A tandem isomerization/prins strategy: Iridium(III)/Bronsted acid cooperative catalysis

Article abstract of DOI:10.1002/anie.201306462

Working together: A mild and efficient isomerization/protonation sequence generates pyran-fused indoles by cooperative catalysis between cationic iridium(III) and Bi(OTf)₃. Three distinct cyclization manifolds lead to the corresponding bioactive scaffolds in good yields. In addition, N-substituted indoles can be synthesized enantioselectively in the presence of a chiral phosphate. Copyright

Full text of DOI:10.1002/anie.201306462

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DOI: 10.1002/anie.201306462
Synthetic Methods
A Tandem Isomerization/Prins Strategy: Iridium(III)/Brønsted Acid
Cooperative Catalysis**
Vince M. Lombardo, Christopher D. Thomas, and Karl A. Scheidt*
Tetrahydropyrans (THPs) are important heterocycles found
in biologically active natural products and small molecules.[1]
There are several established methods to construct THPs
including hetero-Diels–Alder cycloadditions,[2] intramolecu-
generate the requisite oxocarbenium ion 1, b) the need for
reactive carbonyl compounds (e.g., aldehydes) and elevated
temperatures to drive the reaction to completion, and c) the
control of the stereochemical outcome and exchange of
reaction substituents from potentially competing oxonia-
Cope pathways.[8]
lar conjugate additions,[3] and ring-closing metathesis.[4]
A
major approach for pyran synthesis involves the condensation
À
of an aldehyde with a homoallylic partner and subsequent C
An alternative approach to the Prins manifold that
potentially circumvents these issues associated with promot-
ing dehydration and subsequent oxocarbenium formation is
C bond formation (Prins cyclization, Figure 1).[5] This general
Prins strategy has been proven to be efficient for the synthesis
of biologically active small molecules,[6] as well as a key tactic
in the construction of complex natural products.[7] Yet while
the Prins reaction is convergent in nature, recognized draw-
backs to the typical reaction conditions for this transforma-
tion include: a) the use of strong Lewis or Brønsted acids to
a
transition-metal-catalyzed
isomerization/protonation
sequence involving an appropriately functionalized precursor
(Figure 1). Efficient single-flask operations involving alkene
isomerization steps have been utilized in Friedel–Crafts
reactions,[9] as well as asymmetric Claisen rearrangements.[10]
Our strategy to access Prins-type oxocarbenium intermedi-
ates without the need for strong dehydrating conditions
involves the isomerization of the allyl ether 2 to the enol ether
3. The enol ether can then be protonated under mild acidic
conditions to provide the oxocarbenium 1 in the presence of
À
a suitable alkene nucleophile with subsequent C C bond
formation. Protonations of enol ethers have also been used
independently by the groups of Rychnovsky and Dobbs to
promote Prins cyclizations with vinyl and allyl silanes.[11]
Notably, the construction of the pyran 4 would be possible
at ambient temperatures and without the use of carbonyl
functional groups.
As a proof of concept for this Prins process, we crafted our
approach around the indole core as the requisite nucleophilic
alkene component (Figure 1, Nuc). Utilizing indoles in this
process would intersect intermediates in the oxa-Pictet–
Spengler reaction,[12] which has been used to generate many
biologically relevant oxacycles,[13] but can often suffer from
the same limitations as the Prins cyclization. To leverage our
substrate design and maximize potential compound library
synthesis, the appendage of an allyl group on the N-, C2-, and
C3-position of the indole enables the synthesis of three
different types of pyran-fused indole scaffolds (Figure 1).[14]
Substituted indoles are abundant in biologically active
compounds and promising pharmaceuticals[15] For example,
the core structure of the Type 1 class (Figure 1) is found in the
anti-inflammatory drug etodolac.[16] The lead compound
HCV-371, a potent hepatitis C NS5A polymerase inhibitor
discovered by high-throughput screening and chemical opti-
mization, also contains this substitution.[17] Indoles of Type 2
have also been studied for their inhibition of NS5A poly-
merase.[18] Finally, the heterocycles of the Type 3 variant have
been studied for their potential antidepressant and antitumor
properties.[19] Despite the significant interest in these com-
pounds for biological applications, an efficient and unified
approach to obtain these products is lacking.[20] Herein, we
Figure 1. Tandem isomerization cyclization.
