Enantioselective Acyloin Rearrangement of Acyclic Aldehydes Catalyzed by Chiral Oxazaborolidinium Ion

Article abstract of DOI:10.1021/acs.orglett.1c00314

A catalytic enantioselective acyloin rearrangement of acyclic aldehydes to synthesize highly optically active acyloin derivatives is described. In the presence of a chiral oxazaborolidinium ion catalyst, the reaction provided chiral α-hydroxy aryl ketones in high yield (up to 95%) and enantioselectivity (up to 98% ee). In addition, the enantioselective acyloin rearrangement of α,α-dialkyl-α-siloxy aldehydes produced chiral α-siloxy alkyl ketones in high yield (up to 92%) with good enantioselectivity (up to 89% ee).

Full text of DOI:10.1021/acs.orglett.1c00314

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Letter
Enantioselective Acyloin Rearrangement of Acyclic Aldehydes
Catalyzed by Chiral Oxazaborolidinium Ion
Soo Min Cho, Si Yeon Lee, and Do Hyun Ryu*
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ABSTRACT: A catalytic enantioselective acyloin rearrangement
of acyclic aldehydes to synthesize highly optically active acyloin
derivatives is described. In the presence of a chiral oxazabor-
olidinium ion catalyst, the reaction provided chiral α-hydroxy aryl
ketones in high yield (up to 95%) and enantioselectivity (up to
98% ee). In addition, the enantioselective acyloin rearrangement of
α,α-dialkyl-α-siloxy aldehydes produced chiral α-siloxy alkyl ketones in high yield (up to 92%) with good enantioselectivity (up to
89% ee).
he acyloin rearrangement,1−5 involving 1,2-aryl or -alkyl
desired to improve the yield and enantioselectivity of acyloin
Tmigration to the carbonyl group, is a useful synthetic and broaden its substrate scope.
Recently, our group reported the catalytic asymmetric
acyloin rearrangement of cyclic aldehydes3 in the presence of
a chiral oxazaborolidinium ion11,12 (COBI) as a Lewis acid
catalyst (Scheme 1B, a). The catalytic acyloin rearrangement of
cyclopropyl aldehydes, which were formed through enantiose-
lective cyclopropanation of siloxyacrolein with diazo esters,
provided highly optically active cyclobutanones (81−98% ee)
with excellent diastereomeric ratios (up to >20:1). Inspired by
these encouraging results, we envisioned that the reaction of
acyclic aldehydes would provide chiral acyloins under similar
conditions. Herein we report a broadly applicable enantiose-
lective acyloin rearrangement of acyclic aldehydes catalyzed by
the COBI catalyst.
Initially, the asymmetric acyloin rearrangement of α,α-
diphenyl-α-trimethylsiloxy aldehyde 1a was examined in the
presence of 20 mol % COBI catalyst 3a activated by
trifluoromethanesulfonic imide (Table 1, entry 1). When the
reaction was carried out at −40 °C in toluene, the optically
active α-trimethylsiloxy ketone 2a was obtained in 92% yield
with 60% ee. First, changing the solvent to dichloromethane
led to improved enantioselectivity (Table 1, entry 2). In a
screen of various catalyst structures, the simple catalyst 3a with
Ar = R = phenyl yielded the best result (Table 1, entries 2−4).
Although catalyst 3b afforded 2a in good yield, the reaction
time for rearrangement was excessive (Table 1, entry 3).
Because α-triethylsiloxy ketone 2b was obtained with a
method for structural reorganization of organic molecules that
renders the synthesis of various natural products feasible.6,7
Through the acyloin rearrangement, α-hydroxy ketone
(acyloin)8 can be easily synthesized as a versatile building
block8b,9 for many natural products and pharmaceuticals.8b,10
However, the inherent reversibility of this reaction involving an
equilibrium between two isomers1b has made it highly
challenging to develop catalytic enantioselective rearrange-
ments.
