Asymmetric cycloetherification of in situ generated cyanohydrins through the concomitant construction of three chiral carbon centers

Article abstract of DOI:10.1021/acs.orglett.9b00462

The organocatalytic enantio- A nd diastereoselective cycloetherification of in situ generated cyanohydrins through the concomitant construction of three chiral carbon centers is reported. This protocol facilitates the concise synthesis of optically active

Full text of DOI:10.1021/acs.orglett.9b00462

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Asymmetric Cycloetherification of in Situ Generated Cyanohydrins
through the Concomitant Construction of Three Chiral Carbon
Centers
Yosuke Kurimoto, Teruhisa Nasu, Yuki Fujii, Keisuke Asano,* and Seijiro Matsubara*
Department of Material Chemistry, Graduate School of Engineering, Kyoto University, Kyotodaigaku-Katsura, Nishikyo, Kyoto
615-8510, Japan
S
* Supporting Information
ABSTRACT: The organocatalytic enantio- and diastereose-
lective cycloetherification of in situ generated cyanohydrins
through the concomitant construction of three chiral carbon
centers is reported. This protocol facilitates the concise
synthesis of optically active tetrahydropyran derivatives, which
are ubiquitous scaffolds found in various bioactive compounds,
through the simultaneous construction of multiple bonds and
stereogenic centers, including tetrasubstituted chiral carbons.
The resulting products also contain multiple synthetically
important functional groups, which expand their possible
usefulness as chiral building blocks.
Scheme 1. Organocatalytic Asymmetric Cycloetherification
he ability to rapidly increase molecular complexity is of
of Cyanohydrins Generated in Situ from 1,5-Diketones
T
great significance in syntheticchemistry because it provides
concise access to functional molecules including bioactive
compounds. In particular, optically active cyclic molecules
containing multiple chiral carbons provide three-dimensional
scaffolds that promote important functions within organisms.1
Hence, to explore unexploited molecular functions including
pharmaceutical activities, it is necessary to pursue asymmetric
catalysis that facilitates the construction of such architectures in a
single operation from achiral substrates.
In the context of accessing chiral ring structures, the
cyclizations of achiral molecules that possess enantiotopic
functional groups through successive bond formation2 and
desymmetrization3 enables the concomitant generation of
stereochemical complexity. In this study, we present an
organocatalytic enantio- and diastereoselective method for the
cycloetherification of symmetrical 1,5-diketone-bearing enones
that involves the in situ generation of intermediary cyanohydrins
(Scheme 1). This transformation simultaneously constructs two
bonds and three stereogenic centers with control of relative and
absolute stereochemistry while forming a tetrahydropyran
(THP) ring,4 which is a ubiquitous scaffold found in a range of
bioactive natural products and pharmaceuticals.5 In addition, the
resultingproductcontainsthreechiralcarbons,twoofwhichbear
carbonyl-group-containing substituents, with the other bearing a
cyano group;6 these substituents are useful for further
derivatization, thereby increasing synthetic utility.
bifunctional organocatalysts 4 (Figure 1)8 in CH2Cl2 at 25 °C
(Table 1, entries 1−10). Preliminary investigations revealed that
the addition of the cyanating reagent 2 in two parts resulted in
better yields and enantioselectivities (see the Supporting
Information for details), and this protocol was employed in all
reactions. Bifunctional piperidyl-group-containing organocata-
lysts 4c and 4d gave better diastereoselectivities than the
dimethylamino-group-containing 4a and 4b (Table 1, entries 1−
4). In addition, analogous catalysts 4e and 4f (Table 1, entries 5
and 6), and additional catalysts 4g−4j bearing 4-methylpiperidyl
groups (Table 1, entries 7−10) were also investigated; among
them, catalysts 4e, 4f, 4i, and 4j, bearing phenyl groups on the
thiourea or urea moieties, gave higher enantioselectivities (Table
1, entries 5, 6, 9, and 10). Furthermore, the urea-based catalyst
Following our recent studies on asymmetric cycloetherifica-
tions through the dynamic kinetic resolution of reversibly
generated chiral cyanohydrins,7 we began our investigations
using (E)-5-(2-oxo-2-phenylethyl)-1,7-diphenylhept-2-ene-1,7-
dione (1a) and acetone cyanohydrin (2) with 10 mol % of the
Received: February 3, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b00462
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 1. Optimization of Conditions
b
c
entry catalyst
solvent
additive
yield (%)
dr
ee (%)
1
2
3
4
5
6
7
8
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4j
4j
4j
4j
4j
4j
4j
4j
4j
4j
4j
4j
4j
4j
4j
4j
4j
4j
4j
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
benzene
toluene
c-hexane
n-hexane
Et2O
48
67
73
93
45
90
trace
90
24
77
44
5
72
59
64
67
71
14
11
17
9
1.5:1
3.0:1
4.6:1
14:1
17:1
16:1
71
35
69
56
89
81
Figure 1. Bifunctional organocatalysts.
was more reactive than the thiourea-based catalyst within each
category (4a vs 4b; 4c vs 4d; 4e vs 4f; 4g vs 4h; 4i vs 4j). These
investigations identified 4j as the most efficient catalyst for this
transformation. Alternative cyanating reagents were also
investigated (Table 1, entries 11 and 12). Trimethylsilyl cyanide
in the presence of 2-propanol afforded good stereoselectivity but
a lower yield (Table 1, entry 11); the use of trimethylsilyl cyanide
alone provided the product in even better enantioselectivity, but
in much lower yield (Table 1, entry 12).
