Synthesis of cis,cis-diunsaturated α-meromycolic acid by a palladium-catalysed alkyl-alkyl Negishi reaction

Article abstract of DOI:10.1016/j.tetlet.2011.11.021

The first total synthesis of cis,cis-diunsaturated α-meromycolic acid has been accomplished using a convergent strategy and a palladium-catalysed alkyl-alkyl Negishi reaction as the key step.

Full text of DOI:10.1016/j.tetlet.2011.11.021

Tetrahedron Letters 53 (2012) 214–216
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Tetrahedron Letters
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Synthesis of cis,cis-diunsaturated
a-meromycolic acid by a
palladium-catalysed alkyl–alkyl Negishi reaction
⇑
⇑
Giacomo Berretta , Geoffrey D. Coxon
Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, 165 Cathedral Street, Glasgow G4 0RE, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
The first total synthesis of cis,cis-diunsaturated a-meromycolic acid has been accomplished using a con-
vergent strategy and a palladium-catalysed alkyl–alkyl Negishi reaction as the key step.
Received 22 September 2011
Revised 20 October 2011
Accepted 4 November 2011
Available online 10 November 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Fatty acids
Negishi reaction
Synthesis
Tuberculosis
Drug discovery
Mycolic acids
Meromycolate
Palladium-catalysed cross-coupling reactions between organo-
metallic reagents and organic electrophiles are important transfor-
mations in organic synthesis.1 Nevertheless, despite the fact that
the importance of cross-coupling reactions in the synthesis of het-
erocyclic compounds is indisputable, the applicability of these
transformations in the synthesis of lipids has been limited. In par-
ticular, alkyl–alkyl cross-coupling reactions of unactivated alkyl
halides bearing b-hydrogens are known to be challenging sub-
strates due to their reluctance to undergo oxidative addition and
reductive elimination, and their tendency to give b-hydride elimi-
nation.2 Recently, however, progress has been reported in circum-
venting these difficulties for the Negishi reaction.3 In this
communication, we describe the first synthesis of cis,cis-diunsatu-
lated from bacterial cultures and its total synthesis is of paramount
importance to establish a biochemical assay7 to develop PcaA
inhibitors.
During the last 10 years, syntheses of a number of lipids related
to mycolic acids have been reported.8 In these studies, long-chain
alkanes have been synthesised by multi-step-procedures that
required the formation of a double bond, via Wittig or Julia–
Kocienski olefination, followed by its reduction. According to our
disconnection strategy for 1 (Fig. 1), we instead envisioned that
the framework of the ‘proximal’ C1ÀC19 fragment could be syn-
thesised directly by the Negishi coupling of two shorter and easily
available fragments. We also decided to synthesise the two cis dou-
ble bonds by two stereoselective Wittig reactions. Specifically, the
retrosynthetic analysis depicted in Scheme 1 shows that the prox-
imal double bond of 1 may be synthesised from aldehyde 2 and
rated
a-meromycolic acid (1) using a Negishi cross-coupling
reaction as the key step (Fig. 1).
The target molecule 1 is an important intermediate in the syn-
thesis of mycolic acids, which are essential components of the cell
wall of Mycobacterium tuberculosis (Mtb),4 the causative agent of
tuberculosis (TB). In Mtb, compound 1 is linked to an acyl carrier
protein (AcpM) and is the substrate of a cyclopropanating enzyme,
PcaA, which has recently been reported as essential for the viru-
lence and persistence of Mtb,5 and thus is considered a promising
target in TB drug discovery.6 Unfortunately, lipid 1 cannot be iso-
Negishi coupling
Wittig olefination
8
O
19
"proximal"
double bond
1
7
OH
20
31
"distal"
double bond
50
32
⇑
Corresponding authors. Tel.: +44 (0) 1415485754; fax: +44 (0) 1415522562
(G.D.C.).
Wittig olefination
1
E-mail addresses: giacomo.berretta@strath.ac.uk (G. Berretta), geoff.coxon@
strath.ac.uk (G.D. Coxon).
