, PPh3, CH2Cl2; (ii) 1-phenyl-1H-tetra-
zol-5-thiol, K2CO3; (iii) H2O2, Mo7O24(NH4)6$4H2O, IMS.
OH
O
CH3(CH2)17
(i)
CH3(CH2)17
OH
22
21
(ii)
OH
The sulfones were then treated with a single enantiomer of
cyclopropane aldehyde, prepared as described below. The
aldehyde 41 was prepared by standard methods.39 Reaction
with the sulfone 40 (prepared as shown) and base in a modi-
fied Julia–Kocienski reaction, followed by hydrogenation of
the derived E/Z-alkenes gave the ester 42, which was trans-
formed routinely into 44 (Scheme 10).
(iii)
OMe
CH3(CH2)17
CH3(CH2)17
(CH2)7OTHP
23
(CH2)7OTHP
24
Scheme 6. (i) NaOH, cetrimide, pTsCl, CH2Cl2 (97%); (ii)
BrMg(CH2)6OTHP, CuI, THF (75%); (iii) NaH, THF, MeI (94%).
Methylation of the alcohol 23 led to 24 containing the
required relative stereochemistry of the branch methyl and
methoxy groups. In the same way, the diol 25 was converted
into 26 (Scheme 7).
N
HO(CH2)6
S
N
HO(CH2)6Br
O
(i)
N
38
N
OH
OMe
Ph
CH3(CH2)17
OH
(ii)
CH3(CH2)17
(CH2)7OTHP
26
N
O
S
O
Br(CH2)6
S
O
25
N
N
N
HO(CH2)6
N
N
Scheme 7.
(iii)
40
Ph
N
N
39
Ph
Deprotection of the acetals 24 and 26 to alcohols 27 and 28
followed by oxidation and homologation, again using a mod-
ified Julia–Kocienski reaction with 31, then hydrogenation,
generated the esters 32 and 33 (Scheme 8).
(iv)
PrCOO
PrCOO
(CH2)7Br
(v), (vi)
CH=O
42
OMe
41
CH3(CH2)17
(CH2)6CH=O
(vii)
Me
(i)
29
(ii) (91%), (iii) (93%)
OMe
HO
43
O
(CH2)7Br
(87%)
(CH2)7Br
OMe
44
CH3(CH2)17
CH3(CH2)17
CH3(CH2)17
(CH2)7OH
(CH2)15OCOBut
32
Scheme 10. (i) 1-Phenyl-1H-tetrazol-5-thiol, K2CO3 (99.5%); (ii) H2O2,
Mo7O24(NH4)6$4H2O, IMS (90%); (iii) N-bromosuccinimide,
PPh3 (86%); (iv) LiHMDS, THF, 40 (78%); (v) 2,4,6-triisopropylbenzene
sulfonylhydrazide, THF (67%); (vi) K2CO3, MeOH (84%); (vii) PCC
(93%).
Me
27
Me
OMe
OMe
(CH2)7OH
CH3(CH2)17
(CH2)15OCOBut
33
Me
Me
(i) (83%)
28
(ii) (87%), (iii) (100%)
OMe
CH3(CH2)17
O
N
N
(CH2)6CH=O
tBuCOO(CH )
2 8 S
O
A further Julia reaction of 44 with sulfone 36, followed by
hydrogenation generated the bromide 45 containing both
the functionalities of the methoxymycolic acid, which was
further converted into sulfide 46 (Scheme 11).
N
Me
30
N
31
Ph
Scheme 8. (i) PCC; (ii) 31, LiHMDS; (iii) H2, Pd/C.

2574
Juma’a. R. Al Dulayymi et al. / Tetrahedron 63 (2007) 2571–2592
OMe
(CH2)15
The final stage of the syntheses required the oxidation of each
O
S
N
N
O
CH3(CH2)17
of the sulfides 46, 47 and 55 to the corresponding sulfones
and coupling of each to a unit containing the pre-formed pro-
tected hydroxy acid of the mycolate motif (Scheme 1). This
was introduced in the cases of 56 and 59, derived from 46 and
55, respectively (Scheme 14), using the aldehyde 57, the
synthesis of which was reported earlier.31
+
(CH2)7Br
N
44
N
Me
O
36
Ph
(i), (ii)
OMe
CH3(CH2)17
(CH2)16
45
(CH2)7Br
OMe
Me
O
(CH2)7S
O
N
N
CH3(CH2)17
(CH2)16
(iii)
N
N
Me
56
+
Ph
OMe
OAc
O
N
N
CH3(CH2)17
N
(CH2)16
(CH2)7S
OMe
O=CH(CH2)9
57
N
Me
(CH2)23CH3
(i) (68 %), (ii) (83 %)
OAc
(CH2)17
Ph
46
Scheme 11. (i) LiHMDS, THF (92%); (ii) triisopropylbenzene sulfonyl-
hydrazide, THF (91%); (iii) 1-phenyl-1H-tetrazol-5-thiol, K2CO3 (91%).
O
OMe
(CH2)16
CH3(CH2)17
OMe
By repeating this process with sulfone 37, the isomeric
sulfide 47 was obtained (Scheme 12).
Me
58
(CH2)23CH3
OMe
O
N
N
CH3(CH2)17
OMe
(CH2)16
59
S
(CH2)7
57
+
N
N
N
CH3(CH2)17
N
Me
O
(CH2)16
(CH2)7S
N
Ph
N
Me
(i) (60 %), (ii) (90 %)
47
Ph
OAc
OMe
(CH2)16
Scheme 12.
CH3(CH2)17
CO2Me
(CH2)17
The analogous intermediates with the opposite cyclopropane
stereochemistry could be prepared in a similar way. The
known cyclopropane 4839 was converted into the thioether
49 by reaction with diethyl azodicarboxylate, triphenylphos-
phine and 1-phenyl-1H-tetrazol-5-thiol. This in turn was
oxidised to the corresponding sulfone 50 and chain extended
as before to produce bromide 51. Removal of the ester pro-
tecting group, oxidation and a Julia reaction followed by hy-
drogenation led to the required bromide 54. This was further
converted into the sulfide 55 as before (Scheme 13).
60
(CH2)23CH3
Me
Scheme 14. LiHMDS, THF; (ii) KOOCN]NCOOK, AcOH, MeOH, THF.
In the cases of the sulfone derived from 47, a modified alde-
hyde 68 was used, prepared using a more efficient method,
and with a silyl protecting group that proved to be easier
to remove selectively. The aldehyde was prepared as shown
in Scheme 15.42
ButCOO(CH2)10
(i), (ii), (iii)
ButCOO(CH2)11OTHP
N
I(CH2)8OTHP
N
CO2Me
(i)
(iv)-(vi)
N
63
61
PrCOO
OH
62
(vii)
OH
N
PrCOO
S
Ph
49
48
(ii)
OH
N
(viii), (ix)
CO2Me
CO2Me
N
ButCOO(CH2)10
64
(iii), (iv)
(vi)
ButCOO(CH2)10
65
O
S
N
PrCOO
N
(CH2)7Br
PrCOO
O
OH
Ph
O
50
51
(x), (xi)
OH
(v)
OSiMe2But
CO2Me
HO
(CH2)7Br
(CH2)7Br
OMe
ButCOO(CH2)9
CO2Me
(xii)-(xiv)
ButCOO(CH2)10
52
53
(CH2)23CH3
(vii), (viii)
67
66
(xv), (xvi)
OSiMe2But
CO2Me
CH3(CH2)17
(CH2)14
(CH2)7Br
54
Me
(ix)
O=CH(CH2)9
OMe
(CH2)23CH3
68
N
N
CH3(CH2)17
(CH2)14
(CH2)7S
N
Scheme 15. (i) Li, NH3, prop-2-yn-1-ol (94%); (ii) NaBH4, Ni(OAc)2, EtOH,
H2 (83%); (iii) pivaloyl chloride, Et3N, DMAP (91%); (iv) pTsOH, MeOH,
THF (89%); (v) PCC (8%); (vi) Ph3PCHCO2Me, toluene (85%); (vii)
(DHQD)2PHAL, K3Fe(CN)6, K2CO3, OsO4, MeSO2NH2, ButOH, H2O
(97%); (viii) SOCl2, CCl4, NaIO4, RuCl3$H2O (93%); (ix) NaBH4, DMAC,
THF, H2O, H2SO4 (68%);(x)LDA, allyl iodide, HMPA(55%);(xi)imidazole,
DMF, TBDMSC1 (91%); (xii) OsO4, lutidine, NaIO4, dioxane, H2O (93%);
(xiii) LiHMDS, 5-docosan-1-sulfonyl-1-phenyl-1H-tetrazole (83%); (xiv)
H2, Pd/C (87%); (xv) KOH, THF, MeOH, H2O (80%); (xvi) PCC (84%).
N
Me
55
Ph
Scheme 13. (i) Diethyl azodicarboxylate, 1-phenyl-1H-tetrazol-5-thiol,
PPh3, THF (85%); (ii) H2O2, Mo7O24(NH4)6$4H2O, IMS (93%); (iii)
LiHMDS, THF, 6-bromohexanal (74%); (iv) 2,4,6-triisopropyl sulfonylhy-
drazide, THF (80%); (v) K2CO3, MeOH (85%); (vi) PCC (76%); (vii)
LiHMDS, 36, THF (74%); (viii) 2,4,6-triisopropyl sulfonylhydrazide,
THF (80%); (ix) 1-phenyl-1H-tetrazol-5-thiol, K2CO3 (88%).

Juma’a. R. Al Dulayymi et al. / Tetrahedron 63 (2007) 2571–2592
2575
Reaction of the aldehyde 68 with sulfone 69, derived from
47, in the presence of lithium hexamethyldisilazide, fol-
lowed by saturation of the double bond and removal of the
silyl group led to the methyl ester of the corresponding
methoxymycolic acid, 70. This could be converted into the
free acid 71 by reaction with lithium hydroxide in THF/
MeOH/water (Scheme 16).
mass spectrum of 70 showed a molecular isotope ion pattern
starting at 1290 that corresponded to that for the major com-
ponent of the natural sample. The specific rotations provided
rather more insight into which of them corresponded to the
natural component. Thus the natural sample of the methyl
ester showed an [a]2D2 of ꢀ0.83 (the literature value reported
in 1966 was ꢀ0.1).6 Compounds 58 and 60 showed [a]2D2
+7.2 and +7.7, respectively, while the hydroxy esters 72
and 73 gave [a]2D2 +6.0 and +7.0, respectively. In contrast
70 and 71 gave ꢀ1.0 and ꢀ1.1, respectively. The specific ro-
tations of these molecules are determined very largely by the
hydroxy acid and methoxy methyl fragment stereochemis-
tries and are affected to only a very small degree by the
stereochemistry of the cis-cyclopropane. It seems extremely
likely, therefore, that the methoxy methyl fragment is of
S,S-stereochemistry. The fourth possible stereoisomer is
readily available by simple modification of the routes
described above. Currently, the biological properties of the
synthetic methoxymycolic acids are being determined in
order to establish firmly whether the stereochemistry is
critical to biochemical effect and to establish the absolute
stereochemistry present in the natural material.
OMe
O
(CH2)7S
O
N
N
CH3(CH2)17
(CH2)16
69
N
N
Me
Ph
(i), (ii), (iii)
OH
O
OMe
(CH2)16
70
CH3(CH2)17
OMe
(CH2)23CH3
(CH2)17
Me
(iv)
OH
O
OMe
(CH2)16
3. Experimental section
3.1. General
CH3(CH2)17
OH
(CH2)23CH3
(CH2)17
Me
71
Scheme 16. (i) LiHMDS, THF, 68 (80%); (ii) KOOCN]NCOOK, AcOH/
MeOH, THF (85%); (iii) HF, pyridine, THF (83%); (iv) LiOH, THF, MeOH,
H2O (66%).
Chemicals used were obtained from commercial suppliers or
prepared from them by methods described. Solvents, which
had to be dry, e.g., ether and tetrahydrofuran were dried over
sodium wire. Petrol was of boiling point 40–60 ꢁC. Reac-
tions carried under inert conditions were carried out under
a slow stream of nitrogen. Those carried out at low temper-
atures 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 Model 8410 on a capillary column (15 mꢂ
0.53 mm). IR spectra were carried out on a Perkin–Elmer
1600 FTIR spectrometer as liquid films. NMR spectra were
recorded on a Bruker AC250 or Advance 500 spectrometer.
Where signs are given in carbon spectra, + ¼ CH2, ꢀ ¼ CH,
CH3 and no sign is quaternary; in some molecules containing
long carbon chains, it was not possible to identify a signal for
each individual carbon. [a]D values were recorded in CHCl3
on a POLAAR 2001 Optical Activity polarimeter. Mass
spectra were recorded on a Bruker MicroTOF.
In the same way reaction of the aldehyde 68 with sulfone 56
led to the corresponding methoxymycolic acid either pro-
tected as its methyl ester 72 or unprotected 73 (Scheme 17).
OMe
O
(CH2)7S
O
N
N
CH3(CH2)17
(CH2)16
56
N
N
Me
Ph
(i), (ii), (iii)
OH
O
OMe
(CH2)16
72
CH3(CH2)17
OMe
(CH2)23CH3
(CH2)17
Me
(iv)
3.1.1. (E)-3-((R)-2,2-Dimethyl[1,3]dioxolan-4-yl)acrylic
acid methyl ester (13). Pyridinum-p-toluene sulfonate
(1.76 g, 7.02 mmol) was added to a stirred solution of
L-gulono-1,4-lactone (12) (25 g, 140 mmol)37 in anhydrous
formamide (200 mL) at 10 ꢁC, followed by dropwise
addition of 2-methoxypropene (13.14 g, 182.5 mmol). The
cooling bath was removed and the reaction mixture was
stirred for 6 h, when TLC showed one spot. Sodium carbon-
ate decahydrate (30 g) was added, the suspension was stirred
vigorously for 2 h and then filtered over Celite. The filtrate
was evaporated at 50–40 ꢁC and 0.1–0.2 mm Hg. The resi-
due was stirred in water (200 mL), then sodium metaperio-
date (60.1 g, 280 mmol) was added in small portions at
OH
O
OMe
(CH2)16
CH3(CH2)17
OH
(CH2)23CH3
(CH2)17
Me
73
Scheme 17. (i) LiHMDS, THF, 68 (77%); (ii) KOOCN]NCOOK, AcOH/
MeOH, THF (81%); (iii) HF, pyridine, THF (84%); (iv) LiOH, THF, MeOH,
H2O (63%).
The proton and carbon NMR spectra of 58 and 60 were
essentially identical. The proton and carbon NMR spectra
of the synthetic hydroxy esters 70 and 72 were identical to
each other and to those of a natural sample. The MALDI

2576
Juma’a. R. Al Dulayymi et al. / Tetrahedron 63 (2007) 2571–2592
0–5 ꢁC, whilst maintaining the pH at 5.5 by the addition of
2 N sodium hydroxide. After stirring at room temperature
for 2 h, sodium chloride (30 g) was added. The precipitate
was filtered and washed with water (100 mL). The filtrate
was diluted with 10% sodium hydrogen carbonate (150 mL)
followed by the addition of methyl diisopropoxyphosphinyl
acetate (36.7 g, 154.3 mmol) and then 6 M aq potassium car-
bonate (130 mL) at 5 ꢁC. The mixture was stirred for 16 h at
room temperature and then extracted with dichloromethane
(3ꢂ200 mL). The combined organic layers were washed
with brine, water, dried and evaporated to give a pale yellow
oil. Chromatography on silica eluting with 5:2 petrol/ether
gave (E)-3-((R)-2,2-dimethyl[1,3]dioxolan-4-yl)acrylic acid
methyl ester (13) (9.00 g, 34.3%) {[a]2D2 ꢀ42.9 (c 1.25,
CHCl3); lit.:38 [a]D20 ꢀ46 (c 1, CHCl3)}, which showed dH
(500 MHz, CDCl3): 6.88 (1H, dd, J 5.7, 15.8 Hz), 6.10
(1H, dd, J 1.3, 15.8 Hz), 4.66 (1H, br dq, J ca. 1.5, 6.9 Hz),
4.18 (1H, dd, J 6.7, 8.2 Hz), 3.74 (3H, s), 3.67 (1H, dd, J 7.0,
8.2 Hz), 1.44 (3H, s), 1.40 (3H, s); dC (125 MHz, CDCl3):
166.4, 145.0, 121.9, 110.2, 74.9, 68.8, 51.7, 26.4, 25.7.
(1H, dd, J 4.8, 14.9 Hz), 2.24–2.18 (1H, m), 2.16 (1H, dd,
J 8.9, 14.9 Hz), 1.39 (3H, s), 1.33 (3H, s), 0.99 (3H, d, J
6.6 Hz); dC (125 MHz, CDCl3): 173.1, 108.9, 78.7, 66.7,
51.5, 37.3, 32.9, 26.3, 25.2, 15.3; nmax: 2985, 1740,
1065 cmꢀ1
.
3.1.4. (R)-3-((S)-2,2-Dimethyl[1,3]dioxolan-4-yl)butan-1-
ol (10). (R)-3-((S)-2,2-Dimethyl[1,3]dioxolan-4-yl)butyric
acid ethyl ester (9) (10.8 g, 50 mmol) in tetrahydrofuran
(40 mL) was added dropwise over 15 min to a suspension
of lithium aluminium hydride (2 g, 53 mmol) in tetrahydro-
furan (160 mL) at room temperature. The mixture was re-
fluxed for 1 h, when TLC showed that no starting material
was left, then cooled to room temperature and quenched
carefully with freshly prepared satd aq sodium sulfate deca-
hydrate (10 mL) until a white precipitate was formed,
followed by the addition of magnesium sulfate (10 g). The
mixture was stirred vigorously for 10 min and then filtered
through a pad of Celite and washed well with tetrahydro-
furan (2ꢂ50 mL). The combined organic layers were evapo-
rated to give a residue, which was dissolved in 1:1 petrol/
ether (150 mL) and two drops of triethylamine. The solution
was dried by stirring for 1 h over anhydrous potassium car-
bonate. Filtration and evaporation gave a colourless liquid,
(R)-3-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)butan-1-ol (10)36
(8.4 g, 96%) {[a]D22 +18.1 (c 1.35, CHCl3); lit.,40 [a]2D2
+16.8 (CHCl3)}, which showed dH (500 MHz, CDCl3):
4.01–3.96 (2H, m), 3.75–3.70 (1H, m), 3.66–3.60 (2H, m),
2.06 (1H, t, J 5.1 Hz), 1.86–1.78 (1H, m), 1.67–1.61 (1H,
m), 1.44–1.37 (4H, including a 3H-singlet at 1.40), 1.34
(3H, s), 0.97 (3H, d, J 6.6 Hz); dC (125 MHz, CDCl3):
3.1.2. (R)-3-((S)-2,2-Dimethyl[1,3]dioxolan-4-yl)butyric
acid ethyl ester (9). Methyllithium (54 mL, 80 mmol,
1.5 M) was added to a stirred solution of ethyl E-3-((S)-
2,2-dimethyl[1,3]dioxolan-4-yl)acrylate (8 g, 40 mmol) in
dry ether (250 mL) at ꢀ78 ꢁC under nitrogen, stirred at this
temperature for 2.5 h and then allowed to reach ꢀ60 ꢁC fol-
lowed by the addition of water (10 mL). After 5 min, satd aq
ammonium chloride (60 mL) was added, whereupon the tem-
perature rose to ꢀ40 ꢁC. The mixture was allowed to reach
0 ꢁC and quenched with water (100 mL). The organic layer
was separated and the aqueous layer extracted with ether
(2ꢂ50 mL). The combined layers were washed with satd
aq sodium chloride (2ꢂ100 mL) dried and evaporated to
give a yellow oil, which was purified by chromatography
on silica eluting with petrol/ether (8:2) (TLC visualised
with potassium permanganate) to give (R)-3-((S)-2,2-
dimethyl[1,3]-dioxolan-4-yl)butyric acid ethyl ester (9) as
a colourless oil (7.27 g, 84%)35 {[a]D22 +8.34 (c 1.12,
CHCl3)}, which showed dH (500 MHz, CDCl3): 4.07 (2H,
q, J 7.0 Hz), 3.97–3.91 (2H, m), 3.57 (1H, br t, J 6.7 Hz),
2.33 (1H, br dd, J 4.5, 14.9 Hz), 2.18–2.11 (1H, m), 2.07
(1H, br dd, J 8.9, 14.9 Hz), 1.34 (3H, s), 1.27 (3H, s), 1.20
(3H, t, J 7.0 Hz), 0.94 (3H, d, J 7.0 Hz); dC (125 MHz,
CDCl3): 172.5, 108.8, 78.7, 66.7, 60.3, 37.5, 32.9, 26.3,
25.2, 15.3, 14.1; nmax: 2984, 2980, 1732, 1012 cmꢀ1. A small
amount of what was probably a stereoisomer was also
isolated (0.9 g).
108.7, 79.6, 67.2, 60.3, 35.6, 32.8, 26.4, 25.3, 15.1; nmax
3424 cmꢀ1
:
.
3.1.5. (S)-3-((R)-2,2-Dimethyl[1,3]dioxolan-4-yl)butan-1-
ol (15). (S)-3-((R)-2,2-Dimethyl[1,3]dioxolan-4-yl)butyric
acid methyl ester (14) (11.23 g, 60.0 mmol) in tetrahydro-
furan (60 mL) was added as above to a suspension of lithium
aluminium hydride (2.8 g, 73.8 mmol) in tetrahydrofuran
(200 mL). The mixture was refluxed for 1 h and then worked
up as above to give (S)-3-((R)-2,2-dimethyl[1,3]dioxolan-
4-yl)butan-1-ol (15) (8.4 g, 80%) {[a]2D2 ꢀ18.64 (c 1.15,
CHCl3)}, which showed an identical NMR spectrum to
that above.
3.1.6. (R)-3-((S)-2,2-Dimethyl-[1,3]dioxolan-4-yl)-butyr-
aldehyde (11). (R)-3-((S)-2,2-Dimethyl[1,3]dioxolan-4-yl)-
butan-1-ol (10) (6.1 g, 35 mmol) in dichloromethane
(30 mL) was added to a stirred suspension of pyridinium
chlorochromate (16 g, 92 mmol) in dichloromethane
(250 mL) at room temperature. The mixture was stirred
vigorously and refluxed for 30 min, when TLC showed
that no starting material was left. It was cooled, poured
into ether (200 mL) and filtered through a pad of silica,
then washed well with ether and the filtrate was evaporated
to give a residue. Chromatography on silica eluting with
1:1 petrol/ether gave (R)-3-((S)-2,2-dimethyl[1,3]dioxolan-
4-yl)-butyraldehyde (11)36 as a colourless oil (4.82 g,
80%) {[a]2D2 +8.27 (c 1.44, CHCl3)}, which showed dH
(500 MHz, CDCl3): 9.72 (1H, t, J 1.9 Hz), 4.03 (1H, br td,
J 5.1, 6.6 Hz), 3.93 (1H, dd, J 6.6, 8.2 Hz), 3.58 (1H, dd, J
7.0, 8.2 Hz), 2.51 (1H, ddd, J 1.9, 5.4, 16.6 Hz), 2.36–2.29
(1H, m), 2.25 (1H, ddd, J 2.2, 7.9, 16.6 Hz), 1.35 (3H, s),
3.1.3. (S)-3-((R)-2,2-Dimethyl[1,3]dioxolan-4-yl)butyric
acid methyl ester (14). Methyllithium (68 mL, 102 mmol,
1.5 M) was added to a stirred solution of (E)-3-((R)-2,2-
dimethyl[1,3]dioxolan-4-yl)acrylic acid methyl ester (13)
(9.31 g, 50 mmol) in ether (250 mL) at ꢀ78 ꢁC under nitro-
gen. The mixture was stirred at this temperature for 2.5 h
and then allowed to reach ꢀ60 ꢁC followed by the addition
of water (10 mL). After 5 min, satd aq ammonium chloride
(60 mL) was added, whereupon the temperature rose to
ꢀ40 ꢁC. Work up as above gave (S)-3-((R)-2,2-dimethyl-
[1,3]dioxolan-4-yl)butyric acid methyl ester (14) (7.64 g,
82%) {[a]2D2 ꢀ8.16 (c 1.47, CHCl3)}, which showed dH
(500 MHz, CDCl3): 4.02 (1H, br q, J 6.3 Hz), 3.99 (1H, br
q, J 6.6 Hz), 3.67 (3H, s), 3.61 (1H, br t, J 7.0 Hz), 2.42

