Synthesis of bicyclic ethers by a palladium-catalyzed oxidative cyclization-redox relay-π-allyl-Pd cyclization cascade reaction

Article abstract of DOI:10.1039/c9cc03775f

Bicyclic ether scaffolds are found in a variety of natural products and are of interest in probe and drug discovery. A palladium-catalyzed cascade reaction has been developed to provide efficient access to these scaffolds from readily available linear diene-diol substrates. A Pd redox-relay process is used strategically to transmit reactivity between an initial oxypalladative cyclization and a subsequent π-allyl-Pd cyclization at remote sites. The reaction affords a variety of bicyclic ether scaffolds with complete diastereoselectivity for cis-ring fusion.

Full text of DOI:10.1039/c9cc03775f

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Synthesis of bicyclic ethers by a palladium-catalyzed
oxidative cyclization-redox relay-p-allyl-Pd
cyclization cascade reaction†
abcd
Cite this:DOI: 10.1039/c9cc03775f
Received 16th May 2019,
Accepted 17th May 2019
Michaelyn C. Lux,a Melissa L. Boby,b Joshua L. Brooksc and Derek S. Tan
*
DOI: 10.1039/c9cc03775f
rsc.li/chemcomm
Bicyclic ether scaffolds are found in a variety of natural products
and are of interest in probe and drug discovery. A palladium-
catalyzed cascade reaction has been developed to provide efficient
access to these scaffolds from readily available linear diene–diol
substrates. A Pd redox-relay process is used strategically to transmit
reactivity between an initial oxypalladative cyclization and a sub-
sequent p-allyl-Pd cyclization at remote sites. The reaction affords
a variety of bicyclic ether scaffolds with complete diastereoselectivity for
cis-ring fusion.
Bicyclic ether scaffolds are found in diverse natural products, such
as chafuroside B (1), a photoprotective agent,1 goniofupyrone (2),
a
NADH oxidase inhibitor,2 and panacene (3),
a shark
antifeedant3 (Fig. 1a). Our lab has a long-standing interest in
developing efficient, flexible methods to access natural product-
based scaffolds for probe and drug discovery.4 While these bicyclic
ether natural products and related scaffolds have typically been
synthesized using sequential annulation reactions,1a,2a,b,3,5 we
envisioned that such bicycles might be accessed efficiently from
simple substrates using a cascade reaction.6 Indeed, biomimetic
polyepoxide polycyclization cascades have been used previously
to synthesize polycyclic ethers.7 We sought to pursue a conceptually
distinct approach, in which a redox-relay reaction8 could be used to
connect successive cyclization reactions at two remote sites to afford
bicyclic ethers products (Fig. 1b).
Fig. 1 (a) Bicyclic ether scaffolds (blue) are found in a variety of natural
products. (b) Proposed Pd-catalyzed tandem oxidative cyclization-redox
relay-p-allyl-Pd cyclization cascade transmits reactivity tracelessly between
two remote cyclization reactions to generate bicyclic ether scaffolds.
a Tri-Institutional PhD Program in Chemical Biology, Memorial Sloan Kettering
Cancer Center, 1275 York Avenue, New York, New York 10065, USA
b Pharmacology Program, Weill Cornell Graduate School of Medical Sciences,
Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York,
New York 10065, USA
c Chemical Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering
Cancer Center, 1275 York Avenue, New York, New York 10065, USA
d Tri-Institutional Research Program, Memorial Sloan Kettering Cancer Center,
1275 York Avenue, New York, New York 10065, USA. E-mail: tand@mskcc.org
† Electronic supplementary information (ESI) available: Supplementary tables,
synthetic and computational methods, X-ray crystallographic data for derivative of
9a, and analytical data for all new compounds. CCDC 1853052. For ESI and crystallo-
graphic data in CIF or other electronic format see DOI: 10.1039/c9cc03775f
Redox-relay reactions (also known as chain-running, chain-
walking, and metal-walking) have attracted much current inter-
est due to their ability to transmit reactivity tracelessly through
saturated portions of a molecule.8,9 We recently reported a
tandem intramolecular oxypalladation-redox-relay reaction to
generate functionalized tetrahydrofurans.4f Building upon this
work, we envisioned that, under Pd(II) catalysis, a linear diene–diol
substrate (4) could undergo an initial annulation via oxidative
cyclization (5),10 followed by a redox-relay process in which Pd
migration terminates at an olefin to generate a p-allyl-Pd species
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(6), which could then undergo a second annulation (7).11 While side reaction (entries 2–4), and addition of Cs2CO3 resulted in
redox-relay processes have been integrated both before and after substrate decomposition (entry 5). Use of Pd(OAc)2 led instead
annulation reactions,4f,11b this would be the first example in which to oxidation product 11 (entry 6) while Pd(TFA)2 again gave
a redox-relay process would be used to link two successive chromene 10 (entry 7).
