Chiral isoxazolidine-mediated stereoselective umpolung α-phenylation of methyl ketones

Article abstract of DOI:10.1039/c8ob02480d

An effective asymmetric α-phenylation of methyl ketones with triphenylaluminium in the presence of (+)-benzopyranoisoxazolidine has been developed. The reaction proceeds via the in situ formation of a chiral N-alkoxyenamine and the subsequent diastereoselective nucleophilic phenylation to provide α-phenylated products in moderate to good yields, with high enantioselectivities.

Full text of DOI:10.1039/c8ob02480d

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Chiral isoxazolidine-mediated stereoselective
umpolung α-phenylation of methyl ketones†
Cite this: Org. Biomol. Chem., 2018,
16, 8940
Norihiko Takeda, *a Mizuki Furuishi,a Yuri Nishijima,a Erika Futaki,a
Received 6th October 2018,
Accepted 10th November 2018
Masafumi Ueda, *a Tetsuro Shinada b and Okiko Miyata
*
a,b
DOI: 10.1039/c8ob02480d
rsc.li/obc
An effective asymmetric α-phenylation of methyl ketones with tri- scarce.10 To the best of our knowledge, the asymmetric intro-
phenylaluminium in the presence of (+)-benzopyranoisoxazolidine duction of a carbon nucleophile into the α-position of ketones
has been developed. The reaction proceeds via the in situ for- is limited to the umpolung α-alkylation of β-ketoimides
mation of a chiral N-alkoxyenamine and the subsequent diastereo- bearing an Evans’ oxazolidinone as a chiral auxiliary using
selective nucleophilic phenylation to provide α-phenylated pro- Koser’s reagent (PhI(OH)OTs) and dialkylzinc reagents.11 This
ducts in moderate to good yields, with high enantioselectivities.
method involves separate steps for the introduction and
removal of the chiral auxiliary, to furnish the desired enantio-
enriched ketone. Therefore, highly effective asymmetric intro-
duction into the α-position of ketones by an umpolung strategy
remains a frontier area of research in synthetic organic chem-
istry. In this communication, we report the asymmetric
α-phenylation of ketones 1 with triphenylaluminium in the
presence of (+)-benzopyranoisoxazolidine 3 12 for the prepa-
ration of enantioenriched α-phenyl ketones 2 (Scheme 1).
Owing to their simplicity, convenience, and high enantio-
selectivity, asymmetric umpolung α-phenylation of simple
ketones is a straightforward synthetic route to enantioenriched
acyclic α-phenyl ketones. This protocol is advantageous in that
no additional procedure for the introduction and removal of
the chiral isoxazolidine is required.
To accomplish the asymmetric nucleophilic α-phenylation
of ketones, we first optimized the conditions for the umpolung
α-phenylation of ketone 1a (Table 1). The reaction of 1a with
triphenylaluminium (2 equiv.) in the presence of (+)-benzopyr-
anoisoxazolidine 3 (2 equiv.) at 0 °C gave α-phenylated ketone
2a in moderate yield with high enantioselectivity (entry 1). The
absolute configuration of 2a could be determined as (R) because
the optical rotation sign of 2a and that of the one reported in the
literature are negative.13 Pleasingly, an increase in the amount of
Enantioenriched acyclic α-aryl carbonyl compounds are versa-
tile intermediates for the synthesis of biologically active mole-
cules and pharmaceutical agents, including the nonsteroidal
anti-inflammatory drug (NSAID) naproxen,1 antiplatelet agent
clopidogrel,2 and central nervous system stimulant dexmethyl-
phenidate.3 Therefore, a variety of methodologies have been
developed for the asymmetric synthesis of enolizable α-aryl
carbonyl compounds. The nickel-catalysed asymmetric cross-
coupling of α-bromoketones with aryl magnesium4a and aryl
zinc reagents4b and the nickel-catalysed reductive acyl cross-
coupling of acyl chlorides with secondary alkyl halides5 are
particularly reliable methods for the synthesis of enantio-
enriched acyclic α-aryl ketones. A few other methods6 have
also been developed for this purpose, but they often involve
additional steps for the preparation of the starting materials.
Therefore,
a straightforward synthetic route to enantio-
enriched acyclic α-aryl ketones from readily available and
simple ketones is desirable.
Umpolung of the α-carbon atom in carbonyl compounds is
an attractive reaction because it allows the direct introduction
of various substituents into the α-position using
a
nucleophile.7–9 However, the asymmetric nucleophilic intro-
duction into the α-position of ketones and their equivalents is
aKobe Pharmaceutical University, Motoyamakita, Higashinada, Kobe 658-8558,
Japan. E-mail: miyata@kobepharma-u.ac.jp, masa-u@kobepharma-u.ac.jp,
n-takeda@kobepharma-u.ac.jp
bGraduate School of Science, Osaka City University, Sugimoto, Sumiyoshi, Osaka
558-8585, Japan
†Electronic supplementary information (ESI) available: Experimental procedures
and characterization data of all products and starting materials. See DOI:
10.1039/c8ob02480d
