Desymmetrization of gem-diols via water-assisted organocatalytic enantio- And diastereoselective cycloetherification

Article abstract of DOI:10.1039/d0cc05509c

The first desymmetrization of gem-diols forming chiral hemiketal carbons was accomplished via organocatalytic enantio- and diastereoselective cycloetherification, which afforded optically active tetrahydropyrans containing a chiral hemiketal carbon and tetrasubstituted stereocenters bearing synthetically versatile fluorinated groups. The desymmetrization of silanediols was also demonstrated as an asymmetric route to chiral silicon centers.

Full text of DOI:10.1039/d0cc05509c

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Desymmetrization of gem-diols via water-assisted organocatalytic
enantio- and diastereoselective cycloetherification
Ryuichi Murata, Akira Matsumoto,‡ Keisuke Asano,* and Seijiro Matsubara*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
The first desymmetrization of gem-diols forming chiral hemiketal preferentially occupies the axial positions on anomeric carbons
carbons was accomplished via organocatalytic enantio- and in saturated six-membered oxacycles; various cyanohydrins are
diastereoselective cycloetherification, which afforded optically enantioselectively transformed to densely functionalized
active tetrahydropyrans containing a chiral hemiketal carbon and tetrasubstituted chiral carbon units while forming
tetrasubstituted stereocenters bearing synthetically versatile tetrahydropyran (THP) rings. A hydroxy group is also a potent
fluorinated groups. The desymmetrization of silanediols was also small and electronegative functional group, and indeed it is
demonstrated as an asymmetric route to chiral silicon centers.
partially located in the axial position on anomeric carbons of
saccharides in nature (Figure 1b). These concepts inspired us to
investigate the desymmetrization of gem-diols via
Desymmetrization of achiral substrates is an efficient strategy for
constructing tetrasubstituted chiral carbons, which are
fundamental motifs that increase molecular complexity and
diversity, but are among the most challenging targets in synthetic
organic chemistry.1 In particular, the desymmetrization of
achiral diols has been extensively studied as it provides chiral
molecules bearing oxygen-containing functional groups,1
organocatalytic
enantio-
and
diastereoselective
cycloetherification (Scheme 1); this transformation affords
optically active THP derivatives containing a chiral hemiketal
carbon. The desymmetrization of silanediols was also
investigated for the asymmetric construction of chiral silicon
centers.
d–1f
2
which play important roles within organisms. However, to the
best of our knowledge, gem-diols, which are the shortest achiral
diols, have not been employed in this synthetic approach, even
though desymmetrization of gem-diols allows for asymmetric
construction of chiral hemiketal carbons, which are ubiquitous
functional groups found in a variety of bioactive compounds and
pharmaceuticals (Figure 1a).3 In addition, while catalytic
asymmetric ketalization and acetalization have been reported
4
over the last decade, there have been no examples of a catalytic
enantioselective construction of hemiketals.
Fig. 1 Bioactive 2-hydroxy-THPs: (a) chiral hemiketals and (b) equilibrium of D-glucose.
We recently developed methods for asymmetric construction
of tetrasubstituted chiral carbons via enantio- and
diastereoselective cycloetherification of cyanohydrins with
5
bifunctional organocatalysts. In these studies, a cyano group,
which is a small and electronegative functional group,
Department of Material Chemistry, Graduate School of Engineering, Kyoto
University, Kyotodaigaku-Katsura, Nishikyo, Kyoto 615-8510, Japan.
E-mail: asano.keisuke.5w@kyoto-u.ac.jp; matsubara.seijiro.2e@kyoto-u.ac.jp
Fax: +81 75 383 2438; Tel: +81 75 383 7571, +81 75 383 7130
Scheme
1 Desymmetrization of gem-diols via organocatalytic enantio- and
diastereoselective cycloetherification.
†
Electronic Supplementary Information (ESI) available: Experimental procedures,
analytical and spectroscopic data for synthetic compounds, and copies of NMR.
CCDC 2022129; 2022132.
