Forming All-Carbon Quaternary Stereocenters by Organocatalytic Aminomethylation: Concise Access to β2,2-Amino Acids

Article abstract of DOI:10.1002/anie.202009892

The asymmetric synthesis of β^2,2-amino acids remains a formidable challenge in organic synthesis. Here a novel organocatalytic enantioselective aminomethylation of ketenes with stable and readily available N,O-acetals is reported, providing β^2,2-amino esters bearing an all-carbon quaternary stereogenic center in high enantiomeric ratios with a catalytic amount of chiral phosphoric acid. Typically, this transformation probably proceeds through an asymmetric counter-anion-directed catalysis. As a result, a concise, practical, and atom-economic protocol toward rapidly access to β^2,2-amino acids has been developed.

Full text of DOI:10.1002/anie.202009892

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Accepted Article
Title: Forming All-Carbon Quaternary Stereocenters by Organocatalytic
Aminomethylation: Concise Access to β2,2-Amino Acids
Authors: Jiangtao Sun, Kai Wang, Jianliang Yu, Ying Shao, and
Shengbiao Tang
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10.1002/anie.202009892
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Forming All-Carbon Quaternary Stereocenters by Organocatalytic
Aminomethylation: Concise Access to β2,2-Amino Acids
Kai Wang, Jianliang Yu, Ying Shao, Shengbiao Tang and Jiangtao Sun*
Dedicated to the 100th anniversary of the School of Chemistry and Chemical Engineering, Nanjing University
Abstract: The asymmetric synthesis of β2,2-amino acids remains
a formidable challenge in organic synthesis. We report here a
novel organocatalytic enantioselective aminomethylation of
ketenes with stable and readily available N,O-acetals, providing
β2,2-amino esters bearing an all-carbon quaternary stereogenic
center in high enantiomeric ratios with a catalytic amount of chiral
phosphoric acid. Typically, this transformation probably proceeds
through an asymmetric counter-anion-directed catalysis. As a
result, a concise, practical and atom-economy protocol toward
rapidly access to β2,2-amino acids has been developed.
β-Amino acids are important chiral building blocks in organic
synthesis and peptidic foldamers.1 Spcially, the use of β-amino
acids in constructing bioactive peptides is a promising strategy to
obtain analogues that have beneficial effects to medicinal
chemistry and pharmaceutical research.2 For examples, β-amino
acids can effectively enhance the stability of the peptides against
proteolysis,3 and are also compatible with ribosomal translation.4
Thus, substantial effort has been made toward rapidly access to
optically pure β-amino acids.5 However, compared with the
commercially available α- and β3-amino acids,6 the β2-amino
acids,7 especially β2,2-amino acids having an all-carbon
quaternary stereogenic center,8 are difficult to achieve (Figure 1).
To date, the most common method to access β2,2-amino acids is
Scheme 1. Previous reports and our strategy
the utilization of chiral auxiliaries.9 Several catalytic asymmetric
approaches
have
also
been
developed,
including
enantioselective conjugate addition of aldehydes,10 indoles11 or
arylboronic acids,12 to β,β-disubstituted nitroalkenes, palladium-
catalyzed intramolecular and intermolecular allylation of 4-
substituted isoxazolidin-5-ones.13 Despite these advances, the
development of a concise and practical protocol for the catalytic
enantioselective synthesis of β2,2-amino, is still in highly
demanded.
Recently, Chi and co-workers reported an asymmetric amino
methylation of enals through N-heterocyclic carbene (NHC)-acid
cooperative catalysis, yielding β2-amino esters in high optical
purity (Scheme 1a).14 The enolate undergoes Mannich type
reaction with electrophilic iminium ion (from N,O-acetal),15
followed by trapping of the acyl azolium with methanol, to form the
β2-amino esters. Later, Xu, Hu and co-worker developed an
asymmetric counter-anion directed16 aminomethylation to form α-
hydroxyl-β-amino esters (Scheme 1b).17 This transformation
probably proceeds through a Mannich-type reaction of enol
intermediate with methylene iminium ion, and the asymmetric
induction is enabled by the chiral pentacarboxycyclopentadiene
(PCCP) anion. Inspired by these reports and in continuation with
our interest in developing novel aminomethylation reactions,18 we
envision that the phosphoric acid anion and the electrophilic
methylene iminium ion would form chiral ion pair. The subsequent
convergent addition of enolate intermediate to the ion pair would
give β2,2-amino esters (Scheme 1c).
