Rapid and scalable synthesis of chiral bromolactones as precursors to α-exo-methylene-γ-butyrolactone-containing sesquiterpene lactones

Article abstract of DOI:10.1016/j.tet.2018.08.045

The sesquiterpene lactones cover a diverse and pharmacologically important diversity space. In particular, the electrophilic α-exo-methylene-γ-butyrolactone moiety that is preponderant in this natural product family has been shown to readily engage in cov

Full text of DOI:10.1016/j.tet.2018.08.045

Accepted Manuscript
Rapid and scalable synthesis of chiral bromolactones as precursors to α-exo-
methylene-γ-butyrolactone-containing sesquiterpene lactones
Roman Lagoutte, Miryam Pastor, Mathéo Berthet, Nicolas Winssinger
PII:
S0040-4020(18)31027-5
10.1016/j.tet.2018.08.045
TET 29765
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 11 June 2018
Revised Date: 23 August 2018
Accepted Date: 26 August 2018
Please cite this article as: Lagoutte R, Pastor M, Berthet Mathé, Winssinger N, Rapid and scalable
synthesis of chiral bromolactones as precursors to α-exo-methylene-γ-butyrolactone-containing
sesquiterpene lactones, Tetrahedron (2018), doi: 10.1016/j.tet.2018.08.045.
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ACCEPTED MANUSCRIPT
Graphical Abstract
O
O
Br
OH
2 steps
O
Zn0
O
O
R*
R*
R*
*
R’
readily available from
the chiral pool or asymmetic synthesis
present in
5500+ natural products
1600+ bioactive

ACCEPTED MANUSCRIPT
Rapid and scalable synthesis of chiral bromolactones as precursors to α-exo-
methylene-γ-butyrolactone-containing sesquiterpene lactones
Roman Lagoutte, Miryam Pastor, Mathéo Berthet, Nicolas Winssinger*
School of Chemistry and Biochemistry, NCCR Chemical Biology, University of
Geneva, 30 quai Ernest Ansermet, CH-1205 Geneva, Switzerland
E-mail: nicolas.winssinger@unige.ch
Abstract
The sesquiterpene lactones cover a diverse and pharmacologically important diversity
space. In particular, the electrophilic α-exo-methylene-γ-butyrolactone moiety that is
preponderant in this natural product family has been shown to readily engage in
covalent inhibition via conjugate addition of cysteine residues in target proteins.
However, the synthetic accessibility of sesquiterpenes or related probes to investigate
their mode of action remains laborious. Herein, we present a rapid and scalable route
to chiral bromolactones as enabling precursors in the synthesis of sesquiterpene
lactones.
O
O
Br
OH
2 steps
O
Zn0
O
O
R*
R*
R*
* R’
readily available from
the chiral pool or asymmetic synthesis
present in
5500+ natural products
1
600+ bioactive
Keywords
Sesquiterpene lactones, covalent inhibitors, α-exo-methylene-γ-butyrolactones,
bromolactones, enantioselective synthesis, Barbier coupling
1
. Introduction
“Tell him to move to Biology!” This was Prof Robert B. Woodward’s advice, during
a visit at the University of Louvain in the mid-seventies, to Prof Léon Ghosez while
1
discussing the promotion of a colleague. In Woodward’s vision, the organic
chemist’s creativity and ability to synthesize almost any molecules was central to the
design of synthetic probes necessary to elucidate biological mechanisms. This
anecdote farsighted synthetic chemistry’s contribution to chemical biology. While
chemical biology has grown through cross-fertilization with other disciplines,
synthetic organic chemistry remains central to the pursuit of novel chemical entities
as tools capable of modulating cellular processes and probes reporting on diverse
cellular activity. Covalent inhibitors hold a special place in chemical biology, as the
instigator of chemoproteomics, facilitating target identification and assessing target
engagement by virtue of the fact that they remain covalently associated with the
2
-3
protein. While there was a historical reluctance to advance covalent inhibitors in
4
drug discovery efforts, a resurging interest in this inhibition modality has resulted in
5
-8
several therapeutics being recently approved.
Nature has long harnessed covalent inhibition and the biosynthesis of secondary
metabolites has evolved to deliver mildly reactive functionalities in the major classes
of secondary metabolites. An eminent example is the biosynthesis of sesquiterpene
1

ACCEPTED MANUSCRIPT
lactones, a large and structurally diverse family of natural products with a high
tendency for harbouring electrophilic functional groups known to engage cysteine
9
residues in their biological target. Of particular relevance, the α-exo-methylene-γ-
butyrolactone moiety has been shown to be the warhead in a number of natural
1
0
11
12-14
15
products (figure 1), including parthenolide, helenalin,
deoxyelephantopin,
1
6
17
18
ainsliadimer A, EM-23 or IJ-5, to only name a few. To further emphasize the
importance of this class of compounds, a Reaxys search for only natural products
containing this structural motif returns over 5500 entries, over 1600 of which have
1
9
associated yet ill-studied biological activity.
O
O
α-exo-methylene-γ-butyrolactones:
present in 5500+ natural products,
of which 1600+ are bioactive
warhead for covalent interaction
with cysteines in target proteins
O
O
O
*
O
O
O
*
R’
O
R
Parthenolide
IKKβ Cys179
O
O
Deoxyelephantopin
CBS, CTTN, CSTB
PPARγ Cys176
OMe
O
O
O
O
H
O
H
O
O HO
H
OH
O
OH
H
O
O
O
O
OH
Helenalin
H
O
O
O
Ainsliadimer A
NF-κB p65 Cys38
EM-23
TrxR Sec498
IJ-5
IKKα/β Cys46
and Cys120
UbcH5c Cys85
Figure 1. Selected examples of sesquiterpene lactones acting as covalent inhibitors to
their biological targets
In order to access the α-exo-methylene-γ-butyrolactone present in these diverse
natural products, Barbier allylation of aldehydes using bromolactones (Scheme 1) has
proven efficient and versatile. Again, over 3300 natural products contain the resulting
motif, nearly 700 of which have associated biological activity. Operationally simple,
it can be used in a convergent manner for the late-stage introduction of the α-exo-
methylene electrophile. Moreover, studies with the simplest bromolactone showed
2
0
21-23
that remarkably high syn or anti
newly formed stereocentres. For example, the Xu group has successfully used the
diastereoselectivity can be achieved at the two
24
zinc-mediated Barbier allylation for the total synthesis of 8-epigrosheimin.
Likewise, the Harki group accessed simplified analogues of helenalin to probe its
ability to cross-link cysteines 38 and 120 in the p65 portion of NF-κB. In the
context of our study of deoxyelephantopin and its covalent interactome, we too used
the zinc-mediated Barbier allylation of chiral bromolactones with a γ-substituent,
which led to coupling products with three contiguous stereocentres with high anti/anti
2
5
2
6-27
diastereoselectivity induced by the first γ-stereocentre.
With an enantioselective
total synthesis in mind and despite the considerable research efforts towards the
2
8-38
enantioselective γ-functionalization of γ-butenolides,
we were surprised to find
that the straightforward enantioselective preparation of γ-substituted bromolactones
3
9
remained an unmet challenge. We herein present a scalable and versatile synthesis
of high-value enantiopure bromolactones from inexpensive starting materials and
reagents.
2

