The synthesis of single enantiomers of trans-alkene-containing mycolic acids

Article abstract of DOI:10.1016/j.tetlet.2009.10.009

We report routes to single enantiomers of hydroxy and ketomycolic acids containing an α-methyl-trans-alkene unit.

Full text of DOI:10.1016/j.tetlet.2009.10.009

Tetrahedron Letters 50 (2009) 7259–7262
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
The synthesis of single enantiomers of trans-alkene-containing mycolic acids
*
Gani Koza, Richard Rowles, Cornelia Theunissen, Juma’a R. Al-Dulayymi, Mark S. Baird
School of Chemistry, Bangor University, Gwynedd LL57 2UW, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
We report routes to single enantiomers of hydroxy and ketomycolic acids containing an
alkene unit.
a-methyl-trans-
Received 26 August 2009
Revised 24 September 2009
Accepted 2 October 2009
Available online 8 October 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Mycolic acids (MAs) are characteristic components of the cell
envelopes of mycobacteria, often covalently bound to an arabino-
galactan polysaccharide.1 They are also seen as sugar esters such
as trehalose dimycolate (TDM—one of the most potent signalling
agents in the immune system) that are not bound to the cell wall
and there is increasing evidence for the presence of free mycolic
acids.2 MAs can be divided into two elements, the hydroxy-acid,
for which d is generally 21 or 23, and the meromycolate (Fig. 1).
The latter is a long chain which usually contains two groups X
and Y. In the most common classes of MA, the two groups are
cules containing a b-methyl-trans-alkene unit (Type 2 mycolic
acids)3,4 (Fig. 1). The methyl substituent in group Y of this unit is
proximal to the hydroxy-acid group of the MA. The methyl group
in the X position of keto- and methoxy-MAs and at the Y-position
in an
a-methyl-trans-cyclopropane-containing MA is distal from
it.3,4
Type 2 ketomycolic acids 1 with a variety of combinations of
chain lengths a, b and c have been reported (Table 1).3,4,7–9
An analogue, a derivative of a hydroxy-MA with a proximal a-
methyl-trans-alkene, has also been reported.10 The fast growing
Mycobacterium smegmatis synthesizes MAs containing epoxy-
groups as well as keto- and hydroxy-MAs. The keto-compounds
contain about 33% of a trans-alkene. The same percentage is seen
in the hydroxy-mycolate.7 Keto- and hydroxy-MA have been iso-
lated from Mycobacterium tuberculosis and Mycobacterium bovis
BCG; although these predominantly contain a cis-cyclopropane at
the proximal position, about 15% and 14%, respectively, have an al-
cis-cyclopropanes (a-MA), or group X is an a-methyl-b-methoxy
and -methyl-b-keto group (methoxy- and keto-MA, respectively).
a
MAs are generally present in mycobacteria as complex mixtures
containing several different chain lengths of each class, and the de-
tailed composition is dependent on the mycobacterium con-
cerned.3,4 The presence and proportion of individual classes of
MA is known to be important for the virulence of diseases such
as tuberculosis.5,6
kene at that position, predominantly an
The biosynthesis apparently involves conversion of a cis-alkene
a
-methyl-trans-alkene.9
In addition, there are a range of generally less abundant MAs
which contain other combinations of X and Y; these include mole-
into an
a-methyl-trans-alkene caused by MmaS1 and SAM. This
Type-3 mycolic acid
Type-1 mycolic acid
Type-2 mycolic acid
OH
O
Y
X
X
Y
X
Y
[X]
[Y]
Me
α
cis
cis
cis
β
cis
cis
)
OH
α−
(
α−
( )a
α−
( )b
or
or
c
or
or
or
or
or
or
OMe
OMe
trans
or
OMe
( )d
Hydroxy acid
cis
cis
( )
trans
n
Me
methoxy-
Me
methoxy-
Me
methoxy-
O
Me
Me
Meromycolate chain
or
O
O
or
( )
trans
a = 15, 17, 18, 19
b = 10, 14, 15, 16
c = 11, 15, 17, 19, 21
d = 21, 23
cis
trans
)
(
n
[X] = Distal group
[Y] = Proximal group
n
cis
cis
cis
Me
( )
Me
keto-
Me
keto-
Me
keto-
n
Figure 1. Common types of mycobacterial mycolic acid.
* Corresponding author.
