Catalytic Enantioselective [10+4] Cycloadditions

Article abstract of DOI:10.1002/anie.201807830

The first peri- and stereoselective [10+4] cycloaddition between catalytically generated amino isobenzofulvenes and electron-deficient dienes is described. The highly stereoselective catalytic [10+4] cycloaddition exhibits a broad scope with high yields,

Full text of DOI:10.1002/anie.201807830

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Accepted Article
Title: Catalytic Enantioselective [10+4]-Cycloadditions
Authors: Karl Anker Jørgensen, Bjarke Donslund, Nicolaj Inunnguaq
Jessen, Giulio Bertuzzi, Maxime Giardinetti, Teresa Ann
Palazzo, and Mette Louise Christensen
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Catalytic Enantioselective [10+4]-Cycloadditions
Bjarke S. Donslund, Nicolaj Inunnguaq Jessen, Giulio Bertuzzi, Maxime Giardinetti, Teresa A. Palazzo,
Mette Louise Christensen and Karl Anker Jørgensen[a]*
Abstract: The first peri- and stereoselective [10+4]-cycloaddition
between catalytically generated amino isobenzofulvenes and
electron-deficient dienes is described. The highly stereoselective
catalytic [10+4]-cycloaddition exhibits a broad scope with high yields
reflecting a robust higher-order cycloaddition. Experimental and
To achieve isolable [10+4]-cycloadducts and avoid catalyst
trapping, an all-carbon 4-component with judicious substitution
to aid in both reactivity and eliminative catalyst release was
envisioned. Electron-deficient dienes
2 were identified as
promising candidates in early reactivity screenings (Scheme 1,
bottom).[8]
computational investigations support
a kinetic distribution of
intermediate rotamers dictating the enantioselectivity, which relies
heavily on additive effects.
For concise and controlled construction of chiral cyclic structures,
cycloadditions are recognized as highly valuable synthetic
strategies. Diels-Alder reactions and dipolar cycloadditions,
involving 6π-electrons, have been particularly useful and a
multitude of enantioselective catalytic versions have been
developed.[1] Higher-order cycloadditions are relatively
underexplored although the potential for elegant construction of
complex cyclic scaffolds has been demonstrated by the
syntheses of e.g. capnellene and azulenes.[2] This is partially due
to challenges regarding periselectivity and stereocontrol.[3]
Intermolecular higher-order cycloadditions remained elusive in
asymmetric catalysis until the first metal-catalyzed [8+2]-
cycloaddition was reported in 2013.[4] The next development was
organocatalyzed [6+4]- and [8+2]-cycloadditions disclosed in
2017.[5] Shortly after, organocatalyzed [6+2]- and [8+2]-
cycloadditions were reported to provide cyclic scaffolds in high
enantioselectivities.[6]
During the development of catalytic enantioselective [8+2]-
cycloadditions through amino isobenzofulvenes with nitroolefins,
computational investigations indicated the potential for a [10+4]-
cycloadduct as the kinetically favored intermediate (Scheme 1,
top).[6a] However, this proposed off-pathway species was not
observed experimentally. Herein, the possibility to harness this
Scheme 1. Peri- and stereoselective [8+2]- and [10+4]-cycloadditions.
Initially, the reaction between 1H-indene-2-carbaldehyde 1a
and diene 2a (1.5 eq) catalyzed by diphenylprolinol silyl ether 3a
(20 mol%) in CDCl3 was investigated.[9] This afforded a complex
product mixture containing mainly Michael adducts, traces of a
presumed [8+2]-cycloadduct, an isolable amount of the desired
[10+4]-cycloadduct 4a, and a [10+4]-cycloadduct with a shifted
indene double bond (Table 1, entry 1). Application of 3-phenyl
substituted indene 1b gave 4b as a single diastereoisomer in
higher yield and enantioselectivity with no significant formation of
byproducts (entry 2). Addition of molecular sieves (MS) lowered
the yield of 4b while maintaining the enantioselectivity (entry 3).