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O
O
Br
Pd0
O
0
0
Zn or In or
O
0
Me Zn
CrCl (cat), Mn
O
2
2
O
+
O
OH
OH
*
*
*
*
R
ref 20
ref 21-23
R
R
syn product
anti product
O
O
O
Br
O
O
0
0
Zn or In
R2 ref 26-27
O
OH
+
O
OH
*
*
*
R
R1
R2
*
R
1
R2
1
present in 3300+ natural products,
of which 690 with bioactivity
anti/anti product
Scheme 1. Barbier allylation of aldehydes with bromolactones: stereochemical
considerations and impact
2
2
. Results and discussion
.2 Preparation of bromolactones
As a starting point in our investigation, we envisioned that the product of the acid-
mediated hydrolysis and concomitant lactonisation of enantiopure 1, readily
4
0-46
accessible from mannitol,
could be converted into a bromolactone under standard
Appel conditions via 2 (scheme 2). We opted for the aqueous HCl/methanol protocol
and the expected product 2 was obtained. However, much to our surprise, we could
also identify two side-products 3 and 4, resulting from further reaction of 2 with
chloride and methanol as nucleophiles, respectively. We reasoned that treatment with
concentrated aqueous HBr would provide the necessary highly nucleophilic bromide
to directly convert 1 into 5. Thus, when 1 was treated with 48% HBr at room
temperature, 5 was obtained as a single product in high yield. The primary alcohol in
highly polar 5 can readily be masked as TBS ether 6 for ease of manipulation or
subsequent reactions.
Scheme 2. Preparation of bromolactones 5 and 6. Conditions: a. 48% aq. HBr, rt,
6
7%; b. TBSCl, imidazole, CH Cl , rt, 97%.
2 2
With this simple approach to enantiopure bromolactones in hand, we set out to
explore the scope of this reaction. During our studies on deoxyelephantopin, we used
bromolactone 12 as Barbier coupling partner (scheme 3). However, owing to its skip-
diene position the γ-proton is very labile leading 12 to undergo prototropic
rearrangement to 13, making its direct preparation using 48% HBr impossible. We
therefore capitalised on the ability of bromohydrins to eliminate in the presence of
zinc to provide an olefin, and therefore anticipated that its surrogate 12 would deliver
3

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4
7
the desired olefin under the zinc-mediated Barbier allylation conditions. Diol 7,
4
8
readily available from L-tartaric acid was monotosylated, and tosylate 8 converted
into bromide 9 under modified Finkelstein conditions, using anhydrous LiBr in
4
9
refluxing acetone/dimethylformamide. Swern oxidation and Baylis-Hillman reaction
provided secondary alcohol 10 as an inconsequential mixture of diastereomers. It
should be noted that the intermediate aldehyde is very prone to the formation of a
stable hydrate, and consequently aqueous work-up is to be avoided: the Swern
oxidation allows removal of all by-products by simple filtration on silica gel leading
to yields superior to any other oxidation methods we examined. Treatment with 48%
HBr provided bromolactone 11, which indeed underwent bromohydrin elimination in
the presence of zinc (vide infra).
Scheme 3. Preparation of bromolactone 11. Conditions: a. NaH, TsCl, THF, 0 °C,
9
5%; b. LiBr, acetone/DMF, reflux, 72%; c. (COCl) , DMSO, Et N, CH Cl , -78 °C;
2 3 2 2
d. methyl acrylate, DABCO, rt, 57% over two steps; e. 48% aq. HBr, rt, 47%.
To further extend the scope of this reaction, diol 7 was desymmetrised by mono-
silylation as its mono-TBS ether 14 (scheme 4). Swern oxidation and Baylis-Hillman
reaction provided secondary alcohol 15, as an inconsequential mixture of
diastereomers. Treatment with 48% HBr provided diol 16, resulting from TBS ether
cleavage under these conditions. The diol in highly polar 16 could in turn be readily
converted to its isopropylidene acetal 17 under standard conditions, as a valuable
handle for further functionalization.
Scheme 4. Preparation of bromolactones 16 and 17. Conditions: a. NaH, TBSCl,
THF, 0 °C, 98%; b. (COCl) , DMSO, Et N, CH Cl , -78 °C; c. methyl acrylate,
2
3
2
2
DABCO, rt, 52% over two steps; d. 48% aq. HBr, rt, 59%; e. PTSA, acetone, rt, 69%.
Rather than an issue, the TBS ether cleavage with 48% HBr felt advantageous as it
could unmask the alcohol involved in the lactonisation process (scheme 5). As a proof
of concept and using ethylene glycol as starting material, mono-silylation, Swern
oxidation and Baylis-Hillman reaction provided 19, which uneventfully and in high
4

