Quinidine-Catalysed Enantioselective Synthesis of 6- and 4-Trifluoromethyl-Substituted Dihydropyrans

Article abstract of DOI:10.1002/ejoc.201600583

The cinchona alkaloid-catalysed enantioselective formal [4+2] cycloaddition of ethyl 2,3-butadienoate with a range of 1,1,1-trifluoro- and 4,4,4-trifluorobutenones is investigated for the preparation of stereodefined 6- and 4-trifluoromethyl-substituted dihydropyrans. Quinidine proved to be the optimal catalyst, generating the desired products in up to 98 % ee and 81 % yield. Stereo- and chemoselective derivatization of the dihydropyrans through hydrogenation is explored.

Full text of DOI:10.1002/ejoc.201600583

DOI: 10.1002/ejoc.201600583
Full Paper
Organocatalysis
Quinidine-Catalysed Enantioselective Synthesis of 6- and 4-Tri-
fluoromethyl-Substituted Dihydropyrans
[
a]
[a]
[a]
[a]
Kevin Kasten, David B. Cordes, Alexandra M. Z. Slawin, and Andrew D. Smith*
Abstract: The cinchona alkaloid-catalysed enantioselective for- substituted dihydropyrans. Quinidine proved to be the optimal
mal [4+2] cycloaddition of ethyl 2,3-butadienoate with a range catalyst, generating the desired products in up to 98 % ee and
of 1,1,1-trifluoro- and 4,4,4-trifluorobutenones is investigated 81 % yield. Stereo- and chemoselective derivatization of the di-
for the preparation of stereodefined 6- and 4-trifluoromethyl- hydropyrans through hydrogenation is explored.
Introduction
ity, are widely recognised and applied in medicinal chemistry.[7]
Allenoates are versatile synthetic building blocks that are widely
In this context it has previously been demonstrated that 1,1,1-
[
1]
used in the synthesis of carbo- and heterocyclic products.
trifluoro- and 4,4,4-trifluorobutenones can act as reactive reac-
Their simple preparation and commercial availability, combined
with their diverse reactivity profile, have made them attractive
starting materials that have been utilised within a range of syn-
thetic protocols. When utilised in Lewis base catalysis, addition
to the ꢀ-carbon of an allenoate generates a zwitterionic inter-
mediate that shows remarkably diverse reactivity with a range
of electrophilic coupling partners such as Michael acceptors,
dipolarophiles or strained heterocycles. Lewis basic phosphines
have been widely explored as catalysts in such processes,[1c,2]
while the use of tertiary amine Lewis bases has been relatively
less explored and typically show different reaction profiles to
phosphines. Within the latter area, Borhan and co-workers first
demonstrated the use of cinchona alkaloids to catalyse the for-
mal [4+2] cycloaddition of allenoates and chalcones. For ex-
ample, quinidine catalysed the reaction of chalcone 3a (R =
R = Ph, R = H) and allenoate 1a leading to the desired di-
hydropyran 4a in 83 % yield and 95 % ee (Scheme 1, a). Tong
and co-workers extended this protocol through the introduc-
tion of a cyano-group in the α-position of the chalcone (3b,
[
8]
tion partners in cinchona alkaloid catalysed processes as well
[
9]
[10]
as in isothiourea and NHC-mediated
[4+2] cycloaddition
processes. Building upon this precedent, in this manuscript the
catalytic enantioselective formal [4+2]-cycloaddition of allen-
oates with regioisomeric 1,1,1-trifluoro- and 4,4,4-trifluoro-
butenones is demonstrated for the preparation of stereodefined
6
- and 4-trifluoromethyl-substituted dihydropyrans (Scheme 1,
b). Derivatisation of the products through chemo- and stereo-
selective hydrogenation is also demonstrated.
[
3]
1
3
2
1
3
2
[4]
R = R = Ph, R = CN), generating the corresponding dihydro-
paran 4b from allenoate 1b in 90 % ee. Shi and co-workers
1
2
3
subsequently utilised α-keto esters 3c (R = Ph, R = H, R =
[
5]
1
2
3
COOtBu) and α-keto phosphonates 3d [R = Ph, R = H, R =
[
6]
P(O)(OiPr)2] as cycloaddition partners with allenoate 1a using
tertiary amine catalysts, generating dihydropyrans 4c and 4d in
up to 94 % ee. The benefits of incorporating the trifluoromethyl
group within target molecules such as increased chemical and
metabolic stability, increased lipophilicity, and binding selectiv-
[
a] EaStCHEM, School of Chemistry, University of St Andrews,
North Haugh, St Andrews, Fife, KY16 9ST, United Kingdom
E-mail: ads10@st-andrews.ac.uk
http://chemistry.st-andrews.ac.uk/staff/ads/group/index.html
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/ejoc.201600583.
