Synthesis of Illudinine from Dimedone

Article abstract of DOI:10.1021/acs.orglett.6b03887

A total synthesis of the illudalane sesquiterpene illudinine was realized in eight steps and 14% overall yield from commercially available dimedone. The approach features tandem fragmentation/Knoevenagel-type condensation and microwave-assisted oxidative

Full text of DOI:10.1021/acs.orglett.6b03887

Letter
pubs.acs.org/OrgLett
Synthesis of Illudinine from Dimedone
Alec E. Morrison,† Tung T. Hoang,† Melodie Birepinte,† and Gregory B. Dudley*,†,‡
́
†Department of Chemistry and Biochemistry, Florida State University, Tallahassee, Florida 32306, United States
‡C. Eugene Bennett Department of Chemistry, West Virginia University, Morgantown, West Virginia 26506, United States
S
* Supporting Information
ABSTRACT: A total synthesis of the illudalane sesquiterpene illudinine was
realized in eight steps and 14% overall yield from commercially available
dimedone. The approach features tandem fragmentation/Knoevenagel-type
condensation and microwave-assisted oxidative cycloisomerization to establish
the isoquinoline core. Completion of the synthesis involves a recently reported
cascade SNAr/Lossen rearrangement on a densely functionalized aryl bromide and an optimized procedure for O-methylation of
8-hydroxyisoquinolines. The oxidative cycloisomerization proceeds by way of a novel inverse-demand intramolecular dehydro-
Diels−Alder cycloaddition, which has a potentially broader appeal for preparing substituted isoquinolines.
he evolution of chemical synthesis can be tracked in terms
of the ability to produce increasingly complex structures
benzenes and 3,3-dimethylcyclopentanes each pose formidable
synthetic challenges. The convergent synthesis of substituted
benzene derivatives has attracted considerable attention,7 and
new methods continue to emerge.8 On the other hand, direct
synthesis of 3,3-dimethylcyclopentanes remains largely an
unresolved problem, which typically has been circumvented
by serial manipulation of tactically overoxidized intermediates.9
3,3-Dimethylcyclopentanes are ubiquitous in natural prod-
ucts, but they are virtually nonexistent in typical small-molecule
libraries used for pharmacological screening. This is perhaps a
consequence of limited synthetic accessibility. For example,
after illudalic acid emerged from high-throughput screening as a
promising and uniquely selective phosphatase inhibitor, most of
the follow-up pharmacology focused on simplified analogues
that lacked the 3,3-dimethylcyclopentane. These structural
simplifications came at the cost of potency.4,10 This is likewise
true for alcyopterosin A pharmacology, which was largely
examined with the 3,3-dimethyl substitution omitted for
synthetic expediency at the cost of potency.9e Efficient access
to 3,3-dimethylcyclopentanes is needed to explore this naturally
validated but pharmaceutically underexplored chemical space.11
Our approach to illudinine hinged on two hypothetical key
steps (Scheme 1). The first, tandem fragmentation/olefination
(Scheme 2), required a logical but untested expansion of recent
methodology from our laboratory.12 We previously concluded
that hydroxy triflate 1 can undergo anionic fragmentation to
aldehyde 3, which can be intercepted in situ by Horner−
T
by increasingly efficient synthetic sequences.1 Diverse molec-
ular architectures inspire novel methods and strategies, and
emerging methodologies enable new approaches to goal
structures. We have been inspired by the illudalane family of
3,3-dimethylcyclopentane-fused aromatic sesquiterpenes, which
present an attractive array of structural complexities and
unresolved biological activities.
The illudalane sesquiterpenes share a carbon skeleton with
illudalic acid and its alkaloid congener, illudinine (Figure 1).
Figure 1. Illudalane sesquiterpenes.
