NHC-mediated enantioselective formal [4 + 2] cycloadditions of alkylarylketenes and β,γ-unsaturated α-ketocarboxylic esters and amides

Article abstract of DOI:10.1039/c3ob40424b

Chiral N-heterocyclic carbenes (NHCs) promote the asymmetric formal [4 + 2] cycloaddition of alkylarylketenes with β,γ-unsaturated α-ketocarboxylic esters and amides. Divergent diastereoselectivity is observed in this process, with γ-aryl-β,γ-unsaturated

Full text of DOI:10.1039/c3ob40424b

Organic &
Biomolecular Chemistry
View Article Online
View Journal | View Issue
PAPER
NHC-mediated enantioselective formal [4 + 2]
cycloadditions of alkylarylketenes and β,γ-unsaturated
α-ketocarboxylic esters and amides†
Cite this: Org. Biomol. Chem., 2013, 11,
3230
Stuart M. Leckie,a T. Bruce Brown,b David Pryde,c Tomas Lebl,a
Alexandra M. Z. Slawina and Andrew D. Smith*a
Chiral N-heterocyclic carbenes (NHCs) promote the asymmetric formal [4 + 2] cycloaddition of alkylaryl-
ketenes with β,γ-unsaturated α-ketocarboxylic esters and amides. Divergent diastereoselectivity is observed
in this process, with γ-aryl-β,γ-unsaturated α-ketocarboxylic esters and amides giving preferentially syn-
dihydropyranones (up to 68 : 32 dr syn : anti, up to 98% ee), while γ-alkyl-derivatives generate anti-
dihydropyranones (up to 18 : 82 dr syn : anti, up to 75% ee).
Received 28th February 2013,
Accepted 2nd April 2013
DOI: 10.1039/c3ob40424b
www.rsc.org/obc
As part of our research programme aimed at developing
Lewis base-mediated catalytic reaction processes,7 we, simul-
Introduction
Catalytic asymmetric formal [4 + 2] cycloaddition reactions taneously with Ye,8 have utilised NHCs and alkylarylketenes9
offer a versatile and elegant approach to the asymmetric to promote a range of asymmetric processes postulated to
synthesis of poly-functionalised carbo- and heterocyclic proceed via an intermediate disubstituted azolium enolate.
scaffolds.1 A variety of methodologies have been developed Within this area, in 2008 Ye reported the stereocontrolled syn-
within this area, with a range of organocatalytic approaches thesis of either anti- or syn-dihydropyranones via a chiral NHC-
developed within the last decade.2 Among these methods, the
formal inverse-electron demand hetero-Diels–Alder approach
requires the in situ formation of a nucleophilic component,
typically an ammonium or azolium enolate, or an enamine,
combined with an electron deficient enone.3 As representative
examples of this approach, Bode has used chiral NHCs to gene-
rate azolium enolates from enals or α-chloroaldehydes, with
onwards reaction with α-ketocarboxylic esters giving syn-di-
hydropyranones with exquisite diastereo- and enantiocontrol.4
Jørgensen has used enamine catalysis to generate anti-dihydro-
pyranones after oxidation,5 while previous work from
this group has generated ammonium enolates from
carboxylic acids, giving direct access to anti-dihydropyranones
(Scheme 1).6 While versatile and offering high stereoselectivity
in these processes, such strategies are limited to the develop-
ment of mono-substituted enolate intermediates or their
equivalent.
aEaStCHEM, School of Chemistry, University of St Andrews, North Haugh,
St Andrews, KY16 9ST, UK. E-mail: ads10@st-andrews.ac.uk; Tel: +44 (0)1334 463 89
bPfizer Global Research and Development, 388 Ramsgate Road, Sandwich, Kent
CT13 9NJ, UK
cPfizer Neusentis, The Portway Building, Granta Park, Great Abington, Cambridge,
CB21 6GS, UK
†Electronic supplementary information (ESI) available: Spectroscopic and HPLC
data is available for all products. CCDC 922362. For ESI and crystallographic
data in CIF or other electronic format see DOI: 10.1039/c3ob40424b
Scheme 1 Asymmetric organocatalytic formal [4 + 2] cycloadditions.
3230 | Org. Biomol. Chem., 2013, 11, 3230–3246
This journal is © The Royal Society of Chemistry 2013

View Article Online
Organic & Biomolecular Chemistry
Paper
Table 1 Screening of azolium salts for stereoselectivity in the [4 + 2] cyclo-
addition of ethylphenylketene 7 and α-ketoester 6
Entry
Salt
Base
dra
ee majorb (%)
Yieldc
1
2
3
4
5
6
7
8
2
3
3
4
4
5
5
1
1
1
KHMDS
KHMDS
Cs2CO3
KHMDS
Cs2CO3
KHMDS
Cs2CO3
KHMDS
Cs2CO3
Cs2CO3
87 : 13
87 : 13
68 : 32
98 : 2
10
54
34
14
47
16 (ent)
89 (ent)
<5
No reaction
No reaction
No reaction
92
Scheme 2 Synthesis of anti- and syn-dihydropyranones by Ye et al.
61 : 39
67 : 33
66 : 34
52
44
80
9
96
96
10d
catalysed formal [4 + 2] cycloaddition of alkylarylketenes with
a series of 4-oxo-butenoates (Scheme 2).10,11 Using triazolium
precatalyst 1 and an excess of Cs2CO3, anti-dihydropyranones
were generated with high diastereo- and enantiocontrol (>99 : 1
dr anti : syn and up to 92% ee). Through a series of elegant
control experiments the kinetically formed syn-dihydropyra-
none was shown to epimerise to the anti-dihydropyranone
in situ, accounting for the observed excellent dr. Further
studies showed that kinetic deprotonation of the anti-dihydro-
pyranone, followed by stereoselective protonation, gave the syn-
dihydropyranone with good diastereo- and enantioselectivity
(up to >95 : 5 dr syn : anti and up to 90% ee). Building upon
these precedents, this manuscript presents our results con-
cerning the NHC-promoted formal [4 + 2] cycloadditions of
alkylarylketenes and a range of β,γ-unsaturated α-ketocar-
boxylic esters and amides. This series of enone substrates
show notable differences in reactivity and stereoselectivity to
the isomeric 4-oxo-butenoates utilised by Ye, giving divergent
diastereoselective outcomes dependent upon the γ-aryl- or
γ-alkyl-substituent, as well as proving susceptible to isomerisa-
tion of the dihydropyranone products with excess base.
a Determined by 1H NMR spectroscopic analysis of the crude reaction
product. b Determined by chiral HPLC analysis. c Combined yield of all
products. d Performed using 2.4 equivalents of ethylphenylketene 7.
variation of the N-aryl substituent within triazolium precata-
lysts 3–5 led to vastly different reactivity and stereoselectivity.
For example, triazolium precatalyst 3 with Cs2CO3 gave syn-
dihydropyranone with good levels of stereocontrol (eesyn 89%)
but with poor yield (14%, entry 3) whilst no reaction was
observed with triazolium precatalyst 5 (entries 6 and 7).
Optimal stereoselectivity was obtained using triazolium salt 1,
with Cs2CO3 (eesyn 96%, entry 9) giving higher enantioselecti-
vity than KHMDS (eesyn 92%, entry 8). With 2.4 equivalents of
7 the yield increased to 80% (entry 10).
The relative and absolute configuration of the major syn-
diastereoisomer of dihydropyranone 8 was confirmed as
(3R,4R) by X-ray structure analysis (Fig. 1), with the configur-
ation of all other syn-dihydropyranones assigned by analogy.12
Results and discussion
Catalyst and base screening
Model studies screened a range of chiral NHCs to promote the
formal asymmetric [4 + 2] cycloaddition of β,γ-unsaturated
α-ketoester 6 and ethylphenylketene 7, with treatment of
azolium salts 1–5 (10 mol%) with either KHMDS or Cs2CO3
(9 mol%) in Et2O or toluene used to prepare the corresponding
NHC in situ (Table 1, entries 1–9). Modest levels of stereoselec-
Fig. 1 Molecular representation of the X-ray crystal structure of syn-dihydro-
tivity were observed using imidazolinium salt 2 (entry 1), while pyranone 8.
This journal is © The Royal Society of Chemistry 2013
Org. Biomol. Chem., 2013, 11, 3230–3246 | 3231

View Article Online
Paper
Organic & Biomolecular Chemistry
Table 2 Control experiments indicating that excess Cs2CO3 is responsible for the formation of isomeric dihydropyranones 12
Entry
Cs2CO3 (mol%)
Ratioa 11 : 12
dra 11 (syn : anti)
eeb 11 (%) (syn, anti)
dra 12 (syn : anti)
eeb 12 (%) (syn, anti)
Yieldc (%)
1
2
3
9
5
20
>98 : <2
>98 : <2
61 : 39
67 : 33
66 : 44
50 : 50
97, 33
96, 22
78, 31
—
—
58 : 42
—
—
88, 86
71
56
44
a Determined by 1H NMR spectroscopic analysis of the crude reaction product. b Determined by chiral HPLC analysis. c Combined yield of all
products.
Optimisation studies
Using precatalyst 1, further investigation showed that minimis-
ation of excess Cs2CO3 is imperative to both maximise asym-
metric induction and minimise side product formation
resulting from product isomerisation in this process (Table 2,
entries 1–3). For example, treatment of 4-chlorophenylethyl-
ketene 9 with precatalyst 1 (10 mol%), Cs2CO3 (9 mol%) and
ester 10 gave exclusively the dihydropyranone products 11
(67 : 33 dr syn : anti; eesyn 97%, eeanti 33%) in 70% overall yield
(entry 1). The use of excess azolium salt (entry 2) gave similar
results, while excess Cs2CO3 (entry 3) led to the formation of a
61 : 39 mixture of cycloaddition products 11 (dr 50 : 50 syn :
Scheme 3 Treatment of isolated syn-dihydropyranone 11 with Cs2CO3.
anti; eesyn 78%; eeanti 31%) to the isomeric dihydropyranones
12 (dr 58 : 42, eesyn 88%; eeanti 86%).
Control experiments showed that the isomeric dihydropyra-
nones 12 arise from a Cs2CO3 catalysed, rather than an NHC-
catalysed, isomerisation process of the initially formed cyclo-
addition products. For example, treatment of syn-11 (dr 93 : 7,
eesyn 97%, eeanti 22%) with azolium salt 1 and Cs2CO3 returned
exclusively syn-11 (dr 93 : 7, eesyn 97%, eeanti 22%), while treat-
ment with Cs2CO3 alone gave a 44 : 56 mixture of cycloaddition
products 11 (dr <5 : 95 syn : anti, eeanti 89%) isomeric dihydro-
pyranones 12 (dr 58 : 42, eesyn 92%; eeanti 90%; Scheme 3).13
The observation of isomeric dihydropyranones 12 upon treat-
ment of 11 with Cs2CO3 is consistent with deprotonation of 11
at C(4)–H, facilitated by the adjacent C(4)–aryl and vinylogous
ester units, generating a dienolate intermediate 13 that sub-
sequently undergoes protonation at either C(4) or C(6) to give
11 or 12 respectively.14
isomerised dihydropyranone products with poor diastereo-
and enantiocontrol (Scheme 4, entries 1 and 2). Using ethyl-
phenylketene or butylphenylketene under standardised reac-
tion conditions no isomerisation products were observed
(entries 3 and 4), with highest diastereo- and enantiocontrol
observed using ethylphenylketene, giving 18 (66 : 34 dr syn :
anti; eesyn 92%, eeanti 36%) in 99% yield. Notably, the use of a
γ-furan-2-yl substituted β,γ-unsaturated α-ketocarboxylate led
to extensive isomerisation, giving the syn-isomerised product
21 in high ee (entry 5) even using alternative catalytic con-
ditions designed to minimise any residual base (precatalyst 1
15 mol%, Cs2CO3 10 mol%).15
Scope and generality
To minimise product isomerisation in the NHC-catalysed
process it proved experimentally necessary to ensure sub-
stoichiometric quantities of base (Cs2CO3) relative to azolium
salt. Despite these precautions the extent of product isomerisa-
tion is highly substrate dependent. For example, when employ-
ing precatalyst 1 (15 mol%), Cs2CO3 (10 mol%) and a standard
ketoester 10, the use of methylphenylketene or methyl-
With the base-catalysed isomerisation process delineated, the
generality of this asymmetric process was next explored under
optimised conditions, with minimal (typically <5%) isomerisa-
tion noted. Using ethylphenylketene, variation of the ester
functionality of the β,γ-unsaturated α-ketocarboxylate (Me, Et,
i-Pr) is readily tolerated, as is a primary ketoamide, giving
dihydropyranones 8, 11 and 22–28 with comparable yields,
diastereo- and enantioselectivity (dr ∼66 : 34, eesyn up to 98%,
(4-methylphenyl)ketene gave
a mixture of cycloaddition :
3232 | Org. Biomol. Chem., 2013, 11, 3230–3246
This journal is © The Royal Society of Chemistry 2013

View Article Online
Organic & Biomolecular Chemistry
Paper
Scheme 4 NHC promoted asymmetric [4 + 2] cycloaddition of ketenes and ketocarboxylates indicating highly substrate dependant nature of the isomerisation
process. aDetermined by 1H NMR spectroscopic analysis of the crude reaction product. bDetermined by HPLC analysis. cCombined yield of all products. dPerformed
with 10 mol% precatalyst 1, 9 mol% Cs2CO3.
Scheme 5). Notably a number of secondary ketoamides gave
no [4 + 2] cycloaddition product under identical conditions.16
Variation of the aryl unit within both the ketene and α-keto-
carboxylate components were next investigated, with electron-
donating and electron-withdrawing substituents both toler-
ated, albeit with electron-donating substituents leading to
reduced diastereo- and enantiocontrol.
Subsequent studies17 probed the effect of incorporating
γ-alkyl substituents within the β,γ-unsaturated α-ketocarboxy-
late (Scheme 6), with the anti-stereoisomer (up to 75% ee)
formed preferentially in each case (dr up to 82 : 18 anti : syn).
Optimal enantioselectivity (up to 97% ee) was observed for the
minor syn-diastereoisomer.18 Notably, isomerisation products
were not observed in these processes even with the use of
excess base (20 mol% Cs2CO3), while control experiments
involving treatment of the isolated dihydropyranones with
Cs2CO3 led to no change in product diastereo- and enantio-
selectivity, consistent with dienolate formation being dis-
favoured in this system. γ-Methyl and γ-n-pentyl substitution is
readily tolerated, although α-branched alkyl substituted and
β,γ-disubstituted unsaturated α-ketocarboxylate acceptors gave
no cycloaddition products, returning only starting materials.
Proposed mechanism and stereochemical rationale
These studies are consistent with the mechanistic scheme out-
lined in Fig. 2. Base promoted generation of NHC 33, followed
by addition to the ketene, preferentially anti to the aryl unit,19
will generate azolium enolate 34. Asymmetric [4 + 2] cyclo-
addition (or alternatively Michael addition, followed by lacton-
Scheme 5 NHC promoted asymmetric [4 + 2] cycloaddition of alkylarylketenes
isation) to give 35, followed by elimination will generate
dihydropyranone 36 and regenerate the NHC for catalyst
turnover (Fig. 2).
and γ-aryl-β,γ-unsaturated α-ketocarboxylates. aCombined yield of all products.
bDetermined by 1H NMR spectroscopic analysis of the crude reaction product.
cDetermined by HPLC analysis.
This journal is © The Royal Society of Chemistry 2013
Org. Biomol. Chem., 2013, 11, 3230–3246 | 3233

View Article Online
Paper
Organic & Biomolecular Chemistry
lactonisation reaction schemes, no simple stereochemical
model to account for this divergence can be offered at the
present time. Rather than speculate upon the origin of this
stereodivergent process at this time, future studies will explore
in detail this observation.
Conclusions
In conclusion, chiral NHCs promote the formal asymmetric
[4 + 2] cycloaddition of disubstituted alkylarylketenes with
β,γ-unsaturated α-ketocarboxylate derivatives. With γ-aryl sub-
stituted β,γ-unsaturated α-ketocarboxylate derivatives, syn-
dihydropyranones are preferentially formed with moderate
diastereocontrol (typically 66 : 34 dr syn : anti) but high enantio-
control (up to 98% ee for the major syn-diastereoisomer).
γ-Alkyl substituted β,γ-unsaturated α-ketocarboxylates generate
anti-dihydropyranones preferentially (typically 20 : 80 dr syn :
anti, up to 75% ee for major anti-diastereoisomer). Current
studies from this laboratory are focused upon developing
alternative applications of enantiomerically pure NHCs in
asymmetric catalysis and developing a detailed mechanistic
understanding of these reaction processes.
Scheme 6 NHC promoted asymmetric [4 + 2] cycloaddition of alkylarylketenes
and γ-alkyl-β,γ-unsaturated ketocarboxylates. aCombined yield of all products.
bDetermined by 1H NMR spectroscopic analysis of the crude reaction product.
cDetermined by HPLC analysis.
Experimental
General procedure 1: NHC-mediated formal [4 + 2]
cycloaddition protocol
To a flame dried Schlenk flask under an atmosphere of argon
was added azolium salt (0.0245 mmol), base (0.0221 mmol)
and toluene (1.5 mL) and the resultant suspension was stirred
at rt for 30 minutes. The requisite ketoester (0.245 mmol) was
added either as a solid with toluene (1.5 mL) added to wash
any residual solid into the reaction mixture, or as a solution in
toluene (1.5 mL). As soon as the addition of the ketoester was
complete, a solution of the desired ketene (0.319 mmol or
0.588 mmol) in toluene (4 mL) was added over 2 h via syringe
pump. Once the addition was complete the solution was left
to stir at rt overnight before concentration in vacuo to give the
crude product. Purification via column chromatography on
silica gel gave the title compound.
Fig. 2 Proposed catalytic cycle.
This simplistic catalytic cycle is consistent with the con-
nectivity of the dihydropyranone products, although does not
account for the observed divergent diastereocontrol with
γ-alkyl- or γ-aryl substitution with variation of the β,γ-unsatu-
rated α-ketocarboxylate reaction component. On the assump-
tion that irreversible azolium enolate addition to the
β,γ-unsaturated α-ketocarboxylate proceeds under kinetic
control, and that this effect does not arise from an epimerisa-
tion process, this stereochemical divergence arises from differ-
ential steric interactions between the γ-alkyl- or γ-aryl
substituents in the transition state assembly leading to the
dihydropyranone products. Given the complex nature of
these reactants, the possibility of competitive exo- or endo-
cycloaddition pathways, or alternative Michael-addition
Preparation of ethyl 3-ethyl-2-oxo-3,4-diphenyl-3,4-dihydro-2H-
pyran-6-carboxylate ( )-(syn)-8 and ( )-(anti)-8
Following general procedure 1, ( )-triazolium salt 1 (14.0 mg,
0.0245 mmol), Cs2CO3 (7.2 mg, 0.0221 mmol) with ethylphe-
nylketene 7 (86.0 mg, 0.588 mmol) and ketoester 6 (50.0 mg,
0.245 mmol) at rt overnight gave the crude product (67 : 33 dr
syn : anti). Purification via column chromatography on silica
gel (eluent petrol–EtOAc 90 : 10) gave a mixture of lactones
( )-(syn)-8 and ( )-(anti)-8 (65.9 mg, 60%) as a colourless solid;
( )-8 mp 107–109 °C; νmax (KBr) 2973 (C–H), 1761 (CvO), 1730
(CvO), 1664 (CvO), 1497, 1260, 1111, 760, 697; δH (400 MHz,
CDCl3) ( )-(syn)-8 1.00 (3H, t, J 7.2, C(3)CH2CH3), 1.38 (3H, t,
J 7.2, CO2CH2CH3), 2.29–2.39 (2H, m, C(3)CH2), 3.81 (1H, d,
3234 | Org. Biomol. Chem., 2013, 11, 3230–3246
This journal is © The Royal Society of Chemistry 2013

