Catalytic Asymmetric Acyloin Rearrangements of α-Ketols, α-Hydroxy Aldehydes, and α-Iminols by N, N′-Dioxide-Metal Complexes

Article abstract of DOI:10.1021/acs.orglett.0c01626

A highly enantioselective acyloin rearrangement of cyclic α-ketols has been developed with a chiral Al(III)-N,N′-dioxide complex as catalyst. This strategy provided an array of optically active 2-acyl-2-hydroxy cyclohexanones in moderate to good yields with high enantioselectivities. The asymmetric isomerizations of acyclic α-hydroxy aldehydes and α-iminols were achieved as well under modified conditions, affording the corresponding chiral α-hydroxy ketones and α-amino ketones in moderate results. Moreover, further transformations of product to enantioenriched diols were carried out.

Full text of DOI:10.1021/acs.orglett.0c01626

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Letter
Catalytic Asymmetric Acyloin Rearrangements of α‑Ketols,
α‑Hydroxy Aldehydes, and α‑Iminols by N,N′‑Dioxide−Metal
Complexes
Li Dai, Xiangqiang Li, Zi Zeng, Shunxi Dong, Yuqiao Zhou,* Xiaohua Liu, and Xiaoming Feng*
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ABSTRACT: A highly enantioselective acyloin rearrangement of cyclic
α-ketols has been developed with a chiral Al(III)−N,N′-dioxide
complex as catalyst. This strategy provided an array of optically active
2-acyl-2-hydroxy cyclohexanones in moderate to good yields with high
enantioselectivities. The asymmetric isomerizations of acyclic α-
hydroxy aldehydes and α-iminols were achieved as well under modified
conditions, affording the corresponding chiral α-hydroxy ketones and α-amino ketones in moderate results. Moreover, further
transformations of product to enantioenriched diols were carried out.
Scheme 1. Chiral Lewis Acid Mediated Acyloin
Rearrangements
he acyloin rearrangement is the transformation of an α-
Thydroxycarbonyl compound into its structural isomer
through 1,2-carbon-to-carbon migration.1 Since the seminal
report from Prins and Shoppee in 1943,2 acyloin rearrangement
has been gradually utilized to construct otherwise inaccessible
molecular frameworks, especially for the synthesis and structural
modification of natural products.3 However, the reversibility of
such transformations under either acidic, basic, or thermal
conditions4 hampered its wide application in organic synthesis.
In view of the high value of the enantioenriched α-hydroxy
ketones and α-amino ketones,5 the development of catalytic
asymmetric versions of such processes was intriguing but highly
challenging.
In 2003, Brunner and Kagan et al. first disclosed their efforts
toward the asymmetric α-ketol rearrangement. A moderate ee
value was obtained for the isomerization of 1-benzoylcyclo-
pentanol after screening plenty of catalysts.6 In 2007, the
Maruoka group described the asymmetric rearrangement of α,α-
dialkyl-α-siloxy aldehydes to α-siloxy ketones by using a chiral
aluminum catalyst (Scheme 1a, left).7 In 2014, Wulff et al.
reported zirconium/VANOL complex accelerated asymmetric
α-iminol rearrangements with wide substrate scope (Scheme 1a,
right).8 Three years later, the first example of organocatalytic
enantioselective acyloin rearrangement of α,α-disubstituted α-
hydroxy acetals was achieved by Zhu and co-workers.9 Very
recently, the same group developed copper/Box catalyzed highly
enantioselective cyclic α-hydroxy ketone rearrangement and
sequential kinetic resolution processes (Scheme 1b).10
Enantioenriched 2-acyl-2-hydroxy cyclohexan-1-ones, dihydrox-
yhexahydro-benzofuranones, and dihydroxyhexahydro-cyclo-
hepta-furanones were delivered in 35−99% yield with 79−
98% ee. Nevertheless, this still leaves much room for
improvement in terms of substrate scope and catalyst. As part
of our ongoing interest in asymmetric rearrangements11 and
intrigued by the well-established platform of chiral metal−N,N′-
dioxide catalysts,12 we envisioned that this kind of chiral Lewis
acid had the potential to be effective in promoting the acyloin
rearrangement of α-iminol or α-ketol through coordination and
activation of vicinal difunctional groups.13 Herein, we wish to
describe our efforts along this line. The chiral Al(III)−N,N′-
dioxide complex was identified to be an efficient catalyst to
promote enantioselective acyloin rearrangement of cyclic α-
Received: May 12, 2020
https://dx.doi.org/10.1021/acs.orglett.0c01626
© XXXX American Chemical Society
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A

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a
ketols, and various 2-aryl-2-hydroxy cyclohexanones were
readily afforded in moderate to good yields with high
enantioselectivities. Moreover, under slightly modified con-
ditions, the asymmetric isomerizations of acyclic α-hydroxy
aldehydes and α-iminols were achieved as well.
