Asymmetric Synthesis of Chiral 1,4-Enynes through Organocatalytic Alkenylation of Propargyl Alcohols with Trialkenylboroxines

Article abstract of DOI:10.1002/anie.201904520

A highly enantioselective synthesis of 1,4-enynes is described that proceeds through an organocatalytic reaction between propargyl alcohols and trialkenylboroxines. Our strategy relies on acid-mediated generation of the carbocationic intermediate from propargyl alcohols followed by enantioselective alkenylation with trialkenylboroxines. A range of chiral 1,4-enynes were obtained in moderate to good yields with high levels of enantioselectivity. Use of a highly acidic chiral N-triflyl phosphoramide catalyst, which has two distant Lewis basic oxygen atoms, was found to be crucial for both high reactivity and selectivity in the present reaction.

Full text of DOI:10.1002/anie.201904520

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Accepted Article
Title: Asymmetric Synthesis of Chiral 1,4-Enynes via Organocatalytic
Alkenylation of Propargyl Alcohols with Trialkenylboroxines
Authors: Jian-Fei Bai, Kento Yasumoto, Taichi Kano, and Keiji
Maruoka
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201904520
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10.1002/anie.201904520
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Asymmetric Synthesis of Chiral 1,4-Enynes via Organocatalytic
Alkenylation of Propargyl Alcohols with Trialkenylboroxines
Jian-Fei Bai,[a] Kento Yasumoto,[a] Taichi Kano* [a] and Keiji Maruoka*[a,b]
Abstract: A highly enantioselective synthesis of 1,4-enynes is
described via an organocatalytic reaction between propargyl alcohols
and trialkenylboroxines. Our strategy relies on the acid-mediated
generation of the carbocationic intermediate from propargyl alcohols
followed by enantioselective alkenylation with trialkenylboroxines. A
range of chiral 1,4-enynes were obtained in moderate to good yields
with high levels of enantioselectivity. Use of a highly acidic chiral N-
triflyl phosphoramide catalyst, which has two distant Lewis basic
oxygen atoms, was found to be crucial for both high reactivity and
selectivity in the present reaction.
elimination of the hydroxy group (Scheme 2).5-7 To the best of our
knowledge, however, the catalytic asymmetric variant has not
been developed, probably due to the difficulty on enantioface
selection of the carbocation intermediate by the chiral acid
catalyst. Thus, we became interested in a chiral Brønsted acid-
catalyzed synthesis of chiral 1,4-enynes. Herein we report an
organocatalytic enantioselective alkenylation of propargyl
alcohols with trialkenylboroxines.
Chiral 1,4-enynes are important and versatile synthetic
intermediates.1 Both alkenyl and alkynyl groups on the chiral
center at the 3-position can serve as handles for further
elaboration, respectively.2 Various synthetic approaches to 1,4-
enynes have been developed thus far.3 Asymmetric synthesis of
chiral 1,4-enynes has also been achieved by transition metal-
catalyzed enantioselective allylic substitution (Scheme 1).4 In
recent years, the development of effective and environmentally
benign methods using non-metal catalysts has attracted much
attention. In this context, alkenylation of propargyl alcohols is an
alternative promising approach to 1,4-enynes, in which the
carbocation intermediate is generated by the acid-mediated
Scheme 2. Synthesis of 1,4-enynes by alkenylation of propargyl alcohols.
We first examined the reaction of propargyl alcohol 1a with
boroxine 2a in dichloromethane at room temperature. In this
reaction, boroxine 2a was employed as a nucleophile instead of
(E)-stylylboronic acid which readily forms 2a by dehydration.8 A
highly acidic chiral N-triflyl phosphoramide (S)-4a9 was selected
as catalyst with the expectation that the carbocation intermediate
would be generated from propargyl alcohol 1a by elimination of
the hydroxy group, along with the generation of water. When the
reaction was performed in the presence of 5 mol% of (S)-4a, the
desired 1,4-enyne 3a was obtained in good yield but with low
enantioselectivity (Table 1, entry 1). To improve the
stereoselectivity, propargyl alcohol 1b having an acetamido group
at the para-position, which can be the handle for further
functionalization, was then used. To our delight, the
enantioselectivity was drastically increased without loss of
reactivity (entry 2). The fine-tuning of the catalyst structure led to
a slight increase in enantioselectivity, and (S)-4b was found to be
the optimal catalyst (entry 3). On the other hand, the yield and
enantioselectivity were significantly decreased with a phosphoric
acid catalyst (S)-5 (entry 7). Among the solvents tested,
chloroform proved to be most effective in terms of both yield and
enantioselectivity (entry 9). The concentration of the solution was
found to affect the stereoselectivity, and the reaction at a lower
Scheme 1. Transition metal-catalyzed asymmetric synthesis of 1,4-enynes.
