Enantioselective NHC-catalysed redox [4+2]-hetero-Diels-Alder reactions using α-aroyloxyaldehydes and unsaturated ketoesters

Article abstract of DOI:10.1016/j.tetasy.2017.01.002

N-Heterocyclic carbene (NHC)-catalysed redox [4+2]-hetero-Diels-Alder reactions of α-aroyloxyaldehydes with either β,γ-unsaturated α-ketoesters or α,β-unsaturated γ-ketoesters generates substituted syn-dihydropyranones in good yield with excellent enantioselectivity (up to >99:1 er). The product diastereoselectivity is markedly dependent upon the nature of the unsaturated enone substituent. The presence of either electron-neutral or electron-rich aryl substituents gives excellent diastereoselectivity (up to >99:5 dr), while electron-deficient aryl substituents give reduced diastereoselectivity. In these cases, the syn-dihydropyranone products are more susceptible to base-promoted epimerisation at the C(4)-position under the reaction conditions, accounting for the lower diastereoselectivity obtained.

Full text of DOI:10.1016/j.tetasy.2017.01.002

Tetrahedron: Asymmetry xxx (2017) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Enantioselective NHC-catalysed redox [4+2]-hetero-Diels-Alder
reactions using a-aroyloxyaldehydes and unsaturated ketoesters
James E. Taylor a, Alyn T. Davies a, James J. Douglas a, Gwydion Churchill b, Andrew D. Smith a,
⇑
a EaStCHEM, School of Chemistry, University of St Andrews, North Haugh, St Andrews KY16 9ST, UK
b AstraZeneca, Process Research and Development, Macclesfield, Cheshire, SK10 2NA, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
N-Heterocyclic carbene (NHC)-catalysed redox [4+2]-hetero-Diels-Alder reactions of
des with either b,c-unsaturated a-ketoesters or a,b-unsaturated c-ketoesters generates substituted
a-aroyloxyaldehy-
Received 23 December 2016
Accepted 3 January 2017
Available online xxxx
syn-dihydropyranones in good yield with excellent enantioselectivity (up to >99:1 er). The product
diastereoselectivity is markedly dependent upon the nature of the unsaturated enone substituent. The
presence of either electron-neutral or electron-rich aryl substituents gives excellent diastereoselectivity
(up to >99:5 dr), while electron-deficient aryl substituents give reduced diastereoselectivity. In these
cases, the syn-dihydropyranone products are more susceptible to base-promoted epimerisation at the
C(4)-position under the reaction conditions, accounting for the lower diastereoselectivity obtained.
Ó 2017 Published by Elsevier Ltd.
1. Introduction
example, Bode and co-workers demonstrated that azolium enolates
generated from
a-chloroaldehydes react with both b,c-unsaturated
N-Heterocyclic carbenes (NHCs) are versatile organocatalysts
that exhibit a wide range of reactivity.1 Of the multiple activation
modes accessible through NHC catalysis, the generation and use of
azolium enolates has emerged as a powerful strategy for the enan-
tioselective synthesis of complex small-molecules. A number of
methods has been developed for the formation of azolium enolate
intermediates (Scheme 1a). For example, addition of an NHC into a
substituted ketene directly generates an azolium enolate,2 while
deprotonation of acyl azolium intermediates, themselves gener-
ated from either the reaction of NHCs with aldehydes under oxida-
tive conditions3 or the addition of NHCs into activated carboxylic
esters,4 also leads to enolate formation. Another common strategy
for azolium enolate formation is the addition of NHCs into aldehy-
a
-ketoesters and
a
,b-unsaturated -ketoesters to form syn-dihy-
c
dropyranones 3 with excellent enantioselectivity (Scheme 2a).6b In
this case, the use of unsaturated ketoesters bearing either alkyl or
electron-neutral/rich aryl substituents generally formed the
product dihydropyranones in high diastereoselectivity. Notably, the
presence of electron-deficient aryl (4-BrC6H4) or heteroaryl (2-furyl)
substituents lead to a decrease in diastereoselectivity, although the
origin of the reduced dr was not further investigated. This
methodology was subsequently extended to the use of the bench-
stable sodium bisulfate adducts of
a-chloroaldehydes under
biphasic conditions, allowing the use of unsubstituted
chloroacetaldehyde sodium bisulfite to form dihydropyranones
containing a single stereocentre.6c The NHC-catalysed redox hetero-
Diels-Alder reaction of enals with unsaturated ketoesters has also
been reported to proceed with high levels of stereoselectivity.7d
des bearing
undergo a redox process to form the desired enolate.5–10 Examples
of such -reducible aldehydes include
-chloroaldehydes,6 enals,7
-aryloxyaldehydes,8 and formyl cyclopropanes9 (Scheme 1b). We
have previously reported that bench-stable -aroyloxyaldehydes 1
are also efficient redox azolium enolate precursors.10
Azolium enolates generated from NHCs and -reducible aldehy-
a-reducible functional groups, which subsequently
a
a
a-Aroyloxyaldehydes have previously been used as azolium
a
enolate precursors in NHC-catalysed [4+2]-hetero-Diels-Alder
a
reactions with various trifluoromethyl enones (Scheme 2b)10b,d
and
functionalised syn-dihydropyranones 4 with high diastereo- and
enantioselectivity. Azolium enolates generated from
a
,b-unsaturated trichloromethyl ketones10e to form
a
des react with a variety of electrophiles to generate a diverse array
ofproducts. Ofparticular relevance is the reaction of azolium enolates
with substituted enones in enantioselective [4+2]-hetero-Diels-Alder
processes to form stereodefined dihydropyranone products. For
a-
[3+2]-
aroyloxyaldehydes
also
undergo
[2+2]10f
and
cycloadditions,10g as well as enantioselective
a-aminations to
from N-aryl amino acid derivatives.10c
Herein, the NHC-catalysed redox hetero-Diels-Alder reaction of
bench-stable -aroyloxyaldehydes with both b, -unsaturated
ketoesters and ,b-unsaturated -ketoesters is reported to form
a
c
a-
⇑
Corresponding author.
E-mail address: ads10@st-andrews.ac.uk (A.D. Smith).
a
c
http://dx.doi.org/10.1016/j.tetasy.2017.01.002
0957-4166/Ó 2017 Published by Elsevier Ltd.
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2
J. E. Taylor et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
a) Strategies towards azolium enolates
R1
N
(i)
(ii)
(iii)
(iv)
R
O
O
O
O
NHC
R
O
R
R
H
R2
R
•
H
OAr
+ Base
N
N
X
Ar
+ [O], Base
+ Base
azolium enolate
b)α-Reducible aldehydes used as azolium enolate precursors
O
O
O
O
H
O
R
ArO
R
R
H
R
H
H
H
Cl
O
OCOAr
1
Ar = 4-NO2C6H4
Ar = 4-NO2C6H4
Scheme 1. Generation of azolium enolate intermediates.
a) Bode, 2006: NHC-catalysed [4+2] cycloaddition using α-chloroaldehydes
O
O
Cl
N
O
O
R
2 (0.5 mol%)
Et3N (1.5 eq)
EtOAc, rt
O
R
N
N
+
H
MeO2C
R1
Mes
MeO2C
R1
Cl
2
3
up to >95:5 dr
up to >99:1 er
b) Smith, 2013: NHC-catalysed reaction of α-aroyloxyaldehydes with trifluoromethyl enones
O
O
O
R
2 (5 mol%)
Et3N (1.5 eq)
THF, 3Å MS, rt
O
R
+
H
F3C
R1
F3C
R1
OCOAr
Ar = 4-NO2C6H4
4
up to >95:5 dr
up to >99:1 er
c) This work: NHC-catalysed reaction of α-aroyloxyaldehydes with unsaturated ketoesters
O
O
O
O
O
R
R
R2O2C
R1
R1
CO2R2
O
O
R
H
NHC Catalysis
NHC Catalysis
R1
CO2R2
R2O2C
R1
OCOAr
Ar = 4-NO2C6H4
5
6
up to >95:5 dr
up to >99:1 er
up to >95:5 dr
up to >99:1 er
Scheme 2. NHC-catalysed redox [4+2]-hetero-Diels-Alder reactions.
syn-dihydropyranones 5 and 6 with excellent enantioselectivity
(Scheme 2c). The effect of various aryl substituents on the unsatu-
rated ketoesters on the reaction diastereoselectivity is assessed,
with control experiments performed to determine the origin of
the reduced product diastereoselectivity observed in some cases.
Starting the reaction at 0 °C and allowing it to warm slowly to
room temperature using 10 mol % 2 gave an excellent compromise
between reactivity and stereoselectivity, with syn-dihydropyra-
none 9 isolated in 93% yield with >95:5 dr and >99:1 er (Table 1,
entry 5). The relative and absolute configuration of the major pro-
duct was assigned by analogy to that of a known derivative formed
during investigation of the reaction substrate scope (vide infra).
2. Results and discussion
2.1. Reaction optimisation
2.2. Reaction scope with b,c-unsaturated a-ketoesters
The scope of the NHC-catalysed redox reaction of various
aroyloxyaldehydes with a range of b, -unsaturated -ketoesters
was studied under the previously optimised conditions (Table 2).
The reaction worked well with different alkyl -aroyloxyaldehyde
substituents, forming syn-dihydropyranones 10 and 11 in good
yields with excellent levels of stereoselectivity (up to >95:5 dr
a-
First, the reaction of azolium enolates derived from
loxyaldehydes11 with b,
-unsaturated -ketoesters was studied.
Treating -aroyloxyaldehyde 7 and -ketoester 8 with NHC precat-
a-aroy-
c
a
c
a
a
a
a
alyst 2 (20 mol %) and Et3N (1.5 equiv) in THF at room temperature
gave dihydropyranone 9 in a promising 50% yield and 92:8 dr with
excellent enantioselectivity (>99:1 er) for the major syn-
diastereoisomer (Table 1, entry 1).12 Lowering the catalyst loading
led to increased reaction times and decreased diastereoselectivity,
although the enantioselectivity for both diastereoisomers was high
(Table 1, entries 2 and 3). Decreasing the reaction temperature to
ꢀ78 °C led to an increase in diastereoselectivity (>99:1 dr), but
gave lower conversion into the desired product (Table 1, entry 4).
and >99:1 er). The reaction with b,c-unsaturated a-ketoesters
bearing electron-rich aromatic substituents (4-MeC6H4 and 4-
MeOC6H4) gave dihydropyranones 12–15 in high yields, but with
slightly reduced levels of syn-diastereoselectivity (P91:9 dr) com-
pared with the reaction with phenyl substituted
a-ketoester 8.
However, in each case the major syn-diastereoisomer was formed
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J. E. Taylor et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
3
Table 1
Reaction optimisation
O
O
O
O
Cl
N
N
NHC 2
Et3N (1.5 eq)
THF
Ph
O
N
+
Ph
H
Ph
CO2Me
Mes
Ph
CO2Me
OCOAr
7 (1.5 eq)
8
2
9
Ar = 4-NO2C6H4
Entry
NHC (mol %)
T (°C)
Time (h)
Conversiona,b (%)
dra
92:8
85:15
76:24
erc
1
2
3
2 (20)
2 (10)
2 (1)
rt
rt
rt
5
12
48
>90 (50)
>90
>90
>99:1
N/D
>99:1 (syn)
>99:1 (anti)
N/D
4
5
2 (10)
2 (10)
ꢀ78
12
12
45
>90 (93)
>95:5
>95:5
0 to rt
>99:1
a
Determined by 1H NMR analysis of the crude reaction mixture.
Isolated yield after purification by column chromatography in parentheses.
er of major diastereoisomer determined by HPLC analysis.
b
c
Table 2
Scope of the reaction using b,
c
-unsaturated
a
-ketoestersa,b,c
O
2 (10 mol%)
Et3N (1.5 eq)
THF, 3Å MS
0 °C to rt
O
R
O
R
O
H
OCOAr
Ar1
CO2R1
+
CO2R1
Ar1
9–17
(1.5 eq)
Ar = 4-NO2C6H4
O
O
O
O
n-Bu
Ph
O
O
Ph
CO2Me
Ph
CO2Me
Ph
CO2Me
9
10
11
12 h, 93%
3 h, 69%
24 h, 63%
>95:5 dr, >99:1 er
O
>95:5 dr, 98:2 er
O
>95:5 dr, >99:1 er
O
n-Bu
Ph
O
Ph
O
O
CO2Et
CO2Me
CO2Et
12
13
14
Me
MeO
Me
12 h, 77%
16 h, 62%
9 h, 70%
94:6 dr, 96:4 er
91:9 dr, >99:1 er
92:8 dr, >99:1 er
O
O
O
n-Bu
n-Bu
n-Bu
O
O
O
CO2Me
14 h, 72%
CO2Me
16
4 h, 42%
89:11 dr, 99:1 er
CO2Me
17
6 h, 48%
94:6 dr, >99:1 er
15
92:8 dr, >99:1 er
MeO
Br
a
b
c
Isolated yields of single diastereoisomers (>95:5 dr) after column chromatography.
dr determined by 1H NMR analysis of the crude reaction mixtures.
er of major diastereoisomer determined by HPLC analysis.
with high levels of enantioselectivity (P96:4 er). The relative con-
figuration of syn-dihydropyranone 12 could be confirmed through
comparison of its spectroscopic data with the literature,6b while
the absolute configuration was confirmed through comparison of
To investigate the reduced diastereoselectivity observed in cer-
tain cases, a series of control experiments was performed (Table 3).