Illudinine is a metabolite of the jack o-lantern mushroom
(Clitocybe illudens); it was isolated and characterized along with
illudalic acid and illudacetalic acid in 1969.2 The first total
synthesis of these three natural products in 17−19 steps was
described in a 1977 report by Woodward and Hoye,3 who
developed a unified approach based on aromatic substitution
chemistry. Shen reported a 16-step synthesis of illudalic acid by
a similar strategy in 2008 as a means of securing material for
biological evaluation.4 Meanwhile, Deiters developed an alkyne
cyclotrimerization strategy that produced illudinine in 14
steps.5 Various alcyopterosins, which have the same carbon
skeleton, have also been prepared.6
Scheme 1. Synthetic Approach
These structures all feature a densely substituted benzene
core fused to a 3,3-dimethylcyclopentane moiety. Substituted
Received: December 29, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b03887
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 2. Synthesis of Enyne 4 via Tandem Fragmentation/
Knoevenagel-Type Condensation
Scheme 4. Microwave-Assisted Oxidative
Cycloisomerizations
Wadsworth−Emmons (HWE)-type phosphonate nucleophiles
to give 1,6-enynes. Here, we report that phosphonate activation
is not needed in the case of ethyl 4-pyridylacetate (2); reaction
of 1 with 2 yields 1,6-enyne 4 in 75% yield as a mixture of
alkene isomers (ca. 2:1). Considering the anion-stabilizing
properties of the 4-pyridyl substituent, this new process is
perhaps best classified as a tandem fragmentation/Knoevena-
gel-type condensation, and it suggests a broader potential of
our prior methodology.
The second pivotal step in our synthetic approach to
illudinine is a proposed oxidative cycloisomerization by way of
an intramolecular inverse-demand dehydro-Diels−Alder reac-
tion. Dehydro-Diels−Alder reactions13 of tethered alkynylstyr-
enes14 have received increasing attention recently (Scheme 3,
increasing temperatures in various solvents without success. In
general, the starting enyne either decomposed or was recovered
unchanged. A brief screening of metal catalysts was likewise
unproductive. No reaction products consistent with dehydro-
Diels−Alder reaction were ever identified in our (nonexhaus-
tive) survey of conditions, although we cannot rule out the
feasibility of this pathway.
Meanwhile, we were mindful that terminal functionality on
the alkyne would not be inconsistent with our end goals, so we
also investigated bromoalkyne 5 as well as silyl- and
iodoalkynes (X = Me3Si or I, not shown). Bromination of
terminal alkyne 4 under standard conditions provided 5 in
essentially quantitative yield. Bromoalkynes can be competent
dienophiles,20 and computational data suggest that alkyne π
bonds are weaker in bromoalkynes than in terminal alkynes.21
Indeed, productive thermal reactivity was observed by heating a
0.06 M solution of 5 in o-dichlorobenzene (o-DCB) at 200 °C
in the microwave22 (300 W) in a sealed vial under air for 12 h
to produce a 40% isolated yield of isoquinoline 6. The
aforementioned silyl- and iodoalkynes were not viable
substrates. Presumably, thermal inverse-demand dehydro-
Diels−Alder cycloaddition of 5 yields intermediate 5a (Scheme
4), which oxidizes to 6 under the reaction conditions.
Oxidation may occur by concerted extrusion of hydrogen14b
or possibly by serial hydrogen atom abstraction via stabilized
radical intermediate 5b.23 In the end, the operationally simple
thermal cyclization of 5 provides convenient access to
isoquinoline 6 en route to illudinine.
With bromoisoquinoline 6 in hand, the final hurdle to be
cleared before reaching the target illudinine system was a
bromo → methoxy substitution event. Perhaps the best way to
underscore the challenge of this particular transformation is to
recognize that the bromobenzene core is fully substituted and
fused to a potential catalyst inhibitor. Traditional SNAr
protocols and metal-catalyzed aryl ether formation were not
satisfactory in our hands.24 However, treatment of 6 with
acetohydroxamic acid and base (Maloney−Fier conditions25)
produced hydroxyisoquinoline 7 in 89% yield (Scheme 5),
presumably via tandem SNAr/Lossen rearrangement.25
Scheme 3. Dehydro-Diels−Alder Reactions of Tethered
Enynes
eq 1). Inverse-demand Diels−Alder reactions involving (un-
strained) alkynes are rare, even in tethered systems,15 and we
could find no examples involving styrene-type dienes (vinyl-
arenes). However, styrene-type dienes have not been as
thoroughly examined as other diene classes. Because of their
aromatic character, one must extrapolate with caution from
other diene classes to vinylarenes. Our recent isoquinoline
synthesis16 established an alternative inverse-demand dehydro-
Diels−Alder pathway (Scheme 3, eq 2), but it does not provide
all of the requisite functionality for illudinine.