11:1
8.3:1
11:1
>20:1
>20:1
19:1
14:1
9.6:1
7.6:1
6.8:1
6.4:1
19:1
19:1
20:1
15:1
5.8:1
52
87
83
82
88
83
73
71
71
66
77
71
76
70
73
76
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
d
e
Various solvents were next investigated using 4j and 2 as
substrates (Table 1, entries 13−24). The use of CHCl3 resulted
in high diastereoselectivity and good yield (Table 1, entry 13);
however, hydrocarbon solvents resulted in lower stereo-
selectivities (Table 1, entries 14−17), and polar solvents resulted
in lower reactivities and stereoselectivities (Table 1, entries 18−
24). Molecular sieves (MS), as additives, were also investigated
(Table 1, entries 25−28). Among them, MS 5A and MS 13X led
to improved stereoselectivities with only slight losses in yield
(Table 1, entries 27 and 28). These additives might play roles as
bases that remove detrimental acids since similar reaction
outcomeswereobtainedusingCHCl3 passedthroughanalumina
column (Table 1, entry 29).
THF
CPME
f
EtOAc
acetone
CH3CN
EtOH
20
31
<5
71
64
68
64
63
g
CHCl3
CHCl3
CHCl3
CHCl3
MS 3A
MS 4A
MS 5A
17:1
13:1
>20:1
>20:1
>20:1
86
85
85
85
84
g
g
g
MS 13X
h
CHCl3
a
With the established conditions in hand, we next investigated
substrates bearing other substituents on their enone moieties
(Table 2). Electron-donating groups resulted in higher stereo-
selectivities (Table 2, entries 2 and 4), while an electron-
withdrawing group resulted in a lower stereoselectivity (Table 2,
entry3).Inaddition,althoughthe4-bromophenylgroupresulted
in a lower yield and moderate stereoselectivity (Table 2, entry 5),
the 2-naphthyl group provided results comparable to those of the
reaction that afforded 3a (Table 2, entry 6). An aliphatic
substituent was also tolerated in this transformation, providing
3gwithgoodstereoselectivity(Table2,entry7). Furthermore,to
our delight, an α,β-unsaturated ester, which is useful for further
synthetic transformations due to its higher oxidation state,9 gave
the highest enantioselectivity, with 3h formed in high yield and
good diastereoselectivity (Table 2, entry 8). Moreover, a
thioester, which is another synthetically important functional
group,10 was also tolerated in this reaction; 3i was obtained in
high stereoselectivity (Table 2, entry 9). The absolute
configurations of the two main diastereomers of 3e were
determined by X-ray crystallography (see the Supporting
Information for details), and the configurations of all other
products 3 were assigned on the basis of these structures.
We further explored the substrate scope using α,β-unsaturated
esters(Scheme2). Electron-richsubstrate1jwaslessreactive(25
Reactions were run using 1a (0.15 mmol), 2 (0.30 mmol), and the
catalyst (0.015 mmol) in the solvent (0.30 mL) with 2 added in two
b
c
parts. Yield of the major diastereomer. Ratio of the two major
diastereomers among the four diastereomers detected in total.
d
Reaction was run using trimethylsilyl cyanide (0.30 mmol) with 2-
e
propanol (0.30 mmol) instead of 2. Reaction was run using
trimethylsilyl cyanide (0.30 mmol) instead of 2. CPME = cyclopentyl
methyl ether. Molecular sieves (60 mg) were used. CHCl3 was used
after passing it through an alumina column.
f
g
h
°C, 24 h: 15%, >20:1 dr, 91% ee); this reaction was performed at
35 °C for 48 h to afford a slightly higher yield than that at 25 °C
for 24 h, but with lower diastereoselectivity and high
enantioselectivity. However, electron-deficient substrates 1k
and 1l were highly reactive and afforded good stereoselectivities
that are comparable to those of the reaction involving 1h.