ACCEPTED MANUSCRIPT
yield provided bromolactone 20 upon treatment with 48% HBr. While numerous
50-51
syntheses of 20 exist,
this approach demonstrates that TBS is a suitable protecting
group during the preparation of substrates in which the alcohol is involved in the
lactonisation process during the HBr-mediated reaction, thereby paving the way to the
successful design and synthesis of further bromolactones. The acid-labile TES group
may however also be used: and indeed, Baylis-Hillman reaction on aldehyde 21,
5
2
readily available from lactic acid, followed by treatment with 48% HBr provided
bromolactone 23. Importantly, bromolactone 23 was obtained essentially enantiopure
demonstrating the lack of epimerisation in the Baylis-Hillman reaction and concurring
the absence of diastereomers obtained in the HBr-mediated cyclisation leading to 11
and 16.
Scheme 5. Preparation of bromolactones 20 and 23. a. NaH, TBSCl, THF, 0 °C, 98%;
b. (COCl) , DMSO, Et N, CH Cl , -78 °C; c. methyl acrylate, DABCO, rt, 87% over
2
3
2
2
two steps; d. 48% aq. HBr, rt, 76%; e. methyl acrylate, DABCO, rt, 51%; f. 48% aq.
HBr, rt, quantitative.
The mono-TBS ether in 14 can serve the other purpose of allowing functionalization
of the other primary alcohol and ultimately of the bromolactone. In light of their
biosyntheis, sesquiterpene lactones usually have a methyl-substituted olefin adjacent
to the butyrolactone (scheme 6). We envisioned that a gem-disubstituted terminal
olefin substituent could provide a bromolactone with a useful functionalised allylic
alcohol for further modification. In addition, this would provide a further testing
ground for the title transformation as these olefins readily form tertiary cations in the
presence of strong acids. Swern oxidation and treatment with methylmagnesium
bromide provided secondary alcohol 24, as an inconsequential mixture of
diastereomers. Oxidation of the alcohol followed by olefination provided gem-
disubstituted terminal olefin 25. TBAF-mediated desilylation, Swern oxidation and
Baylis-Hillman reaction provided secondary alcohol 26. However long this reaction
5

ACCEPTED MANUSCRIPT
sequence may look, it is noteworthy that, owing the essentially quantitative nature of
the reactions involved, simple precipitation and filtrations through silica are enough to
provide clean crude products to be used in the following steps without further
purification. Accordingly, substrate 26 could be obtained in a few days in 23% yield
over 9 steps and a single final purification by column chromatography.
Treatment of 26 with 48% HBr did indeed promote the formation of the bromolactone
moiety, but as anticipated none of the desired gem-disubstituted olefin 27 was present:
instead, a major undesired product was observed, which we identified as
Markovnikov olefin hydrobromation product bromohydrin 28. The formation of this
by-product may be explained by the protonation of the gem-disubstituted olefin under
the very acidic reaction conditions, followed by trapping of the resulting cation by a
bromide nucleophile.
Scheme 6. Attempted synthesis of bromolactone 27. Conditions: a. (COCl) , DMSO,
2
Et N, CH Cl , -78 °C; b. MeMgBr, Et O, 0 °C, 87% over two steps; c. (COCl) ,
3
2
2
2
2
+
- n
DMSO, Et N, CH Cl , -78 °C; d. Ph P CH Br , BuLi, THF, -78 °C, 91% over two
3
2
2
3
3
steps; e. TBAF, THF, 0 °C, 85%; f. (COCl) , DMSO, Et N, CH Cl , -78 °C; g. methyl
2
3
2
2
acrylate, DABCO, rt, 52% over two steps; h. 48% aq. HBr, rt, see text.
Not disheartened, we took this result as a chance to examine the actual factors behind
the success of this transformation under relatively harsh conditions. As protonation of
the olefin to the tertiary cation was problematic, we first evaluated the importance of
using concentrated 48% HBr (around 8.9 M aqueous HBr) by using HBr at various
dilutions. With 1 M aqueous HBr, substrate 26 underwent slow deacetalation and
lactonisation and the olefin remained intact (29, table 1, entry 1); however, the desired
allylic rearrangement did not take place. Mild heating at 50 °C only resulted in
appearance of some olefin hydrobromation product (30, entry 2). While the
distribution was unchanged with 2 M HBr (entry 3), upon treatment with 3 M or 4.5
M HBr at room temperature, significant hydrobromation took place while no allylic
rearrangement took place (29, entries 4 and 5). This may be explained by the fact that
in 48% HBr, the bromide anion is highly nucleophilic, whereas in diluted aqueous
HBr, the bromide ion is solvated and therefore much less nucleophilic. Nevertheless,
treatment of 25 with LiBr-, NaBr- or KBr-saturated 1 M aqueous HBr had no effect
on the outcome of the reaction: neither hydrobromation nor allylic rearrangement took
place (entries 6 to 8). Unsolvated bromide seems therefore to be required for the
transformation to succeed in forming the bromolactone moiety. Using biphasic
6

ACCEPTED MANUSCRIPT
systems with dichloromethane or benzene as co-solvent (entries 9 and 10) was
successful in delivering the bromolactone portion but did not prevent
hydrobromation; while this may be disappointing, this result is important as
dichloromethane can practically be used as “transfer” solvent for substrates free of
HBr-sensitive functional groups (as above). In order to prevent the parasitic olefin
protonation event, a qualitative consideration of pK s was necessary. With HBr
b
having a pK of roughly -9 and olefins a pK of around -4, we looked at organic
a
b
solvents which could serve as buffers. While methanol (pK -2, entry 11) prevented
b
lactonisation but not hydrobromation, acetone (pK -7, entry 12) successfully
b
prevented hydrobromation but also deacetalation. While not unexpected, this supports
the role of water contained in 48% HBr for the overall transformation as the same
result was observed with 33% HBr in acetic acid (entry 13). Gratifyingly, ethyl
acetate (pK -6.5, entry 14) led to exclusive formation of the desired bromolactone 27,
b
as did acetonitrile (pK -10, entry 15).
b
Table 1. Optimisation of the conditions for the preparation of bromolactone 27
a
b
Entry Conditions
Products observed (conversion)
26 (31%) + 29 (69%)
26 (6%) + 29 (35%) + 46 (59%)
26 (18%) + 29 (82%)
29 (56%) + 30 (44%)
29 (37%) + 30 (63%)
26 (21%) + 29 (79%)
26 (32%) + 29 (68%)
26 (30%) + 29 (70%)
28 (100%)
1
2
3
4
5
6
7
8
9
Aq. 1 M HBr, rt, o/n
Aq. 1 M HBr, 50 °C, o/n
Aq. 2 M HBr, rt, o/n
Aq. 3 M HBr, rt, o/n
Aq. 4.5 M HBr, rt, o/n
Aq. 1M HBr saturated with LiBr rt, o/n
Aq. 1M HBr saturated with NaBr rt, o/n
Aq. 1M HBr saturated with KBr rt, o/n
Biphasic: CH Cl /48% HBr, rt, o/n
2
2
1
0
1
2
3
4
5
Biphasic: benzene/48% HBr, rt, o/n
MeOH/48% HBr, rt, o/n
Acetone/48% HBr, rt, o/n
28 (100%)
1
1
1
1
1
31 (27%) + 32 (73%)
26 (86%) + 33 (14%)
26 (76%) + 33 (24%)
27 (100%, 68% )
27 (100%, 52% )
33% HBr in acetic acid, rt, o/n
c
d, e
EtOAc/48% HBr, rt, o/nc
d
MeCN/48% HBr, rt, o/n
a
Carried out on 0.1 mmol scale, overnight as the allylic rearrangement is the slowest
b
1
c
step; Determined by H-NMR analysis of the crude product; None of acetylated
compound 34 was observed; Isolated yields; 55% isolated yield on gram-scale.
d
e
7