View Article Online
Organic & Biomolecular Chemistry
Paper
J 5.3, C(4)H), 4.30–4.42 (2H, m, C(O)2CH2), 6.63–6.69 (2H, m, (CvO), 1490; δH (400 MHz, CDCl3) 0.58 (3H, t, J 7.4, C(3)
C(5)H and Ph), 6.87–6.91 (2H, m, Ph), 7.04–7.15 (3H, m, Ph), CH2CH3), 1.23 (3H, t, J 7.1, CO2CH2CH3), 1.44–1.53 (1H, m,
7.28–7.40 (4H, m, Ph); ( )-(anti)-8 0.56 (3H, t, J 7.3, C(3) C(3)CHAHB), 1.86–1.95 (1H, m, C(3)CHAHB), 4.12 (1H, d, J 6.4,
CH2CH3), 1.26 (3H, t, J 7.3, CO2CH2CH3), 1.50 (1H, dq, J 14.5, C(4)H), 4.24 (2H, q, J 7.1, C(O)2CH2), 6.61 (1H, d, J 6.4, C(5)H),
7.3, C(3)CHAHB), 1.90 (1H, dq, J 14.5, 7.3, C(3)CHAHB), 7.02–7.06 (2H, m, C(4)Ph(2,6)), 7.22–7.26 (2H, m, C(3)Ph(2,6)),
4.17–4.23 (3H, m, C(O)2CH2 and C(4)H), 6.63–6.69 (2H, m, C(5) 7.34–7.38 (2H, m, C(3)Ph(3,5)), 7.46–7.49 (2H, m, C(2)Ph(3,5)),
H and Ph), 7.04–7.15 (3H, m, Ph), 7.18–7.22 (2H, m, Ph), δC (75 MHz, CDCl3) 8.3 (C(3)CH2CH3), 14.1 (CO2CH2CH3), 28.0
7.28–7.40 (4H, m, Ph); δC (100 MHz, CDCl3) ( )-(syn)-8 9.5 (C(3)- (C(3)CH2), 45.8 (C(4)), 53.4 (C(3)), 62.1 (CO2CH2), 116.9 (C(5)),
CH2CH3), 14.3 (CO2CH2CH3), 29.2 (C(3)CH2), 50.9 (C(4)), 55.1 122.5 (C(4)Ph(4)), 128.3 (C(3)Ph(3,5)), 129.1 (C(4)Ph(2,6)), 130.3
(C(3)), 62.1 (CO2CH2), 118.2 (C(5)), 126.9 (Ph), 127.8 (Ph), 128.2 (C(3)Ph(2,6)), 132.4 (C(4)Ph(3,5)), 134.0 (C(3)Ph(4)), 134.9 (C(3)-
(Ph), 128.3 (Ph), 128.4 (Ph), 129.0 (Ph), 136.2 (Cipso), 136.7 Ph(1)), 135.9 (C(4)Ph(1)), 141.4 (C(6)), 160.0 (CO2), 169.3 (C(2));
(Cipso), 141.2 (C(6)), 160.4 (CO2), 170.1 (C(2)); ( )-(anti)-8 8.4 m/z HRMS (NSI+) C22H24O4NBrCl+ ([M + NH4]+) requires
(C(3)CH2CH3), 14.2 (CO2CH2CH3), 28.5 (C(3)CH2), 46.4 (C(4)), 480.0572; found 480.0570 (−0.4 ppm).
54.0 (C(3)), 61.9 (CO2CH2), 118.1 (C(5)), 127.1 (Ph), 127.7 (Ph),
Ethyl
4-(4-bromophenyl)-3-(4-chlorophenyl)-3-ethyl-2-oxo-
127.9 (Ph), 128.7 (Ph), 128.9 (Ph), 129.2 (Ph), 136.3 (Cipso), 137.7 3,4-dihydro-2H-pyran-6-carboxylate (3R,4R)-11 and (3R,4S)-11
(Cipso), 141.3 (C(6)), 160.3 (CO2), 168.1 (C(2)); m/z HRMS (NSI+)
Table 2, entry 1. Following general procedure 1, triazolium
salt 1 (14.0 mg, 0.0245 mmol), Cs2CO3 (7.2 mg, 0.0221 mmol)
C22H26O4N+ ([M + NH4]+) requires 368.1856; found 368.1861
with ethyl-(4-chlorophenyl)ketene 9 (106 mg, 0.588 mmol) and
ketoester 10 (69.4 mg, 0.245 mmol) at rt overnight gave the
crude product (63 : 37 dr syn : anti). Purification via column
chromatography on silica gel (eluent petrol–CH2Cl2 50 : 50)
gave lactones (3R,4R)-11 and (3R,4S)-11 as colourless solids
(80.7 mg, 71%); (3R,4R)-11 [α]2D0 +182.3 (c 0.1, CHCl3); Chiral
(+1.3 ppm).
Ethyl 3-ethyl-2-oxo-3,4-diphenyl-3,4-dihydro-2H-pyran-6-car-
boxylate (3R,4R)-8 and (3R,4S)-8. Following general procedure
1, triazolium salt 1 (14.0 mg, 0.0245 mmol), Cs2CO3 (7.2 mg,
0.0221 mmol) with ethylphenylketene 7 (86.0 mg, 0.588 mmol)
and ketoester 6 (50.0 mg, 0.245 mmol) at rt overnight gave the
crude product (66 : 34 dr syn : anti). Purification via column
chromatography on silica gel (eluent petrol–EtOAc 90 : 10) gave
lactones (3R,4R)-8 and (3R,4S)-8 (68.7 mg, 80%) as a colourless
solid; Chiral HPLC (3R,4R)-197 Chiralpak AS-H (3% IPA–
hexane, flowrate 1 mL min−1, 254 nm) tR(3S,4S): 16.2 min,
tR(3R,4R): 35.0 min, 96% ee; (3R,4S)-197 Chiralpak AS-H (3%
HPLC Chiralpak AS-H (5% IPA–hexane, flowrate 1 mL min−1
,
254 nm) tR(3S,4S): 18.3 min, tR(3R,4R): 36.5 min, 95% ee;
(3R,4S)-11 [α]2D0 −42.5 (c 0.1, CHCl3); Chiral HPLC Chiralpak
AS-H (10% IPA–hexane, flowrate 1 mL min−1, 254 nm)
tR(3R,4S): 16.0 min, tR(3S,4R): 36.7 min, 18% ee.
Table 2, entry 2. Following general procedure 1, triazolium
IPA–hexane, flowrate 1 mL min−1, 254 nm) tR(3R,4S): 18.5 min, salt 1 (14.0 mg, 0.0245 mmol), Cs2CO3 (4.0 mg, 0.012 mmol)
tR(3S,4R): 35.0 min, 19% ee.
Ethyl 4-(4-bromophenyl)-3-(4-chlorophenyl)-3-ethyl-2-oxo- ketoester 10 (69.4 mg, 0.245 mmol) at rt overnight gave the
3,4-dihydro-2H-pyran-6-carboxylate ( )-(syn)-11 and ( )-(anti)- crude product (66 : 34 syn : anti). Purification via column
11. Following general procedure 1, ( )-triazolium salt chromatography on silica gel (eluent petrol–CH2Cl2 50 : 50)
with ethyl-(4-chlorophenyl)ketene 9 (106 mg, 0.588 mmol) and
1
(14.0 mg, 0.0245 mmol), Cs2CO3 (7.2 mg, 0.0221 mmol) with gave lactones (3R,4R)-11 and (3R,4S)-11 as colourless solids
ethyl-(4-chlorophenyl)ketene 9 (106 mg, 0.588 mmol) and (63.1 mg, 56%); syn diastereoisomer (3R,4R)-11 Chiral HPLC
ketoester 10 (69.4 mg, 0.245 mmol) at rt overnight gave the Chiralpak AS-H (5% IPA–hexane, flowrate
1 ,
mL min−1
crude product (60 : 40 dr syn : anti). Purification via column 254 nm) tR(3S,4S): 18.0 min, tR(3R,4R): 36.2 min, 96% ee; anti
chromatography on silica gel (eluent petrol–CH2Cl2 50 : 50) diastereoisomer Chiral HPLC Chiralpak AS-H (5% IPA–hexane,
gave lactones ( )-(syn)-11 and ( )-(anti)-11 as colourless solids flowrate 1 mL min−1, 254 nm) tR(3R,4S): 21.2 min, tR(3S,4R):
(90.4 mg, 80%); ( )-(syn)-11 mp 118–120 °C; νmax (KBr) 2977 52.0 min, 22% ee.
(C–H), 2937 (C–H), 1767 (CvO), 1734 (CvO), 1672 (CvO),
Ethyl
4-(4-bromophenyl)-3-(4-chlorophenyl)-3-ethyl-2-oxo-
1489; δH (400 MHz, CDCl3) 0.96 (3H, t, J 7.3, C(3)CH2CH3), 1.39 3,4-dihydro-2H-pyran-6-carboxylate ( )-(syn)-11 and ( )-(anti)-
(3H, t, J 7.1, CO2CH2CH3), 2.26–2.36 (2H, m, C(3)CH2), 3.73 11 and ethyl 4-(4-bromophenyl)-5-(4-chlorophenyl)-5-ethyl-
(1H, d, J 5.5, C(4)H), 4.31–4.43 (2H, m, C(O)2CH2), 6.54–6.58 6-oxo-5,6-dihydro-2H-pyran-2-carboxylate
( )-(syn)-12
and
(2H, m, C(4)Ph(2,6)), 6.61 (1H, d, J 5.5, C(5)H), 6.86–6.90 (2H, ( )-(anti)-12. Following general procedure 1, ( )-triazolium salt
m, C(3)Ph(2,6)), 7.10–7.14 (2H, m, C(3)Ph(3,5)), 7.23–7.27 (2H, 1 (14.0 mg, 0.0245 mmol), Cs2CO3 (16.0 mg, 0.0491 mmol)
m, C(4)Ph(3,5)); δC (75 MHz, CDCl3) 9.7 (C(3)CH2CH3), 14.6 with ethyl-(4-chlorophenyl)ketene 9 (106 mg, 0.588 mmol) and
(CO2CH2CH3), 29.7 (C(3)CH2), 50.9 (C(4)), 54.9 (C(3)), 62.6 ketoester 10 (69.4 mg, 0.245 mmol) at rt overnight gave the
(CO2CH2), 117.4 (C(5)), 122.4 (C(3)Ph(4)), 128.4 (C(3)Ph(3,5)), crude product as a 57 : 43 mixture of cycloaddition products
129.9 (C(3)Ph(2,6)), 130.8 (C(4)Ph(2,6)), 132.0 (C(4)Ph(3,5)), ( )-(syn)-11 and ( )-(anti)-11 (13 : 87 dr syn : anti) to the iso-
133.6 (C(3)Ph(4)), 134.8 (C(3)Ph(1)), 135.7 (C(4)Ph(1)), 141.8 meric dihydropyranones ( )-(syn)-12 and ( )-(anti)-12 (58 : 42
(C(6)), 160.5 (CO2), 167.7 (C(2)); m/z HRMS (NSI+) dr syn : anti). Purification via column chromatography on silica
C22H24O4NBrCl+ ([M
+
NH4]+) requires 480.0572; found gel (eluent petrol–CH2Cl2 50 : 50 to 0 : 100) gave cycloaddition
480.0571 (−0.2 ppm); ( )-(anti)-11 mp 89–90 °C; νmax (KBr) products ( )-(syn)-11 and ( )-(anti)-11 as a colourless solid
2978 (C–H), 1771 (CvO), 1733 (CvO), 1662 (CvO), 1638 (34.1 mg, 30%) with spectroscopic data as reported above and
This journal is © The Royal Society of Chemistry 2013
Org. Biomol. Chem., 2013, 11, 3230–3246 | 3235

