Synthesis of hydroxyphthioceranic acid using a traceless lithiation-borylation-protodeboronation strategy

Article abstract of DOI:10.1038/nchem.2010

In planning organic syntheses, disconnections are most often made adjacent to functional groups, which assist in C-C bond formation. For molecules devoid of obvious functional groups this approach presents a problem, and so functionalities must be installed temporarily and then removed. Here we present a traceless strategy for organic synthesis that uses a boronic ester as such a group in a one-pot lithiation-borylation-protodeboronation sequence. To realize this strategy, we developed a methodology for the protodeboronation of alkyl pinacol boronic esters that involves the formation of a boronate complex with a nucleophile followed by oxidation with Mn(OAc) 3 in the presence of the hydrogen-atom donor 4-tert-butylcatechol. Iterative lithiation-borylation- protodeboronation allows the coupling of smaller fragments to build-up long alkyl chains. We employed this strategy in the synthesis of hydroxyphthioceranic acid, a key component of the cell-wall lipid of the virulent Mycobacterium tuberculosis, in just 14 steps (longest linear sequence) with full stereocontrol.

Full text of DOI:10.1038/nchem.2010

ARTICLES
PUBLISHED ONLINE: 27 JULY 2014 | DOI: 10.1038/NCHEM.2010
Synthesis of hydroxyphthioceranic acid using a
traceless lithiation–borylation–protodeboronation
strategy
Ramesh Rasappan and Varinder K. Aggarwal
*
In planning organic syntheses, disconnections are most often made adjacent to functional groups, which assist in C–C bond
formation. For molecules devoid of obvious functional groups this approach presents a problem, and so functionalities must
be installed temporarily and then removed. Here we present a traceless strategy for organic synthesis that uses a boronic
ester as such a group in a one-pot lithiation–borylation–protodeboronation sequence. To realize this strategy, we developed
a methodology for the protodeboronation of alkyl pinacol boronic esters that involves the formation of a boronate complex
with a nucleophile followed by oxidation with Mn(OAc)3 in the presence of the hydrogen-atom donor 4-tert-butylcatechol.
Iterative lithiation–borylation–protodeboronation allows the coupling of smaller fragments to build-up long alkyl chains. We
employed this strategy in the synthesis of hydroxyphthioceranic acid, a key component of the cell-wall lipid of the virulent
Mycobacterium tuberculosis, in just 14 steps (longest linear sequence) with full stereocontrol.
rganic synthesis involves the coupling together of small mol- lithiation–borylation as a new strategy for assembling molecules
ecules, usually followed by functional group interconver- without trace of the functional groups used in their genesis. In
O
sions, and subsequent further coupling until a final target addition, we demonstrate the power of this new approach in a
molecule has been created. The functional groups, which may not short (14 steps), stereoselective and convergent synthesis of hydro-
be present in the final molecule, are there to assist in C–C bond for- xyphthioceranic acid 10, a key component of the cell-wall lipid of
mation, and so are integral in any disconnection analysis. As func- the virulent Mycobacterium tuberculosis (MTB).
tional groups are the focus of attention, strategic disconnections are
usually applied around them, which necessarily constrains both dis- Results and discussion
connections and strategies. No such constraint applies to molecules We began by focusing on the key protodeboronation step and chose a
devoid of functional groups (for example, archaeal membrane lipids representative secondary alkyl pinacol boronic ester 5a for our studies.
exemplified by glycerol dibiphytanyl glycerol tetraether (GDGT-4) Treatment of this ester with carboxylic acids at elevated temperatures,
(Fig. 1a))1 and this liberation provides a blank canvas on which as reported by Brown and Murray for the protodeboronation of
new strategies for molecular assembly can be explored. Ultimately, boranes15, was ineffective, as was the use of TBAF·3H2O, a reagent
such novel strategies could be applied to more-functionalized mol- that we had employed for the protodeboronation of reactive benzylic
ecules, especially if they enable non-intuitive disconnections to be and allylic pinacol boronic esters9,16. We therefore considered the pro-
made that lead to building blocks that are more readily accessible.
tonation of the more-reactive boronate complex formed from the
Previously, we reported the coupling together of carbamates 1 addition of p-MeOPhLi (6a) because such species were found to be
and boronic esters 22–4, two functional groups that are easily acces- reactive nucleophiles17. Unfortunately, treatment of the boronate
sible from nature’s bountiful supply of alcohols and alkenes complex 7 with a range of acids was again unsuccessful.