Juma’a. R. Al Dulayymi et al. / Tetrahedron 63 (2007) 2571–2592
2577
1.29 (3H, s), 0.95 (3H, d, J 6.9 Hz); dC (125 MHz, CDCl3):
201.5, 108.9, 78.4, 66.1, 46.4, 30.3, 26.1, 25.0, 15.4; nmax
2985, 1725, 1215, 1066 cmꢀ1
requires: 457.2608. Found: C, 63.6; H, 9.0; N, 12.7.
C23H38N4O2S requires: C, 63.56; H, 8.81; N, 12.89.] dH
(500 MHz, CDCl3): 7.72–7.68 (2H, m), 7.64–7.58 (3H,
m), 3.73 (2H, distorted t, J 7.9 Hz), 1.95 (2H, pent, J
7.0 Hz), 1.50 (2H, pent, J 7.0 Hz), 1.36–1.25 (24H, br m),
0.89 (3H, t, J 6.6 Hz); dC (125 MHz, CDCl3): 153.5,
133.1, 131.5(ꢀ), 129.7(ꢀ), 125.1(ꢀ), 57.0(+), 31.9(+),
29.7(+), 29.67(+), 29.64(+), 29.6(+), 29.5(+), 29.4(+),
29.2(+), 28.9(+), 22.7(+), 22.0(+), 14.1(ꢀ); nmax: 2918,
:
.
3.1.7. (S)-3-((R)-2,2-Dimethyl[1,3]dioxolan-4-yl)-butyr-
aldehyde (16). (S)-3-((R)-2,2-Dimethyl[1,3]dioxolan-4-yl)-
butan-1-ol (15) (6.79 g, 39 mmol) in dichloromethane
(40 mL) was added to a stirred suspension of pyridinium
chlorochromate (16.8 g, 78 mmol) in dichloromethane
(250 mL) at room temperature. The mixture was stirred
vigorously and refluxed for 30 min; work up as above gave
(S)-3-((R)-2,2-dimethyl[1,3]dioxolan-4-yl)butyraldehyde (16)
as a colourless oil (5.42 g, 81%) {[a]2D2 ꢀ8.6 (c 1.035,
CHCl3)}, which showed an identical NMR spectrum to
that above.
1470, 1343, 1154, 770 cmꢀ1
.
3.1.10. (S)-2,2-Dimethyl-4-((R)-1-methylnonadecyl)-
[1,3]dioxolane (19). Lithium hexamethyldisilazide (34 mL,
36 mmol, 1.06 M) was added dropwise with stirring to (R)-
3-((S)-2,2-dimethyl[1,3]dioxolan-4-yl)-butyraldehyde (11)
(3.3 g, 19.6 mmol) and 5-(hexadecane-1-sulfonyl)-1-phenyl-
1H-tetrazole (18) (10.5 g, 24.1 mmol) in dry tetrahydrofuran
(130 mL) under nitrogen at ꢀ2 ꢁC. The mixture was allowed
to reach room temperature and stirred for 16 h and then
quenched with water (100 mL) and petrol/ether (1:1,
100 mL). The aqueous layer was re-extracted with petrol/
ether (1:1, 2ꢂ50 mL). The combined organic layers were
washed with satd aq sodium chloride (2ꢂ100 mL), dried
and evaporated to give a thick oil. Chromatography on silica
eluting with petrol/ether (10:0.5) gave (S)-2,2-dimethyl-4-
((E,Z)-(R)-1-methylnonadec-3-enyl)-[1,3]dioxolane (6.5 g,
90%) (2.6:1, E/Z). Palladium on charcoal (10%, 1 g) was
added to a stirred solution of the alkenes (6.5 g, 17 mmol)
in ethanol (100 mL) and methanol (25 mL). The mixture
was stirred under hydrogen at atmospheric pressure. When
no more hydrogen was absorbed it was filtered through
Celite and washed with warm ethyl acetate (100 mL). The
clear colourless filtrate was evaporated at 14 mm Hg to
give (S)-2,2-dimethyl-4-((R)-1-methylnonadecyl)-[1,3]-di-
oxolane (19) as a white solid (6.3 g, 97%), mp 34–36 ꢁC
[found [MꢀH]+: 381.3723; C25H49O2 requires: 381.3733]
{[a]2D2 +23 (c 0.62, CHCl3)}, which showed dH (500 MHz,
CDCl3): 4.00 (1H, dd, J 6.0, 7.6 Hz), 3.87 (1H, br q, J
7.2 Hz), 3.61 (1H, br t, J 7.6 Hz), 1.61–1.54 (1H, m), 1.41
(3H, s), 1.36 (3H, s), 1.33–1.21 (33H, br s), 1.12–1.05
(1H, m), 0.97 (3H, d, J 6.6 Hz), 0.89 (3H, t, J 6.6 Hz); dC
(125 MHz, CDCl3): 108.5, 80.4, 67.8, 36.5, 32.8, 31.9,
29.9, 29.70, 29.67, 29.6, 29.4, 27.0, 26.6, 25.5, 22.7, 15.6,
14.1; nmax: 2919, 2851, 1467, 1076, 856 cmꢀ1 (see also Sup-
plementary data).
3.1.8. 5-Hexadecylsulfanyl-1-phenyl-1H-tetrazole (17).
1-Bromohexadecane (16.2 g, 53 mmol) was added with
vigorous stirring to 1-phenyl-1H-tetrazole-5-thiol (8.4 g,
47 mmol) and anhydrous potassium carbonate (15.2 g,
110 mmol) in acetone (165 mL). The mixture was refluxed
for 2.5 h when TLC showed that no starting material was
left. The inorganic salts were filtered off and washed with
acetone; the solution was evaporated to a small bulk and
the residue extracted between dichloromethane (150 mL)
and water (300 mL). The aqueous layer was extracted with
dichloromethane (2ꢂ50 mL). The combined organic phases
were washed with water (300 mL), dried and evaporated to
give a solid. This was dissolved in acetone (50 mL) and
diluted with methanol (100 mL), and left at ambient temper-
ature for 1 h and then at 0 ꢁC for 1 h. The crystals were
filtered off and washed with cold 1:2 acetone/methanol
to yield a white solid, 5-hexadecylsulfanyl-1-phenyl-1H-
tetrazole (17) (18 g, 95%). [Found [M+H+]: 403.2876.
C23H39N4S requires: 403.2889. Found: C, 69.0; H, 9.7; N,
14.2. C23H38N4S requires: C, 68.61; H, 9.51; N, 13.91.]
Mp 48–50 ꢁC; dH (500 MHz, CDCl3): 7.59–7.52 (5H, m),
3.39 (2H, t, J 7.6 Hz), 1.82 (2H, pent, J 7.6 Hz), 1.43 (2H,
pent, J 6.6 Hz), 1.33–1.24 (24H, m), 0.88 (3H, t, J 6.9 Hz);
dC (125 MHz, CDCl3): 154.5, 133.8, 130.0(ꢀ), 129.7(ꢀ),
123.8(ꢀ), 33.4(+), 31.9(+), 29.63(+), 29.62(+), 29.60(+),
29.56(+), 29.50(+), 29.4(+), 29.3(+), 29.1(+), 29.0(+),
28.6(+), 22.6(+), 14.0(ꢀ); nmax
: 2917, 1501, 1091,
759 cmꢀ1
.
3.1.9. 5-(Hexadecane-1-sulfonyl)-1-phenyl-1H-tetrazole
(18). A solution of ammonium molybdate(VI) tetrahydrate
(23.7 g, 19.2 mmol) in ice cold H2O2 (35% w/w, 53 mL)
was added to a stirred solution of 5-hexadecylsulfanyl-1-
phenyl-1H-tetrazole (17) (17 g, 42.2 mmol) in THF
(180 mL) and IMS (360 mL) at 12 ꢁC and stirred at 15–
20 ꢁC for 2 h. A further solution of ammonium molyb-
date(VI) tetrahydrate (9 g, 7.3 mmol) in ice cold H2O2
(35% w/w, 23 mL) was added and the mixture was stirred
at room temperature for 18 h, then poured into 3 L of water
and extracted with dichloromethane (3ꢂ200 mL). The com-
bined organic phases were washed with water (2ꢂ300 mL),
dried and evaporated. The residue was dissolved in methanol
(200 mL) and left at ambient temperature for 1 h and then
at 0 ꢁC for 1 h. A white solid crystallised; this was filtered
and washed with cold methanol to give 5-(hexadecane-
1-sulfonyl)-1-phenyl-1H-tetrazole (18) (16.97 g, 93%), mp
65–67 ꢁC. [Found [M+H+]: 457.2649. C23H38N4SO2Na
3.1.11. (R)-2,2-Dimethyl-4-((S)-1-methylnonadecyl)-
[1,3]dioxolane (20). Lithium hexamethyldisilazide (40 mL,
41 mmol, 1.06 M) was added dropwise to a stirred solution
of (S)-3-((R)-2,2-dimethyl[1,3]dioxolan-4-yl)-butyraldehyde
(16) (5.6 g, 32.5 mmol) and 5-(hexadecane-1-sulfonyl)-1-
phenyl-1H-tetrazole (18) (14.5 g, 33.36 mmol) in dry tetra-
hydrofuran (200 mL) under nitrogen at ꢀ2 ꢁC. The mixture
was allowed to reach room temperature and stirred for 16 h
and then worked as above to give (R)-2,2-dimethyl-4-((E,Z)-
(S)-1-methylnonadec-3-enyl)-[1,3]dioxolane (11.5 g, 93%)
(2.4:1, E/Z), which was hydrogenated and purified as before
to give (R)-2,2-dimethyl-4-((S)-1-methylnonadecyl)-[1,3]-
dioxolane (20) (10.2, 88%) {[a]2D2 ꢀ17.4 (c 1.4, CHCl3)},
which showed an identical NMR spectrum to that above.
3.1.12. (2S,3R)-3-Methyl-henicosane-1,2-diol (21). p-Tol-
uenesulfonic acid monohydrate (1 g, 5.26 mmol) was added

2578
Juma’a. R. Al Dulayymi et al. / Tetrahedron 63 (2007) 2571–2592
to a stirred solution of (S)-2,2-dimethyl-4-((R)-1-methyl-
nonadecyl)-[1,3]dioxolane (19) (10.6 g, 27.7 mmol) in tetra-
hydrofuran (40 mL), methanol (50 mL) and water (5 mL) at
room temperature and then refluxed for 2 h. The solvent was
evaporated and the residue was diluted with petrol/ether
(1:1, 150 mL) and then satd aq sodium bicarbonate
(50 mL) was added. The aqueous layer was re-extracted
with ether (2ꢂ70 mL). The combined organic layers were
washed with satd aq sodium chloride (250 mL), dried and
evaporated to give a white solid (2S,3R)-3-methyl-henico-
sane-1,2-diol (21) (8.95 g, 94%). A small amount of the com-
pound was purified by chromatography on silica eluting with
petrol/ethyl acetate (1:1) for analysis, mp 68–67 ꢁC [found
[MꢀH]+: 341.3404; C22H45O2 requires: 341.3414] {[a]D22
+12.7 (c 1.11, CHCl3)}, which showed dH (500 MHz,
CDCl3): 3.69–3.67 (1H, m), 3.62–3.54 (2H, m), 2.13 (1H,
br s), 2.08 (1H, br s), 1.74–1.68 (1H, br m), 1.60–1.53 (2H,
m), 1.46–1.23 (31H, m), 1.19–1.13 (1H, m), 0.94 (3H, d, J
6.6 Hz), 0.89 (3H, t, J 7.0 Hz); dC (125 MHz, CDCl3):
75.8, 65.2, 35.7, 33.0, 31.9, 29.9, 29.70, 29.67, 29.4, 27.1,
stirred for 30 min, then worked up and purified as above to
give (R)-2-((S)-1-methylnonadecyl)oxirane (12.8 g, 92%)
{[a]2D2 ꢀ0.66 (c 1.054, CHCl3)}, which showed an identical
NMR spectrum to that above.
3.1.16. (8R,9R)-9-Methyl-1-(tetrahydropyran-2-yloxy)-
heptacosan-8-ol (23). A solution of 1-bromo-6-tetrahydro-
pyranyloxyhexane (11.26 g, 42.4 mmol) in tetrahydrofuran
(25 mL) was added dropwise to a suspension of magnesium
turnings (2.1 g, 86 mmol) in tetrahydrofuran (30 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 iodide41 (0.75 g, 3.9 mmol) in dry tetrahy-
drofuran (30 mL) at ꢀ30 ꢁC. After 10 min, a solution of (S)-
2-((R)-1-methylnonadecyl)oxirane (22) (5.5 g, 16.94 mol)
in tetrahydrofuran (10 mL) was added dropwise. The mix-
ture was stirred for 3 h at ꢀ30 ꢁC, allowed to reach
ꢀ15 ꢁC, then quenched with satd aq ammonium chloride
(100 mL) and allowed to reach room temperature. The prod-
uct was extracted with 1:1 petrol/ether (3ꢂ200 mL). The
combined organic layers were washed with satd aq sodium
chloride (250 mL), dried and evaporated to give a colourless
oil. Chromatography on silica eluting with 5:2 petrol/ethyl
acetate gave (8R,9R)-9-methyl-1-(tetrahydropyran-2-yloxy)-
heptacosan-8-ol (23) as a colourless oil (6.35 g, 75%) [found
[M+Na]+: 533.4885; C33H66O3Na requires: 533.4904]
{[a]2D2 +9.15 (c 1.3, CHCl3)}, which showed dH (500 MHz,
CDCl3): 4.59 (1H, br s), 3.91–3.87 (1H, m), 3.74 (1H, td, J
7.0, 9.5 Hz), 3.54–3.51 (2H, m), 3.40 (1H, td, J 6.6,
9.5 Hz), 1.87–1.82 (1H, m), 1.75–1.69 (2H, m), 1.65–1.52
(6H, m), 1.48–1.25 (44H, m), 1.21–1.14 (1H, m), 0.90
(3H, t, J 7.0 Hz), 0.88 (3H, d, J 6.6 Hz); dC (125 MHz,
CDCl3): 98.9, 75.2, 67.7, 62.3, 38.2, 34.4, 33.4, 31.9, 30.8,
30.0, 29.74, 29.70, 29.66, 29.6, 29.5, 29.4, 27.4, 26.24,
26.2, 25.5, 22.7, 19.7, 14.1, 13.6; nmax: 3450, 2921, 2851,
22.7, 14.6, 14.1; nmax: 3420 cmꢀ1
.
3.1.13. (2R,3S)-3-Methyl-henicosane-1,2-diol (25). p-Tol-
uenesulfonic acid monohydrate (1.6 g, 8.4 mmol) was added
to a stirred solution of (R)-2,2-dimethyl-4-((S)-1-methylno-
nadecyl)-[1,3]dioxolane (20) (16.35 g, 42.7 mmol) in tetra-
hydrofuran (60 mL), methanol (90 mL) and water (5 mL)
at room temperature, refluxed for 4.5 h, then worked up
and purified as above to give (2R,3S)-3-methyl-henico-
sane-1,2-diol (25) as a white solid (14.7 g, 97%) {[a]D22
ꢀ12.9 (c 1.34, CHCl3)}, which showed an identical NMR
spectrum to that above.
3.1.14. (S)-2-((R)-1-Methylnonadecyl)oxirane (22). So-
dium hydroxide solution (50%, 34 mL) was added with vig-
orous stirring to (2S,3R)-3-methyl-henicosane-1,2-diol (21)
(8.9 g, 26.1 mmol) and cetrimide (0.5 g) in dichloromethane
(250 mL) at room temperature. A solution of p-toluene-
sulfonyl chloride (6.1 g, 32 mmol) in dichloromethane
(32 mL) was then added over 10 min. The mixturewas stirred
for 30 min when TLC showed that no starting material was
left and then quenched with water (150 mL). The aqueous
layer was extracted with dichloromethane (2ꢂ50 mL). The
combined organic layers were washed with water (100 mL),
dried and evaporated to give a residue. Chromatography on
silica eluting with petrol/ether (10:0.5) gave (S)-2-((R)-1-
methylnonadecyl)oxirane (22) as a white solid (8.23 g,
97%), mp 45–47 ꢁC [found [M+H]+: 325.3470; C22H45O
requires: 325.3470] {[a]2D2 +0.3 (c 1.0, CHCl3)}, which
showed dH (500 MHz, CDCl3): 2.78 (1H, dd, J 4.1,
5.2 Hz), 2.71–2.68 (1H, m), 2.54 (1H, dd, J 2.9, 5.2 Hz),
1.45–1.25 (34H, m), 1.18–1.13 (1H, m), 1.04 (3H, d, J
6.3 Hz), 0.90 (3H, t, J 6.7 Hz); dC (125 MHz, CDCl3): 57.2,
47.0, 36.2, 33.6, 31.9, 29.9, 29.7, 29.68, 29.6, 29.4, 27.1,
1465, 1033 cmꢀ1
.
3.1.17. (8S,9S)-9-Methyl-1-(tetrahydropyran-2-yloxy)-
heptacosan-8-ol. 1-Bromo-6-tetrahydropyranyloxyhexane
(20.4 g, 76.9 mmol) in tetrahydrofuran (75 mL) was added
dropwise to a suspension of magnesium turnings (3.85 g,
158.36 mmol) in tetrahydrofuran (50 mL) under nitrogen.
The mixture was refluxed for 2 h, then cooled to room tem-
perature and added dropwise to a stirred solution of purified
copper iodide (1.36 g, 7.14 mmol) in dry tetrahydrofuran
(70 mL) at ꢀ30 ꢁC. After 30 min, a solution of (R)-2-((S)-
1-methylnonadecyl)oxirane (10 g, 30.8 mmol) in tetra-
hydrofuran (60 mL) was added dropwise. The mixture was
stirred for 3 h at ꢀ30 ꢁC, allowed to reach ꢀ5 ꢁC, then
worked up and purified as above to give (8S,9S)-9-methyl-
1-(tetrahydropyran-2-yloxy)-heptacosan-8-ol as a colourless
oil (10.08 g, 64%) {[a]D22 ꢀ9.49 (c 1.32, CHCl3)}, which
showed an identical NMR spectrum to that above.
22.7, 17.1, 14.1; nmax: 2919, 1473, 1261, 892, 729 cmꢀ1
.
3.1.18. 2-((8R,9R)-8-Methoxy-9-methylheptacosyloxy)-
tetrahydropyran (24). Sodium hydride (3.4 g, 85 mmol,
60% dispersion) was washed with petrol (3ꢂ20 mL) and
then suspended in dry tetrahydrofuran (35 mL), cooled to
5 ꢁC and (8R,9R)-9-methyl-1-(tetrahydropyran-2-yloxy)-
heptacosan-8-ol (23) (6.5 g, 12.76 mmol) in tetrahydrofuran
(35 mL) was added over 5 min. After 15 min, methyl iodide
(10.72 g, 75 mmol) was added. The mixture was stirred for
16 h at room temperature. Satd aq ammonium chloride
3.1.15. (R)-2-((S)-1-Methylnonadecyl)oxirane. Sodium
hydroxide solution (50%, 50 mL) was added to a vigorously
stirred solution of (2R,3S)-3-methyl-henicosane-1,2-diol
(14.7 g, 42.9 mmol) and cetrimide (0.82 g) in dichloro-
methane (450 mL) at room temperature. To this, a solution of
p-toluene-sulfonyl chloride (10 g, 52.5 mmol) in dichloro-
methane (50 mL) was added over 10 min. The mixture was