Figure 1. Disconnection strategy for cis,cis-diunsaturated -meromycolic acid 1.
a
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.11.021

G. Berretta, G. D. Coxon / Tetrahedron Letters 53 (2012) 214–216
215
1
N
BrZn
6
p-TsOH
MeOH
Wittig
N
N
8
(5.6 eq.)
HO
THPO
7a
18
18
CH2Cl2
99%
5% PEPPSI-IPr
9.6 eq LiBr
THF/NMP 2:1
RT, 20 h
O
Ph3P X
COOH
17
12
+
6
17
10
71%
3
2
HBr
H2SO4
110 °C
95%
Wittig
O
Ph3P X OPG
OPG
PPh3
MeCN
O
O
N
+
BrPh3P
Br
17
10
17
OH
OH
18
170 °C
(MW)
94%
18
13
6
4
5
3
Negishi
BrZn
Scheme 3. Synthesis of the phosphonium salt 3.
X
OPG
10
N
+
bromide was used in large excess, in the presence of LiBr as the
lithium ion source, and with a five-fold higher catalyst loading
(Scheme 3). The resulting nitrile 6 was deprotected quantitatively
by p-toluenesulfonic acid in methanol, and treated with aqueous
hydrobromic acid in the presence of sulphuric acid to afford the
6
8
7
Scheme 1. Retrosynthetic analysis of cis,cis-diunsaturated a-meromycolic acid 1.
x
-bromo-carboxylic acid 13 in a 95% yield. Bromide 13 was
promptly converted into the corresponding bromide salt 3 in 94%
yield by treatment with triphenylphosphine in acetonitrile under
microwave irradiation.13
phosphonium salt 3, and that the distal double bond may be pre-
pared from aldehyde 4 and phosphonium salt 5. Interestingly, we
envisioned that phosphonium salts 3 and 5 could be obtained from
a common organohalide 7.
Bromide 7a and iodide 7b were readily prepared from 1,12-
dodecanediol using a 2-tetrahydropyranyl (THP) group to protect
the remaining alcoholic moiety (Scheme 2). The bromination was
achieved by treatment with aqueous hydrobromic acid in refluxing
toluene, while the iodination was accomplished by treatment with
iodine, triphenylphosphine and imidazole in anhydrous THF.9
Organohalides 7a and 7b were used to synthesise the bifunc-
tionalised C19 alkane 6 via a Negishi reaction with alkylzinc bro-
In order to synthesise aldehyde 2 (Scheme 1), nonadecanal (4)
was efficiently prepared from 1-eicosene via the epoxide interme-
diate as previously reported,14 while phosphonium salt 5 was pre-
pared from the halides 7a or 7b. However, numerous attempts to
treat the bromide 7a in the presence of triphenylphosphine in tol-
uene, THF or acetonitrile afforded the phosphonium bromide with
partial or complete deprotection of the THP group.15 Conversely,
the iodide 7b was smoothly converted into the desired phospho-
nium salt 5 using acetonitrile as the solvent (Scheme 4). The result-
ing phosphonium iodide 5 was treated with an equimolar amount
of sodium hexamethyldisilazide to generate the ylide, which
underwent stereoselective cis-olefination with aldehyde 4 in the
presence of DMPU16 in THF at À84 °C in a 52% yield.17 Deprotection
of THP ether 14 was carried out using magnesium bromide diethyl
etherate18 affording alcohol 15 in a quantitative yield and with
conservation of the Z-configuration of the existing double bond.
Alcohol 15 was converted into the corresponding aldehyde 2 using
mide
8 using a Pd–N-heterocyclic carbene-based precatalyst
(PEPPSI-IPr) in the presence of lithium salts.3,10 However, initial at-
tempts to perform this cross-coupling reaction according to the
protocol of Organ et al.10 yielded 6 in low yields (625%).11 Under
these conditions the starting halides could be recovered in high
yields, or unmodified or as corresponding chloride due to LiCl-
mediated transhalogenation.12 Gratifyingly, it was found that bro-
mide 7a underwent cross-coupling in a 71% yield if the alkylzinc
1) NaHMDS
DHP,
OH
Br
Br
OTHP
aq. HBr
p-TsOH,
2) 4
OTHP
11
PPh3
-84 °C
IPh3P
OTHP
12
7b
toluene
70%
CH2Cl2
98%
10
10
17
THF-DMPU
52%
CH3CN
94%
7a
10
5
14
HO
OH
10
MgBr2·OEt2
Et2O
99%
9
I2, PPh3
Imidazole
PCC, MS3Å
NaOAc
DHP
O
I
OTHP
10
OH
OTHP
10
OH
11
p-TsOH
THF-CH2Cl2
67%
17
THF
90%
CH2Cl2
91%
17
10
7b
11
2
15
Scheme 2. Synthesis of organohalides 7a and 7b.
