Short Convergent Synthesis of the Mycolactone Core Through Lithiation-Borylation Homologations

Article abstract of DOI:10.1002/chem.201503122

Using iterative lithiation-borylation homologations, the mycolactone toxin core has been synthesized in 13 steps and 17 % overall yield. The rapid build-up of molecular complexity, high convergence and high stereoselectivity are noteworthy features of thi

Full text of DOI:10.1002/chem.201503122

DOI: 10.1002/chem.201503122
Communication
&
Asymmetric Synthesis
Short Convergent Synthesis of the Mycolactone Core Through
Lithiation–Borylation Homologations
Christopher A. Brown and Varinder K. Aggarwal*[a]
Abstract: Using iterative lithiation–borylation homologa-
tions, the mycolactone toxin core has been synthesized in
13 steps and 17% overall yield. The rapid build-up of mo-
lecular complexity, high convergence and high stereose-
lectivity are noteworthy features of this synthesis.
Scheme 1. Structure of mycolactone A/B 1 and core 2.
The third most common Mycobacterium infection (after M. tu-
berculosis and M. leprae) is that of M. ulcerans, the pathogen
responsible for the severe ulcerative skin disease, Buruli ulcer.[1]
Endemic in tropical Africa, it infects over 5000 patients per
annum with 48% of cases being aged under 15.[1a,2] Transmis-
sion is thought to occur by an aquatic organism bite,[3] with in-
itial manifestation occurring as a painless skin nodule. If diag-
nosed early, simple antibiotic chemotherapy is effective
(80%),[4] however, if untreated, propagation of the infection re-
sults in large skin lesions of necrotic tissue and bone loss
which are only treatable through aggressive surgery, resulting
in scarring and loss of limb function.[2,5] The serious morbidity
due to the socio-economic burden of a young disabled work-
force in rural communities[6,7] resulted in the World Health Or-
ganization identifying Buruli ulcer as one of seventeen neglect-
ed tropical diseases requiring research.[7]
and Altmann.[17] These efforts have enabled further research
into the pathogenesis of Buruli ulcer,[18] aid the invention of
new/simpler diagnostic techniques[19] and allowed structural
activity relationships of the core.[16,17,20] These SAR investiga-
tions have shown that while the northern fragment can be
augmented, a complete side chain is critical for the potency of
1.[20a] The side chain of 1 has already been synthesized by the
groups of Kishi,[21] Negishi[22] and Feringa/Minnaard,[23] so we
therefore focused our efforts towards the synthesis of the lac-
tone core 2. We were particularly keen on applying our recent-
ly developed lithiation–borylation methodology,[24] which is
highly effective in not only controlling stereochemistry but
also simultaneously creating CÀC bonds. Whilst such method-
ology has already been applied to a number of targets,[25] in-
cluding strategies involving iterative homologations for gener-
ating contiguous stereocenters,[26] mycolactone core 2 repre-
sents a considerably higher level of complexity. Herein we de-
scribe our success in applying our lithiation–borylation meth-
M. ulcerans secretes a unique polyketide-derived virulence
factor, an equilibrating mixture of mycolactones A and B,
1 (Scheme 1, 3:2 trans/cis) which inhibits the immune response
and causes necrosis of the infected tissue.[1a,c] Small and co-
workers[8] successfully isolated milligram quantities of 1 allow-
ing structure elucidation by NMR[9] and confirmation of myco-
lactones A/B as the causative toxin through studies in vivo.[10]
A number of congers (C–F) have since been isolated contain-
ing the common lactone 2, varying only by the appended acyl
side chain.[11]
The absolute stereochemistry of firstly the lactone core 2[12]
and then mycolactones A/B 1[13] was determined through total
synthesis by Kishi and co-workers. Multiple synthetic studies
have since followed including a 3rd generation (1.3 g)[14] syn-
thesis of protected core 2 by Kishi, in addition to other accom-
plished syntheses by the groups of Negishi,[15] Blanchard,[16]
odology to
molecule.
a short convergent synthesis of this target
Our retrosynthetic analysis began with disconnection to the
known intermediate 3 (Scheme 2).[12,15] We considered a lithia-
tion–borylation disconnection between C11–C12 as this would
lead to high convergency. Both boronic ester 4 and carbamate
5 could themselves be obtained through consecutive lithia-
tion–borylation reactions of fragments 7 and 10. Indeed,
through our iterative methodology there was the prospect of
coupling boronic ester 7 with building block 6 followed by
carbamate 5 in one pot to give the lactone precursor 3. Simi-
larly carbamate 5 could be constructed in one pot from itera-
tive coupling of boronic ester 10 and carbamates 9 and 6.