Juma’a. R. Al Dulayymi et al. / Tetrahedron 63 (2007) 2571–2592
2579
(50 mL) was added carefully followed by ether (100 mL).
The aqueous layer was extracted with 1:1 petrol/ether
(2ꢂ50 mL). The combined organic layers were washed
with brine (2ꢂ80 mL), dried and evaporated to give a resi-
due; chromatography on silica eluting with 10:2 petrol/ether
gave 2-((8R,9R)-8-methoxy-9-methyl-heptacosyloxy)tetra-
hydropyran (24) (6.25 g, 94%) as a pale yellow oil [found
[M+Na]+: 547.5065; C34H68O3Na requires: 547.5061]
{[a]2D2 +8.76 (c 1.45, CHCl3)}, which showed dH (500 MHz,
CDCl3): 4.59 (1H, br t, J 2.3 Hz), 3.91–3.87 (1H, m), 3.74
(1H, td, J 7.0, 9.5 Hz), 3.53–3.49 (1H, m), 3.39 (1H, td, J
6.6, 9.5 Hz), 3.35 (3H, s), 2.99–2.95 (1H, m), 1.87–1.82
(1H, m), 1.76–1.71 (1H, m), 1.68–1.52 (6H, m), 1.45–1.25
(44H, m), 1.15–1.07 (1H, m), 0.89 (3H, t, J 7.0 Hz), 0.86
(3H, d, J 6.7 Hz); dC (125 MHz, CDCl3): 98.8, 85.4, 67.7,
62.3, 57.7, 35.3, 32.4, 31.9, 30.8, 30.5, 30.0, 29.9, 29.8,
29.7, 29.67, 29.5, 29.4, 27.6, 26.2, 26.1, 25.5, 22.7, 19.7,
refluxed for 30 min, then worked up and purified as above
to give (8S,9S)-8-methoxy-9-methyl-heptacosan-1-ol (28)
(8.00 g, 95%) {[a]2D2 ꢀ10.74 (c 1.20, CHCl3)}, which
showed an identical NMR spectrum to that above.
3.1.22. (8R,9R)-8-Methoxy-9-methylheptacosanal (29).
(8R,9R)-8-Methoxy-9-methylheptacosan-1-ol (27) (4.0 g,
9.1 mmol) in dichloromethane (30 mL) was added to a vigor-
ously stirred suspension of pyridinium chlorochromate
(4.9 g, 22.7 mmol) in dichloromethane (200 mL) at room
temperature. The mixture was refluxed for 45 min, when
TLC showed no starting material, then cooled and poured
into ether (200 mL). It was filtered through a pad of silica,
then washed with ether and the filtrate was evaporated.
Chromatography on silica eluting with 10:1 petrol/ether
gave (8R,9R)-8-methoxy-9-methylheptacosanal (29) (3.5 g,
87%) as a colourless liquid [found [M+Na]+: 461.4312;
C29H58O2Na requires: 461.4329], {[a]2D2 +11.6 (c 1.16,
CHCl3)}, which showed dH (500 MHz, CDCl3): 9.77 (1H,
t, J 1.9 Hz), 3.34 (3H, s), 2.97–2.93 (1H, m), 2.43 (2H, dt,
J 1.9, 7.3 Hz), 1.64 (2H, br pent, J 7.3 Hz), 1.45–1.22
(42H, m), 1.11–1.05 (1H, m), 0.88 (3H, t, J 7.0 Hz), 0.85
(3H, d, J 7.0 Hz); dC (125 MHz, CDCl3): 202.9, 85.5,
57.7, 43.9, 35.3, 32.3, 30.0, 29.7, 29.66, 29.6, 29.2, 27.6,
26.0, 22.7, 22.1, 14.9, 14.1; nmax: 2924, 2850, 1729, 1465,
14.9, 14.1; nmax: 2928, 2846, 1077 cmꢀ1
.
3.1.19. 2-((8S,9S)-8-Methoxy-9-methylheptacosyloxy)-
tetrahydropyran (26). Sodium hydride (5.5 g, 137.5 mmol,
60% dispersion) was washed with petrol (3ꢂ30 mL), sus-
pended in dry tetrahydrofuran (60 mL), cooled to 5 ꢁC and
(8S,9S)-9-methyl-1-(tetrahydropyran-2-yloxy)heptacosan-
8-ol (10.0 g, 19.57 mmol) in tetrahydrofuran (60 mL) was
added over 5 min. After 15 min, methyl iodide (16.19 g,
114 mmol) was added, stirred for 16 h at room temperature,
then worked up and purified as above to give 2-((8S,9S)-
8-methoxy-9-methylheptacosyloxy)tetrahydropyran (26)
(10.32 g, 100%) {[a]D22 ꢀ7.35 (c 1.577, CHCl3)}, which
showed an identical NMR spectrum to that above.
1097 cmꢀ1
.
3.1.23. (8S,9S)-8-Methoxy-9-methylheptacosanal (30).
(8S,9S)-8-Methoxy-9-methylheptacosan-1-ol (28) (7.9 g,
17.92 mmol) in dichloromethane (50 mL) was added to
a stirred suspension of pyridinium chlorochromate (7.2 g,
33.4 mmol) in dichloromethane (250 mL) at room tempera-
ture. The mixture was stirred vigorously and refluxed for
45 min, then worked up and purified as above to give
(8S,9S)-8-methoxy-9-methylheptacosanal (30) (6.5 g, 83%)
{[a]2D2 ꢀ11.3 (c 1.50, CHCl3)}, which showed an identical
NMR spectrum to that above.
3.1.20. (8R,9R)-8-Methoxy-9-methylheptacosan-1-ol
(27). p-Toluenesulfonic acid monohydrate (0.543 g,
2.85 mmol) was added to a stirred solution of 2-((8R,9R)-
8-methoxy-9-methylheptacosyloxy)tetrahydropyran (24)
(6.0 g, 11.43 mmol) in tetrahydrofuran (20 mL), methanol
(70 mL) and water (1 mL) at room temperature. The mixture
was refluxed for 30 min, then evaporated to approximately
half its volume and diluted with satd aq sodium bicarbonate
(50 mL) and a mixture of 1:1 petrol/ether (150 mL) was
added. The aqueous layer was re-extracted with petrol/ether
(2ꢂ50 mL). The combined organic layers were washed with
satd aq sodium chloride (100 mL), dried and evaporated to
give a residue, which was purified by chromatography on sil-
ica eluting with 5:2 petrol/ether to give (8R,9R)-8-methoxy-
9-methylheptacosan-1-ol (27) (4.1 g, 81%) as a colourless
liquid, which solidified later, mp 33–35 ꢁC, {[a]D22 +11.05
(c 1.19, CHCl3}, which showed dH (500 MHz, CDCl3):
3.65 (2H, t, J 6.6 Hz), 3.36 (3H, s), 2.98–2.95 (1H, m),
1.67–1.62 (1H, m), 1.58 (2H, pent, J 6.6 Hz), 1.49 (1H, br
s), 1.45–1.25 (43H, m), 1.15–1.06 (1H, m), 0.89 (3H, t, J
6.7 Hz), 0.86 (3H, d, J 7.0 Hz); dC (125 MHz, CDCl3):
85.5, 63.0, 57.7, 35.3, 32.8, 32.3, 31.9, 30.5, 30.0, 29.9,
29.7, 29.67, 29.4, 29.38, 27.6, 26.1, 25.7, 22.7, 14.9, 14.1;
3.1.24. 2,2-Dimethylpropionic acid (16R,17R)-16-
methoxy-17-methylpentatriacontyl ester (32). Lithium
hexamethyldisilazide (14.35 mL, 14.35 mmol, 1.0 M) was
added dropwise to a stirred solution of (8R,9R)-8-
methoxy-9-methylheptacosanal (29) (3.4 g, 7.74 mmol)
and 5-(1-octanolpivalate-8-sulfonyl)-1-phenyl-1H-tetrazole
(31) (see Supplementary data) (4.04 g, 9.57 mmol) in dry
tetrahydrofuran (100 mL) under nitrogen at ꢀ2 ꢁC. The
mixture was allowed to reach room temperature and stirred
for 16 h, then quenched with satd aq ammonium chloride
(50 mL) and petrol/ether (1:1, 100 mL). The organic layer
was separated and the aqueous layer was re-extracted with
petrol/ether (1:1, 2ꢂ50 mL). The combined organic layers
were washed with satd aq sodium chloride (2ꢂ100 mL),
dried and evaporated to give a thick oil, which was purified
by chromatography on silica eluting with petrol/
ether (10:0.3) to give (E/Z)-2,2-dimethylpropionic acid
(16R,17R)-16-methoxy-17-methylpentatriacont-8-enylester
(2.6:1, E/Z) (4.45 g, 91%). Palladium on charcoal (10%, 1 g)
was added to a solution of the esters (4.3 g, 6.77 mmol) in
ethanol (150 mL). The mixture was stirred while being
hydrogenated at atmospheric pressure. When no more
hydrogen was absorbed it was filtered through a pad of Celite
and washed with ethanol (100 mL). The filtrate was evapo-
rated at 14 mm Hg to give 2,2-dimethylpropionic acid
nmax: 3463, 2912, 2846, 1078 cmꢀ1
.
3.1.21. (8S,9S)-8-Methoxy-9-methylheptacosan-1-ol (28).
p-Toluenesulfonic acid monohydrate (1.0 g, 5.25 mmol)
was added to a stirred solution of 2-((8S,9S)-8-methoxy-
9-methylheptacosyloxy)tetrahydropyran
(26)
(10.0 g,
19.05 mmol) in tetrahydrofuran (40 mL), methanol (70 mL)
and water (1 mL) at room temperature. The mixture was

2580
Juma’a. R. Al Dulayymi et al. / Tetrahedron 63 (2007) 2571–2592
(16R,17R)-16-methoxy-17-methylpentatriacontyl ester (32)
(4.02 g, 93%) as a colourless liquid [found [M+Na]+:
659.6293; C42H84O3Na requires: 659.6313] {[a]2D2 +6.8
(c 1.49, CHCl3)}, which showed dH (500 MHz,
CDCl3): 4.05 (2H, t, J 6.7 Hz), 3.34 (3H, s), 2.97–2.94
(1H, m), 1.62 (2H, pent, J 6.7 Hz), 1.46–1.22 (60H, m),
1.20 (9H, s), 1.12–1.06 (1H, m), 0.88 (3H, t, J 6.7 Hz),
0.85 (3H, d, J 7.0 Hz); dC (125 MHz, CDCl3): 178.5,
85.4, 64.4, 57.7, 38.7, 35.3, 32.4, 31.9, 30.8, 30.5, 30.0,
29.9, 29.7, 29.69, 29.66, 29.6, 29.5, 29.4, 29.2, 28.6, 27.6,
27.2, 26.2, 25.9, 22.7, 14.8, 14.1; nmax: 2923, 1731,
{[a]2D2 ꢀ8.21 (c 1.21, CHCl3)}, which showed an identical
NMR spectrum to that above.
3.1.28. (16R,17R)-1-Bromo-16-methoxy-17-methylpenta-
triacontane. N-Bromosuccinimide (1.6 g, 9.00 mmol) was
added in portions over 15 min to a stirred solution of
(16R,17R)-16-methoxy-17-methylpentatriacontan-1-ol (34)
(3.91 g, 7.07 mmol) and triphenylphosphine (2.1 g, 8 mmol)
in dichloromethane (50 mL) at 0 ꢁC. The mixture was stirred
at room temperature for 1 h and then quenched with satd
aq sodium metabisulfite (50 mL). The aqueous layer was
re-extracted with dichloromethane (2ꢂ30 mL). The com-
bined organic layers were washed with water, dried and
evaporated. The residue was treated with petrol/ether (1:1,
100 mL), refluxed for 30 min, then filtered and washed
with petrol/ether (50 mL). The filtrate was evaporated and
the residue was purified by chromatography on silica eluting
with petrol/ether (10:0.2) to give (16R,17R)-1-bromo-16-
methoxy-17-methylpentatriacontane (3.72 g, 85%) as a
white solid, mp 38–40 ꢁC [found: C, 72.4; H, 12.2;
C37H75OBr requires: C, 72.16; H, 12.27] {[a]2D2 +6.5 (c
1.158, CHCl3)}, which showed dH (500 MHz, CDCl3):
3.43 (2H, t, J 7.0 Hz), 3.36 (3H, s), 2.99–2.96 (1H, m),
1.87 (2H, br pent, J 6.7 Hz), 1.68–1.62 (1H, m), 1.48–1.22
(59H, m), 1.15–1.08 (1H, m), 0.91 (3H, t, J 6.3 Hz), 0.87
(3H, d, J 6.9 Hz); dC (125 MHz, CDCl3): 85.5, 57.7, 35.3,
34.0, 32.8, 32.4, 31.9, 30.5, 30.0, 29.9, 29.7, 29.6, 29.5,
1154 cmꢀ1
.
3.1.25. 2,2-Dimethylpropionic acid (16S,17S)-16-meth-
oxy-17-methylpentatriacontyl ester (33). Lithium hexa-
methyldisilazide (24 mL, 25.44 mmol, 1.06 M) was added
dropwise to a stirred solution of (8S,9S)-8-methoxy-9-
methylheptacosanal (30) (6.4 g, 14.58 mmol) and 5-(1-octa-
nolpivalate-8-sulfonyl)-1-phenyl-1H-tetrazole (31) (7.9 g,
18.7 mmol) in dry tetrahydrofuran (160 mL) under nitrogen
at ꢀ15 ꢁC. The mixture was allowed to reach room
temperature, stirred for 16 h, then worked up as above
to give (E/Z)-2,2-dimethylpropionic acid (16S,17S)-16-
methoxy-17-methylpentatriacont-8-enyl ester as a colourless
liquid (2.6:1, E/Z) (8.04 g, 87%). Hydrogenation and
purification as above gave 2,2-dimethylpropionic acid
(16S,17S)-16-methoxy-17-methylpentatriacontyl ester (33)
as a colourless liquid (8.06, 100%) {[a]2D2 ꢀ6.5 (c 1.503,
CHCl3)}, which showed an identical NMR spectrum to
that above.
29.45, 29.4, 28.8, 28.2, 27.6, 26.1, 22.7, 14.9, 14.1; nmax
2929, 2849, 1099, 717 cmꢀ1
:
.
3.1.29. (16S,17S)-1-Bromo-16-methoxy-17-methylpenta-
triacontane. N-Bromosuccinimide (2.65 g, 14.9 mmol)
was added in portions over 15 min to a stirred solution
of (16S,17S)-16-methoxy-17-methylpentatriacontan-1-ol
(35) (6.25 g, 11.3 mmol) and triphenylphosphine (3.35 g,
12.77 mmol) in dichloromethane (90 mL) at 0 ꢁC. After
1 h, work up and purification as above gave a white solid,
(16S,17S)-1-bromo-16-methoxy-17-methylpentatriacontane
(5.3 g, 76%) {[a]2D2 ꢀ7.35 (c 1.16, CHCl3)}, which showed
an identical NMR spectra to that above.
3.1.26. (16R,17R)-16-Methoxy-17-methylpentatriacon-
tan-1-ol (34). Potassium hydroxide (1.5 g, 26.36 mmol) in
methanol (20 mL) was added to a stirred solution of 2,2-
dimethylpropionic acid (16R,17R)-16-methoxy-17-methyl-
pentatriacontyl ester (32) (4.0 g, 6.28 mmol) in tetrahydro-
furan (50 mL) at room temperature. The mixture was
stirred at 40 ꢁC for 3 h, then quenched with water (100 mL)
and a mixture of petrol/ether (1:1, 100 mL). The aqueous
layer was re-extracted with petrol/ether (2ꢂ50 mL). The
combined organic layers were washed with brine (60 mL),
dried and evaporated to give a white solid, (16R,17R)-16-
methoxy-17-methylpentatriacont-an-1-ol (34) (3.4 g, 98%),
mp 46–48 ꢁC [found [M+H+]: 575.5749; C37H76O2Na
requires: 575.5737] {[a]2D2 +7.9 (c 1.40, CHCl3)}, which
showed dH (500 MHz, CDCl3): 3.66 (2H, t, J 6.6 Hz), 3.36
(3H, s), 2.99–2.96 (1H, m), 1.67–1.64 (1H, m), 1.59 (2H,
pent, J 6.6 Hz), 1.49 (1H, br s), 1.48–1.22 (59H, m), 1.14–
1.07 (1H, m), 0.90 (3H, t, J 7.0 Hz), 0.87 (3H, d, J 6.7 Hz);
dC (125 MHz, CDCl3): 85.5, 63.1, 57.7, 35.3, 32.8, 32.4,
31.9, 30.5, 30.0, 29.9, 29.7, 29.68, 29.63, 29.5, 29.4, 27.6,
26.2, 25.7, 22.7, 14.9, 14.1; nmax: 3373, 2921, 1098,
3.1.30. 5-((16R,17R)-16-Methoxy-17-methylpentatri-
acontyl-1-sulfanyl)-1-phenyl-1H-tetrazole. (16R,17R)-1-
Bromo-16-methoxy-17-methylpentatriacontane
(3.05 g,
4.95 mmol) was added to a stirred solution of 1-phenyl-
1H-tetrazol-5-thiol (0.98 g, 5.5 mmol) and potassium
carbonate (2.7 g, 19.5 mmol) in acetone (60 mL) at room
temperature. The mixture was stirred for 18 h, then the sol-
vent was evaporated and the residue diluted with petrol/ether
(1:1, 150 mL) and water (100 mL). The aqueous layer was
extracted with the same solvent mixture (2ꢂ50 mL). The
combined organic layers were dried and evaporated to give
a pale yellow viscous oil; chromatography on silica eluting
with 10:1 petrol/ether gave 5-((16R,17R)-16-methoxy-17-
methylpentatriacontyl-1-sulfanyl)-1-phenyl-1H-tetrazole
(3.21 g, 91%) as a colourless viscous oil [found [M+Na]+:
735.5912; C44H80ON4SNa requires: 735.5945] {[a]2D2 +6.18
(c 1.21, CHCl3)}, which showed dH (500 MHz, CDCl3):
7.59–7.51 (5H, m), 3.39 (2H, t, J 7.5 Hz), 3.34 (3H, s),
2.97–2.94 (1H, m), 1.82 (2H, br pent, J 7.5 Hz), 1.66–1.60
(1H, m), 1.48–1.22 (59H, m), 1.12–1.05 (1H, m), 0.88
(3H, t, J 6.6 Hz), 0.84 (3H, d, J 6.0 Hz); dC (125 MHz,
CDCl3): 154.0, 133.2, 129.7, 129.2, 123.3, 84.9, 57.2,
1076 cmꢀ1
.
3.1.27. (16S,17S)-16-Methoxy-17-methylpentatriacon-
tan-1-ol (35). Potassium hydroxide (3.4 g, 60.6 mmol)
in methanol (35 mL) was added to a stirred solution of
2,2-dimethylpropionic acid (16S,17S)-16-methoxy-17-
methylpentatriacontyl ester (33) (8.06 g, 12.65 mmol) in
tetrahydrofuran (75 mL) at room temperature. The mixture
was stirred at 40 ꢁC for 3 h, followed by work up and purifi-
cation as above to give (16S,17S)-16-methoxy-17-methyl-
pentatriacontan-1-ol (35) as a white solid (6.63 g, 95%)

