Enantio- And Diastereoselective Construction of Contiguous Tetrasubstituted Chiral Carbons in Organocatalytic Oxadecalin Synthesis

Article abstract of DOI:10.1021/acs.orglett.0c01501

The organocatalytic enantio- and diastereoselective cycloetherification of 1,3-cyclohexanedione-bearing enones involving the in situ generation of chiral cyanohydrins was developed. This transformation offers the first catalytic asymmetric approach to oxa

Full text of DOI:10.1021/acs.orglett.0c01501

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Letter
Enantio- and Diastereoselective Construction of Contiguous
Tetrasubstituted Chiral Carbons in Organocatalytic Oxadecalin
Synthesis
Yuuki Wada, Ryuichi Murata, Yuki Fujii, Keisuke Asano,* and Seijiro Matsubara*
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ABSTRACT: The organocatalytic enantio- and diastereoselective
cycloetherification of 1,3-cyclohexanedione-bearing enones involv-
ing the in situ generation of chiral cyanohydrins was developed.
This transformation offers the first catalytic asymmetric approach
to oxadecalin derivatives containing contiguous tetrasubstituted
chiral carbons at the bridge heads of the fused ring systems.
Depending on substituents, both cis- and trans-decalin-type
scaffolds were synthesized with good to excellent stereoselectivities,
and a range of functional groups accumulated on the chiral
quaternary carbon moieties of the trans-oxadecalin derivatives.
Scheme 1. Enantio- and Diastereoselective Construction of
Contiguous Tetrasubstituted Chiral Carbons of Oxadecalins
ecalin structures comprise a number of bioactive
Dcompounds, and chiral quaternary carbon centers are
often included in the bridge heads of the fused ring systems,
which offers diverse biological potential based on their 3D
complexity.1 It is of significance for pharmaceutical and
biological research to expand a chemical space on the basis
of those privileged platforms, but tetrasubstituted chiral
carbons are among the most synthetically challenging targets,
whereas natural products including such structural entities are
available by virtue of enzymes.2 To construct bicyclic scaffolds
containing all-carbon quaternary centers, annulation via
desymmetrization of enantiotopic diketones is one of the
efficient approaches3 and was employed in the asymmetric
synthesis of carbocyclic partial steroid structures.4 However, to
the best of our knowledge, the catalytic asymmetric route to
oxadecalin derivatives is limited to an enzymatic method,5 in
which only one substrate is valuable because of the substrate
specificity, despite their prevalence in a range of natural
products and bioactive compounds.6,7 In addition, the
incorporation of contiguous tetrasubstituted chiral carbons at
their ring junctions is particularly challenging, and it has not
been attained, although it provides bicyclic structures
integrating functional groups on the fully substituted stereo-
genic centers. In this study, we present the organocatalytic
enantio- and diastereoselective cycloetherification of 1,3-
cyclohexanedione-bearing enones involving the in situ
generation of intermediary cyanohydrins (Scheme 1). This
transformation simultaneously constructs three stereogenic
centers including contiguous tetrasubstituted chiral carbons at
their ring junctions with control of relative and absolute
stereochemistry, forming oxadecalin scaffolds.
Following our recent studies on the construction of
tetrasubstituted chiral anomeric carbons via asymmetric
cycloetherifications of in-situ-generated chiral cyanohydrins,8
our investigations were initiated using (E)-2-methyl-2-(5-oxo-
5-phenylpent-3-en-1-yl)cyclohexane-1,3-dione (1a) and ace-
tone cyanohydrin (3a) with 10 mol % of bifunctional
organocatalysts 4 (Figure 1)9 in CH2Cl2 at 25 °C (Table 1,
entries 1−9). Bifunctional catalysts composed of various
scaffolds including cinchona alkaloids (4a and 4b, Table 1,
entries 1 and 2) resulted in low to moderate stereo-
selectivities.10,11 Cyclohexanediamine-derived catalysts 4c−i
were further examined (Table 1, entries 3−9). Among
dimethylamino-group-containing catalysts 4c−e, catalyst 4e,
Received: May 1, 2020
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© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

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achieved while maintaining noticeable enantio- and diaster-
eoselectivity (Table 1, entry 17).
