Polyunsaturated C-Glycosidic 4-Hydroxy-2-pyrone Derivatives: Total Synthesis Shows that Putative Orevactaene Is Likely Identical with Epipyrone A

Article abstract of DOI:10.1002/anie.201702189

Orevactaene and epipyrone A were previously thought to comprise the same polyunsaturated tail but notably different C-glycosylated 4-hydroxy-2-pyrone head groups. Total synthesis now shows that the signature bicyclic framework assigned to orevactaene is a chimera; the compound is almost certainly identical with epipyrone A, whose previously unknown stereochemistry has also been established during this study. Key to success was the ready formation of the bicyclic core of putative orevactaene by a sequence of two alkyne cycloisomerization reactions using tungsten and gold catalysis. Equally important was the flexibility in the assembly process gained by the use of heterobimetallic polyunsaturated modules whose termini could be selectively and consecutively addressed in a practical one-pot cross-coupling sequence.

Full text of DOI:10.1002/anie.201702189

Angewandte
Communications
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International Edition: DOI: 10.1002/anie.201702189
German Edition: DOI: 10.1002/ange.201702189
Total Synthesis
Polyunsaturated C-Glycosidic 4-Hydroxy-2-pyrone Derivatives: Total
Synthesis Shows that Putative Orevactaene Is Likely Identical with
Epipyrone A
Johannes Preindl, Saskia Schulthoff, Conny Wirtz, Julia Lingnau, and Alois Fꢀrstner*
Dedicated to Prof. Herbert Waldmann on the occasion of his 60th birthday
Abstract: Orevactaene and epipyrone A were previously
thought to comprise the same polyunsaturated tail but notably
different C-glycosylated 4-hydroxy-2-pyrone head groups.
Total synthesis now shows that the signature bicyclic frame-
work assigned to orevactaene is a chimera; the compound is
almost certainly identical with epipyrone A, whose previously
unknown stereochemistry has also been established during this
study. Key to success was the ready formation of the bicyclic
core of putative orevactaene by a sequence of two alkyne
cycloisomerization reactions using tungsten and gold catalysis.
Equally important was the flexibility in the assembly process
gained by the use of heterobimetallic polyunsaturated modules
whose termini could be selectively and consecutively addressed
in a practical one-pot cross-coupling sequence.
O
revactaene (1, also called BMS-213438)[1] and epipyro-
ne A (2, also called D8646-2-6)[2,3] are the most noteworthy
representatives of an exceedingly rare chemotype comprising
a 4-hydroxy-2-pyrone nucleus decorated with a C-glycosidic
substituent and a polyunsaturated side chain (Scheme 1).[4]
Both compounds were isolated from Epicoccum purpurascens
(syn. E. nigrum) strains; whereas 1 exhibits HIV-1 inhibitory
properties,[1] 2 and congeners were originally described as
telomerase inhibitors;[2] later on, 2 was found to show
significant activity against the influenza A virus (H1N1) and
was also patented for use as a fungicide.[3,5] While these
intriguing natural products seem to share an identical
conjugated heptaene tail terminated by a dimethyl-branched
pentyl chain of as yet unknown configuration, they ostensibly
differ in their signature head groups: 2 features a regular b-C-
glycosidic link between a 4-hydroxy-2-pyrone and a galacto-
pyranosyl ring, whereas the pyrone and the carbohydrate part
in 1 are thought to be annulated.[6] No information as to the
configuration of the two chiral centers C32 and C33 exo to the
bicyclic core is available; for the annulated ring itself, the
large 3J coupling constants (9.3–9.5 Hz) between H3, H4, and
H5 seem to indicate an all-trans orientation of the substitu-
Scheme 1. Structures and presumed biosynthesis of putative orevac-
taene (1) and epipyrone A (2); the stereochemistry at the chiral centers
marked * as well as the absolute configuration of either natural
product are unknown.
ents.[1] This particular relative stereochemistry, however,
implies that the incorporated sugar cannot be galactose as
present in 2 but must either be mannose, talose, gulose, or
allose. In addition, the absolute configurations of 1 and 2 are
also unknown (Scheme 1).
Ironically, it turns out that the isolation team was
profoundly misled by what appeared to be a seemingly
secure piece of stereochemical information. As will become
evident below, it is the spectroscopic fingerprint of uniformly
[*] Dr. J. Preindl, S. Schulthoff, C. Wirtz, M. Sc. J. Lingnau,
Prof. A. Fꢀrstner
Max-Planck-Institut fꢀr Kohlenforschung
45470 Mꢀlheim/Ruhr (Germany)
E-mail: fuerstner@kofo.mpg.de
3
large J couplings between H3, H4, and H5 that confirmed
that orevactaene cannot contain an annulated backbone as
originally proposed.[1] Rather, all evidence suggests that
orevactaene is identical with epipyrone A.
