Access to Cyclic β-Amino Acids by Amine-Catalyzed Enantioselective Addition of the γ-Carbon Atoms of α,β-Unsaturated Imines to Enals

Article abstract of DOI:10.1002/anie.201908896

Disclosed herein is a new catalytic approach for an efficient access to cyclic β-amino acids widely found in bioactive small molecules and peptidic foldamers. Our method involves addition of the remote γ-carbon atoms of α,β-unsaturated imines to enals by iminium organic catalysis. This highly chemo- and stereo-selective reaction affords cyclic β-amino aldehydes that can be converted to amino acids bearing quaternary stereocenters with exceptional optical purities. Our study demonstrates the unique power of organic catalytic remote carbon reactions in rapid synthesis of functional molecules.

Full text of DOI:10.1002/anie.201908896

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Accepted Article
Title: Access to Cyclic β-Amino Acids by Amine-Catalyzed
Enantioselective Addition of the γ-Carbon Atoms of α,β-
Unsaturated Imines to Enals
Authors: Guoyong Luo, Zhijian Huang, Shitian Zhuo, Chengli Mou, Jian
Wu, Zhichao Jin, and Yonggui Robin Chi
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201908896
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10.1002/anie.201908896
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Access to Cyclic β-Amino Acids by Amine-Catalyzed
Enantioselective Addition of the γ-Carbon Atoms of α,β-
Unsaturated Imines to Enals
[a,b]
Guoyong Luo,† Zhijian Huang,†[b] Shitian Zhuo,[b] Chengli Mou,[a,b] Jian Wu,* [c] Zhichao Jin,[c] and
Yonggui Robin Chi*[b,c]
Abstract: Disclosed here is a new catalytic approach for a most
efficient access to cyclic β-amino acids widely found in bioactive
small molecules and peptidic foldamers. Our method involves
addition of the remote γ-carbon atoms of α,β-unsaturated imines to
enals via iminium organic catalysis. This highly chemo- and stereo-
selective reaction affords cyclic β-amino aldehydes that can be
converted to amino acids bearing quaternary stereocenters with
exceptional optical purities. Our study demonstrates the unique
power of organic catalytic remote carbon reactions in rapid synthesis
of functional molecules.
1a).[10,11]
The addition of carbon nucleophiles to electron-deficient alkenes
is a common step in forming new carbon-carbon bonds. Among
the electron-deficient alkenes, α,β-unsaturated aldehydes
(enals) can be readily activated by organic catalysts for
asymmetric reactions with various nucleophiles. For example,
reactions of enals with primary or secondary amine catalysts
form α,β-unsaturated iminium intermediates that can undergo
addition reactions with carbon or heteroatom nucleophiles.[1,2]
With N-heterocyclic carbenes (NHCs) as organic catalysts,[3,4] in
the presence of oxidants, enals can be converted to α,β-
unsaturated azolium ester intermediates for further reactions.[5]
The majority of the carbon nucleophiles in organic catalytic 1,4-
addition to enals (and related electron-deficient alkenes) are the
α-carbon atoms of carbonyl compounds or their derivatives and
analogues (Figure 1a).[6] Vinylogous Michael donors[7] have also
found interesting use for construction of C-C bonds at the γ-
carbon centers of carbonyl compounds[8] or their derivatives and
analogues.[9] However, most of vinylogous Michael donors are
restricted to cyclic substrates with at least one of the electron-
rich double bonds incorporated in the ring systems (Figure
1a).[8,9] It remains less explored to use acyclic linear vinylogous
Michael donors in asymmetric addition to enals (via α,β-
unsaturated iminium or azolium ester intermediates) (Figure
Figure 1. Access to cyclic β-amino acids by addition of remote carbon atoms
of unsaturated imines to enals.