Figure 1. Synthetic difficulties to access α- and β-amino acids
To validate the speculation, we commenced our studies by
evaluating the reaction between ketene 1a and N,O-acetal 2a in
dichloromethane at room temperature in the presence of a series
of chiral phosphoric acid (CPA) catalysts (Table 1). A catalytic
amount (5 mol%) of the BINOL-derived CPA C1, having a 2,4,6-
triisopropylbenzene group at the 3,3ʹ-position, afforded the
desired β2,2-amino ester 3a in 32% yield with poor er (entry 1).
Other BINOL-derived CPAs (C2-C5) exhibited similar results to
[a]
K. Wang, J. Yu, Prof. Y. Shao, S. Tang, Prof. J. Sun
Jiangsu Key Laboratory of Advanced Catalytic Materials &
Technology, School of Petrochemical Engineering, Changzhou
University, 1 Gehu Road, 213164 Changzhou, China
E-mail: jtsun@cczu.edu.cn
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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10.1002/anie.202009892
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C1 (entries 2-5). To futher improve the reaction conditions, we
then switched to evaluate the SPINOL-derived CPAs. The use of
CPA C6, bearing a 2,4,6-trimethylbenzene group at the 6,6ʹ-
position, gave promising results. In this case, 3a was isolated in
55% yield and a 72:28 er (entry 6). However, changing the
substituents at the 6,6ʹ-position (C7-C10) can not improve the
reaction (entries 7-10). Using C6 as the catalyst, several solvents
were screened (entries 11-14). The reactions in toluene,
chloroform, cyclopentane and cyclohexane all provided enhanced
er values, and cyclohexane proved to be the best one (95.5:4.5
er; entry 14). It is believed that the non-polar solvent is benefical
to the fomation of intimate ion pairs and thus helps stereocontrol
(Scheme 1c). Then, evaluation of the temperature was performed.
Decrease of the temperature to 10 oC resulted in a slight increase
in enantiomeric ratio but with low yield (30%; entry 15). In contrast,
the symmetric dibenzyl substituents containing either electron-
donating or electron-withdrawing groups were all tolerated,
providing the amino ester derivatives (3f-3j) in moderate to good
yields and good er values. The amines containing unsymmetric
dibenzyl substituents (3k-3n) were suitable substrates too.
However, replacing one benzyl group with methyl group gave 3o
in decreased er (91:9). The similar phenomenon was observed
for diethyl substituted N,O-acetals, and amino ester (3p) was
obtained in 70% yield and 91.5:8.5 er. For acetals bearing a cyclic
amine moiety, such as tetrahydroisoquinoline, piperidine,
morpholine, and azepane, were also viable substrates, affording
3q-3t in good yields and moderate stereoselectivities.
Table 2: Substrate scope of N,O-acetals.[a],[b]
o
the yield was improved to 74% at 40 C without the loss of er
(entry 16). Comparably, higher temperature gave inferior results
(entry 17). Moreover, at dilute conditions (0.05 M), a slight
increase in both the yield and the er was observed. As a result,
3a could be obtained in 76% yield with 97:3 er value (entry 18).
Table 1: Optimization of the reaction conditions.[a]
Entry
CPA
C1
Solvent
CH2Cl2
T (oC)
Yield (%)[b]
e.r.[c]
25
25
25
25
25
25
25
25
25
25
25
25
25
25
10
40
60
40
32
20
24
21
18
55
42
33
24
30
43
38
58
70
30
74
67
76
60:40
51:49
67:33
52:48
57:43
72:28
68:32
65:35
67:33
60:40
86:14
75:25
94.5:5.5
95.5:4.5
96.5:3.5
96.5:3.5
95:5
1
2
C2
C3
C4
C5
C6
C7
C8
C9
C10
C6
C6
C6
C6
C6
C6
C6
C6
CH2Cl2
CH2Cl2
3
CH2Cl2
4
[a] Reaction conditions: 1a (0.2 mmol, 2 equiv), 2 (0.1 mmol, 1 equiv), C6 (5
mol%) in 2 mL cyclohexane, 40 oC, 6h. [b] Isolated yields were listed; the er
values were determined by chiral HPLC analysis. [c] 10 mol% C7 was used.