View Article Online
Paper
Organic & Biomolecular Chemistry
isomeric dihydropyranones ( )-(syn)-12 and ( )-(anti)-12 as a before concentration in vacuo gave the crude product as a
pale yellow oil (41.9 mg, 37%); νmax (ATR) 3001 (C–H), 1748 44 : 56 mixture of cycloaddition products (<5 : >95 dr syn : anti):
(CvO), 1734 (CvO), 1489, 1263, 1177 (C–O), 1096, 1011; δH isomeric dihydropyranones (58 : 42 dr syn : anti). Purification
(300 MHz, CDCl3) ( )-(syn)-12 0.85 (3H, t, J 7.3 C(5)CH2CH3), via column chromatography on silica gel (eluent petrol–CH2Cl2
1.36 (3H, t, J 7.1, CO2CH2CH3), 1.72–1.90 (1H, m, C(5)HAHB), 50 : 50 to petrol–CH2Cl2 0 : 100) gave lactone (3R,4S)-11 as a
2.59–2.79 (1H, m, C(5)HAHB), 4.24 (2H, q, J 7.1, CO2CH2), 5.60 colourless solid (7.9 mg, 24%) with spectroscopic data as
(1H, d, J 4.0, C(2)H), 6.29–6.36 (1H, m, C(3)H), 6.67–6.78 (4H, described above; (3R,4R)-11 [α]2D0 −128.9 (c 0.1, CHCl3); Chiral
m, Ph), 7.29–7.48 (4H, m, Ph); ( )-(anti)-12 0.85 (3H, t, J 7.3 HPLC Chiralpak AS-H (5% IPA–hexane, flowrate 1 mL min−1
,
C(5)CH2CH3), 1.26 (3H, t, J 7.1, CO2CH2CH3), 1.72–1.90 (1H, 254 nm) tR(3R,4S): 23.9 min, tR(3S,4R): 58.0 min, 89% ee; and
m, C(5)HAHB), 2.59–2.79 (1H, m, C(5)HAHB), 4.29–4.41 (2H, m, an in separable mixture of isomeric dihydropyranones (2S,5S)-
CO2CH2), 5.67 (1H, d, J 3.0, C(2)H), 6.29–6.36 (1H, m, C(3)H), 12 and (2R,5S)-12 as a pale yellow oil (13.5 mg, 42%) with spec-
7.29–7.48 (8H, m, Ph); δC (75 MHz, CDCl3) ( )-(syn)-12 9.7 (C(5)- troscopic data as described above; (2S,5S)-12 Chiral HPLC
CH2CH3), 14.2 (CO2CH2CH3), 29.1 (C(5)CH2), 54.2 (C(5)), 62.7 Chiralpak AD-H (20% IPA–hexane, flowrate 0.25 mL min−1
,
(CO2CH2), 76.8 (C(2)), 121.2 (C(3)), 122.9 (C(4)Ph(4)), 128.7 254 nm) tR(2S,5S): 55.0 min, tR(2R,5R): 58.2 min, 92% ee;
(Ph), 129.5 (Ph), 129.6 (Ph), 132.1 (Ph), 134.2 (C(5)Ph(4)), 136.2 (2R,5S)-12 Chiral HPLC Chiralpak IC (10% IPA–hexane, flow-
(Cipso), 138.9 (Cipso), 140.4 (C(4)), 167.5 (C(6)), 170.4 (CO2); δC rate 1 mL min−1, 254 nm) tR(2R,5S): 53.6 min, tR(2S,5R):
(75 MHz, CDCl3) ( )-(anti)-12 9.8 (C(5)CH2CH3), 14.3 62.3 min, 90% ee.
(CO2CH2CH3), 27.5 (C(5)CH2), 53.7 (C(5)), 63.5 (CO2CH2), 76.8
(C(2)), 121.3 (C(3)), 122.9 (C(4)Ph(4)), 129.1 (Ph), 129.4 (Ph),
General procedure 2: NHC-mediated formal [4 + 2]
cycloaddition protocol to minimise isomerisation
129.8 (Ph), 131.6 (Ph), 134.4 (C(5)Ph(4)), 136.2 (Cipso), 139.0
(Cipso), 140.7 (C(4)), 167.6 (C(6)), 170.0 (CO2); m/z (NSI)+ HRMS To a flame dried Schlenk flask under an atmosphere of argon
C22H24O4NBrCl+ ([M
480.0578 (+1.3 ppm).
+
NH4]+) requires 480.0572; found was added azolium salt (0.0368 mmol), base (0.0221 mmol)
and toluene (1.5 mL) and the resultant suspension was stirred
Ethyl
4-(4-bromophenyl)-3-(4-chlorophenyl)-3-ethyl-2-oxo- at rt for 30 minutes. The requisite ketoester (0.245 mmol) was
3,4-dihydro-2H-pyran-6-carboxylate (3R,4R)-11 and (3R,4S)-11 added as a solid. Toluene (1.5 mL) was added to wash any
and ethyl 4-(4-bromophenyl)-5-(4-chlorophenyl)-5-ethyl-6-oxo- residual solid into the reaction mixture, immediately followed
5,6-dihydro-2H-pyran-2-carboxylate (2S,5S)-12 and (2R,5S)-12
Table 2, entry 3. Following general procedure 1, triazolium
salt 1 (14.0 mg, 0.0245 mmol), Cs2CO3 (16.0 mg, 0.0491 mmol)
with ethyl-(4-chlorophenyl)ketene 9 (106 mg, 0.588 mmol) and
ketoester 10 (69.4 mg, 0.245 mmol) at rt overnight gave the
crude product as a 61 : 39 mixture of cycloaddition products
(3R,4R)-11 and (3R,4S)-11 (50 : 50 dr syn : anti) to the isomeric
dihydropyranones (2S,5S)-12 and (2R,5S)-12 (58 : 42 dr syn :
anti). Purification via column chromatography on silica gel
(eluent petrol–CH2Cl2 50 : 50 to 0 : 100) gave cycloaddition pro-
ducts (3R,4R)-11 and (3R,4S)-11 as a colourless solid (65.8 mg,
58%); (3R,4R)-11 Chiral HPLC Chiralpak AS-H (5% IPA–
hexane, flowrate 1 mL min−1, 254 nm) tR(3S,4S): 18.4 min,
tR(3R,4R): 34.8 min, 78% ee; (3R,4S)-11 Chiral HPLC Chiralpak
AS-H (5% IPA–hexane, flowrate 1 mL min−1, 254 nm) tR(3R,4S):
22.2 min, tR(3S,4R): 52.3 min, 31% ee; and isomeric dihydro-
pyranones (2S,5S)-12 and (2R,5S)-12 as a pale yellow oil
(38.5 mg, 34%); (2S,5S)-12 Chiral HPLC Chiralpak AD-H (20%
by a solution of the desired ketene (0.588 mmol) in toluene
(4 mL) over 2 h via syringe pump. Once the addition was com-
plete the solution was left to stir at rt overnight before concen-
tration in vacuo to give the crude product. Purification via
column chromatography on silica gel gave the title compound.
Ethyl 4-(4-bromophenyl)-3-methyl-2-oxo-3-phenyl-3,4-dihydro-
2H-pyran-6-carboxylate ( )-(syn)-14 and ( )-(anti)-14 and ethyl
4-(4-bromophenyl)-5-methyl-6-oxo-5-phenyl-5,6-dihydro-2H-pyran-
2-carboxylate ( )-(syn)-15 and ( )-(anti)-15. Following general
procedure 2, ( )-triazolium salt 1 (20.9 mg, 0.0368 mmol),
Cs2CO3 (8.0 mg, 0.0245 mmol) with methylphenylketene
(77.7 mg, 0.588 mmol) and ketoester 10 (69.4 mg, 0.245 mmol)
at rt overnight gave the crude product as a 81 : 19 mixture of
cycloaddition products ( )-(syn)-14 and ( )-(anti)-14 (50 : 50 dr
syn : anti) to the isomeric dihydropyranones ( )-(syn)-15 and
( )-(anti)-15 (52 : 48 dr syn : anti). Purification via column
chromatography on silica gel (eluent petrol–CH2Cl2 50 : 50 to
0 : 100) gave cycloaddition products ( )-(syn)-14 and ( )-(anti)-
14 as a colourless solid (15.7 mg, 15%); mp 71–73 °C; νmax
(ATR) 2926 (C–H), 2854 (C–H), 1715 (CvO), 1664 (CvO), 1362,
1215 (C–O), 1065; δH (400 MHz, CDCl3) ( )-(syn)-14 1.38 (3H, t,
J 7.1, CH3), 1.80 (3H, s, C(3)Me), 3.85 (1H, d, J 3.9, C(4)H),
4.31–4.43 (2H, m, CH2), 6.49 (1H, d, J 3.9, C(5)H), 6.75–6.79
(2H, m, Ph), 7.11–7.23 (4H, m, Ph), 7.27–7.30 (2H, m, Ph);
( )-(anti)-14 1.27 (3H, s, C(3)Me), 1.30 (3H, t, J 7.1, CH3), 4.11
(1H, d, J 6.3, C(4)H), 4.25 (2H, q, J 7.1, CH2), 6.57 (1H, d, J 6.3,
IPA–hexane, flowrate 0.1 mL min−1
, 254 nm) tR(2S,5S):
103.2 min, tR(2R,5R): 109.3 min, 88% ee; (2R,5S)-12
Chiral HPLC Chiralpak IC (10% IPA–hexane, flowrate
1 mL min−1, 254 nm) tR(2R,5S): 50.1 min, tR(2S,5R): 58.9 min,
86% ee.
Control experiments
Scheme 3. Treatment of (3R,4R)-11 with 20 mol% Cs2CO3.
To a flame dried Schlenk flask under an atmosphere of C(5)H), 7.00–7.03 (2H, m, Ph), 7.30–7.40 (5H, m, Ph),
argon was added dihydropyranone (3R,4R)-11 (93 : 7 dr syn : 7.45–7.48 (2H, m, Ph); δC (100 MHz, CDCl3) ( )-(syn)-14 14.1
anti, 32.4 mg, 0.0737 mmol) in toluene (1.5 mL) was added (CO2CH2CH3), 24.3 (C(3)Me), 49.1 (C(3)), 50.3 (C(4)), 62.2
and the reaction mixture stirred at room temperature overnight (CO2CH2), 118.1 (C(5)), 122.5 (C(4)Ph(4)), 127.6 (Ph), 127.9 (Ph),
3236 | Org. Biomol. Chem., 2013, 11, 3230–3246
This journal is © The Royal Society of Chemistry 2013

View Article Online
Organic & Biomolecular Chemistry
Paper
130.5 (Ph), 131.3 (Ph), 131.5 (Ph), 135.5 (Cipso), 136.6 (Cipso), ( )-(anti)-17. Following general procedure 2, ( )-triazolium salt
142.2 (C(6)), 160.2 (CO2Et), 169.9 (C(2)); ( )-(anti)-14 14.2 1 (20.9 mg, 0.0368 mmol), Cs2CO3 (8.0 mg, 0.0245 mmol) with
(CO2CH2CH3), 24.0 (C(3)Me), 48.4 (C(4)), 50.5 (C(3)), 62.0 methyl-4-methylphenylketene (86.0 mg, 0.588 mmol) and
(CO2CH2), 117.1 (C(5)), 122.2 (C(4)Ph(4)), 125.8 (Ph), 128.1 (Ph), ketoester 10 (69.4 mg, 0.245 mmol) at rt overnight gave the
129.2 (Ph), 132.4 (2 × Ph), 135.0 (Cipso), 140.8 (Cipso), 142.2 crude product as a 68 : 32 mixture of cycloaddition products
(C(6)), 160.3 (CO2Et), 170.1 (C(2)); m/z HRMS (NSI+) ( )-(syn)-16 and ( )-(anti)-16 (52 : 48 dr syn : anti) to the iso-
C21H23O4NBr+ ([M + NH4]+) requires 432.0805; found 432.0814 meric dihydropyranones ( )-(syn)-17 and ( )-(anti)-17 (36 : 64
(+2.1 ppm); and isomeric dihydropyranones ( )-(syn)-15 and dr syn : anti). Purification via column chromatography on silica
( )-(anti)-15 (18.8 mg, 18%) as a colourless oil; νmax (ATR) 2920 gel (eluent petrol–CH2Cl2 50 : 50 to 0 : 100) gave cycloaddition
(C–H), 1753 (CvO), 1746 (CvO), 1435, 1262 (C–O), 1070; δH products ( )-(syn)-16 and ( )-(anti)-16 (40.1 mg, 38%) as a col-
(400 MHz, CDCl3) ( )-(syn)-15 1.21 (3H, t, J 7.2, CH3), 1.74 (3H, ourless solid; mp 135–137 °C; νmax (ATR) 2961 (C–H), 2926
s, C(5)Me), 4.09–4.23 (2H, m, CH2), 5.57 (1H, d, J 4.4, C(2)H), (C–H), 1765 (CvO), 1724 (CvO), 1487, 1323, 1300, 1263
6.24 (1H, d, J 4.4, C(3)H), 6.77–6.80 (2H, m, Ph), 7.31–7.41 (5H, (C–O), 1087, 1074; δH (400 MHz, CDCl3) ( )-(syn)-16 1.38 (3H, t,
m, Ph), 7.47–7.50 (2H, m, Ph); ( )-(anti)-15 1.35 (3H, t, J 7.2, J 7.1, CH3), 1.77 (3H, s, C(3)Me), 2.28 (3H, s, PhMe),3.86 (1H, d,
CH3), 1.74 (3H, s, C(3)Me), 4.30–4.38 (2H, m, CH2), 5.50 (1H, d, J 3.8, C(4)H), 4.31–4.45 (2H, m, CH2), 6.48 (1H, d, J 3.8, C(5)H),
J 3.0, C(2)H), 6.22 (1H, d, J 3.0, C(3)H), 6.77–6.80 (2H, m, Ph), 6.58–6.65 (4H, m, Ph), 6.99 (2H, d, J 8.1, Ph), 7.29–7.34 (2H, m,
7.31–7.41 (5H, m, Ph), 7.44–7.46 (2H, m, Ph); δC (100 MHz, Ph); ( )-(anti)-16 1.26 (3H, s, C(3)Me), 1.31 (3H, t, J 7.1, CH3),
CDCl3) ( )-(syn)-15 14.1 (CO2CH2CH3), 24.7 (C(5)Me), 49.4 2.35 (3H, s, PhMe), 4.10 (1H, d, J 6.4, C(4)H), 4.26 (2H, q, J 7.1,
(C(5)), 62.5 (CO2CH2), 76.4 (C(2)), 119.4 (C(3)), 122.7 (C(4) CH2), 6.58 (1H, d, J 6.4, C(5)H), 7.00–7.06 (2H, m, Ph),
Ph(4)), 127.6 (Ph), 128.2 (Ph), 128.9 (Ph), 130.0 (Ph), 131.4 (Ph), 7.14–7.29 (4H, m, Ph), 7.45–7.49 (2H, m, Ph); δC (100 MHz,
136.8 (Cipso), 140.0 (Cipso), 142.8 (C(4)), 167.4 (CO2Et), 171.4 CDCl3) ( )-(syn)-16 14.3 (CO2CH2CH3), 21.0 (PhMe), 24.4 (C(3)
(C(6)); ( )-(anti)-15 14.1 (CO2CH2CH3), 23.7 (C(5)Me), 49.7 Me), 48.9 (C(3)), 50.2 (C(4)), 62.2 (CO2CH2), 118.4 (C(5)), 122.1
(C(5)), 62.7 (CO2CH2), 76.0 (C(2)), 120.5 (C(3)), 122.7 (C(4)Ph (C(4)Ph(4)), 127.5 (Ph), 128.7 (Ph), 131.3 (Ph), 131.7 (Ph), 133.4
(4)), 127.0 (Ph), 128.3 (Ph), 129.3 (Ph), 129.9 (Ph), 131.4 (Ph), (C(3)Ph(1)), 135.6 (C(4)Ph(1)), 137.7 (C(3)Ph(4)), 142.2 (C(6)),
136.8 (Cipso), 139.5 (Cipso), 144.2 (C(4)), 167.8 (CO2Et), 171.3 160.3 (CO2Et), 170.0 (C(2)); ( )-(anti)-16 14.2 (CO2CH2CH3),
(C(6)); m/z (NSI+) HRMS (NSI+) C21H23O4NBr+ ([M + NH4]+) 21.1 (PhMe), 24.2 (C(3)Me), 48.5 (C(4)), 50.3 (C(3)), 62.1
requires 432.0805; found 432.0801 (−0.9 ppm).
(CO2CH2), 117.1 (C(5)), 122.4 (C(4)Ph(4)), 125.7 (Ph), 129.8 (Ph),
Ethyl 4-(4-bromophenyl)-3-methyl-2-oxo-3-phenyl-3,4-dihydro- 130.5 (Ph), 132.3 (Ph), 135.4 (C(3)Ph(1)), 137.9 (C(4)Ph(1)),
2H-pyran-6-carboxylate (3R,4R)-14 and (3R,4S)-14 and ethyl 137.9 (C(3)Ph(4)), 142.2 (C(6)), 160.2 (CO2Et), 170.3 (C(2)); m/z
4-(4-bromophenyl)-5-methyl-6-oxo-5-phenyl-5,6-dihydro-2H-pyran- HRMS (NSI+) C22H25O4NBr+ ([M + NH4]+) requires 446.0961;
2-carboxylate (2S,5S)-15 and (2R,5S)-15
found 446.0966 (+1.0 ppm) and isomeric dihydropyranones
( )-(syn)-17 and ( )-(anti)-17 (10.3 mg, 10%) as a colourless oil;
νmax (ATR) 2920 (C–H), 2851 (C–H), 17 311 (CvO), 1716
(CvO), 1663 (CvO), 1458, 1260 (C–O), 1072, 1018, 797; δH
(400 MHz, CDCl3) ( )-(syn)-17 1.23 (3H, t, J 7.2, CH3), 1.73 (3H,
s, C(5)Me), 2.37 (3H, s, PhMe), 4.10–4.26 (2H, m, CH2), 5.57
(1H, d, J 4.3, C(2)H), 6.24 (1H, app. t, J 3.6, C(3)H), 6.80–6.85
(2H, m, Ph), 7.16–7.23 (2H, m, Ph), 7.32–7.41 (4H, m, Ph);
( )-(anti)-17 1.36 (3H, t, J 7.1, CH3), 1.73 (3H, s, C(5)Me), 2.37
(3H, s, PhMe), 4.29–4.40 (2H, m, CH2), 5.51 (1H, d, J 2.7, C(2)
H), 6.24 (1H, app. t, J 3.6, C(3)H), 6.80–6.85 (2H, m, Ph),
7.16–7.23 (2H, m, Ph), 7.32–7.41 (4H, m, Ph); δC (75 MHz,
CDCl3) ( )-(syn)-17 14.1 (CO2CH2CH3), 21.0 (PhMe), 24.7 (C(5)
Me), 49.0 (C(5)), 62.5 (CO2CH2), 76.4 (C(2)), 119.3 (C(3)), 122.6
(C(4)Ph(4)), 127.4 (Ph), 129.6 (Ph), 130.0 (Ph), 131.4 (Ph), 136.9
(C(5)Ph(4)), 137.0 (Cipso), 138.2 (Cipso), 142.9 (C(4)), 167.5
(CO2Et), 171.4 (C(6)); ( )-(anti)-17 14.2 (CO2CH2CH3), 21.0
(PhMe), 23.8 (C(5)Me), 49.4 (C(5)), 62.7 (CO2CH2), 75.9 (C(2)),
120.4 (C(3)), 122.6 (C(4)Ph(4)), 126.9 (Ph), 129.9 (Ph), 130.0
(Ph), 131.4 (Ph), 136.4 (Cipso), 136.9 (C(5)Ph(4)), 137.9 (Cipso),
142.2 (C(4)), 167.8 (CO2Et), 171.5 (C(6)); m/z HRMS (NSI+)
C22H25O4NBr+ ([M + NH4]+) requires 446.0961; found 446.0962
(+0.1 ppm).
Scheme 4, entry 1. Following general procedure 2, triazolium
salt 1 (20.9 mg, 0.0368 mmol), Cs2CO3 (8.0 mg, 0.0245 mmol)
with methylphenylketene (77.7 mg, 0.588 mmol) and ketoester
10 (69.4 mg, 0.245 mmol) at rt overnight gave the crude
product as a 80 : 20 mixture of cycloaddition products (3R,4R)-
14 and (3R,4S)-14 (54 : 46 dr syn : anti) to the isomeric dihydro-
pyranones (2S,5S)-15 and (2R,5S)-15 (57 : 43 dr syn : anti).
Purification via column chromatography on silica gel (eluent
petrol–CH2Cl2 50 : 50 to 0 : 100) gave cycloaddition products
(3R,4R)-14 and (3R,4S)-14 (40.8 mg, 40%) as a colourless solid;
(3R,4R)-14 Chiral HPLC Chiralcel OJ-H (20% IPA–hexane, flow-
rate 1 mL min−1, 254 nm) tR(3S,4S): 14.9 min, tR(3R,4R):
21.9 min, 41% ee; (3R,4S)-14 Chiral HPLC Chiralcel OJ-H (20%
IPA–hexane, flowrate 1 mL min−1, 254 nm) tR(2R,5S): 32.5 min,
tR(2R,5S): 44.9 min, 39% ee; and isomeric dihydropyranones
(2S,5S)-15 and (2R,5S)-15 (24.4 mg, 24%) as a colourless oil;
(2S,5S)-15 Chiral HPLC Chiralpak AD-H (3% IPA–hexane, flow-
rate 1 mL min−1, 254 nm) tR(2R,5R): 22.5 min, tR(2S,5S):
30.5 min, 52% ee; (2R,5S)-15 Chiral HPLC Chiralpak AD-H (3%
IPA–hexane, flowrate 1 mL min−1, 254 nm) tR(2R,5S): 31.9 min,
tR(2S,5R): 49.1 min, 52% ee.
Ethyl 4-(4-bromophenyl)-3-ethyl-2-oxo-3-(4-methylphenyl)-
3,4-dihydro-2H-pyran-6-carboxylate ( )-(syn)-16 and ( )-(anti)-
16 and ethyl 4-(4-bromophenyl)-5-methyl-6-oxo-5-(4-methyl-
phenyl)-5,6-dihydro-2H-pyran-2-carboxylate ( )-(syn)-17 and
Ethyl 4-(4-bromophenyl)-3-ethyl-2-oxo-3-(4-methylphenyl)-
3,4-dihydro-2H-pyran-6-carboxylate (3R,4R)-16 and (3R,4S)-
16
and
ethyl
4-(4-bromophenyl)-5-methyl-6-oxo-5-(4-
This journal is © The Royal Society of Chemistry 2013
Org. Biomol. Chem., 2013, 11, 3230–3246 | 3237

