Construction of Quaternary Carbon Center by Catalytic Asymmetric Alkylation of 3-Arylpiperidin-2-ones Under Phase-Transfer Conditions

Article abstract of DOI:10.1002/anie.201913518

A highly enantioselective synthesis of δ-lactams having a chiral quaternary carbon center at the α-position has been developed through an asymmetric alkylation of 3-arylpiperidin-2-ones under phase-transfer conditions. In this transformation, a 2,2-diarylvinyl group on the δ-lactam nitrogen atom plays a crucial role as a novel protecting group and an achiral auxiliary for improving both yield and enantioselectivity of the reaction.

Full text of DOI:10.1002/anie.201913518

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Accepted Article
Title: Construction of a Chiral Quaternary Carbon Center by Catalytic
Asymmetric Alkylation of 3-Arylpiperidin-2-ones under Phase-
Transfer Conditions
Authors: Tomoaki Inukai, Taichi Kano, and Keiji Maruoka
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10.1002/anie.201913518
Angewandte Chemie International Edition
COMMUNICATION
Construction of a Quaternary Carbon Center by Catalytic
Asymmetric Alkylation of 3-Arylpiperidin-2-ones under Phase-
Transfer Conditions
Tomoaki Inukai,[a] Taichi Kano,*[a] and Keiji Maruoka*[a,b,c]
Abstract: A highly enantioselective synthesis of δ-lactams having a
chiral quaternary carbon center at the α-position has been developed
through an asymmetric alkylation of 3-arylpiperidin-2-ones under
phase-transfer conditions. In this transformation, a 2,2-diarylvinyl
group on the δ-lactam nitrogen plays a crucial role as a novel
protecting group and an achiral auxiliary for improving both yield and
enantioselectivity of the reaction.
Nitrogen heterocycles containing a chiral quaternary carbon
center are frequently found in natural products and considered as
an important and useful building block in organic synthesis.
Among them, 3-alkyl-3-arylpiperidine is an attractive structural
motif that constitutes the core structure of biologically active
compounds as shown in Figure 1.1–4 Asymmetric alkylation of 3-
aryl-lactams is a simple and direct method to construct such chiral
quaternary carbon centers;5 however, only a few reports on the
catalytic asymmetric synthesis of 3-alkyl-3-aryl-lactams have
appeared to date with limited success (e.g., Pd-catalyzed
allylation and conjugate addition under phase transfer-conditions)
Scheme 1. Approaches for catalytic asymmetric synthesis of 3-alkyl-3-aryl-
lactams. a) Examples of catalytic asymmetric alkylation. b) Example of catalytic
asymmetric arylation. c) This work.
Figure 1. Bioactive molecules bearing a 3-alkyl-3-arylpiperidine scaffold.
(Scheme 1a).6,7 Asymmetric arylation of 3-alkyl-lactams is an
[a]
[b]
T. Inukai, Prof. Dr. T. Kano
alternative approach toward the construction of the chiral
quaternary carbon center (Scheme 1b). To the best of our
knowledge, however, the catalytic asymmetric reaction has only
been reported for the arylation of 3-alkyl-γ-lactams.8 In contrast to
the previous attempts, phase-transfer-catalyzed asymmetric
alkylation using alkyl halides is undoubtedly one of the most
reliable methods to introduce alkyl substituents in an
enantioselective fashion,9 though such an approach has not been
developed to a useful level, regardless of the lactam ring size.10
Accordingly, we have developed an asymmetric alkylation of 3-
aryl-δ-lactams bearing an N-2,2-diarylvinyl group as a protecting
Department of Chemistry, Graduate School of Science
Kyoto University, Sakyo, Kyoto 606-8502 (Japan)
E-mail: kano@kuchem.kyoto-u.ac.jp
Prof. Dr. K. Maruoka
Department of Organocatalytic Chemistry, Graduate School of
Pharmaceutical Sciences
Kyoto University, Sakyo, Kyoto 606-8501, Japan
Guangdong University of Technology, Guangzhou 510006 (China)
E-mail: maruoka@kuchem.kyoto-u.ac.jp
School of Chemical Engineering and Light Industry
Guangdong University of Technology, Guangzhou 510006 (China)
[c]
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201913518
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COMMUNICATION
Table 1. Effects of N-protecting group in the asymmetric alkylation of 3-
arylpiperidin-2-ones.[a]
group as well as a tunable achiral auxiliary (Scheme 1c). This
novel protecting group for the amide nitrogen of lactams is found
to be well tolerated under strong basic conditions and be removed
by treatment with an acid or BH3. In the latter case, the
corresponding cyclic amine is obtained directly by reduction of the
amide moiety with BH3·THF. Here, we wish to disclose our initial
results on this study.