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
https://doi.org/10.1002/anie.201702189.
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be the effort that it takes to prepare the necessary isomeric
building blocks by separate routes. As will become evident
below, however, this proved unnecessary in the end.
Our first foray commenced with d-arabinose (3;
Scheme 3). Chain extension by Wittig olefination gave
(E)-4, which was detained from undergoing spontaneous
oxa-Michael reactions by the crowded diphenylmethyl ester
group.[11,12] The subsequent dihydroxylation followed Kishiꢀs
rule[13] and led to the manno-configured g-lactone 5 after acid
treatment of the crude material. Perbenzylation of the
hydroxy groups was carried out under acidic conditions to
avoid epimerization adjacent to the lactone. DIBAL-H
reduction of 6 then set the stage for a one-carbon homo-
logation to the corresponding terminal alkyne 7, which
proceeded well upon addition of lithiated TMS-diazomethane
(17),[14] whereas attempted use of the Bestmann–Ohira
reagent 18 was to no avail.
Scheme 2. Retrosynthetic analysis. M=metal or metalloid, R=generic
protecting group, X=halide.
The few studies previously directed towards these intri-
cate targets had left the questions concerning constitution and
stereostructure open.[7,8] In view of five-plus-two basically
unassigned chiral centers located in two separated clusters at
the head and the tail region of 1, respectively, one has to be
prepared to make a library of isomers to clarify this point.
Only a highly convergent approach that
assembles building blocks of unambig-
uous stereostructure may succeed. We
opted for a “stitching” assembly mode,
in which a heterodimetalated linchpin G
allows any combination of the head and
tail pieces E and F to be connected in
a single operation (Scheme 2).[9] This
strategy, however, must also take the
sensitivity of the polyunsaturated frag-
ments and products into consideration.
It appeared to us that a dissymmetric
tetraene-diyl derivative G (M1 ¼ M2, n =
3) might be the best compromise in
terms of accessibility, reactivity, and
stability. Conceptually, epipyrone A (2)
can be disconnected in a similar manner
into building blocks of type F, G, and H.
Alkyl chains featuring 1,3-syn- or
Next, compound 7 was transformed into glycal 9 by
treatment with catalytic amounts of [W(CO)6] and DABCO
under UV irradiation.[15] Upon loss of a CO group, the
coordinatively unsaturated catalyst converts the terminal
alkyne into the corresponding alkenylidene complex 8, which
is intercepted by the tethered -OH group. Although the same
1,3-anti-configured methyl branches are
known to populate sufficiently different
conformational space as to render their
spectral signatures dissimilar.[10] One
can therefore expect that the configu-
ration of the two as yet unassigned
chiral centers in the tail region of 1 can
be firmly established by spectroscopic
means. We were not sure, however, that
the same level of confidence could be
reached for the two hydroxylated cen-
ters at C32 and C33 in the polar tail
branching off the head piece. Therefore,
we deliberately chose carbohydrates as
starting materials to define these two
critical sites in fragment E. The price to
pay for the stereochemical rigor might
=
Scheme 3. a) Ph3P CHCOOCHPh2, 1,4-dioxane, DMF, 61%; b) OsO4 cat., NMO·H2O, acetone/
H2O; c) Amberlyst IR-120H+, Et2O, H2O, 72% (over 2 steps); d) BnOC(NH)CCl3, TfOH, 1,4-
dioxane, 74%; e) DIBAL-H, CH2Cl2, 85%; f) LDA, TMSCHN2, THF, 65%; g) [W(CO)6]
(15 mol%), DABCO, THF, hn, 68%; h) POCl3, DMF, 65%; i) NaClO2, NaH2PO4, H2O2, MeCN,
tBuOH, H2O, 77%; j) 2-(trimethylsilyl)ethanol, Ph3P, DEAD, THF, 80%; k) H2, Pd(OH)2/C cat.,
MeOH; l) TBSOTf, pyridine, CH2Cl2, 95% (over 2 steps); m) LDA, I2, THF, 71%; n) propargyl
alcohol, [(Ph3P)2PdCl2] (10 mol%), CuI (20 mol%), NEt3, 85%; o) 19 (1 mol%), MeNO2, 82%;
p) DMP, CH2Cl2, 90%; q) CHI3, CrCl2, THF, 57%. Bn=benzyl, DABCO=1,4-diazabicyclo-
[2.2.2]octane, DEAD=diethyl azodicarboxylate, DMP=Dess–Martin periodinane, LDA=lithium
diisopropylamide, NMO=N-methylmorpholine N-oxide, TBS=tert-butyldimethylsilyl, Tf=tri-
fluoromethanesulfonyl, TMS=trimethylsilyl, Ts=para-toluenesulfonyl.
