Bisketene Equivalents as Diels-Alder Dienes

Article abstract of DOI:10.1021/jacs.0c06306

2,5-Bis(tert-butyldimethylsilyloxy)furans are established as vicinal bisketene equivalents for application as dienes in the Diels-Alder reaction. Cycloaddition with olefinic dienophiles, under exceptionally mild conditions, enables convergent access to highly substituted para-hydroquinones in unprotected form via a one-pot Diels-Alder/ring-opening/tautomerization sequence. The synthesis of para-benzoquinones from acetylenic dienophiles, including benzynes, is also demonstrated, and 2,5-bis(tert-butyldimethylsilyloxy)pyrroles are established as competent dienes for the synthesis of para-iminoquinones. Application in natural product synthesis enables gram-scale access to the neuroprotective agent (±)-indanostatin.

Full text of DOI:10.1021/jacs.0c06306

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Communication
Bisketene Equivalents as Diels–Alder Dienes
Isuru Dissanayake, Jacob D. Hart, Emma C. Becroft, Christopher J. Sumby, and Christopher G. Newton
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.0c06306 • Publication Date (Web): 18 Jul 2020
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Bisketene Equivalents as Diels–Alder Dienes
Isuru Dissanayake,‡ Jacob D. Hart,‡ Emma C. Becroft, Christopher J. Sumby, Christopher G. Newton*†
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Department of Chemistry, The University of Adelaide, Adelaide, SA 5005, Australia
Diels–Alder, Furan, Ketene, Benzyne, para-Hydroquinone, para-Benzoquinone
ABSTRACT: 2,5-Bis(tert-butyldimethylsilyloxy)furans are established as vicinal bisketene equivalents for application as dienes in
the Diels–Alder reaction. Cycloaddition with olefinic dienophiles, under exceptionally mild conditions, enables convergent access
to highly substituted para-hydroquinones in unprotected form via a one-pot Diels–Alder/ring-opening/tautomerization sequence.
The synthesis of para-benzoquinones from acetylenic dienophiles, including benzynes, is also demonstrated, and 2,5-bis(tert-
butyldimethylsilyloxy)pyrroles are established as competent dienes for the synthesis of para-iminoquinones. Application in natural
product synthesis enables gram-scale access to the neuroprotective agent ()-indanostatin.
The para-hydroquinone (p-HQ) motif is embedded within
a diverse array of pharmaceuticals,1 natural products,2,3
synthetic reagents,4 and ligand families5 (Figure 1a).
Traditional approaches towards the synthesis of highly
substituted derivatives typically involve multi-step
functionalization sequences, initiated from either an aromatic
in a lower oxidation state, or a simple protected p-HQ (Figure
1b).6 Selective redox state adjustment7,8 or protecting group
removal9 can be challenging to achieve in these contexts,
highlighting the need for more convergent, non-oxidative
strategies that deliver p-HQs in unprotected form. Although a
small number of such strategies have been developed, most
notably the Hauser–Kraus reaction of annulated furanones,10
and Moore rearrangement of γ-hydroxy-cyclobutenones,11 the
harsh conditions necessary for substrate preparation and/or
cyclization limits generality (e.g. strong base, organolithium
nucleophiles, high temperatures).
p-HQs can be retrosynthetically disconnected via a Diels–
Alder (DA) transform through their bis-keto tautomer to reveal
vicinal bisketenes as synthons (Figure 1c). The pronounced
instability of this motif,12 coupled with the propensity of
ketenes to undergo [2+2] cycloadditions with olefins,13
necessitates the development of a bisketene equivalent to
realize the proposed strategy. In principle, a variety of
appropriately 2,5-difunctionalized furans may enable direct
access to p-HQs under redox-neutral conditions via a DA/ring-
opening/tautomerization sequence.14 The feasibility of such an
approach was demonstrated by Chan and coworkers in 1980
though
bis(trimethylsilyloxy)furans, followed by NaF promoted
aromatization.15
The authors described 2,5-
DA
reactions
of
simple
2,5-
bis(trimethylsilyloxy)furans as “very sensitive to moisture and
air”, noting that the rate of autoxidation increased with
additional substitution on the furan backbone.16 Consequently
it appears the challenges associated with substrate stability,
combined with a proclivity for users to employ strong acids to
promote cycloadduct unmasking,17 have discouraged efforts to
further develop this strategy.18,19
Figure 1. Motivation for reaction development. PG =
protecting group, LG = leaving group.