[a]
Dr. J.-F. Bai,[+] K. Yasumoto, Prof. Dr. T. Kano, Prof. Dr. K. Maruoka
Department of Chemistry, Graduate School of Science
Kyoto University, Sakyo, Kyoto 606-8502 (Japan)
E-mail: maruoka@kuchem.kyoto-u.ac.jp
kano@kuchem.kyoto-u.ac.jp
[b]
[+]
School of Chemical Engineering and Light Industry
Guangdong University of Technology, Guangzhou 510006 (China)
Current address: Suzhou Research Institute of LICP
Lanzhou Institute of Chemical Physics (LICP)
Chinese Academy of Sciences, Lanzhou 730000 (China)
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201904520
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concentration resulted in higher enantioselectivity (entry 14).
Addition of molecular sieve 5A caused a substantial decrease in
yield (entry 15). When diisopropyl (E)-styrylboronate was used as
developed methodology (Table 2). The reaction proved tolerant to
electron-donating and electron-withdrawing groups on the
aromatic ring on the alkynyl terminus, giving moderate to good
yields and high enantioselectivities (3c-3i). A number of other
propargyl alcohols 1 having heteroaryl, alkenyl, alkyl and silyl
groups performed equally well, and comparable yields and
selectivities were observed (3j-3p). Several boroxines 2 also
served as effective coupling partners, providing the
corresponding products with good yields and enantioselectivities
(3q-3v). While introduction of an α-substituent on the styryl group
slightly reduced the enantioselectivity (3t), the reaction of a
a
nucleophile instead of 2a, decreased yield and
enantioselectivity were observed (entry 16). Use of (E)-
styrylboronic acid pinacol ester led to complete suppression of the
desired alkenylation (entry 17).
Table 1. Catalyst and solvent screening for the alkenylation of propargyl alcohol
1 with boroxine 2a.[a]
boroxine bearing 2-indenyl
enantioselectivities (3u and 3v).10
group showed excellent
Table 2. Alkenylation of propargyl alcohols 1 with boroxines 2.[a]
Entry
1
Catalyst
Solvent
Yield [%][b]
Ee [%][c]
1[d]
1a
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
(S)-4a
(S)-4a
(S)-4b
(S)-4c
(S)-4d
(S)-4e
(S)-5
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
76
76
80
64
70
77
8
28
85
88
85
87
81
–24
87
89
82
4
2
3
4
5
6
7
8[e]
(S)-4b
(S)-4b
(S)-4b
(S)-4b
(S)-4b
(S)-4b
(S)-4b
(S)-4b
(S)-4b
(S)-4b
92
88
85
53
49
84
72
57
61
n.d.
9[e]
10[e]
11[e]
12[e]
13[e,f]
14[g,h]
15[g,h,i]
16[g,h,j]
17[g,h,k]
ClCH2CH2Cl
THF
1,4-dioxane
CHCl3
5
64
91
87
73
-
CHCl3
CHCl3
CHCl3
CHCl3
[a] Use of 1 (0.06 mmol), 2a (0.02 mmol), a catalyst (0.003 mmol) and a
solvent (2 mL). [b] Determined by 1H-NMR with 1,2-dichloroethane as
internal standard. [c] Determined by chiral HPLC methods. [d] Performed for
24 h. [e] Use of 1b (0.072 mmol). The yield is based on 2a. [f] Use of CHCl3
(0.6 mL). [g] Performed for 48 h. [h] Use of CHCl3 (3 mL). [i] Use of molecular
sieve 5A (50 mg). [j] Use of (E)-styryl-B(OiPr)2 instead of 2a. [k] Use of (E)-
styryl-B(pin) instead of 2a. pin = pinacolato. n.d. = not detected. Ad =
adamantyl.
[a] Use of 1 (0.09 mmol), 2 (0.03 mmol), (S)-4b (0.0045 mmol) and CHCl3
(4.5 mL). Yield of isolated product given. The enantiomeric excess was
determined by chiral HPLC methods. [b] Performed for 24 h.