View Article Online
Paper
Organic & Biomolecular Chemistry
methylphenyl)-5,6-dihydro-2H-pyran-2-carboxylate (2S,5S)-17 (2,6)), 132.4 (C(4)Ph3,5)), 135.4 (C(4)Ph(1)), 137.4 (C(3)Ph(1)),
and (2R,5S)-17
141.7 (C(6)), 160.2 (CO2), 169.8 (C(2)); m/z HRMS (NSI+)
C22H25BrO4N+ ([M + NH4]+) requires 446.0961; found 446.0971
(+2.1 ppm).
Ethyl 4-(4-bromophenyl)-3-ethyl-2-oxo-3-phenyl-3,4-dihydro-
2H-pyran-6-carboxylate (3R,4R)-18 and (3R,4S)-18
Scheme 4, entry 3. Following general procedure 1, triazolium
Scheme 4, entry 2. Following general procedure 2, triazolium
salt 1 (20.9 mg, 0.0368 mmol), Cs2CO3 (8.0 mg, 0.0245 mmol)
with methyl-4-methylphenylketene (86.0 mg, 0.588 mmol) and
ketoester 10 (69.4 mg, 0.245 mmol) at rt overnight gave the
crude product as a 87 : 13 mixture of cycloaddition products
(3R,4R)-16 and (3R,4S)-16 (52 : 48 dr syn : anti) to the isomeric salt 1 (14.0 mg, 0.0245 mmol), Cs2CO3 (7.2 mg, 0.0221 mmol)
dihydropyranones (2S,5S)-17 and (2R,5S)-17 (43 : 57 dr syn : with ethylphenylketene 7 (86.0 mg, 0.588 mmol) and ketoester
anti). Purification via column chromatography on silica gel 10 (69.4 mg, 0.245 mmol) at rt overnight gave the crude
(eluent petrol–CH2Cl2 50 : 50 to 0 : 100) gave lactones (3R,4R)- product (65 : 35 dr syn : anti). Purification via column chrom-
16 and (3R,4S)-16 (77.9 mg, 74%) as a colourless solid; atography on silica gel (eluent petrol–EtOAc 90 : 10) gave lac-
(3R,4R)-16 Chiral HPLC Chiralpak AS-H (10% IPA–hexane, tones (3R,4R)-18 and (3R,4S)-18 (104 mg, 99%) as colourless
flowrate 1 mL min−1, 254 nm) tR(3S,4S): 44.3 min, tR(3R,4R): solids; (3R,4R)-18 [α]D20 +86.1 (c 0.2, CHCl3); Chiral HPLC Chir-
65.0 min, 52% ee; (3R,4S)-16 Chiral HPLC Chiralpak AS-H (5% alpak AS-H (3% IPA–hexane, flowrate 1 mL min−1, 254 nm)
IPA–hexane, flowrate 1 mL min−1, 254 nm) tR(3R,4S): 38.7 min, tR(3S,4S): 22.9 min, tR(3R,4R): 46.1 min, 92% ee; (3R,4S)-18
tR(3S,4R): 56.1 min, 51% ee; and isomeric dihydropyranones [α]2D0 −4.2 (c 0.1, CHCl3); Chiral HPLC Chiralpak AS-H (3%
(2S,5S)-17 and (2R,5S)-17 (19.0 mg, 18%) as a colourless oil; IPA–hexane, flowrate 1 mL min−1, 254 nm) tR(3R,4S): 31.2 min,
(2S,5S)-17 Chiral HPLC Chiralpak AD-H (10% IPA–hexane, tR(3S,4R): 67.5 min, 36% ee.
flowrate 0.25 mL min−1
tR(3S,4S): 62.3 min, 52% ee; (2R,5S)-17 Chiral HPLC Chiralpak 2H-pyran-6-carboxylate ( )-(syn)-19 and ( )-(anti)-19. Following
AD-H (10% IPA–hexane, flowrate 1 mL min−1, 254 nm) general procedure 1, ( )-triazolium salt
(14.0 mg,
tR(2R,5S): 65.9 min, tR(2S,5R): 64.1 min, 37% ee. 0.0245 mmol), Cs2CO3 (7.2 mg, 0.0221 mmol) with butylphe-
,
254 nm) tR(3R,4R): 48.2 min,
Ethyl 4-(4-bromophenyl)-3-butyl-2-oxo-3-phenyl-3,4-dihydro-
1
Ethyl 4-(4-bromophenyl)-3-ethyl-2-oxo-3-phenyl-3,4-dihydro- nylketene (102 mg, 0.588 mmol) and ketoester 10 (69.4 mg,
2H-pyran-6-carboxylate ( )-(syn)-18 and ( )-(anti)-18. Following 0.245 mmol) at rt overnight gave the crude product as a
general procedure 1, ( )-triazolium salt
1
(14.0 mg, >98 : <2 mixture of cycloaddition products ( )-(syn)-19 and
0.0245 mmol), Cs2CO3 (7.2 mg, 0.0221 mmol) with ethylphe- ( )-(anti)-19 (52 : 48 dr syn : anti) to isomeric dihydropranones.
nylketene 7 (86.0 mg, 0.588 mmol) and ketoester 10 (69.4 mg, Purification via column chromatography on silica gel (eluent
0.245 mmol) at rt overnight gave the crude product (63 : 37 dr petrol–EtOAc: 90 : 10) gave a mixture of lactones ( )-(syn)-19
syn : anti). Purification via column chromatography on silica and ( )-(anti)-19 (107 mg, 96%) as a colourless oil; νmax (thin
gel (eluent petrol–CH2Cl2 50 : 50) gave lactones ( )-(syn)-18 and film) 2961 (C–H), 1663 (CvO), 1265 (C–O); δH (500 MHz,
( )-(anti)-18 (67.6 mg, 65%) as colourless solids; ( )-(syn)-18 CDCl3) ( )-(syn)-19 0.85–0.92 (3H, m, n-BuCH3), 1.23–1.40 (4H,
mp 60–62 °C; νmax (ATR) 2976 (C–H), 2938 (C–H), 1736 (CvO), m, n-BuCH2), 1.38 (3H, t, J 7.3, CO2CH2CH3), 2.18–2.30 (2H, m,
1670 (CvO), 1487 (CvO), 1261 (C–O), 1099, 1072, 1009; δH C(3)CH2), 3.76 (1H, d, J 5.0, C(4)H), 4.31–4.41 (2H, m,
(400 MHz, CDCl3) 0.99 (3H, t, J 7.3, C(3)CH2CH3), 1.38 (3H, t, CO2CH2CH3), 6.59 (1H, d, J 5.0, C(5)H), 7.19 (2H, d, J 8.5, Ph),
J 7.1, CO2CH2CH3), 2.23–2.41 (2H, m, C(3)CH2), 3.78 (1H, d, 7.26–7.32 (3H, m, Ph), 7.34–7.37 (2H, m, Ph), 7.46 (2H, d, J 8.5,
J 5.3, C(4)H), 4.29–4.44 (2H, m, C(O)2CH2), 6.50–6.55 (2H, m, Ph); ( )-(anti)-19 0.66 (3H, t, J 7.3, n-BuCH3), 0.85–0.92 (2H, m,
C(4)Ph(2,6)), 6.58 (1H, d, J 5.3, C(5)H), 6.82–6.87 (2H, m, Ph), n-BuCH2), 0.98–1.16 (2H, m, n-BuCH2), 1.23–1.40 (1H, m, C(3)
7.10–7.15 (3H, m, Ph), 7.18–7.22 (2H, m, C(4)Ph(3,5)); δC CHAHB), 1.26 (3H, t, J 7.5, CO2CH2CH3), 1.81–1.85 (1H, m, C(3)
(75 MHz, CDCl3) 9.5 (C(3)CH2CH3), 14.3 (CO2CH2CH3), 29.2 CHAHB), 4.18–4.22 (3H, m, C(4)H and CO2CH2CH3), 6.51 (2H,
(C(3)CH2), 50.2 (C(4)), 54.9 (C(3)), 62.3 (CO2CH2), 117.5 (C(5)), d, J 8.5, Ph), 6.61 (1H, d, J 6.5, C(5)H), 6.89–6.91 (2H, m, Ph),
121.9 (C(4)Ph(4)), 127.4 (C(3)Ph(4)), 128.0 (Ph), 128.1 (Ph), 7.04 (2H, d, J 8.5, Ph), 7.09–7.14 (3H, m, Ph); δC (125 MHz,
130.6 (C(4)Ph(2,6)), 131.5 (C(4)Ph3,5)), 135.8 (C(4)Ph(1)), 135.9 CDCl3) ( )-(syn)-19 13.8 (n-BuCH3), 13.9 (CO2CH2CH3), 22.7 (n-
(C(3)Ph(1)), 141.6 (C(6)), 160.4 (CO2), 167.8 (C(2)); m/z HRMS BuCH2), 25.8 (n-BuCH2), 34.9 (C(3)CH2), 45.8 (C(4)), 53.4 (C(3)),
(NSI+) C22H25BrO4N+ ([M + NH4]+) requires 446.0961; found 61.9 (CO2CH2CH3), 117.3 (C(5)), 122.3 (C(4)Ph(4)), 126.7 (Ph),
446.0962 (+0.1 ppm); ( )-(anti)-18 mp 108–110 °C; νmax (ATR) 127.9 (Ph), 128.8 (Ph), 130.3 (Ph), 132.3 (Ph), 135.3 (Cipso), 137.6
2916 (C–H), 1750 (CvO), 1722 (CvO), 1719 (CvO), 1313 (C– (Cipso), 141.5 (C(6)), 160.0 (CO2Et), 169.7 (C(2)); ( )-(anti)-19
O), 1261 (C–O), 1076, 1053, 1011; δH (400 MHz, CDCl3) 0.56 14.1 (n-BuCH3), 14.2 (CO2CH2CH3), 23.0 (n-BuCH2), 26.8 (n-
(3H, t, J 7.4, C(3)CH2CH3), 1.27 (3H, t, J 7.1, CO2CH2CH3), BuCH2), 36.0 (C(3)CH2), 50.5 (C(4)), 54.3 (C(3)), 62.2
1.45–1.56 (1H, m, C(3)CHAHB), 1.84–1.97 (1H, m, C(3)CHAHB), (CO2CH2CH3), 117.3 (C(5)), 121.7 (C(4)Ph(4)), 127.2 (Ph), 127.9
4.16–4.25 (3H, m, C(4)H and C(O)2CH2), 6.61 (1H, d, J 6.5, C(5) (2 × Ph), 130.5 (Ph), 131.4 (Ph), 135.7 (Cipso), 136.2 (Cipso), 141.4
H), 7.03–7.09 (2H, m, C(4)Ph(2,6)), 7.28–7.40 (5H, m, C(3)Ph (C(6)), 160.2 (CO2Et), 167.9 (C(2)); m/z HRMS (NSI+)
(2,3,4,5,6)), 7.44–7.49 (2H, m, C(4)Ph(3,5)); δC (100 MHz, C24H29O4NBr+ ([M + NH4]+) requires 474.1274; found 474.1273
CDCl3) 8.5 (C(3)CH2CH3), 14.2 (CO2CH2CH3), 28.4 (C(3)CH2), (−0.3 ppm).
46.0 (C(4)), 53.9 (C(3)), 62.1 (CO2CH2), 117.5 (C(5)), 122.5 (C(4)-
Ethyl 4-(4-bromophenyl)-3-butyl-2-oxo-3-phenyl-3,4-dihydro-
Ph(4)), 126.9 (Ph), 128.1 (C(3)Ph(4)), 129.0 (Ph), 130.4 (C(4)Ph- 2H-pyran-6-carboxylate (3R,4R)-19 and (3R,4S)-19
3238 | Org. Biomol. Chem., 2013, 11, 3230–3246
This journal is © The Royal Society of Chemistry 2013

View Article Online
Organic & Biomolecular Chemistry
Paper
Scheme 4, entry 4. Following general procedure 1, triazolium CH2CH3), 14.3 (CO2CH2CH3), 28.8 (C(5)CH2), 52.5 (C(5)), 62.6
salt 1 (14.0 mg, 0.0245 mmol), Cs2CO3 (7.2 mg, 0.0221 mmol) (CO2CH2), 77.1 (C(2)), 110.1 (furylC), 111.3 (furylC), 116.3
with butylphenylketene (102 mg, 0.588 mmol) and ketoester (C(3)), 127.1 (Ph), 128.0 (Ph), 128.9 (Ph), 130.7 (C(5)Ph(1)),
10 (69.4 mg, 0.245 mmol) at rt overnight gave the crude 141.1 (C(4)), 142.3 (furylC(5), 149.3 (furylC(1)), 167.9 (CO2),
product as a >98 : <2 mixture of cycloaddition products 170.7 (C(2)); ( )-(anti)-21 9.9 (C(5)CH2CH3), 14.2 (CO2CH2CH3),
(3R,4R)-19 and (3R,4S)-19 (51 : 49 dr syn : anti) to the isomeric 30.1 (C(5)CH2), 52.8 (C(5)), 62.6 (CO2CH2), 77.1 (C(2)), 110.1
dihydropyranones. Purification via column chromatography on (furylC), 111.3 (furylC), 116.5 (C(3)), 127.6 (Ph), 127.9 (Ph),
silica gel (eluent petrol–EtOAc 90 : 10) gave a mixture of lac- 128.7 (Ph), 130.9 (C(5)Ph(1)), 140.7 (C(4)), 142.3 (furylC(5)),
tones (3R,4R)-19 and (3R,4S)-19 (40.3 mg, 36%) as a colourless 149.3 (furylC(1)), 167.8 (CO2), 170.8 (C(2)); HRMS (APCI)+
+
oil; (3R,4R)-19 Chiral HPLC Chiralpak AD-H (2% IPA–hexane, C20H21O5 ([M + H]+) requires 341.1384; found 341.1385
flowrate 1 mL min−1, 254 nm) tR(3R,4R): 8.22 min, tR(3S,4S): (+0.4 ppm).
8.64 min, 88% ee; (3R,4S)-19 Chiral HPLC Chiralpak AD-H (2%
Ethyl
3-ethyl-4-(furan-2-yl)-2-oxo-3-phenyl-3,4-dihydro-2H-
IPA–hexane, flowrate 1 mL min−1, 254 nm) tR(3S,4R): 20.4 min, pyran-6-carboxylate (3R,4R)-20 ethyl 5-ethyl-4-(furan-2-yl)-
tR(3R,4S): 22.5 min, 38% ee.
6-oxo-5-phenyl-5,6-dihydro-2H-pyran-2-carboxylate (2S,5S)-21
Ethyl
3-ethyl-4-(furan-2-yl)-2-oxo-3-phenyl-3,4-dihydro-2H- and (2R,5S)-21
Scheme 4, entry 5. Following general procedure 2, triazolium
salt 1 (20.9 mg, 0.0368 mmol), Cs2CO3 (8.0 mg, 0.0245 mmol)
with ethylphenylketene 7 (86.0 mg, 0.588 mmol) and (E)-
methyl 4-(furan-2-yl)-2-oxobut-3-enoate (47.6 mg, 0.245 mmol)
at rt overnight gave the crude product as a 51 : 49 mixture of
cycloaddition product (3R,4R)-20 (<5 : >95 dr syn : anti) to the
isomeric dihydropyranones (2S,5S)-21 and (2R,5S)-21 (58 : 42
dr syn : anti). Purification via column chromatography on silica
gel (eluent petrol–CH2Cl2 50 : 50 to 0 : 100) gave lactone
(3R,4R)-20 (24.6 mg, 29%) as a colourless solid (3R,4R)-20
Chiral HPLC Chiralpak AS-H (5% IPA–hexane, flowrate 1 mL
min−1, 254 nm) tR(3R,4R): 22.4 min, tR(3S,4S): 31.0 min, 32%
ee; and isomeric dihydropyranones (2S,5S)-21 and (2R,5S)-21
(33.8 mg, 31%) as a pale yellow oil; (2S,5S)-21 Chiral HPLC
pyran-6-carboxylate ( )-(anti)-20 and ethyl 5-ethyl-4-(furan-2-
yl)-6-oxo-5-phenyl-5,6-dihydro-2H-pyran-2-carboxylate ( )-(syn)-
21 and ( )-(anti)-21. Following general procedure 2, ( )-triazo-
lium salt 1 (20.9 mg, 0.0368 mmol), Cs2CO3 (8.0 mg,
0.0245 mmol) with ethylphenylketene 7 (86.0 mg, 0.588 mmol)
and (E)-methyl 4-(furan-2-yl)-2-oxobut-3-enoate (47.6 mg,
0.245 mmol) at rt overnight gave the crude product as a
54 : 46 mixture of cycloaddition product ( )-(anti)-20 (<5 : >95
dr syn : anti) to the isomeric dihydropyranones ( )-(syn)-21 and
( )-(anti)-21 (52 : 48 dr syn : anti). Purification via column
chromatography on silica gel (eluent petrol–CH2Cl2 50 : 50 to
0 : 100) gave ( )-(anti)-20 (41.4 mg, 50%) as a pale yellow oil;
νmax (ATR) 2976 (C–H), 2938 (C–H), 1734 (CvO), 1667 (CvO),
1447, 1252 (C–O), 1096, 1015; δH (300 MHz, CDCl3) 0.61 (3H, t,
J 7.3, C(3)CH2CH3), 1.27 (3H, t, J 7.1, CO2CH2CH3), 1.46–1.59
(1H, m, C(3)CHAHB), 2.03 (1H, dq, J 13.9, 7.3, C(3)CHAHB), 4.20
(2H, q, J 7.1, C(O)2CH2), 4.40 (1H, d, J 6.8, C(4)H), 6.28 (1H, d,
J 3.0, furylC(3)H), 6.35 (1H, dd, J 3.0, 1.8, furylC(4)H), 6.55
(1H, d, J 6.8, C(5)H), 7.27–7.40 (6H, m, C(3)Ph(2,3,4,5,6) and
furylC(5)H); δC (75 MHz, CDCl3) 8.1 (C(3)CH2CH3), 14.1
(CO2CH2CH3), 29.1 (C(3)CH2), 38.1 (C(4)), 53.4 (C(3)), 62.0
(CO2CH2), 109.0 (furylC(3)), 110.6 (furylC(4)), 114.5 (C(5)),
Chiralpak AS-H (20% IPA–hexane, flowrate 0.25 mL min−1
,
254 nm) tR(3S,4S): 28.1 min, tR(3R,4R): 37.8 min, 41% ee;
(2R,5S)-21 Chiral HPLC Chiralpak AS-H (20% IPA–hexane,
flowrate 0.25 mL min−1
tR(2S,5R): 99.4 min, 91% ee.
, 254 nm) tR(2R,5S): 44.2 min,
Expansion of the substrate scope I γ-aryl α-ketoesters
Methyl 3-ethyl-2-oxo-3,4-diphenyl-3,4-dihydro-2H-pyran-6-
126.8 (Ph), 128.0 (C(3)Ph(4)), 128.9 (Ph), 136.6 (C(3)Ph(1)), carboxylate ( )-(syn)-22 and ( )-(anti)-22. Following general
142.0 (C(6)), 143.2 (furylC(5)), 149.4 (furylC(1)), 160.2 (CO2), procedure 1, ( )-triazolium salt 1 (14.0 mg, 0.0245 mmol),
169.7 (C(2)); m/z HRMS (NSI)+ C20H21O5 ([M + H]+) requires Cs2CO3 (7.2 mg, 0.0221 mmol) with ethylphenylketene 7
+
341.1384; found 341.1390 (+1.9 ppm); and isomeric dihydro- (86.0 mg, 0.588 mmol) and (E)-methyl 2-oxo-4-phenylbut-3-
pyranones ( )-(syn)-21 and ( )-(anti)-21 (31.3 mg, 38%) as a enoate (46.6 mg, 0.245 mmol) at rt overnight gave the crude
pale yellow oil; νmax (ATR) 2926 (C–H), 1751 (CvO), 1730 product (64 : 36 dr syn : anti). Purification via column chrom-
(CvO), 1670 (CvO), 1445, 1267 (C–O), 1096; δH (400 MHz, atography on silica gel (eluent petrol–EtOAc 90 : 10) gave a
CDCl3) ( )-(syn)-21 0.87–0.93 (3H, m, C(5)CH2CH3), 1.35 (3H, t, mixture of lactones ( )-(syn)-22 and ( )-(anti)-22 (65.9 mg,
J 7.1, CO2CH2CH3), 2.22–2.38 (1H, m, C(5)CHAHB), 2.87–3.00 60%) as a colourless solid; mp 130–132 °C; νmax (KBr) 3005
(1H, m, C(5)CHAHB), 4.22–4.42 (2H, m, CO2CH2), 5.65–5.67 (C–H), 2954 (C–H), 1764 (CvO), 1762 (CvO), 1736 (CvO),
(1H, m, furylC(3)H), 5.75 (1H, d, J 3.6, C(2)H), 6.18–6.20 (1H, 1734 (CvO), 1664 (CvO), 1662 (CvO), 1260 (C–O), 1113; δH
m, furylC(4)H), 6.75 (1H, d, J 3.6, C(3)H), 7.26–7.36 (4H, m, (300 MHz, CDCl3) ( )-(syn)-22 1.00 (3H, t, J 7.3, CH3), 2.30–2.37
Ph), 7.47–7.53 (2H, m, Ph and furylC(5)H); ( )-(anti)-21 (2H, m, CH2), 3.81 (1H, d, J 5.5, C(4)H), 3.91 (3H, s, OMe),
0.87–0.93 (3H, m, C(5)CH2CH3), 1.28 (3H, t,
J
7.2, 6.67–6.67 (2H, m, Ph), 6.66 (1H, d, J 5.5, C(5)H), 6.87–6.89 (2H,
CO2CH2CH3), 2.22–2.38 (1H, m, C(5)CHAHB), 2.78–2.87 (1H, m, m, Ph), 7.05–7.16 (6H, m, Ph); ( )-(anti)-22 0.57 (3H, t, J 7.4,
C(5)CHAHB), 4.22–4.42 (2H, m, CO2CH2), 5.65–5.67 (2H, m, CH3), 1.51 (1H, dq, J 14.5, 7.3, C(3)CHAHB), 1.92 (1H, dq,
furylC(3)H and C(2)H), 6.18–6.20 (1H, m, furylC(4)H), 6.72 (1H, J 14.5, 7.3, C(3)CHAHB), 3.76 (3H, s, OMe), 4.22 (1H, d, J 6.6,
d, J 3.8, C(3)H), 7.26–7.36 (4H, m, Ph), 7.47–7.53 (2H, m, Ph C(4)H), 6.67–6.67 (1H, d, J 5.5, C(5)H), 7.19–7.23 (2H, m, Ph),
and furylC(5)H); δC (75 MHz, CDCl3) ( )-(syn)-21 10.1 (C(5) 7.32–7.39 (8H, m, Ph); δC (75 MHz, CDCl3) ( )-(syn)-22 9.5
This journal is © The Royal Society of Chemistry 2013
Org. Biomol. Chem., 2013, 11, 3230–3246 | 3239