Treating isolated syn-dihydropyranone 9 (>95:5 dr) with NHC pre-
catalyst 2 (15 mol %) and Et3N (15 mol %) resulted in epimerisation,
returning 9 in 89:11 dr after 65 h at room temperature (Table 3,
entry 1). Furthermore, significant amounts of products 18 and 19
arising from double bond isomerisation were also observed, indi-
cating that the initial deprotonation leading to both epimerisation
and isomerisation is most likely to occur at the C(4) position in
conjugation with the enone.13,14 The use of Et3N (15 mol %) alone
resulted in reduced amounts of both epimerisation (93:7 dr after
65 h) and isomerisation, suggesting that the free NHC is capable
of deprotonating 9 (Table 3, entry 2). Treating 9 with a stoichio-
its specific rotation [96:4 er, ½a D20
ꢁ
= +299.4 (c 0.5, CHCl3)] with
the reported value [(3S,4S)-12, 98.5:1.5 er, ½a D20
ꢁ
= +310.3 (c 1.0,
CHCl3)].6b The incorporation of a more electron-deficient aryl
bromine substituent led to
a
modest 42% yield of
dihydropyranone 16 in reduced 89:11 dr, although the
a
enantioselectivity remained high (99:1 er). An extended aromatic
2-naphthyl substituent was also successfully incorporated,
forming 17 in 48% yield with good stereoselectivity (94:6 dr,
>99:1 er).
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J. E. Taylor et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
Table 3
Investigation into the epimerisation of syn-9
O
O
O
2
syn-9
>95: 5 dr
>99:1 er
Ph
O
Ph
O
Ph
O
Et3N
THF, rt
65 h
+
+
Ph
CO2Me
Ph
CO2Me
Ph
CO2Me
9
18
19
Entry
2 (mol %)
Et3N (mol %)
9/18/19a
dr 9a
dr 18a
1
2
15
—
—
15
15
100
100
50:30:20
92:8:0
48:37:15
27:14:59
89:11
93:7
94:6
59:41
55:45
60:40
52:48
3
4b
—
80:20
a
Determined by 1H NMR analysis of the crude reaction mixtures.
Entry 3 re-subjected to the same conditions for a further 120 h.
b
Table 4
Scope of the reaction using
a
,b-unsaturated
c
-ketoestersa–c
O
2 (5 mol%)
Et3N (1.5 eq)
THF, 3Å MS, rt
O
O
R
O
R
H
EtO2C
R1
+
R1
EtO2C
OCOAr
(1.5 eq)
20–29
Ar = 4-NO2C6H4
O
O
O
O
n-Bu
BnO
EtO2C
O
Ph
EtO2C
2 h, 79%d
O
EtO2C
Ph
Ph
Ph
20
21
22
5 h, 85%
9 h, 85%
>95:5 dr, >99:1 er
90:10 dr, >99:1 er
>95:5 dr, >99:1 er
O
O
O
n-Bu
n-Bu
Ph
O
O
O
EtO2C
Me
EtO2C
EtO2C
23
24
25
Me
OMe
7 h, 65%e
6 h, 80%
6 h, 90%
>95:5 dr, >99:1 er
>95:5 dr, >99:1 er
>95:5 dr, 98.5:1.5 er
O
O
O
Me
O
Me
Ph
O
O
EtO2C
EtO2C
EtO2C
26
27
3 h, 52%
80:20 dr, >99:1 er
Cl
CF3
4 h, 55%
syn-28 + anti-29
80:20 dr, >99:1 er
24 h, 50:50 dr
syn-28: 32%, >99:1 er
anti-29: 35%, >99:1 er
aIsolated yields of single diastereoisomers (>95:5 dr) after column chromatography.
bdr determined by 1H NMR analysis of the crude reaction mixtures.
cer of major diastereoisomer determined by HPLC analysis.
d10 mol % 2 used.
eReaction performed at 40 °C using Cs2CO3 instead of Et3N.
metric amount of Et3N (1 equiv) resulted in increased levels of iso-
merisation into both 18 and 19 (Table 3, entry 3), while increased
reaction times led to further isomerisation and increased epimeri-
sation of the remaining dihydropyranone 9 (Table 3, entry 4). The
NHC and base-promoted epimerisation and isomerisation of the
product syn-dihydropyranones could therefore account for the
reduced diastereoselectivity and lower yields obtained in certain
instances (Table 2).
alongside Et3N (1.5 equiv) in THF at room temperature to form the
corresponding syn-dihydropyranones in high yields and with
excellent stereoselectivity.
a-Aroyloxyaldehydes bearing alkyl
and benzyl substituents were well tolerated, forming products
20–22 in high yields with excellent diastereo- and enantioselectiv-
ity (P90:10 dr, >99:1 er). The relative and absolute configuration
of 21 was confirmed through comparison of its spectroscopic data
and specific rotation [>99:1 er, ½a D20
ꢁ
= +173 (c 1.05, CHCl3)] with the
literature [>99:1 er, ½a D20
ꢁ
= +107 (c 0.82, CHCl3)],6c with all other
2.3. Reactions with
a,b-unsaturated
c-ketoesters
products in this series assigned by analogy. The reaction using an
a
,b-unsaturated
to be heated at 40 °C and required the use of Cs2CO3 as base to
form syn-dihydropyranone 23 in 65% yield as single
diastereoisomer in high enantioselectivity. The absolute
c-ketoester bearing a methyl substituent needed
Next, the use of
ysed redox process with
(Table 4). In this case, only 5 mol % NHC precatalyst 2 was required
a,b-unsaturated
c-ketoesters in the NHC-catal-
a-aroyloxyaldehydes was investigated
a
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J. E. Taylor et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
5
configuration of 23 could also be confirmed through comparison of
2
O
its specific rotation [98.5:1.5 er, ½a D20
ꢁ
= +271 (c 0.32 in CHCl3)] with
O
R
Et3N
O
the literature [>99:1 er, ½a D20
ꢁ
= +251 (c 0.93, CHCl3)].6c The use of
a,
R
H
R2
R1
b-unsaturated
c
-ketoester bearing electron-rich aryl substituents
N
N
OCOAr
N
worked particularly well, forming syn-dihydropyranones 24 and
25 in high yield with excellent levels of stereoselectivity (>95:5
dr, >99:1 er). However, the incorporation of aryl groups
containing electron-withdrawing substituents led to the
formation of 26 and 27 in lower yields with reduced
diastereoselectivity (80:20 dr), although the enantioselectivity
remained high in both cases (>99:1 er). A similar reduction in
diastereoselectivity was observed by Bode and co-workers in the
Ar = 4-NO2C6H4
+H
Mes
30
N
N
N
OH
H
O
R
N
Mes
R
O
ArOCO
N
N
Mes
31
R2
R1
35
−H
O
related NHC-catalysed redox reaction of an
with an ,b-unsaturated -ketoester bearing
substituted aryl ring.6b The reaction of a methyl substituted
aroyloxyaldehyde with a 2-naphthyl substituted ,b-unsaturated
-ketoester under the previously optimised conditions gave the
largest reduction in diastereoselectivity, with syn-28 and anti-29
formed as a 50:50 mixture, although both diastereoisomers were
obtained in excellent enantioselectivity (>99:1 er).
a
-chloroaldehyde
OH
R2
R1
O
R
a
c
a
4-bromo
N
N
R
N
a
-
ArOCO
N
32
Breslow
intermediate
Mes
N
a
N
34
Mes
OH
Azolium
enolate
c
R
N
−H
ArCO2
N
N
33
Mes
The dramatic reduction in diastereoselectivity observed with
Scheme 4. Proposed reaction mechanism.
the 2-naphthyl substituted
a,b-unsaturated c-ketoester was
probed by treating isolated syn-dihydropyranone 28 (>95:5 dr)
with Et3N (1.5 equiv) in THF at room temperature (Scheme 3).
After 16 hours, the dihydropyranone had epimerized into a
50:50 mixture of diastereoisomers, with both obtained in >99:1
er. This is consistent with the result from the initial NHC-catal-
ysed process, suggesting that the initially formed syn-
diastereoisomer is epimerized under the basic reaction condi-
tions. In this case, it is likely that epimerisation occurs at the C
(4) position and that the presence of conjugated electron-defi-
cient aryl substituents in the C(6) position increases the propen-
sity for deprotonation, which accounts for the reduced
diastereoselectivity observed in these cases. However, selective
epimerisation at the C(3) position adjacent to the lactone cannot
be unambiguously ruled out.
3. Conclusion
a
-Aroyloxyaldehydes are efficient azolium enolate precursors
in enantioselective NHC-catalysed [4+2] hetero-Diels-Alder reac-
tions with unsaturated ketoesters. Reactions using either b,
unsaturated -ketoesters or ,b-unsaturated -ketoesters form
c-
a
a
c
the corresponding syn-dihydropyranone products with generally
high diastereoselectivity and excellent enantioselectivity. In cases
where the unsaturated ketoester bears an electron-deficient aryl
substituent, the initially-formed syn-dihydropyranones are more
susceptible to epimerisation at the C(4)-position under the reac-
tion conditions, which lowers the observed diastereoselectivity of
the products.
2.4. Proposed mechanism
4. Experimental
4.1. General
The proposed reaction mechanism is shown in Scheme 4. Ini-
tially, the catalytically active free NHC is generated through depro-
tonation of NHC precursor 2. Nucleophilic addition of the free NHC
Anhydrous reactions were carried out in flame-dried glassware
under an inert atmosphere (N2 or Ar) using standard vacuum line
techniques. Anhydrous THF and Et2O were obtained after passing
through an alumina column (Mbraun SPS-800). Petrol is defined
as petroleum ether 40–60 °C. All other solvents and commercial
30 into the
a-aroyloxyaldehyde generates adduct 31, which is
likely to be the catalytic resting state.10b Reversible
deprotonation of 31 transiently forms Breslow intermediate 32
that can eliminate 4-nitrobenzoate. The resulting enol 33 can be
deprotonated to form the key azolium enolate intermediate 34,
which can undergo an enantioselective asynchronous endo-
hetero-Diels-Alder reaction with an appropriate unsaturated
ketoester. Finally, elimination from intermediate 35 releases the
product syn-dihydropyranone and regenerates the free NHC
catalyst. This mechanistic proposal is consistent with the
computational studies from Bode and co-workers on related
NHC-catalysed [4+2]-hetero-Diels-Alder processes.15
reagents were used as received without further purification.
a-
Aroyloxyaldehydes were prepared according to previously
reported procedures.10
Room temperature (rt) refers to 20–25 °C and a temperature of
0 °C was obtained using an ice/water bath. Reactions involving
heating were performed using DrySyn blocks and a contact ther-
mocouple. Under reduced pressure refers to the use of a rotary
evaporator with vacuum controller.
O
O
O
Me
Me
Me
Et3N (1.5 eq)
THF, rt
O
O
O
+
EtO2C
EtO2C
EtO2C
16 h
syn-28
>95:5 dr
>99:1 er
syn-28
>99:1 er
anti-29
>99:1 er
51:49 dr
Scheme 3. Base-promoted epimerisation of syn-28.
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6
J. E. Taylor et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
Analytical thin layer chromatography was performed on pre-
and benzaldehyde (20.4 mL, 200 mmol) in MeOH (15 mL) were
reacted to give potassium (E)-2-oxo-4-phenylbut-3-enoate
(39.0 g, 91%) as a yellow solid with spectroscopic data in accor-
dance with the literature.18 Mp 246–248 °C {Lit.18 248 °C}; 1H
NMR (400 MHz, D2O) dH: 6.78 (1H, d, J 15.0, PhCH@CH), 7.34–
7.42 (3H, m, Ar(3,4,5)H), 7.39 (1H, d, J 15.0, C PhCH@CH), 7.57–
7.61 (2H, m, Ar(2,6)H).