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In an attempt to address these limitations we initiated
(Figure 2b). Bis(silyloxy)furans 1, 2 and 3 all reached
completion within ~200 minutes, exhibiting only a small rate
retardation with increased silyl group size. Methoxy-derivative
4 proved 3–4 times more reactive, whereas bromide 5
performed the worst, with less than 50% conversion observed
reaction development with a systematic stability study20 of
pertinent 2,5-difunctionalized furans (Figure 2a; see
Supporting Information for additional details). In alignment
with the findings of Chan, 2,5-bis(trimethylsilyloxy)furan (1)
rapidly decomposed when employing standard handling
techniques. Assessment of related candidates revealed diene
stability scales with silyl group size (compare 1–3), arriving at
2,5-bis(tert-butyldimethylsilyloxy)furan (3) as a robust and
conveniently accessed candidate. Introduction of alternate
leaving groups were also explored. Methoxy-derivative 4,
prepared in 3 steps from commercial materials, exhibited a
comparable stability profile relative to 3. Finally, introduction
of bromine (5) proved beneficial, resulting in the most stable
of all substrates prepared.
1
2
3
4
5
6
7
8
after
250
minutes.
Overall,
bis(tert-
butyldimethylsilyloxy)furan (3) strikes the best balance
between ease of synthesis, stability, and DA reactivity, and as
such we elected to focus exclusively on its continued
development.
9
Studies into the ring opening/tautomerization of DA
adducts 6-endo and 6-exo revealed that simply stirring in
MeOH promotes the desired aromatization event, avoiding the
need for addition of an acid, or fluoride source (Figure 2c).
Moreover, conducting the DA reaction in MeOH enabled the
synthesis of p-HQ 7 in 88% isolated yield, directly from furan
3, via a one-pot DA/ring-opening/tautomerization cascade.
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The DA reactivities of furans 1–5 were benchmarked in
PhMe using N-methylmaleimide (NMM) as dienophile
Having identified a suitable vicinal bisketene equivalent
we investigated the scope of p-HQ formation (Table 1). With
respect to diene structure the reaction appears general, and a
library of furans (prepared directly from the corresponding
cyclic anhydrides, see Supporting Information) were readily
converted into p-HQs upon reaction with NMM in MeOH at
65 C. In the case of mono-functionalized derivatives, methyl
(8), allyl (9), and phenyl (10) functionality was well tolerated.
More highly substituted 5 and 6-membered fused bicyclic
furans also reacted smoothly (11–15), including steroid-
inspired pentacyclic derivative 14. The chemoselectivity of
desilylation was highlighted through preparation of silyl enol
(a) Furan stabilities
increasing stability
OTMS
O
OTES
O
OTBS
O
OTBS
O
OTBS
O
<
<
<
<
OTMS
1
OTES
2
OTBS
3
OMe
4
Br
5
[1 step]
[1 step]
[1 step]
[3 steps]
[2 steps]
watera
airb
heatc
acidd
silicae
methanolf
furan remaining:
(b) Diels–Alder reactivity
O[Si]
>95%
>75 – 95%
50 – 75%
<50%
Table 1. Scope of p-HQ formation
O[Si]
O
O
O
durene (internal standard)
PhMe (0.25 M), 23 °C
O
NMe
NMe
O
+
LG
O
LG
1–5
NMM
[3 mol. equiv.]
[1 mol. equiv.]
