Structurally Defined Molecular Hypervalent Iodine Catalysts for Intermolecular Enantioselective Reactions

Article abstract of DOI:10.1002/anie.201507180

Molecular structures of the most prominent chiral non-racemic hypervalent iodine(III) reagents to date have been elucidated for the first time. The formation of a chirally induced supramolecular scaffold based on a selective hydrogen-bonding arrangement provides an explanation for the consistently high asymmetric induction with these reagents. As an exploratory example, their scope as chiral catalysts was extended to the enantioselective dioxygenation of alkenes. A series of terminal styrenes are converted into the corresponding vicinal diacetoxylation products under mild conditions and provide the proof of principle for a truly intermolecular asymmetric alkene oxidation under iodine(I/III) catalysis.

Full text of DOI:10.1002/anie.201507180

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Communications
Chemie
International Edition: DOI: 10.1002/anie.201507180
German Edition: DOI: 10.1002/ange.201507180
Oxidation
Structurally Defined Molecular Hypervalent Iodine Catalysts for
Intermolecular Enantioselective Reactions
Stefan Haubenreisser, Thorsten H. Wçste, Claudio Martínez, Kazuaki Ishihara, and
Kilian MuÇiz*
Abstract: Molecular structures of the most prominent chiral
non-racemic hypervalent iodine(III) reagents to date have been
elucidated for the first time. The formation of a chirally
induced supramolecular scaffold based on a selective hydro-
gen-bonding arrangement provides an explanation for the
consistently high asymmetric induction with these reagents. As
an exploratory example, their scope as chiral catalysts was
extended to the enantioselective dioxygenation of alkenes. A
series of terminal styrenes are converted into the corresponding
vicinal diacetoxylation products under mild conditions and
provide the proof of principle for a truly intermolecular
asymmetric alkene oxidation under iodine(I/III) catalysis.
of these compounds is notably missing. A definite under-
standing of the mode of action of chiral hypervalent iodine
reagents can form the basis to enlarge the differentiation of
prochiral face recognition from the established intramolecu-
lar reaction control to more challenging topics, such as the
asymmetric oxidation of prochiral substrates by intermolec-
ular reaction control, and particularly in terms of catalysis.
Within this context, no definite mechanistic investigation has
so far been reported for the parent iodine(III) reagents 1 and
2a bearing lactic esters and amides as chiral entities
(Figure 1).[11,12] Regarding the important iodine 2a, structural
E
nantioselective catalysis has been recognized as a core
technology toward the supply of chiral molecular entities with
defined absolute configuration. Different methods have been
devised over past decades and synthetic molecular catalysts
based on transition-metal complexes[1] or small organic
compounds[2] represent the most advanced concepts in the
field.[3] Within the context of small organic catalysts, chiral
hypervalent iodine reagents have enabled the development of
significant advances in catalytic oxidation reactions that do
not rely on common transition metals.[4,5] Examples include
the ester derivative 1[6,7] and the amide derivative 2a,[8,9]
which has been identified as a particularly successful reagent.
In contrast to the rapidly growing number of successful
examples of chiral molecular iodine(I/III) catalysts,[5,6,10]
defined structural information on the accurate enantiocontrol
Figure 1. Representative chiral iodine reagents 1 and 2a and success-
ful enantioselective intramolecular reactions with 2a.
information could now be obtained for the derivatives 2b and
2c, which contain sterically enlarged anilide groups. As
unambiguously determined by X-ray analyses (Figure 2) for
both compounds, the amide NH groups engage in hydrogen
bonding with the acetoxy groups located at the iodine
center.[13a] These hydrogen bonds have the expected values
for NH–O contacts of 2.201 and 2.243 Š, and for N-H-O bond
angles of 163.3 and 160.08,[13a] and generate two nine-
membered rings.[14,15]
[*] Dr. S. Haubenreisser, Dr. T. H. Wçste, Dr. C. Martínez,
Prof. Dr. K. MuÇiz
Institute of Chemical Research of Catalonia (ICIQ)
The Barcelona Institute of Science and Technology
Av. Països Catalans 16, 43007 Tarragona (Spain)
E-mail: kmuniz@iciq.es
Prof. Dr. K. Ishihara
Graduate School of Engineering, Nagoya University
B2-3(611), Furo-cho, Chikusa, Nagoya 464-8603 (Japan)
Prof. Dr. K. MuÇiz
Catalan Institution for Research and Advanced Studies (ICREA)
Pg. Lluís Companys 23, 08010 Barcelona (Spain)
Supporting information and ORCID(s) from the author(s) for this
article are available on the WWW under http://dx.doi.org/10.1002/
anie.201507180.