CH2Cl2
5
CH2Cl2
6
CH2Cl2
7
CH2Cl2
8
Further exploration of the reaction scope focused on the ketene
substrates. An array of ketenes were examined by using 2a as
the reaction partner (Table 3). Generally, most of the reactions
conducted were completed in 6 h with moderate to good yields
(50-79%) and good er values (90:10-97.5:2.5). The electronic
properties of the substituent on the phenyl ring had little or no
effect on the enantioselectivity. Electron-donating (3ba-3ca) and
electron-withdrawing (3da-3ha) groups substituted at para and
meta positions on the phenyl ring are good substates. Even the
steric hindered aromatic substrates were also amenable to this
reaction, providing moderate yield and stereoselectivity of the
corresponding products (3ia-3ja). A substrate with a thienyl group
also reacted well, delivering 3ka with good er value. Then, the
variation of alkyl group R2 of the ketenes was evaluated. The
ketenes substituted with an alkyl group, such as methyl, n-butyl,
i-butyl and i-pentenyl reacted well, affording the corresponding
products (3la-3oa) in good yields and high er. The use of ketene
bearing a tetrahydronaphthalene moiety furnished 3pa in 65%
yield with 96.5:3.5 er. However, the use of dialkyl-substituted
CH2Cl2
9
CH2Cl2
10
11
12
13
14
15
16
17
18[d]
toluene
CHCl3
cyclopentane
cyclohexane
cyclohexane
cyclohexane
cyclohexane
cyclohexane
97:3
[a] Reaction conditions: 1a (0.20 mmol), 2a (0.1 mmol), catalyst (5.0 mol%) in 1
mL solvent, rt for 6 h. [b] Isolated yields. [c] Determined by chiral HPLC analysis.
[d] The reaction was carried out in 2 mL of solvent.
Having established the optimal reaction conditions, we next
explored the scope of N,O-acetals (Table 2). Changing the R1
group of N,O-acetals from methyl to ethyl, benzyl, allyl and
propynyl, the desired products (3b-3e) were isolated in good
yields and excellent er values. With respect to the amine moiety,
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10.1002/anie.202009892
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ketene provided product 3qa in moderate yield and 69:31 er.
state TS2 is proposed to rationalize the stereochemcial outcome.
In addition to the ion pairing interaction, a hydrogen bonding
interaction between the phosphoryl oxygen and the enol hydroxy
group is critical to the pseudo bifunctional stereocontrol. The enol
plane is oriented such that its phenyl group is placed right above
the mesitylene plane of the chiral catalyst, thereby effectively
stablized by π-π interaction. Thus, the iminium electrophile
aprroaches the Si-face of the enol molecule, resulting in (R)-3a,
which is in agreement with the observed stereochemical outcome.
Notably, the proposed π-π interaction is also consistent with the
high enantioselectivity observed for aryl ketenes, but not for
dialkyl ketenes which lack this interaction.
Table 3: Substrate scope of ketenes.[a],[b]
[a] Reaction conditions: 1 (0.2 mmol), 2a (0.1 mmol), C6 (5 mol%) in 2 mL
cyclohexane, 40 oC, 6h. [b] Isolated yields were listed; the er values were
determined by chiral HPLC analysis. [c] 5 mol% C9 was used.
To gain insight into the reaciton mechanism, we conducted
control experiment by following Xu and Hu’s procedure (Scheme
2).17 Treatment of N,N,N′,N′-tetrabenzylmethanediamine with
acetyl chloride generated methylene iminium chloride 2a-Cl. The
anion exchange between chiral silver complex C6-Ag and 2a-Cl
gave the chiral ion pair C6-2aʹ. The addition of C6-2aʹ to a mixture
of methanol and 1a in cyclohexane produced 3a in 32% yield and
96.5:3.5 er. This result indicates the chiral ion pair might be the
key reaction intermediate and the asymmetric induction might
result from the chiral phosphoric acid counteranion.
