An improved procedure for the preparation of the β-hydroxy-α- alkyl fatty acid fragment of mycolic acids

Article abstract of DOI:10.1016/j.tet.2006.01.070

An approach to a β-hydroxy-α-alkyl fatty acid intermediate that can be applied in the synthesis of a range of mycolic acids is described.

Full text of DOI:10.1016/j.tet.2006.01.070

Tetrahedron 62 (2006) 3221–3227
An improved procedure for the preparation of the
b-hydroxy-a-alkyl fatty acid fragment of mycolic acids
†
Gianna Toschi and Mark S. Baird
*
Department of Chemistry, University of Wales, Bangor, Gwynedd LL 57 2 UW, UK
Received 25 November 2005; revised 29 December 2005; accepted 19 January 2006
Abstract—Anapproachtoab-hydroxy-a-alkylfattyacidintermediatethatcanbeappliedinthesynthesisofarangeofmycolicacidsisdescribed.
q 2006 Elsevier Ltd. All rights reserved.
1. Introduction
The presence of the hydroxyl group and the relative
configuration between it and the alkyl chain has 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 Minnikin first proposed that, for the same
reasons, the mycolic motif allows the formation of a closely
packed structure among the mycolic acids in the cell wall of
mycobacteria.1,2 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 This motif is therefore critical in defining
some physical and biological properties of these particular
fatty acids.
Mycolic acids (1) (Scheme 1), are major constituents of the
cell envelope of Mycobacterium tuberculosis and other
mycobacteria, some of which are pathogenic to animals and
humans.1,2 Their presence is thought to be linked to the
characteristic resistance of these organisms to most current
antibiotics and other chemotherapeutic agents.3 In every
mycolic acid two moieties can be distinguished: the
meromycolate and the mycolic motif. The structure of the
mycolic motif is common to each mycobacterial mycolic acid,
except for minor variations in the length of the chain in the
a-position (d). The meromycolate moiety, however, is much
more variable.4,5
OH
O
Mycolic acid
1
[X]
[Y]
While different methods for the synthesis of single enantio-
mers of corynomycolic acids (2) have been proposed,15–20 the
preparation of the functionalised analogue (3) has only
recently been reported (Scheme 2).21 The potential of this
compound in the preparation of enantiomerically pure
mycolic acids (1) has also been illustrated. 21 However, the
C-24 chain of (3) is not readily available in large quantities
and had first to be prepared by coupling two smaller units.
α
[X] = Distal position
[Y] = Proximal position
OH
β
a
c
b
d
Meromycolate
moiety
Mycolic
motif
Scheme 1.
The two stereocentres in the a and b-positions relative to the
carboxylic group have both been found to be in the
R-configuration for all the mycolic acids examined,
irrespective of the other functional groups contained in the
meromycolate moiety.6–10
2. Results and discussion
This paper proposes a new method for the synthesis of an
alternative intermediate (11) for the preparation of any
mycolic acid (Scheme 4) which allows any alkyl chain or
labelled alkyl chain to be introduces at the b-position.
Keywords: Mycolic acid synthesis.
*
Corresponding author. Tel.: C44 1248382374; fax: C44 1248370528;
e-mail: chs028@bangor.ac.uk
The b-hydroxy ester (10) was prepared following a similar
method to that described for the preparation of R-a-lipoic
acid (Scheme 3).22 The E-a,b-unsaturated ester (7),
† Current address: Department of Biochemistry, University of Pretoria,
South Africa
0040–4020/$ - see front matter q 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.01.070

3222
G. Toschi, M. S. Baird / Tetrahedron 62 (2006) 3221–3227
OH
R
LDA (2.5 mol
THF,
.
equiv.),
PvO
OH
OH
CO2Me
R
PvO
CO2Me
CO2Me
CH2=CHCH2I
14
9
9
(1.5 mol
.
equiv.), HMPA
10
2
13
11
(2 mol.equiv.),
THF (62%)
OProtected
CO2Me
O
S
TBDMSCl (1.4 mol
.
equiv.)
OHC
R
Imidazole (2.5 mol.equiv.),
DMF (84%)
[X]
a
[Y]
R
+
n
BT
c
b
O
4
23
3
(i) Base
(ii) Hydrogenation
TBDMSO
TBDMSO
OsO4 (4 mol.%),
OProtected
CO2Me
2,6-lutidine
PvO
CO2Me
PvO
CO2Me
N
S
(2 mol.equiv.),
9
9
R
BT
=
[X]
[Y]
R
O
a
c
b
NaIO4 (2.5 mol.equiv.)
dioxane, H2O (92%)
1
12
23
13
Scheme 2.
Scheme 4.
1-PvCl (1.1 mol.equiv.),
Et N (3 mol.equiv.),
3
After having protected the secondary alcohol (11), an
OsO4–NaIO4 oxidation transformed the alkene (12) into the
corresponding aldehyde (13). The reaction was carried out
in the presence of 2,6-lutidine, since it has been reported
that this base suppresses side reactions, improving the
cleavage of the olefin.28 A Julia reaction with the 1H-
tetrazole (15) (Scheme 5), followed by reduction of the
unsaturated intermediate (16), allowed the formation of the
desired long chain at the b-position.29 Finally, deprotection
of the terminal alcohol in the diol (17) and its oxidation gave
the required compound (3).
HO
OH
PvO
OH
THF, CH Cl
2
2
10
10
2-KOH (2 mol.equiv.),
5
6
MeOH, H O (59%)
2
1-PCC (2 mol.equiv.),
CH Cl
2
2
2-Ph P=CHCO Me
(1.1 mol.equiv.),
toluene (72%)
3
2
(DHQD) PHAL (1 mol.%),
2
HO
CO2Me
OH
CO2Me
K Fe(CN) (3 mol.equiv.)
3
6
K CO (3 mol.equiv.),
PvO
9
2
3
PvO
9
7
OsO (4 mol.%),
4
8
MeSO NH (1 mol.equiv.),
2
2
1- 1-Phenyl-1H-tetrazole-5-thiol
(1.05 mol.equiv.), K2CO3
(1.5 mol.equiv.), acetone
t
BuOH, H O (97%)
2
1-SOCl , (2 mol.equiv.), CCl
2
4
2-NaIO (1.5 mol.equiv.),
4
CH3(CH2)21
PT
CH3(CH2)21Br
RuCl . H O, (5 mol.%)
3
2
S
2- H2O2 , (47 mol.equiv.),
(NH4)6Mo7O24 . 4H2O
(5.5 mol.%.),
.
O2
in CCl , CH CN H O (93%)
4
14
15
3
2
N
N
PT =
O
CO2Me
1-NaBH (1 mol.equiv.),
4
HO
CO2Me
N
N
THF, IMS (89%)
O
S
N,N-dimethylacetamide
Ph
PvO
O
2-H SO , ether (55%)
2
4
10
PvO
9
9
O
9
TBDMSO
PvO
LiN(Si(Me)3)2 (1.5 mol.equiv.), THF
Scheme 3.
CO2Me
13
9
CH3(CH2)21
PT
prepared from the diol (5), was transformed into the diol (8)
using a Sharpless dihydroxylation.23 The diol was then
converted into the cyclic sulfate (9) via cyclic sulfite.24 The
sulfate (9) was regioselectively reduced and hydrolysed to
give the (3R)-3-hydroxy ester (10).
S
O2
(15, 1.3 mol.equiv.) (85%)
16
20
H2, Pt /C,
CH3CO2Et,
IMS (95%)
¨
Subsequently, a Frater alkylation with allyl iodide introduced
TBDMSO
TBDMSO
PvO
an allyl chain at the a-position to give (2R,3R)-2-allyl-3-
hydroxy ester (11) (Scheme 4).25,26 The use of such a reactive
electrophile resulted in a much more reliable reactionthan that
previously described,21 which used a very long chain alkyl
iodide. It also gave twice the best yield achieved with a long
chain.21 Nonetheless, it was still very sensitive to the precise
conditions and sometimes produced a minor isomer appa-
rently derived by allylation on oxygen.27
1-KOH, THF,
MeOH, H2O
OHC
CO2Me
CO2Me
8
9
2- PCC,
CH2Cl2 (86%)
23
23
3
17
Scheme 5.

G. Toschi, M. S. Baird / Tetrahedron 62 (2006) 3221–3227
3223
Through NMR comparison of compound (3) with the anti-
and syn-corynomycolate derivatives (18 and 19), prepared
as described by Datta et al.,30 it was possible to show that
the a-alkyl-b-hydroxy groups were still in anti-configu-
ration to each other (Table 1). Thus, the use of different
bases in the process for the elongation of the a-branch did
not produce epimerisation at the a-position via enol-
formation, as has been described when other basic
conditions were employed.12,31
spectrometer. NMR spectra were recorded on a Bruker
Advance 500 spectrometer as solutions in deuterated
chloroform (CDCl3) if not differently indicated. Chemical
shifts are quoted in d relative to chloroform (d 7.27 ppm),
and CDCl3 (d 77.0 ppm). Mass spectra were obtained using
a Bruker MicroTOF time of flight mass spectrometer with
ESI source. The accurate mass of compound (3) was
obtained using a Bruker APEX IV FT ICR mass
spectrometer with a 4.7 T magnet with ESI source.
3.1.1. 2,2-Dimethylpropionic acid 10-hydroxydecyl ester.
Trimethylacetyl chloride (13.2 g, 110 mmol) was added to a
solution of 1,10-decanediol (5, 17.4 g, 100 mmol) and
triethylamine (30 g, 300 mmol) in dry THF (300 ml) and
CH2Cl2 (400 ml) at 5 8C. The mixture was monitored by
TLC and quenched with dil HCl (2 N, 200 ml) after 3 h. The
product was extracted with dichloromethane (3!500 ml)
and the combined organic layers were washed with water
(100 ml), dried and the solvent evaporated. The product was
then purified by chromatography eluting with petrol–ether
(1/1) to give 2,2-dimethylpropionic acid 10-hydroxydecyl
ester (6, 12.6 g, 49%), which has been partly described,32
which showed dH: 4.01 (2H, t, JZ6.6 Hz, CH2OCO), 3.60
(2H, br t, JZ6.6 Hz, CH2OH), 2.2–2.0 (1H, m, OH), 1.7–
1.6 (2H, m), 1.6–1.5 (2H, m), 1.4–1.2 (13H, m), 1.16 (9H, s
(CH3)3); dC: 178.63 (C]O), 64.39 (CH2OC]O), 62.80
(CH2OH), 38.65 (C(CH3)3), 29.19 (CH2), 28.96 (CH2),
28.52 (CH2), 27.24 (CH2), 27.12 (C(CH3)3), 26.97 (CH2);
nmax/cmK1: 3393, 2929, 1732, 1458, 1285, 1158, 1056
(Found (MCH)C: 259.2258; C15H31O3 requires:
259.2268). The diprotected compound, 2,2-dimethylpro-
pionic acid 10-(2,2-dimethylpropionyloxy)decyl ester (20,
6 g, 18%) was also obtained as an oil, which showed dH:
4.00 (4H, t, JZ6.7 Hz, CH2OCO), 1.7–1.5 (4H, m), 1.4–1.2
(12H, m), 1.14 (18H, s (CH3)3); dC: 178.50 (C]O), 64.33
(CH2OC]O), 38.65 (C(CH3)3), 29.19 (CH2), 28.96 (CH2),
28.52 (CH2), 27.24 (CH2), 27.12 (C(CH3)3), 26.97 (CH2);
nmax/cmK1: 2930, 1730, 1480, 1284, 1155 (Found (MC
H)C: 343.2844; C20H39O4 requires: 343.2843). This was
added to a solution of KOH (1.9 g, 34 mmol) in methanol
(100 ml) and water (5 ml). The mixture was refluxed for
1.5 h, monitoring by TLC, then evaporated. The residue was
dissolved in water (50 ml) and extracted with dichloro-
methane (3!75 ml). The combined organic layers were
dried and evaporated to give the crude product; chroma-
tography eluting with 1:1 petrol and ether gave 2,2-
dimethylpropionic acid 10-hydroxydecyl ester (6, 2.5 g,
57%) which showed the same NMR spectra as those above.
Combining the two reactions, gave (6) (59%).
Table 1.
syn-Diastereoisomers
anti-Diastereoisomers
TBDMSO
O
TBDMSO
O
TBDMSO
O
β
O
γ
γ
α
β
α
γ
β
β
O
O
7
O
13
13
3
H
±, 18
13
±, 19
13
23
Atom
b-Hydroxy-a-alkyl
acid (3) (ppm)
anti-Diastereoi- syn-Diasteroi-
somer (18) (ppm) somer (19) (ppm)
C]O
Ca
Cb
Cg
Ha
175.0
51.6
73.2
33.7
175.1
51.6
73.2
33.7
175.2
51.5
73.4
34.8
2.53
(ddd, JZ10.9,
7.0, 3.8 Hz)
2.53 (ddd, JZ10. 2.48
7, 7.0, 3.8 Hz) (dt, JZ9.8, 5.
7 Hz)
This method was based on the formation of alkene (12),
which was obtained with a good yield and could be readily
transformed into any desired a-alkyl-b-hydroxy ester.
Through formation of aldehydes (13) and (3) and their
subsequent coupling with heterocyclic sulfones, every
a-branch or meromycolate chain, including labelled
compounds, can easily be introduced at different points of
the synthesis. Therefore, this method could be used for the
production not only of any natural mycolic acid as a single
enantiomer, but also of intermediates useful for studies of
the biosynthesis of these fatty acids.
3. Experimental
3.1. General
All chemicals were purchased from Aldrich Chemical Co.
Ltd, Lancaster Synthesis Ltd, or Avocado Chemical Co.
Ltd. THF was distilled over sodium and benzophenone
under nitrogen, while dichloromethane was distilled over
calcium hydride. Petrol refers to the fraction bp 40–60 8C.
Organic solutions were dried over anhydrous magnesium
sulfate and solvents were removed at 14 mmHg; residual
traces of solvent were finally removed at 0.1 mmHg. All
glassware used in anhydrous reactions was dried for not less
than 5 h in a 250 8C oven.
3.1.2. (E)-12-(2,2-Dimethylpropionyloxy)dodec-2-enoic
acid methyl ester (7). The alcohol (6, 15 g, 58 mmol) in
dichloromethane (40 ml) was added to PCC (25 g,
116 mmol) in dichloromethane (800 ml) and vigorously
stirred for 2 h when TLC showed no starting material, then
quenched by diluting with ether (500 ml) and filtered on a
pad of Celite and silica. Evaporation and chromatography
using petrol and ether (10:1) to give 2,2-dimethylpropionic
acid 10-oxodecyl ester (21, 12.4 g, 84%) as an oil, dH: 9.73
(1H, br t, JZ1.6 Hz, CHO), 4.04 (2H, t, JZ6.4 Hz,
CH2OCO), 2.39 (2H, br td, J1Z1.6 Hz, J2Zca. 7.3 Hz,
CH2CHO), 1.59 (2H, m), 1.4–1.2 (12H, m), 1.16 (9H, s
(CH3)3); dC: 202.67 (CH]O), 178.52 (C]O), 64.31
Column chromatography was conducted under medium
pressure using silica gel (BDH, particle size 33–70 mm);
TLC was carried out on pre-coated Kieselgel 60 F254 (Art.
5554; Merck) plates. Optical rotations were measured as
solutions in chloroform of known concentration using a
Polar 2001 automatic polarimeter. Infra-red spectra were
recorded as KBr discs (solids) or thin films on NaCl
windows or using a Perkin Elmer 1600 series FT-IR

3224
G. Toschi, M. S. Baird / Tetrahedron 62 (2006) 3221–3227
(CH2OCO), 43.80 (CH2CH]O), 38.65 (C(CH3)3), 29.19
(CH2), 29.17 (CH2), 29.03 (CH2), 28.52 (CH2), 27.24
was dissolved in CCl4 (20 ml). Thionyl chloride (2.0 ml,
27.4 mmol) was added and the mixture was vigorously
refluxed for 2 h. After cooling, the solution was diluted with
CH3CN (20 ml) and ruthenium trichloride hydrate (150 mg,
0.72 mmol) and NaIO4 (4.7 g, 21.7 mmol) were added
followed by water (30 ml). The mixture was stirred at room
temperature for 1 h then diluted with ether (400 ml). The
water layer was extracted with ether (2!50 ml). The
combined organic layers were washed with water (30 ml),
satd aq sodium bicarbonate (30 ml) and brine (30 ml) and
dried. Evaporation and chromatography (7:3 petrol and
ether) gave (4S,5R)-5-[9-(2,2-dimethylpropionyloxy)no-
nyl]-2,2-dioxo-2l6-[1,3,2]-dioxathiolane-4-carboxylic acid
methyl ester (9, 5.5 g, 93%) as an oil; dH: 5.0–4.8 (2H, m,
CHOSO2OCH, including br d, 4.88, JZ7.2 Hz), 4.02 (2H, t,
JZ6.6 Hz, CH2OCO), 3.87 (3H, s, OCH3), 2.0–1.9 (2H, m),
1.65–1.4 (4H, m), 1.4–1.2 (10H, m), 1.17 (9H, s, (CH3)3);
dC: 178.51 (C]O), 165.25 (C]O), 84.05 (CHOCO), 79.76
(CHOCO), 64.25 (CH2OCO), 53.57 (OCH3), 38.61
(C(CH3)3), 32.84 (CH2), 29.14 (CH2), 29.01 (CH2), 28.98
(CH2), 28.69 (CH2), 28.46 (CH2), 27.09 (C(CH3)3), 25.73
(CH2), 24.66 (CH2); nmax/cmK1: 2932, 2858, 1775, 1725,
1399, 1287, 1211, 1160, 1034; [a]1D9C33.7 (c 1.3, CHCl3)
(Found (MCH)C: 409.1889; C18H33O8S requires:
409.1891).
(CH2), 27.12 (C(CH3)3), 25.78 (CH2), 21.97 (CH2); nmax
cmK1: 2928, 1728, 1458, 1285, 1155.
/
The aldehyde (21, 12.2 g, 48 mmol) was dissolved in
toluene (20 ml) and then added to a suspension of
(methoxycarbonylmethylene)triphenylphosphorane (18 g,
54 mmol) in toluene (100 ml). The mixture was stirred
overnight, then the solvent was evaporated to give a white
solid. This was refluxed for 1 h with petrol and ether (1:1,
300 ml) then filtered and the precipitate washed with the
same solution (150 ml). The combined organic layers were
dried and evaporated. Chromatography eluting with petrol
and ether (10:1) gave (E)-12-(2,2-dimethylpropionyloxy)-
dodec-2-enoic acid methyl ester (7, 12.8 g, 86%) as a pale
yellow oil, which showed dH: 6.97 (1H, dt, J1Z15.5 Hz,
J2Z6.9 Hz, CH]CHCO2Me), 5.81 (1H, d, JZ15.5 Hz,
CH]CHCO2Me), 4.04 (2H, t, JZ6.6 Hz, CH2OCO), 3.72
(3H, s, OCH3), 2.25–2.15 (2H, m), 1.7–1.6 (2H, m), 1.5–1.4
(2H, m), 1.4–1.2 (10H, m), 1.19 (9H, s (CH3)3); dC: 178.61
(C]O), 167.16 (C]O), 149.71 (CH]CHCO2Me), 120.83
(CH]CHCO2Me), 64.39 (CH2OCO), 51.33 (OCH3), 38.70
(C(CH3)3), 32.16 (CH2), 29.34 (CH2), 29.25 (CH2), 29.14
(CH2), 29.05 (CH2), 28.58 (CH2), 27.97 (CH2), 27.18
(C(CH3)3), 25.86 (CH2); nmax/cmK1: 2928, 2856, 1728,
1658, 1284, 1157 (Found (MCH)C: 313.2369; C18H33O4
requires: 313.2373).
3.1.5. (R)-12-(2,2-Dimethylpropionyloxy)-3-hydroxy-
dodecanoic acid methyl ester (10). The cyclic sulfate (9,
2.04 g, 5 mmol) was dissolved in N,N-dimethylacetamide
(25 ml) and NaBH4 (190 mg, 5 mmol) was slowly added at
0 8C, stirred at 25 8C for 1 h, then concentrated by
distillation under high vacuum. Ether (25 ml) and 10% aq
H2SO4 (25 ml) were slowly added to the residue and stirred
vigorously for 8 h. The water layer was extracted with ether
(4!75 ml). The combined organic layers were washed
with water and brine, dried and concentrated. Chromato-
graphy (7:3 petrol and ether) gave (R)-12-(2,2-dimethyl-
propionyloxy)-3-hydroxydodecanoic acid methyl ester (10,
900 mg, 55%) as an oil; dH: 4.00 (2H, t, JZ6.7 Hz,
CH2OCO), 3.96 (1H, m, CHOH), 3.67 (3H, s, COOCH3),
3.1–2.9 (1H, br s, OH), 2.47 (1H, dd, J1Z16.1 Hz, J2Z
3.2 Hz, COCH2CHOH), 2.38 (1H, dd, J1Z16.1 Hz, J2Z
9.1 Hz, COCH2CHOH), 1.65–1.55 (2H, m), 1.55–1.35 (3H,
m), 1.4–1.2 (11H, m) 1.15 (9H, s, (CH3)3); dC: 178.58
(C]O), 173.36 (C]O), 67.92 (CHOH), 64.36 (CH2OCO),
51.62 (OCH3), 41.10 (CHOHCH2CO), 38.63 (C(CH3)3),
36.46 (CH2), 30.22 (CH2), 29.37 (CH2), 29.35 (CH2), 29.32
(CH2), 29.09 (CH2), 28.50 (CH2), 27.11 (C(CH3)3), 25.79
(CH2), 25.36 (CH2); nmax/cmK1: 3509, 2930, 2856, 1729,
1725, 1286, 1160; [a]1D9 K11.6 (c 1.1 in CHCl3) (lit. [a]2D0
K13.8 (c 1.48 in CHCl3) for (R)-3-hydroxyhexadecanoic
acid methyl ester)34 (Found (MCH)C: 331.2472;
C18H35O5 requires: 331.2479).
3.1.3. (2S,3R)-12-(2,2-Dimethylpropionyloxy)-2,3-di-
hydroxydodecanoic acid methyl ester (8). The
(DHQD)2PHAL ligand (313 mg, 0.4 mmol), K3Fe(CN)6
(39.6 g, 120 mmol), K2CO3 (16.8 g, 120 mmol) and a
solution 2.5% of OsO4 in tert-butanol (2.0 ml, 1.6 mmol)
were dissolved in 1:1 water and tert-butanol (380 ml) at
room temperature. MeSO2NH2 (3.8 g, 40 mmol) was added
and the mixture, vigorously stirred, was cooled to 2.5 8C
when the alkene (7, 12.5 g, 40 mmol) was added. The
reaction was maintained at this temperature and monitored
by TLC. After 8 h, it was worked up by addition of sodium
sulfite (60 g, 48 mmol), then warmed to room temperature
for 45 min and extracted with dichloromethane
(3!500 ml); the organic layers were washed with 2 N
KOH (100 ml), dried and concentrated to give an oil.
Chromatography using 7:3 petrol and ether gave (2S,3R)-
12-(2,2-dimethylpropionyloxy)-2,3-dihydroxydodecanoic
acid methyl ester (8, 13.4 g, 97%) as an oil; dH: 4.10 (1H,
dd, J1Z5.3 Hz, J2Z1.9 Hz, CHOH), 4.04 (2H, t, JZ
6.6 Hz, CH2OCO), 3.95–3.85 (1H, m, CHOH), 3.83 (3H, s,
OCH3), 3.3–3.2 (1H, br s, OH), 2.1–2.0 (1H, br s, OH),
1.6–1.5 (4H, m), 1.5–1.2 (12H, m), 1.12 (9H, s (CH3)3); dC:
178.67 (C]O), 174.07 (C]O), 73.07 (CHOH), 72.45
(CHOH), 64.42 (CH2OCO), 52.78 (OCH3), 38.71
(C(CH3)3), 33.71 (CH2), 29.38 (CH2), 29.14 (CH2),
28.57 (CH2), 27.18 (C(CH3)3), 25.85 (CH2), 25.65 (CH2);
nmax/cmK1: 3493, 2932, 2858, 1728, 1285, 1157; [a]1D9
C11.5 (c 1.0, CHCl3), (lit. [a]2D4 C11.4 (c 0.57, CHCl3) for
(2S,3R)-2,3-dihydroxydecanoic acid ethyl ester)33 (Found
(MCH)C: 347.2425; C18H35O6 requires: 347.2428).
3.1.6. (2R,3R)-2-Allyl-12-(2,2-dimethylpropionyloxy)-3-
hydroxydodecanoic acid methyl ester (11). The ester
(10, 330 mg, 1 mmol) in THF (5 ml) was added to a stirred
solution of LDA (2.3 ml, 2.5 mmol, 1.1 M in hexanes) in
THF (5 ml) at K55 8C. The temperature was slowly
increased to K15 8C for 3.5 h, then reduced to K25 8C
and 1-iodopropene (252 mg; 1.5 mmol) and HMPA
(360 mg; 2 mmol) in THF (6 ml) was added dropwise at
below K20 8 C, stirred at room temperature for 18 h, then
3.1.4. (4S,5R)-5-[9-(2,2-Dimethylpropionyloxy)nonyl]-
2,2-dioxo-2l6-[1,3,2]dioxathiolane-4-carboxylic acid
methyl ester (9). The dihydroxy ester (8, 5 g, 14.4 mmol)

G. Toschi, M. S. Baird / Tetrahedron 62 (2006) 3221–3227
3225
quenched with satd aq ammonium chloride (10 ml) and
extracted with dichloromethane (3!25 ml). The combined
organic layers were washed with water (10 ml), dried and
evaporated. Chromatography (9:1 petrol and ethyl acetate)
gave (2R,3R)-2-allyl-12-(2,2-dimethylpropionyloxy)-3-
hydroxydodecanoic acid methyl ester (11, 230 mg; 62%)27
as an oil, which showed dH: 5.72 (1H, m, CH]CH2), 5.05
(2H, m, CH]CH2), 4.03 (2H, t, JZ6.6 Hz, CH2OCO), 3.69
(4H, m, including s for COOCH3), 2.6–2.5 (2H, m), 2.5–2.4
(2H, m), 1.4–1.2 (16H, m) 1.18 (9H, s, (CH3)3); dC: 178.44
(C]O), 175.10 (C]O), 134.85 (CH2]CH), 116.93
(CH2]CH), 71.61 (CHOH), 64.28 (CH2OCO), 51.36
(OCH3), 50.59 (CHOHCHCO), 38.58 (C(CH3)3), 35.32
(CH2), 33.56 (CH2), 29.34 (CH2), 29.31 (CH2), 29.28
(CH2), 29.05 (CH2), 28.47 (CH2), 27.07 (C(CH3)3), 25.76
(CH2), 25.56 (CH2); nmax/cmK1: 3518, 2929, 2855, 1728,
1642, 1285, 1162; [a]1D9 C3.1 (c 1.1 in CHCl3) (lit. [a]1D9
K11.5 (c 3.3 in CHCl3) for (2S,3S)-2-allyl-3-hydroxypen-
tanedioic acid dimethyl ester)35 (Found (MCK)C:
409.2368; C21H38KO5 requires: 409.2351).
mp 70–72 8C, which showed dH: 7.55–7.45 (5H, m,
aromatic), 3.40 (2H, t, JZ7.2 Hz, CH2S), 1.82 (2H, m),
1.6 (4H, m), 1.45 (2H, m), 1.35–1.25 (32H, br m), 0.89 (3H,
t, JZ6.6 Hz, CH3); dC: 154.33 (C]N heterocyclic), 133.79
(C–N aromatic), 130.05 (CH aromatic), 129.75 (CH
aromatic), 123.87 (CH aromatic), 33.40 (CH2S), 31.92
(CH2), 29.69 (CH2), 29.65 (CH2), 29.61 (CH2), 29.54
(CH2), 29.43 (CH2), 29.35 (CH2), 29.08 (CH2), 29.02
(CH2), 28.64 (CH2), 22.68 (CH2), 14.10 (CH3); nmax/cmK1
;
3017, 2925, 2853, 1598, 1500 (Found (MCH)C: 487.3837;
C29H51N4SC requires: 487.3829).
3.1.9. 5-(Docosane-1-sulfonyl)-1-phenyl-1H-tetrazole
(15). Ammonium molybdate tetrahydrate (8 g, 0.70 mmol)
was dissolved in stages in aq H2O2 (31 ml, 300 mmol, 35%
w/w) and added slowly the sulfide (22, 6.2 g, 12.7 mmol) in
IMS and THF (3:5, 400 ml). After stirring at room
temperature for 2 h, ammonium molybdate tetrahydrate
(8 g, 0.70 mmol) in aq H2O2 (31 ml, 300 mmol, 35% w/w)
was added and stirred overnight. After partial concentration,
the reaction was quenched with water (150 ml) and
extracted with dichloromethane (3!150 ml). The com-
bined organic layers were dried and evaporated. Chromato-
graphy eluting with 8:1 petrol and ether gave 5-(docosane-
1-sulfonyl)-1-phenyl-1H-tetrazole (15, 6.1 g, 93%) as a
colourless solid, mp 56–59 8C, which showed dH: 7.70 (2H,
m, aromatic), 7.61 (3H, m, aromatic), 3.72 (2H, m, CH2S),
1.95 (2H, m, CH2CH2S), 1.50 (2H, m), 1.4–1.2 (36H, m),
0.89 (3H, t, JZ7.2 Hz, CH3); dC: 153.50 (C]N hetero-
cyclic), 133.06 (C–N aromatic), 131.39 (CH aromatic),
129.67 (CH aromatic), 125.06 (CH aromatic), 56.01
(CH2S), 31.90 (CH2), 29.68 (CH2), 29.64 (CH2), 29.61
(CH2), 29.54 (CH2), 29.44 (CH2), 29.33 (CH2), 29.17
(CH2), 28.87 (CH2), 28.12 (CH2), 22.667 (CH2), 21.91
(CH2), 14.08 (CH3); nmax/cmK1: 3018, 2926, 2854, 1498,
1342, 1152 (Found (MCH)C: 519.3706; C29H51N4O2S
requires: 519.3727).
3.1.7. (2R,3R)-2-Allyl-3-(tert-butyldimethylsilanyloxy)-
12-(2,2-dimethylpropionyloxy)dodecanoic acid methyl
ester (12). Imidazole (465 mg, 6.8 mmol) was added to
the alcohol (11, 1 g; 2.7 mmol) in dry DMF (9 ml), followed
by tert-butyldimethylsilylchloride (530 mg, 3.5 mmol),
then stirred at 40 8C overnight, when TLC showed no
starting material. After concentrating, water was added and
the product was extracted with dichloromethane (3!
50 ml). The combined organic layers were washed with
water (2!15 ml), dried and evaporated. Chromatography
eluting with 9:1 petrol and ether gave (2R,3R)-2-allyl-3-
(tert-butyldimethylsilanyloxy)-12-(2,2-dimethylpropiony-
loxy)dodecanoic acid methyl ester (12, 1.1 g, 84%) as an
oil; dH: 5.72 (1H, ddt, J1Z17.0 Hz, J2Z10.0 Hz, J3Z
7.0 Hz, CH]CH2), 5.03 (1H, dd, J1Z17.0 Hz, J2Z1.6 Hz,
CH]CH2), 4.98 (1H, m, CH]CH2), 4.04 (2H, t, JZ
6.6 Hz, CH2OCO), 3.93 (1H, m, CHOSi), 3.65 (3H, s,
COOCH3), 2.61 (1H, m, CHOHCHCO), 2.37 (2H, m,
CH2CH]CH2), 1.7–1.2 (16H, m), 1.19 (9H, s, (COCH3)3),
0.87 (9H, s, (CCH3)3), 0.05 (3H, s, SiCH3), 0.03 (3H, s,
SiCH3); dC: 178.60 (C]O), 175.02 (C]O), 135.95
(CH2]CH), 116.29 (CH2]CH), 72.78 (CHOSi), 64.40
(CH2OCO), 51.35 (CHCO), 51.26 (OCH3), 38.71
(C(CH3)3), 33.64 (CH2), 31.57 (CH2), 29.70 (CH2), 29.43
(CH2), 29.41 (CH2), 29.18 (CH2), 28.61 (CH2), 27.19
(C(CH3)3), 25.81 (C(CH3)3), 25.73 (CH2), 25.68 (CH2),
24.13 (CH2), 17.97 (SiC(CH3)3), K4.41 (SiCH3), K4.90
(SiCH3); nmax/cmK1: 3078, 2929, 2856, 1731, 1642, 1156;
[a]2D0 K13.3 (c 1.3 in CHCl3) (Found (MCK)C: 523.3229;
C27H52KO5Si requires: 523.3216).
3.1.10. (R)-2-[(R)-1-(tert-Butyldimethylsilanyloxy)-10-
(2,2-dimethylpropionyloxy)decyl]-hexacos-4-enoic acid
methyl ester (16). To a solution of alkene (12, 150 mg,
0.3 mmol) in dioxane–water (3/1, 8 ml) were added 2,6-
lutidine (66 mg, 0.6 mmol), OsO4 (2.5% in 2-methyl-2-
propanol, 62 mg, 75 ml, 0.006 mmol), and NaIO4 (260 mg,
1.2 mmol). After 2 h stirring at 25 8C, the reaction was
complete by TLC; water (10 ml) and dichloromethane
(20 ml) were added. The water layer was extracted by
dichloromethane (3!10 ml). The combined organic layers
were washed with brine (10 ml), dried and concentrated.
Chromatography eluting with 9:1 ether/ petrol gave
(2R,3R)-3-(tert-butyldimethylsilanyloxy)-12-(2,2-dimethyl-
propionyloxy)-2-(2-oxoethyl)dodecanoic acid methyl ester
(13, 130 mg, 92%) as a colourless oil, which was immediately
used without complete characterization (dH: 9.79 (1H, m,
CH]O), 4.05–4.00 (3H, including 4.02, t, JZ6.7 Hz,
CH2OCO), 3.65 (3H, s, COOCH3), 3.18 (1H, dt, J1Z
10.4 Hz, J2Z3.7 Hz, CHCO), 2.94 (1H, dd, J1Z18 Hz, J2Z
10.4 Hz, CH2CH]O), 2.65 (1H, dd, J1Z18 Hz, J2Z3.4 Hz,
CH2CH]O), 1.7–1.2 (16H, m), 1.17 (9H, s, (COCH3)3), 0.85
(9H, s, (CCH3)3), 0.05 (3H, s, SiCH3), 0.04 (3H, s, SiCH3)).
3.1.8. 5-Docosylsulfanyl-1-phenyl-1H-tetrazole (22).
Potassium carbonate (3 g, 21.2 mmol) was added to a
solution of 1-bromodocosane (14, 5.5 g, 14.1 mmol) and
1-phenyl-1H-tetrazole-5-thiol (2.6 g, 14.8 mmol) in acetone
(500 ml). The mixture was vigorously stirred and refluxed at
60 8C overnight. The solvent was evaporated and the residue
was dissolved in water (300 ml) and extracted with
dichloromethane (3!300 ml). The combined organic layers
were dried and evaporated. Recrystallisation from acetone
(100 ml) and methanol (200 ml) gave 5-docosylsulfanyl-1-
phenyl-1H-tetrazole (22, 6.5 g, 96%) as a colourless solid,
Lithium bis(trimethylsilyl)amide (0.4 mmol, 0.4 ml, 1 M, in
hexanes) was added at K10 8C to a solution of the aldehyde

3226
G. Toschi, M. S. Baird / Tetrahedron 62 (2006) 3221–3227
(13, 130 mg, 0.28 mmol) and the sulfone (14, 180 mg,
0.36 mmol) in dry THF (10 ml) under nitrogen. The reaction
was stirred at room temperature for 24 h then quenched with
satd aq ammonium chloride (10 ml) and extracted with
dichloromethane (3!40 ml). The combined organic layers
were dried and concentrated. Chromatography eluting with
10:0.5 petrol and ether gave (E,Z)-(R)-2-[(R)-1-(tert-
butyldimethylsilanyloxy)-10-(2,2-dimethylpropionyloxy)-
decyl]hexacos-4-enoic acid methyl ester ((E)/(Z), 2.7:1)
(16, 185 mg, 85%) as an oil, which showed dH: 5.42 (1H, m,
CH]CH), 5.30 (1H, m, CH]CH), 4.04 (2H, t, JZ6.6 Hz,
CH2OCO), 3.92 (1H, m, CHOSi), 3.64 (3H, s, OCH3), 2.57
(1H, m, CHCO), 2.4–2.1 (2H, m), 2.1–1.9 (2H, m), 1.8–1.6
(2H, m), 1.8–1.3 (55H, m), 1.19 (9H, s, (COCH3)3), 0.87
(9H, s, (CCH3)3), 0.05 (3H, s, SiCH3), 0.03 (3H, s, SiCH3);
dC: 178.68 (C]O), 174.44 (C]O, Z), 174.37 (C]O, E),
132.80 (CH]CH, E), 131.92 (CH]CH, Z), 126.88
(CH]CH, E), 126.25 (CH]CH, Z), 72.96 (CHOSi, Z),
72.83 (CHOSi, E), 64.46 (CH2OCO), 51.85 (CHCO, E),
51.75 (CHCO, Z), 51.32 (OCH3, Z), 51.21 (OCH3, E), 38.74
(C(CH3)3), 33.69 (CH2), 32.55 (CH2), 31.94 (CH2), 30.71
(CH2), 29.72 (CH2), 29.67 (CH2), 29.55 (CH2), 29.51
(CH2), 29.50 (CH2), 29.47 (CH2), 29.38 (CH2), 29.23
(CH2), 29.12 (CH2), 27.22 (C(CH3)3), 25.91 (CH2), 25.75
(C(CH3)3), 23.92 (CH2), 22.69 (CH2), 17.98 (SiC(CH3)3),
MeOH and H2O (21 ml, 10:10:1). The mixture was refluxed
at 70 8C and monitored by TLC. After 4 h, TLC showed no
starting material and the reaction was quenched with water
and extracted with ethyl acetate (3!100 ml), dried and
concentrated. Chromatography eluting with 1:1 petrol and
ether gave (R)-2-[(R)-1-(tert-butyldimethylsilanyloxy)-10-
hydroxydecyl]hexacosanoic acid methyl ester (23, 170 mg,
94%) as an oil, which showed dH: 3.90 (1H, m, CHOSi),
3.66 (5H, m, HOCH2 and OCH3), 2.53 (1H, ddd, J1Z
10.7 Hz, J2Z7.0 Hz, J3Z3.8 Hz, CHCO), 1.6–1.2 (63H,
m), 0.88 (12H, m, CH3, and (CCH3)3), 0.05 (3H, s, SiCH3),
0.03 (3H, s, SiCH3); dC: 175.18 (C]O), 73.25 (CHOSi),
63.09 (CH2OH), 51.66 (CHCO), 51.18 (OCH3), 33.73
(CH2), 32.83 (CH2), 31.92 (CH2), 29.81 (CH2), 29.70
(CH2), 29.65 (CH2), 29.58 (CH2), 29.52 (CH2), 29.49
(CH2), 29.45 (CH2), 29.39 (CH2), 29.35 (CH2), 27.86
(CH2), 27.47 (CH2), 25.78 (C(CH3)3), 23.87 (CH2), 22.67
(CH2), 22.67 (CH2), 17.99 (SiC(CH3)3), 14.07 (CH3),
K4.37 (SiCH3), K4.90 (SiCH3). nmax/cmK1: 3358, 2923,
2859, 1738, 1465; [a]2D2 K4.0 (c 1.2 in CHCl3) (Found
(MCH)C: 697.6542; C43H89O4Si requires: 697.6525).