To overcome this limitation, asymmetric acyloin rearrange-
ments of aldehyde moieties have been developed.2,3 Because
the released steric and strain factors of ketones provide a
thermodynamic advantage compared with aldehydes, the
system undergoes a unidirectional reaction toward ketone
products.1b Currently there are three examples of enantiose-
lective acyloin rearrangements of acyclic aldehyde derivatives
such as protected aldehydes or aldimine compounds.2b−d In
2007, the Maruoka group reported a chiral-organoaluminum-
catalyzed enantioselective rearrangement of α,α-dialkyl-α-
siloxy aldehydes (Scheme 1A, a).2d In 2014, the Wulff group
developed an asymmetric α-iminol rearrangement of α-
hydroxy aldimines catalyzed by a zirconium/VANOL complex
(Scheme 1A, b).2c Three years later, chiral phosphoramides
were used to catalyze the asymmetric rearrangement of α-
hydroxy acetals, as reported by the Zhu group (Scheme 1A,
d).2b To the best of our knowledge, there is only one example
of an asymmetric acyloin rearrangement using acyclic α-
hydroxy aldehyde.2a Very recently, the Feng group reported
the enantioselective acyloin rearrangement of α-hydroxy
aldehydes using an aluminum/N,N′-dioxide complex as the
catalyst (Scheme 1A, c). However, enantioenriched aromatic
acyloins were obtained in low yield (11−54%) with 74−88%
ee. Thus, the development of a new catalytic reaction is highly
Received: January 27, 2021
Published: February 8, 2021
https://dx.doi.org/10.1021/acs.orglett.1c00314
© 2021 American Chemical Society
Org. Lett. 2021, 23, 1516−1520
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After optimization of the reaction conditions for the
enantioselective acyloin rearrangement, we evaluated the
scope of the reaction with a range of α,α-diaryl-α-hydroxy
aldehydes (Table 2). The reaction of electron-rich aldehydes 1
Scheme 1. Enantioselective Catalytic Acyloin
Rearrangement of Various Aldehyde Compounds
a
Table 2. Scope of α,α-Diaryl-α-hydroxy Aldehydes 1
entry
2
Ar
time (h)
yield (%)
ee (%)
b
b
1
2
3
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
Ph
3
12
12
12
12
12
1
1
18
1
90 (86 )
98 (98 )
4-MePh
4-MeOPh
4-FPh
4-ClPh
4-BrPh
2-MePh
2-MeOPh
3-MePh
1-naphthyl
2-naphthyl
88
83
85
80
70
93
88
86
95
85
98
95
95
96
95
98
90
98
94
92
c
4
c d
,
5
6
c d
,
7
8
9
e
10
11
c e
,
2m
18
a
The reactions of α-hydroxy aldehydes 1 (0.2 mmol) were performed
in the presence of catalyst 3a (20 mol %) in dichloromethane (1.0
mL) at −40 °C. All yields refer to isolated products. The ee values
b
were determined by chiral HPLC analysis. On a 1.0 mmol scale.
c
d
The reaction was conducted at 0 °C. 40 mol % catalyst was used.
e
2.0 mL of dichloromethane was used.
provided highly optically active products 2 in excellent yields
(Table 2, entries 2, 3, and 7−11). However, the rearrangement
of halogenated aldehydes 1 showed very low conversion at
−40 °C. When the reaction was performed at 0 °C, acyloins
2f−h were obtained in high yield and ee (Table 2, entries 4−
6). The (S) absolute configurations of 2c−m were confirmed
through a comparison of the optical rotation data of 2c−m
with literature values (see the Supporting Information).
Encouraged by the promising results illustrated in Table 2,
we next investigated the reaction of α-aryl-α-phenyl-α-hydroxy
aldehydes to investigate their migratory aptitude (Table 3).
Under the optimized conditions, a mixture of α-hydroxy
ketones 2n and 2n′ was obtained with moderate selectivity
(3:1), preferring migration of the p-tolyl group in 40% yield
with excellent enantioselectivity (Table 3, entry 1). Changing
the p-tolyl group to a sterically more hindered o-tolyl group
improved the migratory selectivity to 4.5:1 (Table 3, entry 3).
When the strong electron-donating p-methoxyphenyl sub-
stituted aldehyde 1q was used, the migratory selectivity
increased to 10:1 (Table 3, entry 4).2a The unreacted 1q
was recovered in 35% yield with 99% ee (s factor = 16).13
These results matched well with the migration order for the
pinacol rearrangement.2d,14,15a
Table 1. Optimization of the Enantioselective Acyloin
Rearrangement of Aldehydes 1
a
b
c
entry
X
2
3
solvent
yield (%)
ee (%)
d
e
1
2
3
4
5
6
TMS
TMS
TMS
TMS
TES
H
2a
2a
2a
2a
2b
2c
3a
3a
3b
3c
3a
3a
PhMe
92
90
90
50
95
90
60
63
64
14
27
98
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
d
d
f
a
The reactions were performed with aldehyde 1 (0.2 mmol) in the
presence of catalyst 3 (20 mol %) in the solvent (1.0 mL) for 3 h at
b
c
d
−40 °C. Isolated yields. Determined by chiral HPLC analysis. The
To further investigate the substrate scope of the present
catalytic system, we performed the catalytic asymmetric acyloin
rearrangement with α,α-dibenzyl-α-hydroxy aldehyde 4a.
