Bio-inspired formal synthesis of hirsutellones a-C featuring an electrophilic cyclization triggered by remote lewis acid-activation

Article abstract of DOI:10.1002/chem.201303570

A bio-inspired strategy was used to complete the formal synthesis of the antitubercular hirsutellone B and congeners A and C, through construction of its decahydrofluorene core from a linear polyene strand activated at both ends by a silyl enol ether and an allyl acetate. Our synthesis features a key electrophilic cyclization, starting with the remote activation (by [Yb(OTf) ₃] or BF₃×OEt₂) of the allyl acetate and stereoselectively affording the C ring. This was followed by an intramolecular Diels-Alder reaction to get the tricyclic core of the natural product. The stereoselective reduction of the resulting ketone towards the formal intermediate was critical to the success of this strategy. Copyright

Full text of DOI:10.1002/chem.201303570

FULL PAPER
DOI: 10.1002/chem.201303570
Bio-Inspired Formal Synthesis of Hirsutellones A–C Featuring an
Electrophilic Cyclization Triggered by Remote Lewis Acid-Activation
[
a, b]
[a, b]
[a, b]
[a, b]
Xu-Wen Li,
Alexandre Ear,
Alexandre Deville,
Lukas Roger,
Nassima Riache,
[a, b]
[
a, b]
and Bastien Nay*
Abstract: A bio-inspired strategy was
used to complete the formal synthesis
of the antitubercular hirsutellone B
and congeners A and C, through con-
struction of its decahydrofluorene core
from a linear polyene strand activated
at both ends by a silyl enol ether and
an allyl acetate. Our synthesis features
a key electrophilic cyclization, starting
with the remote activation (by [Yb-
AHCTUNGTRENNG(U OTf) ] or BF ·OEt ) of the allyl ace-
3 3 2
tate and stereoselectively affording the
C ring. This was followed by an intra-
molecular Diels–Alder reaction to get
the tricyclic core of the natural prod-
uct. The stereoselective reduction of
the resulting ketone towards the
formal intermediate was critical to the
success of this strategy.
Keywords: biomimetic synthesis ·
electrophilic cyclization
· Lewis
acids · natural products · synthetic
methods
Introduction
Tuberculosis is a serious disease that engenders over nine
million new cases each year, killing 1.7 million people,
mostly in developing countries, and threatening the weakest
[1,2]
of us.
A dramatic resurgence was observed in the 1990s,
associated with overcrowding, poverty, undernutrition, or
immunodeficiency, and also the rapid development of multi-
drug resistance of the microbial agent Mycobacterium tuber-
culosis to marketed drugs (e.g., isoniazid, ethambutol, rifam-
picine). The disease was declared by the WHO as a global
emergency in 1993 and since then, the search for new antitu-
bercular drugs is a priority worldwide. In 2005, the discovery
of hirsutellones (1–3) by Isaka and co-workers from the en-
Figure 1. Structure of hirsutellones A–C (1–3).
of particular interest since a tricyclic decahydrofluorene in-
termediate was found active against M. tuberculosis at a con-
ꢀ
1
centration (1.21 mgmL ) in the same range as the natural
[6]
product. The decahydrofluorene core may thus stand as
the pharmacophoric moiety of hirsutellones, an important
finding for future medicinal works.
[3]
tomopathogenous fungus Hirsutella nivea was therefore
providential, displaying strong and specific antitubercular
activity
at
a
minimum
inhibitory
concentration
Hirsutellones are members of an increasing family of nat-
ural products, the first of which, known as the GKK1032
components, were described in 2001 from a Penicillium
ꢀ
1
(
0.78 mgmL ) only tenfold higher than standard isoniazid
on a resistant strain of M. tuberculosis (Figure 1). Their com-
plexity rapidly intrigued organic chemists who ventured in
their total synthesis. We now wish to describe a concise and
bio-inspired formal synthesis of hirsutellone B (2) and its
congeners A and C.
[7]
strain. Biosynthetic studies on GKK1032s by Oikawa re-
vealed their polyketide synthetases (PKS)/nonribosomal
peptide-synthetase (NRPS) nature, originated from tyrosine
[8]
and nine acetate units. Oikawaꢀs study allowed us to pre-
dict the biosynthetic origin of hirsutellones (Scheme 1). The
most intriguing biosynthetic event is the conversion of
a linear tyrosine-nonaketide precursor (4) into the skeleton
To date, two total syntheses of hirsutellone B (2) have
[4]
been reported by Nicolaou in 2009 and by Uchiro in
[5]
2
011. Among other works, Sorensenꢀs partial synthesis was
7
, which is supposed to take place in an auxiliary enzyme
[
a] X.-W. Li, A. Ear, L. Roger, Dr. N. Riache, A. Deville, Dr. B. Nay
Musꢁum National dꢀHistoire Naturelle
active site after an oxidative activation, following two mech-
anistic hypotheses (Scheme 1, pathways a and b).
[9]
5
7 rue Cuvier (CP 54), 75005 Paris (France)
Considering these biosynthetic hypotheses, we imagined
a biomimetic strategy towards the total synthesis of hirsutel-
lones. Not only would such a strategy bring clues to the bio-
synthetic pathways, but also would give a straightforward
access to the natural product and potential antitubercular
E-mail: bnay@mnhn.fr
[
b] X.-W. Li, A. Ear, L. Roger, Dr. N. Riache, A. Deville, Dr. B. Nay
CNRS, UMR 7245, Unitꢁ Molꢁcules de Communication
et Adaptation des Micro-organismes, Paris (France)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201303570.
[10]
analogues.
Among the two biosynthetic propositions
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16389