View Article Online
Paper
Organic & Biomolecular Chemistry
(C(3)CH2CH3), 29.2 (C(3)CH2CH3), 50.9 (C(4)), 52.9 (CO2Me),
Scheme 5, entry 2. Following general procedure 1, triazolium
51.2 (C(3)), 118.6 (C(5)), 127.2 (Ph), 127.8 (2 × Ph), 128.2 (Ph), salt 1 (14.0 mg, 0.0245 mmol), Cs2CO3 (7.2 mg, 0.0221 mmol)
128.4 (Ph), 129.1 (Ph), 136.1 (Cipso), 136.7 (Cipso), 141.1 (C(6)), with ethylphenylketene 7 (86.0 mg, 0.588 mmol) and (E)-iso-
161.0 (CO2Me), 168.1 (C(2)); ( )-(anti)-22 8.4 (C(3)CH2CH3), propyl 2-oxo-4-phenylbut-3-enoate (53.5 mg, 0.245 mmol) at rt
28.5 (C(3)CH2CH3), 46.3 (C(4)), 52.7 (CO2Me), 54.0 (C(3)), 118.4 overnight gave the crude product (70 : 30 dr syn : anti). Purifi-
(C(5)), 127.0 (Ph), 128.0 (Ph), 128.4 (Ph), 128.7 (Ph), 128.9 (Ph), cation via column chromatography on silica gel (eluent petrol–
129.3 (Ph), 136.3 (Cipso), 137.6 (Cipso), 141.2 (C(6)), 160.7 EtOAc 90 : 10) gave a fully inseparable mixture of lactones
(CO2Me), 170.0 (C(2)); m/z HRMS (NSI+) C21H24O4N+ (3R,4R)-23 and (3R,4S)-23 (73.6 mg, 82%) as a colourless solid;
([M + NH4]+) requires 354.1700; found 354.1706 (+1.7 ppm).
(3R,4R)-23 and (3R,4S)-23 Chiral HPLC Chiralpak AS-H (1%
3-ethyl-2-oxo-3,4-diphenyl-3,4-dihydro-2H-pyran- IPA–hexane, flowrate 1 mL min−1, 254 nm) tR(3R,4R): 17.9 min,
Methyl
6-carboxylate (3R,4R)-22 and (3R,4S)-22
tR(3R,4S): 21.1 min, tR(3S,4R): 35.4 min, tR(3S,4S): 40.0. min,
93% ee syn, 63% ee anti.
Scheme 5, entry 1. Following general procedure 1, triazolium
salt 1 (14.0 mg, 0.0245 mmol), Cs2CO3 (7.2 mg, 0.0221 mmol)
with ethylphenylketene 7 (86.0 mg, 0.588 mmol) and (E)-
methyl 2-oxo-4-phenylbut-3-enoate (46.6 mg, 0.245 mmol) at rt
overnight gave the crude product (60 : 40 dr syn : anti). Purifi-
cation via column chromatography on silica gel (eluent petrol–
N-Benzyl-3-ethyl-2-oxo-3,4-diphenyl-3,4-dihydro-2H-pyran-6-
carboxamide ( )-(syn)-24 and ( )-(anti)-24. Following general
procedure 1, ( )-triazolium salt 1 (14.0 mg, 0.0245 mmol),
Cs2CO3 (7.2 mg, 0.0221 mmol) with ethylphenylketene 7
(86.0 mg, 0.588 mmol) and (E)-N-benzyl-2-oxo-4-phenylbut-3-
enamide (65.0 mg, 0.245 mmol) at rt overnight gave the crude
product (75 : 25 dr syn : anti). Purification via column chrom-
atography on silica gel (eluent petrol–EtOAc 90 : 10) gave a fully
inseparable mixture of lactones ( )-(syn)-24 and ( )-(anti)-24
(19.2 mg, 19%) as a colourless solid; mp 63–65 °C; νmax
(KBr) 3062 (N–H), 3030, 2928 (C–H), 1770 (CvO), 1653
(NCvO); δH (400 MHz, CDCl3) syn ( )-(syn)-24 0.99 (3H, t,
J 7.3, C(3)CH2CH3), 2.31–2.41 (2H, m, C(3)CH2), 3.81 (1H, d,
J 5.4, C(4)H), 4.61 (2H, d, J 5.5, PhCH2NH), 6.63–6.66 (2H,
m, Ph), 6.68 (1H, d, J 5.4, C(5)H), 7.03–7.13 (7H, m, Ph),
7.28–7.41 (6H, m, Ph); ( )-(anti)-24 0.56 (3H, t, J 7.3, C(3)
CH2CH3), 1.50 (1H, dq, J 14.5, 7.3, C(3)CHAHB), 1.91 (1H, dq,
J 14.5, 7.3, C(3)CHAHB), 4.25 (1H, d, J 6.0, C(4)H), 4.40 (1H, dd,
EtOAc 90 : 10) gave
a
mixture of lactones (3R,4R)-22
and (3R,4S)-22 (78.3 mg, 95%); (3R,4R)-22 and (3R,4S)-22
Chiral HPLC Chiralpak AS-H (3% IPA–hexane, flowrate 1 mL
min−1, 254 nm) tR(3R,4R): 20.8 min, tR(3R,4S): 23.6 min,
tR(3S,4R): 34.0 min, tR(3S,4S): 37.8. min, 94% ee (syn), 18%
ee (anti).
Isopropyl 3-ethyl-2-oxo-3,4-diphenyl-3,4-dihydro-2H-pyran-6-
carboxylate ( )-(syn)-23 and ( )-(anti)-23. Following general
procedure 1, ( )-triazolium salt 1 (14.0 mg, 0.0245 mmol),
Cs2CO3 (7.2 mg, 0.0221 mmol) with ethylphenylketene 7
(86.0 mg, 0.588 mmol) and (E)-isopropyl 2-oxo-4-phenylbut-3-
enoate (53.5 mg, 0.245 mmol) at rt overnight gave the crude
product (66 : 34 dr syn : anti). Purification via column chrom-
atography on silica gel (eluent petrol–EtOAc 90 : 10) gave a fully
inseparable mixture of lactones ( )-(syn)-23 and ( )-(anti)-23
(55.1 mg, 62%) as a colourless solid; mp 138–139 °C; νmax
(KBr) 2982 (C–H), 1768 (CvO), 1733 (CvO), 1653 (CvO),
1255, (C–O), 1100; δH (400 MHz, CDCl3) ( )-(syn)-23 0.92 (3H, t,
J 7.3, C(3)CH2CH3), 1.27 (6H, app. t, J 6.3, C(H)(CH3)2),
2.22–2.32 (2H, m, C(3)CH2), 3.72 (1H, d, J 5.3, C(4)H), 5.13 (1H,
sept, J, 6.3, C(H)(CH3)2), 6.54 (1H, d, J 5.3, C(5)H), 6.58–6.62
(2H, m, Ph), 6.79–6.83 (2H, m, Ph), 6.96–7.05 (6H, m, Ph);
( )-(anti)-23 0.48 (3H, t, J 7.3, C(3)CH2CH3), 1.15 (6H, app. t,
J 6.3, C(H)(CH3)2), 1.43 (1H, dq, J 14.4, 7.3, C(3)CHAHB), 1.81
(1H, dq, J 14.4, 7.3, C(3)CHAHB), 4.11 (1H, d, J 6.6, C(4)H), 5.00
(1H, sept, J 6.3, C(H)(CH3)2), 6.53 (1H, d, J 6.6, C(5)H),
7.10–7.13 (2H, m, Ph), 7.21–7.32 (8H, m, Ph); δC (100 MHz,
CDCl3) ( )-(syn)-23 9.4 (CH2CH3), 21.7 (2 × CH3), 29.1 (CH2),
50.8 (C(4)), 55.0 (C(3)), 70.0 (CH), 117.8 (C(5)), 126.7 (Ph), 127.6
(Ph), 127.7 (Ph), 128.1 (Ph), 128.2 (Ph), 128.9 (Ph), 136.1 (Cipso),
J
14.7, 5.8, PhCHAHBNH), 4.51 1H, dd, J 14.7, 5.8,
PhCHAHBNH), 6.68 (1H, d, J 6.0, C(5)H), 7.13–7.19 (3H, m, Ph),
7.21–7.42 (12H, m, Ph); δC (125 MHz, CDCl3) ( )-(syn)-24 9.5
(CH2CH3), 29.2 (CH2CH3), 43.9 (PhCH2), 50.8 (C(4)), 55.5
(C(3)), 114.4 (C(5)), 127.2 (Ph), 127.7 (Ph), 127.8 (Ph), 128.0
(Ph), 128.1 (Ph), 128.3 (Ph), 128.4 (Ph), 129.0 (Ph), 129.0 (Ph),
136.1 (Cipso), 136.8 (Cipso), 137.4 (Cipso), 143.0 (C(6)), 159.3 (C(O)
NH), 168.4 (C(2)); ( )-(anti)-24 8.3 (CH2CH3), 28.2 (CH2CH3),
43.6 (PhCH2), 45.9 (C(4)), 54.2 (C(3)), 114.4 (C(5)), 127.0 (Ph),
127.9 (Ph), 128.0 (Ph), 128.1 (Ph), 128.3 (Ph), 128.8 (Ph), 128.8
(Ph), 128.9 (Ph), 129.2 (Ph), 136.4 (Cipso), 137.3 (Cipso), 137.6
(Cipso), 143.1 (C(6)), 159.2 (C(O)NH), 170.4 (C(2)); m/z HRMS
(NSI+) C27H26O3N+ ([M
412.1908 (+0.2 ppm).
+
H]+) requires 412.1907; found
N-Benzyl-3-ethyl-2-oxo-3,4-diphenyl-3,4-dihydro-2H-pyran-6-
carboxamide (3R,4R)-24 and (3R,4S)-24
Scheme 5, entry 3. Following general procedure 1, triazolium
136.7 (Cipso), 141.4 (C(6)), 159.9 (CO2), 168.1 (C(2)); ( )-(anti)-23 salt 1 (14.0 mg, 0.0245 mmol), Cs2CO3 (7.2 mg, 0.0221 mmol)
8.4 (CH2CH3), 21.9 (2 × CH3), 28.4 (CH2), 46.4 (C(4)), 53.9 (C with ethylphenylketene 7 (86.0 mg, 0.588 mmol) and (E)-N-
(3)), 69.7 (CH), 117.6 (C(5)), 126.9 (Ph), 127.8 (Ph), 128.7 (Ph), benzyl-2-oxo-4-phenylbut-3-enamide (65.0 mg, 0.245 mmol) at
128.8 (Ph), 129.1 (Ph), 129.2 (Ph), 136.4 (Cipso), 137.6 (Cipso), rt overnight gave the crude product (68 : 32 dr syn : anti). Purifi-
141.5 (C(6)), 159.7 (CO2), 170.2 (C(2)); m/z HRMS (NSI+) cation via column chromatography on silica gel (eluent petrol–
C23H28O4N+ ([M + NH4]+) requires 382.2013; found 382.2016 EtOAc 90 : 10) gave a fully inseparable mixture of lactones
(+0.8 ppm).
(3R,4R)-24 and (3R,4S)-24 (90.9 mg, 90%) as a colourless solid;
Isopropyl 3-ethyl-2-oxo-3,4-diphenyl-3,4-dihydro-2H-pyran-6- (3R,4R)-24 and (3R,4S)-24 Chiral HPLC Chiralpak AD-H (10%
carboxylate (3R,4R)-23 and (3R,4S)-23
IPA–hexane, flowrate 1 mL min−1, 254 nm) tR(3R,4R): 11.9 min,
3240 | Org. Biomol. Chem., 2013, 11, 3230–3246
This journal is © The Royal Society of Chemistry 2013