Here we disclose that the γ-carbon atoms of α,β-
unsaturated imines (linear substrates) can directly undergo
nucleophilic addition to enals under the catalysis of chiral
secondary amine catalysts (Figure 1b). Key steps include the
reaction of enal (1) with amine catalyst to form unsaturated
iminium intermediate I, and γ-CH deprotonation of unsaturated
imine substrate (2) to form dienamine intermediate II. Addition
of the γ-carbon atom of II to unsaturated iminium intermediate I
affords intermediate III that can undergo further intramolecular
Mannich reaction to form intermediate IV. Hydrolysis of the
iminium component of intermediate IV leads to cyclic amino
aldehyde product (3) with the regeneration of amine catalyst. In
this cascade reaction, multiple atoms of both the enal and
unsaturated imine substrates are involved with the formation of
two new carbon-carbon bonds. The cyclic amino aldehyde
products (3), obtained as essentially single enantiomers with up
to 99% ee, can be readily transformed to cyclic β-amino acids
after oxidations. Notably, cyclic amino acids (such as 6-
[a]
[b]
Dr. G. Luo, Dr. C. Mou,
School of Pharmacy, Guizhou University of Traditional Chinese
Medicine, Huaxi District, Guiyang 550025, China
Dr. G. Luo, Dr. Z. Huang, Dr. S. Zhuo, Dr. C. Mou, Prof. Dr. Y. R.
Chi
Division of Chemistry and Biological Chemistry, School of Physical
and Mathematical Sciences, Nanyang Technological University,
Singapore 637371, Singapore.
E-mail: robinchi@ntu.edu.sg
[c]
Prof. Dr. J. Wu, Prof. Dr. Z. Jin, Prof. Dr. Y. R. Chi
Laboratory Breeding Base of Green Pesticide and Agricultural
Bioengineering, Key Laboratory of Green Pesticide and Agricultural
Bioengineering, Ministry of Education, Guizhou University, Huaxi
District, Guiyang 550025, China
E-mail: wujian2691@126.com
[†]
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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10.1002/anie.201908896
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memebered cyclic β-amino acid BAY 9379,[12] Tilidin,[13] and
Optically enriched products (3a, 99% ee) were obtained in trace
to 23% yields when using KH2PO4 together with K2HPO4, K3PO4
or K2CO3 as the basic additives (entries 3-5, for more details,
see Table S1 in SI). Through the addition of NaCl as a salt
additive, the yield of 3a dropped to 56% when KH2PO4 alone
was used as the base (entry 6). However, the yield of the
product 3a could be dramatically increased by the addition of
NaCl with K2HPO4/KH2PO4 as the bases (entries 7 vs 3). Other
inorganic salts (e.g., entry 8, see Table S1 in SI for more details)
were also tested as additives for this reaction. As a technical
note, adduct 4a was obtained as the major side product, and its
formation was suppressed by the addition of NaCl (entries 7 vs
3). Several other amine catalysts (B, C and D) we tested were
not effective (entries 9-11).
oryzoxymycin[14]
) exhibit medicinally significant bioactivities
(Figure 1c).[15] These amino acids are also key components in
many pharmaceutical leads such as CEP-28122,[16] VX-787,[17]
VLA-4 Antagonist[18] and 11-methoxytabersonine[19]. In the field
of foldamers research, Gellman and co-workers have pioneered
the creation of new peptidic structures by employing cyclic non-
natural amino acids[20] that include six-membered β-amino
acids[21]
. Our new catalytic reaction provides an efficient
approach to this class of cyclic β-amino acids.
Table 1. Condition optimizations.[a]
Scheme 1. Substrate scope.