Following General Procedure 4.2 (part 2), potassium (E)-2-oxo-
4-phenylbut-3-enoate (7.48 g, 35 mmol) and acetyl chloride
(28.6 mL, 402 mmol) in MeOH (200 mL) were reacted. The crude
was purified by column chromatography (90:10 petrol:EtOAc),
then recrystallised from MeOH to give 8 (1.16 g, 17%) as a yellow
crystalline solid with spectroscopic data in accordance with the lit-
erature.18 Mp 69–71 °C {Lit.18 69–70 °C}; 1H NMR (300 MHz,
CDCl3) dH: 3.94 (3H, s, OCH3), 7.38 (1H, d, J 16.1, HC@C), 7.42–
7.49 (3H, m, ArH), 7.61–7.67 (2H, m, ArH), 7.89 (1 H, d, J 16.2,
HC@C).
coated aluminium plates (Kieselgel 60 F254 silica) and visualisation
was achieved using ultraviolet light (254 nm) and/or staining with
a 1% aqueous KMnO4 solution. Flash column chromatography was
performed on Kieselgel 60 silica in the solvent system stated.
Melting points were recorded on an Electrothermal 9100 melt-
ing point apparatus, (dec) refers to decomposition. Optical rotations
were measured on a Perkin Elmer Precisely/Model-341 polarimeter
operating at the sodium d line with a 100 mm path cell at 20 °C.
HPLC analyses were obtained on either a Gilson HPLC consisting
of a Gilson 305 pump, Gilson 306 pump, Gilson 811C dynamic
mixer, Gilson 805 manometric module, Gilson 401C dilutor, Gilson
213XL sample injector and sample detection was performed with a
Gilson 118 UV/vis detector or a Shimadzu HPLC consisting of a
DGU-20A5 degasser, LC-20AT liquid chromatography SIL-20AHT
autosampler, CMB-20A communications bus module, SPD-M20A
diode array detector and a CTO-20A column oven. Separation
was achieved using Chiralcel OD-H and OJ-H columns or a Chiral-
pak AD-H column. All HPLC traces were compared with an authen-
tic racemic spectrum prepared in analogous fashion using ( )-2.
4.2.2. (E)-Ethyl 2-oxo-4-(p-tolyl)but-3-enoate 36
Following General Procedure 4.2 (part 1), KOH (1.40 g,
24.9 mmol) in MeOH (5 mL), pyruvic acid (1.15 mL, 16.6 mmol)
and p-tolualdehyde (1.96 mL, 16.6 mmol) in MeOH (2 mL) were
reacted to give potassium (E)-2-oxo-4-(p-tolyl)but-3-enoate
(2.78 g, 12.2 mmol, 73%) as yellow solid, with spectroscopic data
in accordance with the literature.18 Mp 242–244 °C (dec); 1H
NMR (400 MHz, D2O) dH: 2.28 (3H, s, ArCH3), 6.74 (1H, d, J 16.4,
ArCH@CH), 7.23 (2H, d, J 8.1, ArH), 7.51 (2H, d, J 8.2, ArH), 7.59
(1H, d, J 16.4, ArCH@CH).
Following General Procedure 4.2 (part 2), potassium (E)-2-oxo-
4-(p-tolyl)but-3-enoate (1.00 g, 4.38 mmol) and acetyl chloride
(3.58 mL, 50.4 mmol) in ethanol (30 mL) were reacted. The crude
was purified by column chromatography (95:5 petrol:EtOAc) to
give 36 (0.560 g, 58%) as a yellow solid, with spectroscopic data
in accordance with the literature.17 Mp 40–42 °C {Lit.17 47–
48 °C}; 1H NMR (300 MHz, CDCl3) dH: 1.41 (3H, t, J 7.1, OCH2CH3),
2.40 (3H, s, ArCH3), 4.39 (2H, q, J 7.1, OCH2CH3), 7.23 (2H, d, J
7.9, ArH), 7.32 (1H, d, J 16.1, ArCH@CH), 7.53 (2H, d, J 8.2, ArH),
7.84 (1H, d, J 16.1, ArCH@CH).
Infrared spectra (mmax) were recorded on a Shimadzu IRAffinity-
1 Fourier transform IR spectrophotometer using either thin film or
solid using Pike MIRacle ATR accessory.
1H, 13C{1H}, and 19F{1H} NMR spectra were acquired on either a
Bruker Avance 300 (1H 300 MHz; 13C{1H} 75 MHz; 19F{1H}
282 MHz), a Bruker Avance II 400 (1H 400 MHz; 13C{1H} 100 MHz;
19F{1H} 376 MHz), or a Bruker Ultrashield 500 (1H 500 MHz) spec-
trometer at room temperature in the deuterated solvent stated.
All chemical shifts are quoted in parts per million (ppm) relative
to the residual solvent peak. All coupling constants, J, are quoted
in Hz. Multiplicities are indicated as s (singlet), d (doublet), t
(triplet), q (quartet), m (multiplet), and multiples thereof. The
abbreviation Ar denotes aromatic and app denotes apparent.
High resolution mass spectrometry (m/z) data was acquired by
electrospray ionisation (ESI), atmospheric pressure chemical ioni-
sation (APCI) or nanospray ionisation (NSI) at the EPSRC UK
National Mass Spectrometry Facility at Swansea University.
4.2. General procedure for the synthesis of b,c-unsaturated a-
ketoesters
4.2.3. (E)-Methyl 4-(4-methoxyphenyl)-2-oxobut-3-enoate 37
Following General Procedure 4.2 (part 1), KOH (1.11 g,
19.8 mmol) in MeOH (4 mL), pyruvic acid (0.917 mL, 13.2 mmol)
and p-anisaldehyde (1.80 g, 1.61 mL, 13.2 mmol) in MeOH
(1.5 mL) were reacted to give potassium (E)-4-(4-methoxyphe-
nyl)-2-oxobut-3-enoate (2.31 g, 72%) as a yellow solid, with spec-
troscopic data in accordance with the literature.16 Mp 250–252 °C
{Lit.16 248 °C}; 1H NMR (400 MHz, D2O) dH: 6.66 (1H, d, J 16.4,
CH@CH), 6.95 (2H, d, J 8.8, ArH), 7.50–7.69 (3H, m, ArH and CH@CH).
Following General Procedure 4.2 (part 2), potassium (E)-2-oxo-
4-(4-methoxyphenyl)but-3-enoate (2.00 g, 8.19 mmol) and acetyl
chloride (6.70 mL, 94.2 mmol) in MeOH (60 mL) were reacted.
The crude was purified by column chromatography (85:15 pet-
rol:EtOAc) to give 37 (1.37 g, 76%) as a yellow crystalline solid,
with spectroscopic data in accordance with the literature.18 Mp
95–96 °C {Lit.18 99–100 °C}; 1H NMR (300 MHz, CDCl3) dH: 3.80
(3H, s, OCH3), 3.86 (3H, s, OCH3), 6.87 (2H, d, J 8.8, ArH), 7.19
(1H, d, J 16.0, ArCH@CH), 7.54 (2H, d, J 8.5, ArH), 7.79 (1H, d, J
16.0, ArCH@CH).
Part 1: Based upon a literature procedure,16 KOH (1.5 equiv) in
MeOH (6 M) was added to a solution of pyruvic acid (1.0 equiv),
the required aryl aldehyde (1.0 equiv) and MeOH (12 M) at 0 °C.
The first equivalent of KOH solution was added dropwise over
30 min, the rest was added as one portion. The reaction mixture
was heated at 40 °C for 1 h before being cooled to 0 °C and stirred
overnight. The precipitate was collected by filtration and washed
with cold MeOH (ꢂ2) and Et2O before being dried under vacuum
to give the desired b,c-unsaturated a-ketoacid potassium salt.
Part 2: Based upon a literature procedure procedure,17 acetyl
chloride (11.5 equiv) was added dropwise to the appropriate alcohol
(0.2 M) at 0 °C before the required potassium salt (1.0 equiv) was
added. The reaction mixture was warmed to rt and stirred for 2 h
before being heated at reflux for 6 h. The solution was cooled to rt,
concentrated under reduced pressure and then partitioned between
CH2Cl2 and H2O. The layers were separated and the aqueous layer
extracted with CH2Cl2 (ꢂ2). The combined organic phases were
washed with a saturated NaHCO3 solution and H2O before being
dried over Na2SO4, filtered and concentrated to give the crude
4.2.4. (E)-Methyl 4-(4-fluorophenyl)-2-oxobut-3-enoate 38
Following General Procedure 4.2 (part 1), KOH (1.36 g,
24.2 mmol) in MeOH (6 mL), pyruvic acid (1.12 mL, 16.1 mmol)
and 4-fluorobenzaldehyde (2.00 g, 1.73 mL, 16.1 mmol) in MeOH
(2 mL) were reacted to give potassium (E)-4-(4-fluorophenyl)-2-
oxobut-3-enoate (2.67 g, 71%) as a yellow solid, with spectroscopic
data in accordance with the literature.19 Mp 205–208 °C (dec); 1H
b,c-unsaturated a-ketoester that was purified by column
chromatography.
4.2.1. (E)-Methyl 2-oxo-4-phenylbut-3-enoate 8
Following General Procedure 4.2 (part 1), KOH (16.8 g,
300 mmol) in MeOH (60 mL), pyruvic acid (13.8 mL, 200 mmol)
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J. E. Taylor et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
7
NMR (500 MHz, D2O) dH: 6.73 (1H, d, J 16.3, ArCH@CH), 7.11 (2H, t,
J 8.2, ArC(2)H), 7.59 (1H, d, J 16.4, ArCH@CH), 7.64 (2H, dd, J 7.4,
5.2, ArC(3)H); 19F NMR (376 MHz, D2O) dF: ꢀ109.0 (ArC(4)F).
Following General Procedure 4.2 (part 2), potassium (E)-4-(4-
fluorophenyl)-2-oxobut-3-enoate (1.00 g, 4.31 mmol) and acetyl
chloride (3.53 mL, 49.6 mmol) in MeOH (40 mL) were reacted.
The crude was purified by column chromatography (95:5 petrol:
EtOAc) to give (E)-methyl 4-(4-fluorophenyl)-2-oxobut-3-enoate
(0.320 g, 36%) as a yellow crystalline solid, with spectroscopic data
were dissolved in anhydrous THF (0.075 M) in a sealed vial con-
taining 3 Å molecular sieves. The solution was cooled to 0 °C before
Et3N (1.5 equiv) was added. The reaction was stirred, allowing to
warm to rt, until complete by TLC analysis. The mixture was
diluted with EtOAc and washed successively with 1 m HCl, satu-
rated NaHCO3 and brine. The organic layer was dried with MgSO4,
filtered and concentrated under reduced pressure to give the crude
product, which was purified by column chromatography.
in accordance with the literature.20 Mp 86–87 °C;
mmax (solid) 1722
4.3.1. (3S,4S)-Methyl 3-benzyl-2-oxo-4-phenyl-3,4-dihydro-2H-
pyran-6-carboxylate 9
Following General Procedure 4.3,1-oxo-3-phenylpropan-2-yl 4-
nitrobenzoate 7 (50 mg, 0.17 mmol), (E)-methyl 2-oxo-4-phenyl-
but-3-enoate 8 (21.0 mg, 0.11 mmol), NHC precatalyst 2 (4.0 mg,
(C@O), 1690 (C@O); 1H NMR (400 MHz, CDCl3) dH: 3.87 (3H, s,
OCH3), 7.06 (2H, t, J 8.6, ArC(3)H), 7.25 (1H, dd, J 16.2, 0.6, CH@CH),
7.58 (2H, dd, J 8.7, 5.4, ArC(2)H), 7.78 (1H, d, J 16.1, CH@CH); 19F
NMR (376 MHz, CDCl3) dF: ꢀ107.3 (tt, J 8.1, 5.5, C(4)F); 13C{1H}
NMR (101 MHz, CDCl3) dC: 53.1 (OCH3), 116.4 (d, J 22.0, C(3)),
120.1 (d, J 2.2, ArCH@CH), 130.3 (d, J 3.1, C(1)), 131.2 (d, J 8.8, C
(2)), 147.2 (ArCH@CH), 162.5 (CO2), 164.7 (d, J 253.9, C(4)), 182.1
(CH@CHCO); HRMS (NSI+) C11H10O3F [M+H]+ found 209.0610,
requires 209.0608 (+0.7 ppm).
