Gold- or Silver-Catalyzed Syntheses of Pyrones and Pyridine Derivatives: Mechanistic and Synthetic Aspects

Article abstract of DOI:10.1002/chem.201503403

3-Oxo-5-alkynoic acid esters, on treatment with a carbophilic catalyst, undergo 6-endo-dig cyclization reactions to furnish either 2-pyrones or 4-pyrones in high yields. The regiochemical course can be dialed in by the proper choice of the alcohol part of the ester and the π-acid. This transformation is compatible with a variety of acid-sensitive groups as witnessed by a number of exigent applications to the total synthesis of natural products, including pseudopyronine A, hispidine, phellinin A, the radininol family, neurymenolide, violapyrone, wailupemycin and an unnamed brominated 4-pyrone of marine origin. Although the reaction proceeds well in neutral medium, the rate is largely increased when HOAc is used as solvent or co-solvent, which is thought to favor the protodeauration of the reactive alkenyl-gold intermediates as the likely rate-determining step of the catalytic cycle. Such intermediates are prone to undergo diauration as an off-cycle event that sequesters the catalyst; this notion is consistent with literature data and supported by the isolation of the gem-diaurated complexes 12 and 15. Furthermore, silver catalysis allowed access to be gained to 2-alkoxypyridine and 2-alkoxyisoquinoline derivatives starting from readily available imidate precursors.

Full text of DOI:10.1002/chem.201503403

DOI: 10.1002/chem.201503403
Full Paper
&
Natural Products
Gold- or Silver-Catalyzed Syntheses of Pyrones and Pyridine
Derivatives: Mechanistic and Synthetic Aspects
Johannes Preindl, KØvin Jouvin, Daniel Laurich, Günter Seidel, and Alois Fürstner*[a]
Abstract: 3-Oxo-5-alkynoic acid esters, on treatment with
a carbophilic catalyst, undergo 6-endo-dig cyclization reac-
tions to furnish either 2-pyrones or 4-pyrones in high yields.
The regiochemical course can be dialed in by the proper
choice of the alcohol part of the ester and the p-acid. This
transformation is compatible with a variety of acid-sensitive
groups as witnessed by a number of exigent applications to
the total synthesis of natural products, including pseudopy-
ronine A, hispidine, phellinin A, the radininol family, neury-
menolide, violapyrone, wailupemycin and an unnamed bro-
minated 4-pyrone of marine origin. Although the reaction
proceeds well in neutral medium, the rate is largely in-
creased when HOAc is used as solvent or co-solvent, which
is thought to favor the protodeauration of the reactive al-
kenyl-gold intermediates as the likely rate-determining step
of the catalytic cycle. Such intermediates are prone to under-
go diauration as an off-cycle event that sequesters the cata-
lyst; this notion is consistent with literature data and sup-
ported by the isolation of the gem-diaurated complexes 12
and 15. Furthermore, silver catalysis allowed access to be
gained to 2-alkoxypyridine and 2-alkoxyisoquinoline deriva-
tives starting from readily available imidate precursors.
Introduction
During the total synthesis of the structurally fairly unique
marine natural products neurymenolide A (1) and its unnamed
sibling 2 we faced the need to develop novel approaches to 2-
pyrones and 4-pyrones, respectively (Scheme 1).[1–3] The skip-
ped unsaturations in the aliphatic tethers of these ansa-com-
pounds are exceptionally isomerization-prone; in case of com-
pound 2, the challenge is further increased by the presence of
a homoallylic bromine substituent at C19 with latent “non-clas-
sical” carbocation reactivity, as well as by the fragile ketene-
acetal motif that links the heterocyclic core to the aliphatic
chain.
In biosynthetic terms, both secondary metabolites are
thought to derive from 1,3,5-tricarbonyl precursors such as 3
formed by chain-extension of a polyunsaturated fatty acid,
which then cyclize to the respective pyrone rings.[4,5] Early at-
tempts at emulating this reactivity mode in the laboratory sug-
gested that the required conditions are too harsh to qualify for
a key step of a projected total synthesis of these exigent tar-
gets.[6,7] It was therefore mandatory to develop a much milder
entry; this new approach must also be regioselective, such
that either a 2-pyrone or a 4-pyrone unit can be accessed with
Scheme 1. Top: Cyclophanic pyrone derivatives of algal origin (in case of 2,
only the relative configuration is known); bottom: putative biosynthetic
pathway to neurymenolide A (1).
pyrones that are difficult to make otherwise, but can also be
extended to the preparation of various N-heterocycles.