Scheme 1 Asymmetric introduction of
α-position of ketones through an umpolung process.
a
nucleophile into the
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Table 1 Optimization of conditions for the asymmetric nucleophilic
α-phenylation of 2a
tion of 1b–f with p-methyl, p-methoxy, p-bromo, p-cyano, and
Boc-protected p-amino groups on the benzene ring proceeded
smoothly at 0 °C to give the desired products 2b–f with high
enantioselectivities. Moreover, various functional groups
(fluoro, trifluoromethyl, methylenedioxy, phenyl, and aryloxy
groups) and heterocycles (dihydrobenzofuran and thiophene)
were well tolerated in the asymmetric phenylation (2g–m). The
asymmetric α-phenylation of 1n successfully afforded 2n with
good enantioselectivity. However, the reaction of 1o, which is
one-carbon dehomologated as compared to 1a, gave
α-phenylated ketone 2o with low enantioselectivity, possibly
because the α-stereocenter of 5o was easily racemized under
the reaction conditions. Aliphatic methyl ketones 1p and 1q
were also used in this reaction, and the corresponding
α-phenylated ketones 2p and 2q were obtained in moderate
yields with good enantioselectivities.15–17
Entry
Ph3Al (eq.)
3 (eq.)
Yielda (%)
eeb (%)
1
2
3
4
2
3
3
1
2
2
1
2
58
66
51
14
94
94
93
85
a Isolated yield. b Determined by HPLC analysis on a chiral stationary
phase.
A plausible reaction pathway for the formation of enantio-
enriched (R)-α-phenyl ketone 2 is depicted in Scheme 2.
This umpolung reaction includes (i) the generation of
N-alkoxyenamine A; (ii) coordination with a nucleophilic
aluminium reagent (A → B); (iii) N−O bond cleavage and a
simultaneous nucleophilic attack of the nucleophilic
aluminium reagent (B → C); and (iv) the hydrolysis of the
imine intermediate C. The stereochemical feature of this
reaction can be rationalized as follows. First, the thermo-
dynamically stable (E)-N-alkoxyenamine A would be formed by
the condensation of ketone 1 and chiral isoxazolidine 3. When
chiral enamine A reacts with triphenylaluminium, two confor-
mations B and B′ can be considered. The σ* (N–O bond
cleavage) and π* orbitals (enamine moiety) are aligned in both
conformations. Conformation B should be favoured over B′
due to the steric repulsion between the methyl group and the
benzene ring. Therefore, a nucleophilic attack by another tri-
phenylaluminium onto the Si (bottom) face is favoured by the
anti-SN2′ displacement, presumably because of the steric inter-
triphenylaluminium (3 equiv.) improved the yield of 2a while
ensuring high enantioselectivity (entry 2). In contrast, a signifi-
cant decrease in the yield was observed when the amount of
triphenylaluminium was reduced to 1 equiv. (entry 4).14
With the optimized reaction conditions in hand (Table 1,
entry 2), we next examined the substrate scope of the asym-
metric umpolung reaction (Table 2). The asymmetric phenyla-
Table 2 Substrate scopea
a Reaction conditions: 1 (0.075 mmol), 3 (0.15 mmol), and Ph3Al
(0.23 mmol) in CH2Cl2 at 0 °C for 2–3 h. b Isolated yield. c Determined
by HPLC analysis on a chiral stationary phase.
Scheme 2 The proposed reaction pathway and stereochemical feature
of asymmetric umpolung phenylation to N-alkoxyenamine.
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Conflicts of interest
There are no conflicts to declare.
Acknowledgements
This study was supported by JSPS KAKENHI Grant Number
17K08216 (O.M.).
Scheme 3 Asymmetric α-phenylation of biologically active ketones.
Notes and references
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We next examined the asymmetric α-phenylation of biologi-
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and the phosphodiesterase inhibitor pentoxifylline were
selected for our asymmetric umpolung reaction (Scheme 3).
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compounds was successfully achieved to obtain the corres-
ponding α-phenylated ketones 2r and 2s in moderate yields,
with moderate to good enantioselectivities. Therefore, our pro-
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α-phenylmethyl ketones.
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94% ee when the amount of 1a was increased to 3 mmol
(Scheme 4). The synthetic utility of the current method was
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8942 | Org. Biomol. Chem., 2018, 16, 8940–8943
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17 The use of triethylaluminium for the asymmetric
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reaction of 1a with triisobutylaluminium in the presence of
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14 The excess amount of Ph3Al plays an important role in 18 We have not yet been able to establish the relative stereo-
enamine formation because it can trap one equivalent of
chemistry of the major diastereomer.
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