However, the best conditions for α,α-diaryl aldehydes were
not the optimal conditions for α,α-dialkyl aldehydes. Because
of easy dimerization of 4a with the COBI catalyst system,
protected α-triethylsiloxy aldehyde 4b was considered as a
substrate for the rearrangement. While the reaction of 4a
provided the dimer product in 90% yield, the reaction of 4b
e
f
reaction was conducted for 18 h. Trimethylsilyl. Triethylsilyl.
dramatically diminished enantioselectivity of 27% (Table 1,
entry 5), we thought that a sterically less hindered group was
needed. Gratifyingly, introduction of a hydroxy group into
aldehyde 1 produced α-hydroxy ketone 2c in 90% yield with
an improved enantioselectivity of 98% (Table 1, entry 6).
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selective reduction of α-hydroxy alkyl ketone 5b to confirm the
absolute structure is illustrated in Scheme 2. The reduction of
Table 3. Enantioselective Acyloin Rearrangement of α-Aryl-
α-phenyl-α-hydroxy Aldehydes 1
a
Scheme 2. Reduction of 5b and Removal of the Triethylsilyl
Group of 6
entry
2
Ar
2:2′
yield (%)
ee (%)
b
1
2
2n
2o
2p
2q
4-MePh
2-naphthyl
2-MePh
3:1
1.9:1
4.5:1
10:1
40
69
40
58
96 (98 )
b
95 (97 )
c
b
5b with L-Selectride generated polar Felkin−Anh product17
6
3
de
,
96 (93 )
b
4
4-MeOPh
92 (99 )
with a high diastereomeric ratio (12:1). The triethylsilyl group
of 6 was removed with tetrabutylammonium fluoride (TBAF)
to afford chiral diol 7. The absolute configuration of 7 was
confirmed through a comparison of the optical rotation data
for 7 with the literature result,18 and the (R) configurations of
all acyloins 5 were assigned accordingly.
The observed stereochemistry for the asymmetric acyloin
rearrangement of the aldehyde using COBI catalyst 3a or 3b
could be explained by pretransition state models 8 or 9 shown
in Figure 1. In the case of α,α-diaryl-α-hydroxy aldehydes, the
a
The reactions of α,α-aryl phenyl-α-hydroxy aldehydes 1 (0.2 mmol)
were performed in the presence of catalyst 3a (20 mol %) in
dichloromethane (1.0 mL). All yields refer to the total yields of
products 2 and 2′. The ee values were determined by chiral HPLC
analysis. Except for the values in parentheses, all of the ee values are
b
c
the results for acyloin 2. ee of 2′. The reaction was conducted for 4
d
e
h at −78 °C. The reaction was conducted for 0.5 h at −78 °C. The
ee of recovered 1q was determined by chiral HPLC analysis after
reduction of the aldehyde using NaBH4 (1.0 equiv).
proceeded well in the presence of catalyst 3b in toluene at −20
°C to afford the rearranged product 5b in 92% yield with 86%
ee (Table 4, entries 1 and 2; for details, see the Supporting
a
Table 4. Scope of α,α-Dialkyl-α-siloxy Aldehydes 4
entry
5
R
yield (%)
ee (%)
b
c
1
5a
5b
5c
5d
5e
5f
Bn
Bn
4-MeOBn
4-FBn
4-ClBn
2-BrBn
<10
−
d
d
2
3
92 (90 )
86 (86 )
84
90
80
88
87
87
76
86
82
89
86
e
4
f
5
e f
,
6
7
8
e
5g
5h
2-naphthyl-CH2
(CH3)2CHCH2
g
78
a
The reactions of α-siloxy aldehydes 4 (0.2 mmol) were performed in
the presence of catalyst 3b (20 mol %) in toluene (1.0 mL) at −20
°C. All yields refer to isolated products. The ee values were
b
determined by chiral HPLC analysis. The reaction was conducted
c
with the α,α-dibenzyl-α-hydroxy aldehyde. A 90% yield of dimerized
d
e
products was obtained. On a 1.0 mmol scale. The reaction was
f
conducted for 18 h. The reaction was conducted at 0 °C.
g
Figure 1. Pretransition state models for enantioselective acyloin
rearrangements of α-hydroxy aldehyde 1c catalyzed by 3a and α-siloxy
aldehyde 4b catalyzed by 3b.