Scheme 2. Substrate Scope of Cyclic α-Ketols 1
Initially, 1-benzoylcyclopentanol 1a was selected as the model
substrate to optimize the reaction conditions (Table 1).6,14 First,
Table 1. Optimization of Reaction Conditions for the
Asymmetric Rearrangement of Cyclic α-Ketol 1a
a
b
c
entry
metal salt
ligand
yield (%)
ee (%)
1
2
3
4
5
6
Fe(OTf)3
In(OTf)3
Al(OTf)3
Al(OTf)3
Al(OTf)3
Al(OTf)3
Al(OTf)3
Al(OTf)3
Al(OTf)3
L3-PiMe2
L3-PiMe2
L3-PiMe2
L3-PiPr2
L3-PrPr2
L3-RaPr2
L3-PiPr2
L3-PiPr2
L3-PiPr2
48
49
47
50
39
28
69
99
98
53
27
55
87
85
69
87
91
91
a
The reactions were carried out with Al(OTf)3/L3-PiPr2 (1:1, 5 mol
%) and 1 (0.1 mmol) with H2O (3 μL) in BrCH2CH2Br (1.0 mL) at
40 °C for the indicated time. Isolated yields. Enantiomeric excess (ee)
was determined by HPLC analysis on a chiral stationary phase.
d
7
8
9
de
,
def
, ,
a
Unless otherwise noted, the reactions were performed with the metal
salt/ligand (1:1, 10 mol %) and 1a (0.1 mmol) in THF (1.0 mL) at
electron-withdrawing group (for instance, CF3) at the para-
position (2f) or methyl substituent at the meta-position (2h) in
the substrate led to diminished yields (59% yield and 67% yield,
respectively). To get more insight into the reaction, the product
2f was subjected to the standard reaction system, and the very
trace of starting compound 1f was observed; the ee value did not
change.4 It is worth mentioning that 2-naphthyl-containing
substrate 1j proceeded the migration process smoothly under
the standard conditions, affording the desired product 2j in
decent yield (63%) with good enantiomeric excess (87% ee).
Meanwhile, piperonyl-substituted α-hydroxy ketone was suit-
able as well, and the corresponding product 2k was isolated in
89% yield with 88% ee. For the reaction of 1l with the
disubstituted aryl ring, elevated reaction temperature (60 °C)
was necessary, and product 2l was obtained with good outcomes
(97% yield, 91% ee). The absolute configurations of the
products 2i and 2l were both determined to be (S) configuration
by X-ray crystallography analysis, which were consistent with the
configurations of chiral 2a, 2e, 2f, and 2j, by comparing the
optical rotation data in the previous report.16 The configurations
of other products were assigned by comparing with the CD
spectrum of compound 2i.
Encouraged by the satisfactory results of cyclic α-ketol, we
attempted to apply the current system to the rearrangement of
α-hydroxy aldehydes 3 (Scheme 3). Unfortunately, only a trace
amount of the desired rearranged product was afforded with
11% ee under the above optimized reaction conditions. After
modification of the reaction parameters, including the use of L3-
PiMe2 as the ligand and Br2CHCHBr2 as solvent, lower reaction
temperature (30 °C), and addition of 4 Å MS (10 mg), the yield
and enantioselectivity of this transformation reached a
satisfactory level (54% yield, 82% ee) after 48 h (see details in
b
c
40 °C for 24 h. Yield of isolated product. Determined by HPLC
analysis on a chiral stationary phase. BrCH2CH2Br (1.0 mL) was
used as the solvent. H2O (3 μL) was added. 5 mol % of catalyst
d
e
f
loading.