11 lmol), Et3N (23 lL, 0.17 mmol) and THF (3 mL) were reacted
for 12 h. The crude (>95:5 dr) was purified by column chromatog-
raphy (90:10 petrol:EtOAc) to give 9 (51 mg, 93%) as a colourless
solid. Mp 106–107 °C; ½a D20
ꢁ
= +398 (c 0.23, CHCl3); Chiral HPLC
analysis, Chiralpak AD-H (90:10 hexane:IPA, flow rate
1.0 mL minꢀ1, 254 nm, 30 °C) tR (R,R) 18.0 min, tR (S,S) 27.8 min,
>99:1 er; mmax (KBr, cmꢀ1) 2956, 2925, 1765, 1628, 1664, 1602,
1495, 1435, 1316, 1100; 1H NMR (400 MHz, CDCl3) dH: 2.33 (1H,
dd, J 10.6, 15.8, C(3)CHAHB), 3.16–3.23 (2H, m, C(3)CHAHB and C
(3)H), 3.55 (1H, t, J 6.8, C(4)H), 3.77 (3H, OCH3), 6.58 (1H, d, J 6.7,
C(5)H), 6.93–7.00 (4H, m, C(3)ArH), 7.15–7.26 (6H, m, C(3)ArH
and C(3)CH2ArH); 13C{1H} NMR (75 MHz, CDCl3) dC: 32.1 (C(3)
CH2), 40.6 (C(3)H), 44.8 (C(4)H), 52.7 (OCH3), 118.8 (C(5)), 126.8
(C(3)CH2ArC(4)), 128.4 (C(4)ArC(4)), 128.4 (ArC), 128.7 (ArC),
128.9 (ArC), 129.2 (ArC), 135.8 (CPh-1), 138.1 (C(3)CH2ArC(1)),
141.9 (C(6)), 161.0 (CO2Me), 168.5 (C(2)); HRMS (ESI+)
4.2.5. (E)-Methyl 4-(4-bromophenyl)-2-oxobut-3-enoate 39
Following General Procedure 4.2 (part 1), KOH (4.55 g,
81.1 mmol) in MeOH (15 mL), pyruvic acid (3.81 mL, 54.1 mmol)
and 4-bromobenzaldehyde (10.0 g, 54.1 mmol) in MeOH (15 mL)
were reacted to give potassium (E)-2-oxo-4-(4-bromophenyl)but-
3-enoate (15.9 g, 84%) as a yellow solid, with spectroscopic data
in accordance with the literature.18 Mp 240 °C (dec) {Lit.18
233 °C}; 1H NMR (400 MHz, D2O) dH: 6.91 (1H, d, J 17.1, C(3)H),
7.59–7.60 (2H, m, Ar(3,5)H), 7.62 (1H, d, J 17.1, C(4)H), 7.65–7.68
(2H, m, Ar(2,6)H).
Following General Procedure 4.2 (part 2), potassium (E)-2-oxo-
4-(4-bromophenyl)but-3-enoate (2.00 g, 6.82 mmol) and acetyl
chloride (5.57 mL, 78.4 mmol) in MeOH (40 mL) were reacted.
The crude was purified by column chromatography (95:5 petrol:
EtOAc) to give 39 (1.21 g, 66%) as a yellow crystalline solid, with
spectroscopic data in accordance with the literature.18 Mp 109–
112 °C {Lit.18 120 °C}; 1H NMR (400 MHz, CDCl3) dH: 3.87 (3H, s,
OCH3), 7.31 (1H, d, J 16.1, ArCH@CH), 7.43 (2H, d, J 8.5, ArH),
7.50 (2H, d, J 8.5, ArH), 7.74 (1H, d, J 16.1, ArCH@CH).
C
20H22O4N [M+NH4]+ found 340.1544, requires 340.1543
(+0.2 ppm).
4.3.2. (3S,4S)-Methyl 3-butyl-2-oxo-4-phenyl-3,4-dihydro-2H-
pyran-6-carboxylate 10
Following General Procedure 4.3, 1-oxohexan-2-yl 4-nitroben-
zoate (50 mg, 0.19 mmol), (E)-methyl 2-oxo-4-phenylbut-3-enoate
8 (25.2 mg, 0.13 mmol), NHC precatalyst 2 (4.2 mg, 10.0
lmol),
Et3N (28 L, 0.19 mmol) and THF (3 mL) were reacted for 3 h.
l
The crude (>95:5 dr) was purified by column chromatography
4.2.6. (E)-Methyl 4-(naphthalen-2-yl)-2-oxobut-3-enoate 40
Following General Procedure 4.2 (part 1), KOH (1.08 g,
19.2 mmol) in MeOH (3 mL), pyruvic acid (0.890 mL, 12.8 mmol)
and 2-naphthaldehyde (2.00 g, 12.8 mmol) in MeOH (3 mL) were
reacted to give potassium (E)-4-(naphthalen-2-yl)-2-oxobut-3-
enoate (2.46 g, 73%) as a yellow solid, with spectroscopic data in
accordance with the literature.18 Mp >320 °C {Lit.18 270–272 °C
(dec)}; 1H NMR (400 MHz, D2O) dH: 6.85 (1H, d, J 16.5, ArCH@CH),
7.50 (2H, s, ArH), 7.65–7.74 (2H, m, ArH, and ArCH@CH), 7.81–7.86
(3H, m, ArH), 7.99 (1H, s, Ar(1)H).
Following General Procedure 4.2 (part 2), potassium (E)-4-(-
naphthalen-2-yl)-2-oxobut-3-enoate (1.00 g, 3.78 mmol) and
acetyl chloride (3.08 mL, 43.5 mmol) in MeOH (30 mL) were
reacted. The crude was purified by column chromatography
(95:5 petrol:EtOAc) to give 40 (0.570 g, 63%) as a yellow solid, with
spectroscopic data in accordance with the literature.18 Mp 94–
96 °C {Lit.18 70–72 °C}; 1H NMR (400 MHz, CDCl3) dH: 3.96 (3H, s,
OCH3), 7.49 (1H, d, J 16.1, ArCH@CH), 7.52–7.61 (2H, m, ArH),
7.77 (1H, dd, J 8.6, 1.8, ArH), 7.84–7.93 (3H, m, ArH), 8.02–8.09
(2H, m, ArCH@CH and ArH).
(95:5 petrol:EtOAc) to give 10 (26 mg, 69%) as a colourless oil.
½
a 2D0
ꢁ
= +156 (c 0.15, CHCl3); Chiral HPLC analysis, Chiralpak AD-H
(95:5 hexane:IPA, flow rate 1.0 mL minꢀ1
,
220 nm) tR (R,R)
16.2 min, tR (S,S) 18.3 min, 98:2 er; mmax (ATR, cmꢀ1) 2954, 1773,
1734, 1661, 1454, 1437, 1323, 1259, 1045; 1H NMR (300 MHz,
CDCl3) dH: 0.81 (3H, t, J 7.1, CH2CH3), 1.08–1.40 (5H, m, CH2 ꢂ 2
and C(3)CHAHB), 1.60–1.70 (1H, m, C(3)CHAHB), 2.79 (1H, d, J 6.9,
C(3)H), 3.79 (1H, t, J 6.7, C(4)H), 3.83 (3H, s, OCH3), 6.68 (1H, d, J
6.4, C(5)H), 7.06 (2H, dt, J 1.8, 5.8, ArC(2)H), 7.23–7.29 (3H, m,
ArC(3)H and ArC(4)H); 13C{1H} NMR (100 MHz, CDCl3) 13.9 (CH3),
22.5 (CH2), 26.0 (CH2), 29.4 (CH2), 41.5 (C(4)), 43.4 (C(3)), 52.7
(OCH3), 118.4 (C(5)), 128.1 (CPhH-2,6), 128.1 (CPh-4), 129.1 (ArC
(3)), 136.0 (ArC(1)), 142.1 (C(6)), 161.1 (CO2Me), 168.8 (C(2));
HRMS (ESI+)
C
17H24O4N [M+NH4]+ found 306.1702, requires
306.1700 (+0.7 ppm).
4.3.3. (3S,4S)-Methyl 3-isobutyl-2-oxo-4-phenyl-3,4-dihydro-
2H-pyran-6-carboxylate 11
Following General Procedure 4.3,4-methyl-1-oxopentan-2-yl 4-
nitrobenzoate 7 (133 mg, 0.50 mmol), (E)-methyl 2-oxo-4-phenyl-
but-3-enoate 8 (63.0 mg, 0.33 mmol), NHC precatalyst 2 (12.0 mg,
4.3. General procedure for the NHC-catalysed redox hetero-
33 lmol), Et3N (70 lL, 0.50 mmol) and THF (5 mL) were reacted for
Diels-Alder reaction with b,
c
-unsaturated
a
-ketoesters
24 h. The crude (>95:5 dr) was purified by column chromatography
(95:5 petrol:EtOAc) to give 11 (60 mg, 63%) as a colourless oil.
The appropriate
a
-aroyloxyaldehyde (1.5 equiv), b,
c
-unsatu-
½
a 2D0
ꢁ
= +279 (c 0.14, CHCl3); Chiral HPLC analysis, Chiralpak AD-H
rated -ketoester (1.0 equiv) and NHC precatalyst 2 (10 mol %)
a
(95:5 hexane:IPA, flow rate 1.0 mL minꢀ1
,
220 nm) tR (R,R)
Please cite this article in press as: Taylor, J. E.; et al. Tetrahedron: Asymmetry (2017), http://dx.doi.org/10.1016/j.tetasy.2017.01.002

8
J. E. Taylor et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
11.9 min, tR (S,S) 13.0 min, >99:1 er; mmax (KBr, cmꢀ1) 2959, 1769,
1708, 1661, 1317, 1265, 1094, 1082; 1H NMR (300 MHz, CDCl3)
dH: 0.83 (3H, d, J 6.6, CH3), 0.88 (3H, d, J 6.6, CH3), 1.04 (1H, app
dt, J 7.0, 14.0, i-BuCH), 1.56 (2H, dt, J 7.0, 13.9, C(3)CHAHB), 1.72
(1H, dd, J 7.0, 14.0, C(3)CHaHa), 2.93 (1H, app q, J 6.9, C(3)H), 3.77
(1H, t, J 6.7, C(4)H), 3.87 (3H, s, OCH3), 6.72 (1H, d, J 6.4, C(5)H),
7.07–7.10 (2H, dt, J 1.8, 5.8, ArC(2)H), 7.27–7.34 (3H, m, ArC(3)H
and ArC(4)H); 13C{1H} NMR (100 MHz, CDCl3) dC: 22.2 ((CH3)2CH),
22.5 ((CH3)2CH), 25.2 ((CH3)2CH), 35.2 (C(3)CH2), 41.2 (C(3)), 41.7
(C(4)), 52.7 (OCH3), 118.4 (C(5)), 128.1 (ArC(2)), 128.1 (ArCC(4)),
129.1 (ArCC(3)), 136.0 (ArC(1)), 142.1 (C(6)), 161.1 (CO2Me),
168.9 (C(2)); HRMS (ESI+) C17H24O4N, [M+NH4]+ found 306.1704;
requires 306.1700 (+1.4 ppm).
4.3.6. (3S,4S)-Ethyl 3-butyl-2-oxo-4-(p-tolyl)-3,4-dihydro-2H-
pyran-6-carboxylate 14
Following General Procedure 4.3, 1-oxohexan-2-yl 4-nitroben-
zoate (200 mg, 0.750 mmol), (E)-ethyl 2-oxo-4-(p-tolyl)but-3-eno-
ate 36 (109 mg, 0.500 mmol), NHC precatalyst
2 (18.4 mg,
50.0 mol), Et3N (105 L, 0.750 mmol) and THF (10 mL) were
l
l
reacted for 9 h. The crude (92:8 dr) was purified by column chro-
matography (95:5 petrol:EtOAc) to give 14 (110 mg, 70%) as a pale
yellow oil. ½a 2D0
ꢁ
= +249.2 (c 0.5, CHCl3); Chiral HPLC analysis, Chi-
ralpak AD-H (95:5 hexane:IPA, flow rate 1 mL minꢀ1, 254 nm,
30 °C) tR (3S,4S): 11.3 min, tR (3R,4R): 13.7 min, >99:1 er; mmax
(film, cmꢀ1) 2957, 1773, 1732; 1H NMR (400 MHz, CDCl3) dH:
0.78 (3H, t, J 7.2, CH2CH3), 1.04–1.38 (7H, m, (CH2)2 and OCH2CH3),
1.54–1.71 (2H, m, CH2), 2.24 (3H, s, ArC(4)CH3), 2.73 (1H, q, J 7.0, C
(3)H), 3.70 (1H, t, J 6.8, C(4)H), 4.24 (2H, q, J 7.1, OCH2CH3), 6.62
(1H, d, J 6.4, C(5)H), 6.91 (2H, d, J 8.1, ArC(2)H), 7.04 (2H, d, J 7.8,
ArC(3)H); 13C{1H} NMR (100 MHz, CDCl3) dC: 13.9 (OCH2CH3),
14.2 (CH2CH3), 21.1 (ArC(4)CH3), 22.5 (CH2), 26.0 (CH2), 29.4
(CH2), 41.1 (C(4)), 43.4 (C(3)), 61.9 (OCH2CH3), 118.4 (C(5)), 127.9
(ArC(2)), 129.8 (ArC(3)), 132.9 (ArC(1)), 137.9 (ArC(4)), 142.1 (C
(6)), 160.6 (CO2Et), 169.0 (C(2)); HRMS (NSI+) C19H28O4N [M
+NH4]+ found 334.2019, requires 334.2013 (+1.8 ppm).