With the established conditions in hand, we next
investigated substrates with other substituents on their enone
moieties (Scheme 2). An electron-rich substrate resulted in a
Scheme 2. Reactions of 1,3-Diketones with the Methyl
a
Group
Figure 1. Organocatalysts.
a
Table 1. Optimization of Conditions
b
c
entry
catalyst
solvent
3
yield (%)
dr
ee (%)
1
2
3
4
5
6
7
8
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4i
4i
4i
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
benzene
toluene
MeCN
THF
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3b
80
69
76
75
91
67
91
73
71
<1
71
86
76
84
46
42
83
8.8:1
8.3:1
7.5:1
14:1
13:1
13:1
20:1
20:1
>20:1
−31
−37
68
60
84
83
87
72
91
a
Reactions were run using 1 (0.15 mmol), 3b (trimethylsilyl cyanide
(0.30 mmol) with 2-propanol (0.30 mmol)), and 4i (0.015 mmol) in
CH2Cl2 (0.30 mL). Yields represent material isolated after silica gel
column chromatography. Diastereomeric ratios were determined by
b
9
1H NMR spectroscopy. Reactions were run using 3a instead of 3b.
c
Reaction was run using 1e (0.10 mmol), 3a (0.20 mmol), and 4i
10
11
12
13
14
15
16
17
(0.010 mmol) in CH2Cl2 (0.20 mL).
>20:1
20:1
20:1
>20:1
10:1
10:1
90
84
85
88
74
76
92
higher enantioselectivity (Scheme 2, 2b), whereas an electron-
deficient substrate resulted in a lower stereoselectivity (Scheme
2, 2c). Substrates with 4-bromophenyl and 2-naphthyl groups
also provided the corresponding products in adequate yields
with high stereoselectivities (Scheme 2, 2d and 2e). The
absolute configurations of 2d were determined by X-ray
crystallography (Scheme 2; see the Supporting Information for
details), and the bicyclic scaffold was identified as a cis-decalin-
type structure; the configurations of all other products 2 were
assigned analogously. In addition, an aliphatic substituent was
also active, providing good stereoselectivity (Scheme 2, 2f). As
a substrate bearing a higher oxidation state, a thioester was also
useful for providing the corresponding product in good yield
with acceptable stereoselectivity (Scheme 2, 2g).
Next, we investigated substituents on the 1,3-diketone that
were incorporated in the chiral quaternary carbon center
(Scheme 3, Table 2). A 1,3-diketone holding a fluoro group
generated the corresponding cis-oxadecalin product 2h
containing a fluorinated quaternary carbon center with
reasonably high stereoselectivity under modified conditions
using 3a as the cyanating reagent; the configurations of 2h
were determined by X-ray crystallography (Scheme 3; see the
Supporting Information for details). Encouraged by the results,
ethyl, allyl, benzyl, methoxy, and siloxy groups were further
4i
4i
4i
4i
EtOAc
CH2Cl2
>20:1
a
Reactions were run using 1a (0.15 mmol), 3 (0.30 mmol), and the
b
catalyst (0.015 mmol) in the solvent (0.30 mL). Isolated yields.
c
1
Diastereomeric ratios were determined by H NMR spectroscopy.
with a phenyl group incorporated on the thiourea moiety,
produced higher enantioselectivity (Table 1, entry 5).
Piperidyl-group-containing catalysts 4f−i exhibited acceptable
stereoselectivities (Table 1, entries 6−9); in particular, catalyst
4i, carrying a phenyl-group-substituted thiourea moiety and a
4-methylpiperidyl group, afforded satisfactory enantio- and
diastereoselectivity (Table 1, entry 9). In contrast, catalyst 4j,
with a less basic nitrogen atom, displayed no catalytic activity,
implying that the bifunctionality of the catalysts containing
amino and thiourea functional groups is essential for this
transformation (Table 1, entry 10). Various solvents were
investigated next using 4i as a catalyst (Table 1, entries 11−
16); the use of CH2Cl2 still provided better results (Table 1,
entry 9). In addition, trimethylsilyl cyanide in combination
with 2-propanol was also investigated, and a higher yield was
B
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a
Scheme 3. Reaction of 1,3-Diketone with the Fluoro Group
Scheme 4. Reactions of 1,3-Diketones with Aryl Groups
a
Table 2. Investigating the 1,3-Diketone Substituents
b
c
entry
R2
Me
yield (%)
dr (cis/trans)
ee (%) (cis, trans)
1
2
3
4
5
6
7
8
83
84
76
83
53
46
<1
94
>20:1
1:1.2
2.2:1
3.7:1
1.2:1
4.3:1
92, 
31, 88
64, 86
43, 74
46, 80
25, 80
Et
allyl
benzyl
MeO
TBSO
i-Pr
Ph
1:20
, 96
a
Reactions were run using 1,3-diketones (0.15 mmol), 3b
(trimethylsilyl cyanide (0.30 mmol) with 2-propanol (0.30 mmol)),
b
and 4i (0.015 mmol) in CH2Cl2 (0.30 mL). Isolated yields.