In the presence of a chiral quaternary ammonium salt (S)-5a,9j
the reaction between N-benzoyl-3-phenylpiperidin-2-one and
benzyl bromide in cyclopentyl methyl ether (CPME) under phase-
transfer conditions gave the benzylated product in low yield and
enantioselectivity (Scheme 2). In contrast to the smooth
conjugate addition under phase transfer conditions,7 the alkylation
of a trace amount of the in-situ generated enolate with alkyl
halides is much slower. We then hypothesized that the
electronical and structural modification in the lactam would result
in the facile formation of the ammonium enolate as well as an
efficient enantioface discrimination, which are attributable to tight
interaction between the catalyst and the enolate, leading to higher
yield and enantioselectivity. Hence, (E)-styryl or 2,2-diphenylvinyl
group was installed as a tunable achiral auxiliary at the amide
Yield [%][b]
ee [%][c]
Entry
1[d]
(S)-5
Ar
t [h]
(S)-5a
(S)-5a
(S)-5a
(S)-5a
(S)-5b
(S)-5c
(S)-5b
(S)-5b
Ph
72
72
24
24
24
24
24
72
2a 54
2b 76
2c 76
2d 79
2d 82
2d 85
2d 47
2d 73
87
79
63
87
88
64
90
93
2[d]
3
4-F-C6H4
3,5-F2-C6H3
4-CF3-C6H4
4-CF3-C6H4
4-CF3-C6H4
4-CF3-C6H4
4-CF3-C6H4
4
5
6
7[e]
8[f]
nitrogen of 3-phenylpiperidin-2-one. Indeed,
a
significant
improvement of both yield and enantioselectivity was observed in
the reaction of the modified 3-phenylpiperidin-2-one 2a.
[a] Reactions were performed on a 0.1 mmol scale in 1 mL of CPME. [b]
Isolated yield. [c] Determined by HPLC using a chiral column. [d] CPME (0.2
mL) was used. [e] Toluene was used as solvent. [f] Performed at –35 °C in
toluene (0.4 mL) using 5 equiv of BnBr, 10 equiv of CsOH·H2O and 20 equiv
of H2O.
Scheme 2. Asymmetric alkylation of 3-phenylpiperidin-2-ones.
With the optimized conditions in hand, we examined the
substrate scope and the results are shown in Table 2. In the
presence of 1 mol% of (S)-5b, the reactions of 3-phenylpiperidin-
2-one 1d with various alkyl bromides gave the corresponding
products in moderate to good yields and high enantioselectivities
(2d–2i). Use of a propargyl bromide, 1-bromo-2-butyne resulted
in a decrease in both yield and enantioselectivity (2j). We then
tested the scope of the reaction by varying the substituents on the
phenyl ring of the modified 3-arylpiperidin-2-one (2k–2s).11
Introduction of a para-methoxy group significantly decreased the
yield (2k, 21%); however, the reaction at higher temperature (–
15 °C) gave 2k in high yield and enantioselectivity. In general,
para and/or meta-substituents did not significantly affect the
enantioselectivity (2k–2p), whereas ortho-substitution resulted in
no conversion (2q). While the electronic nature of the aryl group
has only a small effect on the stereoselectivity, an electron-
deficient heteroaryl substituent such as 3-pyridyl lowered both
yield and enantioselectivity (2r). On the other hand, 3-thiophenyl
group was tolerated, giving 2s in good yield and enantioselectivity.