Juma’a. R. Al Dulayymi et al. / Tetrahedron 63 (2007) 2571–2592
2581
34.8, 32.8, 31.8, 31.4, 29.9, 29.45, 29.4, 29.1, 29.0, 28.9,
28.8, 28.55, 28.5, 28.1, 27.0, 25.6, 22.2, 14.4, 13.6; nmax
2928, 2861, 1097 cmꢀ1
44–46 ꢁC (10.6 g, 91%) {[a]D22 ꢀ6.19 (c 1.39, CHCl3)},
:
which showed an identical NMR spectrum to that above.
.
3.1.34. 6-(1-Phenyl-1H-tetrazole-5-ylsulfanyl)hexane-
1-ol (38). Anhydrous potassium carbonate (36 g, 260 mmol)
was added to a stirred solution of 6-bromohexane-1-ol
(20 g, 110.4 mmol) and 1-phenyl-1H-tetrazole-5-thiol in
acetone (200 mL) at room temperature. The mixture was
stirred at 40 ꢁC for 2 h, at room temperature for 16 h and
then diluted with water (1000 mL) and dichloromethane
(200 mL). The aqueous layer was re-extracted with di-
chloromethane (2ꢂ150 mL). The combined organic layers
were washed with water, brine and evaporated to give 6-
(1-phenyl-1H-tetrazole-5-ylsulfanyl)hexane-1-ol (38) as
a pale yellow oil (30.6 g, 99.5%) [found [M+H+]:
279.1276; C13H19N4OS requires: 279.1274], which showed
dH (500 MHz, CDCl3): 7.53–7.48 (5H, br s), 3.59 (2H, t, J
6.3 Hz), 3.35 (2H, t, J 6.9 Hz), 2.47 (1H, br s), 1.78 (2H,
pent, J 7.3 Hz), 1.53 (2H, pent, J 7.0 Hz), 1.47–1.35 (4H,
m); dC (125 MHz, CDCl3): 154.3, 133.4, 129.9, 129.6,
123.6, 62.2, 33.0, 32.2, 28.8, 28.1, 25.0; nmax: 3394,
3.1.31. 5-((16S,17S)-16-Methoxy-17-methylpentatri-
acontyl-1-sulfanyl)-1-phenyl-1H-tetrazole. (16S,17S)-1-
Bromo-16-methoxy-17-methylpentatriacontane
(9.91 g,
16.09 mmol) was added to a stirred solution of 1-phenyl-
1H-tetrazol-5-thiol (3.2 g, 17.96 mmol) and potassium
carbonate (5.6 g, 40.5 mmol) in acetone (200 mL) at room
temperature. The mixture was stirred for 2 h at 40 ꢁC, then
at room temperature for 16 h, then worked up and purified
as above to give 5-((16S,17S)-16-methoxy-17-methylpenta-
triacontyl-1-sulfanyl)-1-phenyl-1H-tetrazole as a colourless
oil (11.34, 99%) {[a]D22 ꢀ6.5 (c 1.32, CHCl3)}, which
showed an identical NMR spectrum to that above.
3.1.32. 5-((16R,17R)-16-Methoxy-17-methylpentatri-
acontane-1-sulfonyl)-1-phenyl-1H-tetrazole (36). To
a stirred solution of 5-((16R,17R)-16-methoxy-17-methyl-
pentatriacontylsulfanyl)-1-phenyl-1H-tetrazole
(2.23 g,
3.13 mmol) in methylated spirit (70 mL) and tetrahydro-
furan (30 mL) was added dropwise ammonium heptamolyb-
date(VI) tetrahydrate (3.8 g, 3.1 mmol) in ice cold hydrogen
peroxide (35% w/w, 11 mL) at 5 ꢁC. The resulting yellow
solution was stirred for 1 h at room temperature and then an-
other ice cold solution of ammonium heptamolybdate(VI)
tetrahydrate (1.9 g) in hydrogen peroxide (5.5 mL) was
added. The mixture was stirred at room temperature for
16 h and then dichloromethane (60 mL) was added followed
by water (300 mL). The aqueous layer was re-extracted with
dichloromethane (2ꢂ30 mL). The combined organic layers
were washed with water, dried and evaporated to give a
residue; chromatography on silica eluting with petrol/ether
(10:1) gave 5-((16R,17R)-16-methoxy-17-methylpentatri-
acontane-1-sulfonyl)-1-phenyl-1H-tetrazole (36) as a white
solid (1.91 g, 82%), mp 42–44 ꢁC [found [M+Na]+:
767.5869; C44H80O3N4SNa requires: 767.5843] {[a]D22
+5.65 (c 1.90, CHCl3)}, which showed dH (500 MHz,
CDCl3): 7.73–7.71 (2H, m), 7.65–7.61 (3H, m), 3.75 (2H,
distorted t, J 7.9 Hz), 3.36 (3H, s), 2.98–2.96 (1H, m), 1.97
(2H, br pent, J 7.5 Hz), 1.68–1.61 (2H, m), 1.52 (2H, br
pent, J 7.5 Hz), 1.45–1.22 (56H, m), 1.15–1.07 (1H, m),
0.90 (3H, t, J 6.6 Hz), 0.87 (3H, d, J 6.9 Hz); dC (125 MHz,
CDCl3): 153.5, 133.1, 131.5, 129.7, 125.1, 85.5, 57.7, 56.0,
35.3, 32.4, 31.9, 30.5, 30.0, 29.97, 29.7, 29.65, 29.6, 29.5,
29.4, 29.2, 28.9, 28.2, 27.6, 26.2, 22.7, 21.9, 14.9, 14.1;
2930 cmꢀ1
.
3.1.35. 6-(1-Phenyl-1H-tetrazole-5-ylsulfonyl)hexane-1-
ol (39). A solution of ammonium heptamolybdate(VI) tetra-
hydrate (22 g, 17.8 mmol) in ice cold H2O2 (35% w/w,
60 mL) was added dropwise at 5 ꢁC to a stirred solution
of 6-(1-phenyl-1H-tetrazole-5-ylsulfanyl)hexane-1-ol (38)
(31 g, 111.3 mmol) in methylated spirit (300 mL) and tetra-
hydrofuran (250 mL). The resulting yellow solution was
stirred for 1 h and then three more identical solutions of
ammonium heptamolybdate(VI) tetrahydrate in H2O2
(35% w/w) were added over 1 h. The mixture was stirred
at room temperature for 16 h and then diluted with water
(1500 mL) and dichloromethane (300 mL). The aqueous
layer was re-extracted with dichloromethane (2ꢂ200 mL).
The combined organic layers were washed with water, brine,
dried and evaporated to give the product. Chromatography
on silica eluting with 1:1 petrol/ethyl acetate gave 6-(1-
phenyl-1H-tetrazole-5-ylsulfonyl)hexan-1-ol (39) as a col-
ourless oil, which solidified later (31.03 g, 90%) [found
[M+Na]+: 333.0954; C13H18N4O3S requires: 333.0992],
which showed dH (500 MHz, CDCl3): 7.67–7.66 (2H, m),
7.63–7.54 (3H, m), 3.72 (2H, distorted t, J 7.8 Hz), 3.61
(2H, t, J 6.3 Hz), 1.95 (2H, pent, J 7.5 Hz), 1.83 (1H, br
s), 1.58–1.49 (4H, m), 1.45–1.38 (2H, m); dC (125 MHz,
CDCl3): 153.4, 132.9, 131.4, 129.6, 125.0, 62.3, 55.7,
32.0, 27.7, 25.0, 21.8; nmax: 3315, 3073, 2909, 1592, 1496,
nmax: 2924, 2849, 1343, 1157, 1096 cmꢀ1
.
1472, 1349 cmꢀ1
.
3.1.33. 5-((16S,17S)-16-Methoxy-17-methylpentatriacon-
tane-1-sulfonyl)-1-phenyl-1H-tetrazole (37). To a stirred
solution of 5-((16S,17S)-16-methoxy-17-methylpentatria-
contylsulfanyl)-1-phenyl-1H-tetrazole (11.2 g, 15.7 mmol)
in methylated spirit (250 mL) and tetrahydrofuran (200 mL)
was added dropwise ammonium heptamolybdate(VI) tetra-
hydrate (18 g, 14.5 mmol) in ice cold hydrogen peroxide
(35% w/w, 60 mL) at 5 ꢁC. The resulting yellow solution
was stirred for 1 h at room temperature and then another
ice cold solution of ammonium heptamolybdate(VI) tetra-
hydrate (8 g) in hydrogen peroxide (30 mL) was added.
After 16 h, work up and purification as above gave 5-
((16S,17S)-16-methoxy-17-methylpentatriacontane-1-sulfo-
nyl)-1-phenyl-1H-tetrazole (37) as a white solid, mp
3.1.36. 5-(6-Bromohexane-1-sulfonyl)-1-phenyl-1H-tet-
razole (40). N-Bromosuccinimide (6.8 g, 38.25 mmol) was
added in portions over 20 min to a stirred solution of 6-(1-
phenyl-1H-tetrazole-5-ylsulfonyl)hexane-1-ol (39) (9.3 g,
30 mmol) and triphenylphosphine (9.8 g, 37.4 mmol) in di-
chloromethane (160 mL) at 0 ꢁC. The mixture was stirred
at room temperature for 16 h and then quenched with satd
aq sodium metabisulfite (50 mL). The aqueous layer was
re-extracted with dichloromethane (2ꢂ100 mL). The com-
bined organic layers were washed with water, dried and
evaporated to give a residue. This was treated with ether
(200 mL), refluxed for 30 min and the triphenylphospho-
nium oxide filtered off and washed with ether. The filtrate

2582
Juma’a. R. Al Dulayymi et al. / Tetrahedron 63 (2007) 2571–2592
was evaporated and the residue purified by chromatography
on silica eluting with 5:2 petrol/ethyl acetate to give
5-(6-bromohexane-1-sulfonyl)-1-phenyl-1H-tetrazole (40)
(9.6 g, 86%) as a white solid [found [M+Na]+: 395.0121;
C13H17N4O2S79Br requires: 395.0148], which showed dH
(500 MHz, CDCl3): 7.68–7.67 (2H, m), 7.63–7.57 (3H,
m), 3.73 (2H, distorted t, J 7.9 Hz), 3.39 (2H, t, J 7.0 Hz),
1.97 (2H, pent, J 6.6 Hz), 1.86 (2H, pent, J 7.0 Hz), 1.58–
1.48 (4H, m); dC (125 MHz, CDCl3): 153.4, 133.0, 131.4,
16.1(ꢀ), 14.2(ꢀ), 13.6(ꢀ), 9.7(+); nmax: 2922, 1732,
1464, 798 cmꢀ1
.
3.1.38. [(1S,2R)-2-(7-Bromoheptyl)cyclopropyl]metha-
nol (43). Anhydrous potassium carbonate (6 g, 43.4 mmol)
was added to a stirred solution of butyric acid (1S,2R)-
2-(7-bromoheptyl)cyclopropyl methyl ester (42) (5.2 g,
16.35 mmol) in methanol (30 mL) and THF (20 mL) at
room temperature. After 4 h at 45 ꢁC, it was diluted with
water (200 mL) and ether (100 mL). The aqueous layer
was re-extracted with ether (2ꢂ50 mL). The combined or-
ganic layers were washed with brine, dried and evaporated;
chromatography on silica eluting with 10:2 petrol/ether gave
[(1S,2R)-2-(7-bromoheptyl)cyclopropyl]methanol as a col-
ourless oil (43) (3.42 g, 84%) {[a]2D2 ꢀ18.9 (c 1.04, CHCl3)}
[found [M+H]+: 249.0841; C11H22OBr requires: 249.0849],
which showed dH (500 MHz, CDCl3): 3.62 (1H, dd, J 7.3,
11.4 Hz), 3.55 (1H, dd, J 8.2, 11.4 Hz), 3.38 (2H, t, J
7.0 Hz), 1.83 (2H, br pent, J 7.0 Hz), 1.56 (1H, br s),
1.46–1.36 (5H, m), 1.35–1.27 (4H, m), 1.24–1.17 (1H, m),
1.11–1.03 (1H, m), 0.87–0.80 (1H m), 0.68 (1H, dt, J 4.8,
8.6 Hz), ꢀ0.06 (1H, br q, J 5.4 Hz); dC (125 MHz,
CDCl3): 63.1(+), 33.9(+), 32.7(+), 29.9(+), 29.2(+),
129.6, 125.0, 55.8, 33.3, 32.1, 27.3, 27.2, 21.8, 15.2; nmax
2929, 2849, 1099, 717 cmꢀ1
:
.
3.1.37. Butyric acid (1S,2R)-2-(7-bromoheptyl)cyclo-
propyl methyl ester (42). Lithium hexamethyldisilazide
(30 mL, 31.8 mmol, 1.06 M) was added dropwise to
a stirred solution of (1S,2R)-1-butyryloxymethyl-2-formyl-
cyclopropane (41) (5.3 g, 31.1 mmol) and 5-(6-bromo-
hexane-1-sulfonyl)-1-phenyl-1H-tetrazole (40) (12.4 g,
33.2 mmol) in dry tetrahydrofuran (150 mL) under nitrogen
at ꢀ20 ꢁC. The mixture was allowed to reach room temper-
ature, stirred for 16 h, then quenched with satd aq ammoni-
um chloride (200 mL) and petrol/ether (1:1, 200 mL). The
aqueous layer was re-extracted with petrol/ether (1:1,
2ꢂ200 mL). The combined organic layers were washed
with a satd aq sodium chloride (2ꢂ100 mL), dried and
evaporated to give a thick oil. Chromatography on silica
eluting with 10:1 petrol/ether gave butyric acid (1S,2R)-
2-((E/Z)-7-bromohept-1-enyl)cyclopropyl methyl ester
(1:0.27) (7.71 g, 78%). 2,4,6-Triisopropylbenzene sulfonyl-
hydrazide (14.1 g, 47.28 mmol) was added to a stirred solu-
tion of the esters (7.5 g, 23.6 mmol) in tetrahydrofuran
(70 mL) at room temperature. The mixture was stirred at
52 ꢁC for 3 h, followed by the addition of another mole
equivalent of the hydrazide and stirring under the same con-
ditions for 24 h. It was diluted with petrol/ether (1:1,
100 mL) and washed with aq sodium hydroxide (2%,
200 mL). The aqueous layer was re-extracted with ether
(2ꢂ100 mL). The combined organic layers were washed
28.6(+), 28.4(+), 28.1(+), 18.0(ꢀ), 16.0(ꢀ), 9.4(+); nmax
:
3376, 2921, 1029, 722 cmꢀ1
.
3.1.39. (1S,2R)-2-(7-Bromoheptyl)cyclopropane carb-
aldehyde (44). [(1S,2R)-2-(7-Bromoheptyl)cyclopropyl]-
methanol (43) (1.5 g, 6.0 mmol) in dichloromethane
(10 mL) was added to a stirred suspension of pyridinium
chlorochromate (2.2 g, 10.2 mmol) in dichloromethane
(35 mL) at room temperature. The mixture was stirred vigor-
ously for 3 h, then poured into ether (200 mL) and filtered
through a pad of silica, then washed with ether and the fil-
trate was evaporated. Chromatography on silica eluting
with petrol/ether (5:0.5) gave (1S,2R)-2-(7-bromoheptyl)cy-
clopropanecarbaldehyde (44) as a colourless oil (1.38 g,
93%) {[a]2D2 ꢀ10.1 (c 1.62, CHCl3)} [found [M+Na]+:
269.0486; C11H19O79BrNa requires: 269.0511], which
showed dH (500 MHz, CDCl3): 9.34 (1H, d, J 5.4 Hz),
3.38 (2H, t, J 6.9 Hz), 1.88–1.79 (3H, m), 1.61–1.54 (1H,
m), 1.51–1.43 (2H, m), 1.42–1.35 (3H, m), 1.32–1.25 (5H,
m), 1.21 (1H, dt, J 4.8, 7.9 Hz), 1.15 (1H, td, J 5.1,
6.6 Hz); dC (125 MHz, CDCl3): 201.7(ꢀ), 33.9(+), 32.7(+),
29.7(+), 28.9(+), 28.5(+), 28.0(+), 27.96(+), 27.7(ꢀ),
24.7(ꢀ), 14.7(+); nmax: 2930, 2852, 1698, 1463, 1177,
1
with water and dried to give an oil. H NMR showed that
less than 5% starting material was left; the residue was dis-
solved in dichloromethane (75 mL) and acetic acid (7 mL),
then cetrimide (0.4 g) and water (75 mL) were added. The
two phase mixture was stirred vigorously and potassium
permanganate (2.4 g, 15 mmol) was added. After 1.5 h, so-
dium metabisulfite was added to destroy the excess of
potassium permanganate and to dissolve MnO2. The mix-
ture was diluted with petrol/ether (1:1, 100 mL). The aque-
ous layer was re-extracted with ether (2ꢂ100 mL). The
combined organic layers were washed with water, dried
and evaporated; chromatography on silica eluting with
10:1 petrol/ether gave butyric acid (1S,2R)-2-(7-bromohep-
tyl)cyclopropyl methyl ester (42) (5.2 g, 67%) as a pale yel-
low oil {[a]2D2 ꢀ14.31 (c 1.20, CHCl3)} [found [M+Na]+:
341.1083; C15H27O279BrNa requires: 341.1087], which
showed dH (500 MHz, CDCl3): 4.18 (1H, dd, J 6.9,
11.7 Hz), 3.92 (1H, dd, J 8.8, 11.7 Hz), 3.39 (2H, t,
J 6.9 Hz), 2.28 (2H, t, J 7.3 Hz), 1.84 (2H, pent, J
7.0 Hz), 1.64 (2H, sext, J 7.3 Hz), 1.45–1.35 (5H, m),
1.34–1.27 (4H, m), 1.25–1.17 (1H, m), 1.14–1.07 (1H,
m), 0.94 (3H, t, J 7.6 Hz), 0.88–0.82 (1H, m), 0.73 (1H,
dt, J 4.7, 8.5 Hz), 0.01 (1H, br q, J 5.4 Hz); dC (125
MHz, CDCl3): 173.7, 65.0(+), 36.3(+), 33.8(+), 32.7(+),
29.8(+), 29.2(+), 28.7(+), 28.5(+), 28.1(+), 18.5(+),
1055, 643 cmꢀ1
.
3.1.40. (1R,2S)-1-(7-Bromoheptyl)-2-((17R,18R)-17-meth-
oxy-18-methylhexatriacontyl)cyclopropane (45). Lith-
ium hexamethyldisilazide (6 mL, 6.36 mmol, 1.06 M) was
added dropwise to a stirred solution of (1S,2R)-2-(7-bromo-
heptyl)cyclopropanecarbaldehyde (44) (1.3 g, 5.26 mmol)
and 5-((16R,17R)-16-methoxy-17-methylpentatriacontane-
1-sulfonyl)-1-phenyl-1H-tetrazole (36) (3.72 g, 5.0 mmol)
in dry tetrahydrofuran (60 mL) under nitrogen at ꢀ15 ꢁC.
The mixture was allowed to reach room temperature and
stirred for 16 h, then quenched with a satd aq ammonium chlo-
ride (100 mL) and diluted with petrol/ether (1:1, 100 mL).
The aqueous layer was re-extracted with petrol/ether (1:1,
2ꢂ75 mL). The combined organic layers were washed
with brine, dried and evaporated to give a pale yellow oil;
chromatography on silica eluting with petrol/ether (10:1)