(Fig. 1b). We reasoned that if the boronic ester functional group
Renaud’s seminal discovery13,14 that alkyl catechol boronic esters
could be removed from the coupled product 3 (ideally in the undergo facile homolytic protodeboronation in the presence of air
same pot), we would have effected a traceless coupling of two frag- and 4-t-butylcatechol (TBC) was highly attractive to us, but he
ments5–8. The overall sequence would represent a powerful new way had shown that this process was unique to catechol boronic esters;
to assemble molecules, as it would mean that, in terms of retrosyn- it was ineffective with pinacol boronic esters. We reasoned that
thetic analysis, molecules could be disconnected essentially any- the boronate complex 7 should be much more prone to homolytic
where, even remote from functionality (Fig. 1c). Although this cleavage and examined various conditions. We were pleased to
strategy had been applied to benzylic carbamates, the resulting find that, on refluxing boronate complex 7 in 1,2-dichloroethane
benzylic boronic esters (where boron is adjacent to functionality) (DCE) (80 °C), the desired product 8 was obtained in 55% yield
are very easily protodeboronated simply with TBAF·3H2O (TBAF, (Table 1, entry 1). DMF at a higher temperature (130 °C) increased
tetra-N-butylammonium fluoride), so the strategy is not generally the yields obtained (entry 2). Using the more electron-rich
applicable9–12. The major challenge in realizing this strategy is the 1,3-(MeO)2PhLi 6b gave even higher yields of the protodeboronated
protodeboronation of the more-stable secondary alkyl pinacol product 8 (entry 3). In contrast to Renaud’s work, it was necessary
esters, remote from any functionality (for example, 3 → 4), as to perform reactions under argon, because in air oxidation of the
there were no known methods for achieving such a transformation boronate to alcohol 9 competed (entry 4). In related studies,
directly, although there were methods for carrying out the overall Fensterbank and co-workers found that potassium trifluoroborates
transformation indirectly13,14. In this paper we describe a new pro- could be cleaved oxidatively at 120 °C by various oxidants and the
tocol for protodeboronation and its tactical use in conjunction with resulting radical intermediates trapped with TEMPO (2,2,6,6-
School of Chemistry, University of Bristol, Cantock’s Close, Bristol BS8 1TS, UK. e-mail: v.aggarwal@bristol.ac.uk
*
810
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.2010
ARTICLES
c
a
H
H
OCb
O
O
C
A
A
B
HO
i
H
H
LBP
+
E
D
H
pinB
B
i
H
H
H
or
O
O
E
C
D
ii
A
B
C
D
OH
Bpin
ii
H
H
+
GDGT-4
LBP
E
CbO
b
OCb
Bpin
A
C
D
C
D
A
A
B
B
pinB
1
2
FGI
Alcohol
Alkene
C
D
A
B
A
OCb
B
A
B
Bpin
Bpin
4
B
3
Figure 1 | Complex molecules with limited functionality present in nature and the potential traceless strategy for their synthesis. a, Structure of the GDGT
membrane lipid of cosmopolitan pelagic Crenarchaeota. b, Lithiation-borylation-protodeboronation (LBP) strategy for the organic synthesis, showing the
process for combining two fragments (A and B) followed by the removal of the boronic ester, and its repeated use (fragments C and D). c, Possible
disconnections of a molecule using the traceless LBP strategy. Cb, N,N-diisopropyl carbamate; FGI, functional group interconversion.
tetramethylpiperidinyloxy) or methyl vinyl ketone18. Again, our
We briefly tested the scope of the protodeboronation reaction with
aryl boronate complexes were expected to undergo a more-facile several boronic estersthat contained commonlyencounteredfunctional
oxidative cleavage, as the C–B bond is more electron rich than groups (esters (5b), alkenes (5c) and alcohols (see the Supplementary
in the corresponding trifluoroborates. We therefore screened a Information)). Using n-BuLi (Conditions A) or TBAF (Conditions
range of oxidants and found that Cu(OAc)2·H2O and Mn B) as the nucleophile and Mn(OAc)3 as the oxidant, good yields of
(OAc)3·2H2O both performed well (entries
5
and 6). protodeboronated products were obtained in all cases (Fig. 2a). Other
Furthermore, the shorter reaction time and lower temperatures functional groups that are compatible with the process are also pre-
required resulted in cleaner, higher-yielding reactions. Attempts sented in the total synthesis at the end of the paper (see Fig. 5).
to use air with substoichiometric amounts of Cu(OAc)2·H2O
To verify the mechanism, reaction with cyclopropylmethyl-sub-
were less effective (entry 7). The nature of the boronate complex stituted boronic ester 5d was tested (Fig. 2b). In this case, only the
was also examined. We found that the use of n-BuLi (entries 8 ring-opened product of protodeboronation was obtained, which
and 9) or even MeLi (entry 10) was equally effective. indicates that the reaction occurs via a radical intermediate that
Surprisingly, TBAF·3H2O could also be employed with Mn undergoes rapid ring opening to relieve ring strain19.