View Article Online
Organic & Biomolecular Chemistry
Paper
tR(3S,4S): 16.8 min, tR(minor): 24.7 min, tR(major): 46.7 min, bromophenyl)-2-oxobut-3-enoate (69.4 mg, 0.245 mmol) at rt
98% ee (syn), 57% ee (anti). overnight gave the crude product (58 : 46 dr syn : anti). Purifi-
Methyl 3-ethyl-4-(4-methoxyphenyl)-2-oxo-3-phenyl-3,4- cation via column chromatography on silica gel (eluent petrol–
dihydro-2H-pyran-6-carboxylate ( )-(syn)-25 and ( )-(anti)- EtOAc 90 : 10) gave lactones ( )-(syn)-26 and ( )-(anti)-26
25. Following general procedure 1, triazolium salt 1 (14.0 mg, (95.7 mg, 91%) as pale yellow solids; ( )-(syn)-26 mp 45–47 °C;
0.0245 mmol), Cs2CO3 (7.2 mg, 0.0221 mmol) with ethylphe- νmax (KBr) 2990 (C–H), 1763 (CvO), 1738 (CvO), 1265 (C–O),
nylketene 7 (86.0 mg, 0.588 mmol) and (E)-methyl 4-(4- 1112; δH (300 MHz, CDCl3) 1.01 (3H, t, J 7.3, C(3)CH2CH3), 1.39
methoxyphenyl)-2-oxobut-3-enoate (54.0 mg, 0.245 mmol) at rt (3H, t, J 7.1, CO2CH2CH3), 2.25–2.40 (2H, m, C(3)CH2), 3.77
overnight gave the crude product (51 : 49 dr syn : anti). Purifi- (1H, d, J 5.2, C(4)H), 4.32–4.43 (2H, m, C(O)2CH2), 6.58 (1H, d,
cation via column chromatography on silica gel (eluent petrol– J 5.2, C(5)H), 6.63 (1H, d, J 7.7, Ph), 6.70 (1H, t, J 1.6, Ph),
CH2Cl2 50 : 50) gave lactones ( )-(syn)-25 and ( )-(anti)-25 6.87–6.91 (2H, m, Ph), 6.96 (1H, t, J 7.7, Ph), 7.11–7.17 (3H, m,
(55.7 mg, 62%) as pale yellow solids; ( )-(syn)-25 mp Ph), 7.25–7.30 (1H, m, Ph); δC (75 MHz, CDCl3) 9.5 (C(3)-
107–109 °C; νmax (ATR) 2953 (C–H), 2924 (C–H), 1767 (CvO), CH2CH3), 14.3 (CO2CH2CH3), 29.1 (C(3)CH2), 50.5 (C(4)), 55.0
1732 (CvO), 1512, 1253 (C–O), 1111; δH (300 MHz, CDCl3) 1.00 (C(3)), 62.3 (CO2CH2), 117.1 (C(5)), 122.3 (C(4)Ph(3)), 127.5 (2 ×
(3H, t, J 7.2, C(3)CH2CH3), 2.19–2.30 (2H, m, C(3)CH2), 3.72 Ph), 128.0 (Ph), 128.1 (Ph), 129.8 (Ph), 130.9 (Ph), 132.2 (Ph),
(3H, s, CO2Me), 3.77 (1H, d, J 5.4, C(4)H), 3.90 (3H, s, PhOMe), 135.7 (C(4)Ph(1)), 139.0 (C(3)Ph(1)), 141.6 (C(6)), 160.3 (CO2),
6.55–6.66 (5H, m, C(5)H and C(4)Ph(3,5), Ph), 6.84–6.91 (2H, 167.7 (C(2)); m/z HRMS (NSI+) C22H25BrO4N+ ([M + NH4]+)
m, Ph), 7.08–7.13 (3H, m, Ph); δC (75 MHz, CDCl3) 9.5 (C(3)- requires 446.0961; found 446.0956 (−1.2 ppm); ( )-(anti)-26
CH2CH3), 29.1 (C(3)CH2), 49.9 (C(4)), 52.8 (CO2Me), 54.2 (C(3)), mp 140–142 °C; νmax (KBr) 2975 (C–H), 2938 (C–H), 1757
55.4 (PhOMe), 113.7 (C(4)Ph(2,6)), 119.0 (C(5)), 127.1 (Ph), (CvO), 1733 (CvO), 1666 (CvO), 1255 (C–O), 1124, 1107; δH
127.8 (Ph), 128.3 (Ph), 128.4 (C(4)Ph(1)), 130.1 (Ph), 136.2 (C(3)- (300 MHz, CDCl3) 0.51 (3H, t, J 7.4, C(3)CH2CH3), 1.20 (3H, t,
Ph(1)), 140.9 (C(6)), 159.1 (C(4)Ph(4)), 161.0 (CO2), 168.2 (C(2)); J 7.1, CO2CH2CH3), 1.40–1.50 (1H, m, CHAHB), 1.84 (1H, dq,
m/z HRMS (NSI+) C22H26O5N+ ([M + NH4]+) requires 384.1805; J 14.8, 7.4, CHAHB), 4.07–4.19 (3H, m, C(4)H and C(O)2CH2),
found 384.1814 (+2.2 ppm); ( )-(anti)-25 mp 135–138 °C; νmax 6.52 (1H, d, J 6.5, C(5)H), 7.01–7.06 (1H, m, Ph), 7.11–7.33 (7H,
(ATR) 2966 (C–H), 2953 (C–H), 1767 (CvO), 1732 (CvO), 1512, m, Ph), 7.36–7.41 (1H, m, Ph); δC (75 MHz, CDCl3) 8.5 (C(3)-
1254 (C–O), 1109; δH (500 MHz, CDCl3) 0.56 (3H, t, J 7.5, C(3)- CH2CH3), 14.2 (CO2CH2CH3), 28.4 (C(3)CH2), 46.4 (C(4)), 53.6
CH2CH3), 1.48–1.54 (1H, m, CHAHB), 1.86–1.93 (1H, m, (C(3)), 62.1 (CO2CH2), 117.1 (C(5)), 123.1 (C(4)Ph(3)), 126.9
CHAHB), 3.75 (3H, s, CO2Me), 3.80 (3H, s, PhOMe), 4.17 (1H, d, (Ph), 127.2 (Ph), 128.1 (Ph), 128.9 (Ph), 130.8 (Ph), 131.6 (Ph),
J 6.5, C(4)H), 6.65 (1H, d, J 6.5, C(5)H), 6.84–6.87 (2H, m, C(4)- 131.9 (Ph), 137.3 (C(4)Ph(1)), 138.7 (C(3)Ph(1)), 141.8 (C(6)),
Ph(3,5)), 7.10–7.11 (3H, m, Ph), 7.30–7.36 (4H, m, Ph); δC 160.1 (CO2), 169.7 (C(2)); m/z HRMS (NSI+) C22H25BrO4N+
(75 MHz, CDCl3) 8.4 (C(3)CH2CH3), 28.5 (C(3)CH2), 45.4 (C(4)), ([M + NH4]+) requires 446.0961; found 446.0971 (+2.1 ppm).
52.6 (CO2Me), 54.2 (C(3)), 55.4 (PhOMe), 114.6 (C(4)Ph(3,5)),
Ethyl 4-(3-bromophenyl)-3-ethyl-2-oxo-3-phenyl-3,4-dihydro-
118.7 (C(5)), 127.0 (Ph), 127.9 (Ph), 128.9 (Ph), 129.8 (Ph), 132.2 2H-pyran-6-carboxylate (3R,4R)-26 and (3R,4S)-26
Scheme 5, entry 5. Following general procedure 1, triazolium
salt 1 (14.0 mg, 0.0245 mmol), Cs2CO3 (7.2 mg, 0.0221 mmol)
with ethylphenylketene 7 (86.0 mg, 0.588 mmol) and (E)-ethyl-
4-(3-bromophenyl)-2-oxobut-3-enoate (69.4 mg, 0.245 mmol)
at rt overnight gave the crude product (68 : 32 dr syn : anti).
(C(4)Ph(1)), 137.7 (C(3)Ph(1)), 140.9 (C(6)), 159.6 (C(4)Ph(4)),
160.8 (CO2), 170.1 (C(2)); m/z HRMS (NSI+) C22H26O5N+
([M + NH4]+) requires 384.1805; found 384.1812 (+1.7 ppm).
Methyl 3-ethyl-4-(4-methoxyphenyl)-2-oxo-3-phenyl-3,4-
dihydro-2H-pyran-6-carboxylate (3R,4R)-25 and (3R,4S)-25
Scheme 5, entry 4. Following general procedure 1, triazolium Purification via column chromatography on silica gel (eluent
salt 1 (14.0 mg, 0.0245 mmol), Cs2CO3 (7.2 mg, 0.0221 mmol) petrol–EtOAc 90 : 10) gave lactones (3R,4R)-26 and (3R,4S)-26
with ethylphenylketene
7
(86.0 mg, 0.588 mmol) and (73.6 mg, 70%) as pale yellow solids; (3R,4R)-26 [α]2D0 +74.0
(E)-methyl 4-(4-methoxyphenyl)-2-oxobut-3-enoate (54.0 mg, (c 0.1, CHCl3); Chiral HPLC Chiralpak AS-H (10% IPA–hexane,
0.245 mmol) at rt overnight gave the crude product (58 : 42 dr flowrate 1 mL min−1, 254 nm) tR(3S,4S): 17.0 min, tR(3R,4R):
syn : anti). Purification via column chromatography on silica 27.1 min, 89% ee; (3R,4S)-26 [α]2D0 −72.7 (c 0.1, CHCl3); Chiral
gel (eluent petrol–EtOAc 90 : 10) gave lactones (3R,4R)-25 and HPLC Chiralpak AS-H (20% IPA–hexane, flowrate 1 mL min−1
(3R,4S)-25 (59.5 mg, 66%) as pale yellow solids; (3R,4R)-25 254 nm) tR(3R,4S): 16.4 min, tR(3S,4R): 20.6 min, 39% ee.
,
[α]2D0 +105.4 (c 0.4, CHCl3); Chiral HPLC Chiralpak AS-H (10%
Ethyl 4-(4-bromophenyl)-3-ethyl-3-(4-fluorophenyl)-2-oxo-3,4-
IPA–hexane, flowrate 1 mL min−1, 254 nm) tR(3S,4S): 18.9 min, dihydro-2H-pyran-6-carboxylate ( )-(syn)-27 and ( )-(anti)-
tR(3R,4R): 47.0 min, 80% ee; (3R,4S)-25 Chiral HPLC Chiralpak 27. Following general procedure 1, ( )-triazolium salt
AS-H (10% IPA–hexane, flowrate 1 mL min−1, 254 nm) (14.0 mg, 0.0245 mmol), Cs2CO3 (7.2 mg, 0.0221 mmol)
tR(3R,4S): 24.6 min, tR(3S,4R): 39.1 min, 4% ee. with ethyl-(4-fluorophenyl)ketene (96.6 mg, 0.588 mmol) and
1
Ethyl 4-(3-bromophenyl)-3-ethyl-2-oxo-3-phenyl-3,4-dihydro- (E)-ethyl 4-(4-fluorophenyl)-2-oxobut-3-enoate (69.4 mg,
2H-pyran-6-carboxylate ( )-(syn)-26 and ( )-(anti)-26. Following 0.245 mmol) at rt overnight gave the crude product (68 : 32 dr
general procedure 1, ( )-triazolium salt
1
(14.0 mg, syn : anti). Purification via column chromatography on silica
0.0245 mmol), Cs2CO3 (7.2 mg, 0.0221 mmol) with ethyl- gel (eluent petrol–CH2Cl2 50 : 50) gave lactones ( )-(syn)-27 and
phenylketene 7 (86.0 mg, 0.588 mmol) and (E)-ethyl 4-(3- ( )-(anti)-27 (65.9 mg, 60%) as colourless solids; ( )-(syn)-27
This journal is © The Royal Society of Chemistry 2013
Org. Biomol. Chem., 2013, 11, 3230–3246 | 3241

View Article Online
Paper
Organic & Biomolecular Chemistry
mp 62–64 °C; νmax (KBr) 2922 (C–H), 2938, 1763 (CvO), 1735 (400 MHz, CDCl3) 0.96 (3H, t, J 7.3, C(3)CH2CH3), 1.39 (3H, t,
(CvO), 1514, 1262 (C–O), 1131; δH (300 MHz, CDCl3) 0.96 (3H, J 7.1, CO2CH2CH3), 2.24–2.37 (2H, m, C(3)CH2), 3.74 (1H, d,
t, J 7.4, C(3)CH2CH3), 1.38 (3H, t, J 7.2, CO2CH2CH3), 2.31 (2H, J 5.5, C(4)H), 4.30–4.45 (2H, m, C(O)2CH2), 6.54–6.59 (2H, m,
q, J 7.4, C(3)CH2), 3.71 (1H, d, J 5.5, C(4)H), 4.28–4.44 (2H, m, Ph), 6.61 (1H, d, J 5.5, C(5)H), 6.79–6.84 (2H, m, Ph), 7.23–7.30
CO2CH2), 6.51–6.55 (2H, m, C(4)Ph(2,6)), 6.60 (1H, d, J 5.5, C(5)H), (4H, m, Ph); δC (75 MHz, CDCl3) 9.3 (C(3)CH2CH3), 14.2
6.79–6.92 (4H, m, C(3)Ph(2,3,5,6)), 7.20–7.24 (2H, m, C(4)- (CO2CH2CH3), 29.2 (C(3)CH2), 50.39 (C(4)), 54.5 (C(3)), 62.2
Ph(3,5)); δC (75 MHz, CDCl3) 9.4 (C(3)CH2CH3), 14.3 (CO2CH2), 117.0 (C(5)), 121.5 (Ph(4)), 122.0 (Ph(4)), 129.9 (Ph),
(CO2CH2CH3), 29.5 (C(3)CH2), 50.8 (C(4)), 54.5 (C(3)), 60.3 130.4 (Ph), 131.0 (Ph), 131.7 (Ph), 134.9 (Cipso), 135.3 (Cipso),
(CO2CH2), 114.9 (d, J 21.3, C(3)Ph(3,5)), 117.1 (C(5)), 122.0 141.4 (C(6)), 160.1 (CO2), 167.2 (C(2)); m/z HRMS (NSI+)
(C(4)Ph(4)), 129.9 (d, J 8.0, C(3)Ph(2,6)), 130.4 (C(4)Ph(2,6)), C22H24Br2O4N+ ([M
+
NH4]+) requires 524.0067; found
131.7 (C(4)Ph(3,5)), 135.0 (C(3)Ph(1) and C(4)Ph(1)), 141.5 524.0066 (−0.1 ppm); ( )-(anti)-28; mp 65–66 °C; νmax (KBr)
(C(6)), 160.1 (CO2), 161.8 (d, J 235.4, C(3)Ph(4)), 169.5 (C(2)); δF 2974 (C–H), 1773 (CvO), 1734 (CvO), 1490, 1255 (C–O), 1105,
(376 MHz, CDCl3) −115.3; m/z HRMS (NSI+) C22H24BrO4N+ 1077; δH (400 MHz, CDCl3) 0.57 (3H, t, J 7.4, C(3)CH2CH3), 1.29
([M + NH4]+) requires 464.0867; found 464.0864 (−0.7 ppm); (3H, t, J 7.1, CO2CH2CH3), 1.41–1.51 (1H, m, C(3)CHAHB),
( )-(anti)-27; mp 62–64 °C; νmax (KBr) 2977 (C–H), 2938, 1769 1.82–1.95 (1H, m, C(3)CHAHB), 4.10 (1H, d, J 6.4, C(4)H), 4.23
(CvO), 1736 (CvO), 1511, 1256 (C–O), 1105; δH (300 MHz, (2H, q, J 7.1, C(O)2CH2), 6.60 (1H, d, J 6.4, C(5)H), 7.00–7.05
CDCl3) 0.57 (3H, t, J 7.4, C(3)CH2CH3), 1.28 (3H, t, J 7.1, (2H, m, Ph), 7.14–7.19 (2H, m, Ph), 7.44–7.52 (4H, m, Ph); δC
CO2CH2CH3), 1.41–1.55 (1H, m, C(3)CHAHB), 1.83–1.94 (1H, m, (75 MHz, CDCl3) 9.4 (C(3)CH2CH3), 14.2 (CO2CH2CH3), 28.1
C(3)CHAHB), 4.12 (1H, d, J 6.4, C(4)H), 4.22 (2H, q, J 7.1, (C(3)CH2), 45.9 (C(4)), 53.6 (C(3)), 62.2 (CO2CH2), 117.0 (C(5)),
C(O)2CH2), 6.61 (1H, d, J 6.4, C(5)H), 7.01–7.09 (4H, m, C(3)Ph- 122.2 (Ph(4)), 122.6 (Ph(4)), 128.7 (Ph), 130.4 (Ph), 132.1 (Ph),
(3,5) and C(4)Ph(2,6)), 7.24–7.29 (2H, m, C(3)Ph(2,6)), 7.45–7.48 132.5 (Ph), 135.0 (Cipso), 136.6 (Cipso), 141.8 (C(6)), 160.0 (CO2),
(2H, m, C(4)Ph(2,6)); δC (75 MHz, CDCl3) 8.2 (C(3)CH2CH3), 169.3 (C(2)); m/z HRMS (NSI+) C22H24Br2O4N+ ([M + NH4]+)
14.1 (CO2CH2CH3), 28.0 (C(3)CH2), 45.9 (C(4)), 53.2 (C(3)), 62.0 requires 524.0067; found 524.0066 (−0.1 ppm).
(CO2CH2), 115.8 (d, J 21.5, C(3)Ph(3,5)), 117.0 (C(5)), 122.5
Ethyl 3,4-bis(4-bromophenyl)-3-ethyl-2-oxo-3,4-dihydro-2H-
(C(4)Ph(4)), 128.6 (d, J 8.1, C(3)Ph(2,6)), 130.3 (C(4)Ph(2,6)), pyran-6-carboxylate (3R,4R)-28 and (3R,4S)-28
Scheme 5, entry 7. Following general procedure 1, triazolium
132.3 (C(4)Ph(3,5)), 133.0 (d, J 3.4, C(3)Ph(1)), 135.0 (C(4)Ph(1)),
141.6 (C(6)), 159.9 (CO2), 162.2 (d, J 248.0, C(3)Ph(4)), 169.5
(C(2)); δF (282 MHz, CDCl3) −114.4; m/z HRMS (NSI+)
C22H24BrO4N+ ([M + NH4]+) requires 464.0867; found 464.0864
(−0.7 ppm).
salt 1 (14.0 mg, 0.0245 mmol), Cs2CO3 (7.2 mg, 0.0221 mmol)
with ethyl-(4-bromophenyl)ketene (132 mg, 0.588 mmol) and
ketoester 10 (69.4 mg, 0.245 mmol) at rt overnight gave the
crude product (61 : 39 dr syn : anti). Purification via column
chromatography on silica gel (eluent petrol–CH2Cl2 50 : 50)
gave lactones (3R,4R)-28 and (3R,4S)-28 (106 mg, 88%) as col-
Ethyl 4-(4-bromophenyl)-3-ethyl-3-(4-fluorophenyl)-2-oxo-3,4-
dihydro-2H-pyran-6-carboxylate (3R,4R)-27 and (3R,4S)-27
Scheme 5, entry 6. Following general procedure 1, triazolium ourless solids; (3R,4R)-28 [α]2D0 +99.3 (c 0.2, CHCl3); Chiral
salt 1 (14.0 mg, 0.0245 mmol), Cs2CO3 (7.2 mg, 0.0221 mmol) HPLC Chiralpak AS-H (20% IPA–hexane, flowrate 1 mL min−1
,
with ethyl-(4-fluorophenyl)ketene (96.6 mg, 0.588 mmol) and 254 nm) tR(3S,4S): 10.3 min, tR(3R,4R): 17.9 min, 93% ee;
ketoester 10 (69.4 mg, 0.245 mmol) at rt overnight gave the (3R,4S)-28 [α]2D0 −38.1 (c 0.1, CHCl3); Chiral HPLC Chiralpak
crude product (68 : 32 dr syn : anti). Purification via column AS-H (20% IPA–hexane, flowrate 1 mL min−1, 254 nm)
chromatography on silica gel (eluent petrol–CH2Cl2 50 : 50) tR(3R,4S): 11.2 min, tR(3S,4R): 22.9 min, 26% ee.
gave lactones (3R,4R)-27 and (3R,4S)-27 (72.5 mg, 66%) as col-
ourless solids; (3R,4R)-27 [α]2D0 +332.5 (c 0.3, CHCl3); Chiral
HPLC Chiralpak AS-H (20% IPA–hexane, flowrate 1 mL min−1
Expansion of the substrate scope II γ-alkyl α-ketoesters
,
Methyl 3-ethyl-4-methyl-2-oxo-3-phenyl-3,4-dihydro-2H-pyran-
6-carboxylate ( )-(anti)-29 and ( )-(syn)-29. Following general
procedure 1, ( )-triazolium salt 1 (14.0 mg, 0.0245 mmol),
Cs2CO3 (7.2 mg, 0.0221 mmol) with ethylphenylketene 7
(86.0 mg, 0.588 mmol) and (E)-methyl 2-oxopent-3-enoate
(31.4 mg, 0.245 mmol) at rt overnight gave the crude product
(79 : 21 dr syn : anti). Purification by via column chromato-
graphy on silica gel (eluent petrol–CH2Cl2 50 : 50) gave a fully
inseparable mixture of lactones ( )-(anti)-29 and ( )-(syn)-29
(52.4 mg, 78%) as a colourless solid; mp 118–119 °C; νmax
(ATR) 2972 (C–H), 2953 (C–H), 1759 (CvO), 1736 (CvO), 1442,
1256 (C–O), 1109, 1091; δH (400 MHz, CDCl3) ( )-(anti)-29 (3H,
t, J 7.5, CH2CH3), 1.08 (3H, d, J 7.0, C(4)Me), 1.88 (1H, dq,
J 14.5, 7.5, CHAHB), 2.02–2.11 (1H, m, CHAHB), 3.12 (1H, app
quintet, J 7.0, C(4)H), 3.65 (3H, s, OMe), 6.52 (1H, d, J 7.0, C(5)
H), 7.14–7.28 (5H, m, Ph); ( )-(syn)-29 0.82–0.85 (6H, m,
254 nm) tR(3S,4S): 9.5 min, tR(3R,4R): 16.4 min, 89% ee;
(3R,4S)-27 [α]2D0 −78.2 (c 0.1, CHCl3); Chiral HPLC Chiralpak
AS-H (20% IPA–hexane, flowrate 1 mL min−1, 254 nm)
tR(3R,4S): 9.7 min, tR(3S,4R): 24.9 min, 31% ee.
Ethyl 3,4-bis(4-bromophenyl)-3-ethyl-2-oxo-3,4-dihydro-2H-
pyran-6-carboxylate ( )-(syn)-28 and ( )-(anti)-28. Following
general procedure 1, ( )-triazolium salt
1
(14.0 mg,
0.0245 mmol), Cs2CO3 (7.2 mg, 0.0221 mmol) with ethyl-(4-
bromophenyl)ketene (132 mg, 0.588 mmol) and ketoester 10
(69.4 mg, 0.245 mmol) at rt overnight gave the crude product
(65 : 35 dr syn : anti). Purification by via column chromato-
graphy on silica gel (eluent petrol–CH2Cl2 50 : 50) gave lactones
( )-(syn)-28 and ( )-(anti)-28 (80.8 mg, 67%) as colourless
solids; ( )-(syn)-28; mp 116–117 °C; νmax (KBr) 2965 (C–H),
1737 (CvO), 1488, 1399, 1266 (C–O), 1112, 1010, 741; δH
3242 | Org. Biomol. Chem., 2013, 11, 3230–3246
This journal is © The Royal Society of Chemistry 2013