annulation reactions, provided that a single catalyst system could
be identified to catalyze all three processes.
Recognizing the requirement for a basic catalyst system to
suppress chromene formation, we evaluated Sigman’s Pd–PyrOx
Herein, we report the successful implementation of this new (12) catalyst, which has been used with Ca(OH)2.9k While direct
synthetic construct. The reaction provides a wide range of application of the reported reaction conditions to our sterically-
bicyclic ethers with various substituents and ring sizes, with encumbered substrate gave no reaction (entry 8), increasing the
complete diastereoselectivity for cis-ring fusion. Mechanistic temperature to 80 1C led to preferential formation of the desired
studies suggest that this selectivity results from an equilibrium bicyclic product (Æ)-9a (entry 9 and Tables S2 and S3, ESI†).12
process that overcomes poor diastereoselectivity in the initial Residual chromene (10) formation may arise from Pd-mediated
oxidative cyclization. Modest diastereoselectivity in the second, 6-endo cyclization of the substrate 8a followed by b-elimination
p-allyl-Pd cyclization is readily addressed by functionalization of the benzylic alcohol,13 and could be suppressed further in
and epimerization of the side chain, concurrently providing a cyclopentyl methyl ether (CPME) or dioxane (entries 10, 11 and
handle for further derivatization.
Table S4, ESI†).12 Replacement of PyrOx ligand 12 with 2,2-
Development of Pd-catalyzed bicyclization cascade reaction. To bipyridine resulted in exclusive formation of the oxidation side
investigate this concept, we synthesized diene–diol substrate 8a product 11 (entry 12 and Table S5, ESI†), which also increased
in 4 modular steps from methyl vinyl oxirane (Fig. S1, ESI†).12 using PyrOx analogues with electron-donating pyridyl substituents
Initial attempts to effect the cascade reaction of diene–diol 8a (Table S6, ESI†).12 Conversely, PyrOx analogues with more electron-
using our previously described conditions for THF synthesis withdrawing substituents resulted in incomplete, stalled reactions.
(PdCl2, benzoquinone)4f produced chromene 10 rather than the Finally, fine-tuning of catalyst loading afforded optimized conditions
desired bicyclic ether 9a (Table 1, entry 1). We posited that this (9 mol% Pd(OTs)2(MeCN)2, 12 mol% 12) that provided bicyclic
undesired side reaction was caused by adventitious acid from ether 9a in 60% isolated yield (Fig. 2a), with complete cis-
the catalyst, which promotes elimination of the benzylic alco- diastereoselectivity across the ring fusion and 4 : 1 dr (a/b) at
hol followed by phenol endo-cyclization. Indeed, treatment of the vinyl side chain (assigned by nOe and X-ray analyses).12
diene–diol 8a with HCl or TFA also produced chromene 10 Importantly, the side chain was readily equilibrated to the
(Table S1, ESI†).12 Use of other solvents did not suppress this a-diastereomer (20 : 1 dr) by conversion of the vinyl group to
Table 1 Discovery and optimization of Pd-catalyzed bicyclization cascade reaction
Entry
Reagents
Solvent
Temp. (1C)
Product ratioa (8a : 9a : 10 : 11)
1
2
3
4
5
6
7
8
PdCl2, BQb