(OAc)3·2H2O, which shows that even transient boronate complexes
could be cleaved oxidatively (entries 11 and 12).
With a number of simple protocols to effect protodeboronation
of secondary pinacol boronic esters, underpinned with mechanistic
foundations, we embarked on the new strategy for the total synthesis
of hydroxyphthioceranic acid 10, a molecule of significant global
importance in relation to tuberculosis (TB).
Table 1 | Optimization of protodeboronation of model
substrate 5a.
Sulfolipid-1 (SL-1). The alarming rise in drug-resistant TB has made
it one of the most fatal human diseases in recent years, being
responsible for 1.3 million deaths in 2012 alone20. It has been
estimated that over two billion people21 are infected with TB globally,
which makes it a major health challenge of the 21st century21.
Although little is known about the molecular mechanisms of MTB
virulence it is believed that the cell-wall lipids play an important role
+
Nu
–
M
Bpin
Nu, THF
Bpin
–78 °C, 1 h
Ph
Ph
Ph
Ph
5a
7
TBC (5 equiv.),
oxidant (1 equiv.),
DCE, Ar, 80 °C
6a = pMeOPhLi; 6b = 1,3-(MeO)2PhLi
6c = nBuLi; 6d = MeLi; 6e = TBAF
Nu =
in the pathogenesis of this organism22,23
. Furthermore, the
X
8 X = H
extraordinary thick lipid coat acts as an impenetrable waxy barrier to
cytotoxic agents, which makes it especially challenging to combat24.
The major cell-wall lipid of virulent human MTB has been isolated
and identified as SL-1 by Goren et al.25,26 (Fig. 3a). Studies on SL-1
have revealed significant immunomodulatory activity against various
immune cells, which makes it a promising component of potential
vaccines22,27. The complex structure of SL-1 has been characterized as
2,3,6,6′-tetraacyl-α,α′-D-trehalose 2′-sulfate and it has three
polydeoxypropionate arms coupled to the sugar core, which have
been characterized as hydroxyphthioceranic acid 10 and
phthioceranic acid 11 (Fig. 3b)25,26. The more-complex side arm,
hydroxyphthioceranic acid 10, was synthesized in 2013 by the groups
of Minnaard28–31 and Schneider32 in 32 and 23 steps (longest linear
sequence), respectively, and with high diastereocontrol.
9 X = OH
Ph
Ph
Entry
Nu
Oxidant
Time (h)
8:9
Yield (%)*
1†
6a
6a
6b
6b
6b
6b
6b
6c
6c
6d
6e
6e
–
–
–
Air
62
40
40
40
18
18
72
12
12
12
12
8 h
100:0
92:8
95:5
55
72(65)
85(78)
40
96(87)
96
2‡
3‡
4‡
5
69:31
100:0
100:0
88:12
100:0
100:0
100:0
100:0
100:0
Cu(OAc)2
Mn(OAc)3
Cu(OAc)2
Cu(OAc)2
Mn(OAc)3
Mn(OAc)3
Cu(OAc)2
Mn(OAc)3
6
7§,||
8
71
97(95)
98(97)
94
72
98(97)
9
10
11||
12||
*Gas chromatography yield, values in parentheses are the isolated yield. †A 2:1 ratio of product:ate
complex remained. ‡130 °C, dimethylformamide instead of DCE. §10 mol% Cu(OAc)2 under air.
||Toluene instead of DCE, all the reagents were mixed at once at r.t.
Retrosynthesis. Our retrosynthetic analysis (Fig. 3c) began with a
stereocontrolled lithiation–borylation2 disconnection at C17–C18.
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.2010
ARTICLES
Bpin
protodeboronation. Rather than disconnecting 12 in the middle,
we found that disconnection at C11–C12 followed by a further
disconnection at C5–C6 would require a smaller number of
distinct building blocks for the subsequent assembly (13 and 14).