4.3.4. (3S,4S)-Ethyl 3-benzyl-2-oxo-4-(p-tolyl)-3,4-dihydro-2H-
pyran-6-carboxylate 12
Following General Procedure 4.3,1-oxo-3-phenylpropan-2-yl 4-
nitrobenzoate 7 (202 mg, 0.675 mmol), (E)-ethyl 4-(p-tolyl)-2-oxo-
but-3-enoate 36 (98.2 mg, 0.450 mmol), NHC precatalyst
2
(16.6 mg, 45.0 mol), Et3N (94.1 L, 0.675 mmol) and THF
l
l
(10 mL) were reacted for 12 h. The crude (94:6 dr) was purified
by column chromatography (95:5 petrol:EtOAc) to give 12
(122 mg, 77%) as a pale yellow oil, with spectroscopic data in
accordance with the literature.6b
{Lit.6b
Chiralcel OD-H (90:10 hexane:IPA, flow rate 0.5 mL minꢀ1
½
a 2D0
ꢁ
= +299.4 (c 0.5, CHCl3)
4.3.7. (3S,4S)-Methyl 3-butyl-4-(4-methoxyphenyl)-2-oxo-3,4-
dihydro-2H-pyran-6-carboxylate 15
Following General Procedure 4.3, 1-oxohexan-2-yl 4-nitroben-
zoate (200 mg, 0.750 mmol), (E)-methyl 4-(4-methoxyphenyl)-2-
oxobut-3-enoate 37 (110 mg, 0.500 mmol), NHC precatalyst 2
½ ꢁ
a 2D0
= +310.3 (c 1.0, CHCl3)}; Chiral HPLC analysis,
,
254 nm, 30 °C) tR (3R,4R): 19.7 min, tR (3S,4S): 23.5 min, 96:4 er;
mmax (film, cmꢀ1) 2981, 1773, 1732; 1H NMR (400 MHz, CDCl3)
dH: 1.34 (3H, t, J 7.1, OCH2CH3), 2.36 (3H, s, C(4)ArC(4)CH3), 2.43
(1H, dd, J 15.8, 10.5, C(3)H), 3.22–3.32 (2H, m, C(3)CH2), 3.60
(1H, t, J 6.8, C(4)H), 4.31 (2H, q, J 7.1, OCH2CH3), 6.66 (1H, d, J
6.7, C(5)H), 6.93 (2H, d, J 8.1, C(3)CH2ArC(2)H), 7.09 (2H, d, J 6.8,
C(4)ArC(2)H), 7.16 (2H, d, J 7.8, C(4)ArC(3)H), 7.21–7.36 (3H, m, C
(3)CH2ArC(3)H and C(3)CH2ArC(4)H); 13C{1H} (100 MHz, CDCl3)
dC: 14.2 (OCH2CH3), 21.1 (C(4)ArC(4)CH3), 32.1 (C(3)CH2), 40.2 (C
(4)), 44.9 (C(3)), 61.9 (OCH2CH3), 118.8 (C(5)), 126.7 (C(3)CH2ArC
(4)), 128.3 (C(3)CH2ArC(3)), 128.6 (C(3)CH2ArC(2)), 129.0 (C(4)
ArC(2)), 129.9 (C(4)ArC(3)), 132.7 (C(4)ArC(1)), 138.1 (C(4)ArC
(4)), 138.2 (C(3)CH2ArC(4)), 141.9 (C(6)), 160.5 (CO2Et), 168.7 (C
(2)).
(18.4 mg, 50.0 lmol), Et3N (105 lL, 0.750 mmol) and THF (10 mL)
were reacted for 14 h. The crude (92:8 dr) was purified by column
chromatography (95:5 petrol:EtOAc) to give 15 (114 mg, 72%) as a
pale yellow oil. ½a D20
ꢁ
= +245.1 (c 0.5, CHCl3); Chiral HPLC analysis,
Chiralpak AD-H (90:10 hexane:IPA, flow rate 0.5 mL minꢀ1
,
220 nm, 30 °C) tR (3S,4S): 30.5 min, tR (3R,4R): 32.6 min, >99:1 er;
mmax (film, cmꢀ1) 2955, 1771, 1734; 1H NMR (300 MHz, CDCl3)
dH: 0.84 (3H, t, J 7.1, CH2CH3), 1.09–1.43 (5H, m, (CH2)2 and C(3)
CHAHB), 1.58–1.76 (1H, m, C(3)CHAHB), 2.78 (1H, q, J 6.9, C(3)H),
3.73–3.80 (4H, m, ArC(4)OCH3 and C(4)H), 3.85 (3H, s, CO2CH3),
6.69 (1H, d, J 6.5, C(5)H), 6.83 (2H, d, J 8.7, ArC(2)H), 7.00 (2H, d,
J 8.7, ArC(3)H); 13C{1H} NMR (75 MHz, CDCl3) dC: 12.8 (CH2CH3),
21.4 (CH2), 24.9 (CH2), 28.3 (CH2), 39.6 (C(4)), 42.5 (C(3)), 51.6
(CO2CH3), 54.3 (ArC(4)OCH3), 113.4 (ArC(2)), 117.7 (C(5)), 126.7
(ArC(1)), 128.1 (ArC(3)), 140.8 (C(6)), 158.3 (ArC(4)), 160.1 (CO2-
Me), 167.9 (C(2)); HRMS (NSI+) C18H26O5N [M+NH4]+ found
336.1812, requires 336.1805 (+1.9 ppm).
4.3.5. (3S,4S)-Methyl 3-benzyl-4-(4-methoxyphenyl)-2-oxo-3,4-
dihydro-2H-pyran-6-carboxylate 13
Following General Procedure 4.3,1-oxo-3-phenylpropan-2-yl 4-
nitrobenzoate 7 (202 mg, 0.675 mmol), (E)-methyl 4-(4-methoxy-
phenyl)-2-oxobut-3-enoate 37 (99.1 mg, 0.450 mmol), NHC pre-
catalyst 2 (16.6 mg, 45.0
THF (10 mL) were reacted for 16 h. The crude (91:9 dr) was puri-
l
mol), Et3N (94.1
l
L, 0.675 mmol) and
4.3.8. (3S,4S)-Methyl 4-(4-bromophenyl)-3-butyl-2-oxo-3,4-
dihydro-2H-pyran-6-carboxylate 16
fied by column chromatography (90:10 petrol:EtOAc) to give 13
Following General Procedure 4.3, 1-oxohexan-2-yl-4-nitroben-
zoate (200 mg, 0.750 mmol), (E)-methyl 4-(4-bromophenyl)-2-
oxobut-3-enoate 39 (135 mg, 0.500 mmol), NHC precatalyst 2
(18.4 mg, 50.0 lmol), Et3N (105 lL, 0.750 mmol) and THF (10 mL)
were for 4 h. The crude (89:11 dr) was purified by column chro-
(98.3 mg, 62%) as a pale yellow oil. ½a D20
ꢁ
= +277.3 (c 0.5, CHCl3);
Chiral HPLC analysis, Chiralcel OD-H (90:10 hexane:IPA, flow rate
0.5 mL minꢀ1, 220 nm, 30 °C) tR (3R,4R): 40.7 min, tR (3S,4S):
45.0 min, >99:1 er; mmax (film, cmꢀ1) 2955, 1771, 1734; 1H NMR
(300 MHz, CDCl3) dH: 2.41 (1H, dd, J 15.7, 10.6, C(3)H), 3.21–3.30
(2H, m, C(3)CH2), 3.58 (1H, t, J 6.7, C(4)H), 3.80 (3H, s, OCH3),
3.84 (3H, s, CO2CH3), 6.65 (1H, d, J 6.8, C(5)H), 6.86 (2H, d, J 8.8,
C(4)ArC(2)H), 6.93 (2H, d, J 8.8, C(4)ArC(3)H), 7.04–7.11 (2H, m, C
(3)CH2ArC(2)H), 7.20–7.35 (3H, m, C(3)CH2ArC(3)H and C(3)CH2-
ArC(4)H); 13C{1H} NMR (100 MHz, CDCl3) dC: 30.9 (C(3)CH2), 38.7
(C(4)), 43.9 (C(3)), 51.6 (CO2CH3), 54.3 (C(4)ArC(4)OCH3), 113.5 (C
(4)ArC(2)), 118.1 (C(5)), 125.7 (C(3)CH2ArC(1)), 126.4 (C(4)ArC
(1)), 127.6 (C(3)CH2ArC(3)), 127.9 (C(3)CH2ArC(2)), 128.9 (C(4)
ArC(3)), 137.1 (C(3)CH2ArC(1)), 140.5 (C(6)), 158.5 (C(4)ArC(4)),
160.0 (CO2Me), 167.6 (C(2)); HRMS (NSI+) C21H24O5N1 [M+NH4]+
found 370.1655, requires 370.1649 (+1.6 ppm).
matography (95:5 petrol:EtOAc) to give 16 (77.1 mg, 42%) as a pale
yellow oil. ½a 2D0
ꢁ
= +205.3 (c 0.5, CHCl3); Chiral HPLC analysis, Chi-
ralpak AD-H (95:5 hexane:IPA, flow rate 1 mL minꢀ1, 220 nm,
30 °C) tR (3S,4S): 15.1 min, tR (3R,4R): 17.7 min, 99:1 er; mmax (film,
cmꢀ1) 2955, 1773, 1732; 1H NMR (300 MHz, CDCl3) dH: 0.78–1.00
(3H, m, CH2CH3), 1.06–1.47 (5H, m, (CH2)2 and C(3)CHAHB), 1.54–
1.77 (1H, m, C(3)CHAHB), 2.82 (1H, q, J 7.0, C(3)H), 3.79 (1H, t, J
6.7, C(4)H), 3.87 (3H, s, ArC(4)OCH3), 6.67 (1H, d, J 6.4, C(5)H),
6.97 (2H, d, J 8.4, ArC(3)H), 7.44 (2H, d, J 8.5, ArC(2)H); 13C{1H}
NMR (75 MHz, CDCl3) dC: 12.8 (CH2CH3), 21.4 (CH2), 24.9 (CH2),
28.3 (CH2), 39.7 (C(4)), 42.2 (C(3)), 51.7 (CO2CH3), 116.6 (C(5)),
121.1 (ArC(4)), 128.7 (ArC(3)), 131.3 (ArC(2)), 134.0 (ArC(1)),
Please cite this article in press as: Taylor, J. E.; et al. Tetrahedron: Asymmetry (2017), http://dx.doi.org/10.1016/j.tetasy.2017.01.002

J. E. Taylor et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
9
141.3 (C(6)), 159.8 (CO2Me), 167.4 (C(2)); HRMS (NSI+) C17H23BrO5-
spectroscopic data in accordance with the literature.21 1H NMR
(300 MHz, CDCl3) dH: 1.35 (3H, t, J 7.1, CH2CH3), 2.44 (3H, s, ArC
(4)CH3), 4.30 (2H, q, J 7.1, OCH2), 6.87 (1H, d, J 15.6, EtO2CCH),
7.31 (2H, d, J 8.2, ArC(3,5)H), 7.91 (1H, d, J 15.5, CHCOAr), 7.91
(1H, d, J 8.2, ArC(2,6)H).
N [M+NH4]+ found 384.0813, requires 384.0805 (+2.1 ppm).