Heterocyclic substrate 1m required modified conditions to
afford the corresponding product 3m in high yield, but the
enantioselectivitywashighirrespectiveofthereactionconditions
(25 °C, 24 h: 25%, 13:1 dr, 91% ee). Substrates 1n and 1o bearing
4-methylphenyl and 3,5-dimethylphenyl groups, respectively,
also afforded THPs 3n and 3o with high enantioselectivitiesat 35
°C after 48 h (25 °C, 24 h: 3n, 20%, >20:1 dr, 93% ee; 3o, 35%,
>20:1 dr, 94% ee). In addition, aliphatic substrate 1p also gave
B
DOI: 10.1021/acs.orglett.9b00462
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
a
Table 2. Investigating the Michael Acceptor Substituents
Scheme 2. Substrate Scope
b
c
entry
R1 (3)
Ph (3a)
yield (%)
dr
ee (%)
1
2
3
4
5
6
7
8
9
68
57
68
49
38
73
69
71
61
>20:1
20:1
7.3:1
>20:1
12:1
20:1
20:1
20:1
>20:1
85
90
70
89
79
82
89
92
88
4-MeOC6H4 (3b)
4-CF3C6H4 (3c)
4-MeC6H4 (3d)
4-BrC6H4 (3e)
2-naphthyl (3f)
Me (3g)
PhO (3h)
2,6-Me2C6H3S (3i)
a
Reactions were run using 1 (0.15 mmol), 2 (0.30 mmol), and 4j
(0.015 mmol), MS 5A (60 mg) in CHCl3 (0.30 mL) with 2 added in
b
c
two parts. Yield of the major diastereomer. Ratio of the two major
diastereomers among the four diastereomers detected in total.
optically active THP 3p; the use of 4f as the catalyst resulted in a
higher enantioselectivity (84% ee) than 4j (11%, >20:1 dr, 81%
ee), although the yields were low in each case. Furthermore, THP
3q, containing two tetrasubstituted stereogenic centers, was
synthesized with high enantio- and diastereoselectivity, albeit in
modest yield even at 35 °C over 48 h (25 °C, 24 h: 12%, >20:1 dr,
92% ee).
The reaction of methyl ester 1r was also examined under the
optimized conditions (Scheme 3). In this case, only a trace
amount of the THP product 3r was obtained, with the
corresponding cyanohydrin 1r′ isolated instead; 1r′ was much
lessopticallypurethanthecyclizedproducts3listedinScheme2.
These results indicate that the nucleophilic 1,2-addition step that
forms the cyanohydrin does not determine the enantioselectivity
associated with the formation of 3; rather it arises in a
synchronized manner through desymmetrization involving the
asymmetric oxy-Michael addition of the in situ generated
cyanohydrin, one stereoisomer of which is selectively recognized
and activated through multipoint hydrogen bonding interactions
involving the bifunctional organocatalyst.11,12
a
Yields are for the major diastereomer and represent material isolated
after silica gel column chromatography. Diastereomeric ratios relate to
the two major diastereomers among the four diastereomers detected
b
in total. Reactions were run using 1 (0.15 mmol), 2 (0.30 mmol),
and 4j (0.015 mmol), MS 5A (60 mg) in CHCl3 (0.30 mL) with 2
added in two parts. Reactions were run using 1 (0.10 mmol), 2 (0.20
mmol), and 4j (0.010 mmol), MS 5A (40 mg) in CHCl3 (0.20 mL)
c
d
with 2 added in two parts. Reactions were run at 25 °C for 24 h.
e
f
Reactions were run at 35 °C for 48 h. Reaction was run using 4f
instead of 4j.
Scheme 3. Reaction of Methyl Ester 1r
In summary, we demonstrated the organocatalytic enantio-
and diastereoselective cycloetherification of in situ generated
cyanohydrins that involves the concomitant construction of
three chiral carbon centers. This transformation provides a
concise synthetic route to optically active THP derivatives
accompanied by the simultaneous construction of multiple
bonds and stereogenic centers, including tetrasubstituted chiral
carbon centers. The resulting products also contain multiple
synthetically important functional groups in different oxidation
states (ketone, ester, and cyano groups); hence, this synthesis
method facilitates the construction of complex heterocyclic
architectures. Further studies that expand the range of optically
active heterocycles accessible using this methodology, including
those bearing other substitution patterns or scaffolds, are
ongoing in our laboratory and will be reported in due course.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.9b00462.
■
S
Experimental procedures including spectroscopic and
analytical data (PDF)
C
DOI: 10.1021/acs.orglett.9b00462
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Accession Codes
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Organocatalyzed Enantioselective Desymmetrization of Diols in The
CCDC 1895615−1895616 contain the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge CB2
1EZ, UK; fax: +44 1223 336033.
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AUTHOR INFORMATION
Corresponding Authors
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■
*E-mail: asano.keisuke.5w@kyoto-u.ac.jp.
*E-mail: matsubara.seijiro.2e@kyoto-u.ac.jp.
ORCID
Keisuke Asano: 0000-0002-9272-2937
Seijiro Matsubara: 0000-0001-8484-4574
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported financially by the Japanese Ministry of
Education, Culture, Sports, Science and Technology
(15H05845, 16K13994, 17K19120, 18K14214, and
18H04258).K.A.alsoacknowledgestheAsahiGlassFoundation,
Toyota Physical and Chemical Research Institute, Tokyo
Institute of Technology Foundation, the Naito Foundation,
Research Institute for Production Development, the Tokyo
Biochemical Research Foundation, the Uehara Memorial
Foundation, the Kyoto University Foundation, the Institute for
Synthetic Organic Chemistry, Toyo Gosei Memorial Founda-
tion, and the Sumitomo Foundation.
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DOI: 10.1021/acs.orglett.9b00462
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