We began our investigations using (E)-8,8,8-trifluoro-1-
phenyloct-2-ene-1,7-dione (1a) and 3 equiv of water with 10
‡
Present address: Graduate School of Pharmaceutical Sciences, Kyoto University,
6
Yoshida-Shimoadachi, Sakyo, Kyoto 606-8501, Japan.
mol % of a bifunctional organocatalyst (3a
–
3e, Figure 2) in
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Journal Name
Table 1 Optimization of conditionsa
further investigations revealed water plays an impoVrietawnAtrtricoleleOnnlionet
DOI: 10.1039/D0CC05509C
only for generating gem-diol substrates, but also for controlling
the reaction reversibility.10 Using isolated gem-diol 4a, the
product selectivity of 2a over 2a' during the reaction was
monitored in the presence and absence of 3.0 equiv of water
b
c
Entry
1
Catalyst
Solvent
Yield (%)
93
dr
ee (%)
(
Scheme S1 in the SI). Although the ratio of 2a to 2a' gradually
3a
CH
CH
CH
CH
CH
CH
CH
2
2
2
2
2
2
2
Cl
2
Cl
2
Cl
2
Cl
2
Cl
2
Cl
2
Cl
2
>20:1
>20:1
>20:1
>20:1
>20:1
—
97
increased in both cases, the use of water proved to be of
significance for obtaining high product selectivity. In addition,
the absolute configurations of 2a and its enantio- and
diastereomeric purity did not change throughout reaction time
(96–97% ee, >20:1 dr),11 while those of 2a' gradually changed
2
3
4
5
6
7
8
9
3b
3c
3d
3e
3f
89
81
84
87
<5
37
89
36
95
–96
–95
–97
—
(
1
without water: from 77% to 16% ee; with water: from 79% to –
6% ee).
3g
3a
3a
>20:1
>20:1
>20:1
–4
2
H O
63
neat
90
aReactions were run using the substrate (0.15 mmol), H
O (0.45 mmol), and the
2
catalyst (0.015 mmol) in the solvent (0.30 mL). The mixture of 1a and its hydrated
diol 4a (4.6:1–2.6:1) was used as the substrate. bIsolated yields.
2
Scheme 2 Effects of H O.
Fig. 2 Organocatalysts.
2 2
CH Cl at 25 °C (Table 1, entries 1–5). All the bifunctional
organocatalysts we investigated gave high yields and excellent
enantio- and diastereoselectivities (Table 1, entries 1–5):7
quinine- and cinchonidine-derived catalysts 3a and 3b afforded
2
a
with high enantiomeric purity, and quinidine- and cinchonine-
derived catalysts 3c and 3d afforded the opposite enantiomer of
with high enantioselectivities (Table 1, entries 1–4).
Scheme 3 Plausible reaction pathway.
2
a
Moreover, catalyst 3e, having a cyclohexanediamine framework,
also afforded the product in good yield with high
We also investigated the effect of water on the reaction
reversibility (Scheme 2). Isolated products 2a and 2a' were
prepared as racemic forms, then each exposed to the reaction
conditions with or without water. In the absence of water, both
rac-2a and rac-2a' slowly converted to each other.12 Meanwhile,
in the presence of water, rac-2a was not converted to 2a'; instead
all of 2a was recovered as a racemate, implying the conversion
of rac-2a was inhibited. In contrast, rac-2a' was rapidly
converted to 2a in the presence of water, and the resulting 2a had
excellent enantiomeric and diastereomeric purity. Thus, it is
suggested that water accelerates the retro-Michael reaction of 2'
enantioselectivity (Table 1, entry 5). In contrast, catalyst 3f
which has a significantly less basic nitrogen atom, provided only
a trace amount of 2a (Table 1, entry 6), and quinidine (3g
resulted in a significantly lower yield and enantioselectivity than
those exhibited by catalysts 3a 3e (Table 1, entry 7). These
,
)
–
results demonstrate the significance of the bifunctionality of the
catalyst containing amino and thiourea functional groups for not
only the chemical yield but also the enantioselectivity. Various
solvents were next investigated using 3a as the catalyst; this
reaction was hardly affected by solvent effects, and most organic
solvents gave good to excellent yields and stereoselectivities.8
Using water as the solvent also gave promising results, albeit
with lower enantioselectivity (Table 1, entry 8), and even neat
conditions provided 2a with good stereoselectivity, although
with lower yield (Table 1, entry 9).