View Article Online
Organic & Biomolecular Chemistry
Paper
CH2CH3 and C(4)Me), 2.06–2.14 (1H, m, CHAHB), 2.19 (1H, dq, C20H30O4N+ ([M + NH4]+) requires 348.2169; found 348.2174
J 14.6, 7.3, CHAHB), 2.76 (1H, qd, J 7.3, 5.0, C(4)H), 3.79 (3H, s, (+1.3 ppm).
OMe), 6.41 (1H, d, J 5.0, C(5)H), 7.14–7.28 (5H, m, Ph); δC
Methyl 3-ethyl-2-oxo-4-pentyl-3-phenyl-3,4-dihydro-2H-pyran-
(100 MHz, CDCl3) ( )-(anti)-29 7.7 (C(3)CH2CH3), 14.4 (C(4) 6-carboxylate (3R,4R)-30 and (3R,4S)-30
Scheme 6, entry 2. Following general procedure 1, triazolium
Me), 27.8 (C(3)CH2), 32.0 (C(4)), 52.5 (CO2Me), 53.5 (C(3)),
120.7 (C(5)), 127.0 (Ph), 127.8 (Ph), 128.7 (Ph), 137.6 (C(3)-
Ph(1)), 140.6 (C(6)), 160.7 (CO2), 170.5 (C(2)); ( )-(syn)-29 9.3
(C(3)CH2CH3), 16.1 (C(4)Me), 28.9 (C(3)CH2), 36.9 (C(4)), 52.7
(CO2Me), 53.6 (C(3)), 121.2 (C(5)), 127.5 (Ph), 128.0 (Ph), 128.4
(Ph), 136.8 (C(3)Ph(1)), 140.0 (C(6)), 160.9 (CO2), 168.6 (C(2));
m/z HRMS (NSI+) C16H22O4N+ ([M + NH4]+) requires 292.1543;
found 292.1545 (+0.6 ppm).
salt 1 (14.0 mg, 0.0245 mmol), Cs2CO3 (7.2 mg, 0.0221 mmol)
with ethylphenylketene 7 (86.0 mg, 0.588 mmol) and (E)-
methyl 2-oxonon-3-enoate (45.1 mg, 0.245 mmol) at rt over-
night gave the crude product (78 : 22 dr syn : anti). Purification
via column chromatography on silica gel (eluent petrol–CH2Cl2
50 : 50) gave a fully inseparable mixture of lactones (3R,4R)-30
and (3R,4S)-30 (63.4 mg, 78%) as a pale yellow oil; (3R,4R)-30
and (3R,4S)-30 Chiral HPLC Chiralpak AD-H (2% IPA–hexane,
flowrate 1 mL min−1, 254 nm) tR(3S,4S): 8.4 min, tR(3R,4S):
Methyl 3-ethyl-4-methyl-2-oxo-3-phenyl-3,4-dihydro-2H-pyran-
6-carboxylate (3R,4R)-29 and (3R,4S)-29
Scheme 6, entry 1. Following general procedure 1, triazolium 10.0 min, tR(3S,4R): 11.3 min, tR(3R,4R): 12.6 min, 75% ee anti,
salt 1 (14.0 mg, 0.0245 mmol), Cs2CO3 (7.2 mg, 0.0221 mmol) 97% ee syn.
with ethylphenylketene 7 (86.0 mg, 0.588 mmol) and (E)-
Methyl 3-(4-bromophenyl)-3-ethyl-4-methyl-2-oxo-3,4-dihydro-
methyl 2-oxopent-3-enoate (31.4 mg, 0.245 mmol) at rt over- 2H-pyran-6-carboxylate ( )-(anti)-31 and ( )-(syn)-31. Following
night gave the crude product (58 : 42 dr syn : anti). Purification general procedure 1, triazolium salt 1 (14.0 mg, 0.0245 mmol),
via column chromatography on silica gel (eluent petrol–CH2Cl2 Cs2CO3 (7.2 mg, 0.0221 mmol) with ethyl-(4-bromophenyl)
50 : 50) gave a fully inseparable mixture of lactones (3R,4R)-29 ketene (132 mg, 0.588 mmol) and (E)-methyl 2-oxopent-3-
and (3R,4S)-29 (44.4 mg, 66%) as a colourless; (3R,4R)-29 and enoate (31.4 mg, 0.245 mmol) at rt overnight gave the crude
(3R,4S)-29 Chiral HPLC Chiralpak AS-H (5% IPA–hexane, flow- product (67 : 33 dr anti : syn). Purification via column chrom-
rate 1 mL min−1, 254 nm) tR(3S,4R): 13.1 min, tR(3S,4S): atography on silica gel (eluent petrol–EtOAc 90 : 10) gave a fully
15.8 min, tR(3R,4R): 21.5 min, tR(3R,4S): 24.9 min, 70% ee anti, inseparable mixture of lactones ( )-(anti)-31 and ( )-(syn)-31
94% ee syn.
(64.1 mg, 75%) as a pale yellow oil; νmax (film) 2972 (C–H),
Methyl 3-ethyl-2-oxo-4-pentyl-3-phenyl-3,4-dihydro-2H-pyran- 1766 (CvO), 1738 (CvO), 1667 (CvO), 1259 (C–O), 1119 (C–
6-carboxylate ( )-(anti)-30 and ( )-(syn)-30. Following general O); δH (300 MHz, CDCl3) ( )-(anti)-31 0.65 (3H, t, J 7.4,
procedure 1, ( )-triazolium salt 1 (14.0 mg, 0.0245 mmol), CH2CH3), 1.15 (3H, d, J 7.0, C(4)Me), 1.95 (1H, dq, J 14.6, 7.4,
Cs2CO3 (7.2 mg, 0.0221 mmol) with ethylphenylketene 7 C(3)CHAHB), 2.05–2.14 (1H, m, CHAHB), 3.14 (1H, app. quintet,
(86.0 mg, 0.588 mmol) and (E)-methyl 2-oxonon-3-enoate J 7.0, C(4)H), 3.74 (3H, s, OMe), 6.58 (1H, d, J 7.0, C(5)H),
(45.1 mg, 0.245 mmol) at rt overnight gave the crude product 7.08–7.13 (2H, m, C(3)Ph(2,6)), 7.43–7.51 (2H, m, C(3)Ph(3,5));
(82 : 18 dr syn : anti). Purification via column chromatography ( )-(syn)-31 0.85–0.90 (6H, m, C(3)CH2CH3 and C(4)Me),
on silica gel (eluent petrol–CH2Cl2 50 : 50) gave a fully in- 2.14–2.22 (2H, m, CH2), 2.78 (1H, qd, J 7.2, 5.3, C(4)H), 3.86
separable mixture of lactones ( )-(anti)-30 and ( )-(syn)-30 (3H, s, OMe), 6.51 (1H, d, J 5.3, C(5)H), 7.26–7.32 (2H, m, C(3)
(68.4 mg, 84%) as a pale yellow oil; νmax (ATR) 2949 (C–H), Ph(2,6)), 7.43–7.51 (2H, m, C(3)Ph(3,5)); δC (75 MHz, CDCl3)
2918 (C–H), 2868 (C–H), 2839 (C–H), 1664 (CvO), 1456, 1450, ( )-(anti)-31 7.6 (C(3)CH2CH3), 14.3 (C(4)Me), 27.5 (C(3)
1375, 1166 (C–O); δH (400 MHz, CDCl3) ( )-(anti)-30 0.56 (3H, CH2CH3), 32.0 (C(4)), 52.6 (CO2Me), 53.2 (C(3)), 120.3 (C(5)),
t, J 7.5, C(3)CH2CH3), 0.81–0.84 (3H, m, CH3), 1.02–1.33 (6H, 121.9 (C(3)Ph(4)), 128.8 (C(3)Ph(2,6)), 131.9 (C(3)Ph(3,5)), 136.8
m, CH2), 1.34–1.44 (1H, m, CH2), 1.53–1.62 (1H, m, CH2), 1.89 (C(3)Ph(1)), 140.6 (C(6)), 160.4 (CO2), 170.0 (C(2)); ( )-(syn)-31
(1H, dq, J 14.6, 7.3, C(3)CHAHB), 2.04 (1H, dq, J 14.6, 7.3, C(3) 9.14, (C(3)CH2CH3), 16.2 (C(4)Me), 29.0 (C(3)CH2CH3), 37.3
CHAHB), 2.97–3.03 (1H, m, C(4)H), 3.64 (3H, s, OMe), 6.54 (1H, (C(4)), 52.7 (CO2Me), 53.4 (C(3)), 120.6 (C(5)), 121.5 (C(3)Ph(4)),
d, J 6.7, C(5)H), 7.12–7.26 (5H, m, Ph); ( )-(syn)-30 0.75 (3H, t, 129.8 (C(3)Ph(2,6)), 131.5 (C(3)Ph(3,5)), 136.0 (C(3)Ph(1)), 140.0
J 7.0, C(3)CH2CH3), 0.81–0.84 (3H, m, CH3), 1.02–1.33 (6H, m, (C(6)), 160.7 (CO2), 168.0 (C(2)); m/z HRMS (NSI+)
CH2), 1.34–1.44 (1H, m, CH2), 1.53–1.62 (1H, m, CH2), C16H21O4BrN+ ([M + NH4]+) requires 370.0648; found 370.0655
2.08–2.25 (2H, m, C(3)CH2), 2.58–2.63 (1H, m, C(4)H), 3.79 (+1.8 ppm).
(3H, s, OMe), 6.49 (1H, d, J 5.0, C(5)H), 7.16–7.32 (5H, m, Ph);
Methyl 3-(4-bromophenyl)-3-ethyl-4-methyl-2-oxo-3,4-dihydro-
δC (100 MHz, CDCl3) ( )-(anti)-30 7.8 (C(3)CH2CH3), 14.1 2H-pyran-6-carboxylate (3R,4R)-31 and (3R,4S)-31
Scheme 6, entry 3. Following general procedure 1, triazolium
salt 1 (14.0 mg, 0.0245 mmol), Cs2CO3 (7.2 mg, 0.0221 mmol)
with ethyl-(4-bromophenyl)ketene (132 mg, 0.588 mmol) and
(E)-methyl 2-oxopent-3-enoate (31.4 mg, 0.245 mmol) at rt over-
night gave the crude product (67 : 33 dr anti : syn). Purification
via column chromatography on silica gel (eluent petrol–EtOAc
90 : 10) gave a fully inseparable mixture of lactones (3R,4R)-31
and (3R,4S)-31 (82.2 mg, 95%) as a colourless oil; (3R,4R)-31
(C(4)(CH2)4CH3), 22.6 (CH2), 27.0 (CH2), 27.8 (CH2), 29.7 (CH2),
32.0 (CH2), 37.0 (C(4)), 52.5 (CO2Me), 53.0 (C(3)), 120.1 (C(5)),
127.0 (Ph), 127.7 (Ph), 128.7 (Ph), 137.9 (C(3)Ph(1)), 140.5 (C
(6)), 160.6 (CO2), 170.9 (C(2)); ( )-(syn)-30 9.2 (C(3)CH2CH3),
14.1 (C(4)(CH2)4CH3), 22.5 (CH2), 26.8 (CH2), 29.4 (CH2), 30.5
(CH2), 31.7 (CH2), 42.1 (C(4)), 52.7 (CO2Me), 53.2 (C(3)), 119.9
(C(5)), 127.4 (Ph), 127.8 (Ph), 128.4 (Ph), 137.2 (C(3)Ph(1)),
140.3 (C(6)), 160.9 (CO2), 168.7 (C(2)); m/z HRMS (NSI+)
This journal is © The Royal Society of Chemistry 2013
Org. Biomol. Chem., 2013, 11, 3230–3246 | 3243

