Application and scope of Schreiber's gold(I)-catalyzed α-pyrone synthesis to ring a aromatic podolactones

Article abstract of DOI:10.1002/ejoc.201402803

Schreiber's gold(I)-catalyzed synthesis of α-pyrones was adapted to the total synthesis of a ring A aromatic podolactone, urbalactone. The scope of the acetylenic ester partner in the formation of α-pyrones was studied. The total synthesis features, as ke

Full text of DOI:10.1002/ejoc.201402803

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201402803
Application and Scope of Schreiber’s Gold(I)-Catalyzed α-Pyrone Synthesis to
Ring A Aromatic Podolactones
Eduardo Sánchez-Larios,[a] Robert D. Giacometti,[a] and Stephen Hanessian*[a]
Keywords: Pyrones / Anticancer agents / Terpenoids / Lactones / Homogeneous catalysis / Gold
Schreiber’s gold(I)-catalyzed synthesis of α-pyrones was
adapted to the total synthesis of a ring A aromatic podolact-
one, urbalactone. The scope of the acetylenic ester partner
in the formation of α-pyrones was studied. The total synthesis
features, as key steps, α-pyrone formation, Friedel–Crafts
cyclization, Stille coupling, and a N,NЈ-dicyclohexylcarbodii-
mide/4-(N,N-dimethylamino)pyridine lactonization to gener-
ate the γ-lactone. Several α-pyrone intermediates from this
work exhibited in vitro antiproliferative activity against the
A2780 ovarian cancer cell line.
disclosed by Burke and co-workers,[11] whereas Reuvers and
de Groot described the total synthesis of (Ϯ)-3-β-
hydroxynagilactone F.[12]
Introduction
Podolactones constitute a large family of norditerpenoid
natural products[1] that possess a wide cross-section of bio-
logical activities, acting among others, as antifungal,[2] anti-
feedant,[3] and anticancer agents.[4] Their tetracyclic frame-
work is composed of a trans-decalin core subunit that is
flanked by an unsaturated δ-lactone fused to ring B and a
γ-lactone bridging rings A and B, as exemplified by nagi-
lactone F[5] and its trihydroxylated congener, urbalactone
(Figure 1).[6]
Results and Discussion
During the course of our studies, we found that nagilact-
one F exhibits substantial in vitro activity against the
A2780 ovarian cancer cell line with an IC50 = 0.26 μm. En-
couraged by this result, we envisaged the synthesis of unnat-
ural podolactones in which ring A of the trans-decalin core
subunit in urbalactone was replaced by an aromatic coun-
terpart exemplified by generic structure D (Figure 2). The
successful implementation of a synthetic strategy toward
this objective would generate a series of structurally novel
and simpler congeners of urbalactone and related 7-β-hy-
droxypodolactones for biological evaluation. As a general
strategy, we considered the elegant gold(I)-catalyzed synthe-
sis of diversely functionalized α-pyrones that was recently
reported by Schreiber and co-workers[13] to be admirably
suited for exploratory studies leading to the intended proto-
types.[14]
Figure 1. Structures of nagilactone F and urbalactone.
Despite considerable interest concerning the synthesis[1a]
and biosynthesis[7] of podolactones over the years, it is only
recently that the enantioselective total syntheses of nagilact-
one F and related tetranorditerpenoid dilactones were re-
ported from our laboratory using a common chiron as the
starting material.[8] Semisyntheses of nagilactone F from
naturally occurring trans-communic acid and podocarpic
acid were reported by Barrero[9] and Hayashi,[10] respec-
tively. An enantioselective synthesis of nagilactone F was
Accordingly, bis-acetylenic ester A would undergo a
gold(I)-catalyzed [3,3] sigmatropic rearrangement followed
by 6-endo-dig cascade cyclization of the transient enyne al-
lene intermediate to eventually give trisubstituted α-pyrone
B, as reported by Schreiber for related esters (Fig-
ure 2).[13–15] Oxidative cleavage of the styryl appendage fol-
lowed by the introduction of a vinyl group and a second
oxidative cleavage would generate an aldehyde that would
undergo Friedel–Crafts cyclization to afford tricyclic fused
α-pyrone C, as a mixture of diol isomers. Further manipula-
tion would lead to the prototypical tetracyclic ring A aro-
matic congener of urbalactone (D), while maintaining a
skeletal similarity to nagilactone F.