c
1
Diastereomeric ratios were determined by H NMR spectroscopy.
employed instead of the methyl and fluoro groups; however, in
these cases, the stereoselectivity diminished, resulting in
modest ratios of cis- to trans-decalin-type products (1:1.2 to
4.3:1) with moderate enantioselectivities (Table 2, entries 2−
6); a substrate with an isopropyl group resulted in no reaction
(Table 2, entry 7). In contrast, using a substrate with a phenyl
group provided the corresponding product with excellent
enantio- and diastereoselectivity (Table 2, entry 8; Scheme 4,
6a). Furthermore, it is notable that the X-ray crystallographic
analysis identified the bicyclic scaffold of 6a as a trans-decalin-
type structure in contrast with the methyl- and fluoro-
substituted products 2 in Schemes 2 and 3 (Scheme 4; see
the Supporting Information for details). Thus the alteration of
the class of substituents enabled this catalytic method to
construct both cis- and trans-decalin-type scaffolds.
Taking advantage of the high stereoselectivity of arene-
substituted 1,3-diketones 5 for constructing trans-decalin-type
products 6, a range of functional groups were tolerated on the
chiral quaternary carbon moieties (Scheme 4). Both electron-
donating and -withdrawing groups were integrated, affording
the corresponding products in satisfactory yields with high
enantio- and diastereoselectivities (Scheme 4, 6b, 6c, and 6d).
Substrates with halogen groups, which are useful for further
transformations, also provided the corresponding products in
high yields with high stereoselectivities (Scheme 4, 6d and 6e).
Aliphatic substituents generated excellent enantio- and
diastereoselectivities (Scheme 4, 6f, 6g, and 6h). Furthermore,
an ortho substituent was also active but contributed a lower
yield than other substitution patterns (Scheme 4, 6h). In
addition, heteroatom functional groups including alkoxy,
amino, and mercapto groups were also suitable (Scheme 4,
a
Reactions were run using 5 (0.15 mmol), 3b (trimethylsilyl cyanide
(0.30 mmol) with 2-propanol (0.30 mmol)), and 4i (0.015 mmol) in
CH2Cl2 (0.30 mL). Yields represent material isolated after silica gel
column chromatography. Diastereomeric ratios were determined by
b
1H NMR spectroscopy. Reaction was run using 5k (0.10 mmol), 3b
(trimethylsilyl cyanide (0.20 mmol) with 2-propanol (0.20 mmol)),
and 4i (0.010 mmol) in CH2Cl2 (0.20 mL).
6b, 6i, and 6j). Moreover, alkynyl and alkenyl groups, which
are useful not only as tags for imaging12 and ligation13 for
chemical biology studies but also as platforms for further
functionalization,14 were also able to be embedded (Scheme 4,
C
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6k and 6l). Arenes other than functionalized benzenes
including naphtharene and heteroarene also afforded products
in acceptable yields with high enantio- and diastereoselectiv-
ities (Scheme 4, 6m and 6n). The configurations of all
products 6 were assigned analogously based on the X-ray
crystallography of 6a.
Although details were not clarified in this stage on the
difference in the bicyclic stereochemistries of 2 and 6 caused
by the alteration of the class of substituents, we investigated
whether the diastereoselectivity was entirely controlled by the
substrate properties. When triethyl amine was employed as a
catalyst instead of 4i, diastereoselectivities considerably
decreased (Scheme 5).15 These results suggested that the
catalysis to expand the chiral chemical space for exploring
bioactive compounds.
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c01501.
Experimental procedures, results of additional inves-
tigations, characterization data, NMR spectra, HPLC
chromatogram profiles, and ORTEP drawings of
synthesized compounds (PDF)
Accession Codes
CCDC 1995459−1995461 contain the supplementary crys-
tallographic 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.