[*] Dr. V. M. Lombardo, Dr. C. D. Thomas, Prof. K. A. Scheidt
Department of Chemistry, Center for Molecular Innovation and
Drug Discovery, Chicago Tri-Institutional Center for Chemical
Methods and Library Development (CT-CMLD)
Northwestern University
2145 Sheridan Road, Evanston, IL 60208 (USA)
E-mail: scheidt@northwestern.edu
[**] Financial support has been generously provided by the NIH P50
GM086145 and American Cancer Society (RSG-09-016-01-CDD). We
thank Dr. Paul Siu (NU) for assistance with X-ray crystallography
and Dr. Chris Check (NU) for mechanistic discussions.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201306462.
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describe the development of a tandem catalytic isomeriza-
tion/Prins-type cyclization for the efficient construction of
three types of pyran-fused indoles geared toward bioactive
compound library development.[6a,21]
We initially sought to achieve this reaction in a stepwise
manner by first isomerizing the allyl ether 5 into enol ether 6
and subsequently adding an acid source to facilitate cycliza-
tion to the pyran 7 (Table 1). We began our studies by first
hindered base, only low conversion into the pyran and mostly
enol ether was observed (entry 10).
Given our interest in the area of cooperative catalysis,[27]
we were interested to see if the simultaneous addition of the
metal triflate and the iridium complex directly to the reaction
mixture containing 5 would provide a simple protocol for this
transformation and possibly increase the activity of either or
both catalysts. Cooperative catalysis has been successfully
employed with transition metals and Brønsted acids,[28] and
recent independent reports by the groups of Rueping and
Xiao describe the combination of iridium complexes and
Brønsted acids to facilitate reductions of imines.[29] Our
cascade isomerization/protonation strategy seemed a prime
candidate to apply this catalyst combination for the con-
Table 1: Screening of acid sources.
À
struction of C C bonds. To test this hypothesis, 5 was
simultaneously subjected to [IrH2(THF)2(PPh2Me)2]PF6 and
Bi(OTf)3 at 1 mol% each (entry 6): the reaction proceeded to
100% conversion within only 2 hours [versus 12 h for initial
alkene isomeration with IrIII alone, then Bi(OTf)3]. We
attribute the decrease in reaction time to Brønsted acid
acceleration of the isomerization, thereby leading to a coop-
erative or synergistic affect for this system.
We then directed our attention toward the synthesis of
various indole-fused heterocycles to investigate if the coop-
erative or synergistic effect observed could be applied to the
three types of indoles discussed above. Beginning with the
Type 1 scaffold, in which the allyl ether is appended at the C3-
position, the reactions proceeded in high yields with a variety
of different products formed (8–13; Table 2).
The 5-substituted indoles (9 and 10) are compatible with
the cooperative catalysis conditions, including products such
as 10 containing an aryl bromide functionality, which can
serve as a handle for additional functionalization through
metal-catalyzed coupling reactions. Tertiary ethers (11) can
be formed in good yield to give the framework found in
pharmaceutically relevant compounds such as HCV-371.[18]
The geminally disubstituted pyran 12 can be obtained in high
yield, and presents the opportunity for functional-group
manipulation of the diester.[30] When a secondary allylic
ether is employed as a substrate, the corresponding 2,6-
substituted pyran 13 is isolated in 71% yield with excellent
diastereoselectivity (> 20:1 cis/trans).
Entry
Acid source
6/7
Yield [%][c]
1
2
3
4
5
6
7
8
9
10
TMSOTf
CSA
MeSO3H
InCl3
40:60
73:27
54:46
94:6
10:90
35:65
0:100
0:100
0:100
90:10
n.a.
n.a.
n.a.
n.a.
n.a.
n.a.
70
70
65
n.a.
