Enantioselective NHC-catalysed formal [4+2] cycloaddition of alkylaryl-ketenes with β,γ-unsaturated α-ketophosphonates

Article abstract of DOI:10.1055/s-0033-1338851

NHC-mediated enantioselective formal [4+2] cycloadditions of alkylarylketenes with γ-substituted-β,γ-unsaturated α-ketophosphonates is described. A substrate-dependent switch in diastereoselectivity was observed, with γ-aryl α-ketophosphonates providing p

Full text of DOI:10.1055/s-0033-1338851

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▌1243
cElunstear ntioselective NHC-Catalysed Formal [4+2] Cycloaddition of Alkylaryl-
ketenes with β,γ-Unsaturated α-Ketophosphonates
[4+2] Cycloaddition of Alkylarylketenes
Stuart M. Leckie,a Charlene Fallan,a James E. Taylor,a T. Bruce Brown,b David Pryde,c Tomáš Lébl,a Alexandra M.
Z. Slawin,a Andrew D. Smith*a
a
EaStCHEM, School of Chemistry, University of St Andrews, North Haugh, St Andrews, KY16 9ST, UK
Fax +44(1334)463808; E-mail: ads10@st-andrews.ac.uk
b
Pfizer Global Research and Development, 388 Ramsgate Road, Sandwich, Kent, CT13 9NJ, UK
c
Pfizer Neusentis, The Portway Building, Granta Park, Great Abington, Cambridge, CB21 6GS, UK
Received: 01.04.2013; Accepted after revision: 03.05.2013
with β,γ-unsaturated α-ketocarboxylic esters to form di-
Abstract: NHC-mediated enantioselective formal [4+2] cycloaddi-
hydropyranone products with modest diastereocontrol but
tions of alkylarylketenes with γ-substituted-β,γ-unsaturated α-keto-
high enantiocontrol.16 Expanding upon this methodology,
herein we present the results of NHC-catalysed formal
phosphonates is described. A substrate-dependent switch in
diastereoselectivity was observed, with γ-aryl α-ketophosphonates
providing preferentially the syn-dihydropyranone-phosphonates [4+2] cycloadditions of ketenes with β,γ-unsaturated α-
ketophosphonates.17 This series allows direct access to a
range of enantioenriched dihydropyranone-phosphonates
and γ-methyl α-ketophosphonates favouring the anti-dihydropyra-
none-phosphonate. In addition, ketene generation in situ retained
high levels of stereoselectivity and led to improved product yields
that have a close structural resemblance to numerous po-
when compared with the corresponding two-step procedure.
tent anti-influenza agents.18
Key words: N-heterocyclic carbenes, cycloaddition, asymmetric
The [4+2] cycloaddition of ethylphenylketene (2a) with γ-
phenyl-β,γ-unsaturated α-ketophosphonate 3a using NHC
precatalyst 1 (10 mol%) was chosen as the model system
for optimisation (Table 1). Initial results demonstrated
that the choice of base was crucial in this process. The use
of KHMDS as the base gave no desired product (entry 1),
whereas using Et3N (1 equiv) gave dihydropyranone 4 in
48% isolated yield, with moderate diastereoselectivity
(61:39) and good levels of enantiocontrol for the major
syn-diastereoisomer (89% ee; entry 2). The use of Cs2CO3
(9 mol%) gave an improved 79% isolated yield of a 62:38
syn/anti mixture of dihydropyranone-phosphonates 4a
and 4b, with the major syn-diastereoisomer formed in an
excellent 94% ee (entry 3). Adding ketene 2a in one por-
tion gave reduced product conversion (59%) and use of a
stoichiometric amount of base gave no further improve-
ments in reactivity (entries 4 and 5). Finally, dropwise ad-
dition of excess ketene (2.4 equiv) with 9 mol% Cs2CO3
and 10 mol% NHC 1 provided the [4+2] product 4 in 84%
yield, moderate dr (63:37, syn/anti), and high 93% ee for
the syn-diastereoisomer 4a, with the minor anti-diastereo-
isomer 4b formed with low levels of enantiocontrol19
(29% ee, entry 6).
catalysis, asymmetric synthesis, lactones
N-Heterocyclic carbenes (NHCs) are established organo-
catalysts that have been employed in a wide range of syn-
thetic processes generating numerous novel chemical
architectures.1 Over the last decade, NHC-mediated or-
ganocatalysis has been extended beyond that of umpolung
acyl anion equivalent reactivity, initially demonstrated in
the benzoin2 and Stetter3 reactions, to make use of acyl
azolium,4 azolium enolate,1d,g azolium homoenolate,1c,5
and α,β-unsaturated acyl azolium1b,6 intermediates in an
array of transformations.
Our ongoing research programme aimed at developing
catalytic Lewis base mediated reaction processes, has fo-
cused on generating azolium enolates and exploration of
their subsequent reactivity.7,8 In this regard, we have used
chiral NHCs to prepare enantiomerically enriched β-lac-
tams and β-lactones from ketenes and N-sulfonyl imines
or aldehydes, respectively. Alternatively, α-alkyl-α-ary-
lacetic esters can be prepared from alkylarylketenes and
phenols9 with good levels of enantioselectivity, or α-chlo-
roesters can be formed upon treatment with chlorinating
agents.10 Simultaneously, Ye and co-workers have made
significant contributions in this area, resulting in a range
of NHC-catalysed formal [2+2],11,12 [3+2],13 and [4+2]14
cycloadditions accessed from ketenes. In addition, an
asymmetric protonation of ketenes employing sterically
encumbered alcohols15 that generates enantioenriched es-
ters has also been reported. Recently, we applied NHC ca-
talysis to the asymmetric [4+2] cycloaddition of ketenes
To demonstrate the generality of this methodology, a
range of alkylarylketenes (2a–i) were assessed under the
optimised conditions (Table 2).20 The range of ketenes ex-
plored demonstrated good reactivity in this process, giv-
ing dihydropyranone-phosphates with moderate levels of
diastereoselectivity (55:45 to 72:28 dr, syn/anti). Ethyla-
ryl and n-butylphenyl ketenes gave high enantioselectivi-
ty for the major syn-diastereoisomer (90–98% ee, entries
1 and 3–7), with the exception of ethyl(4-methylphe-
nyl)ketene, which resulted in lower enantioselectivity for
the major syn-diastereoisomer (79% ee, entry 2). Aryl-
methylketenes gave syn-dihydropyranone-phosphonates
SYNLETT 2013, 24, 1243–1249
Advanced online publication: 28.05.2013
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0033-1338851; Art ID: ST-2013-R0288-C
© Georg Thieme Verlag Stuttgart · New York

