Highly Acidic Conjugate-Base-Stabilized Carboxylic Acids Catalyze Enantioselective oxa-Pictet–Spengler Reactions with Ketals

Article abstract of DOI:10.1002/anie.201912677

Acyclic ketone-derived oxocarbenium ions are involved as intermediates in numerous reactions that provide valuable products, however, they have thus far eluded efforts aimed at asymmetric catalysis. We report that a readily accessible chiral carboxylic acid catalyst exerts control over asymmetric cyclizations of acyclic ketone-derived trisubstituted oxocarbenium ions, thereby providing access to highly enantioenriched dihydropyran products containing a tetrasubstituted stereogenic center. The high acidity of the carboxylic acid catalyst, which exceeds that of the well-known chiral phosphoric acid catalyst TRIP, is largely derived from stabilization of the carboxylate conjugate base through intramolecular anion-binding to a thiourea site.

Full text of DOI:10.1002/anie.201912677

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Accepted Article
Title: Highly acidic conjugate-base-stabilized carboxylic acids catalyze
enantioselective oxa-Pictet–Spengler reactions with ketals
Authors: Zhengbo Zhu, Minami Odagi, Chenfei Zhao, Khalil A. Abboud,
Helmi Ulrika Kirm, Jaan Saame, Märt Lõkov, Ivo Leito, and
Daniel Seidel
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201912677
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10.1002/anie.201912677
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Highly acidic conjugate-base-stabilized carboxylic acids catalyze
enantioselective oxa-Pictet–Spengler reactions with ketals
Zhengbo Zhu,[a],+ Minami Odagi, [a],[b],+ Chenfei Zhao,[c] Khalil A. Abboud,[d] Helmi Ulrika Kirm,[e] Jaan
Saame,[e] Märt Lõkov,[e] Ivo Leito,[e] and Daniel Seidel[a],*
Abstract: Acyclic ketone-derived oxocarbenium ions, intermediates
that are involved in numerous reactions providing valuable products,
have thus far eluded efforts aimed at asymmetric catalysis. We report
that a readily accessible chiral carboxylic acid catalyst exerts control
over asymmetric cyclizations of acyclic ketone-derived trisubstituted
oxocarbenium ions, achieving the synthesis of highly enantioenriched
dihydropyran products containing
a tetrasubstituted stereogenic
center. The high acidity of the carboxylic acid catalyst, exceeding that
of the well-known chiral phosphoric acid catalyst TRIP, is largely
derived from stabilization of the carboxylate conjugate base via
intramolecular anion-binding to a thiourea site.
Oxocarbenium ions, ubiquitous and highly reactive intermediates
in numerous synthetically useful transformations generating new
stereogenic centers, have long represented a challenge to
asymmetric
catalysis.
Compared
to
organocatalytic
enantioselective reactions involving iminium ions, those
proceeding via transient oxocarbenium ions remain significantly
less developed (Scheme 1a).
Whereas organocatalytic
enantioselective transformations of primary-amine-derived
iminium ions are typically controlled via hydrogen bonding
interactions between the catalyst and the NH proton of the
iminium ion, oxocarbenium ions lack such obvious binding sites
for interaction with a catalyst. Although significant progress has
been made in recent years, enabled by the emergence of
Brønsted acid,[1] cooperative,[2] and chiral anion/anion-binding
catalysis,[3] most organocatalytic enantioselective methods
reported to date have been shown to accommodate only cyclic
oxocarbenium ions. With few exceptions,[4] most cyclic
[a]
Z. Zhu, Dr. M. Odagi, Prof. Dr. D. Seidel
Center for Heterocyclic Compounds, Department of Chemistry
University of Florida, Gainesville, FL 32611 (USA)
E-mail: seidel@chem.ufl.edu
Homepage: http://seidel-group.com/
Dr. M. Odagi
Department of Biotechnology and Life Science, Graduate School of
Technology, Tokyo University of Agriculture and Technology, 2-24-
16, Naka-cho, Koganei city, 184-8588, Tokyo, Japan
Dr. C. Zhao
Scheme 1. Oxocarbenium ions in asymmetric catalysis and previous examples
of catalytic enantioselective oxa-Pictet–Spengler reactions.
