Enantioselective Iridium-Catalyzed Phthalide Formation through Internal Redox Allylation of Phthalaldehydes

Full text of DOI:10.1002/anie.201712015

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Accepted Article
Title: Enantioselective Iridium Catalyzed Phthalide Formation via
Internal Redox Allylation of Phthalaldehydes
Authors: Michael Joseph Krische, James M. Cabrera, and Johannes
Tauber
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201712015
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10.1002/anie.201712015
Angewandte Chemie International Edition
Enantioselective Iridium Catalyzed Phthalide Formation
via Internal Redox Allylation of Phthalaldehydes
James M. Cabrera+, Johannes Tauber+, and Michael J. Krische*
University of Texas at Austin, Department of Chemistry
105 E 24th St. (A5300), Austin, TX 78712-1167 (USA)
<Graphical Abstract>
An Inside Job. Enantioselective phthalide synthesis is achieved through internal redox allylation
of o-phthalaldehydes. Oxidative esterification is balanced by reductive carbonyl addition to
achieve an overall redox neutral process. Using this method, formal syntheses of ent-spirolaxine
methyl ether and CJ-12,954 are achieved.
Keywords: Enantioselective, C-C Bond Formation, Iridium, Hydrogen Transfer, Homogenous
Catalysis.
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10.1002/anie.201712015
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Enantioselective Iridium Catalyzed Phthalide Formation via Internal Redox Allylation of
Phthalaldehydes**
James M. Cabrera+, Johannes Tauber+, and Michael J. Krische*
[*]
Mr. James M. Cabrera, Dr. Johannes Tauber and Prof. M. J. Krische
University of Texas at Austin, Department of Chemistry
105 E 24th St. (A5300), Austin, TX 78712-1167 (USA)
Email: mkrische@mail.utexas.edu
[**]
[+]
The Welch Foundation (F-0038), the NIH (RO1-GM069445) and the UT Austin Center for Green Chemistry and
Catalysis are acknowledged for partial support of this research. The Deutsche Forschungsgemeinschaft (DFG) is
acknowledged for postdoctoral fellowship support (JT).
These authors contributed equally to this work.
Isobenzofuranones or “phthalides” occur frequently in nature and, due to their wide
ranging biological activities, are common architectures in medicinal chemistry.[1] As illustrated
in the Hauser-Kraus annulation, phthalides are also important building blocks in chemical
synthesis.[2] Despite considerable progress, there are relatively few catalytic asymmetric methods
for phthalide synthesis that are atom-efficient and do not employ stoichiometric metals.[3-8] These
include ruthenium catalyzed transfer hydrogenation of ortho-keto-benzoates,[3] biocatalytic
reduction of ortho-keto-benzonitriles,[4] intramolecular ketone hydroacylation,[5] [2+2+2]
cycloadditions,[6] as well as organocatalyzed aldol additions[7] and arylboronic acid additions[8]
to ortho-formyl-benzoates. Our interest in the development of alcohol-mediated C-C coupling[9]
led us to consider a catalytic enantioselective phthalide synthesis based on the redox neutral
allylation of aromatic ortho-dialdehydes or “phthalaldehydes” (Figure 1).[10] Specifically, a
hydrogen auto-transfer process was envisioned in which asymmetric aldehyde allylation would
trigger formation of an iridium lactolate, which upon β-hydride elimination would form the
phthalide and an iridium hydride.[11] β-Hydride elimination from the homoallylic iridium
alkoxide (not shown) is suppressed by coordination
Figure 1. Redox neutral allylation of
phthalaldehydes.
of the adjacent alkene. Deprotonation of the iridium
hydride followed by ionization of allyl acetate would
regenerate the π-allyliridium nucleophile to close the
catalytic cycle. Beyond the mechanistic novelty of
this process, we were motivated by the fact that
despite enormous advances made in the field of
enantioselective carbonyl allylation,[9g,12] application
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10.1002/anie.201712015
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of asymmetric allylation to phthalide formation is limited to a small number of reports involving
additions to ortho-formyl-benzoates for which relatively modest levels of enantiomeric
enrichment were observed.[13,14]
In an initial series of experiments, the parent phthalaldehyde 1a (100 mol%) was exposed
to the chromatographically isolated π-allyliridium C,O-benzoate complexes (S)-Ir-I to (S)-Ir-VI
in the presence of allyl acetate 2a (200 mol%) and Cs2CO3 (100 mol%) in THF (0.1 M) at 100 oC
(Table 1, entries 1-6). This initial screen revealed that the proposed phthalide formation was
indeed feasible and that the iridium catalyst (S)-Ir-VI modified by the “Roche ligand”[15]
enforced the highest levels of enantioselectivity, providing phthalide 3a in 85% yield and 84%
enantiomeric excess (Table 1, entry 6). As illustrated in the reactions catalyzed by (S)-Ir-II, (S)-
Ir-V and (S)-Ir-VI, the addition of water (100 mol%) significantly enhances enantiomeric excess
(Table 1, entries 7-9). Water might help solubilize the base, Cs2CO3, which maintains the
structural integrity of the C,O-benzoate by promoting cyclometallation. The C,O-benzoate
moiety is not kinetically inert under the reaction conditions and the “non-cyclometalated”
catalyst, although less efficient, promotes formation of the opposite enantiomer.10b As illustrated
in reactions catalyzed by (S)-Ir-VI, the use of other bases (K3PO4 and K2CO3) did not diminish
Table 1. Selected optimization experiments in the enantioselective iridium catalyzed internal
redox allylation of phthalaldehyde 1a to form phthalide 3a.a
aYields are of material isolated by silica gel chromatography. Enantioselectivities were determined by chiral stationary phase
HPLC analysis. b(S)-Ir-VI (3 mol%). See Supporting Information for further experimental details.