[a] Department of Chemistry, Université de Montréal,
C.P. 6128, Succ. Centre-ville, Montréal, QC H3C 3J7, Canada
E-mail: stephen.hanessian@umontreal.ca
http://osiris.corg.umontreal.ca
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201402803.
Following Schreiber’s reported protocol,[13] smooth cycli-
zation took place with a variety of aryl acetylenic esters
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Application of Schreiber’s Gold(I)-Catalyzed α-Pyrone Synthesis
we were also able to isolate 13% of a side product (i.e., 2p),
whose structure was confirmed by X-ray crystallography. A
plausible pathway for its formation is shown in Scheme 2.
Figure 2. Synthetic strategy toward ring A aromatic podolactones.
(i.e., 1a–j) in the presence of both (Ph3P)AuCl (5 mol-%)
and AgSbF6 (5 mol-%) to give 3,4,5-trisubstituted α-pyr-
ones 2a–j (Scheme 1), in which the acetylenic alcohol was
kept constant.[16] Aside from 2,3-dimethoxy and p-CF3 ar-
enes 2b and 2f, the yields were generally good to excellent.
Although α-pyrone 2j containing a methoxy ether append-
age was easily obtained, related benzyloxymethyl analog 2k
consisted of a complex mixture under the same conditions.
Scheme 2. Adaptation of Schreiber’s proposed mechanism for 6-
endo-dig cyclization to explain the formation of side product 2p and
oxabicyclic pyrones 2n–o. [a] Reaction conditions: 5 mol-% (Ph3P)
AuCl, 5 mol-% AgSbF6, CH2Cl2, 40 °C. [b] The reaction was per-
formed on a 9.4 mmol scale, and the yield of 2a was 45 %.
The impressive tolerance for substituent and functional
group diversity within the reacting partners in the gold(I)-
catalyzed cascade cycloaddition process allowed Schreiber
and co-workers to construct a variety of 3,4,5-trisubstituted
α-pyrones.[13] In the majority of the reported examples, the
acetylenic ester component harbored alkyl or aryl groups.
Combining these with acetylenic alcohols bearing a broad
variety of appendages led to the corresponding 3,4,5-trisub-
stituted α-pyrones in good to excellent yields.[13] We were
surprised that cyclohexyl α-pyrones 2l and 2m (Scheme 1)
could not be obtained; the starting esters were recovered
under the reaction conditions.[17] It is possible that the 6-
endo-dig cyclization step involving attack of the allene inter-
mediate onto the Au-coordinated alkyne is unfavorable ow-
ing to the presence of a bulky cyclohexyl group (refer to the
mechanism shown in Scheme 2). However, we noted that
extended alkanes are compatible[13] and steric bulk in the
case of substituted aromatic esters (see below) were also
tolerated. Nevertheless, the list in Scheme 1 complements
the variety of substrates that were successfully cyclized by
the Schreiber group.[13]
Scheme 1. Scope of the synthesis of α-pyrones; yields (average of
three runs) of pure isolated products. See the Supporting Infor-
mation for details. CM = complex mixture, NR = no reaction, TBS
= tert-butyldimethylsilyl.
Cyclization products 2a–i were then oxidatively cleaved
to the corresponding aldehydes by a two-step procedure in-
volving dihydroxylation with OsO4 followed by treatment
with NaIO4, which took place in excellent overall yield
This observation led us to endeavor to cyclize acetylenic (Scheme 3). Aldehydes 3a–i were individually treated with
esters 1n and 1o bearing a terminal methoxymethyl (MOM) vinylmagnesium bromide and CuCN·2LiCl to afford race-
ether group (Scheme 2). We were pleased to find that they mic 1,2-vinyl adducts 4a–i, as well as the corresponding 1,4-
led to oxabicyclic pyrones by a mechanism involving oxo- addition products (i.e., 5a–i) as essentially single dia-
carbenium ions and concomitant MOM deprotection, as stereomers in approximate ratios of 2:1 and good overall
postulated by Schreiber in a different context (Scheme 2).[13] yields.[18] Notably, predominant 1,2-addition could be
Notably, during the course of a larger-scale synthesis of 2a, achieved by using LiCl and vinylmagnesium bromide, which
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E. Sánchez-Larios, R. D. Giacometti, S. Hanessian
SHORT COMMUNICATION
led to 4a and 4b in 91 and 83% yield, respectively.[18] Pro-
tection of the allylic hydroxy group in 4a, 4b, and 4d as the
TBS ether followed by oxidative cleavage of the terminal
double bond afforded aldehydes 6a, 6b, and 6d, which were
subjected to Friedel–Crafts cyclization in the presence of
SnCl4 (Scheme 4). Tricyclic diols 8–12 were isolated as chro-
matographically separable mixtures of racemic cis- and
trans-mono-TBS ethers in excellent yields. Having estab-
lished a robust and efficient route to tricyclic α-pyrones cor-
responding to generic structure C (Figure 1), we selected
the 3,4-dimethoxyphenyl analog as a model for the synthe-
sis of a tetracyclic ring A aromatic surrogate of urbalactone.