[b]
oxocarbenium ion intermediates are of the relatively stabilized
pyrylium- or (iso)chroman-type.[5]
Of those, the highly
[c]
[d]
[e]
+
Department of Chemistry and Chemical Biology, Rutgers, The State
University of New Jersey, Piscataway, NJ 08854 (USA)
Dr. K. A. Abboud
Center for X-ray Crystallography, Department of Chemistry
University of Florida, Gainesville, FL 32611 (USA)
H. U. Kirm, J. Saame, Dr. M. Lõkov, Prof. Dr. I. Leito
Institute of Chemistry, University of Tartu, Tartu, Estonia.
enantioselective formation of tetrasubstituted stereogenic centers
has been achieved in only two types of transformations.[6]
Catalytic
enantioselective
reactions
involving
acyclic
oxocarbenium ions remain less common,[7] and there appears to
be only a single example involving an acyclic trisubstituted
oxocarbenium ion in which the corresponding product was
obtained with 47% ee.[8] Here, the challenge for the chiral
catalyst having to distinguish between two potentially similarly
sized carbon-based substituents (vs. distinguishing between a
carbon substituent and a hydrogen atom as in reactions of
disubstituted oxocarbenium ions), is exacerbated by the fact that,
unlike their cyclic counterparts, an acyclic, trisubstituted
These authors contributed equally to this work.
Supporting information for this article is given via a link at the end of
the document.
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oxocarbenium ion can exist as a mixture of E/Z isomers. Among
reactions proceeding via acyclic oxocarbenium ions, a particularly
attractive method for the formation of chiral dihydropyrans is the
oxa-Pictet–Spengler reaction.[9] Only three examples of highly
enantioselective oxa-Pictet–Spengler reactions have been
reported.[10] Some of us achieved enantioselective oxa-Pictet–
Spengler reactions with tryptophol and aldehydes via a dual
catalysis approach involving an amine HCl salt (the chirality of
which is irrelevant) and a chiral bisthiourea compound (Scheme
and other processes that proceed via the intermediacy of iminium
ions.[14] However, 6a had never been employed successfully in
reactions involving oxocarbenium ions. Gratifyingly, 6a was
found to be a highly active catalyst in the title reaction, providing
product 3a in excellent yield and notable ee after a reaction time
of only 30 min (entry 3). Introduction of an additional bromine
substituent on the thiourea aryl group resulted in the presumably
more acidic catalyst 6b, which displayed higher reactivity and
selectivity than 6a (entry 4). This trend did not hold for catalyst
6c containing a cyano substituent instead of bromine (entry 5).
Here, the significantly lower reactivity is likely the result of 6c’s
low solubility (a heterogeneous reaction mixture was observed).
Relatively minor structural variations of the thiourea aryl group led
to the identification of more active and selective catalysts (entries
6–11). A dramatically improved reaction outcome was observed
with catalyst 6d, which provided product 3a in 95% yield and 84%
ee following a reaction time of just 10 min at room temperature
(entry 6). At –30 °C, a significantly slower but still reasonable
reaction rate was maintained that allowed for the isolation of 3a in
97% yield and 94% ee (entry 12).[15]
1b).[10a]
enantioselective
Simultaneously, the List group reported catalytic
oxa-Pictet–Spengler reactions with β-
phenylethanols and aldehydes, employing an imidodiphosphoric
acid catalyst (Scheme 1c).[10b] Scheidt and coworkers recently
disclosed enantioselective oxa-Pictet–Spengler cyclizations with
preformed enol ethers containing a protected indole moiety,
applying
a
cooperative catalysis concept that utilizes
a
combination of a chiral phosphoric acid and an achiral urea
catalyst (Scheme 1d).[10c] Here we report the first examples of
highly enantioselective oxa-Pictet–Spengler reactions that
provide dihydropyran products containing
stereogenic center (Scheme 1e).
a tetrasubstituted
The scope of the catalytic enantioselective oxa-Pictet–
Spengler reaction with ketals is depicted in Scheme 3.