100
80
60
40
20
krel
1
2
3
4
5
0.32
0.22
0.24
1.00
0.02
250
300
0
50
100
150
200
Time (minutes)
(c) Aromatization studies
TBSO
OH
OTBS
O
O
O
O
H
H
PhMe
23 °C
MeOH
23 °C
NMe
NMe
NMe
+
O
78%
OTBS
O
O
O
TBSO
OH
3
NMM
6-endo 92% (+ 6-exo 7%)
7
MeOH, 23 °C
88%
Figure 2. Development of a convenient vicinal bisketene
equivalent. LG = leaving group. a0.025M (CD3)2CO/D2O mixture
b
(9:1) stirred for 1 h. Compressed air bubbled through a 0.025M
c
CDCl3 solution for 10 minutes. Dilute C6D6 solution heated at
d
120 °C in a microwave reactor for 2 h. 0.10M TFA solution in
e
b
aDA at 23 C. Aromatization achieved by addition of TFA at 23
CDCl3 stirred for 1 minute. 1.0 mL of a 0.025M CDCl3 solution
2
h. f0.20M
c
stirred with untreated silica (250 mg) for
CDCl3/CD3OD mixture (1:4) stirred for 1 h.
ºC. DA in PhMe at 23 ºC, aromatization achieved by addition of
d
e
f
g
h
H2SO4 at 23 ºC. 80 C. 60 C. 111 C. 50 C. DA neat at 23
C. iCombined yield of isomers. jDA neat at 55 C.
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ether 15 in 95% yield, and notably, no evidence for olefin
1
2
3
4
5
6
7
8
migration was observed for all substrates screened. With more
sterically demanding silylated intermediates, such as for indole
16 and biaryl 17, the rate of MeOH promoted aromatization
drops significantly. In these cases p-HQ formation can be
expedited through addition of an acid additive. Extension to a
one-pot double DA/double aromatization strategy provided the
BiPhePhos ligand scaffold5a in 53% yield (17), creating
opportunities for a highly convergent approach to a library of
ligand derivatives. With less reactive dienophiles the DA
reaction is best conducted in an aprotic solvent (or neat)
followed by addition of MeOH. Under these conditions,
sulfone (18), ketone (19), ester (20) and aldehyde (21)
activating groups were all tolerated. Finally, orientational
selectivity of the cycloaddition event was demonstrated
through coupling of unsymmetrical mono-functionalized
dienes with methyl acrylate (22 and 23, up to 6:1 in favor of
the expected para-isomer).
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Exploratory studies from Chan and coworkers toward the
synthesis of para-benzoquinones (p-BQ) from 2,5-
bis(trimethylsilyloxy)furans were hampered by competitive p-
HQ formation.15 Optimistic that the 2,5-bis(tert-
butyldimethylsilyloxy)furan motif may be more well suited to
p-BQ formation we probed reactivity with acetylenic
dienophiles (Table 2). Indeed, cycloaddition of several
aDetermined by 1H NMR. bCombined yield of isomers.
of trifluoromethyl functionality (32). 1-Naphthyne is also a
competent dienophile (33), as too are more complex steroid-
derived benzynes (34). Although orientational selectivity22 of
the cycloaddition is not especially high in the case of 35 and
36 (up to 2:1), isomer separation can be achieved via standard
flash chromatography, allowing ready access to the methoxy-
naphthalene-1,4-dione fragment present in both doxo- and
daunorubicin.1
representative
derivatives
with
dimethyl
acetylenedicarboxylate (DMAD), followed by addition of
TFA, provided p-BQs 24–26 in good to excellent yields
(without any evidence for p-HQ formation). Encouraged by
these results we evaluated benzynes as coupling partners.
ortho-Iodotriflates were identified as suitable precursors,
enabling low temperature benzyne generation in the presence
of our furans.21 In contrast to the DMAD-derived
cycloadducts, TFA addition is unnecessary, and intermediate
unmasking can be achieved via a simple acidic workup. A
brief diene screen revealed that increased steric bulk on the
furan backbone resulted in improved yields (27–29). With
respect to benzyne substitution, electron rich substrates react
exceptionally well (30 and 31), however a significant
reduction in yield was observed with incorporation
The generality of our approach is highlighted through
extension to 2,5-bis(tert-butyldimethylsilyloxy)pyrroles as
synthetic equivalents of vicinal ketenimine-ketenes (Figure
3a). While these pyrrole derivatives are less stable than their
corresponding furan congeners (see Supporting Information),
they exhibit comparable reactivity with arynes.23 Thus,
reaction of aryl- and alkylated pyrroles 37 and 38 with
benzyne provided para-iminoquinones (p-IQs) 39 and 40, both
in 61% yield. Notably, p-IQs feature within natural products,24
and derivatives have been demonstrated as versatile
intermediates for the synthesis of complex alkaloids,25 and
BINOL derivatives.26 Moreover, they serve as convenient
precursors to the biologically relevant para-aminophenol
motif (e.g. paracetamol)27 via sodium dithionite promoted
reduction (41 and 42). Further experiments demonstrated
regioselective ring opening of unsymmetrical cycloadducts
can be achieved (Figure 3b). In this example, a two-step
reductive coupling of pyrrole 37 with 1-naphthyne (generated
from ortho-iodotriflate 43) provided phenanthrene 44 in 75%
yield.