The reaction with a less reactive alkylating agent, ethyl iodide
gave 2u in low yield. When a 3-aryl-γ-lactam, 3-phenylpyrrolidin-
2-one having an N-2,2-diarylvinyl group was used instead of 1,
We then tuned the structure of a 2,2-diarylvinyl group (Table
1). Introduction of electron withdrawing groups such as p-fluoro
groups improved the yield, while the enantioselectivity decreased
(entry 2). On the other hand, introducing p-CF3 group was found
to be effective for achieving high yield and enantioselectivity,
although the reaction was performed at lower concentration for
shorter reaction time (entry 4). Fine-tuning of the catalyst led to a
slight increase in yield and enantioselectivity (entry 5). The
reaction in toluene gave 2d with increased enantioselectivity,
albeit in moderate yield (entry 7). Use of CsOH as base at lower
temperature resulted in higher enantioselectivity, while a longer
reaction time was required (entry 8, see also the Supporting
information for details).
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10.1002/anie.201913518
Angewandte Chemie International Edition
COMMUNICATION
the benzylated product was obtained in 17% ee (see the
Supporting Information for details).
The 2,2-diarylvinyl group is well tolerated under reaction
conditions. Treatment of 2d with aqueous KOH even under reflux
conditions led to an essentially quantitative recovery of the
starting material. On the other hand, enamides are known to be
hydrolyzed under acidic conditions,12 and treatment of 2d with
H2SO4 afforded 3-benzyl-3-phenylpiperidin-2-one (3d) in high
yield without loss of enantiopurity (Scheme 3). Treatment of 2d
with BH3 in THF gave 3-benzyl-3-phenylpiperidine (4d) directly as
a result of deprotection and the subsequent reduction of the in-
situ generated 3d.13
Table 2. Substrate Scope.[a-c]
Scheme 3. Deprotection of 3-benzyl-3-phenylpiperidin-2-one.
Further synthetic utility of the present asymmetric alkylation
was successfully demonstrated in the formal synthesis of a
neurokinin-3 antagonist, osanetant,3 as shown in Scheme 4.
Optically enriched 3-allyl-3-aryl-piperidin-2-one 2t, which is
prepared by the asymmetric alkylation of the corresponding 3-
arylpiperidin-2-one with allyl bromide (Table 2), was converted to
the amino alcohol
6 in one-pot through BH3–mediated
deprotection, reduction and hydroboration followed by oxidation
with H2O2 and NaOH. The obtained amino alcohol 6 with high
polarity was converted to 7 by treatment with benzoyl chloride and
triethylamine without purification. Since 7 was an intermediate in
previous total synthesis of osanetant,3b this work contributes to its
formal synthesis. The absolute configuration of the allylation
[a] Reactions were performed on a 0.1 mmol scale in 0.4 mL of toluene. [b]
Isolated yield. [c] Ee was determined by HPLC using a chiral column. [d]
Performed at –15 °C. [e] Performed with Et-I (10 equiv) at –15 °C for 168 h.
Scheme 4. Formal asymmetric synthesis of osanetant.
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10.1002/anie.201913518
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COMMUNICATION
[8]
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rotation of 7 to the literature value (Scheme 4):3c the alkylating
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In summary, we have realized a highly enantioselective
alkylation of 3-arylpiperidin-2-ones by installing an achiral
auxiliary, 2,2-diarylvinyl group on the lactam nitrogen. The
auxiliary was readily removed from the alkylation product by
treatment with an acid or BH3. This methodology certainly
expands the synthetic utility of chiral phase-transfer-catalyzed
alkylation and provides a practical entry to the construction of
chiral quaternary carbon centers in organic synthesis.
Acknowledgements
This work was supported by JSPS KAKENHI Grant Numbers
JP17H06450, JP26220803, and JP18H01975.
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Conflict of interest
The authors declare no conflict of interest.
Keywords: alkylation • asymmetric synthesis • lactams •
organocatalysis • phase-transfer catalysis
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10.1002/anie.201913518
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COMMUNICATION
Entry for the Table of Contents
COMMUNICATION
Tomoaki Inukai, Taichi Kano,*
Keiji Maruoka*
Page No. – Page No.
Construction of a Quaternary Carbon
Center by Catalytic Asymmetric
Alkylation of 3-Arylpiperidin-2-ones
under Phase-Transfer Conditions
δ-Lactams having a chiral quaternary carbon center were synthesized through an
asymmetric alkylation of 3-arylpiperidin-2-ones under phase-transfer conditions. A
2,2-diarylvinyl group on the δ-lactam nitrogen plays a crucial role as a novel
protecting group and an achiral auxiliary for improving both yield and
enantioselectivity of the reaction.
This article is protected by copyright. All rights reserved.