FeCl3
Yb(OTf)3
Bi(OTf)3
[d]
Bi(OTf)3
TfOH
Bi(OTf)3
[e]
[a] 1 mol% [IrH2(THF)2(PPh2Me)2)]PF6 in THF (0.1m). [b] 1 mol% acid
source. [c] Yield of product isolated after column chromatography.
[d] Simultaneous addition of both catalysts: reaction time decreased
from 12 h to 2 h. [e] 2,6-di-tert-butylpyridine (10 mol%) added. CSA=
camphorsulfonic acid, Tf=trifluoromethanesulfonyl, THF=tetrahydro-
furan, TMS=trimethylsilyl. n.a.=yield not determined.
exploring reaction conditions for the isomerization of 5 into 6.
After examining several different reaction conditions, the
iridium catalyst [IrH2(THF)2(PPh2Me)2)]PF6, used previously
by Miyaura and co-workers to convert allyl ethers into E-vinyl
ethers, was determined to be the most effective catalyst for
the isomerization.[22] With the isomerization conditions iden-
tified, both Brønsted acids and metal triflates were evaluated
for their ability to catalyze the efficient cyclization of 5 to 7
(Table 1). Metal triflates can be employed as hidden acid
catalysts which circumvent the difficulties of using small
amounts of strong Brønsted acids.[23] Acids such as TMSOTf,
camphorsulfonic acid (CSA), MeSO3H, and Yb(OTf)3 did not
completely promote cyclization to 7. Lewis acids such as InCl3
and FeCl3 were tested with FeCl3 promoting nearly full
conversion into 7 (90:10, entry 5).[24] In contrast, the addition
of Bi(OTf)3 to the reaction after the isomerization resulted in
full conversion into 7 in high yield (70%, entry 7). In
particular, Bi(OTf)3 has been used as a convenient and mild
source of triflic acid in the presence of water[25] and has been
proven to be effective in catalyzing Prins-type cyclizations.[26]
To assess whether Bi(OTf)3 is a TfOH source in this process,
a control experiment with 2,6-di-tert-butyl pyridine (DTBP)
as an additive was performed. With the addition of this
Moving from the allylic ether at C3 (Type 1) to the the
allylic ether at C2 (Type 2) accesses the isosteric tricylic
pyrans (Table 2). The C2-substituted allyl ether substrates
À
were efficiently generated through a palladium-catalyzed C
H activation utilizing primary alkyl halides.[31] With each of
these substrates, the cyclization reaction provides the pyran
products in moderate yields for the overall two-step tandem
process. The 5-substituted indoles (15 and 16) bearing
electron-withdrawing and electron-donating groups are ame-
nable to the reaction conditions but proceed in moderate
yields. Allyl groups such as cinnamyl and 3,3-dimethyl allyl
(e.g. 17 and 18) were also explored and found to be
compatible, but required a slightly higher iridium catalyst
loading to fully isomerize the alkene. The core structure of the
spirocyclic indole-fused pyran 19 has been utilized as an
antagonist for the m-opiate receptor.[32]
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Table 2: Substrate scope.[a]
Scheme 1. Diastereoselective example. a) 8 mol% [IrH2(THF)2-
(PPh2Me)2)]PF6 in THF (0.1m); b) 10 mol% Bi(OTf)3 added directly to
flask. Thermal ellipsoids shown at 50% probability.[37]
IrIII/Bi(OTf)3 conditions (Scheme 1), thus generating 28 as
a 7:1 mixture of diastereomers via the intermediate oxocar-
benium A. The major product is attributed to a chairlike
transition state (B) with the indole approaching past the
À
newly added C H bond. A crystal structure of the major
diastereomer proved the syn relative stereochemistry of 28. In
contrast to simpler substrates, simultaneous addition of IrIII/
Bi(OTf)3 did not fully facilitate the cyclization of substrate 26,
which is presumably a result of the known attenuated activity
of the iridium catalyst towards internally substituted ole-
fins.[9a] Consequently, a single-flask, sequential approach was
employed in which Bi(OTf)3 was added after isomerization to
the enol ether using increased catalyst loadings of IrIII.[34]
Overall, this Type 3 process offers the highest yields with the
ability to easily access different pyrans and oxepane products,
and the opportunity to incorporate additional stereocenters
with high levels of diastereoselectivity.