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net 6-endo-dig cyclization can also be achieved with
catalytic [(Ph3P)RhCl] in DMF,[16] the tungsten-based
procedure proved to be better scalable.
By virtue of the polarization of the enol ether, the
subsequent Vilsmeier–Haack formylation of 9 gave
aldehyde 10 exclusively,[17] which was transformed
into the corresponding ester 11. While robust benzyl
ethers had been necessary as protecting groups up to
this point, it seemed prudent to replace them by TBS
ethers to avoid any hassle during the final depro-
tection of the polyunsaturated target compound. To
this end, 11 was subjected to hydrogenolysis, which
left the push–pull alkene site intact; the resulting
product was treated with TBSOTf/pyridine to give 12
in excellent yield, leaving the C32 hydroxy group
(orevactaene numbering) uncapped for steric rea-
sons. The use of an extra equivalent of LDA sufficed
to prevent this protic site from intervening in the
subsequent directed lithiation/iodination of the enol,
whereas the hydroxy group is uncritical anyway in the
Sonogashira coupling of the resulting iodide 13 with
propargyl alcohol. Compound 14 was then cyclized
with the help of gold complex 19 as a p-acidic
catalyst[18] to the desired 2-pyrone 15 according to
a procedure previously developed by our group.[19,20]
This gratifying result adds another entry to the
growing list of exigent pyrone derivatives prepared
Scheme 4. a) 21, LDA, LiCl, THF, 79%; b) LDA, BH3·NH3, THF, 75%;
c) (COCl)2, DMSO, NEt3, CH2Cl2; d) CBr4, PPh3, CH2Cl2; e) nBuLi, THF, then
(CH2O)n, 51% (over 3 steps); f) i) 30, THF, then thexylborane; ii) trimethylamine
N-oxide; g) 1-iodopropyne, [(dppf)PdCl2] (10 mol%), aq. KOH, 57%;
h) PhMe2SiLi, CuCN, THF, 90%; i) DMP, CH2Cl2, 92%; j) NaClO2, NaHPO4,
H2O2, tBuOH, H2O; k) 2-(trimethylsilyl)ethanol, DEAD, PPh3, 62% (over
2 steps); l) NIS, 2,6-lutidine, hexafluoroisopropanol, 89%. dppf=1,1’-bis(diphe-
nylphosphino)ferrocene, NIS=N-iodosuccinimide.
by this method.[19–21] Selective oxidation of the primary
hydroxy group in 15 followed by a Takai olefination[22]
furnished product 16 as a first fully functional building
block en route to 1.
were prepared analogously (see the Supporting Information).
The yet missing central module was obtained by alkyla-
tion of sodium acetylide with epichlorohydrin (31); under the
basic conditions, the primary product undergoes spontaneous
deprotonation/ring opening (Scheme 5).[28] Subsequent stan-
nylcupration of enyne 32 thus formed followed by oxida-
tion,[9c] Wittig reaction, and reduction of the ester gave 34 in
good overall yield. This product was oxidized on demand to
the corresponding aldehyde, which reacted with lithiated 38 in
a bora-Wittig process[29] to give the heterodimetalated
For its reliability, auxiliary-controlled enolate alkylation
was used for the preparation of all possible isomers of the tail
region;[23] this route is explicitly spelled out for the S,S series
in Scheme 4. Alcohol 22 was oxidized and the resulting
aldehyde transformed into propargyl alcohol 23 by a Corey–
Fuchs reaction, in which the lithiated alkyne primarily formed
was quenched with paraformaldehyde.[24]
This compound was then subjected to
directed hydroboration/cross-coupling as
concurrently developed in this labora-
tory.[25] Specifically, mixing of 23 with
ethyl trifluoropyruvate (30) forms the cor-
responding hemiacetal, which favors the
formation of a six-membered cyclic bori-
nate in the subsequent hydroboration of
the alkyne with thexylborane; oxidation
with trimethylamine N-oxide followed by
a Suzuki-type cross-coupling of the result-
ing boronic acid ester 25 with
1-iodopropyne provided enyne 26 in appre-
ciable yield. We are unaware of any other
method that allows such a directed alkyny-
lation to be carried out in a single oper-
Scheme 5. a) NaNH2, NH3, acetylene, 49%; b) nBuLi, Bu3SnH, CuCN, THF, 95%;
ation. The elaboration of 26 into segment
29 representing the terminus of 1 and 2 was
uneventful, using a regioselective alkyne
silylcupration as the key step.[26,27] All other
c) SO3·pyridine, DMSO, NEt3, CH2Cl2, 67%; d) Ph3PCHCOOEt, CH2Cl2, 92%; e) DIBAL-H,
CH2Cl2, 87%; f) SO3·pyridine, DMSO, NEt3, CH2Cl2, 77%; g) 38, lithium tetramethylpiperidi-
nide, THF, 84%; h) (S,S)-29, [PdCl2(MeCN)2] (10 mol%), Ph3As, [Ph2PO2][NBu4], DMF; i) 16,
[dppf)PdCl2] (10 mol%), aq. K3PO4, THF, 55%; j) TASF, DMF, 60%. TASF=tris(dimethylami-
stereoisomeric building blocks of this type no)sulfonium difluorotrimethylsilicate.