Table 2. Scope of p-BQ formation
We became interested in the development of a cross-
conjugated extension to further expand the synthetic potential
of our methodology (Figure 4a).28 In principle the simplest
candidate, vinylfuran 45, would enable a diene-transmissive
double DA sequence, which if conducted with two different
dienophiles leads to even more highly functionalized
aromatics. The success of such a strategy is reliant upon both
the inherent diene site-selectivity of 45 (cyclic versus semi-
cyclic), as well as the relative rates of the first and second
cycloadditions, both of which are difficult to infer from the
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(a) Pyrroles as dienes
(a) Bifurcated reactivity of a cross-conjugated derivative
TfO
1
2
3
4
5
6
7
8
OTBS
O
NR
OTBS
NR
NR
OH
I
O
•
+
O
NMe
nBuLi, THF, −78 ºC
then
MeOH, 65 ºC
45
NMM
NMe
OTBS
O
•
O
OTBS
O
1. PhMe, 23 ºC
O
OH
vicinal
ketenimine-
ketenes
39 R = PMP 61%
40 R = Me 61%a
37 R = PMP
38 R = Me
46 95%
OTBS
O
O
N
O
OH
N
O
then
NMe
PhN
NHR
NHAc
O
PTAD
NMe
N
Na2S2O4, Et2O/H2O
O
OTBS
O
N
9
2. TFA, CH2Cl2
O
OH
PhN
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O
OH
OH
47 80% [2 steps]
(b) Gram-scale total synthesis of (±)-indanostatin
41 R = PMP 76%
42 R = Me 89%
paracetamol
O
49
O
39 [X-ray]
NHPMP
OTBS
O
TBSOTf, NEt3, Et2O
Me
Me
(b) Regioselective intermediate unmasking
, MeOH, 23 ºC
0 ºC to 23 ºC
O
O
OTBS
NPMP
OTBS
TfO
I
1. nBuLi, THF, −78 ºC
2. Na2S2O4, Et2O/H2O
85% [>5 gram scale]
93% [>1 gram scale]
O
48
OTBS
methylsuccinic
+
anhydride
OH
O
OH
O
O
SeO2
Me
Me
1,4-dioxane, 100 ºC
then
OH
OH
O
75% [2 steps]
previous
synthesis:
9 steps
37
43
44
acetone, AcOH, 56 ºC
Me
O
OH
OH
70 mg scale
54% [>1 gram scale]
Figure 3. Bis(tert-butyldimethylsilyloxy)pyrroles as vicinal
ketenimine-ketene equivalents. PMP = para-methoxyphenyl.
aDetermined by 1H NMR.
(±)-indanostatin
50
Figure 4. (a) Extension to a cross-conjugated derivative, and
(b) application of p-HQ formation in natural product synthesis.