high fidelity.[8,9] As will be outlined below in some detail, Results and Discussion
a noble-metal catalyzed cyclization reaction shows the re-
Concept
quired profile; it does not only provide access to substituted
The activation of p-bonds by carbophilic catalysts, most nota-
[a] J. Preindl, Dr. K. Jouvin, D. Laurich, Ing. G. Seidel, Prof. A. Fürstner
Max-Planck-Institut für Kohlenforschung
45470 Mülheim/Ruhr (Germany)
bly those based on platinum or gold, provides an opportunity
for the manipulation of functional groups in a way that is
largely orthogonal to established carbonyl chemistry.[10,11] Since
an internal alkyne can be seen as a ketone surrogate, we con-
ceived that a substrate of the general type A is synthetically
E-mail: fuerstner@kofo.mpg.de
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201503403.
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Scheme 2. Bifurcated pathway that allows 2-alkoxy-4-pyrones (F) and 4-hydroxy-2-pyrones (I) to be formed with high selectivity, depending on the nature of
the ester terminus R in the substrate A and/or the chosen carbophilic catalyst; gem-diaurations as conceivable off-cycle events.
equivalent to tricarbonyl compounds such as 3 commonly em-
ployed in (biomimetic) cyclization reactions of the type re-
ferred to above.
Such substrates might lend themselves to regioselective
pyrone formation,[12] provided the adjacent ester group attacks
the activated triple bond in a 6-endo-dig fashion (Scheme 2): if
the resulting intermediate C simply releases a proton, a 2-
alkoxy-4-pyrone F will ensue upon protodemetallation of D. Al-
ternatively, C might be engineered for rapid loss of a (stabi-
lized) cation [R+] with formation of an intermediate of type G,
which would redirect the pathway to the corresponding 4-hy-
droxy-2-pyrone I. It is expected that an increased electrophilici-
ty of the catalyst facilitates the breakdown C ! G. Hence,
access to either pyrone series might be gained from a single
type of substrate upon proper choice of the ester group R
and/or the p-acidic catalyst.
Scheme 3. Model reactions: the choice of the ester terminus determines the
regioselective course of gold catalyzed pyrone formation. a) [(SPhos)AuNTf2]
(8) (1 mol%), HOAc, 94% (6), 94% (7); b) [(XPhos)AuNTf2] (9) (1 mol%),
HOAc, 92% (6).
The model substrates 5a,b differing only in their ester termi-
nus served to test this concept (Scheme 3).[1,13] In line with our
expectations, treatment of 5a (R=tBu) with catalytic amounts
of various complexes of the type LAuCl, after in situ or ex situ
ionization with AgNTf2,[14] resulted in the clean and essentially
quantitative formation of product 6 as judged by NMR. The
cleavage of the tert-butyl group off the putative intermediate
of type C (R=tBu) is obviously fast enough to funnel this spe-
cies exclusively to the desired 2-pyrone product; subsequent
release of a proton with concomitant formation of isobutene
ensures catalyst turnover. Importantly, substrate 5b (R=Bn)
bearing a benzyl rather than a tert-butyl ester furnished the re-
gioisomeric 4-pyrone 7 under otherwise identical conditions.[1]
Best results were obtained with Buchwald-type (dialkyl)biaryl
phosphines as ancillary ligands L.[15] Moreover, the chosen sol-
vent was found to exert a strong influence: clean but slow re-
actions were observed in CH2Cl2, CHCl3, 2-dichloroethane, tolu-
ene, Et2O, MeCN, and nitromethane, whereas the use of THF
led to product mixtures. By far the fastest rates were obtained
when HOAc was used as the reaction medium or as cosolvent
to MeCN or nitromethane.[1] Under these conditions, the reac-
tion proceeded within minutes and the catalyst loading could
be reduced to ꢀ1 mol% without noticeable loss in efficiency.
Several control experiments proved that neither the Brønsted
acid itself nor any residual AgNTf2 are accountable for the
pyrone formation: even after 14 d less than 20% of product 6
had formed in the absence of the gold catalyst, whereas
AgNTf2 (10 mol%) in HOAc or nitromethane required ꢁ 24 h
reaction time for full conversion. Moreover, addition of HNTf2
(5 mol%) to a solution of 5a in HOAc resulted only in the
cleavage of the tert-butyl ester; no pyrone was observed in
this case by NMR, thus excluding that HNTF2 formed in situ by
protonation of the counterion by HOAc is the actual catalyti-
cally competent species.[16]
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Mechanistic Implications
10 proceeded readily even with the most bulky complex
[(XPhos)AuNTf2]; the analogous gold source [(SIPr)AuNTf2]
comprising yet another sterically demanding ligand of a differ-
ent shape also reacted without incident (Scheme 4). The struc-
tures of the resulting gem-diaurated products 12b and 12c in
the solid state show that the long bond lengths entertained
by the gold centers alleviate the crowding (Figures 1 and 2).