Substitution of the tryptophol indole ring with electronically
diverse groups on the 4-, 5-, 6-, and 7-positions was well
tolerated (products 3a–f). Different aryl groups on the ketal
reaction partner were also accommodated (products 3g–m).
High enantioselectivity was maintained with the dimethoxyketal
derived from propiophenone (product 3n).
Other aliphatic
substituents containing terminal functional groups were also
tolerated (products 3o, 3p). Pyrrole-containing ketal provided
product 3q with good ee, and alkyl-alkenyl ketals were also found
to be viable reaction partners (products 3r, 3s). Furthermore,
spirocyclic product 3t was obtained in good enantioselectivity.
The proposed catalytic cycle for the oxa-Pictet–Spengler
cyclization is shown in Scheme 4a. Accordingly, the reaction is
initiated by protonation of ketal 2a by the acid catalyst HA* (e.g.,
6d) to provide ion pair 7, followed by elimination of methanol and
concomitant formation of oxocarbenium intermediate 8. The
latter then reacts with tryptophol (1a) to form mixed ketal 9.
Protonation of 9 by HA* followed by loss of methanol can give
rise to two stereoisomeric oxocarbenium ions (10 and 10′).
Presumably, only one of these isomers is
a competent
Scheme 2. Reaction development. Reactions were performed with 0.1 mmol
intermediate for the subsequent cyclization to form ion pair 11.
Deprotonation/rearomatization furnishes product 3a and releases
HA*. Several experiments provide support for this scenario
(Scheme 4b). The intermediacy of 8 is highly likely, given that the
use of enolether 12 as an alternative starting material to ketal 2a
provided nearly identical results in the catalytic reaction. Mixed
ketal intermediate 9 could be isolated in low yield under carefully
controlled conditions. Exposure of ketal 9 to the standard
reaction conditions provided 3a with very similar levels of
of 1a and 1.2 equiv of 2a. All yields correspond to isolated yields. The ee
a
values were determined by SFC analysis.
Reaction was performed at –30 °C.
As summarized in Scheme 2, tryptophol (1a) and
acetophenone-derived ketal 2a were utilized as the model
substrates in the development of the proposed oxa-Pictet–
Spengler reaction. The bisthiourea-HCl catalyst combination (4),
previously utilized in asymmetric oxa-Pictet–Spengler reactions
with acetals,[10a] exhibited favorable reaction rates and provided
product 3a in good yield but negligible ee (entry 1). The widely
utilized phosphoric acid catalyst (S)-TRIP (5)[11] was found to be
relatively inactive, furnishing 3a with slightly improved ee (entry 2).
We then turned our attention to carboxylic-acid-thiourea 6a, a
catalyst that was designed with the notion that its thiourea
functionality would stabilize the carboxylate conjugate base via
intramolecular anion-binding, thus resulting in a highly acidic
carboxylic acid catalyst.[1i],[12] Catalyst 6a was previously shown
to facilitate catalytic enantioselective Pictet–Spengler reactions[13]
efficiency.
This seemingly rules out a scenario in which
tryptophol (1a) first engages 8 via the indole C2-carbon with
concomitant C–C bond formation (not shown). Another insight
was obtained in a reaction with N-methyltryptophol (13). In
addition to a drastically reduced reaction rate, the corresponding
product 14 was obtained in racemic fashion, consistent with
related studies.[10a,13b,16] This strongly suggests that an interaction
of the indole NH proton with the catalyst is a key feature of at
least one critical intermediate in the catalytic cycle.
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Scheme 3. Reaction scope. Reactions were performed with 0.25 mmol of 1 and 1.2 equiv of 2. All yields correspond to isolated yields. The ee values were
a
determined by SFC analysis. The absolute configuration of product 3d was assigned by X-ray crystallography. All other compounds were assigned by analogy.