ꢀ 2015 The Authors. Published by Wiley-VCH Verlag GmbH & Co.
KGaA. This is an open access article under the terms of the Creative
Commons Attribution Non-Commercial NoDerivs License, which
permits use and distribution in any medium, provided the original
work is properly cited, the use is non-commercial and no modifica-
tions or adaptations are made.
Figure 2. Intramolecular hydrogen-bonding properties of chiral hyper-
valent iodine compounds 2b (Ar=2,4,6-iPr3C6H2) and 2c (Ar=2,6-
iPr2C6H3). All hydrogen atoms except the N-H groups are omitted for
clarity.
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The main stereochemical consequence of this hydrogen
bonding rests in the effective creation of a supramolecular
helical chirality around the central iodine atom.[13b,c] This is
best envisioned through the respective top view representa-
tions (Figure 3, top). The chiral helicity is of C2 symmetry and
forms with complete diastereoselectivity as demonstrated by
1H NMR spectroscopy. X-Ray data and circular dichroism
(CD) spectroscopy (Figure 3, bottom) confirm that the helical
dation reactions based on using the chiral motif 2 as the
catalyst. While intramolecular reactivity has been widely
explored with reagent 2a,[8] related intermolecular asymmet-
ric transformations have remained without demonstration. In
addition, the general scope of compounds 2 as chiral catalysts
still remains to be explored, since the Kita intramolecular
spirolactonization currently stands out as the single successful
example.[8a,b,f]
In early work on chiral hypervalent iodine reagents Wirth
devised an enantioselective dioxygenation reaction under
stoichiometric conditions,[16] which was later extended using
the chiral bislactate derivative 1.[7k] Herein, we now provide
the first catalytic enantioselective version based on the use of
hypervalent iodine compounds 2 of the bislactamide motif.
The initial optimization process focused on a suitable reox-
idant, for which peracetic acid was identified.[14] It is note-
worthy that this oxidant is superior to the commonly
employed mCPBA,[10] which promotes epoxidation in the
present case. Our current hypothesis is that owing to its lower
reactivity, peracetic acid does not promote such a background
reaction.[14,17] The iodine(I/III)-catalyzed diacetoxylation of
styrene 4a was then investigated for several structurally
related aryl iodine(I) catalyst precursors 3. First, the estab-
lished compound 3a was employed. At a catalyst loading of
20 mol%, a reasonable conversion was obtained and the
product 5a was obtained with 84% ee (Table 1, entry 1). A
similar outcome was obtained for new derivative 3b as the
catalyst precursor to 2b (83% ee, entry 2). While an attempt
to lower the catalyst loading led to a decreased conversion
(entry 3), the introduction of a 4-methyl group into the central
Table 1: Enantioselective catalytic diacetoxylation of styrenes: Optimi-
zation.
En-
Catalyst
Loading Yield ee
try[a]
[mol%] [%][a] [%][b]
1
20
61
84
Figure 3. Top: Intramolecular hydrogen-bonding properties of chiral
hypervalent iodine compounds 2b and 2c result in helical chiral
assemblies (all hydrogen atoms except the N-H group are omitted for
clarity). Bottom: CD spectra for compounds 2b (red) and 2c (blue).
2
3
20
10
58
43
83
83
chirality is obtained with identical configuration for both 2b
and 2c and thus directly originates from the absolute
configuration of the chiral lactamide as the stereoinducing
4
10
57
83
1
group. CD and one- and two-dimensional H NMR data[14]
furthermore confirm that the H-bonding persists in solution.
With the demonstration of the effective hydrogen-bonding
motif, the lateral lactamide chains are recognized as a source
of chiral induction for the generation of the supramolecular
helical chirality. It is the helical chirality that is expected to
exercise efficient enantioselection in asymmetric catalytic
oxidation reactions with 2a. In this context, we studied the
requirements to obtain intermolecular enantioselective oxi-
5
6
7
10
55
71
61
86
85
83
10[c]
5[c]
[a] Yield after purification. [b] Determined by HPLC on chiral stationary
phase after conversion into the free diol. [c] With additional 5 mol% of
TfOH.