The remarkable co-catalytic effect of HOAc deserves further
comment. Previous investigations in our laboratory had re-
vealed that the functionalized alkenylgold complex 11 (pre-
pared from 10 by gold-for-boron exchange) reacts instantane-
ously with a second [Ph3PAu]+ fragment to form the gem-di-
aurated species 12a, which turned out to be surprisingly
stable and unreactive (Scheme 4).[17,18] This bias is thought to
reflect the affinity of the transient alkenyl gold species 11 for
the “soft” and polarizable late-transition metal cation, which is
(much) higher than the affinity for the “hard” proton and
therefore becomes competitive. As the proposed organogold
intermediates D and G passed through en route to a pyrone
feature a similar b-oxygenation pattern,[19] they might be simi-
larly susceptible to gem-diauration with formation of off-cycle
intermediates of type E and H, respectively, that sequester the
catalyst in an unreactive form (Scheme 2).[1] Under this proviso,
it seems likely that protodeauration represents the rate-deter-
mining step of the catalytic cycle,[20] which in turn nicely ex-
plains why an acidic medium instigates a significant rate accel-
eration.[21,22]
Figure 1. Structure of complex 12b (L=XPhos) in the solid state; only the
complex cation is depicted, whereas the escorting [NTf2]À anion as well as
co-crystallized CH2Cl2 are omitted for clarity. Selected bond lengths [Š]:
C1ÀAu1 2.140(4), C1ÀAu2 2.117(4), C1ÀC2 1.390(7), C2ÀO1 1.321(5),
Au1ÀAu2 2.816(4).
Scheme 4. a) [(L)AuNTf2], Cs2CO3, THF, 85% (12a, L=PPh3), 87% (12b,
L=XPhos), 73% (12c, L=SIPr); b) [(Ph3P)AuNTf2], Cs2CO3, THF, 80%;
c) [(Ph3P)AuNTf2], CH2Cl2, 93%; d) [(Ph3P)AuOTf], 4-penten-1-ol, toluene,
91%, cf. ref. [23]; e) [(Ph3P)AuNTf2], CDCl3, quant., cf. ref. [27]; SIPr=1,3-
bis(2,6-diisopropylphenyl)imidazolidin2-ylidene.
Figure 2. Structure of complex 12c (L=SIPr) in the solid state; only the
complex cation is depicted, whereas the escorting [NTf2]À anion as well as
co-crystallized CH2Cl2 are omitted for clarity. Selected bond lengths [Š]:
C1ÀAu1 2.109(3), C1ÀAu2 2.122(3), C1ÀC2 1.358(5), C2ÀO1 1.348(4),
Au1ÀAu2 2.829(4).
One might object that this interpretation is based on the
gem-diorganogold species 12a (L=PPh3) comprising Ph3P li-
gands,[17] whereas pyrone formation is best achieved with gold
catalysts endowed with SPhos or XPhos, the sheer size of
which might impede or even suppress an analogous pathway.
A control experiment, however, proved that gem-diauration of
Therefore it seems highly unlikely that gem-diauration can
be precluded solely by choosing bulky ancillary ligands. Similar
conclusions were reached by other authors for different model
compounds.[24] Complexes 12b,c feature structural characteris-
tics similar to those observed for the parent complex 12a.[17]
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Most notable is the fact that the former C=C bond has lost
much of its double bond character, whereas the CÀO bond is
significantly contracted, indicative of build-up of positive
charge density at this site. In the extreme, these complexes
can be thought of as consisting of an oxocarbenium motif sta-
in turn were readily prepared by Claisen condensation (see the
Supporting Information). The reactions proceeded cleanly,
scaled well and tolerated various substituents. Even halogenat-
ed substrates were cyclized without incident (entries 3, 5),
whereas a C-silylated alkyne furnished the desired 2-pyrone in
only modest yield (entry 6); this result echoes previous experi-
ences of our group with substrates of this sort.[29] The product
shown in entry 7 is the antibiotic pseudopyronine A, an inhibi-
tor of microbial fatty acid biosynthesis,[30] whereas entry 8 fea-
tures a building block for the total synthesis of the mycopyro-
nins and related RNA-polymerase inhibiting antibiotics.[31,32]
tert-Butyl ester derivatives are not the only substrates ame-
nable to 4-hydroxy-2-pyrones formation; trimethylsilylethyl 3-
oxoalkanoates are equally suitable and have the additional
bonus of being easy to make by conventional esterification
(entries 9–13). By virtue of the b-cation-stabilizing effect of the
bilized via hyperconjugation by
a flanking dimetalated
center.[25] An aurophilic interaction further supports the partic-
ular assembly mode of these unusual complexes.[26]
While complexes 12a–c invariably comprise an alkoxide sub-
stituent at the b-position, the proposed intermediates D and G
feature
a (vinylogous) b-acyloxy moiety (see Scheme 2).