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tetraene 35. As anticipated, the termini of this compound can
in fact be consecutively addressed: Thus a modified Stille
reaction[30,31] with (S,S)-29 was telescoped with a Suzuki
coupling with iodide 16 to assemble the target framework in
a single operation, which had to be carried out in the dark.
ously confirmed but the ring itself was found to adopt a C4
conformation that brings all substituents in an axial rather
than equatorial orientation. This striking attribute is by no
means a peculiarity of the manno-configured entity com-
prised in 1; rather, the closely related model compounds 39
and 40 derived from d-glucal and d-galactal, respectively,
have the exact same spectroscopic signature.[32]
Collectively, the recorded data show that the
spectral mismatch between synthetic (S,S)-1,
(S,R)-1, 39, and 40 on the one hand and putative
orevactaene on the other hand cannot be attrib-
uted to stereochemical variance; rather, they must
have profound structural reasons. When contem-
plating the different possibilities on the basis of the
available data, it appeared to us that the proposed
bicyclic structure of orevactaene had to be ques-
tioned altogether: in addition to the arguments
arising from the coupling constants and shift
differences outlined above, the original publica-
tion does not mention a long-range coupling
between C6 and H5 across the ether bridge,
although the isolation team had heavily relied on
such means for the determination of the connec-
tivities in the rest of the molecule;[1] importantly,
however, this diagnostic coupling is unmistakable
in the HMQC spectra of our synthetic samples
(Figure 1, red arrow).
Figure 1. Confirmation of the connectivity and stereostructure of (S,S)-1 and list of
Under the premise that the 2-pyrone ring and
the sugar segment might not be annulated as
originally proposed,[1] it seems plausible that
additional reference compounds; for their synthesis, see the Supporting Informa-
tion.
Final deprotection of (S,S)-37 with TASF gave
(S,S)-1 as a first possible stereoisomer of the
orevactaene estate.
Much to our surprise, however, only the
signals of the side chain of (S,S)-1 were in
reasonable agreement with those of the natural
product, whereas the spectral fingerprint of the
head region deviated massively from the reported
data (see the Supporting Information). The
1H NMR shifts were largely off, and the 3J
couplings for the protons H3, H4, and H5 were
all in the range of 3–4 Hz rather than > 9 Hz as
reported for 1.[1] The differences in the 13C NMR
spectra were no less striking. The maximum shift
differences were noted for C3 (12.0 ppm) and C33
(9.2 ppm), which can hardly be explained by
stereochemical arguments. The spectra of isomer
(S,R)-1 (Figure 1) were not matching any better,
which confirms that the configuration of the distal
stereocluster in the tail region does not have
a significant impact on the spectral features of the
Scheme 6. a) BF3·OEt2, CH2Cl2, MS 4 ꢁ, 56% (a-anomer) and 6% (b-anomer);
b) DBU, THF, quant.; c) 2-(trimethylsilyl)ethanol, DIAD, PPh3, THF, 08C!RT, 83%;
d) H2, Pd(OH)2/C cat., THF; e) TBSOTf, pyridine, CH2Cl2, 08C!RT, 83% (over
2 steps); f) i) LiHMDS, THF, ꢀ788C; ii) 45, Sc(OTf)3, 63%; g) Ac2O, Et3N, DMAP,
CH2Cl2; then DBU, 88%; h) (S,S)-29, [PdCl2(MeCN)2] (10 mol%), Ph3As, [Ph2P(O)O]-
[NBu4], DMF; i) 46, aq. K3PO4, [PdCl2(dppf)] (10 mol%), THF, 57%; j) TASF, DMF,
17% (after HPLC).[36] DIAD=diisopropyl azodicarboxylate, LiHMDS=lithium hexa-
methyldisilazide.
head group held apart by the stiff polyene chain.