Scheme 5. Reactions with Et3N as the Catalyst
AUTHOR INFORMATION
Corresponding Authors
■
Keisuke Asano − Department of Material Chemistry, Graduate
School of Engineering, Kyoto University, Kyoto 615-8510,
Japan; orcid.org/0000-0002-9272-2937;
Email: asano.keisuke.5w@kyoto-u.ac.jp
Seijiro Matsubara − Department of Material Chemistry,
Graduate School of Engineering, Kyoto University, Kyoto 615-
8510, Japan; orcid.org/0000-0001-8484-4574;
Email: matsubara.seijiro.2e@kyoto-u.ac.jp
diastereoselectivity as well as the enantioselectivity was rather
controlled by the chiral bifunctional organocatalyst. The
relative and absolute stereochemistry of the major products
would be determined by certain interactions between the
catalyst and the substituents on the 1,3-diketones. This is in
addition to multipoint hydrogen-bonding interactions involv-
ing the enone and hydroxy moieties, through which one
stereoisomer of the in-situ-generated chiral cyanohydrins is
selectively recognized and activated.16
Authors
Yuuki Wada − Department of Material Chemistry, Graduate
School of Engineering, Kyoto University, Kyoto 615-8510,
Japan
Ryuichi Murata − Department of Material Chemistry, Graduate
School of Engineering, Kyoto University, Kyoto 615-8510,
Japan
In summary, the organocatalytic enantio- and diastereose-
lective cycloetherification of 1,3-cyclohexanedione-bearing
enones involving the in situ generation of chiral cyanohydrins
was developed. This transformation afforded various oxadeca-
lin derivatives via the simultaneous construction of three
stereogenic centers including contiguous tetrasubstituted chiral
carbons at the bridge heads of the fused ring systems, which
are otherwise difficult to synthesize. Depending on the class of
substituents on the 1,3-diketones, both cis- and trans-decalin-
type scaffolds were generated with good to excellent
stereoselectivities. On the basis of the high stereoselectivity
of aryl-group-containing 1,3-diketones, a range of functional
groups were also integrated on the chiral quaternary carbon
moieties of the trans-oxadecalin derivatives. This catalytic
method facilitates the synthesis of densely functionalized and
complex heterocyclic configurations containing multiple
tetrasubstituted chiral carbons. In addition, the control
experiments using an achiral catalyst revealed that not only
the enantioselectivity but also the diastereoselectivity was to a
large degree controlled by the chiral bifunctional organo-
catalyst. This unfolds the potential of fully catalyst-controlled
stereodivergent strategies, which we are currently pursuing in
our laboratory along with the elucidation of the stereo-
selectivities and the application of the present asymmetric
Yuki Fujii − Department of Material Chemistry, Graduate
School of Engineering, Kyoto University, Kyoto 615-8510,
Japan
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c01501
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Dr. Hiroyasu Sato (RIGAKU) and Professor Takuya
Kurahashi (Kyoto University) for the X-ray crystallographic
analysis. This work was financially supported by the Japanese
Ministry of Education, Culture, Sports, Science and Technol-
ogy (JP15H05845, 16K13994, JP17K19120, JP18K14214,
JP18H04258, and JP20K05491). K.A. also acknowledges the
Asahi Glass Foundation, 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 Foundation, the Sumitomo Foundation,
D
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Organic Letters
pubs.acs.org/OrgLett
Letter
(10) Results of further catalyst screening are described in the
Supporting Information (Table S1).
(11) Although small amounts of cyanohydrins of the oxadecalin
products were also observed, they were separated by silica gel column
chromatography.
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Ando, J.; Fujita, K.; Kawata, S.; Sodeoka, M. Alkyne-Tag Raman
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Regioselective “Ligation” of Azides and Terminal Alkynes. Angew.
Chem., Int. Ed. 2002, 41, 2596. (b) Tornøe, C. W.; Christensen, C.;
Meldal, M. Peptidotriazoles on Solid Phase: [1,2,3]-Triazoles by
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(14) (a) The Chemistry of Triple-Bonded Functional Groups; Patai, S.,
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John Wiley & Sons: New York, 1989; Vol. 2.
(15) Quinuclidine was also investigated as a catalyst, and it provided
similar results. See the Supporting Information for details (Scheme
S1).
(16) When racemic oxadecalin products 2a and 6a were subjected to
the optimized reaction conditions in the presence of 4i, respectively,
they were recovered as racemate. These results imply that the
cyclizations were irreversible. See the Supporting Information for
details (Scheme S2).
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