Figure 2. Proposed mechanism
In order to demonstrate the synthetic utility of this protocol,
further elaboration has been conducted (Scheme 3). For 1 mmol
scale reaction, 3a was obtained in 75% yield and 97:3 er (Scheme
3a). Reduction of 3a with lithium aluminum hydride in
tetrahydrofura led to amino alcohol 4 in 95% yield without any
erosion of the stereoselectivity (97:3 er). Hydrogenation of 3a
followed by acid-catalyzed hydrolysis produced β2,2-amino acid 5
in 95% yield. Then, a gram-scale reaction was performed in the
presence of 1 mol% of C6, and 3a was obtained in 72% yield with
96:4 er (Scheme 3b). Clearly, the low catalyst loading of CPA
makes this reaction more practical. Next, hydrogenation of 3a with
Pd/C in a hydrogen atomosphere can remove the benzyl group
and the amino group can be further proctected by a tert-
butoxycarbonyl group to furnish compound 6 in 95% yield and
96:4 er. Moreover, after hydrogenation, the β-amino ester can be
converted to β-lactam 7 in 62% yield with 99:1 er under basic
Scheme 2. Control experiment
Based on the above results and literature reports,17 a possible
mechanism is proposed (Figure 2). The reaction of 2a with the
acid catalyst generates methylene iminium ion pair I and releases
a molecule of MeOH. The addition of MeOH to ketene 1a forms
the nucleophile enol II. This step likely favors the E-isomer due
the severe steric repulsion encountered when methanol
approaches the ketene from the same side of the phenyl group,
as shown in the proposed transition state TS1.19 Next, the enol
reacts with the chiral iminium ion pair to deliver the observed
product 3a and regenrates the chiral acid catalyst. The transition
reaction conditions. The absolute configuration of
7 was
determined by X-ray analysis.20 Furthermore, since ketenes can
be obtained by photolytic Wolff rearrangement of α-diazo
ketones,21 we then performed the one-pot reaction of diazo
ketone 8 and 2a in the presence of C6 under blue light irridation
(Scheme 3c). 3a was isolated in 26% yield with 95:5 er. The low
yield probably attributed to the side carbene reactions. Moreover,
we also tested the reaction of 1a with substituted N,O-acetal 9
(Scheme 3d). However, the amide 10 was obtained in 29% yield
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10.1002/anie.202009892
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together with 48% yield of α-phenyl β2,2-amino ester 11 with poor
diastereoselectivity (1.4:1 dr).
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In summary, we have developed a novel phosphoric acid-
catalyzed enantioselective aminomethylation reaction between
ketenes and N,O-acetals under mild reaction conditions,
providing β2,2-amino esters bearing an all-carbon quaternary
stereogenic center in high enantiomeric ratios. This
transformation probably proceeds through the addition of in situ
generated enol intermediate to methylene iminium ion in the
presence of chiral phosphoric acid. Moreover, this protocol is
concise, practical and atom economy. The β2,2-amino esters can
undergo further diversifications to synthesize enantiomerically
pure β2,2-amino acid and β-lactam.
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Acknowledgements
We thank the NSFC (21971026), and the Jiangsu Key Laboratory
of Advanced Catalytic Materials and Technology (BM2012110)
for their financial support.
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Keywords: amino acids • phosphoric acid • ketene • N,O-acetal•
organocatalysis
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COMMUNICATION
Kai Wang, Jianliang Yu, Ying Shao,
ShengbiaoTang and Jiangtao Sun*
Page No. – Page No.
Forming All-Carbon Quaternary
Stereocenters by Organocatalytic
Aminomethylation: Concise Access
to β2,2-Amino Acid
A novel organocatalytic enantioselective aminomethylation of ketenes with stable
and readily available N,O-acetals has been developed, providing chiral β2,2-amino
esters bearing an all-carbon quaternary stereogenic center in high enantiomeric
ratios.
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