We began with the synthesis of boronic ester 10, which was
achieved in three high yielding steps (Scheme 3). Copper-cata-
lyzed formal hydroboration[27] of alkynol 11 with B2pin2 in the
presence of MeOH gave the desired vinyl boronate in 83%
yield as a single regio- and stereoisomer. Subsequent carba-
[a] C. A. Brown, Prof. Dr. V. K. Aggarwal
School of Chemistry, University of Bristol
Cantock’s Close
Bristol, BS8 1TS (UK)
E-mail: V.Aggarwal@bristol.ac.uk
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201503122.
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Communication
Scheme 3. Synthesis of 10. a) CuCl (5 mol%), PPh3 (6 mol%), KOtBu
(20 mol%), B2pin2, MeOH, THF, 83%; b) CbCl, Et3N, THF, 87%; c) BrCH2I or
ClCH2I (3.5 equiv), nBuLi (2.4 equiv), Et2O (0.4m), À788C or À958C, 99%.
formed from the addition of 10 into 6 (1.5 equiv), underwent
1,2-metallate rearrangement in refluxing Et2O to form 14 in
83% yield. NMR analysis of the derived Mosher’s ester showed
that the homologation occurred in 97:3 e.r. Subsequent reac-
tion of 14 with 9 (1.3 equiv) proceeded well, providing alcohol
15 after oxidation in 77%, >97:3 e.r. and 94:6 d.r. The diaste-
reomeric ratio is consistent with reactions that are under full
reagent control employing lithiated carbamates 6 and 9 with
97:3 e.r. Thus, carbamate 15 was formed in 63% yield from 12
in three steps. These three steps could also be carried out se-
quentially, without intermediate purification (“one-pot”), on
identical scale in an increased 81% yield without detriment to
d.r. and further performed on an 8 mmol scale thereby deliver-
ing 3.0 g of 15, with 85% recovery of (+)-sparteine. The poten-
tially reactive carbamate group remained intact allowing us to
circumvent functional group manipulation and, after C5 silyl
protection (82%), we obtained the desired carbamate 5 in
48% over six steps from alcohol 11.
Scheme 2. Retrosynthetic analysis of mycolactone core 2. PG=Protecting
Group, pin=pinacolato, Cb=N,N-diisopropylcarbamoyl, sp=sparteine.
moylation of the alcohol gave carbamate 12 in 87% yield. Mat-
teson one-carbon homologation with chloromethyllithium 13
(formed in situ with 12)[28] gave the desired allylic boronic
ester 10 as a 99:1 mixture with 12. High conversion was ach-
ieved through the addition of precooled nBuLi[29] and using an
excess of the dihalide with respect to the organolithium to
limit competing addition of nBuLi to boronic ester 12 and
thereby favour lithium–halogen exchange. In contrast to vinyl
boronic ester 12, allylic boronic ester 10 was unstable to silica
gel but was nevertheless obtained in high purity by simple fil-
tration and evaporation.
The synthesis of boronic ester 4 started with preparation of
7 g of alkene 8 through a four-step known procedure in 74%
yield and 96:4 d.r. (Scheme 5).[15,17a] Direct formation of allylic
boronate 7 was investigated, employing methallyl boronic
ester 17 and Hoveyda–Grubbs 2nd generation catalyst 19,
which gave 7 in 62% yield but only as a 90:10 E/Z mixture of
With boronic ester 10 in hand, our key lithiation–borylation
reactions were examined (Scheme 4). The boronate complex,
Scheme 4. 1CH = ClCH2I (3.5 equiv), nBuLi (2.4 equiv), Et2O (0.4m), À958C, formation of carbenoids=Carbamate (1.0 equiv), sparteine (1.0 equiv), sBuLi
(1.0 equiv), Et2O (0.4m), À788C, 5 h, Li-B=Carbenoid (1.5 equiv), then RBpin (1.0 equiv), À788C, 2 h, then 408C, 16 h, [O]=NaOH/H2O2, THF, 08C, 2 h,
P=TBSCl (1.4 equiv), imidazole (1.6 equiv), DMF, 258C, 16 h.
