Asymmetric cross-dehydrogenative coupling enabled by the design and application of chiral triazole-containing phosphoric acids

Article abstract of DOI:10.1021/ja407410b

This report describes the development of an enantioselective C-N bond-forming reaction to produce 1,2,3,4-tetrahydroisoquinoline-derived cyclic aminals catalyzed by chiral phosphate anions. Central to the success of this goal was the design of a library of 3,3′-triazolyl BINOL-derived phosphoric acids capable of forming attractive hydrogen-bonding interactions with the peptide-like substrate. We envision this work will offer an alternative to the conventional strategy of increasing catalyst steric bulk to improve enantioselectivity with BINOL-derived phosphoric acids.

Full text of DOI:10.1021/ja407410b

Communication
pubs.acs.org/JACS
Asymmetric Cross-Dehydrogenative Coupling Enabled by the Design
and Application of Chiral Triazole-Containing Phosphoric Acids
Andrew J. Neel, Jorg P. Hehn, Pascal F. Tripet, and F. Dean Toste*
̈
Department of Chemistry, University of California, Berkeley, California 94720, United States
S
* Supporting Information
Scheme 1. Enantioselective CDC Hypothesis
ABSTRACT: This report describes the development of
an enantioselective C−N bond-forming reaction to
produce 1,2,3,4-tetrahydroisoquinoline-derived cyclic ami-
nals catalyzed by chiral phosphate anions. Central to the
success of this goal was the design of a library of 3,3′-
triazolyl BINOL-derived phosphoric acids capable of
forming attractive hydrogen-bonding interactions with
the peptide-like substrate. We envision this work will
offer an alternative to the conventional strategy of
increasing catalyst steric bulk to improve enantioselectivity
with BINOL-derived phosphoric acids.
n recent years, chiral anions have seen increasing application
Ias stereocontrolling elements in catalytic asymmetric
reactions.1 Theoretically, chiral counteranion catalysis has the
potential to be a general strategy, as the only prerequisite for
asymmetric induction is the presence of a cationic reaction
intermediate capable of forming a tight ion pair with the chiral
counteranion. Among the catalysts employed to this end, the
conjugate bases of axially chiral phosphoric acids (PAs), initially
reported by Akiyama and Terada,2 have enjoyed considerable
success in both transition metal-catalyzed3 and metal-free
reactions.4 Although controversy can exist as to whether the
association between the catalyst and substrate is purely
electrostatic in nature,1,5 this concept has provided an
intriguing approach to reaction design.
Our group has an ongoing interest in applying this strategy
to outstanding challenges in organic synthesis. To this end, we
recognized that chiral counteranion catalysis might provide a
novel approach to enantioselective cross-dehydrogenative
coupling (CDC), a term coined by Li6a to describe the
functionalization of C−H bonds alpha to heteroatoms in the
presence of a hydrogen acceptor (Scheme 1A). To date, this
methodology has proven amenable to a range of nucleophiles
and oxidants,6 including several recent reports of enantiose-
lective variants.7 Mechanistically, CDC reactions are proposed
to proceed via initial substrate oxidation to a cationic,
unsaturated intermediate (1) that undergoes subsequent
inter- or intramolecular nucleophilic attack.8 Given our group’s
recent success in developing enantioselective halogenation
reactions by exploiting chiral phosphate anion phase-transfer
catalysis with cationic halogenating reagents,9 we envisioned
that a chiral phosphate (2, Scheme 1B) could undergo anion
exchange with an appropriately chosen cationic oxidant,
ensuring that the phosphate would be in close proximity to
form a tight ion-pair (3) with the substrate upon oxidation.
Preferential attack on one of the prochiral faces of the resulting
ionic complex would provide an enantioenriched product (4)
and release the chiral phosphate.
We elected to initiate our studies using oxopiperidinium salts
as the cationic oxidants,10 as these reagents have demonstrated
utility in a number of dehydrogenative coupling processes,11
although no asymmetric variants have been reported to date.
Thus, beginning with amide-tethered tetrahydroisoquinoline
substrate 5a and oxoammonium salt 7, we screened a number
of conventional axially chiral PAs (Table 1). However, none of
the catalysts initially tested afforded useful levels of
enantioselectivity, despite providing promising conversions to
the desired product 6a (Table 1, entries 1−5). We reasoned
that although the putative substrate−phosphate complex 3 may
be forming, the chiral environment created by these catalysts
was inadequate to differentiate the prochiral faces of the
substrate, leading us to consider alternative interactions beyond
sterics that might influence enantioselectivity.