4.3.9. (3S,4S)-Methyl 3-butyl-4-(naphthalen-2-yl)-2-oxo-3,4-
dihydro-2H-pyran-6-carboxylate 17
Following General Procedure 4.3, 1-oxohexan-2-yl 4-nitroben-
zoate (200 mg, 0.750 mmol), (E)-methyl 4-(naphthalen-2-yl)-2-
oxobut-3-enoate 40 (120 mg, 0.500 mmol), NHC precatalyst 2
4.4.3. (E)-Ethyl 4-(4-methoxyphenyl)-4-oxobut-2-enoate 43
Following General Procedure 4.4, periodic acid (0.37 g,
(18.4 mg, 50.0
lmol), Et3N (105
lL, 0.750 mmol) and THF (10 mL)
1.6 mmol) and (+)-diethyl L-tartrate (0.34 g, 1.6 mmol) in Et2O
were reacted for 6 h. The crude (94:6 dr) was purified by column
(3.2 mL) were stirred for 3 h at rt. The reaction was filtered into a
two-necked round-bottomed flask containing MgSO4 (0.5 g), wash-
ing with THF (4.1 mL), before 1-(4-methoxyphenyl)-2-(triph-
enylphosphoranylidene)ethanone (1.0 g, 2.4 mmol) was added at
0 °C. The crude product was purified by column chromatography
(70:30 petrol:Et2O, Rf 0.25) to give 43 (0.48 g, 83%) as a yellow
oil, which solidified over time, with spectroscopic data in accor-
dance with the literature.21 Mp 40–42 °C; 1H NMR (300 MHz,
CDCl3) dH: 1.35 (3H, t, J 7.2 CH2CH3), 3.90 (3H, s, OCH3), 4.30 (2H,
q, J 7.1, OCH2), 6.87 (1H, d, J 15.5, EtO2CCH), 6.98 (2H, d, J 9.0,
ArC(3,5)H), 7.92 (1H, d, J 15.5, CHCOAr), 8.01 (2H, d, J 9.0, ArC
(2,6)H).
chromatography (95:5 petrol:EtOAc) to give 17 (81.7 mg, 48%) as
a colourless solid. Mp 99–101 °C; ½a D20
ꢁ
= +297.0 (c 0.5, CHCl3); Chi-
ral HPLC analysis, Chiralpak AD-H (95:5 hexane:IPA, flow rate
1 mL minꢀ1
, 254 nm, 30 °C) tR (3R,4R): 22.0 min, tR (3S,4S):
25.0 min, >99:1 er; mmax (solid) 2951, 1757, 1736; 1H NMR
(400 MHz, CDCl3) dH: 0.83 (3H, t, J 7.3, CH2CH3), 1.11–1.49 (5H,
m, (CH2)2 and C(3)CHAHB), 1.63–1.78 (1H, m, C(3)CHAHB), 2.90
(1H, q, J 7.0, C(3)H), 3.88 (3H, s, CO2CH3), 3.99 (1H, t, J 6.7, C(4)
H), 6.77 (1H, d, J 6.3, C(5)H), 7.19 (1H, dd, J 8.5, 1.9, ArH), 7.44–
7.52 (2H, m, ArH), 7.57 (1H, d, J 1.8, ArC(2)H), 7.74–7.85 (3H, m,
ArH); 13C{1H} NMR (75 MHz, CDCl3) dC: 12.8 (CH3CH2), 21.4
(CH2), 25.0 (CH2), 28.4 (CH2), 40.6 (C(4)), 42.4 (C(3)), 51.7 (CO2CH3),
117.2 (C(5)), 124.5 (ArC(8)), 125.3 (ArC), 125.5 (ArC), 126.1 (ArC
(2)), 126.6 (ArC(6)), 126.8 (ArC), 127.7 (ArC(2a)), 128.0 (ArC),
131.9 (ArC(1)), 132.4 (ArC(6a)), 141.1 (C(5)), 163.3 (CO2CH3),
167.7 (C(2)); HRMS (NSI+) C21H26O4N1 [M+NH4]+ found 356.1862,
requires 356.1856 (+1.6 ppm).
4.4.4. (E)-Ethyl 4-(4-chlorophenyl)-4-oxobut-2-enoate 44
Following General Procedure 4.4, periodic acid (0.37 g,
1.6 mmol) and (+)-diethyl L-tartrate (0.33 g, 1.6 mmol) in Et2O
(3.2 mL) were stirred for 3 h at rt. The reaction was filtered into a
two-necked round-bottomed flask containing MgSO4 (0.5 g), wash-
ing with THF (4.0 mL), before 1-(4-chlorophenyl)-2-(triph-
enylphosphoranylidene)ethanone (1.0 g, 2.4 mmol) was added at
0 °C. The crude product was purified by column chromatography
(95:5 petrol:EtOAc, Rf 0.29) to give 44 (0.57 g, 99%) as a yellow
solid, with spectroscopic data in accordance with the literature.21
Mp 62–63 °C; 1H NMR (300 MHz, CDCl3) dH: 1.35 (3H, t, J 7.1,
CH3), 4.30 (2H, q, J 7.1, OCH2), 6.90 (1H, d, J 15.5, EtO2CCH), 7.49
(2H, d, J 8.7, ArC(3,5)H), 7.87 (1H, d, J 15.6, CHCOAr), 7.95 (1H, d,
J 8.7, ArC(2,6)H).
4.4. General procedure for the synthesis of
ketoesters
a,b-unsaturated c-
Based upon a literature procedure,21 periodic acid (1 equiv.)
was added portionwise to a solution of (+)-diethyl -tartrate
L
(1 equiv.) in anhydrous Et2O (0.5 M). The solution was stirred at
rt for 3 h before being filtered into a dried two-necked round-bot-
tomed flask containing MgSO4 (1.0 g/7 mL Et2O), washing with THF
(1 mL/0.8 mL EtO). The resulting solution was cooled to 0 °C before
the appropriate phosphorane (1.5 equiv.) was added in one por-
tion. The reaction was stirred overnight (cf. 16 h), allowing to
warm slowly to rt. The reaction was filtered and concentrated
under reduced pressure to give the crude product, which was puri-
fied by column chromatography.
4.4.5. (E)-Ethyl 4-oxo-4-(4-(trifluoromethyl)phenyl)but-2-
enoate 45
Following General Procedure 4.4, periodic acid (0.68 g,
3.0 mmol) and (+)-diethyl L-tartrate (0.51 mL, 3.0 mmol) in Et2O
(6.0 mL) were stirred for 3 h at rt. The reaction was filtered into a
two-necked round-bottomed flask containing MgSO4 (1.0 g), wash-
ing with THF (7.5 mL), before 1-(4-(trifluoromethyl)phenyl)-2-
(triphenylphosphoranylidene)ethanone (2.0 g, 4.5 mmol) was
added at 0 °C. The crude product was purified by column chro-
matography (90:10 petrol:Et2O, Rf 0.24) to 45 (0.85 g, 70%) as a yel-
low solid. Mp 61–63 °C; mmax (film, cmꢀ1) 1721, 1672, 1630, 1414,
1315, 1294, 1163, 1123, 1111; 1H NMR (300 MHz, CDCl3) dH: 1.35
(3H, t, J 7.1 CH3), 4.31 (2H. q. J 7.1, OCH2), 6.91 (1H, d, J 15.6, EtO2-
CCH), 7.78 (2H, d, J 8.4, ArC(3,5)H), 7.87 (1H, d, J 15.5, CHCOAr),
8.09 (2H, d, J 8.3, ArC(2,6)H); 13C{1H} NMR (75 MHz, CDCl3) dC:
4.4.1. (E)-Ethyl 4-oxopent-2-enoate 41
Following General Procedure 4.4, periodic acid (0.95 g,
4.2 mmol) and (+)-diethyl L-tartrate (0.72 mL, 4.2 mmol) in Et2O
(8.5 mL) were stirred for 3 h at rt. The reaction was filtered into a
two-necked round-bottomed flask containing MgSO4 (1.0 g), wash-
ing with THF (10.5 mL), before 1-(triphenylphosphoranylidene)
propan-2-one (2.0 g, 6.3 mmol) was added at 0 °C. The crude pro-
duct was purified by column chromatography (80:20 hexane:
Et2O, Rf 0.24) to give 41 (0.61 g, 68%) as a colourless oil, with spec-
troscopic data in accordance with the literature.22 1H NMR
(300 MHz, CDCl3) dH: 1.32 (3H, t, J 7.2 CH2CH3), 2.36 (3H, s, COCH3),
4.26 (2H, q, J 7.2, OCH2), 6.64 (1H, d, J 16.1, EtO2CCH), 7.01 (1H, d, J
16.1, CHCOMe).
1
3
14.3 (CH3), 61.7 (OCH2), 123.6 (q, JCF 272.8, CF3), 126.1 (q, JCF
2
3.7, ArC(2)H), 129.3 (ArC(3)H), 133.8 (EtO2C@CH), 135.1 (q, JCF
32.8, ArC(1)), 135.7 (C@CHCOAr), 139.4 (ArC(4)), 165.4 (CO2Et),
188.9 (COAr); 19F{1H} NMR (282 MHz, CDCl3) dF: ꢀ63.69 (CF3);
HRMS (APCI+) C13H12O3F3 [M+H]+ found 273.0732, requires
273.0733 (ꢀ0.4 ppm).
4.4.2. (E)-Ethyl 4-oxo-4-(p-tolyl)but-2-enoate 42
Following General Procedure 4.4, periodic acid (0.39 g,
1.7 mmol) and (+)-diethyl
L-tartrate (0.35 g, 1.7 mmol) in Et2O
4.4.6. (E)-Ethyl 4-(naphthalen-2-yl)-4-oxobut-2-enoate 46
(3.5 mL) were stirred for 3 h at rt. The reaction was filtered into a
two-necked round-bottomed flask containing MgSO4 (0.5 g), wash-
ing with THF (4.3 mL), before 1-(p-tolyl)-2-(triphenylphospho-
ranylidene)ethanone (1.0 g, 2.5 mmol) was added at 0 °C. The
crude product was purified by column chromatography (95:5 pet-
rol:EtOAc, Rf 0.36) to give 42 (0.39 g, 78%) as a yellow oil, with
Following General Procedure 4.4, periodic acid (1.06 g,
4.6 mmol) and (+)-diethyl L-tartrate (0.80 mL, 4.6 mmol) in Et2O
(9.0 mL) were stirred for 3 h at rt. The reaction was filtered into a
two-necked round-bottomed flask containing MgSO4 (1.5 g), wash-
ing with THF (11.5 mL), before 1-(naphthalen-2-yl)-2-(triph-
enylphosphoranylidene)ethanone (3.00 g, 7.0 mmol) was added
Please cite this article in press as: Taylor, J. E.; et al. Tetrahedron: Asymmetry (2017), http://dx.doi.org/10.1016/j.tetasy.2017.01.002

10
J. E. Taylor et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
at 0 °C. The crude product was purified by column chromatography
(80:20 hexane:Et2O, Rf 0.38) to give 46 (1.24 g, 70%) as a yellow
solid. Mp 57–59 °C; mmax (film, cmꢀ1) 1717, 1667, 1624, 1464,
1364, 1304, 1246, 1175, 1123; 1H NMR (300 MHz, CDCl3) dH:
1.38 (3H, t, J 7.2 CH3), 4.33 (2H. q. J 7.2, OCH2), 6.96 (1H, d, J
15.5, EtO2CCH), 7.52–7.68 (2H, m, ArH), 7.86–8.10 (4H, m, ArH),
8.09 (1H, d, J 15.5, CHCOAr), 8.46–8.55 (1H, m, ArH); 13C{1H}
NMR (75 MHz, CDCl3) dC: 14.4 (CH3), 61.6 (OCH2), 124.2 (ArC),
127.2 (ArC), 128.0 (ArC), 129.1 (ArC), 129.2 (ArC), 129.9 (ArC),
131.3 (ArC), 132.6 (C@CCO2), 132.7 (ArC), 134.2 (ArC), 136.0
(ArC), 136.6 (C@CCO), 165.9 (CO2), 189.4 (CO); HRMS (NSI+)
OCH2CH3), 5.80 (1H, d, J 7.0, C(5)H), 7.16–7.21 (2H, m, ArH),
7.26–7.40 (6H, m, ArH), 7.60–7.63 (2H, m, ArH).
4.5.3. (3S,4S)-Ethyl 3-(2-(benzyloxy)ethyl)-2-oxo-6-phenyl-3,4-
dihydro-2H-pyran-4-carboxylate 22
Following General Procedure 4.5, 4-(benzyloxy)-1-oxobutan-2-
yl 4-nitrobenzoate (257 mg, 0.75 mmol), (E)-ethyl 4-oxo-4-phenyl-
but-2-enoate (102 mg, 0.50 mmol), NHC precatalyst 2 (9.2 mg,
25.0 lmol), Et3N (105 lL, 0.75 mmol) and THF (5 mL) were reacted
for 9 h. The crude (90:10 dr) was purified by column chromatogra-
phy (85:15 petrol:EtOAc, Rf 0.25) to give 22 (161 mg, 85%) as white
C
16H15O3 [M+H]+ found 255.1017, requires 255.1016 (+0.5 ppm).
solid. Mp 77–78 °C (hexane); ½a D20
ꢁ
= +169.1 (c 0.55, CHCl3); Chiral
HPLC analysis, Chiralcel OD-H (95:5 hexane:IPA, flow rate
4.5. General procedure for the NHC-catalysed redox hetero-
Diels-Alder reaction with ,b-unsaturated -ketoesters
1 mL minꢀ1
, 254 nm, 30 °C) tR (3R,4R): 23.2 min, tR (3S,4S):
a
c
25.1 min, >99:1 er; mmax (film, cmꢀ1) 1767 (C@O), 1715 (C@O),
1657 (C@C); 1H NMR (300 MHz, CDCl3) dH: 1.23 (3H, t, J 7.1, OCH2-
CH3), 1.72–1.83 (1H, m, C(3)CHAHB), 2.37–2.48 (1H, m, C(3)CHAHB),
3.04 (1H, q, J 6.7, C(3)H), 3.50 (1H, t, J 6.5, C(4)H), 3.60–3.72 (2H, m,
C(3)CH2CH2), 4.09–4.20 (2H, m, OCH2CH3), 4.50 (2H, d, J 2.1, OCH2-
Ar), 5.86 (1H, d, J 6.9, C(5)H), 7.27–7.40 (8H, m, ArH), 7.61–7.66
(2H, m, ArH); 13C{1H} NMR (75 MHz, CDCl3) dC: 14.2 (CH3), 27.8
(CH2), 37.6 (C(3)H), 42.1 (C(4)H), 61.7 (OCH2CH3), 67.4 (OCH2CH2),
73.2 (OCH2Ph), 98.2 (C(5)H), 125.0 (ArCH), 127.8 (ArCH), 128.5
(ArCH), 128.6 (ArCH), 129.6 (ArCH), 132.0 (ArC), 138.2 (ArC),
152.4 (C(6)), 169.4 (C(2)), 170.4 (CO2Et); HRMS (NSI+) C23H25O5
[M+H]+ found 381.1697, requires 381.1697 (+0.1 ppm).
