Enantioselective Hydroamidation of Enals by Trapping of a Transient Acyl Species

Article abstract of DOI:10.1002/anie.201803556

An enantioselective synthesis of β-chiral amides through asymmetric and redox-neutral hydroamidation of enals is reported. In this reaction, a chiral N-heterocyclic carbene (NHC) catalyst reacts with enals to generate the homoenolate intermediate. Upon highly enantioselective β-protonation through proton-shuttle catalysis, the resulting azolium intermediate reacts with imidazole to yield the key β-chiral acyl species. This transient intermediate provides access to diversified β-chiral carbonyl derivatives, such as amides, hydrazides, acids, esters, and thioesters. In particular, β-chiral amides can be prepared in excellent yield and ee (40 chiral amides, up to 95 % yield and 99 % ee). This modular strategy overcomes the challenge of disruption of the highly selective proton-shuttling process by basic amines.

Full text of DOI:10.1002/anie.201803556

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Accepted Article
Title: Enantioselective hydroamidation of enals by trapping of a
transient acyl species
Authors: Pengfei Yuan, Jiean Chen, Jing Zhao, and Yong Huang
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201803556
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Enantioselective hydroamidation of enals by trapping of a
transient acyl species
Pengfei Yuan,[a] Jiean Chen,*[a] Jing Zhao,*[b] Yong Huang*[a]
Dedicated to Professor David W. C. MacMillan on the occasion of his 50th birthday ((optional))
Abstract: An enantioselective synthesis of β-chiral amides by
asymmetric and redox-neutral hydroamidation of enals is reported.
In this reaction, a chiral N-heterocyclic carbene (NHC) catalyst
reacts with enals to generate the homoenolate intermediate. Upon
highly enantioselective β-protonation via proton-shuttle catalysis, the
resulting azolium intermediate reacts with imidazole to yield the key
β-chiral acyl species. This transient intermediate provides access to
diversified β-chiral carbonyl derivatives, such as amides, hydrazides,
acids, esters, and thioesters. In particular, β-chiral amides can be
prepared in excellent yield and ee (40 chiral amides, up to 95% yield
and 99% ee). This modular strategy overcomes the challenge of the
disruption by basic amines of the high selective proton-shuttling
process.
of enals (Scheme 1c).
Amides are versatile synthetic intermediates that can be
converted to various heterocylic scaffolds. They are also an
essential functionality common in biomolecules and
pharmaceutical agents.[1] Replacement of natural amino acid
residues with a chiral amide often yields analogues with
increased conformal rigidity, enhanced metabolic stability, and
improved membrane permeability.[2] Chiral amides containing a
β-stereogenic center comprise an important class of natural
amino acid surrogates.[3] Consequently, tremendous efforts have
been directed toward devising synthetic routes to β-chiral
amides using enantioselective catalysis. So far, the two
established general approaches to β-chiral amides require
reductive environments. Asymmetric 1,4-conjugate addition of
organometallic reagents, catalyzed by transition metals, allows
convenient installation of a β-substituent to α,β-unsaturated
amides with high enantioselectivity (Scheme 1a).[4] Alternatively,
various β-disubstituted α,β-unsaturated amides can be
hydrogenated to generate the desired β-chiral methine motif
(Scheme 1b).[5] However, both the reductive nature of these
transformations, and the involvement of coordinative transition
metal species limit the reaction scope. Reactions involving
substrates containing basic nitrogen atoms in general, and
heterocycles in particular, are very challenging. In this paper, we
report our findings of an organocatalytic and redox-neutral
pathway to β-chiral amides via enantioselective hydroamidation
Scheme 1. Asymmetric synthesis of β-chiral amides.
From the perspective of redox economy, the oxidation
state of enals is the same as that of amides, acids and esters
and direct conversion of enals to amides is a redox-neutral
process. Instead of hydride addition, an alternative process can
be envisioned linking
a direct protonation process with
nucleophilic addition. Conversion of enals to homoenaloates,
mediated by NHCs, is a well-established strategy with which to
generate a nucleophilic β-carbon.[6] Upon β-protonation and
tautomerization, the resulting acyl azolium intermediate can
react with nucleophiles to yield β-chiral carboxylic acid
derivatives. Recently, asymmetric β-protonation/esterification
and β-protonation/thioesterification were reported by Scheidt
and by our laboratory.[7] During our studies, we discovered that
enantiomeric control of the β-protonation is very sensitive to the
choice of the proton-shuttle. Bridgehead tertiary amines,
DABCO and quinuclidine for example, exhibit unparalleled
reaction efficiency and selectivity and, in contrast, simple tertiary
amines and pyridine derivatives afford slow reactions and low
enantioselectivity. The sensitivity to basic sites makes
enantioselective hydroamidation far more challenging, as amine
substrates will inevitably compete for protons and form non-
selective proton shuttles. In addition, primary and secondary
amines react with enals in several side pathways, such as
imine/iminium formation and aza-Michael addition.[8] As a result,
few reports are available of asymmetric hydroamidation of enals.
In order to address this issue, we proposed a strategy
which uses a transient acyl trap (TAT).[9] Ideally, a TAT should
be far less basic than quinuclidine, whose conjugate acid has
[a]
[b]
Mr. P. Yuan, Prof. Dr. J. Chen and Prof. Dr. Y. Huang
State Key Laboratory of Chemical Oncogenomics, Key Laboratory
of Chemical Genomics, Peking University, Shenzhen Graduate
School
Shenzhen, 518055 China
E-mail: chenja@pkusz.edu, huangyong@pkusz.edu.cn
Prof. Dr. J. Zhao
State Key Laboratory of Coordination Chemistry, Institute of
Chemistry and BioMedical Sciences, School of Chemistry and
Chemical Engineering, Nanjing University, Nanjing 210093, China
Email: jingzhao@nju.edu.cn
pKa
= 11, and protons in the reaction system, located
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
exclusively at the bridgehead nitrogen. At the same time, the
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TAT needs to be sufficiently nucleophilic[10] toward the acyl
azolium intermediate, in order to lead to effective NHC turnover.
As shown in Scheme 2, although primary amines are
nucleophiles competent for NHC turnover, they are
indistinguishable from quinuclidine in terms of pKa. Similarities
in basicity will lead to several active proton-shuttling species and
compromise asymmetric induction. Azoles are several orders of
magnitude less basic than amines and are known to react with
acyl azolium species leading to NHC turnover.[1c,7c,7f,11] However,
basicity and nucleophilicity vary largely depending on the nature
of the heterocycle. We decided to search for an azole suitable
as a TAT that can effectively promote the enantioselective
hydroamidation reaction with good enantiomeric control.
yield was observed using DMAP as a TAT. Although DMAP has
been frequently employed as an acyl transfer catalyst for NHC
turnover, the corresponding acetyl pyridinium species is quite
unstable and decomposes before the addition of amine (entry 9).
Pyrrole failed to promote the hydroamidation (entry 10) but high
yield was observed using 1,2,3-triazole as the TAT. However,
moderate ee was obtained. The relatively high acidity of 1,2,3-
triazole (pKa = 9.4) likely interferes with the proton-shuttling
process. In summary,
a delicate balance of acidity and
nucleophilicity is vital to secure the highly enantioselective β-
protonation and the efficient acyl trapping process. Increasing
the reaction temperature to 40 °C further improved the reaction
yield to 92% (entry 12).
Table 1. Identification of a suitable TAT for asymmetric hydroamidation.[a]
entry
TAT
PS
T (°C)
30
yield (%)[b]
ee (%)[c]
1
—
DABCO
DABCO
DABCO
Et3N
trace
74
12
60
17
53
70
88
9
-
2
imidazole
imidazole
imidazole
imidazole
imidazole
HOAT
30
93
56
59
58
92
7
3[d]
4
30
30
5
DIPEA
30
Scheme 2. Balance of basicity and nucleophilicity for asymmetric
hydroamidation of enals. [a] The pKa values were obtained from the ibond
database (http://ibond.nankai.edu.cn) and the Nu values were obtained from
Mayr’s database (http://www.cup.lmu.de/oc/mayr/reaktionsdatenbank)
6
quinuclidine
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
30
7
30
8
HOBT
30
6
9
DMAP
30
-
β-Methyl cinnamaldehyde and benzylamine were chosen
as standard substrates for an initial investigation of reaction
conditions (Table 1). Biphenol-derived phosphoric acid (PA) in
combination with DABCO, was used as the proton-shuttling
catalyst (PSC). In the absence of a TAT, little hydroamidation
product was observed (entry 1) and the major side product was
identified by GC-MS analysis as the corresponding imine. We
found that imidazole is an excellent TAT for hydroamidation,
yielding the desired β-chiral amide (1) in 74% yield and 93% ee
(entry 2). The weak basicity of imidazole probably results in
exclusive residence of protons on DABCO. In the absence of PA,
the reaction was significantly slower and less selective,
indicating the essential role of the PSC (entry 3).[7f] Replacement
of DABCO with other tertiary amines led to low conversion and
ee, with the exception of quinuclidine, which also contains a
bridgehead nitrogen (entries 4-6). Other TATs were also
examined and we found that carboxylic acid activators, HOAT[12]
and HOBT, were both good TAT agents, but the reactions
proceeded in nearly a racemic manner (entries 7 and 8). The
pKa values of HOAT and HOBT (3.3 and 4.6, respectively) are
much lower than that of the conjugate acid of DABCO (pKa =
8.9), making non-selective proton transfer predominant. Low
10
11
12
13
pyrrole
30
6
48
68
95
86
1,2,3-triazole
imidazole
imidazole
30
98
92[e]
21
40
50
[a] Reactions conditions: a solution of enal (0.1 mmol), TAT (0.1 mmol), PS (0.2
mmol), NHC precursor (0.01 mmol) and PA (0.01 mmol) in toluene was stirred at
the indicated temperature overnight. The reaction was cooled to r.t. and
benzylamine (0.12 mmol) was added. The mixture was stirred at r.t. for another
10 h. [b] Determined by GC analysis using biphenyl as internal standard. [c]
Determined by chiral HPLC. [d] PA was omitted from the reaction. [e] Isolated
yield.
With the optimized reaction conditions for the asymmetric
hydroamidation in hand, we surveyed the scope of nitrogen
nucleophiles (Table 2). Primary alkyl amines are well tolerated
and the corresponding β-chiral amides are obtained in good to
high yield and excellent ee (Products 1-8). Enals with a sterically
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demanding β-alkyl group, such as isopropyl (product 8), react
with considerably lower enantioselectivity. The cyclic amines
piperidine (9), morpholine (10) and thiazolidine (11) react, giving
comparable yield and selectivity. The reactions involving acyclic
secondary amines are very slow, for steric reasons. The
transient acyl imidazole exhibits good reactivity towards weaker
nitrogen nucleophiles, such as anilines and pyrazoles (products
12-15). Pyrazole is also an effective TAT and the β-chiral acyl
pyrazole (15) is an isolable acyl transfer reagent. It reacts with
various amines, hydrazines and acyl hydrazines to deliver β-
chiral amides and hydrazides (16, 17, 20). The reaction can be
extended to complex drug scaffolds. A reaction employing both
a structurally exotic enals and a hydrazide affords the estrone
analogue (19) containing a β-chiral hydrazide functionality.
Various functional groups, such as ketone, indole, ether and
chlorine, are tolerated. By changing the PSC from DABCO to
quinuclidine, products containing a β-trifluoromethyl group can
be prepared in high yield and ee. (compounds 20-22). E-enals
lead to products with R configuration, except for β-CF3, for which
the olefin geometry is opposite. When a mixture of E/Z (1/1)
isomers were subjected to the standard reaction conditions, the
product was obtained in 63% yield and 80% ee. Control
experiments show that the Z-isomer reacts considerably slower
and isomerization from Z to E also occurs during the reaction.
We found that this isomerization can be accelerated by UV light.
Consequently, performing the reaction under a 365 nm UV lamp
significantly improves the enantioselectivity for substrates with
geometric isomers. This method represents a major advantage
for starting materials that are difficult to prepare as pure E-
isomers.
[a] The reaction was performed at 20 oC. [b] Pyrazole was used as TAT
instead of imidazole. [c] Quinuclidine was used as PSC instead of DABCO, the
reaction was conducted at 0 oC.
Table 2. Scope of nitrogen nucleophiles.
We next examined the scope of the enals. Compounds
containing heterocyclic moieties are challenging substrates, due
to catalyst deactivation by coordination, for both transition metal-
catalyzed hydrogenation and Michael addition reactions.