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arene core of 2a greatly enhanced the reactivity (57%
demonstrated for products 5t–w. Finally, 3-vinyl estra-1,3,5-
isolated yield of 5a, 83% ee, entry 4). Further modification of
the aniline substitution led to identification of 3c as the most
active and enantioselective catalyst precursor (86% ee,
entry 5). The yield of isolated product could be enhanced by
addition of trifluoromethansulfonic acid (TfOH) as Brønsted
acidic co-catalyst (entry 6), which resulted in a reasonable
conversion even at a 5 mol% catalyst loading (entry 7).
New aryl iodide 3c displays additional advantageous
features. In contrast to other catalyst precursors 3, it is fully
soluble at the start of the reaction and can be fully recovered
afterwards, while compounds 3a, 3b, and 3d suffer degrada-
tion over time. In the same context, the isolated active catalyst
2c has an unprecedentedly high stability in solution and
prolonged life-time in the isolated form.[14] It is further
noteworthy that the enantioselectivity of the catalytic reac-
tion is identical to that from a stoichiometric reaction with
preformed 2c. This result corroborates again the involvement
of hydrogen bonding in the catalytic transformation.[14]
The optimized conditions proved to be generally appli-
cable, and a total of twenty-four differently substituted
styrenes 4a–x could be converted into the corresponding
dioxygenation products 5a–x in an enantioselective and
completely chemoselective manner (Figure 4). Besides
parent styrene 4a, several para-substituted styrenes 4b–
l could be cleanly diacetoxylated and the products 5b–
l were obtained with up to 94% ee. Likewise, meta-substituted
products 5m–p were obtained with up to 90% ee, and ortho-
substituents led to diacetoxylation in 86–90% ee (products
5q–s). Higher-substitution pattern was equally tolerated as
(10)-trien-17-one 4x was converted into the corresponding
diol 5x under catalyst control and with complete chemo-
selectivity.[14] In view of these results and given the inherent
advantage that hypervalent iodine catalysis does not suffer
from potential product contamination by the presence of
residual transition metal ions, the metal-free catalysis de-
scribed provides reactivity that can complement established
enantioselective transition-metal-based procedures.[18] The
benign use of peracetic acid as the terminal oxidant adds to
the overall attractiveness of the process since no by-products
other than the solvent acetic acid and water are produced.
The observed results can be rationalized by the underlying
catalytic cycle depicted in Figure 5. At the reaction outset,
peracetic acid oxidizes iodine(I) precursor 3c to the active
catalyst 2c. Its established H-bonding motif offers a chance to
Figure 5. Catalytic cycle.
study the enantioselection in the prochiral alkene recognition.
As explored in detail by Gade and Kang, triflic acid activation
of PhI(OAc)2 via protonolysis is a prerequisite to accelerate
diacetoxylation reactions.[19] This points to a different role of
the two acetate groups in 2c. One engages in hydrogen
bonding for the generation of a cyclic stereochemical arrange-
ment. The second one should be prone to dissociation and
thus to formation of the iodine(III) catalyst state A, which is
no longer of C2-symmetry, but rather C1-symmetry. This
catalyst state with its free coordination site at iodine(III)
engages in the required efficient prochiral face differentiation
of the unsaturated hydrocarbon substrate within a preferential
coordination C. Subsequent nucleophilic attack of acetate to
the exposed re-face establishes the correct S-configured
Figure 4. Scope of the enantioselective catalytic diacetoxylation of
styrenes.
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À
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lective vicinal dioxygenation of alkenes under entirely
intermolecular reaction control. The reaction proceeds
under mild conditions and provides the corresponding
oxidation products with up to 94% ee. The successful
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for the first time that the broad potential of asymmetric
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Acknowledgments
Financial support for this project was provided from the
Spanish Ministry for Economy and Competitiveness
(CTQ2011-25027 grant to K.M., and Severo Ochoa Excel-
lence Accreditation 2014-2018 to ICIQ, SEV-2013-0319), the
Deutsche Forschungsgemeinschaft (WO 1924/1-1 to T.H.W.)
and Cellex-ICIQ Programme (fellowship to C.M.). We thank
E. Escudero-Adµn for the X-ray structural analyses.
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Keywords: alkenes · chirality · diacetoxylation ·
hydrogen bonding · hypervalent iodine
How to cite: Angew. Chem. Int. Ed. 2016, 55, 413–417
Angew. Chem. 2016, 128, 422–426
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Received: August 2, 2015
Revised: October 16, 2015
Published online: November 24, 2015
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