THF
PhH
DMF
Dioxane
Dioxane
THF
65
65
75
75
75
65
65
22
80
80
80
80
0 : 0 : 100 :
51 : 0 : 49 :
0 : 0 : 100 :
0 : 0 : 100 :
Decomp
0
0
0
0
PdCl2, BQb
PdCl2, BQb
PdCl2, BQb
c
PdCl2, BQ, Cs2CO3
Pd(OAc)2, BQb
Pd(TFA)2, BQb
Pd(OTs)2(CH3CN)2, BQ, 12, Ca(OH)2d
Pd(OTs)2(CH3CN)2, BQ, 12, Ca(OH)2d
Pd(OTs)2(CH3CN)2, BQ, 12, Ca(OH)2d
Pd(OTs)2(CH3CN)2, BQ, 12, Ca(OH)2
Pd(OTs)2(CH3CN)2, BQ, 2,2-bipyridine, Ca(OH)2
86 : 0 : 0 : 14
THF
68 : 0 : 32 :
100 : 0 : 0 :
6 : 62 : 27 :
0
0
5
5
d
PhCF3
PhCF3
CPME
Dioxane
PhCF3
9
10
11
12
0 : 85e : 10 :
0 : 82 : 3 : 14
0 : 0 : 0 : 100
d
a
b
Ratios of major products determined by 1H-NMR analysis of crude reaction product; all products racemic. 10 mol% Pd catalyst, 2 equiv.
c
d
benzoquinone, 16 h. 10 mol% PdCl2, 2 equiv. benzoquinone, 2 equiv. Cs2CO3, 16 h. 8 mol% Pd(OTs)2(MeCN)2, 3 equiv. benzoquinone, 10 mol%
PyrOx ligand 12 or 2,2-bipyridine, 1 equiv. Ca(OH)2, 3 Å MS, 16 h. 4 : 1 dr, major diastereomer as shown (*). Abbreviations: BQ = 1,4-
e
benzoquinone; CPME = cyclopentylmethyl ether; decomp = decomposition; DMF = N,N-dimethylformamide; TFA = trifluoroacetic acid;
THF = tetrahydrofuran; Ts = p-toluenesulfonyl.
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Fig. 3 Extension of bicyclization cascade to [5,5]- and [5,7]-ring systems.
Reaction conditions: 9 mol% Pd(OTs)2(MeCN)2, 12 mol% 12, 3 equiv.
benzoquinone, 1 equiv. Ca(OH)2, 3 Å MS, CPME, 80 1C, 16 h. Yields reported
are an average of two independent experiments on E40 mg scale. All
products are racemic.
corresponding electron-rich phloroglucinol substrate (not shown).12
Tertiary alcohol nucleophiles (R2) were accommodated in the
second, p-allyl-Pd cyclization (14a, 14b), including a highly
activated bis-benzylic/allylic alcohol (14b). Inclusion of the large
angular phenyl substituent in 14b required longer reaction time
but also afforded complete a-diastereoselectivity at the vinyl side
chain. Substitution of the terminal olefin (R3) was also tolerated,
surprisingly with inverted b-diastereopreference at the side
chain (15a, 15b).
We next explored alternate alkyl chain lengths (Fig. 3).12 The
1,4-dienes 18a–d underwent the desired cascade reaction to
form [5,5]-bicyclic products 19a–d in good to excellent yields.
Interestingly, inverted b-diastereopreference was observed at
the vinyl side chain (nOe analysis).12 In contrast, attempted
cyclization of 1,6-diene 20 yielded mainly unreacted starting
material and a complex mixture of products, rather than the
desired [5,7]-bicyclic ether 21.
Fig. 2 (a) Substrate scope of the Pd-catalyzed bicyclization cascade
reaction. Yields reported are an average of two independent experiments
on E40 mg scale. dr values are reported for crude reaction products based
on 1H-NMR analysis. All products are racemic. Reaction conditions: 9 mol%
Pd(OTs)2(MeCN)2, 12 mol% 12, 3 equiv. benzoquinone, 1 equiv. Ca(OH)2,
300 mg mmolÀ1 3 Å MS, CPME, 80 1C, 16 h. a Diastereomers separable by
column chromatography, combined yield shown. b Also prepared on 1 mmol
scale (42%) and 1 g scale (38%). c Reaction time 40 h. (b) Functionalization of
the vinyl side chain allows epimerization to major diastereomer.