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isomers. Olefin metathesis with vinylic boronic ester 18 has
been reported to occur with much higher selectivity[30] and
was therefore explored. We were pleased to find that subject-
ing alkene 8 and vinylic boronic ester 18 to the identical cross
metathesis conditions, yielded 20 as a single geometric isomer
(0.4 mmol scale, 68% yield). However, upon scale up we en-
countered two major problems: i) a dramatic reduction in con-
version (10% after 14 h, 3.8 mmol scale), and; ii) the formation
of 1,2-disubstituted alkene 21 (15%). The latter observation
has been described previously,[30] possibly due to the transposi-
tion of boron from the internal to the terminal position of
alkene 18 and subsequent metathesis with 8. As this product
was only observed by GC-MS after extended reaction times
(over 10 h), it was attributed to a transmuted catalyst of 19
causing the isomerization of 18.[31] Therefore, it was imperative
to increase conversion over a short reaction time to avoid cata-
lyst degradation. Through running the reaction at higher con-
centration (1.0m) and adding the catalyst portion-wise (5+
5 mol%), we increased conversion to 45% and reduced the
amount of 21 formed (5%). Finally, periodic degassing of the
reaction every two hours removed the ethylene content of the
solution and further pushed the equilibrium towards vinyl bor-
onate 20, achieving a 60% yield on a 5.3 mmol scale over 10 h
with minimal formation of alkene 21 (<5%).
20 in 66% over three steps. Once again, these three steps
could also be carried out sequentially, without intermediate
purification (“one-pot”), in an increased 86% yield. As a result,
significant amounts (>900 mg) of 3 was obtained over eight
steps from (R)-3-hydroxybutyrate in 38% overall yield.
Completion of the synthesis followed literature precedent
(Scheme 6).[12,15] Selective deprotection of the primary silyl
ether with TBAF (85%), followed by a two-step TEMPO/Pinnick
oxidation, yielded acid 23 in 81%. Lactonisation of the 12-
membered core proceeded efficiently under Yamaguchi condi-
tions (81% yield), and subsequent global deprotection with
HF·pyridine gave the mycolactone core 2 in 80%. In forming
the lactone ring, minor diastereomers observed in the forma-
tion of 3 were separated completing the synthesis of lactone
2, which was identical in all respects to the literature, in a total
of 13 steps and 17% overall yield.
Scheme 6. Completion of synthesis. a) TBAF, THF, 85%; b) i. TEMPO
(15 mol%), BAIB, CH2Cl2/H2O (2:1); then b) ii. NaClO2, 2-methyl-2-butene,
Na2H2PO4 buffer/tBuOH (2:1), 81%; c) (C6H2Cl3)COCl, DMAP, PhH, 81%;
d) HF·pyridine, THF, 80%.
In conclusion, the shortest synthesis of the mycolactone
core to date has been completed both in terms of longest
linear sequence (13 vs 14[14] steps) and total step count (17 vs
28[14] steps). Moreover if the sequenced iterative homologation
is counted as one step, then the mycolactone core is achieved
in only 11 steps. Although a scalable route has already been
accomplished, our synthesis is able to rapidly deliver significant
amounts (>100 mg) of highly enantio- and diastereoenriched
mycolactone core through utilization of simple carbamate
building blocks. Both in terms of step count and scale, the syn-
thesis showcases the power of lithiation–borylation methodol-
ogy for the efficient and convergent synthesis of complex mol-
ecules.
Scheme 5. Olefin metathesis of 8.
With our two key building blocks in hand, we examined our
final iterative lithiation–borylation process. Matteson one-
carbon homologation of 20 proceeded in near quantitative
yield and homologation of 7 with lithiated carbamate 6
(1.5 equiv) gave our required fragment 4 in 81% isolated yield.
Oxidation and NMR analysis showed it to be 97:3 d.r., consis-
tent with the homologation of 6 with analogous allylic boro-
nate 10. For the final step, lithiation of 5 in the presence of
(À)-sparteine was required, but in explorative lithiation–deuter-
ation experiments we isolated diene 22[32] in 10% yield, in ad-
dition to the required deuterated product (90%). This showed
that 10% lithiation of 5 occurred at the allylic position fol-
lowed by E2 elimination of the carbamate. We therefore used
an excess of carbamate 5 (1.5 equiv) with respect to boronic
ester 4 (1.0 equiv), and the final homologation and subsequent
oxidation gave known intermediate 3 in 82% yield and high
d.r.[33] with 950 mg prepared. With isolation and chromato-
graphic purification of each intermediate, 3 was formed from
Acknowledgements
We thank EPSRC (EP/I038071/1) and the European Research
Council (FP7/2007-2013, ERC grant no. 246785) for financial
support. We thank Dr. Eddie Myers and Dr. Daniele Leonori for
helpful suggestions.
Keywords: asymmetric synthesis
·
boron
·
iterative
homologation · mycolactone · natural products
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Communication
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Supporting Information for full details.
Received: August 7, 2015
Published online on September 1, 2015
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