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10.1002/anie.201712015
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yield or enantioselectivity (Table 1, entries 10, 11). Finally, if the reaction is run at higher
concentration (0.2 M), the loading of catalyst (S)-Ir-VI could be decreased (3 mol%) without any
erosion in performance (Table 1, entry 12).
To assess the scope of this process, optimal conditions identified for the formation of
phthalide 3a were applied to symmetric phthalaldehydes 1a-1f (Table 2). The desired phthalides
3a-3f were formed in good yield with generally high levels of enantioselectivity. These results
inspired us to explore the use of α-substituted allyl donors (Table 3). Toward this end, o-
phthalaldehyde 1a was exposed to allyl pronucleophiles 2b-2j in the presence of chiral catalyst
(S)-Ir-VI. Here, lower temperatures are required to preserve kinetic selectivity in the formation
of the (E)-σ-allyliridium haptomer[10c] and to enhance enantioselectivity. Thus, notwithstanding
minor changes in reaction temperature, the standard conditions enabled access to products of
crotylation 3g,[10c,i] cyclopropylallylation 3h,[10o] trimethylsilylallylation 3i,[10g] as well as adducts
incorporating aliphatic (3j), aromatic (3k-3n) and heteroaromatic (3o) side chains. In each case,
complete levels of branched regioselectivity were accompanied by good to complete levels of
anti-diastereoselectivity and uniformly high levels of enantioselectivity.
Table 2. Enantioselective iridium catalyzed internal redox allylation of symmetric dialdehydes
1a-1f to form phthalides 3a-3f.a
aYields are of material isolated by silica gel chromatography. Enantioselectivities were determined by chiral stationary phase
HPLC analysis. See Supporting Information for further experimental details.
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10.1002/anie.201712015
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Table 3. Enantioselective iridium catalyzed internal redox allylation of phthalaldehyde 1a using
substituted allylic acetates 2b-2j to form phthalides 3g-3o.a
aYields are of material isolated by silica gel chromatography. Enantioselectivities were determined by chiral stationary phase
HPLC analysis. See Supporting Information for further experimental details. b2d (300 mol%). cTHF (1 M).
Site-selective internal redox allylation of non-symmetric o-phthalaldehydes requires
discrimination between aldehyde moieties in the C-C bond forming event. To assess the
influence of remote electronic effects on the chemoselectivity of such processes, the 4-
substituted phthalaldehydes 1g-1i were subjected to standard conditions for internal redox
allylation (eq. 1). For 1g-1i, the mesomeric effect of the remote 4-substituent increases and, in
the case of 1h and 1i, was anticipated to deactivate the p-substituted aldehyde moiety to favor
formation of 3q and 3r over the constitutionally isomeric products iso-3q and iso-3r,
respectively. However, the observed levels of regioselectivity were quite modest. In contrast, the
ortho-methoxy substituted phthalaldehydes 1j and 1k could be engaged with significantly higher
levels of selectivity (eq. 2). By exploiting synergistic steric and electronic effects, the 3,5-
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dimethoxy-substituted phthalaldehyde 1k was converted to 3t with good levels of site-selectivity.
In the internal redox allylation of the ortho-methoxy substituted phthalaldehydes 1j and 1k, the
π-allyliridium C,O-benzoate complex derived from 3,4-dinitrobenzoic acid and the “Roche
ligand,”[15] (S)-Ir-VII, displayed superior performance compared to the catalysts (S)-Ir-I through
(S)-Ir-VI. The assignment of absolute stereochemistry for adducts 3a-3t was made in analogy to
phthalide 3l, which was determined by single crystal X-ray diffraction, and phthalide 3t, which
was evaluated by comparison of its optical rotation to that of an authentic sample.[16]
Underscoring the utility of this method in target oriented synthesis, the preparation of 3t
constitutes a formal synthesis of two different phthalide natural products: ent-spirolaxine methyl
ether[17] and CJ-12,954 (Figure 2).[18] Both compounds have been shown to exhibit antibiotic
activity against the Gram-negative bacteria Helicobacter pylori.[19]
Figure 2. Formal syntheses of ent-spirolaxine methyl ether and CJ-12,954.
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In summary, we report an enantioselective hydrogen auto-transfer[20] reaction that
converts o-phthalaldehydes to phthalides. In this processes, asymmetric aldehyde allylation
trigger formation of an iridium lactolate, which upon β-hydride elimination delivers the
phthalide. Thus, reductive carbonyl addition is balanced by oxidative esterification to achieve an
overall redox neutral process. Beyond the parent enantioselective allylation, diverse substituted
allyl donors were found to participate in this process. Additionally, as illustrated by the formation
of phthalide 3t, the synergistic steric and electronic influence of substituents of the o-
phthalaldehydes enable site-selective internal redox allylation. Finally, the formation of phthalide
3t represents formal asymmetric syntheses of two related natural products, ent-spirolaxine
methyl ether and CJ-12,954, highlighting the synthetic utility of this process.
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