Though clearly less electron releasing, even such a motif pro-
vides sufficient activation for diauration to proceed. Thus, Yu
and co-workers managed to isolate the gem-diaurated coumar-
in intermediate 18 formed upon treatment of the glucosyl al-
kynylbenzoate with [Ph3PAu]+ (Scheme 4).[27] Along similar
lines, we found that the enamide substructure of an indole is
amenable to gem-diauration, a fact that is relevant for the dis-
cussion of the N-heterocycle formations outlined below. In this
case, the mono-aurated species 14 can be formed as a discrete
species, which reacts further on exposure to an extra equiva-
lent of [(Ph3P)AuNTf2]. The contracted N1ÀC1 bond (1.378(3) Š)
in 15 indicates considerable N-acyliminium character inherent
to this remarkable diaurated complex (Figure 3).[25,28] In any
case, the examples shown in Scheme 4 collectively support the
notion that (moderately) electron rich p-systems are highly
prone to diauration. This bias likely represents a serious com-
petition for productive catalyst turnover and has to be taken
into consideration in any of the noble-metal catalyzed hetero-
cycle syntheses discussed herein.
silyl group,[33]
a putative intermediate of type C (R =
CH2CH2SiMe3) collapses in a fashion analogous to that for R =
tBu. This variant also allowed a set of products to be formed in
which the pyrone ring is annulated to a glucose moiety; for
the sake of the acid labile silyl ether protecting groups, these
particular cyclization reactions were performed in nitro-
methane rather than HOAc. The success of these model studies
paved the way for an application to the radicinol series (see
below).
2-Alkoxy-4-pyrones
The ready formation of the 2-benzyloxy-4-pyrone 7 from the
model compound 5b (R = Bn) under otherwise identical con-
ditions suggested that the course of the reaction is largely de-
termined by the very nature of the ester terminus in the start-
ing material (Scheme 3). Thus, substrates derived from a pri-
mary or secondary alcohol component lead to intermediates
of type C that evolve via simple proton loss to the correspond-
ing 2-alkoxy-4-pyrones F. The examples shown in Table 2 (en-
tries 1–5) prove that this reactivity pattern is general; some of
the products served as model compounds for the total synthe-
sis of the algal metabolite 2 mentioned in the Introduction.
The very mild conditions of this new method transpire from
the successful formation of the pyrones shown in entries 4 and
5 which contain a protected alcohol substituent at a homoallyl-
ic site in the tether; release of the masked “non-classical”
cation would obviously be detrimental. Moreover, the presence
of double bonds in the cyclization precursor does not obstruct
the necessary activation of the alkyne unit by the p-acidic cata-
lyst, although coordination of gold to an alkene is thermody-
namically perhaps even more favorable.[11] Equally noteworthy
is the successful cyclization of a substrate containing more
than one acetylene unit (entry 5): although the triple bond
conjugated to the carbonyl group is actually the least electron
rich and hence the least affine to the carbophilic gold catalyst,
it is the only site featuring a nucleophile at an appropriate dis-
tance and hence provides a productive outlet. The selective
formation of the polyunsaturated products shown in entries 4
and 5 is therefore thought to reflect kinetic control, which in
Figure 3. Structure of complex 15 in the solid state; only the complex cation
is depicted for clarity. Selected bond lengths [Š]: N1ÀC1 1.378(3), C1ÀC2
1.387(3), C2ÀAu1 2.117(2), C2ÀAu2 2.127(2), Au1ÀP1 2.270(8), Au2ÀP2
2.261(7), Au1ÀAu2 2.764(4).