Scheme 4. Friedel–Crafts cyclization and tetrabutylammonium
fluoride (TBAF)-mediated deprotection to obtain tricyclic diols 8–
12. The structures and relative configuration were determined from
the corresponding acetate esters of 8 and 9, while X-ray crystal-
lography was used to confirm the relative stereochemistry in 10 and
11. [a] BF3·OEt2 was employed for the Friedel–Crafts cyclization.
DMAP = 4-(N,N-dimethylamino)pyridine.
Scheme 3. 1,2- and 1,4-Vinyl addition products; yields (average of
three runs) of pure isolated products. Diastereomeric ratios were
1
determined by H NMR spectroscopic analysis of the crude sam-
ples. [a] LiCl was used as a Lewis acid.[18] NMO = N-methylmorph-
oline-N-oxide.
sulted in the formation of racemic trans-diol 21 as the major
Toward this objective, we started with 3-bromo-4,5-di- product (20:1dr), albeit in modest yield. Attempted carb-
[20]
methoxybenzaldehyde (13),[16] which was converted into the onylation with CO(g) and Pd(OAc)2
or Vilsmeier form-
corresponding acetylene using the Ohira–Bestmann rea- ylation was unsuccessful. However, Stille vinylation[21] pro-
gent.[19] Quenching the lithium anion with methyl chloro- ceeded in excellent yield to provide vinyl adduct 22, which
formate afforded ester 14, which was saponified and sub- was oxidatively cleaved as described above to give corre-
sequently esterified in the presence of acetylenic alcohol 15 sponding carboxylic acid 23 in excellent overall yield. Con-
to afford bis-acetylenic ester 16 in excellent overall yield ventional lactonization was achieved in the presence of
(Scheme 5). Gold(I)-catalyzed cyclization proceeded N,NЈ-dicyclohexylcarbodiimide (DCC)/DMAP to afford
smoothly to give α-pyrone 17 in 70% yield. Application of lactone 24. An X-ray crystal structure confirmed the rela-
the oxidative cleavage protocol led to 18, which was exclu- tive configuration.[16] Removal of the TBS protecting group
sively converted into the 1,2 adduct – allylic alcohol 19 – in proved problematic at first with conventional reagents such
40% yield over three steps. Unlike 4a, no 1,4-addition was as TBAF/AcOH (6% yield), aq. HCl (decomposition), tri-
observed, presumably because of the presence of the bro- fluoroacetic acid (TFA)/CH2Cl2 (decomposition), BF3·OEt2
mine atom. The racemic mixture was protected as the TBS (no reaction), HF·pyridine (12% yield), and Et3N·3HF
ether and the vinyl group was oxidatively cleaved to afford (10% yield). However, treatment of 24 with tris(dimethyl-
aldehyde 20. Exposing the aldehyde to SnCl4 in toluene re- amino)sulfonium difluorotrimethylsilicate (TASF)[22] af-
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Application of Schreiber’s Gold(I)-Catalyzed α-Pyrone Synthesis
forded the intended prototypical ring A aromatic analog of
urbalactone in 75% yield (Scheme 5).
The highly diastereoselective Friedel–Crafts cyclization
observed in the case of 20 is of interest in light of the fact
that in the absence of the bromine atom, the selectivities
only modestly favored cis isomer 9 over trans isomer 8
(1.5:1dr) and trans isomer 10 over cis isomer 11 (2.6:1dr,
Scheme 4). The cyclization was more efficient if SnCl4 was
used as the Lewis acid, although the yield was modest in
the case of the bromodimethoxy case, presumably owing to
steric hindrance and the potentially deactivating influence
Figure 3. Plausible mechanism for the Friedel–Crafts cyclization of
20.
of the bromine atom (Scheme 5). Cyclization of 3,4-dimeth- ing projects, we evaluated the in vitro antiproliferative ac-
oxy analog 6a in the presence of other Lewis acids resulted tivity of nagilactone F in A2780 ovarian cancer cell lines.
in low yields or decomposition (BF3·OEt2, 23%; TiCl4, We were pleased to find inhibition at IC50 = (0.26Ϯ0.1) μm.