ACCEPTED MANUSCRIPT
In complete analogy and using these buffered conditions, we were able to access
olefin-substituted bromolactone 37 as well as alkyne-substituted bromolactone 40, as
potentially valuable fragments for the synthesis of unnatural analogues of
5
3
sesquiterpene lactones (scheme 7). Briefly, as above, Swern oxidation and Wittig
olefination of 14 provided primary olefin 35. TBAF-mediated desilylation, Swern
oxidation and Baylis-Hillman reaction provided secondary alcohol 36. Finally,
treatment with 48% HBr with ethyl acetate as co-solvent provided bromolactone 37.
Alternatively, Swern oxidation and a Corey-Fuchs reaction sequence on 14 provided
terminal alkyne 38. TBAF-mediated desilylation, Swern oxidation and Baylis-
Hillman reaction provided secondary alcohol 39. Finally, treatment with 48% HBr
with ethyl acetate as co-solvent provided alkyne-substituted bromolactone 40.
Scheme 7. Synthesis of bromolactones 37 and 40. Conditions: a. (COCl) , DMSO,
2
+
- n
Et N, CH Cl , -78 °C; b. Ph P CH Br , BuLi, THF, -78 °C, 43% over two steps; c.
3
2
2
3
3
TBAF, THF, 0 °C, 37%; d. (COCl) , DMSO, Et N, CH Cl , -78 °C; e. methyl
2
3
2
2
acrylate, DABCO, rt, 82% over two steps; f. 48% aq. HBr, EtOAc rt, 56%; g.
COCl) , DMSO, Et N, CH Cl , -78 °C; h. CBr , Ph P, CH Cl , 0 °C, 65% over two
(
2
3
2
2
4
3
2
2
n
steps; BuLi, THF, -78 °C, 92%; i. TBAF, THF, 0 °C, 95%; j. (COCl) , DMSO, Et N,
2
3
CH Cl , -78 °C; k. methyl acrylate, DABCO, rt, 49% over two steps; l. 48% aq. HBr,
2
2
EtOAc rt, 51%.
2
.2. Mechanism
These observations allow us to propose a general course for this HBr-mediated
complex transformation (scheme 8). Under the acid aqueous conditions, deacetalation
readily takes place, leading to a very polar intermediate, which rapidly undergoes
kinetic 5-exo-trig lactonisation to the polar α-exo-methylene-β-hydroxy-γ-
butyrolactone. The resulting electrophilic α-exo-methylene-γ-butyrolactone
undergoes hydrobromation. This hydrobromation step is akin to the conjugate
addition of bromide as nucleophile and a very well-established transformation of α,β-
unsaturated carbonyl compounds using concentrated HBr either as 48% HBr in water
or 33% in acetic acid. Finally, under the very acidic conditions, the resulting β-
hydroxy-γ-butyrolactone intermediate undergoes dehydration to the desired endo-
butenolide. It is important to note that throughout the transformation, no epimerisation
can take place at the stereocentre to become the γ-position of the γ-butyrolactone,
which guarantees a full transfer of chirality from the substrate. Furthermore, once the
endo-butenolide is formed, if a deprotonation/tautomerisation event were to take place
at the γ-position towards a thermodynamically favourable dienolate/dienol,
irreversible elimination of the bromide takes place: this is very important for the
8

ACCEPTED MANUSCRIPT
2
design of the bromolactone and its substrate, as an sp substituent in the γ-position,
such as vinyl, carbonyl or aryl groups, readily leads to such degradation and no
bromolactone is obtained under the present reaction conditions.
Scheme 8. Proposed course for the HBr-mediated transformation.
2
.3. Synthetic applications to open-chain analogues of sesquiterpene lactones
Open-chain analogues have proven to be very efficient probes for the study of their
biologically active α-exo-methylene-γ-butyrolactone containing sesquiterpene lactone
2
5-26
counterparts.
Thus, with a range of bromolactones in hand, we set out to probe
their synthetic utility by applying a small yet relevant subset in the synthesis of open-
chain analogues of deoxyelephantopin and 15-deoxygoyazensolide.
Thus, using bromolactone 6, a simplified analogue of deoxyelephantopin
recapitulating all the polar interactions of the parent natural product (scheme 9).
Briefly, zinc-mediated Barbier coupling of 6 with aldehyde 42 provided secondary
alcohol 43 with high anti/anti diastereoselectivity, which was methacryloylated under
standard conditions. The TBS ether in 44 could in turn be readily and quantitatively
removed in the presence of lactones and esters by treatment with dilute HCl in
methanol, making it a valuable handle for further functionalization.
Scheme 9. Synthetic application of bromolactone 6. Conditions: a. amberlyst 15,
0
THF/H O, rt, then filtration over celite onto 6; b. Zn , THF, aq. NH Cl, 67%; c.
2
4
methacrylic anhydride, DMAP, Et N, CH Cl , 0 °C, 81%; d. 2 M HCl, MeOH, rt,
3
2
2
8
0%.
As already mentioned, the primary alcohol in bromolactone 5 was masked as its TBS
ether bromolactone 6, out of sheer practical convenience as bromolactone 5 was
highly polar and the resulting Barbier product even more so. However, alcohol-
9