Scheme 1. Cinchona alkaloid-catalysed formal [4+2] cycloadditions of allen-
oates and enones.
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Results and Discussion
methanol and ethanol (Table 2, entries 1 and 2) gave highest
enantioselectivity (91 % ee and 89 % ee respectively), although
methanol required extended reaction times and only gave
product in 33 % yield. Using 10 or 5 mol-% of quinidine in
ethanol the product ee remained approximately constant al-
though reduced product conversion and isolated yield were ob-
served (entries 3 and 4). Aprotic polar solvents exhibited an
increase in reaction rate with good yields but only moderate
enantioselectivity (entries 5–9). The use of ethyl acetate or tolu-
ene gave good conversion in short reaction times (maximum
Synthesis of 6-(Trifluoromethyl)dihydropyrans –
Optimisation:
Initial studies probed the ability of a variety of cinchona alka-
loid derivatives as catalysts for the formal [4+2] cycloaddition
of allenoates and 1,1,1-trifluorobut-3-en-2-ones. The reaction of
ethyl 2,3-butadienoate 1a and 1,1,1-trifluoro-4-phenylbut-3-en-
2-one 5a to give 7a was chosen as a model system for reaction
optimisation. A range of cinchona alkaloids was screened for
catalytic activity and product enantioselectivity (Table 1). Quin-
idine 6a and quinine 6b behaved similarly giving the antipodic
products 7a and 7a(ent) in good yields and promising enan-
tioselectivity (entries 1 and 2, up to 83 % ee). Cinchonine 6c and
cinchonidine 6d, which lack the phenolic methoxy-substituent,
showed a significant decrease in product ee (entries 3 and 4,
both 37 % ee). Bulkier 9-O-protected quinidine derivatives were
also screened; with 9-O-methylnaphthyl-quinidine 6e and 9-O-
trimethylsilylquinidine 6f resulted in lower product yield with
comparable product enantioselectivities (entries 5 and 6). The
effect of temperature on the reaction was also evaluated using
quinidine as the catalyst. Notably, a reduction in temperature
to 0 °C led to a marginal increase in ee, while a substantial loss
in product conversion and isolated yield was observed at –78 °C
5
h, entries 10–11), although moderate enantio-selectivities
were observed. Performing the reaction with water as the sol-
vent gave low selectivity in favour of 7a(ent) (entry 12). In an
attempt to further improve the product enantioselectivity and
reaction rate, a range of additives was tested in either ethanol
or toluene as the solvent (entries 13–15). Marginally improved
ee was observed when 20 mol-% of benzoic acid, phenol or
hexafluoroisopropanol (HFIP) were used in ethanol (95–
9
1 % ee), but lower yields were obtained. As a compromise be-
Table 2. Solvent and additive screen for the reaction of 1a with 5a.
(
entries 1, 7 and 8).
Table 1. Catalyst screen.
Entry
Solvent[a]
Additive[b]
t [h]
Yield [%][c]
ee [%][d]
1
2
MeOH
EtOH
EtOH
EtOH
–
–
–
–
–
–
–
–
72
48
72
192
114
47
21
15
20
5
4
2
96
48
48
33
68
45
46
82
79
77
78
80
73
85
55
49
63
52
91
89
88
90
85
82
79
76
75
83
79
18 (ent)
95
93
3[
e]
[f]
4
5
6
7
8
9
CH
2
Cl
2
acetone
MeCN
THF
Et
2
O
–
–
–
1
0
1
2
3
4
5
EtOAc
toluene
1
1
1
1
1
H
2
O
–
EtOH
EtOH
EtOH
PhCOOH
HFIP
PhOH
91
[
a] 0.1 M. [b] 20 mol-%. [c] Isolated yield. [d] Determined by HPLC analysis
against racemic sample. [e] 10 mol-% 6a (QD). [f] 5 mol-% 6a (QD).
Entry
Catalyst[a]
T [°C]
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
6a
6b
6c
6d
6e
6f
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
0
78
76
64
36
78
36
67
16
76
83
37
37
80
83
81
79
6a
6a
–78
[
a] 20 mol-%. [b] Isolated yield. [c] Determined by HPLC analysis against race-
mic sample.
