Achieving Enantioselectivity in Difficult Cyclohexa-1,3-diene Diels-Alder Reactions with Sulfur-Stabilized Silicon Cations as Lewis Acid Catalysts

Article abstract of DOI:10.1021/acs.orglett.8b02945

A novel cationic silicon-sulfur Lewis pair with a chiral H₈-binaphthyl backbone is reported. It catalyzes otherwise sluggish Diels-Alder reactions of cyclohexa-1,3-diene and chalcone derivatives in good yields and decent enantioselectivities (up to 81% ee). The enantioinduction is highest with a [1,1′-biphenyl]-4-yl substituent at the carbonyl carbon atom. This moiety can be later converted into a carboxyl group by Baeyer-Villiger oxidation. The same oxidant also epoxidizes the double bond in the cycloadduct, and the epoxide engages in a lactonization with the carboxylic acid. Synthetically interesting hexahydro-3,6-methanobenzofuran-2(3H)-one skeletons are obtained in one pot.

Full text of DOI:10.1021/acs.orglett.8b02945

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Achieving Enantioselectivity in Difficult Cyclohexa-1,3-diene Diels−
Alder Reactions with Sulfur-Stabilized Silicon Cations as Lewis Acid
Catalysts
Polina Shaykhutdinova and Martin Oestreich*
Institut fur Chemie, Technische Universitat Berlin, Straße des 17. Juni 115, 10623 Berlin, Germany
̈
̈
S
* Supporting Information
ABSTRACT: A novel cationic silicon−sulfur Lewis pair with a chiral H8-binaphthyl backbone is reported. It catalyzes
otherwise sluggish Diels−Alder reactions of cyclohexa-1,3-diene and chalcone derivatives in good yields and decent
enantioselectivities (up to 81% ee). The enantioinduction is highest with a [1,1′-biphenyl]-4-yl substituent at the carbonyl
carbon atom. This moiety can be later converted into a carboxyl group by Baeyer−Villiger oxidation. The same oxidant also
epoxidizes the double bond in the cycloadduct, and the epoxide engages in a lactonization with the carboxylic acid. Synthetically
interesting hexahydro-3,6-methanobenzofuran-2(3H)-one skeletons are obtained in one pot.
Scheme 1. Difficult Cyclohexa-1,3-diene Diels−Alder
Reaction (Top) and Chiral Sulfur-Stabilized Silicon Cations
as Lewis Acid Catalysts (Bottom)
he ability of cationic silicon Lewis acids to catalyze
Tchallenging Diels−Alder reactions of cyclohexa-1,3-diene
and unreactive dienophiles1,2 led to the development of chiral
silicon cations to realize asymmetric variants of these difficult
transformations.3−8 Our laboratory currently focuses on the
promotion of enantioselective cycloadditions of cyclohexa-1,3-
diene and chalcone derivatives4,7 catalyzed by sulfur-stabilized
silicon cations.4,9 After systematic structural modifications of
the catalyst system we eventually arrived at the bis-
(binaphthyl)-based Lewis acids (S,S)-1 and (S,S)-2 that
induced 34% and 53% ee in the model Diels−Alder reaction
of cyclohexa-1,3-diene (3) and chalcone (4), respectively (3 +
4 → 5, Scheme 1, top).4b,c With the goal of further improving
the enantiomeric excesses of the cycloadducts as well as
understanding the influence of the relevant structural elements
on the asymmetric induction we replaced the binaphthyl
backbone in (S,S)-1 and (S,S)-2 by the H8-binaphthyl
skeleton, resulting in the new catalysts (S,S)-6 and (S,S)-7
(Scheme 1, bottom). Here we report the synthesis and
spectroscopic characterization of the silicon Lewis acids (S,S)-
6 and (S,S)-7 and their application in Diels−Alder reactions of
cyclohexa-1,3-diene (3) and various chalcones, leading to
substantially improved enantioselectivities.