Scheme 4. Synthesis of the aldehyde 2.

216
G. Berretta, G. D. Coxon / Tetrahedron Letters 53 (2012) 214–216
References and notes
Ph3P Br
COOH
17
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Angew. Chem. Int. Ed. 2003, 42, 384–387; (c) Frisch, A. C.; Beller, M. Angew.
Chem. Int. Ed. 2005, 44, 674–688.
1) NaHMDS (2 eq.),
RT
3
1
(0% in THF-DMPU;
8% in THF)
+
3. Valente, C.; Belowich, M. E.; Hadei, N.; Organ, M. G. Eur. J. Org. Chem. 2010,
2010, 4343–4354.
O
2
2) , -84 °C
4. Takayama, K.; Wang, C.; Besra, G. S. Clin. Microbiol. Rev. 2005, 18, 81–101.
5. (a) Glickman, M. S.; Cox, J. S.; Jacobs, W. R. Mol. Cell 2000, 5, 717–727; (b)
Barkan, D.; Liu, Z.; Sacchettini, J. C.; Glickman, M. S. Chem. Biol. 2009, 16, 499–
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(c) Elamin, A. A.; Stehr, M.; Oehlmann, W.; Singh, M. J. Microbiol. Methods 2009,
79, 358–363.
17
2
10
O
COOH
17
P
Ph
(Step 2)
Ph
16 (>50%)
Scheme 5. Synthesis of 1 and unexpected formation of 16.
8. (a) Al Dulayymi, J. R.; Baird, M. S.; Roberts, E. Tetrahedron Lett. 2000, 41, 7107–
7110; (b) Al Dulayymi, J. R.; Baird, M. S.; Roberts, E. Chem. Commun. 2003, 228–
229; (c) Al Dulayymi, J. R.; Baird, M. S.; Roberts, E. Tetrahedron 2005, 61, 11939–
11951; (d) Al Dulayymi, J. R.; Baird, M. S.; Roberts, E.; Minnikin, D. E.
Tetrahedron 2006, 62, 11867–11880; (e) Al-Dulayymi, J. R.; Baird, M. S.;
Mohammed, H.; Roberts, E.; Clegg, W. Tetrahedron 2006, 62, 4851–4862; (f) Al
Dulayymi, J. R.; Baird, M. S.; Roberts, E.; Deysel, M.; Verschoor, J. Tetrahedron
2007, 63, 2571–2592.
9. Garegg, P. J.; Johansson, R.; Ortega, C.; Samuelsson, B. J. Chem. Soc., Perkin Trans.
1 1982, 681–683.
10. Organ, M. G.; Avola, S.; Dubovyk, I.; Hadei, N.; Kantchev, E. A. B.; O’Brien, C. J.;
Valente, C. Chem. Eur. J. 2006, 12, 4749–4755.
PCC under mild conditions in the presence of molecular sieves
(MS3Å)19 and sodium acetate in a 91% yield.