The building blocks 13 and 14 can be prepared easily from
the commercially available alcohol 15. Furthermore, coupling
together enantiopure building blocks in the assembly of 12
would result in complete stereocontrol without diastereoisomer
a
Bpin
Ph
CO2tBu
pMeOPh
5b
5c
A = 81%
B = 67%
A = 94%
B = 87%
Conditions
Conditions:
i. nBuLi (1.2 equiv.),
–78 °C, 1 h, THF
b
Bpin
contamination,
diastereocontrolled processes.
a
considerable benefit over alternative
Ph
Ph
ii. TBC, Mn(OAc)3,
DCE, 80 °C, 12 h
3:1 (trans:cis),
5d
76%
Total synthesis of hydroxyphthioceranic acid 10. Our synthesis
began with the conversion of the commercially available
monoacetylated 1,5-diol 15 into the required building blocks 13
and 14 (Fig. 4). Alcohol 15 can also be prepared easily on a
multigram scale via enzymatic resolution of the corresponding
diol, which itself can be prepared from simple materials without
OH
OH
nBuLi
tBu
nBu
–
Bpin
+
Li
Ph
the need for chromatographic purification33–35
.
Following
Ph
Mn(OAc)2,
LiOAc,
carbamoylation of alcohol 15, the acetate was hydrolysed and the
primary alcohol protected as the methoxymethyl (MOM) ether to
give building block 13 in quantitative yield.
nBuBpin
Building block 14 was also prepared from the same monoacetate
15 (Fig. 4). After protection as the t-butyldiphenylsilyl (TBDPS)
ether, hydrolysis of the ester and carbamoylation led to carbamate
16. Lithiation followed by treatment with pinacolborane (HBpin)
gave pinacol boronic ester 17 in good yield36. To prepare boronic
ester 14 with the stereochemistry required, we needed to deproto-
nate ethyl carbamate with s-BuLi/(+)-sparteine. Fortunately, both
enantiomers of sparteine are commercially available (see
Figure 2 | Brief survey of the scope and mechanism of the
protodeboronation reaction. a, Functional groups tested for compatibility
with protodeboronation under two sets of conditions. Conditions A: n-BuLi,
TBC, Mn(OAc)3·2H2O, DCE, 12 h, 80 °C; Conditions B: TBAF, TBC,
Mn(OAc)3·2H2O, DCE, 12 h, 80 °C. b, Radical clock to probe the mechanism
of the protodeboronation reaction. The formation of the ring-opened product
indicates that protodeboronation occurs via a radical intermediate as shown.
This would lead to polydeoxypropionate 12, which could be Supplementary Information for details), although O’Brien’s syn-
assembled by combining the appropriate building blocks through thetic (+)-sparteine surrogate can also be employed37,38. Thus,
non-selective lithiation–borylation reactions followed by deprotonation of ethyl carbamate with s-BuLi/(+)-sparteine
a
b
O
C15H31
C15H31
HOOC
7
Hydroxyphthioceranic acid 10
O
OH
O
OH
HO
HO
Minnaard group28: 32 steps (LLS), 34 steps (TS)
Schneider group32: 23 steps (LLS), 34 steps (TS)
This work: 14 steps (LLS), 17 steps (TS)
HO3S
C15H31
O
O
O
7
O
OH
O
OH
O
O
14
C14H29
C15H31
7
HOOC
O
Phthioceranic acid 11
c
C15H31Bpin
+
18
C15H31
6
12
HOOC
17
5
11
10
RO
OCb
OH
12
OR1
pinB
14
+
OR1
12
RO
11
RO
OCb
Bpin
14
+
6
RO
OR1
AcO
OH
MOMO
OCb
5
15
Bpin
13
Figure 3 | Complex molecules of interest in this study associated with the cell-wall lipid of MTB. a, Structure of SL-1 the major cell-wall lipid of virulent
human MTB. b, Structures of two polydeoxypropionates that are coupled to the sugar core of SL-1, hydroxyphthioceranic acid 10 and phthioceranic acid 11.
Syntheses of 10 have recently been reported by the Minnaard group28 and by the Schneider group32. c, Retrosynthetic analysis of hydroxyphthioceranic acid
10. This shows how we envisaged building the molecule from simpler fragments. LLS, longest linear sequence; TS, total number of steps.
812
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.2010
ARTICLES
i. iPr2NCOCl,
Et3N, 98%
process. Desilylation with TBAF followed by carbamoylation
afforded the intermediate carbamate 20 in 97% yield.