from the literature-known H8-binaphthyl diiodide according to
our previously reported procedure.4b,c Reaction of the
To investigate the effect of the various structural elements of
these catalysts on their enantioselective performance, we
synthesized the precursors (S)-8 and (S)-9 with thioether
groups of different steric demand (Scheme 2). The new
enantiomeric building blocks (S)-10 and (S)-11 were prepared
Received: September 14, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b02945
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 2. Preparation of the H8-Binaphthyl-Based Hydrosilanes (S,S)-8 and (S,S)-9
dihydrosilepine (S)-12 with the lithiated thioethers (S)-10 and
(S)-11 afforded the hydrosilanes (S)-8 and (S)-9 in moderate
yields. Hydride abstraction with trityl tetrakis(pentafluoro-
phenyl)borate10 [Ph3C]+[B(C6F5)4]− resulted in the formation
of the corresponding sulfur-stabilized silicon cations (S,S)-6
and (S,S)-7 (Figure 1). The 29Si HMQC NMR spectra of the
Table 1. Testing the Silicon Cations (S,S)-1, (S,S)-2, (S,S)-
6, and (S,S)-7 in the Model Diels−Alder Reaction
a b
,
d
e
entry
sulfur-stabilized silicon cation
yield (%)
ee (%)
f
1
(S,S)-6
(S,S)-1
(S,S)-7
(S,S)-2
74
61
79
86
67
34
66
53
2
3
4
a
All reactions were performed according to the general procedure
GP6 at a dienophile concentration of 0.5 M. Reactions were
conducted on a 0.249 mmol scale. Data are based on multiple runs.
b
Diastereomeric ratios (trans:cis and endo:exo) determined by GLC
c
Figure 1. Sulfur-stabilized silicon cations (S,S)-6 and (S,S)-7 and
analysis of the crude material prior to purification. Determined by
their 29Si NMR chemical shifts.
GLC analysis using triphenylmethane as an internal standard.
d
Analytically pure cycloadduct after flash column chromatography
e
on silica gel. Determined by HPLC analysis using a chiral stationary
cationic silicon species (S,S)-6 and (S,S)-7 showed only one
resonance signal at δ 41.1 and 39.6 ppm, respectively. These
29Si NMR resonances are in good agreement with those found
for our previously reported binaphthyl-based silicon cations
(S,S)-1 (δ 39.5 ppm) and (S,S)-2 (δ 38.3 ppm).
f
phase. A reaction on a 1.00 mmol scale using 2.5 mol % of (S,S)-6
afforded 5 with 64% ee and in 92% isolated yield (see Supporting
Information for details).
We first tested the H8-binaphthyl silicon cation (S,S)-6 in
the model reaction of cyclohexa-1,3-diene (3) and chalcone
(4) (Table 1). The reaction was performed in 1,2-Cl2C6H4 at
room temperature and was stopped after 3 h.11 Full conversion
of dienophile 3 was achieved, and cycloadduct 5 was isolated
in good yield and with an enantiomeric excess of 67%,
exhibiting a significant increase in enantioselectivity, compared
to 34% ee previously obtained with the parent catalyst (S,S)-1
(entry 1 vs entry 2). We assume that the reason for the
improved enantioinduction is the increased steric demand of
the H8-binaphthyl system as a result of the larger dihedral
angle between the two partially hydrogenated naphthalene
rings. We expected even higher ee values with Lewis acid (S,S)-
7 with the substituted phenyl thioether group. However, the
bulky thioether moiety had no influence on the asymmetric
induction in this case (entry 3 vs entry 1) but was slightly
better than (S,S)-2 (entry 4). It is worth mentioning that
exactly this structural modification led to improved catalyst
performance in our earlier study (entry 2 vs entry 4).4c
Although both catalysts (S,S)-6 and (S,S)-7 induced the
same level of enantioselection in the model reaction, we
decided to explore the dienophile scope with Lewis acid (S,S)-
6 for its easier accessibility. Cyclohexa-1,3-diene (3) along with
a series of differently substituted chalcones were subjected to
the standard reaction conditions, affording the corresponding
cycloadducts with excellent endo/exo selectivities and in good
to moderate yields (Scheme 3). In our recent work, we had
already shown that an aryl group (R2) attached to the carbonyl
carbon atom is essential for achieving good enantioselectivities.