ACCEPTED MANUSCRIPT
substituted bromolactones can directly be used for Barbier coupling with aldehydes.
Thus, coupling of bromolactone 27 and aldehyde 42 successfully provided secondary
alcohol 46 (scheme 10).
0
Scheme 10. Bromolactone 27 as coupling partner. Conditions: a. Zn , THF, aq.
NH Cl, 48%.
4
Bromolactone 11 was designed as an enantiopure surrogate to labile bromolactone 12;
we however needed to determine whether it could undergo bromohydrin elimination
under the Barbier conditions (scheme 11). To this end, we reacted 11 with the
enantioenriched aldehyde partner we used in our synthesis of analogues of
deoxyelephantopin, and we were delighted to observe partial elimination under our
standard Barbier coupling conditions. The Barbier coupling is a fast and rather
exothermic reaction; in contrast, bromohydrin elimination is rather slow and may not
undergo complete elimination in the timeframe of the coupling. We thus reasoned that
heat would benefit the more difficult bromohydrin elimination. Accordingly, the
desired olefin 49 was cleanly obtained after re-submission of the mixture of 49 and 50
to the reaction conditions at 50 °C. Alternatively, carrying out the Barbier coupling at
room temperature follow by heating at 50 °C directly provided 49 as intermediate in
our asymmetric synthesis of nordeoxyelephantopin the transformation in a one pot
two steps manner is essential to avoid premature degradation of the organozinc
species and ensure diastereoselectivity of the Barbier coupling.
Scheme 11. Bromolactone 11 as enantiopure surrogate for bromolactone 12.
0
Conditions: a. amberlyst 15, THF/H O, rt, then filtration over celite onto 11; b. Zn ,
2
0
THF, aq. NH Cl, rt then 50 °C, 43% from 47; c. Zn , THF, aq. NH Cl, 50 °C.
4
4
10

ACCEPTED MANUSCRIPT
We further demonstrated the late-stage use of this valuable surrogate in a formal
5
4
synthesis of 15-deoxygoyazensolide. To this end, we envisioned a late-stage ring-
closing metathesis (scheme 12) in complete analogy with Hale’s work on
5
5
Eremantholide A. The substrate to the ring-closing metathesis would arise from a
Barbier coupling between surrogate 11 and enantiopure aldehyde 53, hitherto
unknown and for which we developed a synthesis in analogy with Smith’s work on
5
6
3
(2H)-furanones. L-Lactic acid was protected as its acetal 54, obtained with
excellent enantio- and diastereopurity after recrystallization at -78 °C. Based on
5
7
Seebach’s work on self-regenerating stereocenters, allylation provided olefin 55 as a
single diastereomer, which was ozonolysed and the resulting aldehyde protected as its
dimethyl acetal 56. In situ Weinreb amide formation and treatment with
methyllithium provide methyl ketone 57. Treatment with two equivalents of LDA and
methacrolein provided β-hydroxy ketone 58. In his original 1981 report, Smith III
first oxidised his β-hydroxy ketones to the β-diketones with Collins’ reagent and
subsequently cyclised with mild aqueous acid, stating that “the oxidation were carried
out under acidic conditions, it might be possible in “one pot” to effect direct
cyclization to the desired 3(2H)-furanone”. Only published in 1983, the Dess-Martin
5
8
periodinane oxidation of alcohols into their carbonyl counterpart felt adapted owing
to the release of acetic acid as a by-product. And indeed, DMP oxidation of 58
provided 3(2H)-furanone 59 in a single step and good yield. IBX in refluxing ethyl
5
9
acetate proved to be superior in terms of cleanliness, yield and ease of workup but it
also led to partial cleavage of the acetal.
Scheme 12. Retrosynthetic analysis towards 15-deoxygoyazensolide and preparation
t
of fragment 59. Conditions: a. BuCHO, pentane, PTSA, H SO , Dean-Stark, 45 °C,
2
4
followed by three recrystallizations at -78 °C, 57%, 97% de; b. LDA, THF, allyl
bromide, -78 °C, 78%; c. O , CH Cl , -78 °C, then Me S then HC(OMe) , PPTS, rt,
3
2
2
2
3
n
6
3%; d. MeNHOMe.HCl, BuLi, THF, -78 °C, then MeLi, 71%; e. LDA,
methacrolein, THF, -78 °C, 72%; f. DMP, CH Cl , rt, 60%.
2
2
11

ACCEPTED MANUSCRIPT
The dimethyl acetal in 59 was readily cleaved under acidic conditions and crude
aldehyde 53 was directly used in the Barbier coupling with bromolactone 11 (Scheme
1
3). While coupling and bromohydrin olefination took place, the dienone suffered
conjugate reduction to its isopropyl derivative 60, which was confirmed by submitting
9 to the Barbier conditions and resulted in complete reduction of the γ,δ-olefin at
5
room temperature within the timeframe of the Barbier coupling (not shown). The
dienone in 59 was thus masked by conjugate addition of thiophenol at the δ position.
Diastereomers 61 were deacetalated as above and Barbier coupling provided
secondary alcohol 63 with high diastereoselectivity. Oxidation of the sulfide with
hydrogen peroxide in HFIP, followed by sulfoxide elimination under microwave
irradiation provided dienone 64. Finally, methacryloylation provided 52, which
unfortunately never agreed to undergoing ring-closing metathesis under Hale’s
conditions or any other of the various conditions we explored, only resulting in linear
dimerization products or the recovery of unreacted starting material. In addition to the
poor reactivity of the type III olefin, i.e. gem-disubstituted and highly electron-poor,
already found in Hale’s substrate, the extra rotor may have placed our substrate
outside of the narrow reactivity window successfully exploited by Hale. Nevertheless,
this venture further demonstrated the utility of bromolactone 11 for the introduction
of γ-vinyl-substituted α-exo-methylene-γ-butyrolactones for the synthesis of
sesquiterpene lactone derivatives.
Scheme 13. Attempted synthesis of 15-deoxygoyazensolide. Conditions: a. amberlyst
0
1
5, CH Cl , rt; b. Zn , THF, aq. NH Cl, rt then 50 °C, 23% from 59; c. PhSH, Et N,
2
2
4
3
0
DCM, rt, 96%; d. amberlyst 15, CH Cl , rt; e. Zn , THF, aq. NH Cl, rt then 50 °C,
2
2
4
4
7% from 61; f. 37% H O , HFIP, rt then pyridine, PhMe, 180 °C (microwave), 82%
2 2
over two steps; g. methacrylic anhydride, DMAP, Et N, CH Cl , 0 °C, 54%.
3
2
2
This small selection of examples was essentially aimed at demonstrating the viability
of using these bromolactones as coupling partners together with aldehydes in the
Barbier allylation, resulting in a motif present in thousands of natural products. The
secondary alcohol obtained in the course of the Barbier allylation should however
12