the linear precursor 9 (Scheme 1, bottom frame), being
doubly activated thanks to an electron-accepting 2,4,6-trien-
1
-yl carboxylate tail and a nucleophilic silyl enol ether head.
This linear precursor was foreseen from (R)-(+)-citronellal
0, with no use of protecting group if we consider that the
1
silyl and R groups in 9 are important to the expected cycli-
zation process.
Starting from (R)-(+)-citronellal (10), the trienoate 11
was readily constructed in 74% yield by a Horner–Wads-
worth–Emmons (HWE) reaction with the deprotonated 6-
[11]
phosphonohexa-2,4-dienoate 12 (Scheme 2).
Taking ad-
Scheme 1. Two divergent polycyclization hypotheses for the biosynthesis
of hirsutellone skeleton 7. Both pathways (a) and (b) are supported by
Nicolaouꢀs total synthesis of hirsutellone B (1) and by this work (bottom
frame), respectively.
Scheme 2. Synthesis of the bio-inspired substrate 9. LDA=lithium diiso-
propylamide; DIBAL-H=diisobutylaluminium hydride; DMAP=4-di-
methylaminopyridine.
(
Scheme 1), we identified pathway b involving a terminal al-
lylic alcohol (electrophilic tail in 6) as a straightforward al-
ternative strategy to perform a biomimetic cyclization. Basi-
cally, the other biosynthetic pathway had previously been
experienced by Nicolaou and co-workers who used an epox-
ide resembling intermediate 5 (electrophilic head for path-
way a) as the activated precursor leading to the decahydro-
fluorene core of hirsutellones. In the two pathways, an
electrophilic cyclization of ring C is followed by an intramo-
lecular Diels–Alder (IMDA) reaction leading to the full tri-
cyclic core. Both synthetic strategies are in agreement with
the hypothetical biosyntheses, yet with a complete inversion
of the electronic activation, that is, head-to-tail (the follow-
ing work) versus tail-to-head (Nicolaouꢀs work).
vantage of the electron-deficiency of 11, the trisubstituted
double bond was selectively dihydroxylated in the presence
of OsO and N-methylmorpholine-N-oxide (NMO), giving
4
the diol 13 in 83% yield (based on recovered starting mate-
rial, b.r.s.m.) as a 1:1 mixture of diastereoisomers. Then re-
duction of the ester and selective acetylation of the resulting
alcohol afforded the 2,4,6-trien-1-yl acetate 14 in 67% yield
over two steps and definitely installed the necessary electro-
philic tail for the biomimetic cyclization.
[4]
[12]
After cleavage of the diol into the aldehyde 16,
a second HWE reaction with the lithium salt of a-silyloxy-
[13]
phosphonate 15 furnished the bio-inspired substrate 9 in
5% yield with complete Z geometry. Six steps were thus
4
Results and Discussion
necessary to obtain this polyene, which was then submitted
to screening for the best cyclization conditions (Table 1).
Short synthesis of the linear polyunsaturated precursor 9:
Our initial attempts to construct a biomimetic linear precur-
sor like 6 or a tetramate analogue proved unsuccessful de-
spite the many disconnections we envisaged. The formal in-
Lewis acid-promoted electrophilic cyclizations; a bio-in-
spired route towards hirsutellones: Considering the allyl
acetate of substrate 9, Tsuji–Trost conditions were first ap-
[4]
[14,15]
termediate 8 was thus envisioned to be constructed from
plied,
using [Pd AHCTUNGERTNNUN(G PPh ) ] or [Pd ACHTUNGTERUNNGN( dba) ] (dba=dibenzyli-
3 4 2 3
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Chem. Eur. J. 2013, 19, 16389 – 16393