In chiral PA/phosphate catalysis, asymmetric induction has
generally been achieved by strategically installing bulky groups
that serve to project the catalyst’s axial chirality (Figure 1A),
Received: July 18, 2013
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ja407410b | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
from the phosphate moiety, providing an alternative type of
organizational element (Figure 1C). With respect to both
modularity and function, the 1,2,3-triazole seems well suited to
this purpose.15
Table 1. Selected Catalyst Optimization Data for
Enantioselective CDC Amidation
a
The advent of click chemistry,16 in particular the copper-
catalyzed azide/alkyne cycloaddition (CuAAC),17 has provided
a tool for rapid generation of 1,2,3-triazole-containing
compounds that have found widespread application. From
the standpoint of modular catalyst design, the click chemistry
approach is ideal in that the broad alkyne/azide scope allows
for the facile preparation of numerous sterically and electroni-
cally diverse derivatives from a common intermediate. In
addition to synthetic accessibility, the 1,2,3-triazole displays
interesting hydrogen-bonding properties, as exemplified by its
ability to serve as an effective anion binder18 and peptide bond
surrogate.19 With respect to this latter feature, we hypothesized
that, in addition to the ionic phosphate−substrate association,
the amide bond-containing substrate 5 might undergo attractive
hydrogen-bonding interaction with the triazole, resulting in
additional rigidity within the chiral pocket created by the
catalyst and stabilization of one diastereomeric transition state.
To this end, a library of 3,3′-triazolyl-BINOL-derived PAs
was prepared using an operationally simple two-pot procedure
(Scheme 2, 9a−l). In this manner, all derivatives were
b
c
entry
catalyst
conversion (%)
ee (%)
1
2
(S)-C8-TRIP
(S)-TCYP
(R)-STRIP
(R,R)-Ph-DAP
(S)-VAPOL PA
(S)-9b
86
95
64
69
97
99
92
92
91
75
8
16
30
3
d
4
−10
5
31
6
−69
−78
−80
−77
−81
−84
nd
7
(S)-9g
8
(S)-9h
9
(S)-9i
10
(S)-9l
e
f
11
(S)-9l
91(83)
12
none
82
a
b
c
See Supporting Information for complete optimization data.
Determined by HPLC using 1,4-dinitrobenzene internal standard.
Determined by chiral HPLC. Negative sign indicates that opposite
enantiomer predominates. p-Xylene was used as solvent with 5 mol %
a
d
Scheme 2. Synthesis of Catalyst Library
e
f
catalyst. Value in parentheses reflects isolated yield.
a
See Supporting Information for detailed experimental procedures and
reaction conditions.
synthesized from a single intermediate (bis-alkyne 8), allowing
rapid access to catalysts bearing a range of N-1 aryl and alkyl
substituents. It was subsequently determined that lipophilic
groups at the 6 and 6′ positions were necessary in order to
improve the solubility of 9 in common organic solvents.
We were pleased to find that when these novel catalysts were
tested in our model reaction, a significant increase in
enantioselectivity was observed while maintaining excellent
levels of conversion (Table 1, entries 6−11). Notably, the
major enantiomer produced using the triazolyl PA catalysts was
opposite to that produced using the purely steric PA catalysts in
all cases (vide infra). Furthermore, we were surprised to
discover that the reaction reached comparable conversion even
in the absence of the PA (Table 1, entry 12), suggesting a
remarkable acceleration of the enantiodetermining step in the
presence of the catalyst. A series of experiments revealed that
N-acyl oxoammonium salt 7, tribasic sodium phosphate, and p-
xylene provided the optimal balance of yield and enantiose-
lectivity (see Supporting Information for details).
Figure 1. Axially chiral PA design principles.
coercing the prochiral substrate into a position within the chiral
pocket that minimizes unfavorable steric interactions with the
catalyst (Figure 1B).12 Thus, achieving high levels of
enantioselectivity often hinges on the identification and
synthesis of catalysts bearing increasingly large substituents.
Although remarkable success has been realized using this
strategy,13 the enzyme-inspired principle of preferentially
stabilizing one diastereomeric transition state via attractive,
non-covalent interactions14 has not been explored in the realm
of PA catalysis, despite having seen great success with other
classes of organic catalysts. In principle, judiciously chosen
atoms or groups incorporated at the 3 and 3′ positions of the
binaphthyl backbone would be appropriately positioned to
form attractive interactions with a substrate at a site remote
B
dx.doi.org/10.1021/ja407410b | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
Using this set of conditions, the scope of this process was
explored. Benzylic groups bearing both electron-rich and
electron-poor groups at the para position were tolerated on
the nucleophilic nitrogen atom (Table 2, 6a−d), resulting in
the absolute configuration of the newly formed stereocenter in
the presence of an existing one.