Due to the recognised influence of the reaction solvent on
cinchona alkaloid conformation and therefore product ee, an
extensive solvent screen of this reaction process was per-
Figure 1. Molecular representation of the X-ray crystallographic analysis of
(S)-7a.
[
11]
formed.
At room temperature polar protic solvents such as
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tween product ee and yield, as well as reaction rate, ethanol
was chosen as the optimum solvent for this transformation.
With strongly electron-withdrawing p-nitrophenyl- and p-
mesyl-phenyl substituents lower product ee values were ob-
The relative and absolute configuration at C(4) was unambig- served (7g, 7h), whilst high ee but reduced product conversion
uously identified to be (S)-7a through X-ray crystallographic was obtained with an electron-rich p-anisyl- or p-tolyl substitu-
analysis, with the configuration within all subsequent examples ent (7i, 7j). Pleasingly, heteroaromatic and aliphatic substituents
[
12]
assigned by analogy (Figure 1).
such as thienyl (7k) and pentyl groups (7l) were also tolerated,
however slow conversion to product, resulting in lower isolated
yield, was observed with n-pentyl-alkyl substitution (7l).
Further studies probed the challenging effect of introducing
an α-methyl substituent within the enone moiety (Table 4). Due
to a significant decrease in reaction rate in EtOH, toluene was
chosen as the reaction solvent, although long reaction times
Scope and Limitations
I. Using 1,1,1-Trifluorobut-3-en-2-ones as the Reaction
Component
(5–10 d) were required for significant product formation. How-
ever, all products 9a–9g were prepared in excellent enantio-
Having developed optimum reaction conditions in the model selectivity. Notable trends indicate that electron-withdrawing p-
system, the scope of the reaction was probed through variation nitrophenyl substituent gave high product conversion and yield
with the trifluoromethylenone (Table 3). Generally, good yield (9g), whilst a significant decrease in product yield was observed
and high product enantioselectivity were obtained with a range for the o-bromophenyl- compared to the p-bromo-substituted
of substituted 4-aromatic and heteroaromatic substituents analogue (9e and 9f).
within the enone. Phenyl-, 1-, and 2-naphthyl-substituents gave
essentially identical yields and product ee values (7a–7c). The
incorporation of a bromine in the o-, m- and p-position of the
phenyl-substituent was tolerated (7d–7f), although o-substitu-
tion led to reduced product yield and enantioselectivity.
Table 4. Scope for the reaction of 1a with 3-methyl-1,1,1-trifluoromethylbut-
3
-en-2-ones.
Table 3. Scope for the reaction of 1 with 1,1,1-trifluoromethylbut-3-en-2-ones.
II. Using Isomeric 4,4,4-Trifluorobut-2-en-1-ones as the
Reaction Component
Having developed methodology utilising 1,1,1-trifluorobut-3-
en-2-ones for the preparation of 6-(trifluoromethyl)dihydro-
pyrans, the use of isomeric 4,4,4-trifluorobut-2-en-1-ones for
the preparation of stereodefined 4-trifluoromethyl-substituted
dihydropyrans was investigated (Table 5). A brief investigation
of the effect of solvent using quinidine 6a as the catalyst re-
vealed that the reaction proceeded to give the product in good
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ee in a range of solvents. Acetone provided the best compro-
mise between high yield and enantioselectivity.
Table 5. Solvent screen for the reaction of 1a with 10a.
Entry
Solvent[a]
t [d]
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
toluene
EtOH
THF
CH Cl
2 2
acetone
MeCN
1
6
2
6
2
2
4
71
21
79
72
74
80
74
85
95
84
89
92
88
89
Figure 2. Postulated mechanism for amine catalysed formal [4+2] cycloaddi-
tion of allenaotes and enones.
AcOEt
[
a] 0.1
M. [b] Isolated yields. [c] Determined by chiral HPLC analysis against
Product Derivatisation
racemic sample.
The tetrahydropyran motif is present in many bioactive mol-
Using acetone as the reaction solvent, the generality of this ecules, such as the anti-osteoporotic diospongine, making
[
14]
procedure was next examined (Table 6). Good yields and excel- methods for accessing these architectures highly desirable.
lent enantioselectivities were generally obtained with aromatic To showcase the utility of the methodology developed in this
and heteroaromatic substituents (11a–11e). Only p-nitrophenyl manuscript, derivatisation of 7a and 11a to enantioenriched
substitution exhibited modest enantioselectivity, consistent tetrahydropyran scaffolds via hydrogenation was investigated
with the selectivity observed in the isomeric series.