Accordingly, we paid special attention to enals with a β-
heteroaryl substituent (Table 3). The presence of additional
basic sites appears not to affect the highly selective protonation
process. Moderate to good yields and high ee are obtained for
enals with various substituted β-pyridyl groups (compounds 23-
27). Other β-heteroaryl systems, including benzofuryl, furyl,
thienyl and benzothienyl, are well tolerated (compounds 28-34).
Remarkably, the use of propargyl amine leads to a product with
a terminal alkyne moiety (33), a functional group incompatible
with previous transition metal-catalyzed processes.
Table 3. Scope of enals containing a heterocyclic moiety.
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To further demonstrate the synthetic utility of this reaction,
we converted the β-chiral hydrazide products into several
pharmacologically relevant heteroarenes (Scheme 3a).[13]
Products 16 and 17 were transformed to the corresponding
analogues of 1,3,4-oxadiazole-2(3H)-thione (44), 1,2,4-triazole
(45), 1,3,4-oxadiazole (46) and 1,3,4-thiadiazole (47). The
transient β-chiral acyl imidazole species can also be intercepted
by non-nitrogen nucleophiles. This maneuver leads to
a
streamlined synthesis of various β-chiral carboxylic acid
derivatives. Basic workup affords the carboxylic acid 48.
Treatment with t-butyl hydroperoxide gives the perester 49. The
corresponding esters and thioesters are obtained using alcohols,
phenols and thiols, respectively (compounds 50-53). All
derivatization reactions proceed with little loss of optical purity.
[a] 5.0 equiv. DABCO was used.
We applied this transformation to the synthesis of novel
peptide mimetics by replacing one natural amino acid with a β-
chiral amide (Table 4). Despite their attenuated nucleophilicity, a
series of amino acid esters, as the hydrochlorides, react
smoothly with the transient β-chiral acyl imidazole, affording the
desired peptidomimetics in moderate yield and excellent
stereoselectivity. Amino acids with either L- or D-configuration
show little or no discrepancy in reactivity or selectivity. Serine,
cysteine, tyrosine and lysine were protected before the ligation.
A tripeptide mimetic (43) was prepared using Gyl-Gyl-OMe, in
63% yield and 95% ee. Multiple hydrogen-bond donors and
acceptors present in the substrate do not interfere with the
delicate proton-shuttling process. It is perceivable that this new
ligation method might be applied to longer peptides and offer a
unique strategy for the modification of the N-terminus of
biologically relevent peptides and peptidomimetics.
Scheme 3. Derivatization of β-chiral hydrazides and the transient acyl
imidazole species. [a] CS2, KOH, EtOH, reflux. [b] N-methyl-N-nitroso-N’-
nitroguanidine, H2O; KOH, H2O, reflux; acidified with 68% HNO3. [c] POCl3,
reflux. [d] Lawesson’s reagent, DCM, reflux.
In summary, we have developed a new approach to asymmetric
hydroamidation of enals by tethering NHC catalysis, proton-
shuttling catalysis and a transient-acyl-trapping strategy. The
use of a TAT overcomes the longstanding problem of basic
amines disrupting the enantioselective protonation step. The
combination of an NHC, a bridgehead nitrogen base (PSC) and
an azole (TAT) constitutes a robust system for asymmetric β-
protonation of various enals. The transient acyl azole species
can be converted to a wide range of chiral carboxylic acid
derivatives with high enantioselectivity. Synthetic applications
demonstrate that this method can be used for the modification of
peptides and synthesis of chiral heteroarenes. Exploration of this
strategy using biomolecules with more complex molecular
structures is currently in progress.
Table 4. Ligation with amino acids and peptides.
Acknowledgements
This work is financially supported by the National Natural
Science Foundation of China (21622103 for J. Z., 21602007 for
J. C. and 21572004 for Y. H.), the China Postdoctoral Science
Foundation (2017T100010 for J. C) and Shenzhen Basic
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Keywords: proton-shuttling catalysis • asymmetric
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Entry for the Table of Contents (Please choose one layout)
Layout 1:
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Pengfei Yuan,[a] Jiean Chen,*[a] Jing
Zhao,*[b] Yong Huang*[a]
Enantioselective hydroamidation of
enals by trapping of a transient acyl
species
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