ACCEPTED MANUSCRIPT
6
0
readily undergo a Barton-McCombie deoxygenation. Furthermore, it should be
noted that sesquiterpene lactones exist at various stages of oxidation beyond the α-
exo-methylene: accordingly, a wealth of further modifications of this motif are
6
1
62
available in the literature, including epoxidation, dihydroxylation, conjugate
2
6, 63
64
65
reduction,
conjugate addition of C-nucleophiles, ring-closing metathesis or
cross-metathesis, to only name a few, to further extend the scope of natural products
potentially reachable from these bromolactones.
6
6
Conclusion
In summary, we have developed an efficient and versatile route allowing rapid access
to enantiopure bromolactones. This route takes advantage of a sequence of
operationally simple and scalable reactions, owing to the nature of the reagents and
the high yielding transformations involved. Furthermore, this synthesis benefits from
very cheap and readily available starting materials from the chiral pool, such as
tartaric acid available in both enantiomeric forms. In fact, any chiral α-hydroxy
aldehyde, whereby the alcohol is masked as its TBS ether or with any acid-labile
protecting group, may be substrate and precursor to bromolactones, provided that the
resulting bromolactone can sustain the buffered yet strongly acidic reaction
conditions. Finally, we anticipate that having access to a broad range of
bromolactones as valuable precursors to α-exo-methylene-γ-butyrolactones will
further stimulate the study of the vast pharmacologically important yet ill-studied
diversity space of the sesquiterpene lactones and their unnatural analogues, thereby
facilitating the understanding of their mode of action and ultimately their potential use
in the clinics as the drugs of tomorrow.
Experimental Section
Compound 5 – To a solution of 1 (1.61 g, 7.5 mmol, 1 equiv) in CH
2
Cl (7.5 mL)
2
at room temperature was added 48% aqueous HBr (75 mL) and stirring was
continued overnight. The reaction mixture was poured in water and extracted
with EtOAc. The combined organic layers were carefully washed with saturated
aqueous NaHCO
3
and brine, dried over Na
2
SO , filtered through a pad of silica
4
and concentrated in vacuo. Purification by column chromatography (silica,
cyclohexane/EtOAc 5:1 to 1:2) provided bromolactone 5 as a pale yellow solid
1
(
1.03 g, 5.0 mmol, 67 %). R
CDCl
.10 (t, J=1.4 Hz, 2H, H-1), 4.00 (dd, J=12.3, 3.8 Hz, 1H, H-5a), 3.80 (dd, J=12.3, 5.0
f
= 0.32 (cyclohexane/EtOAc 1:2). H-NMR (400 MHz,
3
, 25 °C): δ 7.43 (q, J=1.4 Hz, 1H, H-3), 5.10 (ddq, J=5.3, 3.4, 1.6 Hz, 1H, H-4),
4
1
3
Hz, 1H, H-5b), 2.21 (s, 1H, OH) ppm. C-NMR (100 MHz, CDCl
3
, 25 °C): δ 171.2
(C-6), 149.8 (C-3), 132.5 (C-2), 82.1 (C-4), 62.2 (C-5), 20.8 (C-1) ppm.
Compound 6 – To a solution of TBSCl (830 mg, 5.5 mmol, 1.1 equiv) in dry
CH Cl (7.5 mL) was added imidazole (509 mg, 7.5 mmol, 1.5 equiv). The
2
2
resulting mixture was stirred at room temperature for 30 min. To the resulting
cloudy solution was added 5 (1.03 g, 5.0 mmol, 1 equiv). Stirring was continued
until disappearance of the starting as monitored by TLC. Filtration over a pad of
silica, washing with pentane/ether 2:1), concentration in vacuo and purification
by column chromatography (silica, pentane/ether 10:1 to 2:1) provided silyl
ether 6 as a pale yellow solid (1.56 g, 4.85 mmol, 97%). R
f
= 0.45
1
3
(cyclohexane/EtOAc 5:1). H-NMR (400 MHz, CDCl , 25 °C): δ 7.43 (q, J=1.4 Hz,
1H, H-3), 5.00 (dddd, J=5.9, 4.7, 3.1, 1.6 Hz, 1H, H-4), 4.10 (t, J=1.4 Hz, 2H, H-1),
13