Bio-Inspired Synthesis of Hirsutellones A–C
FULL PAPER
Table 1. Attempts of cyclization of the linear intermediate 9.
catalyst for the electrophilic cyclization, furnishing
the key intermediate 20 after the remote departure
of the acetate leaving group. Such a cyclization of
a silyl enol ether on an electrophilic polyene is
unique owing to the remote mode of activation as
is shown in intermediate 21 (Scheme 3).
The stereoselectivity of the electrophilic cycliza-
tion was in all cases controlled by the sole methyl
substituent of 9 adopting an equatorial position in
the activated conformer 21 (Scheme 3). The cycliza-
tion unveiled the fumaroyl dienophile and diene
partners for an IMDA reaction that was expected
to follow an exo selectivity relatively to the internal
[
a]
Entry
Conditions
Product
AHCTUNGTRENNG(UN yield [%])
1
2
3
4
5
6
7
8
9
[Pd
[TiCl
[AlClEt
[AlClEt
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
(PPh
3
)
4
] (0.1), THF, reflux
Cl
, ꢀ78!ꢀ208C
] (10), CH Cl
, ꢀ788C!RT
Cl
, ꢀ78!ꢀ308C
] (1.5), CH Cl , 08C
] (1.5), MeOH, 08C!RT
Cl , 08C
Cl
, ꢀ788C
, 08C!RT
17 (30)
18 (69)
19 (38)
20 (50)
20 (67)
no reaction
20 (51)
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
4
] (1.5), CH
2
2
[17]
[
b]
carbonyl.
Interestingly, Uchiro and co-workers
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
2
2
2
2
[c]
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
] (10), CH
2
2
previously reported a total synthesis of hirsutello-
ne B through an intermediate bearing a fumaroyl
[Yb
[Yb
A
T
N
T
E
N
N
3
2
2
A
H
U
G
R
N
U
G
3
[4]
dienophile similar to our compound 20. However,
[Sc
BF
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
(OTf)
3
] (1.5), CH
(10), CH
Cl
2
2
[
d]
during their synthesis, this highly reactive inter-
mediate had to be protected as a transient cycload-
duct with 1,2,3,4,5-pentamethylcyclopentadiene
during five steps before the IMDA reaction oc-
curred.
3
·OEt
2
2
2
20 (52)
20 (<5%)
CSA (10), CH
2
2
[
a] Number of catalyst equivalents in parentheses; [b] 1m solution in toluene; [c] 1m
solution in hexane; [d] 87% b.r.s.m.
deneacetone) in THF heated at reflux (Table 1, entry 1).
Only the IMDA cycloadduct 17 was obtained in 30% yield,
being attributed to a thermal effect. This compound is remi-
niscent of equisetin, a fungal polyketide, whose biosynthesis
indeed involves a Diels–Alder reaction to form the decalin
[16]
core.
Lewis acids were then considered not only to promote the
first electrophilic cyclization of ring C, but eventually the
final IMDA reaction. Only a partial cyclization was ob-
served with TiCl (Table 1, entry 2), stereoselectively form-
4
ing rings B and C (18) of hirsutellones whereas the terminal
allyl acetate was chlorinated. When a toluene solution of
[
AlClEt ] was used instead, the same bicyclization occurred,
2
but surprisingly, a Friedel–Crafts alkylation of toluene was
also observed, furnishing compound 19 (Table 1, entry 3)
and showing the high reactivity of the terminal position of 9.
This problem was overcome by the use of a hexane solution
of the same catalyst, which finally provided stereoselectively
the expected monocyclization product 20, albeit in a moder-
ate yield of 50% (Table 1, entry 4). The use of [Yb
ACHTUNGTNRENUNG( OTf) ]
3
in CH Cl at 08C significantly improved the yield of 20 to
2
2
6
7% (Table 1, entry 5), whereas the same reaction was in-
hibited in a protic solvent like methanol (Table 1, entry 6).
Replacing [Yb(OTf) ] by [Sc(OTf) ] in CH Cl only provid-
Scheme 3. First attempts and difficulties in synthesizing the tricyclic core
8 of hirsutellone B.
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
ACHTUNGTRENNUNG
3
3
2
2
ed 20 in a moderate yield of 51% (entry 7). Better efficacy
was finally observed with BF ·OEt in CH Cl at ꢀ788C, iso-
End game: overcoming the ketone reduction trick: The
decahydrofluorene core of hirsutellones was obtained by
submitting intermediate 20 to o-xylene heated at reflux. The
reaction furnished the cycloadduct 22 in 92% yield with
a 5:1 selectivity in favor of the exo product as expected.
With this pleasing result in hand, we wished to complete
a formal synthesis of hirsutellones after the selective reduc-
tion of the carbonyl group of 22. In fact, this was more chal-
3
2
2
2
lating 20 in 52% yield, which was corrected to 87% yield
based on the recovered starting material (Table 1, entry 8).
Finally, we found no significant conversion when a Brønsted
acid (camphorsulfonic acid, CSA) was used (Table 1,
entry 9). Even though the one-step formation of the tricyclic
core of hirsutellones through domino IMDA reaction was
not achieved at this stage, BF ·OEt was retained as the best
3
2
Chem. Eur. J. 2013, 19, 16389 – 16393
ꢂ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
16391