diverging reactivity reported for related cross-conjugated
furans.29 Fortuitously, NMM reacted with complete selectivity
for the (desired) cyclic diene site of 45.30 Moreover, the
second DA reaction is markedly slower than the first, allowing
not only a change in dienophile, but bifurcation of reactivity:
addition of MeOH promoted aromatization to generate vinyl-
substituted p-HQ 46, whereas addition of 4-phenyl-1,2,4-
one can imagine employing more robust silyloxy
substituents in attempts to further tweak furan stability, and
indeed we anticipate in some cases this may provide improved
results, generally speaking it appears the tert-
butyldimethylsilyl functionality strikes an excellent balance
between diene stabilization and ease of intermediate
unmasking. In essence, the methodology disclosed herein
represents a transform-based strategy33 in which two C–C
bonds of several para-quinone ring systems are made
simultaneously via a cycloaddition event. This approach
avoids the need for lengthy sequences of redox manipulations
and/or functional group interconversions, both of which are
commonplace in more classical structure-goal strategies.33 As
such, we believe the methodology developed herein has the
potential to permit more step-economic syntheses of para-
quinones, and a proof-of-principle application has been
demonstrated through a gram-scale three-step total synthesis
of ()-indanostatin.
triazole-3,5-dione (PTAD) enabled
a hetero-Diels–Alder
reaction. Although subsequent deprotection and aromatization
can be achieved in excellent yield via in situ addition of TFA,
in this particular case purification is simplified by a stepwise
approach, yielding tetracyclic p-HQ 47 in 80% yield over two-
steps from 45.
Finally, to demonstrate scalability of p-HQ formation, as
well as the applicability of our methodology in natural product
synthesis, we pursued the total synthesis of the
neuroprotective agent ()-indanostatin3b (Figure 4b). The
marked base sensitivity of our envisioned dienophile, 1,3-
cyclopentenedione (49), has precluded its application as a
coupling partner in conceptually related anionic (formal) DA
strategies towards p-HQs.31 Pleasingly, methylfuran 48
(synthesized in one step from methylsuccinic anhydride)
reacted smoothly with 49 in MeOH at room temperature,
providing gram-scale quantities of p-HQ 50 in 93% yield, and
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website.
without the need for chromatographic purification.
A
Experimental procedures and spectral data (PDF)
Crystal structure of 39 (CIF)
subsequent one-pot oxidation32/alkylation procedure (via the
intermediate trione hydrate) yielded over one gram of ()-
indanostatin in only three steps total (cf. 9 steps for the
previous total synthesis31).
AUTHOR INFORMATION
Corresponding Author
In conclusion, we have established the 2,5-bis(tert-
butyldimethylsilyloxy)furan motif as
Christopher G. Newton – Email: chris.newton@uga.edu
a general vicinal
bisketene equivalent for application as a diene in the DA
reaction. A mild, user-friendly protocol provides access to a
variety of highly substituted p-HQs by reaction with olefinic
dienophiles. In turn, employing acetylenic dienophiles
provides efficient access to p-BQs, or p-IQs when 2,5-bis(tert-
butyldimethylsilyloxy)pyrroles are utilized as dienes. While
Authors
Isuru Dissanayake – Department of Chemistry, The University of
Adelaide, Adelaide, SA 5005, Australia
Jacob D. Hart – Department of Chemistry, The University of
Adelaide, Adelaide, SA 5005, Australia
Emma C. Becroft – Department of Chemistry, The University of
Adelaide, Adelaide, SA 5005, Australia
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1
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University of Adelaide, Adelaide, SA 5005, Australia
Present Addresses
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(14) Review on the DA chemistry of substituted furans: Bur, S.;
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Methods and Applications of Cycloaddition Reactions in Organic
Syntheses, Nishiwaki, N., Ed. John Wiley & Sons, Inc: 2014; pp 355.
(15) Brownbridge, P.; Chan, T. H., Chemistry of 2,5-
Bis(trimethylsiloxy) Furans. I: Preparation and Diels-Alder Reactions.
Tetrahedron Lett. 1980, 21, 3423.
(16) Chan reports that in the presence of water, 2,5-
bis(trimethylsilyloxy)furans hydrolyze to the corresponding succinic
acid, and in the presence of oxygen they form the corresponding
bis(trimethylsilyl) maleate.
Author Contributions
‡I.D. and J.D.H. contributed equally to this work.
Notes
9
The authors declare no competing financial interest.
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ACKNOWLEDGMENT
This work was supported by an Australian Research Council
Discovery Early Career Award for C.G.N. (DE180100462).
Financial support from the University of Adelaide is gratefully
acknowledged. We thank Associate Professor David Huang
(University of Adelaide) for assistance with rate calculations.
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