A bulkier diphenylprolinol silyl ether 3b also facilitated the reaction,
but with no major improvement in enantioselectivity (entries 4, 5).
Curiously, reaction rate and enantioselectivity for the reaction with
3b and MS was found to vary with solvent batch.
reactivity and develop
a catalytic enantioselective [10+4]-
cycloaddition is investigated. To the best of our knowledge,
[10+4]-cycloadditions have been reported in two instances in non-
catalytic reactions employing dialkyl isobenzofulvenes without
control of enantioselectivity.[7] Since only one example of an
intermolecular [6+4]-cycloaddition has been achieved catalytically
in high enantioselectivity with cyclopentenone and tropone,[4a] the
development of
a
general procedure for
a
catalytic
enantioselective [10+4]-cycloaddition would represent
a
significant step forward for controlling peri- and stereoselectivity
of higher-order cycloadditions.
[a]
Dr. B. S. Donslund, N. I. Jessen, G. Bertuzzi, Dr. M. Giardinetti, Dr.
T. A. Palazzo, M. L. Christensen, Prof. Dr. Karl Anker Jørgensen
Department of Chemistry, Aarhus University.
Langelandsgade 140, 8000 Aarhus C (Denmark)
E-mail: kaj@chem.au.dk
Supporting information for this article is given via a link at the end of
the document.
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Table 1. Optimization of [10+4]-cycloaddition
Application of CDCl3, filtered through activated basic
alumina (F in Table 1) to remove DCl traces, led only to trace
product formation (entry 6). Acid additives were found to restore
reactivity in
a reproducible fashion. Catalyst 3b with p-
methoxybenzoic acid (20 mol%) provided 4b in 69% yield and
92% ee (entry 7), while the less bulky catalyst 3a gave 4b in 80%
yield and 83% ee (entry 8). The nature of the acid additive was
important, exemplified by p-nitrobenzoic acid causing lower yield
and selectivity (entry 9). Applying catalyst 3b with reversed
stoichiometry ensured full conversion within 20 h and increased
the yield, while maintaining the enantioselectivity (entry 10).
Combining the effects of MS and an acid additive was beneficial
for yield and selectivity (entries 10-11, for additional results see
SI).
The substrate scope was then investigated (Scheme 2). In
general, excellent diastereoselectivity was observed. Phenyl
groups of varying electronic nature on the 3-position of 1H-
indene-2-carbaldehydes 1 led to the formation of [10+4]-
cycloadducts 4b-e in high yields and enantioselectivities. ortho-
Tolyl and 1-naphthyl substituted indenes delivered 4f and 4g,
respectively, in high yields and enantioselectivities, as 1:1
diastereomeric mixtures due to hindered axial rotation. 2-
Naphthyl and 5-(1,3-(benzodioxyl)) substituted 4h,i were
achieved in high yields and enantioselectivities as single
diastereomers. A heteroaromatic substituent was well-tolerated
and 4j was formed in excellent yield and enantioselectivity. In a
10-fold scale-up with no procedural modifications, the excellent
stereoselectivity was maintained and a slight improvement to 95%
yield was achieved. Unfortunately, only indenes 1 carrying
aromatic substituents at position 3 were found to be reactive
towards 2a (Me-, t-Bu- and vinyl-substituted indenes were tested).
[a]
Entry
1
CDCl3
3
additive
yield (%)[b]
ee (%)[c]
11
1
1a
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
-
3a
3a
3a
3b
3b
3b
3b
3b
3b
3b
3b
-
<5
45
36
17
7
2
-
-
44
3
MS
-
45
4
-
-
51
5
MS
-
44
6
MS, F
MS, F
MS, F
MS, F
MS, F
F
-
<5
69
80
31
82
64
-
7
p-MeO-BA
p-MeO-BA
p-NO2-BA
p-MeO-BA
p-MeO-BA
92
8
83
9
78
10[d]
11[d]
92
84
[a] MS = activated 4Å molecular sieves added, F = filtered through basic
alumina. [b] Yield measured by NMR of the crude reaction mixture with SiEt4 as
internal standard. [c] Determined by chiral-stationary phase UPCC. [d] 2a (1.0
eq) and 1b (1.5 eq). BA = benzoic acid.