The appropriate
a-aroyloxyaldehyde (1.5 equiv), a,b-unsatu-
rated -ketoester (1.0 equiv) and NHC precatalyst 2 (5 mol %) were
c
dissolved in anhydrous THF (0.075 M) in a sealed vial containing
3Å molecular sieves. Et3N (1.5 equiv.) was added and the reaction
stirred until complete by TLC analysis. The mixture was diluted
with EtOAc and washed successively with 1 M HCl, saturated
NaHCO3 and brine. The organic layer was dried with MgSO4, fil-
tered and concentrated under reduced pressure to give the crude
product, which was purified by column chromatography.
4.5.1. (3S,4S)-Ethyl 3-butyl-2-oxo-6-phenyl-3,4-dihydro-2H-
pyran-4-carboxylate 20
4.5.4. (3S,4S)-Ethyl 3-benzyl-6-methyl-2-oxo-3,4-dihydro-2H-
Following General Procedure 4.5,1-oxohexan-2-yl 4-nitroben-
zoate (200 mg, 0.75 mmol), (E)-ethyl 4-oxo-4-phenylbut-2-enoate
pyran-4-carboxylate 23
In
nitrobenzoate 7 (196 mg, 0.65 mmol), (E)-ethyl 4-oxopent-2-eno-
ate 41 (62 mg, 0.44 mmol), NHC precatalyst 2 (8.0 mg, 21.8 mol),
a
modified procedure, 1-oxo-3-phenylpropan-2-yl 4-
(102 mg, 0.500 mmol), NHC precatalyst 2 (18.4 mg, 50.0
lmol),
Et3N (105 L, 0.75 mmol) and THF (10 mL) were reacted for 5 h.
l
l
The crude (>95:5 dr) was purified by column chromatography
and Cs2CO3 (142 mg, 0.44 mmol) were dissolved in THF (4.4 mL)
in a sealed vial and heated at 40 °C for 7 h. The mixture was then
diluted with EtOAc and washed successively with 1 M HCl (ꢂ2),
NaHCO3 (ꢂ2), and brine (ꢂ2) before being dried over MgSO4 and
concentrated under reduced pressure. The crude (>95:5 dr) was
purified by column chromatography (95:5 petrol:EtOAc, Rf 0.20)
to give 23 (79 mg, 65%) as white solid, with spectroscopic data in
(95:5 petrol:EtOAc) to give 20 (129 mg, 85%) as colourless solid.
Mp 61–63 °C; ½a 2D0
ꢁ
= +185.5 (c 0.5, CHCl3); Chiral HPLC analysis,
Chiralcel OJ-H (95:5 hexane:IPA, flow rate 1 mL minꢀ1, 254 nm,
30 °C) tR (3S,4S): 17.2 min, tR (3R,4R): 22.3 min, >99:1 er; mmax
(solid) 2953 (C–H), 1761 (C@O), 1719 (C@O); 1H NMR (400 MHz,
CDCl3) dH: 0.91 (3H, t, J 7.1, CH2CH3), 1.25 (3H, t, J 7.1, OCH2CH3),
1.31–1.54 (5H, m, (CH2)2 and C(3)CHAHB), 1.99–2.13 (1H, m, C(3)
CHAHB), 2.68–2.79 (1H, m, C(3)H), 3.53 (1H, t, J 6.3, C(4)H), 4.17
(2H, qd, J 7.1, 2.5, OCH2CH3), 5.88 (1H, d, J 6.5, C(5)H), 7.32–7.41
(3H, m, ArC(2)H and ArC(4)H), 7.61–7.66 (2H, m, ArC(3)H); 13C
{1H} NMR (100 MHz, CDCl3) dC: 12.8 (CH2CH3), 13.0 (OCH2CH3),
21.5 (CH2), 25.8 (CH2), 28.3 (CH2), 39.5 (C(3)), 40.8 (C(4)), 60.5
(OCH2CH3), 96.9 (C(5)), 123.8 (ArC(3)), 127.5 (ArC(2)), 128.4 (ArC
(4)), 130.9 (ArC(1)), 151.1 (C(6)), 168.2 (C(2)), 169.2 (CO2Et); HRMS
(NSI+) C18H26O4N [M+NH4]+ found 320.1864, requires 320.1856
(+2.4 ppm).
accordance to the literature.6c Mp 88–89 °C (hexane); ½a 2D0
ꢁ
=
+270.9 (c 0.32, CHCl3) {Lit.6c = +250.6 (c 0.93, CHCl3)}; Chiral HPLC
analysis, Chiralcel AD-H (95:5 hexane:IPA, flow rate 1 mL minꢀ1
,
254 nm, 30 °C) tR (3R,4R): 11.0 min, tR (3S,4S): 13.2 min, 98.5:1.5
er; mmax (film, cmꢀ1) 1771 (C@O), 1726 (C@O), 1688 (C@C); 1H
NMR (300 MHz, CDCl3) dH: 1.21 (3H, t, J 7.1, OCH2CH3), 1.83 (3H,
s, C(6)CH3), 2.61 (1H, dd, J 14.3, 10.1, C(3)CHAHB), 2.75–2.82 (1H,
m, C(3)H), 2.92 (1H, t, J 6.4, C(4)H), 3.42 (1H, dd, J 14.2, 4.6, C(3)
CHAHB), 4.13 (2H, q, J 7.2, OCH2), 4.95 (1H, dd, J 6.8, 1.1, C(5)H),
7.04–7.10 (2H, m, ArC(2)H), 7.12–7.27 (3H, m, ArC(3)H and ArC(4)
H); 13C{1H} NMR (75 MHz, CDCl3) dC: 14.2 (CH2CH3), 18.9 (CCH3),
33.3 (CH2), 40.4 (C(3)H), 42.8 (C(4)H), 61.5 (OCH2), 98.7 (C(5)H),
126.9 (ArCH), 128.8 (ArCH), 129.1 (ArCH), 138.3 (ArC), 152.4 (C
(6)), 169.3 (C(2)), 170.7 (CO2Et); HRMS (NSI+) C16H19O4 [M+H]+
found 275.1280, requires 275.1278 (+0.8 ppm).
4.5.2. (3S,4S)-Ethyl 3-benzyl-2-oxo-6-phenyl-3,4-dihydro-2H-
pyran-4-carboxylate 21
Following General Procedure 4.5,1-oxo-3-phenylpropan-2-yl 4-
nitrobenzoate 7 (238 mg, 0.80 mmol), (E)-ethyl 4-oxo-4-phenyl-
but-2-enoate (108 mg, 0.53 mmol), NHC precatalyst 2 (19.5 mg,
53
l
mol), Et3N (0.11 mL, 0.80 mmol) and THF (5 mL) were reacted
4.5.5. (3S,4S)-Ethyl 3-butyl-2-oxo-6-(p-tolyl)-3,4-dihydro-2H-
pyran-4-carboxylate 24
Following General Procedure 4.5, 1-oxohexan-2-yl 4-nitroben-
zoate (200 mg, 0.75 mmol), (E)-ethyl 4-oxo-4-(p-tolyl)but-2-eno-
for 2 h. The crude (>95:5 dr) was purified by column chromatogra-
phy (95:5 petrol:EtOAc) to give 21 (140 mg, 79%) as a colourless
oil, with spectroscopic data in accordance with the literature.6c
½
a 2D0
ꢁ
= +173.0 (c 1.05, CHCl3) {Lit.6c = +107.2 (c 0.82, CHCl3)};
ate 42 (109 mg, 0.50 mmol), NHC precatalyst
2
(9.2 mg,
Chiral HPLC analysis Chiralpak AD-H (90:10 hexane:IPA, flow rate
1.0 mL minꢀ1, 254 nm, 30 °C) >99:1 er; 1H NMR (300 MHz, CDCl3)
dH: 1.29 (3H, t, J 7.1, OCH2CH3) 2.77 (1H, dd, J 14.2, 10.2,
PhCHAHB), 2.97–3.03 (1H, m, C(3)H), 3.25 (1H, dd, J 6.9, 5.9, C(4)
25.0 mol), Et3N (105 L, 0.75 mmol) and THF (5 mL) were reacted
l
l
for 6 h. The crude (>95:5 dr) was purified by column chromatogra-
phy (90:10 hexane:Et2O, Rf 0.19) to give 24 (127 mg, 80%) as
colourless needles. Mp 64–65 °C (hexane); ½a D20
ꢁ
= +158.4 (c 0.38,
CHCl3); Chiral HPLC analysis, Chiralcel OD-H (95:5 hexane:IPA,
H) 3.55 (1H, dd,
J
14.2, 4.6, PhCHAHB), 4.22 (2H, q,
J
7.1,
Please cite this article in press as: Taylor, J. E.; et al. Tetrahedron: Asymmetry (2017), http://dx.doi.org/10.1016/j.tetasy.2017.01.002

J. E. Taylor et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
11
flow rate 1 mL minꢀ1, 254 nm, 30 °C) tR (3S,4S): 8.3 min, tR (3R,4R):
9.0 min, >99:1 er;
max (film, cmꢀ1) 1763 (C@O), 1719 (C@O), 1684
(5 mL) were reacted for 3 h. The crude (80:20 dr) was purified by col-
umn chromatography (90:10 petrol:EtOAc, major-syn Rf 0.16,
minor-anti Rf 0.09) to give 27 (105 mg, 52%) as white solid. Mp
m
(C@C); 1H NMR (300 MHz, CDCl3) dH: 0.91 (3H, t, J 7.1, (CH2)3CH3),
1.25 (3H, t, J 7.2, OCH2CH3), 1.31–1.52 (5H, m, C(3)HaHb and CH2
ꢂ2), 1.98–2.15 (1H, m, C(3)HaHb), 2.36 (3H, s, ArC(4)CH3), 2.73
(1H, q, J 6.5, C(3)H), 3.51 (1H, t, J 6.3, C(4)H), 4.17 (2H, qd, J 7.2,
1.9, OCH2), 5.82 (1H, d, J 6.5, C(5)H), 7.18 (2H, d, J 8.1, ArC(3)H),
7.53 (2H, d, J 8.3, ArC(2)H); 13C{1H} NMR (75 MHz, CDCl3) dC:
14.0 (CH3), 14.2 (CH3), 21.4 (CH3), 22.6 (CH2), 26.9 (CH2), 29.5
(CH2), 40.7 (C(3)H), 42.0 (C(4)H), 61.6 (OCH2), 97.1 (C(5)H), 124.9
(ArC), 129.2 (ArCH), 129.3 (ArCH), 139.7 (ArC), 152.4 (C(6)), 169.6
(C(2)), 170.5 (CO2Et); HRMS (NSI+) C19H25O4 [M+H]+ found
317.1751, requires 317.1747 (+1.1 ppm).
145–147 °C (hexane); ½a D20
ꢁ
+172.9 (c 0.31 in CHCl3); Chiral HPLC
analysis, Chiralcel OD-H (95:5 hexane:IPA, flow rate 1 mL minꢀ1
,
254 nm, 30 °C) tR (3S,4S): 18.8 min, tR (3R,4R): 15.4 min, >99:1 er;
mmax (film, cmꢀ1) 1775 (C@O), 1719 (C@O), 1659 (C@C); 1H NMR
(300 MHz, CDCl3) dH: 1.30 (3H, t, J 7.2, OCH2CH3), 2.78 (1H, dd, J
14.4, 9.9, C(3)HaHb), 2.98–3.06 (1H, m, C(3)H), 3.30 (1H, t, J 6.4, C
(4)H), 3.55 (1H, dd, J 14.2, 4.7, C(3)HaHb), 4.23 (2H, q, J 7.2, OCH2),
5.92 (1H, d, J 7.0, C(5)H), 7.17–7.19 (2H, m, C(3)CH2ArC(2)H), 7.24–
7.36 (3H, m, C(3)CH2ArC(3)H and C(3)CH2ArC(4)H), 7.63 (2H, d, J
8.5, C(6)ArC(2)H), 7.73 (2H, d, J 8.5, C(6)ArC(3)H); 13C{1H} NMR
(75 MHz, CDCl3) dC: 14.3 (CH3), 33.3 (CH2Ph), 40.8 (C(3)H), 42.8 (C
1
4.5.6. (3S,4S)-Ethyl 3-butyl-6-(4-methoxyphenyl)-2-oxo-3,4-
dihydro-2H-pyran-4-carboxylate 25
Following General Procedure 4.5, 1-oxohexan-2-yl 4-nitroben-
zoate (200 mg, 0.75 mmol), (E)-ethyl 4-(4-methoxyphenyl)-4-oxo-
but-2-enoate 43 (117 mg, 0.50 mmol), NHC precatalyst 2 (9.2 mg,
(4)H), 62.0 (OCH2), 100.3 (C(5)H), 124.0 (q, JCF 272, CF3), 125.2
(ArCH), 125.7 (q, 3JCF 3.8, C(6)ArC(3,5)H), 127.1 (ArCH), 129.0 (ArCH),
2
129.1 (ArCH), 131.4 (q, JCF 32.5, C(6)ArC(4)), 135.2 (ArC), 137.9
(ArC), 151.4 (C(6)), 168.4 (C(2)), 170.0 (CO2Et); HRMS (NSI+) C22H23
-
O4NF3 [M+NH4]+ found 422.1574, requires 422.1574 (+0.1 ppm).