(Scheme 2). Treatment of 7a (87 % ee) with Pd/C and H (1 atm)
2
gave a 74:26 mixture of tetrahydropyran diastereoisomers 12
and 13 in 80 % combined yield. However, hydrogenation of 7a
Table 6. Scope for the reaction of 1a with 4,4,4-trifluoromethylbut-2-en-1-
ones.
(83 % ee) using Wilkinson's catalyst (50 bar H
, 60 °C) selectively
2
reduced the exocyclic olefin, giving 14 in 93 % yield and
>
>
95:5 dr. Further hydrogenation of 14 with Pd/C gave 12 in
94:6 dr and 74 % yield. The relative configuration within 12–
[
15]
15 and 17 was confirmed by nOe and Karplus analyses.
Scheme 2. Selective hydrogenation of dihydropyran 7a using Pd/C and Wilk-
inson's catalyst.
Consistent with the computational work of Yu et al. we pos-
tulate the mechanism of this transformation proceeds via the
addition of the tertiary amine Lewis base to the ꢀ-position of
The same protocols were applied to dihydropyran 11a. Using
The resultant adduct I subse- Pd/C as the catalyst a separable 55:45 mixture of tetrahydro-
[
13]
the allenoate 1a (Figure 2).
quently reacts in an s-cis conformation with the enone 5a with pyran 15 (> 95:5 dr) and ring-opened product 16 in 74 % com-
[
15,16]
the resultant enolate II undergoing cyclisation to give the six- bined yield.
The formation of 16 presumably arises from
membered ring III. Final elimination results in regeneration of hydrogenation, followed by benzylic hydrogenolysis.[ How-
17]
the cinchona catalyst and formation of dihydropyran product ever, treating 11a with Wilkinson's catalyst gave the expected
7
a.
mono-hydrogenated dihydropyran 17 in 77 % yield
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and > 95:5 dr. Notably 15 and 17 showed no loss of stereointeg- (EPSRC), UK National Mass Spectrometry Facility at Swansea
rity upon hydrogenation, whereas 16 was isolated with slightly University, is thanked for support.
diminished ee (Scheme 3).
Keywords: Organocatalysis · Enantioselective catalysis ·
Oxygen heterocycles
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[
[
Conclusions
To conclude, quinidine promotes the catalytic enantioselective
formal [4+2] cycloaddition of allenoates with isomeric 1,1,1-tri-
fluoro- and 4,4,4-trifluorobutenones, allowing the preparation
of stereodefined 4- and 6-trifluoromethyl-substituted dihydro-
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Example Procedure for the Enantioselective Organocatalytic
Generation of Dihydropyrans: To a stirred solution of ethyl 2,3-
butadienoate 1a (0.12 mmol) and the appropriate enone
(
6
0.10 mmol) in the appropriate solvent (0.1
a (0.02 mmol) at room temperature. After stirring at room temper-
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Supporting Information (see footnote on the first page of this
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K. K.). The Engineering and Physical Sciences Research Council
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These data can be obtained free of charge from The Cambridge Crystal-
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[15] The relative configuration of these diastereoisomers was confirmed by
nOe and Karplus analyses; for more details see supporting information.
[16] Combined yield includes separated fractions of 15 (23 % yield) and 16
(22 % yield) as well as the overlapping fractions.
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Received: May 12, 2016
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Organocatalysis
K. Kasten, D. B. Cordes,
A. M. Z. Slawin, A. D. Smith* .......... 1–7
Quinidine-Catalysed Enantioselect-
ive Synthesis of 6- and 4-Tri-
fluoromethyl-Substituted Dihydro-
pyrans
The quinidine-catalysed enantioselect- ones is demonstrated for the prepara-
ive formal [4+2]-cycloaddition of ethyl tion of stereodefined C(6) – and 4-tri-
2
,3-butadienoate with a range of 1,1,1- fluoromethyl-substituted dihydropyr-
trifluoro- and 4,4,4-trifluorobuten- ans (up to 98 % ee and 81 % yield).
DOI: 10.1002/ejoc.201600583
Eur. J. Org. Chem. 0000, 0–0
www.eurjoc.org
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© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim