Modular total syntheses of mycolactone A/B and its [2H]-isotopologue

Article abstract of DOI:10.1039/c7ob01943b

A modular total synthesis of mycolactone A/B, the exotoxin produced by Mycobacterium ulcerans, has been achieved through the orchestration of several Pd-catalyzed key steps. While this route leads to a mixture of the natural product and its C12 epimer (4:

Full text of DOI:10.1039/c7ob01943b

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2017, DOI: 10.1039/C7OB01943B.
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Takeharu Haino et al.
Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
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DOI: 10.1039/C7OB01943B
Journal Name
COMMUNICATION
Modular total syntheses of mycolactone A/B and its [2H]-
isotopologue
Sarah Saint-Auret,a Hajer Abdelkafi,a Didier Le Nouen,b Laure Guenin-Macé,c Caroline Demangel,c
Received 00th January 20xx,
Accepted 00th January 20xx
Philippe Bissereta and Nicolas Blancharda*
DOI: 10.1039/x0xx00000x
www.rsc.org/
A modular total synthesis of mycolactone A/B, the exotoxin Since 2006, we have been engaged in a Diversity Oriented
produced by Mycobacterium ulcerans has been achieved through Synthesis approach to mycolactone A/B analogs that led us to
the orchestration of several Pd-catalyzed key steps. While this report some structure-activity relationship data and to uncover
route leads to a mixture of the natural product and its C12 epimer a fully functional analog of mycolactone A/B mimicking its
(4:1 ratio), this was inconsequential from the biological activity activity in in vivo inflammation disorders models.8 In addition to
standpoint. Compared to previously reported routes, this synthetic its necrotic potential, mycolactone A/B has inhibitory properties
blueprint allows the late-stage modification of the toxin, as on cytokines production by immune cells.1c,9 Considering the
exemplified with the preparation of [22,22,22-2H3]-mycolactone translational potential of mycolactone A/B and its analogues,8c
A/B.
a modular synthetic scheme is of prime importance to further
advance our understanding of this promising therapeutic agent
through in vivo studies. A second current challenge is the
quantification of mycolactone from biological samples that
could be addressed by isotope dilution mass spectrometry
(IDMS)10 using the appropriately stable isotope labeled
mycolactone.
We report herein our preliminary results of a flexible synthetic
blueprint that culminates in a total synthesis of mycolactone
A/B (as a 12S/12R = 80:20 mixture of diastereomers) that is
indistinguishable in its ability to inhibit T-cell interleukin-2
production compared to the toxin isolated from the culture of
M. ulcerans. In addition, this de novo strategy led to the
[22,22,22-2H3]-isotopologue of the natural product, which could
be used as an internal standard for IDMS.
Buruli ulcer is a dramatic skin disease in human currently
reported in more than 30 countries in Africa, South America and
Western Pacific regions, with >2000 new cases in 2015.1 Since
the clinical description of this third most common
mycobacterial disease in 1948,2 intense research efforts have
been deployed by the scientific community to understand and
control this infection caused by the environmental
Mycobacterium ulcerans.1c,3 In 1999, the discovery of
mycolactone A/B as the major virulence factor of M. ulcerans
was a breakthrough as it opened a molecular perspective on this
devastating disease.4 Mycolactone A/B, a complex macrolidic
polyketide secreted by Mycobacterium ulcerans (Scheme 1),
belongs to a larger family comprising nine mycolactones (C, D,
E plus its minor metabolite, F, dia-F, S1 and S2) isolated from M.
ulcerans or M. marinum as major or minor species and affecting
several animal species.1c,5 Pioneering studies by Kishi confirmed
the gross structure and elucidated the complete
stereochemistry of the exotoxin in 2001,6 and several research
groups have since then contributed to elegant total and partial
syntheses.1c,7
The retrosynthetic analysis of mycolactone A/B and its
[22,22,22-2H3]-isotopologue is depicted in Scheme 1 and calls
for an esterification reaction between the C1C20 fragments
1a,b and the fatty carboxylic acid C1’C16’ 2 1c
.
The second
disconnection relies on a late stage methylation reaction of the
C8-Br -bond of compound which in turn could be obtained
via the formation of the C13C14 s-bond thanks to a Suzuki
cross-coupling of the organoborane with the (E)-trisubstituted
vinyliodide . Organoborane could be prepared by a chemo-
and diastereoselective hydroboration reaction of the
isopropenyl-macrolactone , itself obtained from skipped diene
by a dihydroxylation reaction followed by elimination. Further
disconnection focuses on the (Z)-trisubstituted C8C9
s
3
5
4
5
6
7
vinylbromide motif of
7
that could be prepared in a single step
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J. Name., 2013, 00, 1-3 | 1
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Journal Name
1. PhI(OAc)2
TsO
1. TBSCl
Im., CH2Cl
DOI: 10.1039/C7OB201943B
TsO
5
View Article Online
TEMPO (10 mol%)
CH2Cl2
20
20
6
69%
2. (—)-Ipc2Ballyl
Et2O, -78 °C then
NaBO3•4H2O
2. Methyl acrylate
[Ru]-2 (7 mol%)
1,2-DCE, 60 °C
OH
OH
OP
OP
OH
OH
O
O
O
O
51% (2 steps)
10, d.r. > 93:7
9
94%
R
R
1
1
22
22
1. H2, PtO2
(12 mol%)
AcOEt
5
TsO
TsO
1. TBSCl, Im.
DMF
7
7
O
1'
OP
1a, R = Me
1b, R = CD3
1
HO
( )3
MeO2C
Esterification
reaction
2. Lithium acetylide
THF/DMSO (1:1)
0 °C, 72%
2. DIBAL-H
toluene
-78 to 20 °C
quant. (2 steps)
O
OTBS
OTBS
11
12
HO 1'
O
(2 steps)
R
13
9
16'
9
8
R
8
Allyl bromide
PdBr2(PhCN)2 (5 mol%)
NaHCO3
OH
Br
OH
OH
TBSO
TBSO
16'
Mycolactone A/B, R = Me
THF, 20 °C, 97%
1
OP
OTBS
OTBS
[22,22,22-2H3]-Mycolactone A/B, R = CD3
13
OP
OP
2
2-Methyl-2-butene
[Ru]-2 (2 mol%)
CH2Cl2, 20 °C, 99%
14, R = H
15, R = Me
[> gram scale]
Suzuki
cross-coupling
14
I
ethylenediamine delivered the desired terminal alkyne 13 in
good yield. This seemingly trivial step required a careful
optimization as a competitive E2-elimination of the tosylate was
a serious concern in a variety of solvents and temperatures.
4
O
O
14
13
13
[BL2]
11
Si
tBu
tBu
OP
OP
8
O
O
O
O
Br
Br
Late stage
functionalization
of C8-Br
Scheme 2. Synthesis of the C1C13 Sector of Mycolactone A/B.
Kaneda stereoselective bromoallylation11 of 13 led exclusively
to (Z)-14 (97%) which was then engaged in a cross-metathesis
with 2-methyl-2-butene, leading to 15 (99%) on gram scale.
OP
OP
3
5
Dihydroxylation
/ elimination
(Z)-Stereoselective
bromoallylation
Diastereo-
selective
allylation
11
O
9
11
Dihydroxylation of the C11C12-p-system of 15 proceeded in
8
O
LG
Br
Br
high yield and with an excellent diastereoselectivity (d.r. > 97:3,
Scheme 3) as proven by the complementary Mosher esters of
the C11-hydroxy function.12 1,2-Diol 16 could then be
transformed into the desired isopropenyl alcohol 17 in good
yield using a straightforward four-step sequence (54%).
Oxidation to the carboxylic acid 18 proceeded in good yield,
thus setting the stage for the macrolactonization of the seco-
acid. Among the different strategies13 evaluated for the
6
PO
5
( )3
6
OP
7
OP
8
OP
using
a
Kaneda
stereoselective
palladium-catalyzed
bromoallylation reaction11 of the corresponding alkyne, itself
prepared in a few steps from homoallylic ether 8.
Scheme 1. Retrosynthetic analysis of mycolactone A/B and its [22,22,22-2H3]-
isotopologue.
macrolactonization of 18
, Yamaguchi conditions proved
superior and led to the desired 12-membered macrolactone 19
in 48% (three steps) reproducibly. We then focused on the
In the forward sense, oxidation of primary alcohol 98a,b to the
corresponding aldehyde followed by its reaction with the
forging of the C13C14-
between organoborane
intermediate organoborane
proceed exclusively at the 1,1-disubstitued C12C13-
19, although the trisubstituted C8C9- -system is more electron-
s
5
-bond via a Suzuki cross-coupling
and vinyliodide 4 14
Generation of the
in such a complex setting should
-system of
commercially
available
(–)-diisopinocampheyl
borane
.
proceeded smoothly at -78 °C to deliver homoallylic alcohol 10
in good yield and diastereoselectivity, on a decagram scale
(Scheme 2).8a,b As noted in our first-generation synthesis of
mycolactone analogs, the nature of the oxidative work-up
proved crucial, with sodium perborate being the most practical
oxidant and leading to the cleanest crude reaction. Protection
of the C5-hydroxy group as a silyl ether followed by chain
extension towards C1 relied on a cross-metathesis reaction with
methyl acrylate using second generation Grubbs precatalyst
5
p
p
deficient. In addition, this hydroboration reaction installs the
C12-stereocenter and should thus occur diastereoselectively
thanks to the conformational bias imposed by the C11
stereogenic center in the a-position of the C12C13 p
-system.15
The reluctance of the 1,1-disubstituted alkene of 19 to undergo
hydroboration with 9-BBN-H in a variety of reaction conditions
was quite surprising. After considerable experimentation, it was
discovered that the hydroboration proceeded with complete
chemoselectivity and correct diastereoselectivity (d.r. = 80:20,
unseparable C12 epimers) using 9-BBN-H dimer in THF under
ultrasonic irradiation. Although not very common in
[Ru]-2, leading to the
Reduction of the C2C3-
a
,
b
p
-unsaturated ester 11
-deficient system of the latter under
.
PtO2-catalyzed hydrogenation conditions was then followed by
reduction of the ester function to the primary alcohol 12
.
Protection as a silyl ether followed by displacement of the
tosylate with the commercially available lithium acetylide•1,2-
2 | J. Name., 2012, 00, 1-3
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COMMUNICATION
1. DIBAL-H,
-78 °C, 97%
2. MnO2, CH2Cl2
3. CrCl2, CHI3
11
HO
View Article Online
DOI: 10.1039/C7OB01943B
OTBS
OTBS
1. Ac2O, pyr.
2. SOCl2, pyr.
AD-mix β
NH2SO2Me
HO
HO
EtO2C
Bu3Sn
15
Br
Br
85% (2 steps)
4. nBuLi, Bu3SnCl
Et2O, -78 °C
3. DIBAL-H
CH2Cl2
4. TBAF, THF
54% (4 steps)
tBuOH/H2O (1:1)
4 °C, 89%
TBSO
OTBS
TBSO
OTBS
TBSO
( )3
R
23, d.r. > 96:4
24
OTBS
OTBS
4'
8'
1'
O
HO
5'
16, d.r. > 97:3
17, R = CH2OH
1. PhI(OAc)2
TEMPO cat.
2. NaClO2
I
d.r. > 96:4
EtO2C
[900 mg scale]
7'
25
18, R = CO2H
1. Pd(PPh3)4 (8 mol%)
CuTC, Ph2P(O)O-, Bu4N+
13
26, Z-Δ4'-5'/E-Δ4'-5' = 1:1
14
13
Cl3C6H2COCl
iPr2NEt
DMAP
1. [9-BBN]2
THF
ultra-sound
12
DMF, 20 °C, 1 h, 89% (2 steps)
2. LiOH, THF/EtOH/H2O, 81%
3. hν (12 mW.cm-2), acetone,
quant.
11
O
9
8
16'
12
O
O
OTBS
O
Si
Br
benzene
48%
(3 steps)
2. 4, AsPh3
(30 mol%)
Pd(dppf)Cl2
(15 mol%)
Cs2CO3
tBu tBu
OTBS OTBS
O
O
Br
8
OTBS
19
H2O, DMF
60% (2 steps)
OTBS
1. 26, Cl3C6H2COCl
iPr2NEt, DMAP
THF
12
OH
OH
20, 12S/12R = 80:20
92% (a), 50% (b)
O
O
22a, R = Me
22b, R = CD3
R
22
2. HF•pyr
THF/pyr.
100% (a,b)
3. TBAF, THF
97% (a), 61% (b)
R2Zn
Pd(PPh3)4
(7 mol%)
12
12
O
AcOH
DOWEX
(50WX8-400)
O
O
O
Si
O
Si
tBu tBu
tBu tBu
O
O
O
O
R
O
R
Mycolactone A/B
(R = Me, 12S/12R = 80:20)
THF, 90 °C
THF
60 °C
5
[22,22,22-2H3]-Mycolactone A/B
OTBS
12S/12R = 80:20
21a, R = Me, 75% (brsm)
21b, R = CD3, 75%
OH
(R = CD3, 12S/12R = 80:20)
12S/12R = 80:20
22a, R = Me, 63%
22b, R = CD3, 55%
OH
OH
OH
hydroboration of alkenes, these conditions were pioneered by
Brown in 198516 and have found applications in a few total the desired C1’-C16’ protected fragment 26 as a Z-D4’,5’/E-D4’,5’
syntheses.17
= 1:1 mixture. The latter is also found in the natural exotoxin of
M. ulcerans due to the severe allylic strain1,21 imposed by the
substitution pattern of the C4’C5’-p-system.
Scheme 3. C1C20-Fragments syntheses via hydroboration/Suzuki Cross-Coupling.
Scheme 4. Synthesis of the C1’C16’ fragment 26 and completion of the syntheses
of mycolactone A/B and of its [22,22,22-2H3]-isotopologue.
Under optimized conditions, the hydroboration/Suzuki cascade
proceeded smoothly in 60%, delivering the C1C20 fragment 20
(as a 12S/12R = 80:20 mixture of diastereomers). A late-stage
methylation of the C8-position was finally required; this task in
a quite complex setting was met by palladium-catalyzed Negishi
cross-couplings with dimethylzinc or d6-dimethylzinc in THF at
90 °C, leading to 21a and 21b. Final deprotections of the C5-
silyloxy groups under acidic conditions delivered the complete
C1C20 fragments 22a (63%) and 22b (55%) both as a
unseparable 12S/12R = 80:20 mixture of diastereomers.
Completion of mycolactone A/B and [22,22,22-2H3]-
mycolactone A/B syntheses was readily accomplished by
esterification under Yamaguchi conditions of 22a,b with 26
,
followed by stepwise deprotections of the orthogonal silyl
ethers as already reported by Altmann and co-workers.8i
Having in hand the complete C1-C20 fragments of the natural
mycolactone A/B and of its [22,22,22-2H3]-isotopologue, we
turned our attention to the southern C1’-C16’-fragment 26 with
the goal of improving our first-generation synthesis9a,b of this
crucial sector of the natural product. Indeed, screening of
catalytic systems for the key Stille cross-coupling between iodo-
trienoate 25 and dienyl stannane 24 pointed to the Fürstner
modification18 (Pd(PPh3)4, copper(I) thiophene carboxylate
(CuTC)19 and Bu4N(Ph2P(O)O- as a tin salts scavenger20 in DMF).
An excellent 89% yield was obtained for the last two steps,
Figure 1. Comparative immunosuppressive activities of synthetic (as a 12S/12R =
80:20 mixture of diastereomers) and natural mycolactone A/B as evaluated by
inhibition of IL-2 production by activated human T cells.
namely formation and cross-coupling of dienylstannane 24
.
Hydrolysis of the ester followed by visible-light
photoisomerization of the conjugated pentaenyl system led to
The ability of this synthetic mycolactone (as a 12S/12R = 80:20
mixture of diastereomers) to inhibit the activation-induced
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Journal Name
C. Small, D. Beachboard and Y. Kishi, Org. Lett., 2008, V1i0ew, 5A3rt8ic5le. (Ocn)liHne.
J. Kim and Y. Kishi, J. Am. Chem. Soc., 2008, 130, 1842; (d) T.
Spangenberg, S. Aubry and Y. Kishi, Tetrahedron Lett., 2010, 51,
1782; (e) S. M. Hande, Y. Kazumi, W. G. Lai, K. L. Jackson, S. Maeda
and Y. Kishi, Org. Lett., 2012, 14, 4618; (f) Y. Xing, S. M. Hande and Y.
Kishi, J. Am. Chem. Soc., 2012, 134, 19234.
production of IL-2 by Jurkat cells was measured and compared
to results obtained with the toxin isolated from the culture of
M. ulcerans (Figure 1). In this T cell model, the natural
mycolactone dose-dependently suppressed the production of
IL-2 upon stimulation using phorbol 12-myristate 13-acetate
DOI: 10.1039/C7OB01943B
6
7
(a) A. B. Benowitz, S. Fidanze, P. L. C. Small and Y. Kishi, J. Am. Chem.
Soc., 2001, 123, 5128; (b) S. Fidanze, F. Song, M. Szlosek-Pinaud, P. L.
C. Small and Y. Kishi J. Am. Chem. Soc., 2001, 123, 10117.
(a) M. K. Gurjar and J. Cherian, Heterocycles, 2001, 55, 1095; (b) F.
Song, S. Fidanze, A. B. Benowitz and Y. Kishi, Org. Lett., 2002, 4, 647;
(c) R. Summeren, B. L. Feringa and A. Minnaard, Org. Biomol. Chem.,
2005, 3, 2524. (d) M. D. Alexander, S. D. Fontaine, J. J. La Clair, A. G.
Dipasquale, A. L. Rheingold and M. D. Burkart, Chem. Commun.,
2006, 4602; (e) F. Song, S. Fidanze, A. B. Benowitz and Y. Kishi,
Tetrahedron, 2007, 63, 5739; (f) K. Ko, M. D. Alexander, S. D.
Fontaine, J. E. Biggs-Houck, J. J. La Clair and M. D. Burkart, Org.
Biomol. Chem., 2010, 8, 5159; (g) K. L. Jackson, W. J. Li, C. L. Chen
and Y. Kishi, Tetrahedron, 2010, 66, 2263; (h) G. W. Wang, N. Yin and
E.-i. Negishi, Chem. Eur. J., 2011, 17, 4118. (i) P. Gersbach, A.
Jantsch, F. Feyen, N. Scherr, J.-P. Dangy, G. Pluschke and K.-H.
Altmann, Chem. Eur. J., 2011, 17, 13017; (j) C. A. Brown and V. K.
Aggarwal, Chem. Eur. J., 2015, 21, 13900.