B. Nay et al.
[
8]
lenging than expected since, as agreeing with Uchiroꢀs result
biosynthesis of GKK1032s and adapted to hirsutellones in
[5]
[9]
on related tricyclic intermediates, NaBH4 reduction fur-
nished a mixture of the desired (S)- and the undesired (R)-
alcohols 8 and 23 in a 1:3 ratio, respectively, and 68%
global yield. Unfortunately, the use of more hindered reduc-
Scheme 1 (pathway b). It shows that from a linear biosyn-
thetic precursor like 4, an oxidation at the terminal position
of the acyl chain is conceivable to trigger the cyclization.
Moreover, during the stereoselective sequence from the
chiral intermediate 9 to the tricyclic compound 8, we were
able to control the formation of seven new stereocenters,
which originate from the stereochemistry of the methyl sub-
stituent in 9. This work thus provides an expedient biomim-
etic access to the antitubercular pharmacophore of the natu-
ral product and may be useful to design diversity oriented
strategies and biological tools in the future.
ing reagents such as L-selectride, LiAlH ACHTNUGTERNNN(UG OtBu) , or the
3
[18]
Luche conditions mainly resulted in the formation of the
undesired alcohol 23 (Scheme 3).
To circumvent this difficulty and improve our strategy, the
stereoselective reduction of the cyclohexylketone 20 was en-
visaged. According to the classical Felkin–Anh model, the
reduction occurred in favor of the undesired alcohol 25
when performed with NaBH or LiHAl
A
H
U
G
R
N
U
G
At last, to decide between both biosynthetic pathways
(head-to-tail vs. tail-to-head), further biological experiments
may be needed in vivo. In fact, this question may be an-
swered the day when the biological macrocyclization of the
paracyclophane ring will be understood.
4
3
diastereomeric excess (de) in both cases). Nevertheless, the
[18]
Luche conditions gratifyingly afforded the allylic alcohol
4 in 67% yield with an anti-Felkin–Anh selectivity suppos-
2
edly resulting from coordination and cyclohexyl conforma-
tional effects (Scheme 4). Finally, the decahydrofluorene
Acknowledgements
We acknowledge receipt of scholarships by the China Scholarship Coun-
cil for X.W.L. and by the French Ministry of Research for A.E. and N.R.
We thank the ANR (project ANR-12-BS07-0028-01 SYNBIORG) and
the CNRS (interdisciplinary call Physics–Chemistry–Biology) for fund-
ing.
[
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Scheme 4. Formal synthesis of hirsutellone B through the stereoselective
reduction of enone 20.
[
[
10] Concerning biomimetic synthesis, see: Biomimetic Organic Synthesis
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(
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2
6
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Supporting Information.
(
Scheme 4), allowing us to complete the formal synthesis of
[4,5]
hirsutellone B (2),
(
and the natural analogues A (1) and C
[
19]
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2
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This work, in addition to providing a bio-inspired formal
synthesis of hirsutellone B (2), also gives clues to the alter-
native biosynthetic pathway suggested by Oikawa for the
[
14] Such conditions were previously applied to (2E,4E,6E)-octatrienyl
acetate leading to (3E,5E)-1,3,5,7-octatetraene through elimination
and showing that such substrates can be reactive in the presence of
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Bio-Inspired Synthesis of Hirsutellones A–C
FULL PAPER
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Received: September 9, 2013
Published online: October 18, 2013
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