Scheme 2. Peri- and stereoselective [8+2]- and [10+4]-cycloadditions. Isolated yields. Diastereomeric ratio determined by NMR of crude reaction mixture.
Enantiomeric excess determined by chiral-stationary phase UPCC. See SI. [a] Reaction performed at 40 oC. [b] Reaction performed with 10 mol% p-MeO-BA. [c]
Reaction performed on 1.0 mmol scale. [d] Extensive degradation of 2 observed. [e] Indene 1b applied as limiting reagent with 2 eq of 2.
Successful variations of the benzofused ring were
performed with indenes bearing methoxy-, chloro- and methyl
substituents granting access to cycloadducts 4k-n in high yields
and enantioselectivities. An attempt to introduce a methyl
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Scheme 3. Synthetic elaborations of [10+4]-cycloadducts. For details see SI.
[a] Enantiomeric excess of one diastereomer determined following flash
chromatography.
substituent at position 11 resulted only in trace product formation
(results not shown).
Various 4π-components 2 were also tested and it was found
that the phenyl ketone could be decorated with halogens,
electron-donating, and electron-withdrawing groups affording 4o-
q in good to high yields and enantioselectivities. Similar good
results were obtained with a methyl ketone (4r). Employment of
esters as electron-withdrawing groups resulted in slightly lower
enantioselectivity, however, the high yield was maintained (4s,t).
The nitrile containing cycloadduct 4u was also obtained, albeit in
low yield and enantioselectivity. As an alternative to the
cyclopentenone core of the 4π-component, a lactone was found
to deliver cycloadduct 4v with an enantioselectivity comparable to
other esters (4s,t). However, as was observed with the nitrile
substituted 4π-component, extensive degradation of the lactone
substrate occurred, resulting in low yield.
The absolute configuration of 4k was determined by X-ray
crystallographic analysis and the stereochemistry of the
remaining cycloadducts 4 was assigned analogously (see SI).
Having demonstrated the stereoselective formation of a range of
[10+4]-cycloadducts 4, the possibility of selectively modifying the
tetracyclic products was explored (Scheme 3). Specifically, the
indene moiety was targeted for application as a nucleophile.
Treatment with Michael acceptor 5 in the presence of quinuclidine
delivered 6 containing an all-carbon quaternary stereocenter in
40% yield, maintaining the high enantiomeric excess. The
reaction of 4j with cinnamaldehyde 7 was facilitated by a catalytic
amount of pyrrolidine (necessary for reactivity) and quinuclidine.
Michael addition onto iminium-ion activated cinnamaldehyde is
proposed, followed by intramolecular [4+2]-cycloaddition through
an enol/enamine, granting access to the multi-bridged polycyclic
compound 8 in 76% yield with maintained enantiomeric excess as
a mixture of two diastereoisomers. This structure is proposed
based on NMR analysis and is supported by computational NMR
(see SI).
In the [10+4]-cycloaddition between 3-substituted 1H-
indene-2-carbaldehydes 1 through amino isobenzofulvenes and
electron-deficient dienes 2, excellent diastereoselectivity is
observed. Products 4 are formed with anti-configuration in
agreement with the reaction proceeding through an exo-transition
state. This is expected to be favorable in [6+4]-cycloadditions due
to unfavorable interactions in the endo-approach.[10] However,
application of symmetry rules and FMO analysis in large polyene
systems is complicated.[11]
A
significant effect on
enantioselectivity was exerted by acid additives and water in the
reaction when catalyst 3b was employed (Table 1). This was
hypothesized to arise from effects on the formation and
distribution of two rotamers of the amino isobenzofulvene
intermediate (INT-IA/INT-IB, Scheme 4). Unfortunately, we have
not been able to observe the intermediates by NMR analysis.