Our current understanding of the cascade sequence is
shown in Figure 2. The catalytic cycle begins with in situ
generation of an active cationic iridium complex (D) by
[a] 1 mol% [IrH2(THF)2(PPh2Me)2)]PF6 in THF (0.1m) 1 mol% Bi(OTf)3
added simultaneously. [b] Diastereomeric ratios determined by 1H NMR
spectroscopy (500 MHz). [c] 6 mol% of iridium catalyst was needed for
full conversion.
The placement of the ether group on the nitrogen atom of
the indole (Type 3) provides increased substrate diversity
compared Types 1 and 2 because of the ease of synthesizing
different allyl ether precursors from readily available alde-
hydes.[33] As with Types 1 and 2, 5-substituted indoles were
tolerant to the reaction conditions, thus generating the pyrans
21 and 22 in excellent yield. In addition to aromatic
substituents, products such as 24, which have alkyl substitu-
tion at the C3-position, can be obtained in high yields.
Interestingly, in addition to six-membered pyrans, cyclization
to afford the seven-membered oxepane 25 could also be
achieved in this Type 3 approach, and was not possible for
Types 1 and 2 analogues.
Internal substitution of the allyl ether substituent provides
the opportunity to introduce stereochemical complexity to
the overall isomerization/cyclization process. Hence, a 1,1-
disubstituted-styrene ether substrate (26) was subjected to the
Figure 2. Catalytic cycle.
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sparging hydrogen gas (from a balloon) into a suspension of C
in THF. After association with the substrate 5 to form the
In summary, a mild and efficient process to generate
a wide variety of heterocycle-fused indoles has been devel-
oped utilizing cooperative catalysis between an iridium(III)
catalyst and Bi(OTf)3. Three distinct cyclization manifolds
(Types 1–3) lead to bioactive scaffolds which can be obtained
in good yields through a one-pot reaction with low catalyst
loadings while avoiding the traditional harsh reaction con-
ditions of Prins-type reactions. In addition, N-substituted
indoles can be synthesized enantioselectively by an oxocar-
benium/chiral phosphate counterion approach which pro-
vides a clear roadmap for further study of this asymmetric
variant. The creation of focused pyran indole libraries
through this method and subsequent biological evaluation
are currently underway.
À
complex E, a migratory insertion takes place and adds Ir H
across the olefin, thus generating the iridium complex F. A b-
hydride elimination of the iridium complex subsequently
furnishes the vinyl ether G which is equipped to be
protonated. The triflic acid produced from Bi(OTf)3 effec-
tively protonates G, thereby generating the key oxocarbe-
nium ion H which then can undergo an oxa-Pictet–Spengler
reaction to generate the cyclized iminium ion I. The
aromatization of I regenerates the Brønsted acid (TfOH)
and ultimately furnishes the pyran-fused indole 7.
Based on this reaction pathway, the tandem isomeriza-
tion/cyclization provides a test platform for an enantioselec-
tive variant with chiral Brønsted acids. Chiral phosphoric acid
(CPA) catalysis has emerged as a powerful strategy to
promote various asymmetric transformations.[35] While the
addition of nucleophiles to imines activated by CPAs is well
developed, the generation of oxocarbenium ions and subse-
quent additions are far less advanced with only recent highly
enantioselective ketalizations and aldol-type reactions being
described.[36] Outside of these examples however, there are
few cases of oxocarbenium/chiral counterion catalysis utiliz-
ing CPAs in instances of carbon nucleophile addition.[36a]
Given the process described in Figure 2, chiral phosphoric
acid 30 could protonate the enol ether and the subsequent
conjugate base would form a contact ion-pair to generate
enantioenriched heterocyclic-fused indoles (Scheme 2).
Received: July 24, 2013
Published online: November 11, 2013
Keywords: bismuth · cooperative catalysis · cyclization ·
heterocycles · synthetic methods
.
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