In addition to these findings, the replacement of the aryl group
R1 by a cyclohexyl group also led to markedly diminished
enantioselectivity (4 → 5 vs 13 → 29). However, additional
para-substitution of the R1 phenyl ring had no effect on
enantioinduction, giving products 30 and 31 with similar
enantiomeric excesses as the parent 5 (14 → 30 and 15 → 31
vs 4 → 5). As already found in our previous dienophile
screening, chalcones with para-substitution of the R2 aryl
group (as in 16−18) as well as chalcone bearing a β-naphthyl
group (as in 19) gave the highest enantioselectivities for the
cycloadducts 32−35 with ee values up to 81%. We did achieve
91% ee with the chalcone 18, but this result could not be
reliably reproduced. The reported data are generally based on
multiple runs. The introduction of bulkier para-substituents
such as the voluminous triisopropyl silyl group in 20 or linear
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DOI: 10.1021/acs.orglett.8b02945
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Scheme 3. Enantioselective Diels−Alder Reactions of Cyclohexa-1,3-diene (3) and Chalcones Catalyzed by the Sulfur-
a b
,
Stabilized Silicon Cation (S,S)-6
a
b
All reactions were performed according to the general procedure GP6 at a dienophile concentration of 0.5 M. Diastereomeric ratios (trans:cis and
c
1
endo:exo) determined by GLC or H NMR analysis of the crude material prior to purification. Data are based on multiple runs. Determined by
d
GLC analysis using triphenylmethane as an internal standard. Analytically pure cycloadduct after flash column chromatography on silica gel.
e
f
g
Determined by HPLC analysis using a chiral stationary phase. Dienophile concentration of 0.25 M. Dienophile concentration of 0.13 M.
h
i
Prepared with cyclopentadiene (45). Conversion was not determined.
alkyne in 21 caused a decrease in enantioselectivity compared
to the phenyl-substituted case 34 (20 → 36 and 21 → 37 vs
18 → 34). After identifying the biphenyl group as the best R2
substituent to provide good enantioinduction, we focused on
variation of R1. Unfortunately, contrary to a previously
described trend, para-substitution as in 22−25 as well as
ortho-/meta-substitution as in 26/27 were detrimental to
enantioselection, leading to cycloadducts 38−41 and 42/43,
respectively, with slightly or considerably diminished enantio-
meric excesses. The same outcome was observed in a tert-
butyl-substituted case (32 vs 44).
endo/exo selectivity dropped significantly, and the products 46
and 47 were isolated as racemic mixtures (Scheme 3, gray
box). These observations had already been made with the
catalysts (S,S)-1 and (S,S)-2 that yielded preferentially exo-
cycloadducts with no asymmetric induction. Although
examples of such anomalous exo-selectivity in [4 + 2]-
cycloadditions have been reported in the literature,12,13 the
absence of enantioinduction is still not clear.
In our preliminary study of the suitability of various
dienophiles for enantioselective Diels−Alder reactions, we
found that cycloadditions with cinnamates failed as a result of
ester cleavage or simply no conversion. To overcome this
limitation, the strategy involving the use of a biphenyl group in
We also examined the catalysis of selected dienophiles 4 and
18 with cyclopentadiene (45). However, in both cases, the
C
DOI: 10.1021/acs.orglett.8b02945
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Letter
ORCID
34 as an auxiliary to induce high enantioselectivity followed by
removal of this substituent via Baeyer−Villiger oxidation to
access the desired esters seemed viable.14 However, applying
the typical Baeyer−Villiger procedure to enantioenriched
cycloadducts 34, 39, and 44 furnished the corresponding
hydroxy lactones 48−50 (Scheme 4). Selective Baeyer−
Polina Shaykhutdinova: 0000-0001-6121-1299
Martin Oestreich: 0000-0002-1487-9218
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Scheme 4. Hydroxylactonization of the Diels−Alder Adduct
by a Baeyer−Villiger/Epoxidation/Epoxide Opening
■
This research was supported by the Deutsche Forschungsge-
meinschaft (Oe 249/12-1). M.O. is indebted to the Einstein
Foundation (Berlin) for an endowed professorship.
a
Reaction Sequence
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ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b02945.
Synthetic procedures and NMR spectra of the
compounds synthesized in this paper, as well as
analytical data for the unknown compounds (PDF)
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AUTHOR INFORMATION
Corresponding Author
■
*E-mail: martin.oestreich@tu-berlin.de.
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