MOMO
OCb
AcO
OH
A further lithiation of carbamate 20 and addition of the same
boronic ester building block 14 gave the homologated boronic
ester 21 in 85% yield. Unfortunately, the final protodeboronation
of this much more hindered boronic ester was found to be consider-
ably more challenging: the boronate complex did not even form
with aryllithium reagents, but did with n-BuLi, although the
desired product 22 was isolated in only a disappointing 18% yield.
Fortunately, using MeLi under the standard protocol with TBC
and Mn(OAc)3·2H2O gave the protodeboronated product in 61%
yield. The two-stage reaction of LBP was also carried out in one
pot to give product 22 in a similar yield (54%) (Fig. 5). Evidently,
the protodeboronation step is sensitive to the steric environment
around boron and it was extremely useful to have a suite of
methods available at our disposal that could be used according to
need. Desilylation with TBAF followed by carbamoylation afforded
the final carbamate 12 in 96% yield (Fig. 5).
ii. K2CO3, 98%
iii. MOMCl,
DIPEA, 99%
15
13 6 g
i. TBDPS-Cl, 98%
ii. K2CO3, 98%
iPr2NCOCl
Et3N, 97%
HO
OTBDPS
CbO
OTBDPS
16
5 g
sBuLi,
TMEDA,
PinBH, 72%
EtOCb, sBuLi.
(+)-sparteine
pinB
OTBDPS
OTBDPS
pinB
Et2O, –78 to 50 °C,
12 h
17 6 g
8 g
14
99:1 d.r., 92%
The final stereoselective coupling of carbamate 12 and pinacol
boronic ester 24 initially proved challenging because boronic ester
24 was not soluble in diethyl ether at −78 °C, which resulted in
poor yields. Fortunately, it was soluble in t-butyl methyl ether
(TBME). Thus, stereoselective deprotonation of carbamate 12
with s-BuLi/(+)-sparteine in TBME followed by addition of
boronic ester 24 and heating gave an intermediate boronic ester
that was oxidized directly to alcohol 25 in 88% isolated yield (d.r.
>95:5). Deprotection of the MOM group followed by chemoselective
oxidation of the primary alcohol to the acid39–41 in the presence of
the secondary alcohol afforded hydroxyphthioceranic acid 10, the
target natural product, in 90% isolated yield (Fig. 5). The acid 10
was converted into the corresponding methyl ester with
TMSCHN2 (TMS, trimethylsilyl) and was found to be identical in
all respects with the reported data.
Figure 4 | Synthesis of building blocks 13 and 14 used in the synthesis of
hydroxyphthioceranic acid 10. DIPEA, N,N-diisopropylethylamine.
followed by the addition of pinacol boronic ester 17 and heating
gave the homologated product 14 in 92% yield and 99:1 d.r.
With substantial quantities of the required building blocks in
hand, we set about their union using our lithiation–borylation–
protodeboronation (LBP) sequence (Fig. 5). Thus, deprotonation
of carbamate 13 with s-BuLi/TMEDA (N,N,N′,N′-tetramethylethy-
lenediamine) followed by the addition of boronic ester 14 gave
the homologated boronic ester 18 in 91% isolated yield (1:1 d.r.)2.
For protodeboronation, although the use of aryllithium or
TBAF was unsuccessful, the use of n-BuLi with TBC and
Mn(OAc)3·2H2O gave the protodeboronated product 19 in 68%
yield (Fig. 5). The two-stage LBP was also carried out in one pot
to give product 19 in a similar yield (63%) as that of the two-step
In conclusion, we have shown that lithiation–borylation followed
by protodeboronation provides a new traceless strategy for linking
fragments together derived from easily accessible alcohols and
(a), (b), one pot, 63%
(b) i. nBuLi, THF,
(a) sBuLi, TMEDA,
OR
–78 °C, 1 h
OTBDPS
pinB
Et2O, –78 to 50 °C
MOMO
14
13
MOMO
OTBDPS
+
ii. TBC, Mn(OAc)3,
DCE, 80 oC, 68%
d.r. 1:1, 91%
19
18
5 g
Bpin
MOMO
OCb
i. TBAF, 94%
ii. iPr2NCOCl, Et3N,
(c), (d), one pot, 54%
CH2Cl2, 97%
(c) 14, sBuLi
(d) i. MeLi,
Et2O, –78 °C
TMEDA, Et2O
MOMO
OTBPDS
MOMO
OTBDPS
MOMO
OCb
ii. Mn(OAc)3,
TBC, DCE,
80 °C, 61%
8
–78 to 50 °C,
d.r. 1:1, 85%
20
2 g
4 g
Bpin
21
22
i. TBAF, 99%
ii. iPr2NCOCl, Et3N,
toluene, 96%
pinB
24
14
i. sBuLi, (+)–sparteine,
TBME, –78 to 60 °C
MOMO
C15H31
MOMO
OCb
ii. H2O2, NaOH,
THF, r.t., 88%
12
1.3 g
OH
d.r. > 95:5
25
i. conc. HCl, 92%
ii. TEMPO, NaOCl,
NaClO2, buffer
HO
O
CCl4:CH3CN (1:3),
65 oC, 12 h, 90%
10
OH
Figure 5 | Total synthesis of hydroxyphthioceranic acid 10. The starting materials and reagents used to construct hydroxyphthioceranic acid 10 are shown
in this figure. Bold arrows indicate a one-pot transformation. This figure shows how just two simple building blocks, 13 and 14, can be combined through
iterative LBP (one pot) ultimately to construct hydroxyphthioceranic acid 10 in just nine steps with full stereocontrol. r.t., room temperature.
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813

NATURE CHEMISTRY DOI: 10.1038/NCHEM.2010
ARTICLES
21. World Health Organization. WHO Fact Sheets on Tuberculosis (2009).
www.who.int/tb/publications/2009/tbfactsheet_2009update_one_page.pdf
22. Zhang, L., Goren, M. B., Holzer, T. J. & Andersen, B. R. Effect of Mycobacterium
tuberculosis-derived sulfolipid I on human phagocytic cells. Infect. Immun.
56, 2876–2883 (1988).
23. Glickman, M. S. & Jacobs, W. R. Jr. Microbial pathogenesis of Mycobacterium
tuberculosis: dawn of a discipline. Cell 104, 477–485 (2001).
24. Converse, S. E. et al. MmpL8 is required for sulfolipid-1 biosynthesis and
Mycobacterium tuberculosis virulence. Proc. Natl Acad. Sci. USA 100,
6121–6126 (2003).
boronic esters. A new protocol for the protodeboronation of alkyl
pinacol boronic esters was developed for this strategy, which involved
the formation of a boronate complex (with RLi or TBAF) followed by
oxidation with Mn(OAc)3 in the presence of TBC. This new discon-
nection was successfully applied to a total synthesis of hydroxyphthio-
ceranic acid 10 in just 14 steps, with essentially complete stereocontrol.
The practicality of the synthesis has been demonstrated by carrying
out the sequence on a multigram scale. Moreover, our 14-step syn-
thesis is substantially shorter than any previous synthesis, which
demonstrates the power of the LBP strategy.
25. Goren, M. B., Brokl, O., Das, B. C. & Lederer, E. Sulfolipid I of Mycobacterium
tuberculosis, strain H37RV. Nature of the acyl substituents. Biochemistry
10, 72–81 (1971).
Received 28 February 2014; accepted 18 June 2014;
published online 27 July 2014
26. Goren, M. B., Brokl, O., Roller, P., Fales, H. M. & Das, B. C. Sulfatides of
Mycobacterium tuberculosis: the structure of the principal sulfatide (SL-I).
Biochemistry 15, 2728–2735 (1976).
27. Young, D. & Dye, C. The development and impact of tuberculosis vaccines.
Cell 124, 683–687 (2006).
28. Geerdink, D. et al. Total synthesis, stereochemical elucidation and biological
evaluation of Ac2SGL; a 1,3-methyl branched sulfoglycolipid from
Mycobacterium tuberculosis. Chem. Sci. 4, 709–716 (2013).
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Acknowledgements
We thank the Engineering and Physical Science Research Council (EP/I038071/1) and the
European Research Council (FP7/2007-2013, ERC grant no. 246785) for financial support.
R.R. thanks the Marie Curie Fellowship program (EC FP7, No 329578). We thank A. Scott
for technical assistance.
Author contributions
V.K.A. conceived the project and wrote the manuscript with R.R. R.R planned and carried
out the experiments. R.R. and V.K.A. discussed the experiments and results.
Additional information
Supplementary information and chemical compound information are available in the
online version of the paper. Reprints and permissions information is available online
at www.nature.com/reprints. Correspondence and requests for materials should be addressed
to V.K.A.
Competing financial interests
The authors declare no competing financial interests.
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