Juma’a. R. Al Dulayymi et al. / Tetrahedron 63 (2007) 2571–2592
2583
gave
(1R,2S)-1-(7-bromoheptyl)-2-(Z/E)-(17R,18R)-17-
mixture was stirred for 5 h at 40 ꢁC, at room temperature
for 16 h and then diluted with water (50 mL) and dichloro-
methane (100 mL). The aqueous layer was re-extracted
with dichloromethane (2ꢂ50 mL). The combined organic
layers were washed with water, brine, dried and evaporated.
Chromatography on silica eluting with 10:1 petrol/ether
gave 5-{7-[(1R,2S)-2-((17R,18R)-17-methoxy-18-methyl-
hexatriacontyl)cyclopropyl]heptylsulfanyl}-1-phenyl-1H-
tetrazole (46) (3.21 g, 91%) as a colourless viscous oil
{[a]2D2 +3.9 (c 1.21, CHCl3)} [found [M+Na]+: 887.7553;
C55H100N4OSNa requires: 887.7510], which showed dH
(500 MHz, CDCl3): 7.60–7.54 (5H, m), 3.41 (2H, t, J
7.3 Hz), 3.34 (3H, s), 2.98–2.94 (1H, m), 1.84 (2H, br
pent, J 7.5 Hz), 1.64–1.61 (1H, m), 1.48–1.22 (72H, m),
1.18–1.05 (4H, m), 0.89 (3H, t, J 7.0 Hz), 0.86 (3H, d, J
6.0 Hz), 0.68–0.62 (2H, m), 0.57 (1H, dt, J 4.1, 7.9 Hz),
ꢀ0.32 (1H, br q, J 5.1 Hz); dC (125 MHz, CDCl3):
154.0, 133.8, 130.0(ꢀ), 129.7(ꢀ), 123.9(ꢀ), 85.5(ꢀ),
57.7(ꢀ), 35.4(ꢀ), 33.4(+), 32.4(+), 31.9(+), 30.5(+),
30.2(+), 30.1(+), 30.0(+), 29.9(+), 29.74(+), 29.7(+),
29.65(+), 29.4(+), 29.3(+), 29.1(+), 29.07(+), 28.7(+),
28.6(+), 27.6(+), 26.2(+), 22.7(+), 15.8(ꢀ), 15.7(ꢀ),
14.9(ꢀ), 14.1(ꢀ), 10.9(+); nmax: 2926, 2851, 1509, 1464,
methoxy-18-methylhexatriacont-1-enyl)cyclopropane (6:1
Z/E) (3.38 g, 92%) as a colourless liquid, which solidified
later. 2,4,6-Triisopropylbenzene sulfonylhydrazide (2.7 g,
9.0 mmol) was added to a stirred solution of the above cyclo-
propanes (3.3 g, 4.31 mmol) in tetrahydrofuran (25 mL) at
room temperature and stirred at 52 ꢁC for 3 h, followed by
the addition of another mole equivalent of the hydrazide
and stirring under the same condition for 24 h. The mixture
was diluted with petrol/ether (1:1, 100 mL) and washed with
aq sodium hydroxide (100 mL, 2%). The aqueous layer was
re-extracted with petrol/ether (1:1, 2ꢂ50 mL). The com-
bined organic layers were washed with brine, dried and
1
evaporated to give a colourless residue (3.63 g). H NMR
showed that a very small amount of starting material was
left. The residue was dissolved in dichloromethane
(25 mL) and to this were added acetic acid (2 mL), cetrimide
(0.2 g) and water (50 mL). The two phase mixture was vig-
orously stirred and potassium permanganate (0.5 g) was
added. After 1.5 h, it was worked up as before to give a
residue; chromatography on silica eluting with petrol/ether
(10:0.5) gave a white solid, (1R,2S)-1-(7-bromoheptyl)-
2-((17R,18R)-17-methoxy-18-methylhexatriacontyl)cyclo-
propane (45) (3.03 g, 91%), mp 32–34 ꢁC {[a]D22 +5.5 (c 1.29,
CHCl3)}, which showed dH (500 MHz, CDCl3): 3.41 (2H, t,
J 6.9 Hz), 3.35 (3H, s), 2.98–2.95 (1H, m), 1.87 (2H, pent,
J 6.7 Hz), 1.68–1.62 (1H, m), 1.48–1.22 (72H, br m), 1.18–
1.08 (4H, m), 0.9 (3H, t, J 7.0 Hz), 0.87 (3H, d, J 7.0 Hz),
0.72–0.62 (2H, m), 0.58 (1H, dt, J 4.1, 8.0 Hz), ꢀ0.31 (1H,
br q, J 5.1 Hz); dC (125 MHz, CDCl3): 85.4(ꢀ), 57.7(ꢀ),
35.4(ꢀ), 33.9, 32.9(+), 32.4(+), 31.9(+), 30.5(+), 30.2(+),
30.1(+), 30.0(+), 29.9(+), 29.7(+), 29.42(+), 29.4(+),
28.8(+), 28.7(+), 28.65(+), 28.2(+), 27.6(+), 26.2(+),
1097 cmꢀ1
.
3.1.43. 5-{7-[(1R,2S)-2-((17S,18S)-17-Methoxy-18-methyl-
hexatriacontyl)cyclopropyl]heptylsulfanyl}-1-phenyl
1H-tetrazole(47). (1R,2S)-1-(7-Bromoheptyl)-2-((17S,18S)-
17-methoxy-18-methylhexatriacontyl)cyclopropane (7.0 g,
9.13 mmol) in tetrahydrofuran (25 mL) was added to a stirred
solution of 1-phenyl-1H-tetrazol-5-thiol (1.72 g, 9.65 mmol)
and potassium carbonate (4.8 g, 34.7 mmol) in acetone
(75 mL) at room temperature. The mixture was stirred for
5 h at 40 ꢁC, then at room temperature for 16 h, then worked
up and purified as before to give 5-{7-[(1R,2S)-2-((17S,18S)-
17-methoxy-18-methylhexatriacontyl)cyclopropyl]heptyl-
sulfanyl}-1-phenyl-1H-tetrazole (47) as a slightly off white
solid (7.65 g, 97%) {[a]2D2 ꢀ5.11 (c 1.31, CHCl3)}, which
showed an identical NMR spectrum to that above.
22.7(+), 15.8(ꢀ), 15.7(ꢀ), 14.9(ꢀ), 14.1(ꢀ), 10.9(+); nmax
:
2922, 1464, 1098, 720 cmꢀ1
.
3.1.41. (1R,2S)-1-(7-Bromoheptyl)-2-((17S,18S)-17-
methoxy-18-methylhexatriacontyl)cyclopropane. Lithium
hexamethyldisilazide (15.0 mL, 15.9 mmol, 1.06 M) was
added dropwise to a stirred solution of (1S,2R)-2-(7-bromo-
heptyl)cyclopropanecarbaldehyde (44) (3.1 g, 12.54 mmol)
and 5-((16S,17S)-16-methoxy-17-methylpentatriacontane-
1-sulfonyl)-1-phenyl-1H-tetrazole (37) (9.4 g, 12.6 mmol)
in dry tetrahydrofuran (150 mL) under nitrogen at ꢀ15 ꢁC.
The mixture was allowed to reach room temperature
and stirred for 16 h, then worked up and purified as above
to give (1R,2S)-1-(7-bromoheptyl)-2-(Z/E)-(17S,18S)-17-
methoxy-18-methylhexatriacont-1-enyl)cyclopropane (6:1)
(8.35 g, 87%) as a colourless liquid, which solidified later.
Hydrogenation and purification as above gave (1R,2S)-1-
(7-bromoheptyl)-2-((17S,18S)-17-methoxy-18-methylhexa-
triacontyl)cyclopropane as a thick yellow liquid (7.22 g,
75%) {[a]2D2 ꢀ5.84 (c 1.16, CHCl3)}, which showed an iden-
tical NMR spectrum to that above.
3.1.44. Butyric acid (1R,2S)-2-(1-phenyl-1H-tetrazol-5-
ylsulfanylmethyl)cyclopropyl methyl ester (49). Diethyl
azodicarboxylate (12.2 g, 70 mmol) in tetrahydrofuran
(20 mL) was added to a stirred solution of (1R,2S)-1-butryl-
oxymethyl-2-hydroxymethylcyclopropane (48)39 (6.9 g,
40 mmol), triphenylphosphine (15.3 g, 58.3 mmol) and 1-
phenyl-1H-tetrazol-5-thiol (9.7 g, 54.4 mmol) in tetrahydro-
furan (120 mL) maintaining the temperature at 0–5 ꢁC
throughout the addition. After 18 h at room temperature,
the solvent was evaporated and the residue was treated
with petrol/ether (5:2, 150 mL), stirred at room temperature
for 45 min then filtered and the filter cake was washed with
petrol/ether. The filtrate was evaporated to give a brown oil,
which was purified by chromatography on silica eluting with
5:2 petrol/ether to give butyric acid (1R,2S)-2-(1-phenyl-1H-
tetrazol-5-ylsulfanylmethyl)cyclopropylmethyl ester (49) as
a slightly yellow viscous oil (11.32 g, 85%) {[a]2D4 ꢀ1.2 (c
1.06, CHCl3)} [found [M+Na]+: 355.1185; C16H20N4NaO2S
requires: 355.1199], which showed dH (500 MHz, CDCl3):
7.60–7.53 (5H, m), 4.34 (1H, dd, J 6.6, 12.3 Hz), 3.96
(1H, dd, J 9.2, 12.0 Hz), 3.59 (1H, dd, J 7.9, 13.5 Hz),
3.43 (1H, dd, J 7.9, 13.5 Hz), 2.27 (2H, t, J 7.6 Hz),
1.64 (2H, sext, J 7.6 Hz), 1.51 (1H, d pent, J 5.7, 8.0 Hz),
3.1.42. 5-{7-[(1R,2S)-2-((17R,18R)-17-Methoxy-18-
methylhexatriacontyl)cyclopropyl]heptylsulfanyl}-1-
phenyl-1H-tetrazole (46). (1R,2S)-1-(7-Bromoheptyl)-
2-((17R,18R)-17-methoxy-18-methylhexatriacontyl)cyclo-
propane (45) (2.9 g, 3.78 mmol) in tetrahydrofuran (10 mL)
was added to a stirred solution of 1-phenyl-1H-tetrazol-
5-thiol (0.75 g, 4.2 mmol) and potassium carbonate (2 g,
14.5 mmol) in acetone (50 mL) at room temperature. The

2584
Juma’a. R. Al Dulayymi et al. / Tetrahedron 63 (2007) 2571–2592
1.43–1.36 (1H, m), 0.97 (1H, dt, J 5.4, 8.2 Hz), 0.93 (3H, t, J
7.3 Hz), 0.40 (1H, q, J 5.7 Hz); dC (125 MHz, CDCl3):
173.5, 154.3, 133.8, 130.1(+), 129.7(+), 123.8(+), 63.7(ꢀ),
36.2(ꢀ), 34.2(ꢀ), 18.4(ꢀ), 16.4(+), 15.5(+), 13.6(+),
11.0(ꢀ); nmax: 2965, 2875, 1732, 1500, 1174, 983,
C15H27Br79NaO2 requires: 341.1087] {[a]2D4 +10.03 (c
1.50, CHCl3)}, which showed spectroscopic data identical
to those for its enantiomer 42 (see Supplementary data).
3.1.47. [(1R,2S)-2-(7-Bromoheptyl)cyclopropyl] metha-
nol (52). [(1R,2S)-2-(7-Bromoheptyl)cyclopropyl]methanol
(52) [found [M+Na]+: 271.0623; C11H21BrNaO requires:
271.0668] {[a]2D4 +12.87 (c 1.65, CHCl3)} was prepared
from butyric acid (1R,2S)-2-(7-bromoheptyl)cyclopropyl-
methyl ester (51) using the same method as for the enantio-
mer 43. The spectroscopic data were identical to those for 43
(see Supplementary data).
763 cmꢀ1
.
3.1.45. Butyric acid (1R,2S)-2-(1-phenyl-1H-tetrazol-5-
sulfonylmethyl)cyclopropyl methyl ester (50). A solution
of ammonium heptamolybdate(VI) tetrahydrate (18.59 g,
15.06 mmol) in ice cold H2O2 (35% w/w, 50 mL) was added
with stirring to butyric acid (1R,2S)-2-(1-phenyl-1H-
tetrazol-5-ylsulfanylmethyl)cyclopropylmethyl ester (49)
(10.00 g, 30.12 mmol) in tetrahydrofuran (125 mL) and
IMS (250 mL) at 10 ꢁC and stirred at rt for 2 h. A further so-
lution of heptamolybdate (5.03 g, 4.07 mmol) in ice cold
H2O2 (35% w/w, 15 mL) was added and the mixture was
stirred for 19 h, then poured into water (1.5 L) and extracted
with dichloromethane (1ꢂ300 mL, 2ꢂ80 mL). The com-
bined organic layers were washed with water (700 mL),
dried and evaporated to give a residue, which was purified
by chromatography on silica eluting with 2:1 petrol/ether
to give a thick pale yellow oil, butyric acid (1R,2S)-2-
(1-phenyl-1H-tetrazol-5-sulfonylmethyl)cyclopropylmethyl
ester (50) (10.18 g, 93%) [found [M+Na]+: 387.1079;
C16H20N4O4SNa requires: 387.1097] {[a]2D4 +52.7 (c 1.45,
CHCl3)}, which showed dH (500 MHz, CDCl3): 7.71–7.69
(2H, m), 7.65–7.59 (3H, m), 4.37 (1H, dd, J 5.7, 12.0 Hz),
4.03 (1H, dd, J 5.4, 15.0 Hz), 3.92 (1H, dd, J 8.2, 12.0 Hz),
3.67 (1H, dd, J 8.9, 15.0 Hz), 2.31 (2H, t, J 7.6 Hz), 1.67
(2H, sext, J 7.6 Hz), 1.52–1.43 (2H, m), 1.03 (1H, dt, J 5.7,
8.5 Hz), 0.97 (3H, t, J 7.6 Hz), 0.60 (1H, q, J 5.7 Hz); dC
(125 MHz, CDCl3): 173.3, 153.7, 133.1, 131.5(+),
129.7(+), 125.2(+), 63.4(ꢀ), 56.8(ꢀ), 36.1(ꢀ), 18.4(ꢀ),
14.7(+), 13.6(+), 9.7(ꢀ), 8.7(+); nmax: 2967, 1731, 1343,
3.1.48. (1R,2S)-2-(7-Bromoheptyl)cyclopropane carb-
aldehyde (53). (1R,2S)-2-(7-Bromoheptyl)cyclopropane
carbaldehyde (53) was prepared as a colourless oil (76%)
[found [M+Na]+: 269.0486; C11H19BrNaO requires:
269.0511] {[a]2D4 +8.19 (c 1.28, CHCl3)} from [(1R,2S)-
2-(7-bromoheptyl)cyclopropyl]methanol (52) using the
same method as described for the enantiomer 44. The spec-
troscopic data were identical to those for 44 (see Supplemen-
tary data).
3.1.49. (1S,2R)-1-(7-Bromoheptyl)-2-((17R,18R)-17-meth-
oxy-18-methylhexatriacontyl)cyclopropane (54). Lith-
ium hexamethyldisilazide (2.97 mL, 3.15 mmol, 1.06 M)
was added dropwise to a stirred solution of (1R,2S)-2-(7-
bromoheptyl)cyclopropane carbaldehyde (53) (0.5 g,
2.02 mmol) and 5-((16R,17R)-16-methoxy-17-methylpenta-
triacontan-1-sulfonyl)-1-phenyl-1H-tetrazole (36) (1.81 g,
2.42 mmol) in dry tetrahydrofuran (25 mL) under nitrogen
at ꢀ15 ꢁC. The mixture was allowed to reach room tempera-
ture and stirred for 2 h, then quenched with satd aq ammoni-
um chloride (25 mL) and petrol/ether (1:1, 50 mL). The
aqueous layer was re-extracted with petrol/ether (1:1, 2ꢂ
25 mL). The combined organic layers were washed with
brine (25 mL), dried and evaporated to give a pale yellow
oil, which was purified by chromatography on silica eluting
with petrol/ether (9:1) to give (1S,2R)-1-(7-bromoheptyl)-
2-((E/Z)-(17R,18R)-17-methoxy-18-methylhexatriacontyl)-
cyclopropane (7:1) (1.14 g, 74%). Hydrogenation and
purification as above gave (1S,2R)-1-(7-bromoheptyl)-2-
((17R,18R)-17-methoxy-18-methylhexatriacontyl)cyclopro-
pane (54) as a viscous colourless oil (0.92 g, 80%) {[a]D24
+5.17 (c 1.44, CHCl3)}; dH (500 MHz, CDCl3): 3.42 (2H, t,
J 7.0 Hz), 3.35 (3H, s), 2.98–2.95 (1H, m), 1.87 (2H, pent, J
6.9 Hz), 1.66–1.6 (1H, m), 1.48–1.2 (72H, m), 1.18–1.06
(4H, m), 0.9 (3H, t, J 7.0 Hz), 0.87 (3H, d, J 7.0 Hz), 0.68–
0.64 (2H, m), 0.57 (1H, dt, J 4.1, 7.9 Hz), ꢀ0.32 (1H, q, J
5.4 Hz); dC (125 MHz, CDCl3): 85.5(ꢀ), 57.7(ꢀ), 35.4(ꢀ),
32.9(+), 32.4(+), 31.9(+), 30.5(+), 30.2(+), 30.1(+), 30.0(+),
29.9(+), 29.7(+), 29.42(+), 29.4(+), 28.8(+), 28.7(+),
28.65(+), 28.2(+), 27.6(+), 26.2(+), 22.7(+), 15.8(ꢀ),
15.7(ꢀ), 14.9(ꢀ), 14.1(ꢀ), 10.9(+); nmax: 2922, 1464, 1098,
1153, 765 cmꢀ1
.
3.1.46. Butyric acid (1R,2S)-2-(7-bromoheptyl)cyclo-
propylmethyl ester (51). Lithium hexamethyldisilazide
(33.68 mL, 35.7 mmol, 1.06 M) was added dropwise to
a stirred solution of butyric acid (1R,2S)-2-(1-phenyl-1H-
tetrazol-5-sulfonylmethyl)cyclopropyl methyl ester (50)
(10.0 g, 27.46 mmol) and 6-bromohexanal (4.67 g,
26.09 mmol) in dry THF (130 mL) under nitrogen at
ꢀ20 ꢁC, allowed to reach room temperature and stirred for
16 h, then worked up as above to give butyric acid
(1R,2S)-2-((E/Z)-7-bromohept-1-enyl)cyclopropylmethyl
esters (2:1, E/Z) (6.44 g, 74%). 2,4,6-Triisopropylbenzene
sulfonylhydrazide (14.88 g, 49.85 mmol) was added to
a stirred solution of the esters (5.75 g, 18.12 mmol) in tetra-
hydrofuran (150 mL) and stirred at 50 ꢁC for 20 h. Further
hydrazide (3.7 g, 12.40 mmol) was added and the reaction
mixture was stirred at 50 ꢁC for 22 h then diluted with pet-
rol/ether (1:1, 200 mL) and aq sodium hydroxide (100 mL,
2%). The aqueous layer was re-extracted with petrol/diethyl
ether (1:1, 2ꢂ50 mL) and the combined organic layers were
washed with water (100 mL), dried and evaporated. 1H
NMR showed that there was still some starting material
left. The hydrogenation was repeated as before to give
a product, which was purified by chromatography on silica
eluting with petrol/ether (10:1) to give butyric acid
(1R,2S)-2-(7-bromoheptyl)cyclopropyl methyl ester (51) as
a colourless oil (4.61 g, 80%) [found [M+Na]+: 341.1021;
720 cmꢀ1
.
3.1.50. 5-{7-[(1S,2R)-2-((17R,18R)-17-Methoxy-18-
methylhexatriacontyl)cyclopropyl]heptylsulfanyl}-1-
phenyl-1H-tetrazole (55). (1S,2R)-1-(7-Bromoheptyl)-2-
((17R,18R)-17-methoxy-18-methylhexatriacontyl)cyclopro-
pane (54) (0.5 g, 0.65 mmol) in tetrahydrofuran (10 mL) was
added to a stirred solution of 1-phenyl-1H-tetrazol-5-thiol
(0.13 g, 0.73 mmol) and potassium carbonate (0.35 g,