4-Hydroxy-2-pyrones
Entries 1–8 in Table 1 show an assortment of 4-hydroxy-2-py-
rones formed by gold-catalyzed cyclization of the correspond-
ing b-keto esters comprising a tert-butyl ester terminus, which
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in A (26), an annulated pyrone derivative with consid-
erable radical scavenging capacity that exists in nature
as two equilibrating diastereomers.[36,37] To this end,
commercial 19 was subjected to a high yielding
Hundsdieker reaction to afford the corresponding al-
kenyl bromide 20,[38] which was then cross coupled
with ethyl propiolate[39] to give ester 21 amenable to
a Claisen condensation with lithio tert-butyl acetate
(Scheme 5). The resulting b-ketoester 22, when treated
with catalytic amounts of 8 in HOAc, furnished the de-
sired 2-pyrone 23, which is hardly soluble in the
medium; for its isolation, it only has to be rinsed and
dried. Cleavage of the ketal with BCl3 as described in
the literature affords hispidine 24,[40] which is the his-
torically first 2-pyrone to be isolated from natural sour-
ces.[37,41]
Table 1. Gold-catalyzed preparation of 4-hydroxy-2-pyrones.[a]
Entry Substrate
1
Product
Yield [%]
94 (X=H)
2
3
97
(X=Me)
82
(X=Br)
4
5
6
99 (X=H)
85 (X=F)
45
A formal [3+3] cycloaddition[42] between 23 and
enal 29 gave the annulated product 25 in good yield,
provided that strictly anhydrous conditions were se-
cured. Final acetal cleavage released phellinin A (26) as
a yellow/orange powder that is only sparingly soluble
in MeOD or CD2Cl2; it consists of a mixture of diaste-
reomers which equilibrate in solution and therefore
cannot be separated.[36] The required enal partner 29
was prepared in a few straightforward steps from Ro-
mascone (27). The key step is the V(O)(OSiPh3)3 cata-
lyzed Meyer-Schuster rearrangement of propargyl alco-
hol 28 to form the targeted enal 29 in good overall
yield.[43,44]
7
8
96
83
97
9
(R=Me)[b]
94
10
(R=Ph)[b]
11
83[b,c]
89
12
13
(R=H)[b,c]
91
The Radicinol Family
(R=Ac)[b,c]
Plant pathogens are a prolific source of possible herbi-
cidal lead structures. In this context, the radicinol
family of bicyclic 2-pyrone derivatives deserves men-
tioning, which derives from different phytopathogenic
fungi of the Stemphylium, Cochliobus, Bipolaris, Phoma
and Alternaria genera (Figure 4).[45] The composition of
[a] Unless stated otherwise, all reactions were carried out with [(SPhos)AuNTf2]
(5 mol%) as the catalyst in HOAc as the solvent. [b] Using only 1 mol% of the cata-
lyst. [c] In nitromethane; TBS=tert-butyldimethylsilyl; THP=tetrahydropyranyl.
turn implies that gold-alkyne p-complex formation is fast and
reversible.[34,35]
the crude extracts depends not only on the particular strain
but is also strongly affected by the natural substrate (or culture
medium) on which they grow. Interestingly, the different
fungal strains seem capable of permutating the configurations
and, in part, the oxidation level at the C3 and C4 positions,
whereas C5 remains invariably (S)-configured. Since the phyto-
toxic activity of the individual family members is strongly cor-
related with the stereostructure,[45] it is of considerable interest
to extend the screening to the missing isomers comprising
a non-natural (5R)-center.
Interestingly, even substrates of type A containing a tert-
butyl ester terminus can be converted into the corresponding
4-pyrones, provided that the gold catalyst is replaced by the
less electrophilic silver salt AgNTf2 in the presence of N,N’-di-
methylethylenediamine (DMEDA) as a proton scavenger (en-
tries 6–8). We therefore conclude that the approach described
herein constitutes the arguably most general entry into the 2-
alkoxy-4-pyrone series known to date.[9] Its successful imple-
mentation into the total synthesis of the exceptionally taxing
marine natural product 2 highlights its preparative signifi-
cance.[2]
Commercial phenylthio b-d-glucopyranoside (33) served as
a convenient point of departure (Scheme 6). Selective tosyla-
tion of the primary position, benzylation of the remaining hy-
[46]
droxyl groups, reduction of the sulfonate ester with LiAlH4
and S-oxidation with mCPBA gave product 35 as a mixture of
the diastereomeric sulfoxides. Treatment with two equivalents
of LDA at low temperature furnished the corresponding lithiat-
ed glycal derivative 36,[47] which was quenched with trimethyl-
silylethyl chloroformate to give ester 37 in excellent yield. This
Applications to Natural Product Synthesis: Hispidine and
Phellinin A
The ability to engage polyunsaturated precursors in cyclization
opened an expedient entry into styrylpyrones such as phellin-
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compound underwent a 1,4-addition/elimina-
tion process[48] on treatment with lithio pent-
1-yn-3-ene generated in situ from the gem-di-
bromide 38[49] and BuLi; gratifyingly, both
diastereomeric sulfoxides reacted similarly
well, thus making a separation unnecessary.
In line with our expectation, compound 39
was readily transformed into pyrone 40 on
exposure to catalytic amounts of complex 8
in nitromethane; subsequent deprotection
with BCl3 gave ent-27. Interestingly, when the
cyclization reaction was performed in HOAc,
pyrone formation was accompanied by a se-
lective replacement of the BnO-group at C3
by an acetate moiety to give 42a (R=Ac) as
an 8.2:1 mixture of diastereomers, which
were readily separable by flash chromatogra-
phy. Careful analysis of the NOE contacts and
Table 2. p-Acid-catalyzed preparation of 2-alkoxy-4-pyrones.[a]
Entry Catalyst Substrate Product
Yield [%]
94
1
8[b]
2
3
8[b]
8
89 (X=H)
66
(X=Br)
4
8
95[c]
3
the J coupling constants proved that inver-
5
8
86[c]
sion is the dominant stereochemical course;
yet, it is likely that a cationic intermediate of
type 41 is operative under the acidic condi-
tions, which gains stabilization by orbital
overlap with the adjacent pyrone ring and
the vinylogous ether oxygen substituent; the
incoming acetate nucleophile approaches
this species preferentially trans to the benzyl
ether substituent for stereoelectronic rea-
sons.[50] In any case, global deprotection of
the major isomer 42a afforded ent-29 in high
overall yield.
85
[d]
[d]
6
7
AgNTf2
AgNTf2
(R=C6H13)
87
(R=Ph)
[d]
8
AgNTf2
88
[a] Unless stated otherwise, all reactions were carried out with a catalyst loading of 5 mol% in
HOAc as the solvent. [b] With 1 mol% of catalyst. [c] MeCN/HOAc (5:1). [d] With AgOTs and
DMEDA (5–7.5 mol% each) in CHCl3 as the solvent; DMEDA=N,N’-dimethylethylenediamine;
MOM=Methyloxymethyl.
The remarkable ease and selectivity of this
substitution reaction suggested that direct
access to 3-methoxy-3-epi-radicinol (ent-32)
might also be gained if one engages MeOH
instead of HOAc as external nucleophile. In fact,
treatment of 39 with complex 8 (1 mol%) in MeOH
in the presence of dilute HCl gave pyrone 42b (R=
Me) with a single methyl ether in place (d.r. 2.8:1).
Debenzylation of the major isomer furnished ent-32,
the constitution and stereostructure of which are un-
ambiguous. Because the data of the synthetic materi-
al, however, deviate from those of the natural prod-
uct reported in the literature (for a comparison, see
the Supporting Information), questions remain as to
whether the structure of this particular natural prod-
uct has been properly assigned by the isolation
team.[45c]
As outlined above, this study deliberately sought
access to the non-natural (5R)-series. Yet, we like to
emphasize that the proper natural products could be
obtained analogously by starting from cheap l-rham-
nose instead of d-glucose.
Scheme 5. Preparation of hispidine (24) and phellinine A (26): a) NBS, Et3N (5 mol%),
MeCN/H2O (9:1), 91%; b) (i) ethyl propiolate, LDA, THF, À788C; (ii) ZnBr2, [(Ph3P)4Pd]
(5 mol%), À788C!RT, 68%; c) tert-butyl acetate, LDA, THF, À788C, then 21, 89%; d) 8
(2 mol%), HOAc, 90%; e) BCl3, CH2Cl2, À208C!RT, 63%; f) Ac2O, piperidine, EtOAc, 858C,
82%; g) BCl3, CH2Cl2, 508C, 36%; h) LiAlH4, THF, 08C!RT, 90%; i) DMSO, oxalyl chloride,
CH2Cl2, À788C, then Et3N, À788C!RT; j) Ph3P=CHC(O)Me, toluene, reflux, 67% (over
both steps); k) [(Ph3P)2PdCl2] (5 mol%), Bu3SnH, NH4Cl, aq. THF, 76%; l) HCꢂCMgBr, THF,
08C!RT, 95%; m) [V(O)(OSiPh3)3] (5 mol%), Ph3SiOH (3 mol%), toluene, 1208C (micro-
wave), 81%; LDA=lithium diisopropylamide; NBS=N-bromosuccinimide.
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Figure 4. Naturally occurring members of the radicinol family.
Scheme 7. a) [(Ph3P)AuNTf2] (10 mol%), MeNO2/HOAc (4:1), 81%; b) 9
(5 mol%), MeNO2, 78%; c) (i) 9 (5 mol%), MeNO2/HOAc (4:1); (ii) Ac2O, Et3N,
CH2Cl2, 08C, 73% (over both steps); d) 8 (3 mol%), MeCN/HOAc (4:1), 97%.
The arguably most challenging applications are still the cycli-
zations leading to neurymenolide A (1)[1] and its 4-pyrone sib-
ling 2[2] already mentioned in the Introduction. They mandated
selective transformation of one out of six or five p-systems in
the cyclization precursors 48 and 50, respectively, not counting
the highly enolized b-ketoester units. As the skipped arrays
render these substrates exceptionally labile, the successful and
regioselective formations of 49 and 51 highlight the mildness
of the new method. This aspect is further illustrated by the
fact that the homoallylic bromide in 50 with latent “non-classi-
cal” carbocation reactivity as well as the fragile ketene-acetal
substructure in 51 were not affected. In either total synthesis,
a ring closing alkyne metathesis reaction served to forge the
macrocyclic array.[53,54]
Scheme 6. a) TsCl, pyridine, 08C, 68%; b) NaH, BnBr, DMF, 08C!RT, 87%;
c) LiAlH4, Et2O, reflux, 89%; d) mCPBA, CH2Cl2, 08C, 94% (d.r. 1.8:1); e) (i) LDA,
THF, À788C; (ii) Me3SiCH2CH2C(O)Cl, HMPA, 96-99%; f) (i) 38, nBuLi, THF,
À788C!08C; (ii) 37, À788C ! À558C, 82-85%; g) 8 (1 mol%), MeNO2, 94%;
h) BCl3, CH2Cl2, À788C, 88%; i) 8 (1 mol%), HOAc, 82% (R=Ac, d.r. 8.2:1); j) 8
(1 mol%), MeOH, HCl, 91% (R=Me, d.r. 2.8:1); k) K2CO3, aq. MeOH, 90%;
l) BCl3, CH2Cl2, À788C, 91%; m) BCl3, CH2Cl2, À788C, 72%.
N-Heterocycles
Examples from the Literature
In an attempt to extend this chemistry to the preparation of
six-membered N-heterocycles, several readily available amide
derivatives were screened to test how the N- rather than the
O-atom of such substrates could be coaxed to serve as the in-
ternal nucleophile; a few selected examples are shown in
Scheme 8.[55,56] For the sake of convenience, this screening was
performed in the benzo-annulated series.
In addition to the case studies outlined above, a number of
recent reports in the literature highlight the broad scope of
our new pyrone synthesis. Specifically, the final step en route
to the cytotoxic agent violapyrone C (44) consisted of a high
yielding cyclization of the b-ketoester 43 (Scheme 7).[51] Like-
wise, a concise entry into the marine natural product wailupe-
mycin G (47) features a gold-catalyzed ring closure after yet
another gold-catalyzed furan-yne cyclization had set the naph-
thol unit in substrate 45.[52]
Although some literature reports suggest that N-tosylated
amide derivatives can react as N-nucleophiles,[57] substrate 52
gave exclusively product 53 with the nitrogen substituent in
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Figure 5. Selection of 2-alkoxypyridine and -isoquinoline derivatives formed
by silver-catalyzed 6-endo-dig cyclization reactions (AgOTs, DMEDA, 5 mol%
each, CHCl3, 08C!RT); in all cases, small amounts of the isomeric 5-exo-dig
products were formed which could be separated by flash chromatography;
therefore, the reported yields refer to the pure samples of the depicted
compounds.
Scheme 8. Preliminary substrate screening: a) [(Johnphos)Au]SbF6 (61)
(5 mol%), HOAc, 66%; b) 61 (5 mol%), MeNO2/H2O (4:1), 608C, 80%;
c) Et3OBF4, CH2Cl2, Et3N; d) 61 (5 mol%), CH2Cl2, 52% (58), 35% (59);
e) AgOTs (5 mol%), DMEDA (5 mol%), CHCl3, 08C!RT, 80% (58), <9% (59);
f) BBr3, CH2Cl2, 08C!RT, 96%; g) TMSI, MeCN, 808C, quant.
workup;[65] the indicated yields refer to pure samples of the de-
picted products. A notable exception, however, was observed
in the cyclization of the silylated precursor, which furnished
the 5-exo-product as the only detectable isomer in 81% yield.