Entry Catalyst
Base
Additive
Yield [%]
3a[c] / 4a[d]
64 / 6
Ee[e]
3a / 4a
99 / 93
1
2
3
4
A
A
A
A
KH2PO4
K2HPO4
-
-
-
-
trace / -
23 / 10
trace / -
trace / -
56 / -
- / -
99 / 94
- / -
[b]
K2HPO4, KH2PO4
[b]
K3PO4, KH2PO4
K2CO3, KH2PO4
KH2PO4
[b]
5
6
A
A
A
A
B
C
D
-
- / -
NaCl
NaCl
LiBr
99 / -
99 / 93
99 / 86
- / -
[b]
[b]
7
K2HPO4, KH2PO4
72 (69)[d] / 4
8
K2HPO4, KH2PO4
55 / 7
9
As entry 7
trace / -
20 / -
10
11
As entry 7
29 / -
- / -
As entry 7
0 / -
[a] Reaction conditions: 1a (0.2 mmol), 2a (0.1 mmol), amine (0.03 mmol),
base (0.1 mmol), additive (0.1 mmol) in 1 mL CH3OH/H2O (99:1) at 60 oC for
12 h. [b] 100 mol% of each base was used. [c] NMR yield based on 2a using
trimethoxylbenzene as internal standard. [d] Isolated yields of 3a and 4a
based on 2a. [e] Enantiomeric excess of 3a and 4a was determined via HPLC
analysis on chiral stationary phase.
We started by using enal 1a and α,β-unsaturated imine 2a
as model substrates to develop the γ-carbon addition and
cascade reaction (Table 1). Our original attempt in using NHC
catalysts under oxidative condition to realize
a
similar
transformation was unsuccessful. We then moved to examine
chiral secondary amines as the catalysts. We were delighted to
find that by using the Hayashi-Jørgensen type prolinol TMS
ether[22] as the amine catalyst, KH2PO4 as the base, the
proposed cyclic amino aldehyde product (3a) could be obtained
as essentially a single enantiomer with 64% yield and 99% ee
(entry 1). A mixture of CH3OH with water (99:1 v/v) was found as
an optimal solvent (see Table S1 in SI for examples of other
solvents). Trace product was observed when KH2PO4 was
replaced with K2HPO4 (entry 2). Dual basic additives were then
examined for further condition optimization (entries 3-5).
With an acceptable condition (Table 1, entry 7) in hand, we
examined the generality of the reactions with regards to both
substrates (Scheme 1). With 2a as a model unsaturated imine
substrate, we first tested derivatives of cinnamaldehyde as the
enal substrates (3b-3f). Placing various substituents on the para
position of the β-phenyl group of cinnamaldehyde were well
tolerated, with the corresponding products obtained in 66-73%
yields and excellent ee values (3b-3e). When a methyl unit was
placed on the ortho-carbon of the β-phenyl ring of
cinnamaldehyde, a longer reaction time was needed with a drop
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10.1002/anie.201908896
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on product yield (3f, 43% yield) likely due to the steric hindrance.
Changing the phenyl group into other heteroaryl (3g) and
naphthyl (3h) substituents did not influence the reaction
outcomes. The phenyl group of cinnamaldehyde could also be
replaced by an alkene unit (3i). Aliphatic enal could give the
desired product (3j) in a low yield (12%) even after an extended
reaction time.
because that the salt additive can facilitate the precipitation of
product 3a from the reaction solution and thus suppress its
transformation to the side-product 4a. Only trace formation of 4a
was observed from the reaction of 1a and the enone substrate
2a (Scheme 2b). Notably, the formation of 3a and 3a were not
observed in our model reactions while using unsaturated imine
2a as the substrate, showing that hydrolysis of unsaturated
imine is minimal under our optimal reaction conditions (see SI
for additional control experiments). Based on these results, the
side-product 4a is expected to be afforded via elimination of
TsNH2 from 3a, rather than from the reaction between enal 1a
and enone 2a (generated in situ via hydrolysis of 2a during the
catalytic reaction).
We next moved to examine the imine substrates (2) using
cinnamaldehyde (1a) as a model electrophile. Placing halogen
substituents on the phenyl ring of the unsaturated imine
substrates led to the corresponding products 3k and 3l with 44%
and 65% yield respectively. The β-phenyl substituent of the
unsaturated imine could be replaced by a naphthyl unit (3m).
The β-aryl substituent of the imine can be changed to an alkyl
(3n) or a carboxylic ester (3o) unit, albeit with yields decreased.
The γ-phenyl substituted imine could give the desired product
(3p) in a low yield (16%). We also investigated imines with other
N-protecting groups. Both 2- and 4-nitrobenzenesulfonyl
protected imines (3q and 3r) were tolerated to give the
corresponding products in 68% and 59% yield respectively.