different metal salts were investigated in the presence of N,N′-
dioxide L3-PiMe2. It was pleasant to find that in situ formed
chiral Lewis acid catalysts could promote the rearrangement of
compound 1a under mild conditions,6 and Al(OTf)3 gave better
results than Fe(OTf)3 and In(OTf)3 in terms of enantiose-
lectivity (entries 1−3, 55% ee vs 53% ee, 27% ee). To our
delight, increasing the steric hindrance of the amide substituents
from 2,6-Me2C6H3 to 2,6-iPr2C6H3 resulted in higher
enantioselectivity (entry 4, 87% ee vs 55% ee). Then,
representative N,N′-dioxides with different skeletons were
examined. L3-PiPr2 derived from L-pipecolinic acid was proved
to be superior to L-proline-derived L3-PrPr2 or L-ramipril-based
L3-RaPr2 (entries 5 and 6, 87% ee vs 85% ee, 69% ee). The
subsequent survey of solvents indicated that BrCH2CH2Br
could provide an improved yield compared to THF (entry 7,
69% yield vs 50% yield; for more details, see SI, Page 7).
Interestingly, the addition of water (3 μL, ca. 1.7 equiv) into the
reaction system led to further improvement in the yield and
enantiomeric excess (entry 8, 99% yield, 91% ee.).15 When the
reaction was carried out with 5 mol % catalyst loading, both the
yield and enantioselectivity were maintained (entry 9).
With the optimal reaction conditions in hand, the substrate
scope of 1-aroylcyclopentanols was next examined (Scheme 2).
It was found that the substituent pattern and the electronic
property of the aryl moiety displayed a limited influence on the
enantioselectivity (2a−2l, 84−92% ee). However, the strong
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Scheme 3. Substrate Scope of Acyclic α-Hydroxy Aldehydes
3
Scheme 4. Substrate Scope of Acyclic α-Hydroxy Aldimines
5
a
a
a
The reactions were carried out with Sc(OTf)3/L2-PiPr3 (1:1, 10 mol
%) and 5 (0.1 mmol) in toluene (1.0 mL) at 40 °C for 24 h. Isolated
yields. Enantiomeric excess (ee) was determined by HPLC analysis on
a chiral stationary phase.
a
The reactions were carried out with Al(OTf)3/L3-PiMe2 (1:1, 10
to be (R) by comparing the optical rotation with the previous
report.8a
mol %), 3 (0.1 mmol) with H2O (3 μL), and 4 Å MS (10 mg) in
Br2CHCHBr2 (1.0 mL) at 30 °C for 48 h. Isolated yields.
Enantiomeric excess (ee) was determined by HPLC analysis on a
chiral stationary phase.
To exhibit the practicability of this methodology, a gram-scale
synthesis of 2a was performed under the standard reaction
conditions with 5.0 mmol of 1a, and the corresponding product
2a was isolated in 99% yield with 92% ee. The transformations of
the product were performed as well. Treatment of the chiral
compound 2a with vinylmagnesium bromide gave rise to the
diol compound 7 in 73% yield with >19:1 dr (Scheme 5).16b
Similarly, reduction of the compound 2a with LiAlH4 provided
diol compound 8 in high yield with 9:1 dr and 90% ee.16b
SI).17 Under these conditions, representative α-hydroxy
aldehydes 3 were tested. Although the enantioselective control
of such rearrangement was in the good level, a notable difference
in the reactivity was observed. Generally, aryl-substituted
alcohols with substituents at the ortho- or para-position
furnished the expected products in higher yields than that
with meta-substituted ones (4c−4e, 4i). The absolute
configurations of products 4a−4g were determined to be (R)
by comparing the optical rotation with the previous report.18
The asymmetric rearrangement of α-hydroxy aldimines was
explored as well. The acyclic 1,1-diphenyl-2-(phenylimino)-
ethanol 5a was selected as the model substrate.8a After extensive
investigation, we concluded that excellent ee but moderate yield
of the corresponding product 6a was obtained when the
In(OTf)3/L2-PiPr3 complex was employed as the catalyst (41%
yield, 93% ee, see SI for details). The low yield of the In(III)-
mediated process resulted from the unknown side reaction.
Comparatively, the use of Sc(OTf)3 as the metal precursor
afforded a high yield but moderate enantioselectivity (99% yield,
68% ee). Then the substrate scope of α-hydroxy aldimines was
examined with ScIII as the catalyst (Scheme 4; see Scheme S1 in
page 13 of SI for the results of In(III)-mediated reactions).