Juma’a. R. Al Dulayymi et al. / Tetrahedron 63 (2007) 2571–2592
2585
2.53 mmol) in acetone (30 mL) at room temperature. The re-
action mixture was stirred for 5 h at 40 ꢁC, at room temper-
ature for 16 h and then diluted with water (50 mL) and
dichloromethane (100 mL). The aqueous layer was re-
extracted with dichloromethane (2ꢂ25 mL). The combined
organic layers were washed with brine (2ꢂ50 mL), dried
and evaporated to give an oil, which solidified later. The
crude product was purified by chromatography on silica
eluting with petrol/ether (5:1) to give 5-{7-[(1S,2R)-2-
((17R,18R)-17-methoxy-18-methylhexatriacontyl)cyclopro-
pyl]heptylsulfanyl}-1-phenyl-1H-tetrazole (55) as a colour-
less viscous oil (0.5 g, 88%) [found [M+Na]+: 887.7434;
C55H100N4NaOS requires: 887.7510] {[a]2D5 +4.44 (c 1.07,
CHCl3)}, which showed dH (500 MHz, CDCl3): 7.61–7.54
(5H, m), 3.41 (2H, t, J 7.6 Hz), 3.35 (3H, s), 2.98–2.94
(1H, m), 1.83 (2H, pent, J 7.3 Hz), 1.65–1.61 (1H, m),
1.47–1.25 (72H, m), 1.17–1.08 (4H, m), 0.9 (3H, t, J
7.0 Hz), 0.87 (3H, d, J 7.0 Hz), 0.68–0.62 (2H, m),
0.57 (1H, dt, J 4.1, 8.2 Hz), ꢀ0.33 (1H, q, J 5.1 Hz); dC
(125 MHz, CDCl3): 154.0, 133.8, 130.0(ꢀ), 129.8(ꢀ),
123.9(ꢀ), 85.5(ꢀ), 57.7(ꢀ), 35.4(ꢀ), 33.4(+), 32.4(+),
31.9(+), 30.5(+), 30.2(+), 30.1(+), 30.0(+), 29.9(+),
29.8(+), 29.74(+), 29.7(+), 29.4(+), 29.3(+), 29.1(+),
29.07(+), 28.7(+), 28.6(+), 27.6(+), 26.2(+), 22.7(+),
15.8(ꢀ), 15.7(ꢀ), 14.9(ꢀ), 14.1(ꢀ), 10.9(+); nmax: 2926,
3.1.52. 5-{7-[(1R,2S)-2-((17S,18S)-17-Methoxy-18-
methylhexatriacontyl)cyclopropyl]heptane-1-sulfonyl}-
1-phenyl-1H-tetrazole (69). A solution of ammonium
heptamolybdate(VI) tetrahydrate (4.8 g, 3.88 mmol) in 35%
H2O2 (w/w) (13 mL) was added dropwise at 5 ꢁC to a stirred
solution of 5-{7-[1R,2S]-2-((17S,18S)-17-methoxy-18-meth-
ylhexatriacontyl)cyclopropyl]heptylsulfanyl}-1-phenyl-1H-
tetrazole (47) (7.5 g, 8.66 mmol) in methylated spirit
(120 mL) and tetrahydrofuran (120 mL). The resulting
yellow solution was stirred for 1 h then three more identical
solutions of ammonium heptamolybdate(VI) tetrahydrate in
35% H2O2 (w/w) were added over 1 h. The mixture was
stirred at room temperature for 16 h, then worked up and
purified as above to give 5-{7-[(1R,2S)-2-((17S,18S)-17-me-
thoxy-18-methylhexatriacontyl)cyclopropyl]heptane-1-sul-
fonyl}-1-phenyl-1H-tetrazole (69) as a white solid (6.53 g,
84%) {[a]2D2 ꢀ4.81 (c 1.391, CHCl3)}, which showed an
identical NMR spectrum to that above.
3.1.53. (R)-2-{(R)-1-Acetoxy-18-[(1R,2S)-2-((17R,18R)-
17-methoxy-18-methylhexatriacontyl)cyclopropyl]octa-
decyl}hexacosnoic acid methyl ester (58). Lithium hexa-
methyldisilazide (0.76 mL, 0.767 mmol, 1 M) was added
dropwise to a stirred solution of ((1R,2R)-1-acetoxy-11-
oxoundecyl)hexacosanoic acid methyl ester (57) (0.25 g,
0.393 mmol)31 and 5-{7-[1R,2S]-2-((17R,18R)-17-methoxy-
18-methylhexatriacontyl)cyclopropyl]heptane-1-sulfonyl}-
1-phenyl-1H-tetrazole (56) (0.52 g, 0.59 mmol) in dry THF
(15 mL) under nitrogen at ꢀ12 ꢁC. The reaction was exo-
thermic and the temperature rose to ꢀ5 ꢁC resulting in
a dark orange solution. The mixture was allowed to reach
room temperature and stirred for 2 h, cooled to 0 ꢁC and
quenched with satd aq ammonium chloride (5 mL). The
product was extracted with petrol/ether (2ꢂ50 mL), dried
and evaporated to give a thick oil, which was purified
by chromatography on silica eluting with petrol/ether
(5:0.5) to give (R)-2-{(E/Z)-(R)-1-acetoxy-18-[(1R,2S)-2-
((17R,18R)-17-methoxy-18-methylhexatriacontyl)cyclopro-
pyl]octadec-11-enyl}hexacosanoic acid methyl ester (2.5:1)
(0.35 g, 68%) as a thick colourless oil, which showed dH
(500 MHz, CDCl3) (major isomer): 5.40–5.38 (2H, br m),
5.09 (1H, br dt, J 4.0, 8.0 Hz), 3.68 (3H, s), 3.34 (3H, s),
2.98–2.94 (1H, m), 2.62 (1H, ddd, J 4.5, 7.0, 10.8 Hz),
2.03 (3H, s), 1.97 (3H, br s), 1.64–1.59 (2H, m), 1.55–1.52
(1H, m), 1.46–1.22 (133H, br m), 1.17–1.05 (4H, m), 0.88
(6H, t, J 7.0 Hz), 0.85 (3H, d, J 7.0 Hz), 0.68–0.64 (2H, br
m), 0.57 (1H, br dt, J 4.1, 8.2 Hz), ꢀ0.33 (1H, br q, J
5.1 Hz); minor isomer: 5.35 (2H, br m), the remaining sig-
nals were obscured by the major isomer; dC (125 MHz,
CDCl3) (for the mixture): 173.6, 170.3, 130.4, 130.3,
129.91, 129.9, 85.4, 74.1, 57.7, 51.5, 49.6, 35.6, 35.3,
32.6, 32.4, 31.9, 31.7, 30.5, 30.23, 30.2, 30.0, 29.9, 29.8,
29.7 (v br), 29.66, 29.63, 29.6, 29.52, 29.5, 29.44, 29.4,
29.36, 29.3, 29.23, 29.2, 28.72, 28.7, 28.1, 27.6, 27.5,
27.2, 26.2, 25.0, 22.7, 21.0, 15.8, 14.9, 14.1, 10.9. Dipotas-
sium azodicarboxylate (1.5 g, 8.04 mmol) was added with
stirring to the above methyl esters (0.35 g, 0.268 mmol) in
dry THF (10 mL) and methanol (5 mL) at 10 ꢁC under nitro-
gen, 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 ꢁC and poured slowly into satd aq
ammonium chloride (5 mL). The product was extracted
2851, 1509, 1464, 1097 cmꢀ1
.
3.1.51. 5-{7-[(1R,2S)-2-((17R,18R)-17-Methoxy-18-
methyl-hexatriacontyl)cyclopropyl]heptane-1-sulfonyl}-
1-phenyl-1H-tetrazole (56). A solution of ammonium hep-
tamolybdate(VI) tetrahydrate (2.1 g, 1.7 mmol) in H2O2
(35% w/w, 6 mL) was added dropwise at 5 ꢁC to a stirred
solutionof5-{7-[1R,2S]-2-((17R,18R)-17-methoxy-18-meth-
ylhexatriacontyl)cyclopropyl]heptylsulfanyl}-1-phenyl-1H-
tetrazole (46) (2.9 g, 3.35 mmol) in methylated spirit
(40 mL) and tetrahydrofuran (40 mL). The resulting yellow
solution was stirred for 1 h then three more identical solu-
tions of heptamolybdate in H2O2 were added over 1 h. The
reaction mixture was stirred at room temperature for 16 h
and then diluted with water (100 mL) and dichloromethane
(50 mL). The aqueous layer was re-extracted with dichloro-
methane (2ꢂ50 mL). The combined organic layers were
washed with water, brine, dried and evaporated to give the
crude product. Chromatography on silica eluting with petrol/
ether (10:2) gave 5-{7-[(1R,2S)-2-((17R,18R)-17-methoxy-
18-methylhexatriacontyl)cyclopropyl]heptane-1-sulfonyl}-
1-phenyl-1H-tetrazole (56) as a white solid (2.19 g, 73%),
mp 37–39 ꢁC {[a]D22 +4.13 (c 1.92, CHCl3)} [found
[M+Na]+: 919.7435; C55H100N4O3SNa requires: 919.7408],
which showed dH (500 MHz, CDCl3): 7.71–7.69 (2H, br dd, J
1.3, 7.9 Hz), 7.63–7.57 (3H, m), 3.74 (2H, distorted t, J
8.2 Hz), 3.35 (3H, s), 2.98–2.95 (1H, br pent, J 4.1 Hz), 1.97
(2H, br pent, J 7.6 Hz), 1.65–1.62 (1H, m), 1.52 (2H, br
pent, J 7.6 Hz), 1.48–1.22 (70H, m), 1.17–1.05 (4H, m), 0.89
(3H, t, J 7.0 Hz), 0.86 (3H, d, J 7.0 Hz), 0.69–0.65 (2H, m),
0.58 (1H, dt, J 3.8, 8.0 Hz), ꢀ0.32 (1H, br q, J 5.1 Hz); dC
(125 MHz, CDCl3): 153.5, 133.1, 131.4(ꢀ), 129.7(ꢀ),
125.1(ꢀ), 85.4(ꢀ), 57.7(ꢀ), 56.1(+), 35.4(ꢀ), 32.4, 31.9(+),
30.5(+), 30.2(+), 30.0(+), 29.9(+), 29.74(+), 29.7(+), 29.6(+),
29.4(+), 29.1(+), 28.9(+), 28.7(+), 28.6(+), 28.1(+), 27.6(+),
26.2(+), 22.7(+), 21.9(+), 15.8(ꢀ), 15.7(ꢀ), 14.9(ꢀ),
14.1(ꢀ), 10.9(+); nmax: 2908, 1596, 1499, 1464, 1343, 1153,
1099, 760 cmꢀ1
.

2586
Juma’a. R. Al Dulayymi et al. / Tetrahedron 63 (2007) 2571–2592
with petrol/ether (1:1, 3ꢂ30 mL). The combined organic
layers were washed with water (20 mL), dried and evapo-
rated to give a thick oil, which solidified slowly; however,
(63) (23 g, 0.07 mol) was added at 2 ꢁC. The reaction mix-
ture was stirred at 2–4 ꢁC for 8 h. When TLC showed no
starting material, sodium metabisulfite (20 g, 0.105 mol)
was added carefully. The mixture was allowed to reach
room temperature and stirred for 45 min, then extracted
with dichloromethane (3ꢂ500 mL), dried and evaporated.
Chromatography on silica eluting with petrol/ethyl acetate
(5:1, then 1:1) gave (2S,3R)-13-(2,2-dimethylpropionyl-
oxy)-2,3-dihydroxytridecanoic acid methyl ester (64) as a
colourless oil (24.74 g, 97%) [found [M+Na]+: 383.2395;
C19H36NaO6 requires: 383.2404] {[a]2D4 +11.1 (c 1.03,
CHCl3)}, which showed dH (500 MHz, CDCl3): 4.10 (1H,
br d, J 2 Hz), 4.04 (2H, t, J 6.6 Hz), 3.89 (1H, br dt, J 2.0,
7.6 Hz), 3.82 (3H, s), 3.08 (1H, br s), 2.04 (1H, br s), 1.61
(4H, br pent, J 6.6 Hz), 1.50–1.43 (1H, m), 1.38–1.26
(13H, m), 1.19 (9H, s); dC (125 MHz, CDCl3): 178.7,
174.1, 73.1(+), 72.7(+), 64.4(ꢀ), 52.8(+), 38.7, 33.7(ꢀ),
29.5(ꢀ), 29.43(ꢀ), 29.4(ꢀ), 29.2(ꢀ), 28.6(ꢀ), 27.2(+),
1
the H NMR spectra showed that there was still starting
material left. The procedure was repeated twice for another
24 h and the residue was purified by chromatography on sil-
ica eluting with petrol/ether (5:1) (Rf ¼0.5) to give (R)-2-
{(R)-1-acetoxy-18-[(1R,2S)-2-((17R,18R)-17-methoxy-18-
methylhexatriacontyl)cyclopropyl]octadecyl}hexacosanoic
acid methyl ester (58) as a semi solid (0.29 g, 83%) {[a]D22
+7.17 (c 1.32, CHCl3)} [found [M+Na]+: 1332.3147;
C88H172O5Na requires: 1332.3097]; dH (500 MHz,
CDCl3): 5.09 (1H, br dt, J 4.1, 8.2 Hz), 3.68 (3H, s), 3.34
(3H, s), 2.97–2.94 (1H, m), 2.62 (1H, ddd, J 4.5, 7,
10.8 Hz), 2.03 (3H, s), 1.68–1.58 (4H, m), 1.56–1.48 (1H,
m), 1.46–1.22 (138H, br m), 1.18–1.05 (4H, m), 0.89 (6H,
t, J 6.6 Hz), 0.85 (3H, d, J 6.9 Hz), 0.69–0.63 (2H, m),
0.56 (1H, dt, J 3.8, 8.0 Hz), ꢀ0.33 (1H, br q, J 4.8 Hz); dC
(125 MHz, CDCl3): 173.6, 170.3, 85.4(ꢀ), 74.1(ꢀ),
57.7(ꢀ), 51.5(ꢀ), 49.6(ꢀ), 35.3(ꢀ), 32.4(+), 31.9(+),
31.7(+), 30.5(+), 30.2(+), 30.0(+), 29.9(+), 29.7(+),
29.6(+), 29.5(+), 29.43(+), 29.4(+), 29.35(+), 28.7(+),
28.1(+), 27.6(+), 27.5(+), 26.2(+), 25.0(+), 22.7(+),
21.0(ꢀ), 15.8(ꢀ), 14.9(ꢀ), 14.1(ꢀ), 10.9(+); nmax: 2920,
25.9(ꢀ), 25.7(ꢀ); nmax: 3449, 2930, 2855, 1729 cmꢀ1
.
3.1.56. (2S,3R)-5-[10-(2,2-Dimethylpropionyloxy)decyl]-
2,2-dioxo-2l6-[1,3,2]-dioxathiolane-4-carboxylic acid
methyl ester. (2S,3R)-13-(2,2-Dimethylpropionyloxy)-2,3-
dihydroxytridecanoic acid methyl ester (64) (24.5 g,
68.1 mmol) was dissolved in CCl4 (120 mL). Thionyl chlo-
ride (10.9 mL, 149.72 mmol, 2.2 mol equiv) was added and
the mixture was vigorously refluxed for 2 h. After cooling,
the solution was carefully diluted with CH3CN (120 mL),
followed by the addition of ruthenium trichloride hydrate
(1.41 g, 6.8 mmol, 0.1 mol equiv) and NaIO4 (36.4 g,
170.13 mmol, 2.5 mol equiv) and then water (240 mL) was
added dropwise at first and then slowly. The mixture was
stirred overnight and then poured into ether (600 mL). The
organic layer was separated and the aqueous layer was re-
extracted with ether (2ꢂ200 mL). The combined organic
layers were washed with water (100 mL), satd aq sodium
bicarbonate (100 mL) and brine (100 mL), then dried
and evaporated to give a dark residue. Sodium thiosulfate
pentahydrate was added to remove the iodine and the
mixture was extracted with dichloromethane (2ꢂ200 mL).
The organic layer was dried and evaporated to give a very
dark residue; chromatography on silica eluting with petrol/
ether (1:1) gave a colourless oil, (2S,3R)-5-[10-(2,2-
dimethylpropionyloxy)decyl]-2,2-dioxo-2l6-[1,3,2]-dioxa-
thiolane-4-carboxylic acid methyl ester (26.75 g, 93%)
[found [M+Na]+: 445.1857; C19H34NaO8S requires:
445.1867] {[a]2D4 +32.76 (c 1.23, CHCl3)}, which showed
dH (500 MHz, CDCl3): 4.95 (1H, td, J 5.1, 7.3 Hz), 4.89
(1H, br d, J 7.3 Hz), 4.05 (2H, t, J 6.6 Hz), 3.90 (3H, s),
2.01–1.96 (2H, m), 1.62 (2H, br pent, J 6.6 Hz), 1.57–1.45
(2H, m), 1.39–1.26 (12H, m), 1.20 (9H, s); dC (125 MHz,
CDCl3): 178.6, 165.4, 84.1(+), 79.8(+), 64.4(ꢀ), 53.7(+),
38.7, 33.0(ꢀ), 29.4(ꢀ), 29.3(ꢀ), 29.2(ꢀ), 29.1(ꢀ),
28.8(ꢀ), 28.6(ꢀ), 27.2(+), 25.8(ꢀ), 24.8(ꢀ); nmax: 2930,
1743, 1469, 1375, 1237, 1162, 719 cmꢀ1
.
3.1.54. (E)-13-(2,2-Dimethylpropionyloxy)tridec-2-enoic
acid methyl ester (63). (Methoxycarbonylmethylene)tri-
phenylphosphorane (43.25 g, 0.127 mol) was added to
a stirred solution of 2,2-dimethylpropionic acid 11-oxoun-
decyl ester (see Supplementary data) (30.00 g, 0.111 mol)
in toluene (500 mL). After 16 h at room temperature, the tol-
uenewas evaporated to givea residue, which was diluted with
petrol/ether (5:2, 500 mL) and refluxed for 30 min. The solid
was filtered off and washed with petrol/ether (150 mL). The
filtrate was evaporated to give a residue, which was again di-
luted with petrol/ether (5:2, 500 mL) and refluxed for 30 min.
The solid was filtered off and washed with petrol/ether (5:2)
and then the filtrate was evaporated. Chromatography on sil-
ica eluting with petrol/ether (5:2) gave a colourless oil, (E)-
13-(2,2-dimethylpropionyloxy)tridec-2-enoic acid methyl
ester (63) (31 g, 85%) [found [M+Na]+: 349.2339;
C19H34NaO4 requires: 349.2349], which showed dH
(500 MHz, CDCl3): 6.97 (1H, dt, J 7.0, 15.5 Hz), 5.81 (1H,
td, J 1.6, 15.5 Hz), 4.04 (2H, t, J 6.6 Hz), 3.72 (3H, s), 2.19
(2H, dq, J 1.3, 7.6 Hz), 1.61 (2H, pent, J 6.6 Hz), 1.45 (2H,
pent, J 6.6 Hz), 1.37–1.25 (12H, m), 1.19 (9H, s); dC
(125 MHz, CDCl3): 178.6, 167.2, 149.7(+), 120.8(+),
64.4(ꢀ), 51.3(+), 38.7, 32.2(ꢀ), 29.42(ꢀ), 29.4(ꢀ),
29.3(ꢀ), 29.2(ꢀ), 29.1(ꢀ), 28.6(ꢀ), 28.0(ꢀ), 27.2(+),
25.9(ꢀ); nmax: 2928, 2855, 1729, 1158 cmꢀ1
.
3.1.55. (2S,3R)-13-(2,2-Dimethylpropionyloxy)-2,3-di-
hydroxytridecanoic acid methyl ester (64). The
(DHQD)2PHAL ligand (0.55 g, 0.70 mmol, 0.01 mol
equiv), K3Fe(CN)6 (69.27 g, 0.21 mol, 3 mol equiv),
K2CO3 (29.08 g, 0.21 mol, 3 mol equiv) and OsO4 (2.8 mL,
2.81 mmol, 0.04 mol equiv; 2.5 wt % solution in 2-methyl-
2-propanol) were dissolved in 1:1 water and 2-methyl-2-
propanol (800 mL) at room temperature. Then MeSO2NH2
(6.67 g, 0.07 mol, 1 mol equiv) was added and the mixture
was cooled to 2 ꢁC while being vigorously stirred. (E)-13-
(2,2-Dimethylpropionyloxy)tridec-2-enoic acid methyl ester
2856, 1774, 1724 cmꢀ1
.
3.1.57. (R)-13-(2,2-Dimethylpropionyloxy)-3-hydroxytri-
decanoic acid methyl ester (65). (2S,3R)-5-[10-(2,2-Di-
methylpropionyloxy)decyl]-2,2-dioxo-2l6-[1,3,2]dioxathio-
lane-4-carboxylic acid methyl ester (22 g, 51.88 mmol) was
dissolved in N,N-dimethylacetamide (300 mL) and NaBH4
(2.26 g, 59.67 mmol, 1.15 mol equiv) was slowly added at
0 ꢁC. The mixture was stirred at room temperature for 1 h