25.0 lmol), Et3N (105 lL, 0.75 mmol) and THF (5 mL) were reacted
for 6 h. The crude (>95:5 dr) was purified by column chromatogra-
4.5.9. (3S,4S)-Ethyl 3-methyl-6-(naphthalen-2-yl)-2-oxo-3,4-
dihydro-2H-pyran-4-carboxylate 28 and (3S,4R)-Ethyl 3-
methyl-6-(naphthalen-2-yl)-2-oxo-3,4-dihydro-2H-pyran-4-
carboxylate 29
Following General Procedure 4.5, 1-oxopropan-2-yl 4-nitroben-
zoate (167 mg, 0.75 mmol), (E)-ethyl 4-(naphthalen-2-yl)-4-oxo-
but-2-enoate 46 (127 mg, 0.50 mmol), NHC precatalyst 2 (9.2 mg,
phy (85:15 hexane:Et2O, Rf 0.17) to give 25 (149 mg, 90%) as white
solid. Mp 61–62 °C (hexane); ½a D20
ꢁ
= +123.6 (c 0.39, CHCl3); Chiral
HPLC analysis, Chiralcel OD-H (95:5 hexane:IPA, flow rate
1 mL minꢀ1
,
254 nm, 30 °C) tR (3R,4R): 13.9 min, tR (3S,4S):
14.5 min, >99:1 er; mmax (film, cmꢀ1) 1751 (C@O), 1726 (C@O),
1661 (C@C); 1H NMR (300 MHz, CDCl3) dH: 0.91 (3H, t, J 7.1, CH2-
CH3), 1.25 (3H, t, J 7.2, OCH2CH3), 1.31–1.49 (5H, m, C(3)HaHb),
1.99–2.11 (1H, m, C(3)HaHb), 2.72 (1H, q, J 6.5, C(3)H), 3.50 (1H,
t, J 6.3, C(4)H), 3.82 (3H, s, ArC(4)OCH3), 4.17 (2H, qd, J 7.1, 1.9,
OCH2), 5.74 (1H, d, J 6.5, C(5)H), 6.89 (2H, d, J 8.9, ArC(3)H), 7.57
(2H, d, J 9.0, ArC(2)H); 13C{1H} NMR (75 MHz, CDCl3) dC: 14.0
(CH3), 14.2 (CH3), 22.6 (CH2), 26.9 (CH2), 29.5 (CH2), 40.8 (C(3)H),
41.9 (C(4)H), 55.5 (OCH3), 61.6 (OCH2), 96.0 (C(5)H), 114.0 (ArC),
124.6 (ArCH), 126.4 (ArCH), 152.1 (C(6)), 160.7 (ArC), 169.6 (C
(2)), 170.6 (CO2Et); HRMS (NSI+) C19H25O5 [M+H]+ found
333.1699, requires 333.1697 (+0.7 ppm).
25.0 lmol), Et3N (105 lL, 0.75 mmol) and THF (5 mL) were reacted
for 24 h. The crude (50:50 dr) was purified by column chromatog-
raphy (90:10 petrol:EtOAc, anti Rf 0.29, syn Rf 0.23) to give syn-28
(49 mg, 32%) as white solid and anti-29 (55 mg, 35%) as white solid.
syn-28: Mp 101–103 °C (hexane); ½a D20
ꢁ
= +220.3 (c 0.34, CHCl3);
Chiral HPLC analysis, Chiralcel OD-H (95:5 hexane:IPA, flow rate
1 mL minꢀ1
, 254 nm, 30 °C) tR (3S,4S): 26.7 min, tR (3R,4R):
24.1 min, >99:1 er; mmax (film, cmꢀ1) 1771 (C@O), 1715 (C@O),
1651 (C@C); 1H NMR (300 MHz, CDCl3) dH: 1.27 (3H, t, J 7.2, OCH2-
CH3), 1.37 (3H, d, J 6.9, C(3)CH3), 2.97 (1H, pent, J 6.7, C(3)H), 3.49
(1H, t, J 6.3, C(4)H), 4.15–4.26 (2H, m, OCH2), 6.02 (1H, d, J 6.6, C(5)
H), 7.48–7.53 (2H, m, ArH), 7.65 (1H, dd, J 8.7, 1.9, ArC(2)H), 7.78–
7.91 (3H, m, ArH), 8.16–8.22 (1H, m, ArH); 13C{1H} NMR (75 MHz,
CDCl3) dC: 12.7 (C(3)CH3), 14.2 (CH2CH3), 35.7 (C(3)H), 43.9 (C(4)H),
61.8 (OCH2), 98.5 (C(5)H), 122.1 (ArCH), 124.6 (ArCH), 126.8
(ArCH), 127.1 (ArCH), 127.7 (ArCH), 128.4 (ArCH), 128.8 (ArCH),
129.0 (ArC), 133.1 (ArC), 133.7 (ArC), 152.4 (C(6)), 170.0 (C(2)),
170.3 (CO2Et); HRMS (NSI+) C19H19O4 [M+H]+ found 311.1282,
requires 311.1278 (+1.3 ppm).
4.5.7. (3S,4S)-Ethyl 6-(4-chlorophenyl)-3-methyl-2-oxo-3,4-
dihydro-2H-pyran-4-carboxylate 26
Following General Procedure 4.5, 1-oxopropan-2-yl 4-nitroben-
zoate (167 mg, 0.75 mmol), (E)-ethyl 4-(4-chlorophenyl)-4-oxo-
but-2-enoate 44 (119 mg, 0.50 mmol), NHC precatalyst 2 (9.2 mg,
25.0 lmol), Et3N (105 lL, 0.75 mmol) and THF (5 mL) were reacted
for 4 h. The crude (80:20 dr) was purified by column chromatogra-
phy (70:30 hexane:Et2O, minor-anti Rf 0.29, major-syn Rf 0.23) to
give 26 (81 mg, 55%) as white solid. Mp 93–95 °C (hexane);
anti-29: Mp 92–94 °C (hexane); ½a D20
= ꢀ91.9 (c 0.37, CHCl3);
ꢁ
½
a 2D0
ꢁ
= +248.5 (c 0.27, CHCl3); Chiral HPLC analysis, Chiralcel OD-H
Chiral HPLC analysis, Chiralcel OD-H (95:5 hexane:IPA, flow rate
(95:5 hexane:IPA, flow rate 1 mL minꢀ1, 254 nm, 30 °C) tR (3R,4R):
14.3 min, tR (3S,4S): 15.7 min, >99:1 er; mmax (film, cmꢀ1) 1765
(C@O), 1721 (C@O), 1657 (C@C); 1H NMR (300 MHz, CDCl3) dH:
1.26 (3H, t, J 7.2, OCH2CH3), 1.34 (3H, d, J 7.0, C(3)CH3), 2.92 (1H,
pent, J 6.7, C(3)H), 3.44 (1H, t, J 6.3, C(4)H), 4.19 (2H, qd, J 7.1, 3.2,
OCH2), 5.86 (1H, d, J 6.6, C(5)H), 7.35 (2H, d, J 8.7, ArC(2)H), 7.57
(2H, d, J 8.8, ArC(3)H); 13C{1H} NMR (75 MHz, CDCl3) dC: 12.6 (C
(3)CH3), 14.2 (CH2CH3), 35.6 (C(3)H), 43.8 (C(4)H), 61.8 (OCH2),
98.4 (C(5)H), 126.3 (ArC), 128.9 (ArCH), 130.5 (ArCH), 135.6 (ArC),
151.6 (C(6)), 169.6 (C(2)), 170.2 (CO2Et); HRMS (NSI+) C15H16O4Cl
[N+H]+ found 295.0735, requires 295.0732 (+1.1 ppm).
1 mL minꢀ1
, 254 nm, 30 °C) tR (3R,4S): 15.2 min, tR (3S,4R):
15.9 min, >99:1 er; mmax (film, cmꢀ1) 1769 (C@O), 1728 (C@O),
1661 (C@C); 1H NMR (300 MHz, CDCl3) dH: 1.33 (3H, t, J 7.2, OCH2-
CH3), 1.40 (3H, d, J 6.9, C(3)CH3), 3.10–3.20 (1H, m, C(3)H), 3.38
(1H, dd, J 9.1, 4.0, C(4)H), 4.27 (2H, q, J 7.2, OCH2), 5.86 (1H, d, J
4.2, C(5)H), 7.48–7.53 (2H, m, ArH), 7.65 (1H, dd, J 8.7, 1.7, ArC(2)
H), 7.79–7.93 (3H, m, ArH), 8.15–8.23 (1H, m, ArH); 13C{1H} NMR
(75 MHz, CDCl3) dC: 14.3 (CH2CH3), 15.0 (C(3)CH3), 35.7 (C(3)H),
45.0 (C(4)H), 62.0 (OCH2), 98.0 (C(5)H), 122.0 (ArCH), 124.5 (ArCH),
126.8 (ArCH), 127.0 (ArCH), 127.7 (ArCH), 128.4 (ArCH), 128.8
(ArCH), 128.8 (ArC), 133.1 (ArC), 133.7 (ArC), 150.9 (C(6)), 170.3
(CO2Et), 171.5 (C(2)); HRMS (NSI+) C19H19O4 [M+H]+ found
311.1282, requires 311.1278 (+1.3 ppm).
4.5.8. (3S,4S)-Ethyl 3-benzyl-2-oxo-6-(4-(trifluoromethyl)
phenyl)-3,4-dihydro-2H-pyran-4-carboxylate 27
Following General Procedure 4.5, 1-oxo-3-phenylpropan-2-yl 4-
nitrobenzoate 7 (224 mg, 0.75 mmol), (E)-ethyl 4-oxo-4-(4-(trifluo-
romethyl)phenyl)but-2-enoate 45 (136 mg, 0.50 mmol), NHC pre-
Acknowledgements
We thank the European Research Council under the European
Union’s Seventh Framework Programme (FP7/2007-2013) ERC
catalyst 2 (18.3 mg, 50.0 lmol), Et3N (105 lL, 0.75 mmol) and THF
Please cite this article in press as: Taylor, J. E.; et al. Tetrahedron: Asymmetry (2017), http://dx.doi.org/10.1016/j.tetasy.2017.01.002

12
J. E. Taylor et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
7. For seminal examples, see: (a) He, M.; Struble, J. R.; Bode, J. W. J. Am. Chem. Soc.
2006, 128, 8418–8420; (b) Phillips, E. M.; Wadamoto, M.; Chan, A.; Scheidt, K.
A. Angew. Chem. Int. Ed. 2007, 46, 3107–3110; (c) Wadamoto, M.; Phillips, E. M.;
Reynolds, T. E.; Scheidt, K. A. J. Am. Chem. Soc. 2007, 129, 10098–10099; (d)
Kaeobamrung, J.; Kozlowski, M. C.; Bode, J. W. Proc. Natl. Acad. Sci. U.S.A. 2010,
107, 20661–20665.
8. (a) Kawanaka, Y.; Phillips, E. M.; Scheidt, K. A. J. Am. Chem. Soc. 2009, 131,
18028–18029; (b) Phillips, E. M.; Wadamoto, M.; Roth, H. S.; Ott, A. W.; Scheidt,
K. A. Org. Lett. 2009, 11, 105–108.
Grant Agreement No. 279850 (J.E.T. and A.T.D.) as well as the
EPSRC, UK and AstraZeneca plc, UK (Case award to J.J.D.) for finan-
cial support. A.D.S. thanks the Royal Society, London, UK, for a
Wolfson Merit Award. We also thank the EPSRC UK National Mass
Spectrometry Facility at Swansea University.
A. Supplementary data
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Please cite this article in press as: Taylor, J. E.; et al. Tetrahedron: Asymmetry (2017), http://dx.doi.org/10.1016/j.tetasy.2017.01.002