With the optimized conditions in hand, a variety of propargyl
alcohols 1 and boroxines 2 were tested to study the scope of the
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While propargyl alcohols 1 having a p-acetamidophenyl group
proved to be an excellent substrate for the reaction, the
application of the present method to a propargyl alcohol 6 with a
p-hydroxyphenyl substituent also provided satisfactory results
(Scheme 3a). On the other hand, introduction of a methyl group
to p-acetamido group significantly decreased the reaction rate
and stereoselectivity (Scheme 3b) The reactions of propargyl
alcohols 10 and 12 having an ortho-substituted phenyl group gave
almost racemic products, respectively (Scheme 3c). Interestingly,
the acetamido group at the ortho-position was hydrolyzed during
the reaction. These results suggested that a hydrogen bond donor,
which can be engaged in a hydrogen bonding with the oxygen
atom of the catalyst, might be required as a substituent at the para
position for high yield and stereoselectivity.
Scheme 4. Transformation and absolute configuration determination of
alkenylation products.
Based on the above preliminary results, plausible catalytic
cycle and transition states TS1 and TS2 were proposed (Figure
1). First, the acid catalyst 4 promotes the elimination of hydroxy
group of propargyl alcohol 1 (X = AcNH) or 6 (X = OH), and the
generated cationic intermediate interacts with the catalyst through
the hydrogen bonding as shown in either TS1 or TS2.11,12 The
Lewis basic oxygen atom on the phosphorus atom is close to the
sterically hindered aryl substituent of the catalyst, and might
preferably interact with the sterically less hindered acetamido or
hydroxy group as shown in TS1. Interconvertible cis and trans
isomers of the cationic intermediate are generated during this
process, and one geometric isomer might preferentially
participate in the reaction. The boroxine or the corresponding
boronic acid,13 which is generated in-situ by hydrolysis of the
boroxine, can be activated as a nucleophile by formation of the
ate complex with the deprotonated catalyst, and the carbon-
carbon bond formation with the neighboring cationic intermediate
might then occur to afford the product 3 or 7 stereoselectively.
The borane salt of the catalyst is readily hydrolyzed as the catalyst
is regenerated. In this reaction, interaction of two distant oxygen
atoms of the catalyst with both nucleophile and electrophile may
be crucial for obtaining high yields and selectivities.11 In this
scenario, the two oxygen atoms of the phosphoric acid catalyst as
Lewis bases might be too close to each other (Table 1, entry 3 vs.
7).
Scheme 3. Alkenylation of propargyl alcohols having
substituted phenyl group.
a para- or ortho-
When the product 3b was treated with 4N HCl, the acetamido
group was hydrolyzed to amino group, which can be used as a
synthetic handle for further functionalization, without loss of
optical purity (Scheme 4a). Hydrogenation of the alkenyl and
alkynyl groups of 3p afforded the product 15 bearing two different
alkyl groups (Scheme 4b). The absolute stereochemistry at the
benzylic carbon of 15 was determined to be S by comparison with
15 which was synthesized from the known compound.
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Figure 1. Proposed catalytic cycle and transition state models.
An organocatalytic asymmetric synthesis of 1,4-enynes has
been realized. In this process, readily available propargyl alcohols
bearing a hydrogen bond donor and trialkenylboroxines can be
employed and a highly acidic chiral N-triflyl phosphoramide was
found to be the optimal Brønsted acid catalyst. This asymmetric
alkenylation of propargyl alcohols with trialkenylboroxines offers
an alternative approach to the asymmetric synthesis of 1,4-
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range of chiral compounds having alkynyl, alkenyl or alkyl carbon
chains.
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Acknowledgements
This work was supported by JSPS KAKENHI Grant Numbers
JP17H06450, JP26220803 and JP18H01975.
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presence of dehydrating agents such as MgSO4 and MS5A (Table 1,
entry 14 vs. 15).
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Entry for the Table of Contents (Please choose one layout)
Layout 2:
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Jian-Fei Bai, Kento Yasumoto, Taichi
Kano,* Keiji Maruoka*
Page No. – Page No.
Asymmetric Synthesis of Chiral 1,4-
Enynes via Organocatalytic
Alkenylation of Propargyl Alcohols
with Trialkenylboroxines
Chiral 1,4-enynes were synthesized by an organocatalytic alkenylation of propargyl
alcohols with trialkenylboroxines with high enantioselectivity. A highly acidic chiral N-
triflyl phosphoramide, which has two distant Lewis basic oxygen atoms, was
identified as an effective catalyst in terms of both reactivity and selectivity.
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