Similarly, the fluoro substituent at meta-position 5c exhibited
lower reactivity than that with a para-substituted one, 5b. Of
note, substrate 5d containing 2-naphthyl rings isomerized to the
product 6d in good yield with excellent enantioselectivity (78%
yield, 98% ee). Although high yield (99% yield) was obtained for
α-hydroxy aldimine 5e bearing an electron-rich Ar group,
slightly lower enantiomeric excess (53% ee) was given. Another
substituent, for example, N-MeOC6H4-protected aldimine, was
compatible in this system, generating the desired rearranged
product 6f in 97% yield with 77% ee. The absolute
configurations of the products 6a, 6b, and 6f were determined
Scheme 5. Gram-Scale Synthesis of 2a and Its Further
Transformations
In summary, we have realized the acyloin rearrangements of
cyclic α-ketols, as well as α-hydroxy aldehydes and aldimines,
with chiral N,N′-dioxide complexes of Al(III) or Sc(III) salts
under mild reaction conditions. The corresponding chiral α-
hydroxy ketones and α-amino ketones were produced in
moderate to good yields with high enantioselectivities. Further
studies on other asymmetric rearrangement reactions are
underway.
ASSOCIATED CONTENT
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AUTHOR INFORMATION
Corresponding Authors
■
Yuqiao Zhou − Key Laboratory of Green Chemistry
&Technology, Ministry of Education, College of Chemistry,
Sichuan University, Chengdu 610064, China;
Email: yuqiao.zhou@scu.edu.cn
Xiaoming Feng − Key Laboratory of Green Chemistry
&Technology, Ministry of Education, College of Chemistry,
Sichuan University, Chengdu 610064, China; orcid.org/
0000-0003-4507-0478; Email: xmfeng@scu.edu.cn
Authors
Li Dai − Key Laboratory of Green Chemistry &Technology,
Ministry of Education, College of Chemistry, Sichuan University,
Chengdu 610064, China
Xiangqiang Li − Key Laboratory of Green Chemistry
&Technology, Ministry of Education, College of Chemistry,
Sichuan University, Chengdu 610064, China
Zi Zeng − Key Laboratory of Green Chemistry &Technology,
Ministry of Education, College of Chemistry, Sichuan University,
Chengdu 610064, China
Shunxi Dong − Key Laboratory of Green Chemistry
&Technology, Ministry of Education, College of Chemistry,
Sichuan University, Chengdu 610064, China; orcid.org/
0000-0002-3018-3085
Xiaohua Liu − Key Laboratory of Green Chemistry &Technology,
Ministry of Education, College of Chemistry, Sichuan University,
Chengdu 610064, China; orcid.org/0000-0001-9555-0555
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c01626
(4) (a) Lee, S. D.; Chan, T. H.; Kwon, K. S. Rearrangement of α-
Acyloxyacetates into 2-Hydroxy-3-ketoesters. Tetrahedron Lett. 1984,
25, 3399. (b) Rubin, M. B.; Inbar, S. Equilibria among Anions of.alpha.-
Hydroxy.beta.-Diketones and.alpha.-Ketol Esters. J. Org. Chem. 1988,
Notes
The authors declare no competing financial interest.
̈
53, 3355. (c) Brunner, H.; Stohr, F. Metal-Catalyzed Enantioselective
ACKNOWLEDGMENTS
■
α-Ketol Rearrangements. Eur. J. Org. Chem. 2000, 2000, 2777.
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We acknowledge the National Natural Science Foundation of
China (Nos. 21890723 and 21801175) and the Fundamental
Research Fund for the Central Universities for financial support.
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(12) For selected reviews of N,N′-dioxide, see: (a) Liu, X. H.; Lin, L.
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Component Inverse Electron-Demand Aza-Diels-Alder Reaction:
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(14) In Zhu’s work (ref 10), they declared that the α-dicarbonyl group
was essential for high ee.
(15) In order to probe the role of water in this system, we tried to get
the crystals of the Al(III)-N,N′-dioxide complex in the presence of
water. However, we have not gotten the suitable crystals yet for X-ray
E
https://dx.doi.org/10.1021/acs.orglett.0c01626
Org. Lett. XXXX, XXX, XXX−XXX