Juma’a. R. Al Dulayymi et al. / Tetrahedron 63 (2007) 2571–2592
2587
and then the solvent was distilled under high vacuum. The
residue was diluted with tetrahydrofuran (250 mL) and
then water (0.5 mL) and concentrated sulfuric acid (2 mL)
were added. The mixture was stirred for 4 h until a clear
solution was obtained followed by the addition of sodium
metabisulfite (25 g) and the mixture was stirred for another
30 min. It was then filtered through a pad of silica and
washed with tetrahydrofuran. The filtrate was evaporated
to give a residue, which was purified by chromatography
on silica eluting with petrol/ethyl acetate (10:3) gave (R)-
13-(2,2-dimethylpropionyloxy)-3-hydroxytridecanoic acid
methyl ester (65) (12.14 g, 68%) [found [M+Na]+:
367.2427; C19H36NaO5 requires: 367.2455] {[a]2D6 ꢀ10 (c
1.23, CHCl3)}, which showed dH (500 MHz, CDCl3): 4.04
(2H, t, J 6.6 Hz), 4.01–3.97 (1H, m), 3.71 (3H, s), 2.51
(1H, dd, J 3.2, 16.4 Hz), 2.41 (1H, dd, J 9.2, 16.4 Hz),
1.61 (2H, pent, J 6.6 Hz), 1.55–1.50 (1H, m), 1.44–1.38
(2H, m), 1.36–1.25 (14H, m), 1.19 (9H, s); dC (125 MHz,
CDCl3): 178.6, 173.4, 68.0(+), 64.4(ꢀ), 51.7(+), 41.1(ꢀ),
38.7, 36.5(ꢀ), 29.5(ꢀ), 29.44(ꢀ), 29.42(ꢀ), 29.4(ꢀ),
29.2(ꢀ), 28.6(ꢀ), 27.2(+), 25.8(ꢀ), 25.4(ꢀ); nmax: 3517,
propionyloxy)-1-hydroxyundecyl]pent-4-enoic acid methyl
ester (3.6 g, 9.375 mmol) in dry DMF (40 mL) at room
temperature. The reaction mixture was stirred for 15 min
followed by the addition of tert-butyldimethylsilylchloride
(1.83 g, 12.18 mmol) in DMF (10 mL) at 10 ꢁC under a nitro-
gen atmosphere. The reaction mixture was allowed to reach
room temperature and stirred for 16 h. When TLC showed
that no starting material was left, the solvent was removed
under high vacuum and the residue was diluted with di-
chloromethane (100 mL) and water (100 mL). The organic
layer was separated and the aqueous layer was re-extracted
with dichloromethane (2ꢂ50 mL). The combined organic
layers were washed with brine, dried and evaporated to
give a pale yellow oily residue, which was purified by chro-
matography on silica eluting with petrol/ether (5:1) to give
(2R,3R)-2-allyl-3-(tert-butyldimethylsilanyloxy)-13-(2,2-
dimethylpropionyloxy)tridecanoic acid methyl ester (66) as
a colourless oil (4.23 g, 91%) [found [M+Na+]: 521.3604;
C28H54O5SiNa requires: 521.3633] {[a]2D4 ꢀ12.34 (c 1.32,
CHCl3)}, which showed dH (500 MHz, CDCl3): 5.74 (1H,
tdd, J 7.0, 10.1, 17.0 Hz), 5.05 (1H, br dd, J 1.9, 17.0 Hz),
4.98 (1H, br dd, J 1.9, 10.1 Hz), 4.04 (2H, t, J 6.6 Hz),
3.94 (1H, br qd, J 1.6, 6.0 Hz), 3.65 (3H, s), 2.62 (1H, br
ddd, J 4.5, 6.3, 10.8 Hz), 2.36–2.31 (1H, m), 2.26–2.1 (1H,
m), 1.61 (2H, pent, J 6.9 Hz), 1.51–1.40 (4H, m), 1.37–
1.25 (12H, m), 1.19 (9H, s), 0.87 (9H, s), ꢀ0.05 (3H, s),
ꢀ0.03 (3H, s); dC (125 MHz, CDCl3): 178.6, 174.0,
135.9(+), 116.3(ꢀ), 72.8(+), 64.4(ꢀ), 51.32(+), 51.3(+),
38.7, 33.6(ꢀ), 31.6(ꢀ), 29.7(ꢀ), 29.5(ꢀ), 29.46(ꢀ),
29.2(ꢀ), 28.6(ꢀ), 27.2(+), 25.9(ꢀ), 25.7(+), 24.1(ꢀ), 18.0,
2922, 2854, 1732 cmꢀ1
.
3.1.58. (2R,3R)-2-Allyl-[11-(2,2-dimethylpropionyloxy)-
1-hydroxyundecyl]pent-4-enoic acid methyl ester. Butyl-
lithium (3.05 mL, 6.40 mmol, 2.2 mol equiv) was added to
a stirred solution of diisopropylamine (0.65 g, 6.40 mmol,
2.2 mol equiv) in dry THF (40 mL) under nitrogen at
ꢀ78 ꢁC. The mixture was allowed to reach room tempera-
ture and then cooled to ꢀ78 ꢁC before (R)-13-(2,2-dimethyl-
propionyloxy)-3-hydroxytridecanoic acid methyl ester (65)
(1 g, 2.91 mmol) in dry THF (20 mL) was added dropwise.
The mixture was allowed to slowly warm to 0 ꢁC in the cool-
ing bath over 2 h and then re-cooled to ꢀ65 ꢁC before allyl
iodide (0.32 mL, 3.49 mmol, 1.2 mol equiv) and HMPA
(1.01 mL, 5.81 mmol, 2 mol equiv) in dry THF (2 mL)
were added dropwise. The mixture was allowed slowly to
warm up to ꢀ5 ꢁC over 2 h. Ammonium chloride (10 mL)
was added and extracted with ether/ethyl acetate (1:1,
3ꢂ50 mL). The combined organic layers were washed
with brine (50 mL), dried and evaporated to give a residue,
which was purified by chromatography on silica eluting
with petrol/ethyl acetate (4:1) to give (2R,3R)-2-allyl-
[11-(2,2-dimethylpropionyloxy)-1-hydroxyundecyl]pent-4-
enoic acid methyl ester as a pale yellow oil (614 mg, 55%)
[found [M+Na]+: 407.2751; C22H40NaO5 requires:
407.2768] {[a]2D5 +1.94 (c 1.19, CHCl3)}, which showed
dH (500 MHz, CDCl3): 5.75 (1H, br ddd, J 7.0, 10.0,
17.0 Hz), 5.10 (1H, br qd, J 1.0, 17.0 Hz), 5.04 (1H, br qd,
J 1.0, 10.0 Hz), 4.04 (2H, t, J 6.7 Hz), 3.71 (3H, s), 3.70–
3.66 (1H, m), 2.54 (1H, ddd, J 5.1, 6.3, 11.3 Hz), 2.49
(1H, br d, J 8.2 Hz), 2.47–2.37 (2H, m), 1.61 (2H, br pent,
J 6.6 Hz), 1.50–1.40 (3H, m), 1.35–1.25 (13H, m), 1.19
(9H, s); dC (125 MHz, CDCl3): 178.6, 175.3, 134.9(+),
117.1(ꢀ), 71.7(+), 64.4(ꢀ), 51.5(+), 50.6(+), 38.7,
35.5(ꢀ), 33.8(ꢀ), 29.5(ꢀ), 29.44(ꢀ), 29.40(ꢀ), 29.2(ꢀ),
28.6(ꢀ), 27.2(+), 25.9(ꢀ), 25.7(ꢀ); nmax: 3524, 2930,
ꢀ4.4(+), ꢀ4.9(+); nmax
1158 cmꢀ1
: 2930, 2856, 1732, 1462,
.
3.1.60. (2R,3R)-3-(tert-Butyldimethylsilanyloxy)-13-(2,2-
dimethylpropionyloxy)-2-(2-oxoethyl)tridecanoic acid
methyl ester. Lutidine (1.51 g, 14.05 mmol) was added to
a stirred solution of (2R,3R)-2-allyl-3-(tert-butyldimethyl-
silanyloxy)-13-(2,2-dimethylpropionyloxy)tridecanoic acid
methyl ester (66) (3.5 g, 7.03 mmol) in dioxane/water (3:1,
100 mL) followed by the addition of osmium tetroxide
(1.4 mL, 0.14 mmol, 2.5% w/w in 2-methyl-2-propanol) at
room temperature. The mixture was stirred for 5 min and
then sodium metaperiodate (6.03 g, 28.1 mmol) was added.
After 2 h stirring, TLC showed that no starting material was
left. The reaction mixture was diluted with dichloromethane
(100 mL) and the organic layer was separated and the aque-
ous layer was re-extracted with dichloromethane (2ꢂ
50 mL). The combined organic layers were washed with
brine, dried and evaporated to give a crude product. Chroma-
tography on silica eluting with petrol/ether (5:2) gave
(2R,3R)-3-(tert-butyldimethylsilanyloxy)-13-(2,2-dimethyl-
propionyloxy)-2-(2-oxoethyl)tridecanoic acid methyl ester
as a pale yellow oil (3.34 g, 93%) [found [M+Na+]:
523.3415; C27H52O6SiNa, requires: 523.3425], which
showed dH (500 MHz, CDCl3): 9.8 (1H, br s), 4.05–4.02
(3H, including t, J 6.6 Hz), 3.68 (3H, s), 3.19 (1H, br td, J
3.8, 10.4 Hz), 2.96 (1H, br dd, J 10.5, 18.3 Hz), 2.68 (1H,
dd, J 3.5, 18.3 Hz), 1.61 (2H, pent, J 6.6 Hz), 1.41–1.25
(16H, m), 1.19 (9H, s), 0.87 (9H, s), ꢀ0.072 (3H, s),
ꢀ0.064 (3H, s); dC (125 MHz, CDCl3): 200.6(+), 178.6,
172.6, 71.8(+), 67.1(ꢀ), 64.4(ꢀ), 51.9(+), 45.3(+),
40.0(ꢀ), 38.7, 33.6(ꢀ), 29.5(ꢀ), 29.4(ꢀ), 29.2(ꢀ),
28.6(ꢀ), 27.2(+), 25.9(ꢀ), 25.7(+), 17.9, ꢀ4.6(+), ꢀ4.7(+).
2854, 1736, 1642 cmꢀ1
.
3.1.59. (2R,3R)-2-Allyl-3-(tert-butyldimethylsilanyloxy)-
13-(2,2-dimethylpropionyloxy)tridecanoic acid methyl
ester (66). Imidazole (0.95 g, 14.06 mmol) was added to a
stirred solution of (2R,3R)-2-allyl-[11-(2,2-dimethyl-

2588
Juma’a. R. Al Dulayymi et al. / Tetrahedron 63 (2007) 2571–2592
3.1.61. (R)-2-[(R)-1-(tert-Butyldimethylsilanyloxy)-11-
(2,2-dimethylpropionyloxy)undecyl]hexacosanoic acid
methyl ester (67). Lithium hexamethyldisilazide (8.33 mL,
8.83 mmol, 1.06 M) was added dropwise to a stirred solution
of (2R,3R)-3-(tert-butyldimethylsilanyloxy)-13-(2,2-dime-
thylpropionyloxy)-2-(2-oxoethyl)tridecanoic acid methyl
ester (2.9 g, 5.66 mmol) and 5-(docosan-1-sulfonyl)-1-
phenyl-1H-tetrazole42 (3.52 g, 6.79 mmol) in dry THF
(50 mL) under nitrogen at ꢀ10 ꢁC. The mixture was allowed
to reach room temperature and stirred for 3 h. When TLC
showed that no starting material was left, it was worked up
and purified as before to give (E/Z)-(R)-2-[(R)-1-(tert-butyl-
dimethylsilanyloxy)-11-(2,2-dimethylpropionyloxy)undecyl]-
hexacos-4-enoic acid methyl ester (2.7:1) (3.73 g, 83%).
Palladium on carbon (10%) (1.0 g) was added to a stirred
solution of the esters (3.7 g, 4.67 mmol) in ethyl acetate
(50 mL) and ethanol (50 mL) under hydrogen. When no fur-
ther hydrogen was absorbed, the mixture was filtered through
Celite and washed with ethyl acetate. The filtrate was evapo-
rated to give a residue, which was purified by chromatography
(petrol/ether, 10:1) to give (R)-2-[(R)-1-(tert-butyldimethyl-
silanyloxy)-11-(2,2-dimethylpropionyloxy)undecyl]hexa-
cosanoic acid methyl ester (67) as colourless oil (3.24 g,
87.3%) [found [M+Na+]: 817.6986; C49H98O5SiNa requires:
817.7076] {[a]2D5 ꢀ3.84 (c 1.38, CHCl3)}, which showed dH
(500 MHz, CDCl3): 4.05 (2H, t, J 6.6 Hz), 3.92–3.89 (1H,
m), 3.65 (3H, s), 2.55–2.51 (1H, m), 1.63–1.24 (64H, m),
1.20 (9H, s), 0.88 (3H, t, J 7.0 Hz), 0.87 (9H, s), 0.048
(3H, s), 0.025 (3H, s); dC (125 MHz, CDCl3): 178.6,
175.1, 73.2(ꢀ), 64.4(+), 51.6(ꢀ), 51.2(ꢀ), 38.7, 33.7(+),
31.9(+), 29.8(+), 29.7(+), 29.64(+), 29.6(+), 29.54(+),
29.5(+), 29.4(+), 29.3(+), 29.2(+), 28.6(+), 27.8(+), 27.5(+),
27.2(ꢀ), 25.9(+), 25.8, 25.75(ꢀ), 23.8(+), 22.7(+), 18.0,
14.1(ꢀ), ꢀ4.4(ꢀ), ꢀ4.9(ꢀ); nmax: 2923, 2853, 1732, 1458,
3.1.63. (R)-2-[(R)-1-(tert-Butyldimethylsilanyloxy)-
11-oxoundecyl]hexacosanoic acid methyl ester (68).
(R)-2-[(R)-1-(tert-Butyldimethylsilanyloxy)-11-hydroxyun-
decyl]hexacosanoic acid methyl ester (0.5 g, 0.774 mmol) in
dichloromethane (10 mL) was added to a stirred suspension
of pyridinium chlorochromate (0.42 g, 1.93 mmol) in di-
chloromethane (20 mL) at room temperature. The mixture
was stirred vigorously for 3 h; when TLC showed no starting
material, the mixture was diluted with ether (50 mL) and fil-
tered through a pad of silica and Celite, washed with ether
and the filtrate evaporated to give a residue. This was purified
by chromatography on silica eluting with petrol/ether (5:2) to
give (R)-2-[(R)-1-(tert-butyldimethylsilanyloxy)-11-oxoun-
decyl]hexacosanoic acid methyl ester as a colourless oil
(68) (0.46 g, 84%) [found [M+Na+]: 731.6306; C44H88O4-
SiNa requires: 731.6344] {[a]2D5 ꢀ4.48 (c 1.38, CHCl3)},
which showed dH (500 MHz, CDCl3): 9.77 (1H, t, J
1.9 Hz), 3.92–3.89 (1H, m), 3.66 (3H, s), 2.52 (1H, ddd, J
11.0, 7.0, 3.8 Hz), 2.42 (2H, dt, J 1.9, 7.6 Hz), 1.63 (2H,
pent, J 6.3 Hz), 1.55–1.22 (60H, m), 0.88 (3H, t, J 7 Hz),
0.87 (9H, s), 0.05 (3H, s), 0.027 (3H, s); dC (125 MHz,
CDCl3): 202.8(ꢀ), 175.1, 73.2(ꢀ), 51.6(ꢀ), 51.2(ꢀ),
43.9(+), 33.7(+), 31.9(+), 29.8(+), 29.7(+), 29.65(+),
29.6(+), 29.5(+), 29.4(+), 29.35(+), 29.3(+), 29.2(+),
27.9(+), 27.5(+), 25.8(ꢀ), 23.8(+), 22.7(+), 22.1(+), 18.0,
14.1(ꢀ), ꢀ4.4, ꢀ4.9(ꢀ); nmax: 2924, 2853, 1738, 1464 cmꢀ1
.
3.1.64. 5-(7-[(1S,2R)-2-((17R,18R)-17-Methoxy-18-
methylhexatriacontyl)cyclopropyl]heptylsulfonyl)-1-
phenyl-1H-tetrazole (59). A solution of ammonium
heptamolybdate(VI) tetrahydrate (0.36 g, 0.29 mmol) in ice
cold H2O2 35% (w/w, 5 mL) was added dropwise to a stirred
solution of 5-{7-[(1S,2R)-2-((17R,18R)-17-methoxy-18-
methylhexatriacontyl)cyclopropyl]heptylsulfanyl}-1-phenyl-
1H-tetrazole (55) (0.50 g, 0.58 mmol) in THF (15 mL) and
IMS (15 mL) at 5 ꢁC and stirred at room temperature for
1 h, then three more identical solutions of ammonium hepta-
molybdate(VI)tetrahydrate in ice cold H2O2 (35% w/w) were
added over the next hour. The reaction mixturewas stirred for
16 h at room temperature and then diluted with water
(100 mL) and dichloromethane (50 mL). The organic layer
was separated and the aqueous layer was re-extracted with di-
chloromethane (2ꢂ25 mL). The combined organic layers
were washed with brine (50 mL), dried and evaporated
to give a residue, which was purified by chromatography
on silica eluting with petrol/diethyl ether (5:1) to give 5-(7-
[(1S,2R)-2-((17R,18R)-17-methoxy-18-methylhexatriacon-
tyl)cyclopropyl]heptylsulfonyl)-1-phenyl-1H-tetrazole (59)
(0.48 g, 93%) [found [M+Na+]: 919.7435; C55H100N4NaO3S
requires: 919.7408] {[a]2D5 +4.40 (c 1.0, CHCl3)}, which
showed dH (500 MHz, CDCl3): 7.72–7.69 (2H, m), 7.64–
7.59 (3H, m), 3.74 (2H, distorted t, J 7.9 Hz), 3.35 (3H, s),
2.97–2.94 (1H, m), 1.96 (2H, pent, J 7.6 Hz), 1.66–1.61
(1H, m), 1.53–1.48 (2H, m), 1.45–1.24 (70H, m), 1.18–
1.06 (4H, m), 0.89 (3H, t, J 7.0 Hz), 0.86 (3H, d, J 7.0 Hz),
0.69–0.64 (2H, m), 0.58 (1H, dt, J 3.8, 7.9 Hz), ꢀ0.32 (1H,
q, J 5.1 Hz); dC (125 MHz, CDCl3): 153.5, 133.1,
131.4(ꢀ), 129.7(ꢀ), 125.1(ꢀ), 85.5(ꢀ), 57.7(ꢀ), 56.1(+),
35.4(ꢀ), 31.9(+), 30.5(+), 30.2(+), 30.0(+), 29.9(+),
29.8(+), 29.7(+), 29.4(+), 29.2(+), 29.0(+), 28.7(+),
28.6(+), 28.2(+), 27.6(+), 26.2(+), 25.1(+), 22.7(+),
1158 cmꢀ1
.
3.1.62. (R)-2-[(R)-1-(tert-Butyldimethylsilanyloxy)-11-
hydroxyundecyl]hexacosanoic acid methyl ester. (R)-2-
[(R)-1-(tert-Butyldimethylsilanyloxy)-11-(2,2-dimethylpro-
pionyloxy)undecyl]hexacosanoic acid methyl ester (67)
(2.9 g, 3.65 mmol) in tetrahydrofuran (10 mL) was added
to a stirred solution of potassium hydroxide (3.07 g,
54.7 mmol) in tetrahydrofuran/methanol/water (150 mL,
10:10:1). The mixture was refluxed at 70 ꢁC. After 3 h,
TLC showed that no starting material was left and the mix-
ture was quenched with water (25 mL) and extracted with
ethyl acetate (3ꢂ75 mL). The combined organic layers
were dried and evaporated to give a residue, which was pu-
rified by chromatography on silica eluting with petrol/ether
(5:2) to give (R)-2-[(R)-1-(tert-butyldimethylsilanyloxy)-
11-hydroxyundecyl]hexacosanoic acid methyl ester as a col-
ourless thick oil (2.07 g, 80%) [found [M+Na+]: 733.6477;
C44H90O4SiNa requires: 733.6501] {[a]2D5 ꢀ4.45 (c 1.01,
CHCl3)}, which showed dH (500 MHz, CDCl3): 3.92–3.89
(1H, m), 3.66 (3H, s), 3.64 (2H, t, J 6.6 Hz), 2.53 (1H,
ddd, J 10.7, 7.0, 3.6 Hz), 1.62–1.21 (65H, m), 0.88 (3H,
t, J 7.0 Hz), 0.87 (9H, s), 0.052 (3H, s), 0.028 (3H, s); dC
(125 MHz, CDCl3): 175.1, 73.2(ꢀ), 63.1(+), 51.6(ꢀ),
51.2(ꢀ), 33.7(+), 32.8(+), 31.9(+), 29.8(+), 29.7(+),
29.64(+), 29.6(+), 29.55(+), 29.54(+), 29.5(+), 29.45(+),
29.4(+), 29.3(+), 27.9(+), 27.5(+), 25.8(ꢀ), 25.7(+),
23.8(+), 22.7(+), 18.0, 14.1(ꢀ), ꢀ4.4(ꢀ), ꢀ4.9(ꢀ); nmax
3356, 2925, 2853, 1741, 1464 cmꢀ1
:
22.0(+), 15.8(ꢀ), 15.7(ꢀ), 14.9(ꢀ), 14.1(ꢀ), 10.9(+); nmax
:
.
2908, 1596, 1499, 1464, 1343, 1153, 1099, 760 cmꢀ1
.