Despite the configurational guarantee pro-
vided by the choice of d-arabinose as the sub-
strate, we scrupulously confirmed the connectivity
and stereostructure of synthetic (S,S)-1 by 1D and
2D NMR spectroscopy (Figure 1): the all-trans
substitution pattern on the pyran was unambigu-
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orevactaene and epipyrone A are the same chemical entity.
Conflict of interest
Unfortunately, this tantalizing question cannot be answered
based on the literature data because their spectra had been
recorded in different solvents ([D6]DMSO versus
[D4]methanol).[1–3,5,33] Therefore, the need arose for us to
prepare authentic epipyrone A (2). This formidable task was
somewhat alleviated by the fact that the sugar contained in 2
is almost certainly galactose[2,3,5,8] and only the configuration
of the chiral centers in the tail remains undefined.
The authors declare no conflict of interest.
Keywords: cross-coupling · glycolipids · natural products ·
pyrones · structure determination
The necessary C-glycosylated pyrone segment was pre-
pared by acid-catalyzed reaction of commercial 42 with
galactopyranosyl fluoride 41[34] (Scheme 6).[8] The resulting
major a-anomeric product was epimerized to the b-anomer
43[8] prior to elaboration into alkenyl bromide 46 by
deprotonation of the benzylic methyl substituent, addition
of the known aldehyde 45,[35] and elimination of the resulting
secondary alcohol. The matching shorter linchpin 47 is
literature-known;[9a] this amendment notwithstanding, the
modularity of the synthesis blueprint paid valuable dividends
at this point as the final assembly step could follow the
telescope process outlined above. Final deprotection of the
resulting polyene 48 gave (S,S)-2.[36] This endgame was
repeated with all isomeric tail pieces to obtain the complete
set of conceivable isomers that might represent epipyrone A
(see the Supporting Information).
The NMR data compiled in the Supporting Information
show that synthetic 2 is identical with putative orevactaene as
well as with epipyrone A as far as can be judged from the
spectra of these amphiphilic, light-sensitive, and rather
unstable compounds; they confirm our hypothesis that the
bicyclic structure assigned by the isolation team to the core
region of orevactaene is most likely a chimera.[1] While the
spectra of compounds (S,S)-2 and (R,R)-2 are actually both
closely matching, their optical rotations in MeOH are of
opposite sign, with the [a]D values of (S,S)-2 (+ 14.2) and
epipyrone (+ 27.8)[3] being in no more but fair agreement; as
a comparison with the reported rotational data in DMSO
proved pointless,[37] however, some ambiguity remains in this
regard.
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Acknowledgements
Generous financial support by the MPG is gratefully
acknowledged. We thank Dr. H. Sommer for advice concern-
ing the directed hydroboration and the analytical depart-
ments of our Institute for excellent support.
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Communications
Chemie
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Manuscript received: February 28, 2017
Revised: April 3, 2017
Final Article published: && &&, &&&&
6
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Angew. Chem. Int. Ed. 2017, 56, 1 – 7
These are not the final page numbers!

Angewandte
Communications
Chemie
Communications
Total Synthesis
J. Preindl, S. Schulthoff, C. Wirtz,
J. Lingnau, A. Fꢁrstner*
&&&& — &&&&
Polyunsaturated C-Glycosidic 4-Hydroxy-
2-pyrone Derivatives: Total Synthesis
Shows that Putative Orevactaene Is Likely
Identical with Epipyrone A
The wrong head: Synthesis shows that
the proposed structure of orevactaene is
a chimera; rather than comprising a head
group in which the sugar is annulated to
a 2-pyrone, the compound is a regular b-
C-glycoside and hence most likely identi-
cal with epipyrone A. A tungsten-cata-
lyzed glycal formation, a gold-catalyzed
pyrone cyclization, and a stitching
assembly process using a heterobimetal-
lic linchpin were key for solving the riddle.
Angew. Chem. Int. Ed. 2017, 56, 1 – 7
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
7
These are not the final page numbers!