Interestingly, diphenylphosphinyl imine substrate also reacted
fine to give 3s with 34% yield (isolated after reduction of the
aldehyde to alcohol due to the instability of the amino aldehyde
adduct). No desired product was observed when aldimine was
employed as the substrate under the current reaction condition.
In all these catalytic reactions (3a-s), the cyclic β-amino
aldehyde products were obtained as single diastereomers. The
reaction likely gave trans-Mannich adduct that subsequently
underwent an epimerization to the thermodynamically more
stable isomer with excellent diastereoselectivity (see SI for a
detailed mechanistic discussion).
The amino aldehyde adducts from our catalytic reactions
could be converted to the corresponding cyclic β-amino acids.
As
a
technical note, it was easier to remove the
nitrobenzenesulfonyl (nosyl, Ns) protecting group of the amine
than the toluenesulfonyl (tosy, Ts) group. The aldehyde moiety
of the Ns protected amino aldehyde 3r could be readily oxidized
to the corresponding carboxylic acid (5) in 84% yield. The Ns
group on the amino group could be removed in the presence of
a thiophenol and base[23] to give the unprotected amino acid (6)
in 80% yield. In both transforming steps (from 3r to 5 and to 6),
the optical purity of the products was not affected (Scheme 3).
Scheme 3. Conversion of 3r to unprotected cyclic amino acids.
The reaction is amenable for scale up without loss in yields
or ee values. Here we demonstrated a preparation of 3a in 1.5
gram scale with 67% yield and 99% ee.
In summary, we have developed a new reaction between
α,β-unsaturated imines and enals. Key steps in this catalytic
process involves 1,4-addition of the remote γ-carbon atoms of
unsaturated imines to enals under the catalysis of chiral amines.
The reaction affords cyclic β-amino aldehydes with exceptional
chemo- and stereoselectivities. The amino aldehydes can be
converted to cyclic β-amino acids bearing quaternary
stereocenters that are difficult to prepare using previous
methods. We expect this study to encourage further exploration
of remote carbon atoms in organic catalytic reactions for rapid
assembly of useful molecules.
Scheme 2. Control experiments.
Acknowledgements
We acknowledge financial support from the National Natural
Science Foundation of China (No. 21772029, 21562012,
21762012, 21801051), National Key Technologies R&D
Program (No. 2014BAD23B01), “Thousand Talent Plan”, The 10
Talent Plan (Shicengci) of Guizhou Province, S&T Planning
Project of Guizhou Province (No. [2017]1402, [2017]5788), the
Department of Science and Technology of Guizhou Province for
Basic Research (No. [2019]1020), Guizhou Province Returned
Oversea Student Science and Technology Activity Program,
Guizhou University, the Guizhou Province First-Class Disciplines
To understand the reaction pathway for the formation of by-
product 4a and the role of NaCl, multiple control experiments
were conducted (Scheme 2). Under the optimized reaction
condition, 3a was employed as the reaction starting material,
1
and the yield of by-product 4a was monitored by H NMR. As
shown in Scheme 2a, without the addition of NaCl, 4a could be
afforded from 3a in moderate yields under otherwise identical
reaction conditions. However, the formation of 4a was
significantly suppressed by the addition of NaCl. This might
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10.1002/anie.201908896
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vinylogous Michael addition • acyclic vinylogous Michael donor •
amine catalysis
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Layout 2:
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Guoyong Luo,† Zhijian Huang,† Shitian
Zhuo, Chengli Mou, Jian Wu,* Zhichao
Jin, and Yonggui Robin Chi*
Page No. – Page No.
Access to Cyclic β-Amino Acids by
Amine-Catalyzed Enantioselective
Addition of the γ-Carbon Atoms of
α,β-Unsaturated Imines to Enals
Direct Vinylogous Michael addition of the remote γ-carbon atoms of α,β-unsaturated
imines to enals is realized via iminium organic catalysis, providing a quick access to
enantiopure cyclic amino acids.
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