ACCEPTED MANUSCRIPT
3
.92 (dd, J=10.9, 4.4 Hz, 1H, H-5a), 3.82 (dd, J=10.9, 5.1 Hz, 1H, H-5b), 0.87 (s, 9H,
C(CH
CDCl
C(CH
3
)
3
), 0.07 (s, 3H, Si(CH
, 25 °C): δ 170.8 (C-6), 150.4 (C-3), 132.2 (C-2), 81.3 (C-4), 62.8 (C-5), 25.7
), 20.8 (C-1), 18.2 (C(CH ), -5.5 (Si(CH ) ppm.
3
)
2
), 0.06 (s, 3H, Si(CH
3
)
2
) ppm. 13C-NMR (100 MHz,
3
(
)
3 3
)
3 3
)
3 2
Compound 11 – To a solution of 10 (2.2 g, 7.0 mmol, 1 equiv) in CH
2
Cl (14 mL)
2
at room temperature was added 48% aqueous HBr (14 mL) and stirring was
continued overnight. The reaction mixture was poured in water and extracted
with EtOAc. The combined organic layers were carefully washed with saturated
aqueous NaHCO
3
and brine, dried over Na
2
SO , filtered through a pad of silica
4
and concentrated in vacuo. Purification by column chromatography provided
bromolactone 11 as a pale yellow solid (1 g, 3.3 mmol, 47%). R
f
= 0.37
1
3
(cyclohexane/EtOAc 5:1). H-NMR (400 MHz, CDCl , 25 °C): δ 7.45 (q, J=1.5 Hz,
1
H, H-3), 5.26 (dq, J=3.2, 1.5 Hz, 1H, H-4), 4.12 (ddd, J =6.7, 5.3, 3.2 Hz, H-5), 4.11
(t, J=1.5 Hz, 2H, H-1), 3.58 (dd, J=10.6, 5.3 Hz, 1H, H-6a), 3.46 (ddd, J=10.6, 6.7,
1
3
0.8 Hz, 1H, H-6b) ppm. C-NMR (100 MHz, CDCl
3
, 25 °C): δ 170.2 (C-7), 148.9 (C-
3), 132.8 (C-2), 81.1 (C-4), 70.9 (C-5), 33.1 (C-6), 20.5 (C-1) ppm.
Compound 16 – To a solution of 15 (1.8 g, 5 mmol, 1 equiv) in CH
2
Cl (10 mL) at
2
room temperature was added 48% aqueous HBr (10 mL) and stirring was
continued overnight. The reaction mixture was poured in water and extracted
with EtOAc. The combined organic layers were carefully washed with saturated
aqueous NaHCO
3
and brine, dried over Na
2 4
SO , filtered through a pad of silica
and concentrated in vacuo. Purification by column chromatography (silica,
CH
2
Cl
2
/MeOH, 1:0 to 10:1) provided bromolactone 16 as a pale yellow solid (699
1
mg, 2.95 mmol, 59 %). R
f
= 0.15 (EtOAc). H-NMR (400 MHz, MeOD, 25 °C): δ
7
.65 (t, J=1.3 Hz, 1H, H-3), 5.18 (dt, J=3.3, 1.5 Hz, 1H, H-4), 4.18 (q, J=1.4 Hz, 2H,
H-1), 3.83 (td, J=6.2, 3.4 Hz, 1H, H-5), 3.66 (dd, J=11.2, 6.3 Hz, 1H, H-6a), 3.62
1
3
(ddd, J=11.2, 6.5 Hz, 1H, H-6b) ppm. C-NMR (100 MHz, MeOD, 25 °C): δ 173.4
(C-7), 152.9 (C-3), 132.7 (C-2), 83.5 (C-4), 72.6 (C-5), 63.9 (C-6), 21.4 (C-1) ppm.
Compound 17 – To a stirred solution of bromolactone 16 (420 mg, 1.77 mmol, 1
equiv) in acetone (17.7 mL) at room temperature was added PTSA monohydrate
(
30 mg, 0.18 mmol, 0.1 equiv) and the resulting mixture was stirred at the same
temperature until disappearance of the starting material as monitored by TLC.
The reaction mixture was diluted with Et O, washed with saturated aqueous
NaHCO , dried over Na SO , filtered over silica and concentrated in vacuo.
Purification by column chromatography (silica, cyclohexane/EtOAc 201:1 to 2:1)
2
3
2
4
provided bromolactone 17 as a pale yellow solid (340 mg, 1.22 mmol, 69%). R
f
=
1
3
0.44 (cyclohexane/EtOAc 2:1). H-NMR (400 MHz, CDCl , 25 °C): δ 7.39 (q, J=1.4
Hz, 1H, H-3), 5.03 (dq, J=3.3, 1.6 Hz, 1H, H-4), 4.41 (ddd, J=6.7, 5.4, 3.8 Hz, 1H, H-
5
), 4.12 (t, J=1.4 Hz, 2H, H-1), 4.09 (dd, J=8.9, 6.7 Hz, 1H, H-6a), 3.83 (dd, J=8.9,
1
3
5
.5 Hz, 1H, H-6b), 1.43 (d, J=0.7 Hz, 3H, H-9a), 1.35 (s, 3H, H-9b) ppm. C-NMR
, 25 °C): δ 170.3 (C-7), 148.7 (C-3), 132.9 (C-2), 110.6 (C-8), 80.0
C-4), 74.3 (C-5), 64.7 (C-6), 26.0 (C-9), 25.0 (C-9), 20.6 (C-1) ppm.
(
(
100 MHz, CDCl
3
Compound 20 – To a solution of 19 (1.3 g, 5 mmol, 1 equiv) in CH
2
Cl (10 mL) at
2
room temperature was added 48% aqueous HBr (10 mL) and stirring was
continued overnight. The reaction mixture was poured in water and extracted
14