Scheme 9 outlines a way to integrate the new pyrone and
pyridine syntheses into a one-pot transformation. This model
study was thought to probe whether aromatic polyketide de-
rivatives such as the isoquinoline alkaloid WJ35[66] might be
within reach of this methodology. To this end, a Sonogashira
coupling between 2-iodobenzamide (62) and methyl deca-2,9-
diynoate was used to form compound 63, which was subject-
ed to a Claisen condensation with excess lithio tert-butyl ace-
tate. As the resulting product 64 turned out to be unstable,
the crude material was treated with Et3O·BF4 to form the corre-
sponding imidate, which was activated with catalytic AgOTs/
DMEDA to give the double-cyclization product 65 comprising
a 4-pyrone and an isoquinoline nucleus; this sequence pro-
ceeded in 67% yield over three steps. Somewhat surprisingly,
the use of BBr3 allowed the pyrone ring to be selectively de-
protected, whereas Me3SiI cleaved both alkoxide substituents
in 65. For solubility reasons, either compound was isolated
after O-acylation in the form of esters 66 and 67.
an exocyclic position.[58] In contrast, oxazolines such as 54 fur-
nished the corresponding isoquinolone derivatives on treat-
ment with catalytic [(JohnPhos)Au]SbF6 (61) in HOAc, but the
N-substituent in 55 (or congeners) could not be cleaved under
a variety of conditions. Gratifyingly though, the corresponding
imidate 57, which is readily formed from amide 56 on treat-
ment with [Et3O·BF4][59] followed by deprotonation of the re-
sulting salt with Et3N,[60] afforded the targeted isoquinoline de-
rivative 58;[61] however, a significant amount of the isomeric 5-
exo-dig cyclization product 59 was also formed (58/59
ꢁ1.5:1).[62] To avoid premature cleavage of the imidate group,
the reaction was best carried out in neutral medium.
Although 58 and 59 are separable by flash chromatography,
an optimization was deemed necessary. To this end, a large
number of ligands, counterions and solvents were screened,
but the product ratio did not vary by much. Therefore the
screening was extended to other carbophilic catalysts, of
which AgOTs in the presence of DMEDA furnished the best
result.[63,64] In this case, less than 10% of 59 were formed, and
analytically pure isoquinoline 58 could be isolated in 80%
yield on a >1 gram scale. On treatment with either BBr3 or
TMSI, the corresponding 2-isoquinolone 60 was released in es-
sentially quantitative yield.
Conclusion
Although carbophilic catalysts have fertilized many different
areas of organic synthesis,[10,11] it is fair to say that they are par-
ticularly enriching for heterocyclic chemistry. Upon proper
choice of the p-acid and the reaction conditions, it is possible
to add a host of carbon-, oxygen, nitrogen or sulfur nucleo-
Figure 5 shows an assortment of 2-alkoxypyridine derivatives
which were obtained analogously. In all cases, small amounts
of the regioisomers formed by 5-exo-dig ring closure were de-
tected in the crude material, but could be readily removed on
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by the isolation of relevant model complexes. In view of this
sound basis, a number of extensions of the underlying concept
can be envisaged, which we hope will materialize in the near
future.
Experimental Section
All experimental details can be found in the Supporting Informa-
tion. The material includes compound characterization, crystallo-
graphic abstracts and copies of spectra of new com-
pounds. CCDC 1417652 (12b), 1417653 (12c), and 1417651 (15)
contain the supplementary crystallographic data for this paper.
These data are provided free of charge by The Cambridge Crystal-
lographic Data Centre.
Acknowledgements
Generous financial support by the MPG is gratefully acknowl-
edged. We thank Dr. M. Corbet, Dr. W. Chaladaj, Dr. T. Fukuda,
Dr. L. Hoffmeister and Dipl.-Chem. G. Pototschnig for explora-
tory studies or singular applications, as well as Mrs. Conny
Wirtz, Julia Lingnau and Petra Phillipps for excellent NMR sup-
port. We are also grateful to Dr. Oliver Knopff, Firmenich SA,
Geneva, for a sample of Romascone, and to Umicore AG & Co
KG, Hanau, for a generous gift of various noble metal salts.
Keywords: diauration · gold · heterocycles · natural products ·
silver
Scheme 9. a) Methyl deca-2,9-diynoate, [(Ph3P)2PdCl2] (3.5 mol%), CuI
(8 mol%), Et3N, DMF, 73%; b) tert-butyl acetate, LDA, THF, À788C, then 63;
c) Et3OBF4, CH2Cl2, Et3N; d) AgOTs (10 mol%), DMEDA (10 mol%), CHCl3, 08C,
68% (over three steps); e) BBr3, CH2Cl2, 08C; f) propionic acid anhydride,
Et3N, CH2Cl2, 38% (over both steps); g) TMSI, MeCN, 608C; h) propionic acid
anhydride, Et3N, CH2Cl2, 77% (over both steps).
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Received: August 27, 2015
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Published online on November 23, 2015
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