(a) A.-C. Chany, V. Casarotto, M. Schmitt, C. Tarnus, L. Guenin-Macé,
C. Demangel, O. Mirguet, J. Eustache and N. Blanchard, Chem. Eur.
J., 2011, 17, 14413; (b) A.-C Chany, R. Veyron-Churlet, C. Tresse, V.
Mayau, V. Casarotto, F. Le Chevalier, L. Guenin-Macé, C. Demangel
and N. Blanchard, J. Med. Chem., 2014, 57, 7382. (c) L. Guenin-Macé,
L. Baron, A.-C. Chany, C. Tresse, S. Saint-Auret, F. Jönsson, F. Le
Chevalier, P. Bruhns, G. Bismuth, S. Hidalgo-Lucas, J.-F. Bisson, N.
Blanchard and C. Demangel, Sci. Trans. Med., 2015, 7, 289ra85.
(a) M. T. Silva, F. Portaels and J. Pedrosa, Lancet Infect. Dis., 2009, 9,
699, (b) D. S. Walsh, F. Portaels and W. M. Meyers, Dermatol. Clin.,
2011, 29, 1.
(PMA) and calcimycin with
a half maximal inhibitory
concentration (IC50) of 17 nM. The synthetic mycolactone had a
comparable dose-dependent suppressive effect with an IC50 of
6,7 nM.12
In conclusion, we have reported
a total synthesis of
mycolactone A/B as a 12S/12R mixture of diastereomers that
ultimately proved inconsequential on the biological activity.
Indeed, the ability of this synthetic mycolactone A/B to inhibit
T-cell interleukin-2 production is indistinguishable from the one
observed with the toxin isolated from the culture of M.
ulcerans. In addition, the flexible synthetic blueprint also
allowed the synthesis of [22,22,22-2H3]-mycolactone A/B as a
potential internal standard for isotope dilution mass
spectrometry. Considering the translational potential of
mycolactone A/B, this work opens new perspectives for the
late-stage modification advanced mycolactones intermediates,
especially in the macrolactonic core. Advances toward specific
probes based on mycolactone A/B chemical structure and able
to decipher the biology of this complex disease are underway
and will be reported in due course.
8
9
The authors thank the Université de Strasbourg, Investissement
d’Avenir (Idex Unistra), CNRS, Fondation « Raoul Follereau »,
Fondation « Pour Le Développement De La Chimie Des
Substances Naturelles Et Ses Applications » and Roche for a
generous gift of methyl 3-hydroxy-2-methylpropionate.
10 (a) B. Echeverria, J. Etxebarria, N. Ruiz, Á. Hernandez, J. Calvo, M.
Haberger, D. Reusch and N.-C. Reichardt, Anal. Chem., 2015, 87,
11460; (b) J. Villanueva, M. Carrascal and J. Abian, J. Proteomics,
2014, 96, 184.
11 K. Kaneda, T. Uchiyama, Y. Fujiwara, T. Imanaka and S. Teranishi, J.
Org. Chem., 1979, 44, 55.
12 See Supporting Information for details.
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4 | J. Name., 2012, 00, 1-3
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Organic & Biomolecular Chemistry
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DOI: 10.1039/C7OB01943B
Journal Name
COMMUNICATION
Modular total synthesis of mycolactone A/B and its [2H]-
isotopologue
Sarah Saint-Auret,a Hajer Abdelkafi,a Didier Le Nouen,b Laure Guenin-Macé,c Caroline Demangel,c
Philippe Bissereta and Nicolas Blancharda*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
Table of contents entry:
Graphic maximum size 8 cm x 4 cm and one sentence of text,
maximum 20 words, highlighting the novelty of the work.
OH
OH
8
O
O
R
OP
OP
O
8
O
O
O
Br
Mycolactone A/B
(R = Me) and its
[2H]-isotopologue
(R = CD3)
OP
Late-stage
functionalization
of C8
OH
OH
OH
A new synthetic blueprint of mycolactone A/B is reported,
granting access to the natural product and its [2H]–
isotopologue.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
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