1244
S. M. Leckie et al.
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Table 1 Optimisation of the NHC-Mediated [4+2] Cycloaddition
N
N
N
Ph
BF4
Ph
Ph
O
O
Et
O
Et
OTBS
Ph
Ph
Ph
Ph
1 (10 mol%)
O
O
OMe
OMe
OMe
OMe
+
base (9 mol%)
PhMe, r.t., 16 h
P
Ph
Et
P
O
O
2a
O
(syn)-4a
(anti)-4b
OMe
OMe
Ph
P
3a
O
Entry
Ketene (equiv)
Base
dr (syn/anti)a
% ee (syn, anti)b
Yield (%)c
1
1.5
1.5
1.5
1.5f
1.5
2.4
KHMDS
Et3N
–
–
<5d
48
2e
3
61:39
62:38
64:36
54:46
63:37
89, 31
94, 30
–
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
79
4
59d
63
5g
6
93, 45
93, 29
84
a Determined by 1H and 31P NMR spectroscopic analysis of the unpurified reaction mixture.
b Determined by chiral HPLC analysis.
c Isolated yield of both diastereoisomers.
d Conversion determined by 1H and 31P NMR spectroscopic analysis of the unpurified reaction mixture.
e 1.0 equiv of base used.
f Added in one portion.
g 1.1 equiv of base used.
with reduced levels of enantiocontrol (53% ee, entries 8
N
and 9). While good yields were generally observed across
the range of alkylarylketenes screened, ethyl(4-methoxy-
phenyl)ketene gave only 24% isolated yield of the corre-
N
N
Ph
Ph
BF4
Ph
OTBS
O
O
Et
1 (10 mol%)
Cs2CO3 (9 mol%)
PhMe, r.t., 16 h
sponding dihydropyranone-phosphonate (entry 3),
suggesting that electron-donating substituents on the aro-
matic group are poor substrates in this process. Consistent
with the observations of Ye et al.,11,14a ortho-substituted
ketenes were not tolerated in this protocol.19 High levels
of enantioselectivity were observed for the syn-dihydro-
pyranone-phosphonates 4a and 6a–10a (90–98% ee),
whereas the minor anti-diastereoisomer was formed in
consistently low enantioselectivity across the series (12–
37% ee).21
Et
Ar
Ar
O
O
OMe
OMe
OMe
Ph
P
or
Ph
P
OMe
O
Cs2CO3 (20 mol%)
PhMe, r.t., 16 h
O
(syn)-5a
Ar = 4-MeC6H4
(syn)-5a
isomerisation
not observed
Scheme 1 Control experiments
The acceptor substrate scope was next probed by screen-
ing a range of γ-aryl-β,γ-unsaturated α-ketophosphonates
(3a–d) under the optimised reaction conditions (Table 3).
Pleasingly, both electron-donating (4-MeOC6H4) and
electron-withdrawing (4-FC6H4) aromatic groups were
tolerated (entries 2 and 3, respectively), giving dihydropy-
ranone-phosphonates 13 and 14 in moderate diastereose-
lectivity (up to 65:35 dr, syn/anti), good yield (up to 80%),
and excellent enantioselectivity (90–94% ee, syn). Isopro-
pylphosphonate 3d could also be used, giving dihydropy-
ranone-phosphonate 15 (58:42 dr, syn/anti; 87% ee, syn),
although a reduced isolated yield was obtained (33%, en-
try 4).
In our previous work the product dihydropyranones
proved susceptible to base-catalysed isomerisation, so
control experiments to probe such a pathway in this sys-
tem were conducted (Scheme 1). Isolated (syn)-5a was
exposed to both standard reaction conditions (10 mol%
NHC precatalyst 1, 9 mol% Cs2CO3 in toluene at r.t. for
16 h) and basic reaction conditions (20 mol% Cs2CO3, in
toluene at r.t. for 16 h). 1H NMR and chiral HPLC analy-
ses revealed consistent levels of diastereo- and enantio-
control, suggesting the dihydropyranone-phosphonates
are stable under these conditions and, as such, an isomer-
isation pathway is unlikely within this system.
Single crystal X-ray structure analysis of syn-dihydropy-
ranone-phosphonate 13a allowed unambiguous determi-
Synlett 2013, 24, 1243–1249
© Georg Thieme Verlag Stuttgart · New York