E-mail address: m.baird@bangor.ac.uk (M.S. Baird).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.10.009

7260
G. Koza et al. / Tetrahedron Letters 50 (2009) 7259–7262
Me
Table 1
Me
O
S
N
Typical chain lengths of major b-methyl-trans-alkene-containing mycobacterial
ketomycolic acids (1)
N
O
CH2CHO
(CH2)13OCOBut
(i), (ii)
O
(CH2)15OCOBut
N
+
N
O
O
2
O
3
Ph
Me
OH
O
O
(iii), (iv)
CH3(CH2)a
(CH2)c
OH
(CH2)dCH3
Me
Me
(CH2)b
O
N
N
(v), (vi)
Me
O
(CH2)15
O
(CH2)15Br
S
N
N
O
O
4
O
5
Ph
Species
a
b
c
d
Ref.
3
Mycobacterium tuberculosis, Mycobacterium bovis,
M. bovis BCG, Mycobacterium microti
M. tuberculosis, M. bovis, M. bovis BCG, M. microti
M. tuberculosis canetti
Mycobacterium avium, complex (MAC)
Mycobacterium marinum
Mycobacterium scrofulaceum
Mycobacterium aurum
M. aurum
17 19 15 23
Scheme 1. Reagents: (i) LiHMDS, THF (86%); (ii) H2, Pd/C, EtOAc/EtOH (96%); (iii)
KOH, THF, MeOH, H2O (97%); (iv) N-bromosuccinimide, PPh3, NaHCO3, CH2Cl2
(92%); (v) 1-phenyl-1H-tetrazole-5-thiol, K2CO3, acetone (95%); (vi) H2O2,
(NH4)6Mo7O24ꢁ4H2O, THF/IMS (81%).
17 19 13 23
17 17 17 23
17 17 17 21
17 15 17 21
15 17 17 21
15 13 19 19
15 13 17 19
3
3
3
3
3
8
8
ButMe2Si
Me
O
O
O
S
N
N
O
O
(CH2)15
+
N
OMe
(CH2)21CH3
O
N
O
O
O
5
6
Ph
(i)-(iv)
OAc
is then cyclopropanated by the CmaA2 gene, again with SAM, to
give the
-methyl-trans-cyclopropane.11–15 Inactivation of CmaA2
Me
O
Me
OAc
O
(v)
a
(CH2)17
OMe
(CH2)21CH3
O
causes the accumulation of unsaturated derivatives in both meth-
oxy- and keto-MA and the lack of trans-cyclopropanes.16 It should
be noted, however, that there are alternative models for the crea-
tion of these functional groups.17 It is also interesting that the
(CH2)17
OMe
(CH2)21CH3
7
8
Scheme 2. Reagents: (i) LHMDS (86%); (ii) Pd/C, EtOAc (96%); (iii) HFꢁpyridine
labelling pattern of an
a-methyl-trans-cyclopropane-containing
keto-MA of M. tuberculosis derived from [1-13C]acetic acid places
(83%); (iv) Ac2O, pyridine (94%); (v) periodic acid (80%).
a labelled carbon at the cyclopropane carbon nearest to the methyl
group, while in an unsaturated
a2-MA from M. smegmatis, the label
The hydroxy-acid unit was introduced in the form of 6, pre-
pared as described earlier from l-aspartic acid.36 A further modified
Julia reaction between the aldehyde 6 and sulfone 5 gave a mixture
of alkenes which was hydrogenated. The silyl ether was changed to
acetyl to avoid the presence of two identical protecting groups at a
later stage to yield 7, and the acetal group was converted into alde-
hyde 8 with periodic acid (Scheme 2).
in the proximal -methyl-trans-alkene is on the carbon adjacent to
a
the methyl group – consistent with biochemical alkylation at
opposite ends of a cis-alkene.18 Another type of mycolic acid iso-
lated from M. smegmatis and Mycobacterium aurum,8 Mycobacte-
rium chelonei,19 and Mycobacterium fortuitum,20 contains an
a-
methyl-trans-alkene at the proximal position and a cis-alkene at
the distal position.21–23 Examples with a cis-cyclopropane or an
The alcohol 9,28 was protected as a TBDMS ether, the THP-group
was removed and the resulting alcohol was oxidized to the aldehyde
10 (Scheme 3). A Julia–Kocienski reaction between 10 and the sul-
fone 1137 gave an E/Z-alkene mixture which was hydrogenated to
give 12. This was converted into the sulfone 13. In the same way
the enantiomer of 9 was converted into the enantiomer 14.
a
-methyl-trans-oxirane at the distal position have also been re-
ported.3 In the former case the specific rotation of its methyl ester
has been reported to be +1.4 (CHCl3),24 while that of the acetoxy
methyl ester is reported as +3 (CHCl3), and that of a deacetoxy
derivative of a mycolate containing only an a-methyl-trans-alkene
chiral centre corresponds to a molecular rotation (MD) of ꢀ19.5.24
In addition, the specific rotation of a wax ester containing the
a-
ButMe2SiO
OH
methyl-trans-alkene unit has been reported to be +4.3
(CHCl3).8,25,26 This allows the contribution to the molecular rota-
(i)-(iii)
H3C(CH2)17
H3C(CH2)17
(CH2)7OTHP
(CH2)6CH=O
tion from the
a-methyl-trans-alkene unit to be calculated, as the
10
9
Me
Me
only other chiral centres in these molecules are at the hydroxy-
acid position, the contribution of which to the molecular rotation
O
N
N
N
N
ButCOO(H2C)9
11
S
(iv), (v)
is known (+40), leading to a value of ꢀ25 for the
a-methyl-trans-
O
ButMe2SiO
alkene (for 30% of methyl branched molecules); this in turn sug-
gests that this subunit has an (R)-stereochemistry based on model
compounds.9
ButMe2SiO
Ph
O
N
H3C(CH2)17
N
N
(CH2)16
H3C(CH2)17
S
(CH2)16OCOBut
13
(vi)-(ix)
N
Me
O
12
As part of a study to determine the biological significance of
individual MAs and particularly of their stereochemistry, we have
Me
Ph
ButMe2SiO
reported routes to a-, methoxy- and keto-MAs as single stereoiso-
mers, as well as to related wax esters.27–31 We now report the first
synthesis of type-2 hydroxy-MA 16 (R = R0 = H) and 18 and the re-
lated keto-MA (21).
O
N
N
H3C(CH2)17
N
(CH2)16
S
N
14
Me
O
In order to fix the (R)-stereochemistry of the b-methyl-trans-al-
kene fragment, aldehyde 2,32–34 was chain-extended using a mod-
ified Julia–Kocienski reaction,35 followed by hydrogenation of the
derived alkenes to give 3. The pivalate group was removed and
the primary alcohol was converted into sulfone 5 via bromide 4
(Scheme 1).
Ph
Scheme 3. Reagents: (i) TBDMSCl, imidazole, DMF (91%); (ii) PPTS, THF/ MeOH
(80%); (iii) PCC, CH2Cl2 (94%); (iv) LiHMDS, 11, THF (76%); (v) H2, Pd/C, THF/IMS
(70%); (vi) LiAlH4ꢁTHF (90%); (vii) N-bromosuccinimide, PPh3, CH2Cl2 (81%); (viii) 1-
phenyl-1H-tetrazole-5-thiol, K2CO3, acetone (99%); (ix) H2O2, (NH4)6Mo7O24ꢁ4H2O,
THF/IMS (85%).

G. Koza et al. / Tetrahedron Letters 50 (2009) 7259–7262
7261
ture,10,14 and to minor signals in fractions of
a-mycolates derived
Me
OAc
O
OSiMe2But
from M. tuberculosis.46
(i)
Oxidation of either 16 (R = Ac, R0 = Me) or 17 gave the corre-
sponding protected keto-MAs.47 However, attempted deprotection
of these using LiOH led to epimerization at the position adjacent to
the ketone. In order to avoid this, the alcohol 17 was first protected
as THP-ether 19, followed by hydrolysis of the esters and then
reprotection at the alcohol group as a silyl ether 20. Removal of
the THP-group, oxidation, and then deprotection now proceeded
without epimerization,48 leading to the free acid 21 (Scheme 5),
matching the major trans-alkene ketomycolate reported for M.
marinum.49
CH3(CH2)17
(CH2)17
OMe
13 + 8
(CH2)15
15
(CH2)21CH3
(ii),(iii)
Me
OH
Me
OR
O
CH3(CH2)17
(CH2)17
OR'
(CH2)15
16
(CH2)21CH3
Me
Scheme 4. Reagents: (i) KHMDS, 1,2-dimethoxyethane (44%); (ii) HFꢁpyridine, THF
[16 (R = Ac, R0 = Me), 91%]; (iii) LiOH, MeOH, THF, H2O [16 (R = H, R0 = H), 65%)].
These results provide the first synthetic approaches to both keto
and hydroxy-MAs containing a proximal (R)-a-methyl-trans-al-
kene unit, and a comparison of molecular rotations with those in
the literature confirmed the stereochemistry of this subunit. It
has been proposed that alkylation of a cis-alkene by SAM (S-aden-
osylmethionine) provides a common intermediate cation leading
to each of the other MA functionalities.50 Although the actual
mechanism may well be different, this does provide a model by
which to analyse the stereochemistry of the various classes of
MA. It is known that the stereochemistry at the distal groups in
methoxy-MA is (S,S);7,11 using 22 as a model for a MA precursor,
formal addition of a methyl cation to the distal carbon of the alkene
from the bottom face would produce cation 23; trapping could lead
to 24 and hence to the (S,S)-molecule 25 (Scheme 6).
The modified Julia–Kocienski reaction using a 1-phenyl-1H-tet-
razole sulfone and an aldehyde with potassium bis (trimethyl-
silyl)amide in 1,2-dimethoxyethane is known to lead to an E-
alkene with good stereoselectivity, especially if the sulfone or alde-
hyde is
a
-substituted.38–40 Reaction of the sulfone 13 with alde-
hyde 8 gave the trans-alkene 15 (Scheme 4). It is also clearly
essential that no epimerization occurs adjacent to the aldehyde
during this process. There is considerable precedent for the reten-
tion of the chirality.39,41–44 Removal of the silyl group gave 16
(R = Ac, R0 = Me) and hydrolysis of the two esters produced the free
hydroxy-acid 16 (R = H, R0 = H).45 The ½a D21
of this, ꢀ2.07 (CHCl3,
ꢂ
If the same species were involved at the proximal position, this
would be consistent with the stereochemistry proposed for the
0.743
l
mol), corresponding to MD ꢀ26, is in agreement with that
reported for the hydroxymycolates of M. smegmatis (MD ꢀ16,
though it must be noted that these only contain 30% trans-alkene).9
In the same way the enantiomer 14 was converted into 17 and
free hydroxy-MA 18 (Fig. 2).46 The 1H NMR spectra of each of these
in the alkene region were identical to those reported in the litera-
proximal a
-methyl-trans-cyclopropane unit 30 (Scheme 7).28
In applying this to the stereochemistry of trans-alkene myco-
lates, one possibility is that alkylation again occurs from the bot-
tom face, this time to the proximal carbon of the alkene, leading
Me
OR
O
OH
H
H C
H
from
bottom
H
H
H
CH (CH )n
(CH )mCO H
CH (CH )n
(CH )mCO H
CH3(CH2)17
(CH2)17
OR'
23
22
(CH2)15
(CH2)21CH3
17R = Ac, R' = Me
18 R = R' = H
from top
(trans)
Me
OCH
OH
Figure 2.
(CH )mCO H
S
CH (CH )n
S
CH (CH )n
24
H
(CH )mCO H
H C
25
Me
OAc
O
OTHP
Scheme 6.
CH3(CH2)17
(CH2)17
OMe
(CH2)15
19
(CH2)21CH3
Me
H
(i)-(iii)
Me
H
H
H
- H+
CH3(CH2)n
CH3(CH2)n
(CH2)mCO2H
(CH2)mCO2H
ButMe2Si
(CH2)17
R
S
23
27
H3C
H
26
O
O
OTHP
H
H
CH3(CH2)17
OH
H
(CH2)mCO2H
CH3(CH2)n
(CH2)15
20
21
(CH2)mCO2H
CH3(CH2)n
(CH2)21CH3
H3C
28
H
Me
(iv)-(vi)
Me
H
H3C
attack from
OH
O
bottom face
H
attack from
top face
O
(CH2)mCO2H
CH3(CH2)17
(CH2)17
OH
(CH2)mCO2H
H
(CH2)15
CH3(CH2)n
(CH2)21CH3
Me
CH3(CH2)n
29
30
H3C
H
H
H3C
Scheme 5. Reagents: (i) LiOH, MeOH, H2O, THF (72%); (ii) TBDMSCl, imidazole,
DMF; (iii) K2CO3, MeOH/H2O, then KHSO4, (70%); (iv) PPTS, MeOH, H2O, THF (73%);
(v) PCC (89%); (vi) HFꢁpyridine (44%).
Scheme 7.

7262
G. Koza et al. / Tetrahedron Letters 50 (2009) 7259–7262
H
H
29. Al Dulayymi, J. R.; Baird, M. S.; Roberts, E.; Minnikin, D. E. Tetrahedron 2006, 62,
H
H
11867–11880.
(CH2)mCO2H
(CH2)mCO2H
CH3(CH2
)
n
CH3(CH2
)
n
30. Koza, G.; Baird, M. S. Tetrahedron Lett. 2007, 48, 2165–2169.
31. Baird, M. S.; Al-Dulayymi, J. R.; Mohammed, H.; Roberts, E.; Clegg, W.
Tetrahedron 2006, 62, 4851–4862.
CH3
CH3
32
31
32. Nilsson, K.; Ullenius, C. Tetrahedron 1994, 50, 13173–13180.
33. Leonard, J.; Mohialdin, S.; Reed, D.; Ryan, G.; Swain, P. A. Tetrahedron 1995, 51,
12843–12858.
Scheme 8.
34. Munakata, R.; Ueki, T.; Katakai, H.; Tako, K.-i.; Tadano, K.-i. Org. Lett. 2001, 3,
3029–3032.
formally to 31; elimination of a proton would then lead to the (R)-
35. (a) Baudin, J. B.; Hareau, G.; Julia, S. A.; Ruel, O. Tetrahedron Lett. 1991, 32,
1175–1178; (b) Blakemore, J. R.; Kocienski, P. J.; Marzcak, S.; Wicha, J. Synthesis
1999, 1209–1215; (c) Smith, N. D.; Kocienski, P. J.; Street, S. D. A. Synthesis
1996, 652–666.
36. Frick, J. A.; Klassen, J. B.; Bathe, A.; Abramson, J. M.; Rappoport, H. Synthesis
1992, 621–623.
a
-methylalkene 32 (Scheme 8).
The trans-MA content of the cell wall is linked to its permeabil-
ity and growth in vitro.18 The keto- and hydroxy-MAs described
above are currently being tested to determine whether or not they
show specific effects in a range of appropriate biological screens.
37. This was obtained from 9-bromononanol by protection of the alcohol with
trimethylacetyl chloride, Et3N, CH2Cl2 (85%), then reaction with 1-phenyl-1H-
tetrazole-5-thiol, K2CO3, acetone (91%), followed by oxidation of the derived
sulfone [H2O2, (NH4)6Mo7O24ꢁ4H2O, THF/IMS (97%)].
References and notes
38. Blackemore, P. R.; Coke, W. J.; Kocienski, P. J.; Morley, A. Synlett 1998, 1, 26–28.
39. Brandl, T.; Hoffmann, R. W. Eur. J. Org. Chem. 2004, 4373–4378.
40. Pospisil, J.; Marko, I. E. Org. Lett. 2006, 8, 5983–5986.
41. Takano, D.; Nagamitsu, T.; Ui, H.; Shiomi, K.; Yamaguchi, Y.; Masuma, R.;
Kuwajima, I.; Omura, S. Org. Lett. 2001, 3, 2289–2291.
1. For a review see: Barry, C. E.; Lee, R. E.; Mduli, K.; Sampson, A. E.; Schroeder, B.
G.; Slayden, R. A.; Yuan, Y. Prog. Lipid Res. 1998, 37, 143–179.
2. Ojha, A. K.; Baughn, A. D.; Sambandan, D.; Hsu, T.; Trivelli, X.; Guerardel, Y.;
Alahari, A.; Kremer, L.; Jacobs, W. R.; Hatfull, G. F. Mol. Microbiol. 2008, 69, 164–
174.
3. Watanabe, M.; Aoyagi, Y.; Mitome, H.; Fujita, T.; Naoki, H.; Ridell, M.; Minnikin,
D. E. Microbiology 2002, 148, 1881–1902.
4. Watanabe, M.; Aoyagi, Y.; Ridell, M.; Minnikin, D. E. Microbiology 2001, 147,
1825–1837.
5. For example, see: Glickman, M. S.; Cox, J. S.; Jacobs, W. R. Mol. Cell 2000, 5, 717–
727.
6. Rao, V.; Gao, F.; Chen, B.; Jacobs, W. R.; Glickman, M. S. J. Clin. Invest. 2006, 116,
1660–1667.
7. Asselineau, C.; Tocanne, G.; Tocanne, J. F. Bull. Soc. Chim. Fr. 1970, 1455–1459.
8. Lanéelle, M.-A.; Lacave, C.; Daffé, M.; Lanéelle, G. Eur. J. Biochem. 1988, 177,
631–635.
9. Quémard, A.; Lanéelle, M.-A.; Marrakchi, H.; Promé, D.; Daffé, M. Eur. J. Biochem.
1997, 250, 758–763.
10. Yuan, Y.; Barry, C. E. Proc. Natl. Acad. Sci. U.S.A. 1996, 93, 12828–12833.
11. Dubnau, E.; Lanéelle, M.-A.; Soares, S.; Bénichou, A.; Vaz, T.; Promé, D.; Promé,
J.-C.; Daffé, M.; Quémard, A. Mol. Microbiol. 1997, 23, 313–322.
12. Yuan, Y.; Mead, D.; Schroeder, B. G.; Zhu, Y. Q.; Barry, C. E. J. Biol. Chem. 1998,
273, 21282–21290.
13. Takayama, K.; Wang, C.; Besra, G. S. Clin. Microbiol. Rev. 2005, 18, 81–101.
14. George, K. M.; Yuan, Y.; Sherman, D. R.; Barry, C. E. J. Biol. Chem. 1995, 270,
27292–27298.
42. Lautens, M.; Colucci, J. T.; Hiebert, S.; Smith, N. D.; Bouchain, G. Org. Lett. 2002,
4, 1879–1882.
43. Pollex, A.; Abraham, L.; Muller, J.; Hiersemann, M. Tetrahedron Lett. 2004, 45,
6915–6918.
44. Kao, C.-L.; Bonsova, S. A.; Kim, H. J.; Liu, H.-w. J. Am. Chem. Soc. 2006, 128, 5600–
5607.
45. Compound 16 (R = R0 = H): dH (500 MHz, CDCl3): 5.33 (1H, dt, J 6.6, 15.45 Hz),
5.23 (1H, dd, J 7.55, 15.45 Hz), 3.70–3.69 (1H, m), 3.52–3.51 (1H, m), 2.45 (1H,
br pent, J 4.7 Hz), 2.05–2.00 (1H, m), 1.97 (2H, q, J 6.9 Hz), 1.79–1.71 (1H, m),
1.66–1.59 (2H, m), 1.64–1.23 (139H, br m, including br s at 1.26), 0.94 (3H, d, J
6.6 Hz), 0.89 (6H, t, J 6.95 Hz), 0.86 (3H, d, J 7.25 Hz); dC: 177.3, 136.5, 128.5,
75.4, 72.2, 50.5, 37.3, 36.7, 34.4, 33.4, 32.6, 31.9, 30.0, 29.7, 29.6, 29.52, 29.46,
29.4, 29.1, 27.4, 22.7, 21.0, 16.6, 14.1; m
max: 3534, 2922, 2854, 1751, 1466 cmꢀ1
[found M+Na+: 1234.39; C82H162NaO4 requires: 1234.24]; ½a D21
ꢀ2.07 (CHCl3,
ꢂ
0.743 lmol).
46. Compound 18 showed
1234.18; C82H162NaO4 requires: 1234.24].
½ ꢂ +1.67 (CHCl3, 1.287 l
a 2D0 mol); [Found M+Na+:
47. The protected ketone derived by PCC oxidation of 17 showed dH (500 MHz,
CDCl3): 5.33 (1H, dt, J 6.6, 15.1 Hz), 5.24 (1H, dd, J 7.25, 15.1 Hz), 5.09 (1H, dt, J
4.1, 8.15 Hz), 3.68 (3H, s), 2.62 (1H, ddd, J 4.45, 6.95, 11.05 Hz), 2.50 (1H, sext, J
6.95 Hz), 2.41 (2H, dt, J 2.25, 7.25 Hz), 2.03 (3H, s), 1.97 (2H, q, J 6.6 Hz), 1.63–
1.18 (137H, m, including s at 1.26), 1.05 (3H, d, J 6.6 Hz), 0.94 (3H, d, J 6.6 Hz),
0.89 (6H, t, J 6.95 Hz); dC: 215.2, 173.7, 170.3, 128.4, 74.1, 51.5, 49.6, 46.3, 41.2,
37.3, 36.7, 33.1, 32.6, 31.9, 31.7, 29.8, 29.7, 29.64, 29.59, 29.54, 29.51, 29.48,
29.43, 29.39, 29.3, 29.2, 28.1, 27.5, 27.4, 27.3, 25.0, 23.7, 22.7, 21.0, 16.4, 14.1;
15. Mikusova, K.; Mikus, M.; Besra, G. S.; Hancock, I.; Brennan, P. J. J. Biol. Chem.
1996, 271, 7820–7828.
16. Glickman, M. S.; Cahill, S. M.; Jacobs, W. R. J. Biol. Chem. 2001, 276, 2228–2233.
17. Asselineau, C.; Asselineau, J.; Lanéelle, G.; Lanéelle, M.-A. Prog. Lipid Res. 2002,
41, 501–523.
18. Schroeder, B. G.; Barry, C. E. Bioorg. Chem. 2001, 29, 164–177.
19. Minnikin, D. E.; Minnikin, S. M.; Goodfellow, M.; Stanford, J. L. J. Gen. Microbiol.
1982, 128, 817–822.
m
max: 2932, 2853, 1748, 1711, 1466 cmꢀ1; ½a D22
ꢂ
+3.52 (CHCl3, 1.094 lmol);
[found M+Na+: 1288.22; C85H164NaO5 requires: 1288.25]. That from 16 (R = Ac,
R0 = Me), ½a 2D3
ꢀ2.39 (CHCl3, 0.55 lmol), showed essentially identical NMR
ꢂ
spectra.
48. Koza, G.; Al Dulayymi, J. R.; Theunissen, C.; Baird, M. S. Tetrahedron 2009,
10214–10229.
20. Lacave, C.; Lanéelle, M.-A.; Daffé, M.; Montrozier, H.; Rols, M.-P. Eur. J. Biochem.
1987, 163, 369–378.
49. The ketone 21 showed dH (500 MHz, CDCl3): 5.32 (1H, td, J 6.65, 15.45 Hz), 5.24
(1H, dd, J 7.55, 15.45 Hz), 2.50 (1H, pent, J 6.6 Hz), 2.47 (1H, m), 2.42 (2H, dt, J
1.55, 6.95 Hz), 2.36 (1H, t, J 7.55 Hz), 1.97 (2H, q, J 6.95 Hz), 1.65–1.17 (139H, br
m, including br s at 1.26), 1.05 (3H, d, J 6.95 Hz), 0.95 (3H, d, J 6.95 Hz), 0.89
(6H, t, J 6.65 Hz); dC: 215.5, 177.9, 136.5, 128.4, 72.2, 50.6, 46.4, 41.2, 37.3, 36.7,
35.6, 33.1, 32.6, 31.9, 29.8, 29.7, 29.64, 29.59, 29.54, 29.51, 29.48, 29.43, 29.39,
21. Etemadi, A. H. Bull. Soc. Chim. Fr. 1967, 195–199.
22. Wong, M. Y. H.; Gray, G. R. J. Biol. Chem. 1979, 254, 5741–5744.
23. Danielson, S. J.; Gray, G. R. J. Biol. Chem. 1982, 257, 12196–12203.
24. Etemadi, A. H. Bull. Soc. Chim. Fr. 1964, 868–870.
25. Kusamram, K.; Polgar, N.; Minnikin, D. E. J. Chem. Soc., Chem. Commun. 1972,
111.
26. Markovits, J.; Pinte, F.; Etemadi, A. H. Compt. Rend. Hebd. Acad. Sci. Ser. C 1966,
263, 960.
27. Al Dulayymi, J. R.; Baird, M. S.; Roberts, E. Tetrahedron 2005, 61, 11939–11951.
28. Al Dulayymi, J. R.; Baird, M. S.; Roberts, E.; Deysel, M.; Verschoor, J. Tetrahedron
2007, 63, 2571–2592.
29.3, 29.1, 28.9, 27.4, 27.3, 25.7, 23.7, 22.7, 22.6, 21.0, 19.4, 16.4, 14.1; mmax
3420, 3019, 2926, 2855, 1521, 1420, 1215 cmꢀ1
+2.90 (CHCl3,
0.471
mol); [found M+Na+: 1232.36; C82H160NaO4 requires: 1232.22].
:
;
½ ꢂ
a 2D3
l
50. Yuan, Y.; Crane, D. C.; Musser, J. M.; Sreevatsan, S.; Barry, C. E. J. Biol. Chem.
1997, 272, 10041–10049.