View Article Online
Paper
Organic & Biomolecular Chemistry
and (3R,4S)-31 Chiral HPLC Chiralpak OJ-H (20% IPA–hexane,
Notes and references
flowrate 0.25 mL min−1
, 254 nm) tR(3R,4R): 56.0 min,
tR(3S,4R): 61.4 min, tR(3S,4S): 65.8 min, tR(3R,4S): 73.8 min,
71% ee anti, 94% ee syn.
Methyl 3-(4-methoxyphenyl)-3,4-dimethyl-2-oxo-3,4-dihydro-
2H-pyran-6-carboxylate ( )-(anti)-32 and ( )-(syn)-32. Following
1 For reviews see: (a) H. B. Kagan and O. Riant, Chem. Rev.,
1992, 92, 1007; (b) U. Pindur, G. Lutz and C. Otto, Chem.
Rev., 1993, 93, 741; (c) D. A. Evans and J. S. Johnson, in
Comprehensive Organic Catalysis, ed. E. N. Jacobsen,
A. Pfaltz and H. Yamamoto, Springer, Berlin, 1999, p. 1177;
(d) K. Narasaka, Synthesis, 1991, 1; (e) K. A. Jørgensen,
Angew. Chem., Int. Ed., 2000, 39, 3558; (f) E. J. Corey, Angew.
Chem., Int. Ed., 2002, 41, 1650; (g) Y. Hayashi, in Cyclo-
addition Reactions in Organic Synthesis, ed. S. Kobayashi
and K. A. Jørgensen, Wiley-VCH, Weinheim, 2002, p. 5;
(h) S. Kobayashi, in Cycloaddition Reactions in Organic Syn-
thesis, ed. S. Kobayashi and K. A. Jørgensen, Wiley-VCH,
Weinheim, 2002, p. 187.
general procedure 1, ( )-triazolium salt
1
(14.0 mg,
0.0245 mmol), Cs2CO3 (7.2 mg, 0.0221 mmol) with ethyl(4-
methoxyphenyl)ketene (104 mg, 0.588 mmol) and (E)-methyl
2-oxopent-3-enoate (31.4 mg, 0.245 mmol) at rt overnight gave
the crude product (80 : 20 dr anti : syn). Purification via column
chromatography on silica gel (eluent petrol–EtOAc 85 : 15) gave
a fully inseparable mixture of lactones ( )-(anti)-32 and
( )-(syn)-32 (61.0 mg, 86%) as a colourless oil; νmax (film) 2971
(C–H), 1759 (CvO), 1732 (CvO), 1664 (CvO), 1610 (CvO),
1255 (C–O), 1119 (C–O); δH (300 MHz, CDCl3) ( )-(anti)-32 0.64
(3H, d, J 7.4, C(3)CH2CH3), 1.14 (3H, d, J 6.9, C(4)Me), 1.93
(1H, dq, J 14.6, 7.4, CHAHB), 2.12 (1H, dq, J 14.6, 7.4, CHAHB),
3.14 (1H, app. quintet, J 6.9, C(4)H), 3.77 (3H, s, CO2Me), 3.79
(3H, s, OMe), 6.60 (1H, d, J 6.9, C(5)H), 6.82–6.86 (2H, m, C(3)
Ph(3,5)), 7.12–7.16 (2H, m, C(3)Ph(2,6)); ( )-(syn)-32 0.86–0.95
(6H, m, C(3)CH2CH3 + C(4)Me), 2.18–2.28 (2H, m, CH2), 2.82
(1H, qd, J 7.2, 5.0, C(4)H), 3.80 (3H, s, OMe), 3.89 (3H, s,
CO2Me), 6.48 (1H, d, J 5.0, C(5)H), 6.85–6.89 (2H, m, C(3)Ph-
(3,5)), 7.26–7.30 (2H, m, C(3)Ph(2,6)); δC (75 MHz, CDCl3)
( )-(anti)-32 7.6 (C(3)CH2CH3), 14.4 (C(4)Me), 27.8 (C(3)-
CH2CH3), 31.9 (C(4)), 52.5 (CO2Me), 52.7 (C(3)), 55.3 (OMe),
114.0 (C(3)Ph(3,5)), 120.6 (C(5)), 128.2 (C(3)Ph(2,6)), 129.4 (C(3)-
Ph(1)), 140.4 (C(6)), 158.9 (C(3)Ph(4)), 160.7 (CO2), 170.7 (C(2));
( )-(syn)-32 9.3 (C(3)CH2CH3), 16.0 (C(4)Me), 28.9 (C(3)-
CH2CH3), 36.8 (C(4)), 52.6 (CO2Me), 53.0 (C(3)), 55.3 (OMe),
113.7 (C(3)Ph(3,5)), 121.3 (C(5)), 128.7 (C(3)Ph(1)), 129.1 (C(3)-
Ph(2,6)), 139.9 (C(6)), 158.6 (C(3)Ph(4)), 160.9 (CO2), 168.9
(C(2)); m/z HRMS (NSI+) C17H24O5N+ ([M + NH4]+) requires
322.1649; found 322.1651 (+0.6 ppm).
2 For an excellent overview of organocatalytic [4 + 2] cyclo-
addition approaches see: P. Merino, E. Marqués-López,
T. Tejero and R. P. Herrera, Synthesis, 2010, 1.
3 For
selected
representative
examples
see:
(a) F. A. Hernández-Juan, D. M. Cockfield and D. J. Dixon,
Tetrahedron Lett., 2007, 48, 1605; (b) H. Xie, L. Zu,
H. R. Oueis, H. Li, J. Wang and W. Wang, Org. Lett., 2008,
10, 1923; (c) S. Samanta, J. Krause, T. Mandal and
C.-G. Zhao, Org. Lett., 2007, 9, 2745; (d) Y. Zhao, X.-J. Wang
and J.-T. Liu, Synlett, 2008, 1017; (e) B. Han, J.-L. Li, C. Ma,
S.-J. Zhang and Y.-C. Chen, Angew. Chem., Int. Ed., 2008, 47,
9971; (f) B. Han, Z.-Q. He, J.-L. Li, R. Li, K. Jiang, T.-Y. Liu
and Y.-C. Chen, Angew. Chem., Int. Ed., 2009, 48, 5474;
(g) S. Kobayashi, T. Kinoshita, H. Uehara, T. Sudo and
I. Ryu, Org. Lett., 2009, 11, 3934.
4 (a) M. He, G. J. Uc and J. W. Bode, J. Am. Chem. Soc., 2006,
128, 15088; (b) M. He, B. J. Beahm and J. W. Bode, Org.
Lett., 2008, 10, 3817; (c) J. Kaeobamrung, M. C. Kozlowski
and J. W. Bode, Proc. Natl. Acad. Sci. U. S. A., 2010, 107,
20661. For the [4 + 2] process of azolium enolates with
azadienes see: (d) M. He, J. R. Struble and J. W. Bode,
J. Am. Chem. Soc., 2006, 128, 8418.
Methyl 3-(4-methoxyphenyl)-3,4-dimethyl-2-oxo-3,4-dihydro-
2H-pyran-6-carboxylate (3R,4R)-32 and (3R,4S)-32
Scheme 6, entry 4. Following general procedure 1, triazolium
salt 1 (14.0 mg, 0.0245 mmol), Cs2CO3 (7.2 mg, 0.0221 mmol)
with ethyl(4-methoxyphenyl)ketene (104 mg, 0.588 mmol) and
(E)-methyl 2-oxopent-3-enoate (31.4 mg, 0.245 mmol) at rt over-
night gave the crude product (60 : 40 dr anti : syn). Purification
via column chromatography on silica gel (eluent petrol–EtOAc
85 : 15) gave a fully inseparable mixture of lactones (3R,4R)-32
and (3R,4S)-32 (62.1 mg, 88%) as a colourless oil; (3R,4R)-32
and (3R,4S)-32 Chiral HPLC Chiralpak AS-H (10% IPA–hexane,
flowrate 1 mL min−1, 254 nm) tR(3S,4R): 15.7 min, tR(3S,4S):
21.1 min, tR(3R,4R): 28.8 min, tR(3R,4S): 34.7 min, 74% ee anti,
95% ee syn.
5 K. Juhl and K. A. Jørgensen, Angew. Chem., Int. Ed., 2003,
42, 1498.
6 (a) D. Belmessieri, L. C. Morrill, C. Simal, A. M. Z. Slawin
and A. D. Smith, J. Am. Chem. Soc., 2011, 133, 2714. For
alternative reaction processes using this approach see:
(b) C. Simal, T. Lebl, A. M. Z. Slawin and A. D. Smith,
Angew. Chem., Int. Ed., 2012, 51, 3653; (c) L. C. Morrill,
T. Lebl, A. M. Z. Slawin and A. D. Smith, Chem. Sci., 2012,
3, 2088.
7 For an excellent recent review of Lewis-base mediated reac-
tion processes see: S. E. Denmark and G. L. Beutner,
Angew. Chem., Int. Ed., 2008, 47, 1560. For a representative
set of manuscripts from our research group see:
(a) J. E. Thomson, K. Rix and A. D. Smith, Org. Lett., 2006,
8, 3785; (b) J. E. Thomson, C. D. Campbell, C. Concellón,
N. Duguet, K. Rix, A. M. Z. Slawin and A. D. Smith, J. Org.
Chem., 2008, 73, 2784; (c) C. D. Campbell, N. Duguet,
K. A. Gallagher, J. E. Thomson, A. G. Lindsay,
A. O’Donoghue and A. D. Smith, Chem. Commun., 2008,
Acknowledgements
The authors would like to thank the Royal Society for a Univer-
sity Research Fellowship (ADS), and the EPSRC and Pfizer
(CASE funding for SML) for funding. We also thank the EPSRC
National Mass Spectrometry Service Centre (Swansea).
3244 | Org. Biomol. Chem., 2013, 11, 3230–3246
This journal is © The Royal Society of Chemistry 2013

View Article Online
Organic & Biomolecular Chemistry
Paper
3528; (d) C. Joannesse, C. Simal, C. Concellón,
J. E. Thomson, C. D. Campbell, A. M. Z. Slawin and
A. D. Smith, Org. Biomol. Chem., 2008, 6, 2900;
(e) J. E. Thomson, A. F. Kyle, C. Concellón, K. A. Gallagher,
P. Lenden, L. C. Morrill, A. J. Miller, C. Joannesse,
A. M. Z. Slawin and A. D. Smith, Synthesis, 2008, 2805;
(f) C. Joannesse, C. P. Johnston, C. Concellón, C. Simal,
D. Philp and A. D. Smith, Angew. Chem., Int. Ed., 2009, 48,
8914; (g) P. A. Woods, L. C. Morrill, R. A. Bragg,
L. C. Morrill and A. D. Smith, Org. Lett., 2010, 12, 2660;
(h) K. B. Ling and A. D. Smith, Chem. Commun., 2011, 47,
373; (i) D. Belmessieri, C. Joannesse, P. A. Woods,
C. MacGregor, C. Jones, C. D. Campbell, C. P. Johnston,
N. Duguet, C. Concellón, R. A. Bragg and A. D. Smith, Org.
Biomol. Chem., 2011, 9, 559; ( j) C. D. Campbell,
C. J. Collett, J. E. Thomson, A. M. Z. Slawin and
A. D. Smith, Org. Biomol. Chem., 2011, 9, 4205;
(k) C. D. Campbell, C. Concellón and A. D. Smith, Tetra-
hedron: Asymmetry, 2011, 22, 797; (l) C. Joannesse,
L. C. Morrill, C. D. Campbell, A. M. Z. Slawin and
A. D. Smith, Synthesis, 2011, 1865; (m) P. A. Woods,
T. B. Brown, A. M. Z. Slawin and A. D. Smith, Tetrahedron:
Asymmetry, 2010, 21, 601; (t) C. Concellón, N. Duguet and
A. D. Smith, Adv. Synth. Catal., 2009, 351, 3001;
(u) J. Douglas, K. B. Ling, C. Concellón, G. Churchill,
A. M. Z. Slawin and A. D. Smith, Eur. J. Org. Chem., 2010,
5863; (v) J. Douglas, J. E. Taylor, G. Churchill,
A. M. Z. Slawin and A. D. Smith, J. Org. Chem., 2013, DOI:
10.1021/jo4003079.
9 For select reviews of the ability of NHCs to catalyse organo-
catalytic processes see: (a) D. Enders, O. Niemeier and
A. Henseler, Chem. Rev., 2007, 107, 5606; (b) N. Marion,
S. Diez-Gonzalez and S. P. Nolan, Angew. Chem., Int. Ed.,
2007, 46, 2988; (c) J. L. Moore and T. Rovis, Top. Curr.
Chem., 2009, 291, 77; (d) A. T. Biju, N. Kuhl and F. Glorius,
Acc. Chem. Res., 2011, 44, 1182; (e) H. Vora and T. Rovis,
Aldrichimica Acta, 2011, 44, 3; (f) E. Phillips, A. Chan and
K. Scheidt, Aldrichimica Acta, 2009, 42, 55; (g) H. U. Vora,
P. Wheeler and T. Rovis, Adv. Synth. Catal., 2012, 354, 1617.
For
a
review of azolium enolate chemistry see:
(h) J. Douglas, G. Churchill and A. D. Smith, Synthesis,
2012, 2295.
L. C. Morrill, R. A. Bragg and A. D. Smith, Chem.–Eur. J., 10 Y.-R. Zhang, H. Lv, D. Zhou and S. Ye, Chem.–Eur. J., 2008,
2011, 17, 11060; (n) C. Joannesse, C. P. Johnston, 14, 8473.
L. C. Morrill, P. A. Woods, M. Kieffer, T. A. Nigst, H. Mayr, 11 Throughout this manuscript the anti- and syn-descriptors
T. Lebl, D. Philp, R. A. Bragg and A. D. Smith, Chem.–Eur.
J., 2012, 18, 2398.
8 NHC induced azolium enolate reactivity was concurrently
that are used refer to the relative configuration of the aryl
unit derived from the ketene and the γ-substituent of the
β,γ-unsaturated α-ketocarboxylate.
and independently reported: (a) Y.-R. Zhang, L. He, X. Wu, 12 The relative and absolute configuration within 8 was
P.-L. Shao and S. Ye, Org. Lett., 2007, 10, 277; (b) N. Duguet,
C. D. Campbell, A. M. Z. Slawin and A. D. Smith, Org.
Biomol. Chem., 2008, 6, 1108. For representative examples
from the Ye group see: (c) H. Lv, Y.-R. Zhang, X.-L. Huang
and S. Ye, Adv. Synth. Catal., 2008, 350, 2715;
proven by X-ray analysis; all other derivatives were assigned
by direct analogy and showed consistent trends in
1H NMR. Crystallographic data for 8 has been deposited
with the Cambridge Crystallographic Data Centre as sup-
plementary publication number CCDC 922362.
(d) Y.-R. Zhang, H. Lv, D. Zhou and S. Ye, Chem.–Eur. J., 13 The relative configuration within isomerised dihydro-
2008, 14, 8473; (e) H. Lv, L. You and S. Ye, Adv. Synth.
Catal., 2009, 351, 2822; (f) X.-N. Wang, P.-L. Shao, H. Lv
and S. Ye, Org. Lett., 2009, 11, 4029; (g) H. Lv, X.-Y. Chen,
L.-h. Sun and S. Ye, J. Org. Chem., 2010, 75, 6973;
(h) P.-L. Shao, X.-Y. Chen, L.-H. Sun and S. Ye, Tetrahedron
Lett., 2010, 51, 2316; (i) X.-N. Wang, Y.-Y. Zhang and S. Ye,
Adv. Synth. Catal., 2010, 352, 1892; ( j) T.-Y. Jian, P.-L. Shao
and S. Ye, Chem. Commun., 2011, 47, 2381; (k) P.-L. Shao,
pyranone 21 was proven by nOe analysis (see ESI† for
full details), with the absolute configuration assigned
based upon the assumption that the quaternary stereo-
centre at C(3) within 20 is not altered during the base-
catalysed isomerisation. In this model the absolute
configuration of the major syn-diastereoisomer can be
deduced as (2S,5R) and the minor anti diastereoisomer as
(2R,5R).
X.-Y. Chen and S. Ye, Angew. Chem., Int. Ed., 2010, 49, 8412; 14 The absolute configuration of (anti)-11 is (3R,4S). See ESI†
(l) T. Wang, X.-L. Huang and S. Ye, Org. Biomol. Chem., for details of this stereochemical determination.
2010, 8, 5007; (m) L. He, H. Lv, Y.-R. Zhang and S. Ye, 15 In this system deprotonation at C(4) presumably leads to a
J. Org. Chem., 2008, 73, 8101; (n) X.-L. Huang, X.-Y. Chen
and S. Ye, J. Org. Chem., 2009, 74, 7585; (o) T.-Y. Jian, L. He,
C. Tang and S. Ye, Angew. Chem., Int. Ed., 2011, 50, 9104;
dienolate. Protonation at C(6) leads to isomerisation pro-
ducts, while alternatively protonation at C(4) could lead to
product epimerisation and high anti-selectivity.
(p) X.-N. Wang, L.-T. Shen and S. Ye, Org. Lett., 2011, 13, 16 See ESI† for full information regarding the full range of
6382; (q) X.-L. Huang, L. He, P.-L. Shao and S. Ye, Angew. α-ketocarboxylates screened in this process.
Chem., Int. Ed., 2009, 48, 192. For representative examples 17 During our attempts to probe the scope of the NHC cata-
from this group see: (r) N. Duguet, A. Donaldson,
S. M. Leckie, J. Douglas, P. Shapland, T. B. Brown,
G. Churchill, A. M. Z. Slawin and A. D. Smith, Tetrahedron:
Asymmetry, 2010, 21, 582; (s) N. Duguet, A. Donaldson,
S. M. Leckie, E. A. Kallström, C. D. Campbell, P. Shapland,
lysed formal [4 + 2] cycloaddition between alkylarylketenes
and β,γ-unsaturated α-ketocarboxylates several limitations
were found (See ESI† for full details). The use of an ortho-
substituted ketene such as ethyl(2-chlorophenyl)ketene
or ethyl(2-methylphenyl)ketene gave no conversion to
This journal is © The Royal Society of Chemistry 2013
Org. Biomol. Chem., 2013, 11, 3230–3246 | 3245

View Article Online
Paper
the desired cycloaddition products returning only the
Organic & Biomolecular Chemistry
details). Upon the assumption that the stereocentre at C(3)
within 29 is formed with same absolute configuration in
both the aryl and the alkyl α-ketocarboxylate series using
the NHC derived from precatalyst 1, the absolute configur-
ation of the major anti-diastereoisomer can be deduced as
(3R,4S).
unreacted α-ketocarboxylate and the corresponding acetic
acid from hydrolysis of the ketene. Additionally, iso-propyl-
phenylketene and cyclohexamethylene ketene also resulted
in no conversion to the desired products. It would appear
that increasing the steric encumbrance of the ketene dis-
favours this formal [4 + 2] reaction pathway.
19 (a) C. E. Cannizzaro, T. Strassner and K. N. Houk, J. Am.
Chem. Soc., 2001, 123, 2668; (b) C. E. Cannizzaro and
K. N. Houk, J. Am. Chem. Soc., 2004, 126, 10992.
18 The relative configuration within the major anti-diastereo-
isomer of 29 was proven by nOe analysis (see ESI† for full
3246 | Org. Biomol. Chem., 2013, 11, 3230–3246
This journal is © The Royal Society of Chemistry 2013