ACCEPTED MANUSCRIPT
with EtOAc. The combined organic layers were carefully washed with saturated
aqueous NaHCO
3
and brine, dried over Na
2
SO , filtered through a pad of silica
4
and concentrated in vacuo. Purification by column chromatography provided
bromolactone 20 as a pale yellow oil (672 mg, 3.8 mmol, 76 %). R
f
= 0.48
1
(
cyclohexane/EtOAc 2:1). H-NMR (400 MHz, CDCl
Hz, 1H, H-3), 4.85 (q, J=1.7 Hz, 2H, H-4), 4.09 (q, J=1.7 Hz, 2H, H-1) ppm. C-NMR
3
, 25 °C): δ 7.53 (quint, J=1.7
1
3
3
(100 MHz, CDCl , 25 °C): δ 171.5 (C-5), 149.1 (C-3), 131.0 (C-2), 70.2 (C-4), 20.8
(C-1) ppm.
Compound 23 – To a solution of 22 (26 mg, 0.094 mmol, 1.0 equiv) in CH
Cl
2 2
(0.15 mL) at room temperature was added 48% aqueous HBr (0.15 mL) and
stirring was continued for 18h. At 0°C, a saturated solution of NaHCO was
3
slowly added. The layers were separated and the aqueous layer was extracted
with CH Cl . The combined organic layers were washed with brine, dried over
Na SO , filtered and concentrated in vacuo. Purification by column
chromatography (silica, pentane/Et
2
2
2
4
2
O 5:1 to 0:1) provided bromolactone 23 as a
1
colourless oil (17.9 mg, 0.094 mmol, quant.). R
NMR (500 MHz, CDCl
f
= 0.28 (pentane/Et
2
O 1:1). H
3
, 25°C): δ 7.39 (d, J=1.4 Hz, 1H, H-3), 5.09 (dddd, J=8.4, 6.9,
.3, 1.6 Hz, 1H, H-4), 4.09 (t, J=1.4 Hz, 2H, H-1), 1.46 (d, J=6.8 Hz, 3H, H-5) ppm.
5
1
3
C NMR (167 MHz, CDCl
3
, 25°C): δ 170.8 (C-6), 153.4 (C-3), 131.0 (C-2), 77.6 (C-
4), 21.0 (C-1), 18.7 (C-5) ppm.
Compound 27 – To a solution of 26 (1.76 g, 6.9 mmol, 1 equiv) in EtOAc (6.9
mL) at room temperature was added 48% aqueous HBr (6.9 mL) and stirring
was continued overnight. The reaction mixture was poured in water and
extracted with EtOAc. The combined organic layers were carefully washed with
saturated aqueous NaHCO
3
and brine, dried over Na
2 4
SO , filtered through a pad
of silica and concentrated in vacuo. Purification by column chromatography
(
silica gel, cyclohexane/EtOAc 10:1 to 1:1) provided bromolactone 27 as a pale
1
yellow solid (940 mg, 3.8 mmol, 55 %). R
NMR (400 MHz, CDCl
H-8), 5.07 (d, J=1.4 Hz, 1H, H-8), 5.05 (d, J=1.6 Hz, 1H, H-4), 4.13 (dd, J=13.6, 6.6
f
= 0.39 (cyclohexane/EtOAc 1:1). H-
3
, 25 °C): δ 7.33 (q, J=1.4 Hz, 1H, H-3), 5.09 (t, J=1.4 Hz, 1H,
13
Hz, 1H, H-5), 4.10 (t, J=1.5 Hz, 2H, H-1), 1.84 (d, J=1.3 Hz, 3H, H-7) ppm. C-NMR
100 MHz, CDCl , 25 °C): δ 170.5 (C-9), 149.5 (C-3), 142.1 (C-6), 132.4 (C-2),
15.1 (C-8), 82.9 (C-4), 76.3 (C-5), 20.7 (C-1), 18.6 (C-7) ppm.
(
1
3
Compound 37 – To a solution of 36 (466 mg, 1.93 mmol, 1 equiv) in EtOAc (3.8
mL) at room temperature was added 48% aqueous HBr (3.8 mL) and stirring
was continued overnight. The reaction mixture was poured in water and
extracted with EtOAc. The combined organic layers were carefully washed with
saturated aqueous NaHCO
3
and brine, dried over Na
2 4
SO , filtered through a pad
of silica and concentrated in vacuo. Purification by column chromatography
(
silica gel, cyclohexane/EtOAc 10:1 to 1:1) provided bromolactone 37 as an off-
1
white solid (242 mg, 1.1 mmol, 56 %). R
NMR (400 MHz, CDCl
1
1
4
f
= 0.36 (cyclohexane/EtOAc 1:1). H-
3
, 25 °C): δ 7.40 (q, J=1.4 Hz, 1H, H-3), 5.85 (ddd, J=17.0,
0.4, 6.4 Hz, 1H, H-6), 5.43 (dt, J=17.1, 1.2 Hz, 1H, H-7), 5.35 (dt, J=10.5, 1.2 Hz,
H, H-7), 4.97 (dq, J=5.7, 1.6 Hz, 1H, H-4), 4.30 (ddt, J=6.8, 5.7, 1.2 Hz, 1H, H-5),
1
3
.09 (t, J=1.4 Hz, 2H, H-1) ppm. C-NMR (100 MHz, CDCl , 25 °C): δ 170.7 (C-8),
3
15

ACCEPTED MANUSCRIPT
1
1
49.4 (C-3), 134.3 (C-6), 130.7 (C-2), 119.5 (C-7), 83.5 (C-4), 73.3 (C-5), 20.7 (C-
) ppm.
Compound 40 – To a solution of 39 (720 mg, 3 mmol, 1 equiv) in EtOAc (6 mL)
at room temperature was added 48% aqueous HBr (6 mL) and stirring was
continued overnight. The reaction mixture was poured in water and extracted
with EtOAc. The combined organic layers were carefully washed with saturated
aqueous NaHCO
3
and brine, dried over Na
2
SO , filtered through a pad of silica
4
and concentrated in vacuo. Purification by column chromatography (silica gel,
cyclohexane/EtOAc 10:1 to 1:1) provided bromolactone 40 as a pale yellow solid
1
(
352 mg, 1.53 mmol, 51 %). R
f
= 0.34 (cyclohexane/EtOAc 1:1). H-NMR (400
MHz, CDCl
3
, 25 °C): δ 7.49 (q, J=1.5 Hz, 1H, H-3), 5.07 (dt, J=6.1, 1.6 Hz, 1H, H-4),
.57 (dd, J=5.5, 3.3 Hz, 1H, H-5), 4.12 (q, J=2.4, 1.9 Hz, 2H, H-1), 2.61 (d, J=2.2 Hz,
H, H-7), 2.46 (d, J=5.1 Hz, 1H, OH) ppm. 13C-NMR (100 MHz, CDCl
, 25 °C): δ
70.0 (C-8), 148.3 (C-3), 133.5 (C-2), 82.1 (C-4), 78.8 (C-6), 76.7 (C-7), 63.3 (C-5),
0.4 (C-1) ppm.
4
1
1
2
3
Supporting information
Supplementary data related to this article can be found at
Acknowledgements
We thank the Swiss National Science Foundation for generous support.
Declaration of Interests
The authors declare no conflict of interest.
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