Determined by chiral HPLC after removal of the TES protecting
group followed by reprotection with 3,5-dinitrobenzoate.
Information15b). With the modified optimization, the range of
α,α-dialkyl-α-siloxy aldehydes was examined. As shown in
Table 4, regardless of the electronic properties of the
substituents on the benzyl group, optically active acyloins 5
were obtained (Table 4, entries 3−7). Notably, our catalytic
system successfully yielded simple alkyl substrate 5h with good
enantioselectivity (Table 4, entry 8).
The obtained α-hydroxy aryl ketone (benzoin) moieties are
known to be valuable intermediates that can be used for the
preparation of functionalized compounds such as chiral diols,
diol derivatives, amino alcohols, etc.2b,16 The diastereomeric
hydrogen-bonding coordination of aldehyde 1c to 3a
represented by 8 was similar to that previously suggested for
enantioselective Strecker reactions with aldimines.19 In
pretransition state complex 8, the aldehyde was placed above
the phenyl group of catalyst 3a, which effectively blocked the re
face (back) migration of the Ph2 group of aldehyde 1c.
Carbonyl activation by the COBI catalyst facilitated concerted
migration of the Ph1 group of 1c (path a in pretransition state
8), generating an oxocarbenium ion intermediate. The proton
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shift provided α-hydroxy ketone 2c with the (S) configuration
as the major enantiomer.
ACKNOWLEDGMENTS
■
This work was supported by grants from the National Research
Foundation of Korea (NRF) funded by the Korean Govern-
ment (MSIT) (NRF-2019R1A4A2001440 and
2019R1A2C2087018) and by the 111 Project (D18012).
Interestingly, the acyloin rearrangement of α,α-dialkyl
aldehydes unexpectedly yielded α-siloxy ketone 5b with the
(R) configuration. Presumably, the mode of coordination of
α,α-dibenzyl-α-siloxy aldehyde 4b to COBI 3b was the same as
previously postulated for enantioselective 1,2-addition of
aldehydes with COBI.11a In pretransition state model 9, the
benzyl (CH2Ph1) group was placed above the 3,5-dimethyl-
phenyl group of 3b as a result of π−π interactions between Ph1
and the 3,5-dimethylphenyl group. At that time, the migrating
σ bond (C−C1) was parallel to the carbonyl π bond, while the
other σ bond (C−C2) was orthogonal. Because the parallel σ
bond could migrate to the carbonyl π bond during the acyloin
rearrangement,6 only the benzyl (CH2Ph1) group could
participate in the concerted migration pathway (path a in
pretransition state 9). As a result, α-siloxy ketone 5b with the
(R) configuration was formed as the major enantiomer
through silyl group shift.
In summary, we developed a Lewis acid-catalyzed
enantioselective acyloin rearrangement of acyclic α,α-diaryl
and α,α-dialkyl aldehydes. This synthetic method provided
highly optically active α-hydroxy or α-siloxy ketones in high
yields. Moreover, the catalytic system was applied to the
reaction of differently α,α-disubstituted-α-hydroxy aldehydes
and afforded isomeric ketones with good migratory selectivities
(up to 10:1) and excellent enantioselectivities. The absolute
configurations of the products were predicted using the
pretransition state models in Figure 1 and were confirmed
by comparison with reported literature. We believe that the
resulting acyloins could be valuable precursors for the synthesis
of bioactive compounds. Additional extensions of the substrate
scope and application of this approach are underway.
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ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c00314.
General information, experimental procedures, charac-
terization of products, and full analytical data with
spectra (PDF)
AUTHOR INFORMATION
■
Corresponding Author
Do Hyun Ryu − Department of Chemistry, Sungkyunkwan
University, Jangan, Suwon 16419, Korea; orcid.org/
0000-0001-7615-4661; Email: dhryu@skku.edu
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natural products, see: Song, Z.-L.; Fan, C.-A.; Tu, Y.-Q. Semipinacol
Rearrangement in Natural Product Synthesis. Chem. Rev. 2011, 111,
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Authors
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T.; Gould, S. J.; Laufer, R. S.; Dmitrienko, G. I. Isoprekinamycin Is a
Diazobenzo[a]fluorene Rather than a Diazobenzo[b]fluorene. J. Am.
Chem. Soc. 2000, 122, 8325−8326.
Soo Min Cho − Department of Chemistry, Sungkyunkwan
University, Jangan, Suwon 16419, Korea
Si Yeon Lee − Department of Chemistry, Sungkyunkwan
University, Jangan, Suwon 16419, Korea
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c00314
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The authors declare no competing financial interest.
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