34% with TBS deprotection; AlCl3, decomposition). A Disappointingly, synthetic tetracyclic ring A prototype 25
plausible mechanism to explain the exclusive formation of was inactive in the same test, which may reflect on the im-
the trans-diol in the case of bromo 3,4-dimethoxy analog portance of the overall structural integrity of the natural
21 is shown in Figure 3. Diol products 8 and 9 were not podolactone, although the underlying mechanism of the in-
interconvertible under the reaction conditions, which sug- hibition is not known at this time.
gests that they are formed under nonequilibrating condi-
In contrast, we were pleased that a number of the trisub-
stituted α-pyrone intermediates and their corresponding di-
tions.[23]
Although anticancer activities of selected podolactones hydropyrone analogs were active with IC50 values as low as
have been reported,[4] they date back over two decades and 2.9 μm, depending on the nature and the position of the
are rather limited in scope. In connection with other ongo- aromatic substituent (Figure 4; see also Table S1 in the Sup-
Scheme 5. Total synthesis of a ring A aromatic congener of urbalactone. TBSOTf = tert-butyldimethylsilyl trifluoromethanesulfonate.
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E. Sánchez-Larios, R. D. Giacometti, S. Hanessian
SHORT COMMUNICATION
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[10]
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In conclusion, we have adapted Schreiber’s gold(I)-cata-
lyzed synthesis of 3,4,5-trisubstituted α-pyrones to the total
synthesis of a ring A aromatic congener of the podolactone
urbalactone. The scope of the cyclization was expanded to
include a number of substituted aryl acetylenic esters, which
were further manipulated and subjected to Friedel–Crafts
cyclization to give novel tricyclic dihydronaphthalenes har-
boring a fused α-pyrone ring. A number of α-pyrone inter-
mediates were found to exhibit single digit micromolar anti-
proliferative activity on A2780 ovarian cancer cells. Further
studies to probe the scope of the Schreiber’s gold(I)-cata-
lyzed cyclization and synthetic efforts toward the total syn-
thesis of podolactones are in progress.
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[14]
[15]
Supporting Information (see footnote on the first page of this arti-
cle): Detailed experimental procedures; 1H NMR and 13C NMR
spectra for all new compounds; and crystallographic data for 2p,
10, 11, and 24.
[16]
[17]
For the preparation of aryl acetylenic esters and other experi-
mental details see the Supporting Information.
The color of the reaction mixture changes from bright yellow
to dark yellow-brown during the course of the cyclization reac-
tions.
During the exploration of the reaction conditions for the ad-
dition of the vinyl cuprate to model substrate 3a, copper salts
such as CuBr·SMe2, CuI, and CuCN·2LiCl were tested. At
first, we noticed that the initial preparation of the vinyl cuprate
at –78 °C followed by the addition of a THF solution of 3a
resulted in a ca. 2:1 mixture of 4a/5a. If 3a or 3b was first
premixed with LiCl in THF at –78 °C followed by the addition
of vinylmagnesium bromide, a ca. 12:1 mixture of 4a/5a was
obtained; for details see the Supporting Information.
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Acknowledgments
E. S. L. thanks Consejo Nacional de Ciencia y Tecnología (CON-
ACyT), Mexico for a Research Postdoctoral Fellowship. The Natu-
ral Sciences and Engineering Research Council of Canada
(NSERC) and Sigma-Tau (USA) are acknowledged for generous
financial support. The authors thank Dr. Giuseppe Giannini
(Sigma-Tau, Italy) for the anticancer tests. R. D. G. is grateful to
NSERC for a postgraduate scholarship (CGS-D).
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Application of Schreiber’s Gold(I)-Catalyzed α-Pyrone Synthesis
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[23]
During the equilibration experiments of diols 8 and 9 with
SnCl4, it was possible to isolate trace amounts of a product
containing one alcohol and one chlorine atom. These products
presumably come from a dehydroxylation–chlorination se-
quence assisted by the Lewis acid at the benzylic position.
Received: June 23, 2014
Published Online: July 22, 2014
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