Having established the utility of catalysts 9 in this CDC
amidation reaction, we wished to gain insight into the role that
the triazole substituents may be playing in asymmetric
induction. Thus, pyrazolyl (10a) and imidazolyl (10b) PAs
were prepared (Scheme 3), which were expected to impose
Table 2. Substrate Scope for Enantioselective CDC
Scheme 3. Enantioselective CDC Using Heterocyclic 1,2,3-
Triazole Isosteres
steric environments similar to that of 9l, but with inherently
different electronic properties. When these isosteric analoges
were tested in the CDC reaction with substrate 5a, similar
levels of conversion were observed, but with significantly
reduced enantioselectivity compared to 9l, albeit with the same
sense of enantioinduction. The observation that 9a−l (Table 1,
entries 1−5 and Supporting Information), 10a, and 10b all
provide the product enantiomer opposite that given by
conventional PAs may be rationalized by either (1) attractive
interactions between the heterocyclic substituents and substrate
that override the selectivity based purely on sterics or (2) a
fundamentally different steric environment created by these
catalysts (Table 1, entries 1−5).20,21 However, the diminished
enantioselectivites afforded by 10a and 10b vs 9l suggest that
electronic rather than steric properties of the triazolyl
substituents in catalysts 9 are primarily responsible for the
high enantioselectivities reported herein.22
In conclusion, we have used click chemistry to synthesize a
library of axially chiral PAs based on BINOL bearing 1,2,3-
triazoles at the 3 and 3′ positions. Using these molecules as
catalysts, we were able to achieve enantioselectivities in a novel
C−N bond-forming reaction that were unattainable using
conventional PAs. These results suggest that, in addition to
being an easily modified catalyst substituent, the triazole may
serve an organizational function other than simply creating a
sterically hindered environment around the catalyst active site.
Future work will be aimed at elucidating the specific
interactions responsible for this divergent selectivity.
a
Isolated yield. All reactions conducted on 0.1 mmol scale with respect
b
c
to substrate. Determined by chiral HPLC. Catalyst 9l gave the
product with 64% ee. Diastereomeric ratio (d.r.) determined by
analysis of crude H NMR spectrum.
d
1
both good yields and enantioselectivities. Furthermore, ortho-
methoxy-substituted benzylic substrate 6e afforded the product
in excellent enantiomeric excess (ee). We next turned our
attention to substrates bearing N-aryl groups. Although only
modest selectivities were observed using N-phenyl substrate 6f
and its 3-methyl-substituted analogue 6g, switching to ortho
substitution (6h) resulted in a dramatic increase in
enantioselectivity, although reactivity was sluggish. A range of
ortho functional groups were tolerated, including naphthyl (6i),
chloro (6j), and, perhaps surprisingly, hydroxyl (6k). More-
over, substrates with bulky alkyl substituents underwent the
transformation with good enantioselectivity (6l, m). Addition-
ally, the tetrahydroisoquinoline N-aryl ring could be substituted
with both electron-donating and -withdrawing groups, while
still maintaining excellent levels of enantioselectivity (6n−p).
Finally, both antipodes of the amino acid valine were
incorporated into the substrate scaffold as their corresponding
methyl esters and subjected to the standard reaction conditions
(Table 2, entries 17 and 18). In the absence of catalyst, a 1:1
mixture of diastereomers was produced. However, when 9h was
employed, L-valine-derived substrate 5q produced the product
6q as a 7:1 mixture of diastereomers, while D-valine-derived
substrate 5r afforded a 3:1 mixture in favor of the opposite
diastereomer 6r, demonstrating the catalyst’s ability to control
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental details and characterization data. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
fdtoste@berkeley.edu
Notes
The authors declare no competing financial interest.
C
dx.doi.org/10.1021/ja407410b | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
̌
G. L.; Wu, J.; Toste, F. D. Nature 2011, 470, 245. (e) Coric,
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I.; List, B.
ACKNOWLEDGMENTS
■
We thank the University of California, Berkeley, Amgen and the
NIHGMS (RO1 GM104534) for financial support. J.P.H.
gratefully acknowledges the support from the German National
Academy of Sciences, Leopoldina, through a postdoctoral
fellowship.
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