followed by enantio- and diastereoselective formation of
2, while
water inhibits the degradation of , which is favorable for
2
attaining efficient stereoselective construction of chiral
hemiketal carbons (Scheme 3).13 In addition, all the products
resulting from the interconversion were optically active (Scheme
2). In the absence of 3a, no interconversion took place, even in
During the optimization studies shown in Table 1, in order to
construct the chiral hemiketal carbon of 2a it proved to be
necessary to suppress the formation of dihydropyran by-product
the presence of water (Scheme S2 in the SI). These results
indicate that 3a selectively catalyzes the conversion of 2' in the
presence of water.
With the optimized conditions using 3.0 equiv of water, we
then explored the substrate scope (Table 2).14 Both electron-rich
2
a' (Scheme S1 in the SI). By-product 2a' may be also formed
via intramolecular oxy-Michael addition of an enol form of 1a;9
2
| J. Name., 2012, 00, 1-3
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Table 2 Substrate scopea
to the construction of tetrasubstituted difluoVroiewmAerttihclyelOennliene-
containing stereocenters.19 In addition, because substrates
bearing difluoromethyl, difluoroethyl, pentafluoroethyl, or
longer perfluoroalkyl groups gave higher amounts of the
dihydropyran by-product 2' after 24 h, longer reaction times
DOI: 10.1039/D0CC05509C
were used, which improved the yield of the desired products
via the interconversion of 2' to while maintaining high
stereoselectivities (Table 2, 2l 2m
2n, and 2o).20 Moreover, this
method also enabled the desymmetrization of silanediols to
yield silicon-containing oxacyclic products with high enantio-
2
2
,
,
5
6
and diastereoselectivities, albeit in moderate yields. Thus, chiral
silicon centers were constructed with high stereoselectivities;
such species are also challenging synthetic targets in asymmetric
catalysis (Scheme 4).21,22 The absolute configurations of 2d and
the corresponding dihydropyran by-product 2d' were determined
by X-ray crystallography (see the SI), and the configurations of
all other 2, 6, and 2' products were assigned analogously.
Conclusions
In conclusion, desymmetrization of gem-diols to form chiral
hemiketal carbons was accomplished for the first time via
aReactions were run using the substrate (0.15 mmol), H
organocatalytic
enantio-
and
diastereoselective
2
O (0.45 mmol), and 3a
(
2 2
0.015 mmol) in CH Cl (0.30 mL). Yields represent material isolated after silica cycloetherification and afforded optically active THP derivatives,
gel column chromatography. bIsolated diols 4 were used as the substrate. cThe
mixtures of 1 and its hydrated diol 4 (2.0:1–1:3.3) were used as the substrate.
which are otherwise difficult to achieve. The use of water is
important not only for generating the gem-diols, but also for
controlling the interconversion between the desired hemiketal
products and the by-products that do not contain a hemiketal
carbon. The desymmetrization of silanediols was also
demonstrated as a catalytic asymmetric route to construct
silicon-stereogenic silanes. This synthetic method facilitates the
construction of densely functionalized heterocyclic architectures
bearing chiral hemiketals and silicon centers. This method is also
useful as an approach to construct tetrasubstituted chiral carbons
bearing synthetically versatile fluorinated groups. Further
dIsolated ketones 1 were used as the substrate. eReaction was run for 397 h. Yields
of the reactions for 24 h. gReaction was run for 489 h. hReaction was run for 579
f
i
h. Reaction was run for 168 h.