Instead, the hypothesis was probed indirectly by employment of
the C2-symmetric catalyst 3c,[12] for which INT-IA and INT-IB are
equivalent due to the rotational symmetry axis of the catalyst
(Scheme 5). Interestingly, the presence of an acid additive and
water were found to have no measurable effect on the
enantioselectivity when 3c was employed. This suggests an effect
on the distribution or reactivity of the two rotamers of the amino
isobenzofulvene formed from catalyst 3b and indenes 1. The
positive effect on enantioselectivity observed upon removal of
water under the optimized conditions could owe to a shut-down of
reversibility of iminium-ion formation and hence eliminate the
potential for equilibration between INT-IA and INT-IB. To
investigate if the rotational barrier between the two is too high to
allow for direct interconversion at room temperature, the
intermediate was optimized computationally. A scan of the
relevant dihedral revealed a barrier of >21 kcal/mol suggesting
that INT-IA and INT-IB are distinct intermediates (see SI). From
the absolute configuration of the [10+4]-cycloadducts 4, reaction
through INT-IA is expected to be predominant, however, INT-IB
was calculated to be 3.7 kcal/mol lower in energy. This suggests
that INT-IA is kinetically formed under the optimized reaction
conditions, or that it could be a Curtin-Hammett scenario. To
investigate further, the formation of 4b and ent-4b from INT-IA and
INT-IB, respectively, was studied computationally by reaction
pathway analysis.[13] By visual inspection, it was deemed unlikely
that INT-IB could lead to 4b with diene 2a approaching from the
sterically hindered face (see SI).
The calculations suggest that formation of either INT-IA or
INT-IB is an endergonic process, and that conjugate addition to 2a
proceeds via low barriers and is energetically viable. No
concerted pathways for the formation of INT-IIIA or INT-IIIB were
found, suggesting a step-wise cycloaddition. Reasonable barriers
for the closure of zwitterionic species INT-IIA and INT-IIB were
located.
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Scheme 4. Relative free energies in kcal/mol (B3LYP-gd3/6-31G(d,p) SMD (CHCl3)) are presented in bold (rotational TS energy in italics is an electronic energy
relative to INT-IB). Calculations were performed with ent-3b, however, the relevant mirror-image structures are displayed to aid the reader. For corrected single-
point electronic energies,[14] see SI.
Pathway
A
leading to 4b contains higher energy
suggest that the observed stereoselecitvities arise from kinetically
controlled amino isobenzofulvene formation. High yields, coupled
with high peri-, diastereo- and enantioselectivity, and a broad
substrate scope make this methodology valuable towards the
development of complex enantioenriched scaffolds.
intermediates but lower barriers, while pathway B leading to ent-
4b contains lower energy intermediates but higher barriers. Both
pathways contain reasonable barriers for reactivity at room
temperature. The computed free energies suggest that the
enantioselectivity is determined not by conjugate addition to 2, but
could indicate a kinetic preference for formation of amino
isobenzofulvene INT-IA.
Acknowledgements
The authors are grateful for crystallographic analysis by Line
Næsborg and Jeremy D. Erickson and financial support from
Carlsberg Foundation Semper Ardens, Aarhus University and
DNRF.
Keywords: higher-order cycloadditions • organocatalysis •
asymmetric synthesis • isobenzofulvenes • DFT calculations
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In conclusion, the first catalytic [10+4]-cycloaddition has
been developed. Experimental and computational evidence
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Bjarke S. Donslund, Nicolaj Inunnguaq
Jessen, Giulio Bertuzzi, Maxime
Giardinetti, Teresa A. Palazzo, Mette
Louise Christensen and Karl Anker
Jørgensen*
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Catalytic Enantioselective [10+4]-
Cycloadditions
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