Catalyst 6i was used.
Scheme 4. Proposed catalytic cycle (a) and mechanistic studies (b).
In order to identify a possible correlation between catalyst
activity and acidity, and to determine the impact of conjugate-
base-stabilization on the pKa values of our chiral carboxylic acid
catalysts, detailed acidity measurements were conducted for
several catalysts and control compounds. Due to the multiple
advantages of acetonitrile,[17] all acidity measurements were
conducted in this solvent. The results of this study are
summarized in Figure 1, along with literature values of several
known acids for comparative purposes. Catalyst 6a was
determined to have a pKa of 12.4 in acetonitrile, whereas the
more active and selective catalyst 6d was found to be slightly
less acidic with a pKa of 12.7. To put these values into
perspective, 6a and 6d are about as acidic as trifluoroacetic
acid,[18] and thus one order of magnitude more acidic than the
widely used chiral phosphoric acid catalyst (S)-TRIP (5).[19] The
pKa of the truncated carboxylic acid 15 lacking the thiourea
moiety is 19.2 while the pKa of the truncated thiourea 16 lacking
the carboxylic acid moiety is 24.3. Remarkably, these findings
imply that conjugate-base-stabilization by the weakly acidic
thiourea is responsible for an increase in carboxylic acid acidity
of nearly 7 orders of magnitude! Moreover, dual hydrogen
bonding interactions of the carboxylate anion with both thiourea
NH protons appear to be crucial, as judged by the fact that
trifluoroacetamide derivative 17 (pKa = 18.1), possessing only
one hydrogen bond donor site, is only one order of magnitude
more acidic than 15.
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In conclusion, we have achieved the first highly enantiose-
lective reactions of acyclic trisubstituted oxocarbenium ions.
The unique carboxylic acid catalysts employed in this study
derive their unusually high acidity (exceeding that of the chiral
phosphoric acid (S)-TRIP by one order of magnitude) from
conjugate-base-stabilization via intramolecular anion binding to
a thiourea receptor, an interaction that is responsible for an
increase in acidity of nearly 7 orders of magnitude.
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Acknowledgements
This material is based upon work supported by the National
Science Foundation under CHE–1856613 (grant to D.S.). M.O.
thanks the Program for Advancing Strategic International
Networks to Accelerate the Circulation of Talented Researchers
(R2801) from the Japan Society for the Promotion of Science
[8]
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(JSPS).
We further acknowledge the National Science
Foundation (grant# 1828064 to K.A.A.) and the University of
Florida for funding the purchase of the X-ray equipment. The
work at Tartu was supported by the EU through the European
Regional Development Fund (TK141 “Advanced materials and
high-technology devices for energy recuperation systems”) and
by the institutional research grant IUT20-14 from the Estonian
Research Council.
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Keywords: Asymmetric catalysis • Brønsted acid catalysis•
oxocarbenium ions • oxa-Pictet–Spengler reaction • pKa
determination
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Entry for the Table of Contents
COMMUNICATION
Zhengbo Zhu, Minami Odagi, Chenfei
Zhao, Khalil A. Abboud, Helmi Ulrika
Kirm, Jaan Saame, Märt Lõkov, Ivo
Leito, and Daniel Seidel
Page No. – Page No.
Highly acidic conjugate-base-
stabilized carboxylic acids catalyze
enantioselective oxa-Pictet–Spengler
reactions with ketals
A chiral carboxylic acid catalyst exerts control over asymmetric cyclizations of
acyclic ketone-derived trisubstituted oxocarbenium ions, achieving the synthesis of
highly enantioenriched dihydropyran products containing
a tetrasubstituted
stereogenic center. The high acidity of the carboxylic acid catalyst, exceeding that
of the well-known chiral phosphoric acid catalyst TRIP, is largely derived from
stabilization of the carboxylate conjugate base via intramolecular anion-binding to a
thiourea site.
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