Attempts to carry out the Wittig reaction between phospho-
nium bromide 3 and aldehyde 2 in THF/DMPU failed to produce
the desired compound, leading instead to the formation of diph-
enylphosphorylalkylcarboxylic acid 16 as major product (Scheme
5). Gratifyingly, omitting the DMPU from the reaction mixture re-
sulted in the synthesis of compound 1 despite the by-product 16
still being present as the major component under these condi-
tions.20 The conversion of phosphonium salts, containing a long-
11. It has previously been reported that a pendent cyano group may have a
deleterious influence on the alkyl–alkyl Negishi cross-coupling reaction: Zhou,
J. Ph.D. thesis, Massachusetts Institute of Technology, 2005.
chain
x-carboxyalkyl group, into the corresponding phosphoryl
derivatives has been previously reported to take place in the pres-
ence of bases and polar solvents only after several days.21 Con-
versely, preliminary results22 from our studies indicated that this
side-reaction is rapid and may be the principal cause of the low
yields reported23 in Wittig reactions of phosphonium salts with
pendent carboxy groups. Specifically, we suspect that this base-
promoted side-reaction may be due to intramolecular coordination
of the carboxylate group on the phosphonium moiety, where
DMPU has the role to solvate the sodium ion.
12. Commercially available organozinc reagents (Rieke Metals, Inc.) contain 1–
3 wt% chloride salt. Since the organochlorides are less reactive than the
corresponding bromides under these conditions, we believe that the
transhalogenation may affect the formation of the desired product.
13. (a) Kiddle, J. J. Tetrahedron Lett. 2000, 41, 1339–1341; (b) Cvengros, J.; Toma, S.;
Marque, S.; Loupy, A. Can. J. Chem. 2004, 82, 1365–1371; (c) Herrero, M. A.;
Kremsner, J. M.; Kappe, C. O. J. Org. Chem. 2008, 73, 36–47.
14. Coxon, G. D.; Douglas, J. D.; Minnikin, D. E. Chem. Phys. Lipids 2003, 126, 49–53.
15. Attempts to use directly the resulting
x-hydroxyalkyl-phosphonium salt in the
Wittig reaction afforded the expected alkenol in poor yields and low Z-
stereoselectivity, as previously reported during similar Wittig reactions with
phosphonium salts bearing a pendent hydroxy group: Ref. 23.
16. Mukhopadhyay, T.; Seebach, D. Helv. Chim. Acta 1982, 65, 385–391.
17. The desired Z-isomer was synthesised in >98% geometrical purity (the Z:E ratio
was determined by 13C NMR analysis).
In conclusion, the first synthesis of cis,cis-diunsaturated a-mer-
omycolic acid has been accomplished using a convergent strategy
using readily available starting materials: 1,12-dodecanediol, 1-
eicosene and 6-cyanohexyl zinc bromide. The Negishi cross-cou-
pling reaction has proved to be a useful transformation for the
synthesis of long-chain fatty acids. Studies on biochemical applica-
tions of compound 1 are in progress and will be published in due
course.
18. Kim, S.; Park, J. H. Tetrahedron Lett. 1987, 28, 439–440.
19. Herscovici, J.; Antonakis, K. J. Chem. Soc., Chem. Commun. 1980, 561–562.
20. All compounds were fully characterised with relevant spectral data and were
in agreement with the expected values. Compound 1 was isolated as pure Z,Z-
isomer: 1H NMR (400 MHz, CDCl3) d 5.35 (m, 4H), 2.35 (t, J = 7.5 Hz, 2H), 2.01
(m, 8H), 1.63 (m, 2H), 1.37–1.18 (m, 76H), 0.88 (t, J = 6.8 Hz, 3H). 13C NMR
(101 MHz, CDCl3) d 178.7, 130.1, 130.0, 33.9, 32.1, 29.9, 29.9, 29.8, 29.7, 29.7,
29.7, 29.6, 29.5, 29.5, 29.5, 29.4, 29.2, 27.4, 24.9, 22.9, 14.3. HRMS (ESÀ, m/z):
Calculated for C50H95O2 (MÀH+)À = 727.7338; found 727.7344.
21. Narayanan, K. S.; Berlin, K. D. J. Org. Chem. 1980, 45, 2240–2243.
22. Berretta, G. Ph.D. thesis, University of Strathclyde, 2011.; (b) Berretta, G.;
Coxon, G. D. Unpublished results.
Acknowledgment
This work was supported by the University of Strathclyde
through a Ph.D. studentship to G.B.
23. Maryanoff, B. E.; Reitz, A. B.; Duhl-Emswiler, B. A. J. Am. Chem. Soc. 1985, 107,
217–226.