Scheme 4 Desymmetrization of silanediols.
and electron-poor enones were tolerated, affording the studies to expand the scope of this methodology and its
corresponding products in good yields, high enantioselectivities, application in the asymmetric synthesis of bioactive compounds
and excellent diastereoselectivities (Table 2, 2b and 2c). Enones are currently underway in our laboratory and will be reported in
bearing 4-bromophenyl, 2-naphthyl, and heterocyclic groups due course.
gave comparable results (Table 2, 2d–2f). In addition, an alkyl
group-bearing enone provided the product in comparable yield
with good stereoselectivity (Table 2, 2g). Furthermore, an α,β-
Conflicts of interest
unsaturated ester and thioester, which are useful for further There are no conflicts to declare.
transformations because of their higher oxidation state,15,16
afforded the products with high stereoselectivities in moderate
yields (Table 2, 2h and 2i). We also investigated the substituents Acknowledgements
2
(
R ) on the ketone; although electron-withdrawing groups were
This work was supported financially by the Japanese Ministry of
necessary to promote the formation of gem-diols,17 various
fluorinated substrates were useful. We observed that
chlorodifluoromethyl and bromodifluoromethyl ketones
provided the desired products in high yields with good
stereoselectivities (Table 2, 2j and 2k). Halodifluoromethyl
groups afford access to a wide variety of difluoroalkylated
compounds,18 which offer unique pharmacological properties
associated with the fluorinated functional groups; however, the
lack of enantioselective approaches to such units on sterically
congested chiral carbons has limited their synthetic application
Education, Culture, Sports, Science and Technology
(
JP15H05845, JP17K19120, JP18K14214, JP18H04258, and
JP20K05491). K.A. also acknowledges the Institute for
Synthetic Organic Chemistry, Toyo Gosei Memorial Foundation,
the Sumitomo Foundation, Fukuoka Naohiko Memorial
Foundation, Inoue Foundation for Science, and Mizuho
Foundation for the Promotion of Sciences. A.M. also
acknowledges the Japan Society for the Promotion of Science for
Young Scientists for the fellowship support.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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Journal Name
1
0 For selected examples of organic reactions using VwieawteArrt,icsleeeO:n(linae)
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stereoselective desymmetrization of the gem-diol.
2
3
4
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(
b) E. J. Kang and E. Lee, Chem. Rev., 2005, 105, 4348; (c) A.
(Scheme S2 in the SI). In addition, when a cyclic enol ether,
which is analogous to 2', was exposed to the reaction
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achiral bifunctional catalyst, optically active 2a and 2a' were
converted to racemic 2a' and 2a, respectively (Scheme S3 in
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2 and 2'
involved a retro-Michael addition.
Borovika and P. Nagorny, J. Am. Chem. Soc., 2012, 134, 8074; 14 See Schemes S4–S6 in the SI for more details.
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7
8
9
Results of further catalyst screening are described in the SI 22 In CH Cl at 25 °C for 24 h, 6a was obtained in 7% yield with
2 2
(
Table S1).
Results of further solvent screening are described in the SI
Table S2).
3 2
>20:1 dr and 95% ee; in CHCl at 50 °C for 48 h without H O,
6a was obtained in 35% yield with >20:1 dr and 90% ee. See
Scheme S8 in the SI for more details.
(
B. Parhi, J. Gurjar, S. Pramanik, A. Midya and P. Ghorai, J.
Org. Chem., 2016, 81, 4654.
4
| J. Name., 2012, 00, 1-3
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DOI: 10.1039/D0CC05509C
OMe
H
N
H
NH
THP with
a chiral hemiketal
N
S
NH
carbon and silicon centers
1
R
O
O
HO OH
F3C
CF3
OH
R2
O
X
R1
R2
X
H2O, CH2Cl2, 25 °C, 24 h
achiral gem-diol
X = C, Si)
desymmetrization via
asymmetric cycloetherification
up to 99% yield
(
>20:1 dr
7% ee
9
The first desymmetrization of gem-diols forming chiral hemiketal carbon and silicon centers was
accomplished via organocatalytic enantio- and diastereoselective cycloetherification.