Because the initial oxidative cyclization forms a 5-membered
the corresponding methyl ester 17 in two steps and 85% yield, ring in all cases, this indicates that the p-allyl-Pd cyclization
which concurrently provided a functional group handle for plays an important role in the efficiency of the overall cascade.
downstream derivatization (Fig. 2b).
Mechanistic studies of Pd-catalyzed bicyclization cascade reaction.
Scope of Pd-catalyzed bicyclization cascade reaction. We next We carried out preliminary studies to probe the mechanism of
investigated the scope of the bicyclization cascade. Substrates the cascade reaction. Exclusive formation of cis-fused products
8b–f (Fig. S1, ESI†) with substituents para to the phenol were requires complete diastereoselectivity in the initial oxidative
designed to evaluate electronic effects. All were successfully cyclization, which is highly unusual for 5-membered ring-
converted to bicyclic products 9b–f (Fig. 2a), with electron- forming oxypalladations.4f,10c,14 In contrast, we found that
withdrawing substituents resulting in slightly lower yields substrates unable to undergo the second, p-allyl-Pd cyclization
(9c,d) while an electron-donating substituent resulted in formed monocyclic products with little or no diastereoselectivity
increased yield (9f). Complete diastereoselectivity for cis-ring (Fig. S2a, ESI†). Based on these results, we propose that cis-fusion
fusion was observed in all cases, with diastereoselectivity at the in the cascade reaction results from an equilibrium process, in
vinyl side chain modestly favoring the a-diastereomer. Bicyclic which the initial oxidative cyclization13b,15 and redox-relay steps
ether 9b was also synthesized effectively on 1 mmol and 1 g scales. are reversible,9a,16 while the p-allyl-Pd cyclization is irreversible
To assess the impacts of substituents at other positions, we but does not proceed to trans-fused products due to ring strain in
synthesized additional substrates by variations on the general the transition state, ultimately leading to formation of solely cis-
route.12 Consistent with the electronic trends above, dimethoxy- fused products under the Curtin–Hammett principle (Fig. S2b,
substituted scaffold 13 was formed in good yield from the ESI†). The p-allyl-Pd cyclization is presumed to proceed with
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inversion of configuration relative to Pd for alkoxides.17 Thus, the
mixture of vinyl side chain diastereomers arises from a mixture
of p-allyl-Pd diastereomers formed from single-bond rotamers
present during the redox-relay process.9h Reactions with enantio-
enriched substrates and catalysts did not identify any matched/
mismatched cases, consistent with substrate control over this
stereocenter.12
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Strategic use of a redox-relay process to transmit reactivity
between two successive cyclization reactions has provided
versatile, efficient access to bicyclic ether scaffolds from readily
available, linear diene–diol substrates. The redox-relay process
leverages a Pd migration terminating at an olefin to generate a
reactive p-allyl-Pd species, a useful synthetic construct that has
received limited attention to date.18 The reaction provides
complete diastereoselectivity for cis-ring fusion despite poor
diastereoselectivity in the initial oxidative cyclization. Mechanistic
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We thank Dr George Sukenick, Rong Wang, and Dr Sylvi
Rusli (MSK) for expert NMR and mass spectral support,
Dr Kristin Kirschbaum and Kelly Lambright (University of
Toledo) for X-ray analysis, and Dr Maria Chiriac, Dr Adam
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Financial support from the NSF (GRFP DGE1746886 to M. C. L.),
NIH (T32 GM115327–Tan to M. C. L., T32 CA062948–Gudas to
J. L. B., and CCSG P30 CA008748 to C. B. Thompson), and MSK
Center for Experimental Therapeutics is gratefully acknowledged.
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Conflicts of interest
There are no conflicts of interest to declare.
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