Juma’a. R. Al Dulayymi et al. / Tetrahedron 63 (2007) 2571–2592
2589
3.1.65. (R)-2-{(R)-1-Acetoxy-18-[(1S,2R)-2-((17R,18R)-
17-methoxy-18-methylhexatriacontyl)cyclopropyl]-octa-
decyl}hexacosanoic acid methyl ester (60). Lithium
hexamethyldisilazide (0.41 mL, 0.427 mmol, 1.06 M) was
added dropwise to a stirred solution of ((1R,2R)-1-ace-
toxy-11-oxoundecyl)hexacosanoic acid methyl ester (57)
(0.174 g, 0.274 mmol) and 5-(7-[(1S,2R)-2-((17R,18R)-17-
methoxy-18-methylhexatriacontyl)cyclopropyl]heptylsul-
fonyl)-1-phenyl-1H-tetrazole (59) (0.30 g, 0.33 mmol) in
dry THF (10 mL) under nitrogen at ꢀ10 ꢁC. The mixture
was allowed to reach room temperature and stirred for 1 h.
When TLC showed no starting material, it was quenched
with a satd aq ammonium chloride (5 mL) and diethyl ether
(10 mL). The organic layer was separated and aqueous layer
was re-extracted with diethyl ether (3ꢂ10 mL). The com-
bined organic layers were washed with brine (20 mL), dried
and evaporated to give a white solid, which was purified by
chromatography on silica eluting with petrol/ether (10:1) to
give (R)-2-{(E/Z)-(R)-1-acetoxy-18-[(1S,2R)-2-((17R,18R)-
17-methoxy-18-methylhexatriacontyl)cyclopropyl]octadec-
11-enyl}-hexacosanoic acid methyl ester in ratio 2.3:1
(0.22 g, 60%). Hydrogenation with dipotassium azodicar-
boxylate and purification as before gave (R)-2-{(R)-1-
acetoxy-18-[(1S,2R)-2-((17R,18R)-17-methoxy-18-meth-
ylhexatriacontyl)cyclopropyl]octadecyl}hexacosanoic acid
methyl ester as a semi solid (60) (194 mg, 90%) [found
[M+Na+]: 1332.3147; C88H172NaO5 requires: 1332.3097]
{[a]2D5 +7.69 (c 1.04, CHCl3)}, which showed dH (500
MHz, CDCl3): 5.09 (1H, br td, J 3.8, 7.9 Hz), 3.68 (3H, s),
3.34 (3H, s), 2.98–2.95 (1H, m), 2.62 (1H, ddd, J 4.4, 7.0,
10.8 Hz), 2.04 (3H, s), 1.68–1.58 (4H, m), 1.56–1.48 (1H,
m), 1.46–1.20 (138H, m), 1.19–1.05 (4H, m), 0.89 (6H, t,
J 6.6 Hz), 0.85 (3H, d, J 6.9 Hz), 0.69–0.63 (2H, m), 0.57
(1H, dt, J 4.1, 7.9 Hz), ꢀ0.32 (1H, q, J 5.1 Hz); dC
(125 MHz, CDCl3): 173.7, 170.3, 85.5(ꢀ), 74.1(ꢀ),
57.7(ꢀ), 51.5(ꢀ), 49.6(ꢀ), 35.4(ꢀ), 32.4(+), 31.9(+),
31.7(+), 30.5(+), 30.3(ꢀ), 30.2(+), 30.0(+), 29.9(+), 29.7(+),
29.65(+), 29.6(+), 29.5(+), 29.44(+), 29.4(+), 29.36(+),
28.7(+), 28.1(+), 27.6(+), 27.5(+), 26.2(+), 25(+), 22.7(+),
acontyl)cyclopropyl]octadec-11-enyl}hexacosanoic acid
methyl ester in ratio (1.7:1) (0.52 g, 77%) as a thick colour-
less oil. Hydrogenation with dipotassium azodicarboxylate
as before and chromatography on silica eluting with petrol/
ether (20:1) gave (R)-2-{(R)-1-(tert-butyldimethylsilany-
loxy)-18-[(1R,2S)-2-((17R,18R)-17-methoxy-18-methylhexa-
triacontyl)cyclopropyl]octadecyl}hexacosanoic acid methyl
ester as a colourless viscous oil (0.405, 81%) [found
[M+Na+]: 1404.3887; C92H184O4SiNa requires: 1404.3856;
found: C, 79.634; H, 13.435; C92H184O4Si requires: C,
79.925; H, 13.413] {[a]2D5 +1.18 (c 0.93, CHCl3)}, which
showed dH (500 MHz, CDCl3): 3.92–3.89 (1H, m), 3.66
(3H, s), 3.34 (3H, s), 2.98–2.95 (1H, m), 2.53 (1H, ddd, J
3.8, 7.0, 10.7 Hz), 1.66–1.10 (147H, m), 0.94–0.84 (18H,
3ꢂCH3, SiC(CH3)3, CHCH3), 0.69–0.64 (2H, m),
0.57 (1H, dt, J 3.8, 7.6 Hz), 0.053 (3H, s), 0.03 (3H, s),
ꢀ0.32 (1H, br q, J 5.1 Hz); dC (125 MHz, CDCl3): 175.1,
85.5(ꢀ), 73.2(ꢀ), 57.7(ꢀ), 51.6(ꢀ), 51.2(ꢀ), 35.4(ꢀ),
33.7(+), 32.4(+), 31.9(+), 30.5(+), 30.2(+), 30.0(+),
29.9(+), 29.8(+), 29.7(+), 29.65(+), 29.6(+), 29.4(+),
29.35(+), 28.7(+), 27.8(+), 27.6(+), 27.5(+), 26.2(+),
25.8(ꢀ), 23.7(+), 22.7(+), 18.0, 15.8(ꢀ), 14.9(ꢀ), 14.1(ꢀ),
10.9(+), ꢀ4.4(ꢀ), ꢀ4.9(ꢀ); nmax: 2922, 2852, 1740, 1465,
1099 cmꢀ1
.
3.1.67. (R)-2-{(R)-1-(tert-Butyldimethylsilanyloxy)-18-
[(1R,2S)-2-((17S,18S)-17-methoxy-18-methylhexatri-
acontyl)cyclopropyl]octadecyl}hexacosanoic acid methyl
ester. Lithium hexamethyldisilazide (1.24 mL, 1.32 mmol,
1.06 M) was added dropwise to a stirred solution of (R)-2-
[(R)-1-(tert-butyldimethylsilanyloxy)-11-oxoundecyl]hexa-
cosanoic acid methyl ester (68) (0.35 g, 0.49 mmol) and
5-{7-[(1R,2S)-2-((17S,18S)-17-methoxy-18-methylhexatria-
contyl)cyclopropyl]heptane-1-sulfonyl}-1-phenyl-1H-tet-
razole (69) (0.911 g, 1.01 mmol) in dry THF (25 mL) under
nitrogen at ꢀ12 ꢁC. The mixture was allowed to reach room
temperature and stirred for 2 h, when TLC showed that no
starting material was left. It was quenched at 0 ꢁC with
satd aq ammonium chloride (5 mL). Worked up and purified
as above to give (E/Z)-(R)-2-{(R)-1-(tert-butyldimethyl-
silanyloxy)-18-[(1R,2S)-2-((17S,18S)-17-methoxy-18-methyl-
hexatriacontyl)cyclopropyl]octadec-11-enyl}hexacosanoic
acid methyl ester (0.94 g, 80%) as a thick colourless oil.
Hydrogenation with dipotassium azodicarboxylate and
purification as before gave (R)-2-{(R)-1-(tert-butyldime-
thylsilanyloxy)-18-[(1R,2S)-2-((17S,18S)-17-methoxy-18-
methylhexatriacontyl)cyclopropyl]octadecyl}hexacosanoic
acid methyl ester as a colourless viscous oil (0.68 g, 85%)
{[a]2D5 ꢀ4.4 (c 1.62, CHCl3)}, which showed dH (500 MHz,
CDCl3): 3.91 (1H, br dt, J 5.1, 7 Hz), 3.66 (3H, s), 3.34
(3H, s), 2.96 (1H, br pent, J 4.1 Hz), 2.53 (1H, ddd, J
3.8, 7.3, 11.0 Hz), 1.7–1.05 (147H, m), 0.94–0.831 (18H,
2ꢂCH3, SiC(CH3)3, CHCH3), 0.67–0.64 (2H, m), 0.57
(1H, br dt, J 4.1, 7.9 Hz), 0.052 (3H, s), 0.03 (3H, s),
ꢀ0.32 (1H, br q, J 5.1 Hz); dC (125 MHz, CDCl3):
175.1, 85.4(ꢀ), 73.2(ꢀ), 57.7(ꢀ), 51.6(ꢀ), 51.2(ꢀ),
35.3(ꢀ), 33.7(+), 32.4(+), 31.9(+), 30.5(+), 30.3(ꢀ),
30.2(+), 30.0(+), 29.9(+), 29.8(+), 29.7(+), 29.66(+),
29.6(+), 29.58(+), 29.56(+), 29.4(+), 29.36(+), 28.7(+),
27.8(+), 27.6(+), 27.5(+), 26.2(+), 25.8(ꢀ), 23.7(+),
22.7(+), 18.0, 15.8(ꢀ), 14.9(ꢀ), 14.1(ꢀ), 10.9(+),
22.6(+), 21.0(ꢀ), 15.8(ꢀ), 14.9(ꢀ), 14.1(ꢀ), 10.9(+); nmax
:
2920, 1743, 1469, 1375, 1237, 1162, 719 cmꢀ1
.
3.1.66. (R)-2-{(R)-1-(tert-Butyldimethylsilanyloxy)-18-
[(1R,2S)-2-((17R,18R)-17-methoxy-18-methylhexatri-
acontyl)cyclopropyl]octadecyl}hexacosanoic acid methyl
ester.
Lithium
hexamethyldisilazide
(0.787 mL,
0.835 mmol, 1.06 M) was added dropwise to a stirred
solution of (R)-2-[(R)-1-(tert-butyldimethylsilanyloxy)-11-
oxoundecyl]hexacosanoic acid methyl ester (68) (0.35 g,
0.49 mmol) and 5-{7-[(1R,2S)-2-((17R,18R)-17-methoxy-
18-methylhexatriacontyl)cyclopropyl]heptane-1-sulfonyl}-
1-phenyl-1H-tetrazole (56) (0.575 g, 0.64 mmol) in dry THF
(20 mL) under nitrogen at ꢀ12 ꢁC. The reaction was exo-
thermic and the temperature rose to ꢀ5 ꢁC resulting in
a dark orange solution. The mixture was allowed to reach
room temperature and stirred for 2 h, when TLC showed
that no starting material was left, cooled to 0 ꢁC and
quenched with satd aq ammonium chloride (5 mL). The
product was extracted with petrol/ether (2ꢂ50 mL), dried
and evaporated to give a thick oil, which was purified by
chromatography on silica eluting with petrol/ether (20:1)
to give (E/Z)-(R)-2-{(R)-1-(tert-butyldimethylsilanyloxy)-
18-[(1R,2S)-2-((17R,18R)-17-methoxy-18-methylhexatri-
ꢀ4.4(ꢀ), ꢀ4.9(ꢀ); nmax
1099 cmꢀ1
: 2922, 2852, 1740, 1465,
.

2590
Juma’a. R. Al Dulayymi et al. / Tetrahedron 63 (2007) 2571–2592
3.1.68. (R)-2-{(R)-1-Hydroxy-18-[(1R,2S)-2-((17R,18R)-
17-methoxy-18-methylhexatriacontyl)cyclopropyl]octa-
decyl}hexacosanoic acid methyl ester (72). A dry polyeth-
ylene vial equipped with a rubber septum was charged with
(R)-2-{(R)-1-(tert-butyldimethylsilanyloxy)-18-[(1R,2S)-2-
((17R,18R)-17-methoxy-18-methylhexatriacontyl)cyclopro-
pyl]octadecyl}hexacosanoic acid methyl ester (0.35 g,
0.253 mmol) and pyridine (0.4 mL) in dry tetrahydrofuran
(15 mL) and stirred at room temperature under argon. To it
was added hydrogen fluoride–pyridine complex (1.2 mL).
The mixture was stirred at 43 ꢁC for 17 h; when TLC showed
that no starting material was left, the mixture was neutralised
by pouring slowly into satd aq sodium bicarbonate until no
more CO2 was liberated. The product was extracted with pet-
rol/ether (5:2) (3ꢂ25 mL), dried, evaporated to give a white
solid and purified by chromatography eluting with petrol/
ether (5:1) to give (R)-2-{(R)-1-hydroxy-18-[(1R,2S)-2-
((17R,18R)-17-methoxy-18-methylhexatriacontyl)cyclopro-
pyl]octadecyl}hexacosanoic acid methyl ester as a white
solid (72) (0.27 g, 84%), mp 63–64 ꢁC [found [M+Na+]:
1290.3046; C86H170O4Na requires: 1290.2991; found: C,
81.208; H, 13.614; C86H170O4 requires: C, 81.444; H,
13.509] {[a]2D5 +6.0 (c 1.15, CHCl3)}, which showed dH
(500 MHz, CDCl3): 3.72 (3H, s), 3.69–3.64 (1H, m), 3.34
(3H, s), 2.97–2.94 (1H, m), 2.44 (1H, tt, J 5.4, 9.5 Hz),
1.74–1.06 (148H, m), 0.91–0.84 (9H, including t, J 6.6 Hz
for 2ꢂCH3, and d, J 6.6 Hz for CHCH3), 0.68–0.63 (2H,
m), 0.57 (1H, dt, J 4.1, 8.2 Hz), ꢀ0.32 (1H, br q, J
5.1 Hz); dC (125 MHz, CDCl3): 176.2, 85.5(ꢀ), 72.3(ꢀ),
57.7(ꢀ), 51.5(ꢀ), 50.9(ꢀ), 35.7(+), 35.4(ꢀ), 32.4(+),
31.9(+), 30.5(+), 30.2(+), 30.0(+), 29.9(+), 29.7(+),
29.63(+), 29.6(+), 29.58(+), 29.56(+), 29.55(+), 29.5(+),
29.4(+), 29.36(+), 28.7(+) 27.6(+), 27.4(+), 26.2(+),
35.3(ꢀ), 32.4(+), 31.9(+), 30.5(+), 30.2(+), 30.0(+),
29.9(+), 29.74(+), 29.7(+), 29.64(+), 29.6(+), 29.58(+),
29.56(+), 29.55(+), 29.5(+), 29.4(+), 29.36(+), 28.7(+),
27.57(+), 27.4(+), 26.2(+), 25.7(+), 22.7(+), 15.8(ꢀ),
14.9(ꢀ), 14.1(ꢀ), 10.9(+); nmax: 3355, 2923, 2852, 1712,
1462 cmꢀ1
.
3.1.70. (R)-2-{(R)-1-Hydroxy-18-[(1R,2S)-2-((17S,18S)-
17-methoxy-18-methylhexatriacontyl)cyclopropyl]octa-
decyl}hexacosanoic acid (71). Lithium hydroxide monohy-
drate (75.64 mg, 1.845 mmol) was added to a stirred solution
of(R)-2-{(R)-1-hydroxy-18-[(1R,2S)-2-((17S,18S)-17-meth-
oxy-18-methylhexatriacontyl)cyclopropyl]octadecyl}hexa-
cosanoic acid methyl ester (70) (156 mg, 0.123 mmol) in
tetrahydrofuran (15 mL), methanol (2 mL) and water
(1.2 mL) at room temperature. The mixture was stirred at
43 ꢁC for 24 h, when TLC showed that a very small amount
of starting material was left. It was cooled to room tempera-
ture, quenched with satd ammonium chloride (5 mL), diluted
with petrol/ether (1:1) (30 mL) and then acidified with 5%
HCl. The organic layer was separated and the aqueous layer
was re-extracted with petrol/ethyl acetate (1:1) (2ꢂ50 mL).
The combined organic layers were dried, evaporated and
purified by chromatography on silica eluting with petrol/
ethyl acetate (7:2) to give (R)-2-{(R)-1-hydroxy-18-
[(1R,2S)-2-((17S,18S)-17-methoxy-18-methylhexatriacontyl)-
cyclopropyl]octadecyl}hexacosanoic acid (71) as a white
solid (102 mg, 66%), mp 65–67 ꢁC [found [M+Na+]:
1276.2771; C85H168O4Na requires: 1276.2835] {found: C,
81.0; H, 13.1; C85H168O4 requires: C, 81.40; H, 13.50}
{[a]2D5 ꢀ1.07 (c 1.4, CHCl3)}, which showed dH (500 MHz,
CDCl3): 3.73–3.70 (1H, m, CHOMe), 3.35 (3H, s, OMe),
2.99–2.96 (1H, m, CHOH), 2.49–2.45 (1H, m, CHCO),
1.79–1.71 (1H, m, saturated alkane), 1.67–1.61 (2H, m, sat-
urated alkane), 1.55–1.08 (146H, m, saturated alkane),
0.91–0.85 (9H, including t, J 6.6 Hz, for 2ꢂCH3, a doublet
J 6.6 Hz, for CHCH3), 0.69–0.64 (2H, m, 2ꢂ–CH-cyclopro-
pane), 0.57 (1H, dt, J 3.7, 7.9 Hz, one HCH, of the cyclopro-
pane), ꢀ0.32 (1H, br q, J 4.7 Hz, one HCH-cyclopropane);
dC (125 MHz, CDCl3): 179.2, 85.6(ꢀ), 72.1(ꢀ), 57.7(ꢀ),
50.8(ꢀ), 35.6(+), 35.3(ꢀ), 32.4(+), 31.9(+), 30.5(+),
30.2(+), 30.0(+), 29.9(+), 29.7(+, v br), 29.6(+), 29.59(+),
29.5(+), 29.4(+), 29.36(+), 28.7(+), 27.6(+), 27.3(+),
26.2(+), 25.7(+), 22.7(+), 15.8(ꢀ), 14.9(ꢀ), 14.1(ꢀ),
25.7(+), 22.7(+), 15.8(ꢀ), 14.9(ꢀ), 14.1(ꢀ), 10.9(+); nmax
:
3355, 2923, 2852, 1712, 1462 cmꢀ1
.
3.1.69. (R)-2-{(R)-1-Hydroxy-18-[(1R,2S)-2-((17S,18S)-
17-methoxy-18-methylhexatriacontyl)cyclopropyl]octa-
decyl}hexacosanoic acid methyl ester (70). A dry polyeth-
ylene vial equipped with a rubber septum was charged with
(R)-2-{(R)-1-(tert-butyldimethylsilanyloxy)-18-[(1R,2S)-2-
((17S,18S)-17-methoxy-18-methylhexatriacontyl)cyclopro-
pyl]octadecyl}hexacosanoic acid methyl ester (0.6 g,
0.434 mmol) and pyridine (0.5 mL) in dry tetrahydrofuran
(15 mL) and stirred at room temperature under argon. To it
was added hydrogen fluoride–pyridine complex (1.8 mL).
The mixture was stirred at 43 ꢁC for 17 h, when TLC showed
that no starting material was left, then worked up and
purified as above to give (R)-2-{(R)-1-hydroxy-18-[(1R,2S)-
2-((17S,18S)-17-methoxy-18-methylhexatriacontyl)cyclopro-
pyl]octadecyl}hexacosanoic acid methyl ester (70) as a
white solid (0.46 g, 83%), mp 59–61 ꢁC [found [M+Na+]:
1290.2974; C86H170O4Na requires: 1290.2991] {found: C,
81.699; H, 13.518; C86H170O4 requires: C, 81.444; H,
13.509} {[a]2D5 ꢀ1.04 (c 1.15, CHCl3)}, which showed dH
(500 MHz, CDCl3): 3.72 (3H, s), 3.69–3.64 (1H, m), 3.34
(3H, s), 2.97–2.94 (1H, br pent, J 4.4 Hz), 2.46–2.41 (2H,
m, CHCO, OH, after shaking with D2O, integration showed
only one proton), 1.74–1.12 (147H, m), 0.90–0.83 (9H, in-
cluding t, J 7.0 Hz, for 2ꢂCH3, d, J 7.0 Hz, for CHCH3),
0.68–0.64 (2H, m), 0.565 (1H, dt, J 4.1, 8.2 Hz), ꢀ0.326
(1H, br q, J 5.1 Hz); dC (125 MHz, CDCl3): 176.2,
85.4(ꢀ), 72.3(ꢀ), 57.7(ꢀ), 51.5(ꢀ), 50.9(ꢀ), 35.7(+),
10.9(+); nmax: 3516, 2917, 2850, 1718, 1462 cmꢀ1
.
3.1.71. (R)-2-{(R)-1-Hydroxy-18-[(1R,2S)-2-((17R,18R)-
17-methoxy-18-methylhexatriacontyl)cyclopropyl]octa-
decyl}hexacosanoic acid (73). Lithium hydroxide monohy-
drate (48.6 mg, 1.185 mmol) was added to a stirred solution
of (R)-2-{(R)-1-hydroxy-18-[(1R,2S)-2-((17R,18R)-17-
methoxy-18-methylhexatriacontyl)cyclopropyl]octadecyl}-
hexacosanoic acid methyl ester (72) (100 mg, 0.079 mmol)
in tetrahydrofuran (10 mL), methanol (1.5 mL) and water
(0.8 mL) at room temperature. The mixture was stirred at
43 ꢁC for 24 h. When TLC showed no starting material, the
reaction was worked up and purified as above to give (R)-2-
{(R)-1-hydroxy-18-[(1R,2S)-2-((17R,18R)-17-methoxy-18-
methylhexatriacontyl)cyclopropyl]octadecyl}hexacosanoic
acid (73) as a yellowish solid (62 mg, 63%) [found [MꢀH+]:
1252.2804; C85H167O4 requires: 1252.2859] {[a]2D5 +6.95 (c
1.05, CHCl3)}, which showed dH (500 MHz, CDCl3): 3.73–
3.70 (1H, m, CHOMe), 3.35 (3H, s, OMe), 2.99–2.95 (1H,

Juma’a. R. Al Dulayymi et al. / Tetrahedron 63 (2007) 2571–2592
2591
5. Watanabe, M.; Aoyagi, Y.; Ridell, M.; Minnikin, D. E.
Microbiology 2001, 147, 1825–1837.
6. Minnikin, D. E.; Polgar, N. J. Chem. Soc., Chem. Commun.
1966, 648–649; J. Chem. Soc., Chem. Commun. 1967, 916–
918, 1172–1174.
m, CHOH), 2.48–2.44 (1H, m, CHCO), 1.79–1.71 (1H, m,
saturated alkane), 1.67–1.61 (2H, m, saturated alkane),
1.55–1.08 (146H, m, saturated alkane), 0.903–0.83 (9H, in-
cluding t, J 7.0 Hz, for 2ꢂCH3, d, J 7.0 Hz, for CHCH3),
0.68–0.63 (2H, m, 2ꢂ–CH-cyclopropane), 0.56 (1H, br dt,
J 4.1, 8.2 Hz, one HCH of the cyclopropane), ꢀ0.326 (1H,
br q, J 5.1 Hz, one HCH-cyclopropane); dC (125 MHz,
CDCl3): 178.8, 85.6(ꢀ), 72.1(ꢀ), 57.7(ꢀ), 50.7(ꢀ),
35.6(+), 35.3(ꢀ), 32.4(+), 31.9(+), 30.5(+), 30.3(+),
30.2(+), 30.0(+), 29.9(+), 29.7(+), 29.66(+), 29.6(+),
29.58(+), 29.5(+), 29.4(+), 29.36(+), 28.7(+), 27.6(+),
27.3(+), 26.1(+), 25.7(+), 22.7(+), 15.8(ꢀ), 14.9(ꢀ),
7. Asselineau, C.; Tocanne, G.; Tocanne, J. F. Bull. Soc. Chim. Fr.
1970, 4, 1455–1459.
ꢀ
8. Lacave, C.; Laneelle, M.-A.; Montrozier, H.; Rols, M.-P.;
Asselineau, C. Eur. J. Biochem. 1987, 163, 369–378.
ꢀ
ꢀ
9. Daffe, M.; Laneelle, M. A.; Guillen, L. V. Eur. J. Biochem.
1988, 177, 339–340.
ꢀ
ꢀ
10. Daffe, M.; Laneelle, M. A.; Lacave, C. Res. Microbiol. 1991,
14.1(ꢀ), 10.9(+); nmax: 3516, 2917, 2850, 1718, 1462 cmꢀ1
.
142, 397–403.
11. Durand, H.; Welby, M.; Laneelle, G.; Tocanne, J.-F. Eur. J.
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action was cooled to room temperature, diluted with petrol/
ether (1:1) (30 mL) and ammonium chloride (5 mL) then
acidified with 5% HCl. The organic layer was separated
and the aqueous layer was extracted with petrol/ether
(2ꢂ20 mL). The combined organic layers were dried, evapo-
rated to give a white solid, which was purified by chromato-
graphy on silica eluting with petrol/ethyl acetate (5:2) to
give (R)-2-{(R)-1-hydroxy-18-[(1R,2S)-2-((17R,18R)-17-
methoxy-18-methylhexatriacontyl)cyclopropyl]octadecyl}-
hexacosanoic acid (73) (32 mg, 67%), which showed an
identical spectrum to that above.
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We thank Prof. D. E. Minnikin (Univ. of Birmingham) for
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Supplementary data associated with this article can be found
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