One of the major challenges posed by electron-deficient
dienes is their tendency to dimerize,17 oligomerize, or otherwise
decompose18 faster than they react with unstrained alkyne
dienophiles. The dimerization pathway19 is suppressed in
vinylarenes, and it is not unreasonable to anticipate a
differential impact of aromaticity on other competing reaction
pathways. Therefore, despite a lack of encouraging precedent,
we proceeded with focused investigations into the pivotal
dehydro-Diels−Alder reaction (Scheme 4).
O-Methylation of 7 would generate illudinine ethyl ester (9),
but N- vs O-selectivity is a challenge.26 Most methylation
conditions overwhelmingly favored N-methylation to zwitterion
8 (Table 1, entries 1−4).24 Trimethylsilyldiazomethane
(TMSCHN2) has been shown to be good for O-methylation
of phenols and enols in the presence of nucleophilic
heterocycles.26 Here, Aoyama and Shioiri’s conditions26a
Our investigations into the proposed dehydro-Diels−Alder
reaction began with 4-pyridylenyne 4. Enyne 4 was heated at
B
DOI: 10.1021/acs.orglett.6b03887
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
In conclusion, the synthesis of illudinine has been
accomplished in eight steps (14% overall yield) from dimedone.
Key steps include the tandem fragmentation/Knoevenagel-type
condensation of triflate 1 to give enyne 4 and the oxidative
cycloisomerization of enyne 5 to deliver isoquinoline 6, each of
which represents a substantial extension of previous knowledge.
Tactical hurdles en route from 6 to illudinine were overcome in
ways that are broadly instructive. In terms of synthetic strategy,
serial execution of ring-opening fragmentation and ring-closing
cycloisomerization reactions provides an attractive and general
approach to diverse value-added synthetic targets, especially
3,3-dimethylcyclopentane derivatives that are otherwise difficult
to prepare. Efforts to develop strategically related approaches to
other terpenoid natural products and to novel polycyclic
aromatic systems are in progress.
Scheme 5. Tandem SNAr/Lossen Rearrangement
Table 1. Methylation Optimization
a
entry
conditions
8/9
1
2
3
4
K2CO3, MeI, acetone, 50 °C
NaH, MeI, DMF, 0 °C→rt
Me2CO3, DBU, 90 °C
MeOH, DEAD, PPh3, THF, 0 °C→rt
TMSCHN2, DIPEA, MeCN/MeOH (9:1)
TMSCHN2, toluene/MeOH (9:1)
TMSCHN2, toluene/i-BuOH (9:1)
TMSCHN2, benzene/MeOH (9:1)
TMSCHN2, benzene/i-BuOH (9:1)
TMSCHN2, benzene/i-BuOH (19:1)
100:0
100:0
100:0
>95:<5
65:35
55:45
40:60
55:45
30:70
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b03887.
b
5
c
6
d
7
Experimental procedures, spectroscopic characterization
8
1
data, and H and 13C NMR spectra (PDF)
e
9
f
10
a
AUTHOR INFORMATION
Experiments involved <5 mg of 7 except entry 9 (19 mg of 7);
■
product ratios estimated by 1H NMR analysis of concentrated mixture
after consumption of 7. Entries 5−10: rt, 12−18 h, 0.1 M 7. No
change in the absence of DIPEA. Negligible conversion to products in
Corresponding Author
*E-mail: gregory.dudley@mail.wvu.edu.
ORCID
b
c
d
the absence of MeOH. Trace amounts of 7 observed in crude
e
product mixture. Methoxyisoquinoline 9 isolated in 63% yield.
Gregory B. Dudley: 0000-0001-6133-3747
Notes
f
Incomplete conversion.
The authors declare no competing financial interest.
(Table 1, entry 5) produced a mixture of 8 and 9 that, although
favoring 8, was sufficiently encouraging to warrant further
optimization for the synthesis of 9.
ACKNOWLEDGMENTS
We thank the National Science Foundation (NSF CHE
1300722) for support of this work.
■
Mechanistic studies27 support a reaction pathway involving
desilylation and protonation of TMSCHN2 to produce an
+
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DOI: 10.1021/acs.orglett.6b03887
Org. Lett. XXXX, XXX, XXX−XXX