3.1.13. (R)-2-[(R)-1-(tert-Butyldimethylsilanyloxy)-10-
oxodecyl]hexacosanoic acid methyl ester (3). The alcohol
(23, 100 mg, 0.14 mmol) in dichloromethane (5 ml) was
added to PCC (80 mg, 0.36 mmol) in dichloromethane
(30 ml). The mixture was vigorously stirred for 2 h when
TLC showed no starting material, then diluted with ether
(50 ml) and filtered on a pad of Celite and silica. The solvent
was evaporated; chromatography (1:1 petrol/ether) gave
(R)-2-[(R)-1-(tert-butyldimethylsilanyloxy)-10-oxo-decyl]-
hexacosanoic acid methyl ester (3, 90 mg, 91%) as an oil,
dH: 9.77 (1H, t, JZ1.9 Hz, CHO), 3.9 (1H, m, CHOSi), 3.66
(3H, s, OCH3), 2.53 (1H, ddd, J1Z10.9 Hz, J2Z7.0 Hz,
J3Z3.8 Hz, CHCO), 2.39 (2H, br dt, J1Z7.5 Hz, J2Z
1.9 Hz, CH2CHO), 1.7–1.2 (60H, m), 0.88 (12H, m, CH3,
and (CCH3)3), 0.05 (3H, s, SiCH3), 0.03 (3H, s, SiCH3); dC:
202.64 (CH]O), 175.00 (C]O), 73.23 (CHOSi), 51.65
(CHCO), 51.17 (OCH3), 43.89 (CH2CH]O), 33.71 (CH2),
31.92 (CH2), 29.75 (CH2), 29.69 (CH2), 29.65 (CH2), 29.58
(CH2), 29.44 (CH2), 29.34 (CH2), 29.28 (CH2), 29.14
(CH2), 27.86 (CH2), 27.46 (CH2), 25.76 (C(CH3)3), 23.85
(CH2), 22.67 (CH2), 22.10 (CH2), 17.98 (SiC(CH3)3), 14.07
(CH3), K4.38 (SiCH3), K4.90 (SiCH3). nmax/cmK1: 2924,
2953, 2710, 1738, 1464; [a]2D5 K6.4 (c 1.4 in CHCl3)
(Found (MCH)C: 695.63651; C43H87O4Si requires:
695.63681).
14.11 (CH3), K4.38 (SiCH3), K4.91 (SiCH3); nmax/cmK1
:
2922, 2853, 1732, 1464, 1157; [a]2D0 K5.9 (c 1.1 in CHCl3)
(Found (MCK)C: 817.6502; C48H94KO5Si requires:
817.6502).
3.1.11. (R)-2-[(R)-1-(tert-Butyldimethylsilanyloxy)-10-
(2,2-dimethylpropionyloxy)-decyl]-hexacosanoic acid
methyl ester (17). The alkene (16, 550 mg, 0.7 mmol)
was dissolved IMS and ethyl acetate (1:3, 32 ml) then Pd on
C (10%, 100 mg) was added. The mixture was stirred under
hydrogen, until no more was absorbed, then diluted with
diethyl ether (150 ml) and filtered on a pad of Celite. The
filtrate was evaporated; chromatography eluting with petrol
and ether (9:1) gave (R)-2-[(R)-1-(tert-butyldimethyl-
silanyloxy)-10-(2,2-dimethylpropionyloxy)decyl]hexacosa-
noic acid methyl ester (17, 520 mg, 95%) as an oil, which
showed dH: 4.05 (2H, t, JZ6.6 Hz, CH2OCO), 3.90 (1H, m,
CHOSi), 3.66 (3H, s, OCH3), 2.53 (1H, ddd, J1Z11 Hz,
J2Z7.0 Hz, J3Z3.5 Hz, CHCO), 1.6–1.2 (62H, m), 1.21
(9H, s, (COCH3)3), 0.87 (12H, m, CH3, and (CCH3)3), 0.05
(3H, s, SiCH3), 0.03 (3H, s, SiCH3); dC: 178.64 (C]O),
174.10 (C]O), 73.20 (CHOSi), 64.44 (CH2OCO), 51.60
(CHCO), 51.21 (OCH3), 38.72 (C(CH3)3), 33.67 (CH2),
31.92 (CH2), 29.80 (CH2), 29.70 (CH2), 29.65 (CH2), 29.58
(CH2), 29.48 (CH2), 29.45 (CH2), 29.35 (CH2), 29.20
(CH2), 29.05 (CH2), 28.61 (CH2), 27.85 (CH2), 27.65
(CH2), 27.21 (C(CH3)3), 25.91 (CH2), 25.76 (C(CH3)3),
23.92 (CH2), 22.69 (CH2), 17.98 (SiC(CH3)3), 14.11 (CH3),
K4.38 (SiCH3), K4.93 (SiCH3); nmax/cmK1: 2923, 2852,
1732, 1458, 1155; [a]2D3 K4.7 (c 1.1 in CHCl3) (lit. [a]2D0
K35.1 (c 1.34 in CHCl3) for methyl (3R)-tert-butyl-
dimethylsilyloxy-(2R)-methylpentanoate)36 (Found (MC
K)C: 819.6649; C48H96KO5Si requires: 819.6659).
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3227
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