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[4+2] Cycloaddition of Alkylarylketenes
1245
Table 2 Alkylarylketene Substrate Scope
N
N
N
Ph
BF4
Ph
O
O
Ph
R
Ar
OTBS
R
O
Ar
1 (10 mol%)
O
O
OMe
OMe
OMe
OMe
+
Cs2CO3 (9 mol%)
PhMe, r.t., 16 h
Ph
P
Ph
P
Ar
R
O
O
2a–i
(2.4 equiv)
O
OMe
(syn)-4a–12a
(anti)-4b–12b
Ph
P
OMe
3a
O
Entry
Ar
Ph
R
Product (a/b)
dr (syn/anti)a
% ee (syn, anti)b
Yield (%)
1
2
3
4
5
6
7
8
9
Et
4
5
63:37
65:35
72:28
65:35
68:32
71:29
55:45
67:33
67:33
93, 29
79, 32
90, 35
98, –d
93, –d
90, –d
94, 37
53, 36
53, 12
84
69
24
49
63
63
85
54
82
4-MeC6H4
4-MeOC6H4
4-FC6H4
4-ClC6H4
4-BrC6H4
Ph
Et
Et
6
Et
7
Et
8
Et
9
n-Bu
Me
Me
10
11
12
Ph
4-MeC6H4
a Determined by 1H and 31P NMR spectroscopic analysis of the unpurified reaction mixture.
b Determined by chiral HPLC analysis.
c Isolated yield of both diastereoisomers.
d Minor anti diastereoisomer not isolated following chromatography, see experimental for details.20
Table 3 β,γ-Unsaturated α-Ketophosphonate Scope
N
N
N
Ph
BF4
Ph
Ph
O
O
Et
OTBS
Et
O
Ph
R1
Ph
1 (10 mol%)
O
O
OR2
OR2
OR2
OR2
+
Cs2CO3 (9 mol%)
PhMe, r.t., 16 h
R1
P
P
Ph
Et
O
O
O
2a
OR2
(2.4 equiv)
(syn)-4a,13a–15a
(anti)-4b,13b–15b
R1
P
O
OR2
3a–d
Entry
R1
Ph
R2
Product (a/b)
dr (syn/anti)a
% ee (syn, anti)b
Yield (%)c
1
2
3
4
Me
Me
Me
i-Pr
4
13
14
15
63:37
60:40
65:35
58:42
93, 29
90, 18
94, 29
87, 52
84
76
80
33
4-MeOC6H4
4-FC6H4
Ph
a Determined by 1H and 31P NMR spectroscopic analysis of the unpurified reaction mixture.
b Determined by chiral HPLC analysis.
c Isolated yield of both diastereoisomers.
© Georg Thieme Verlag Stuttgart · New York
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1246
S. M. Leckie et al.
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nation of the relative and absolute configuration as ty in this process is consistent with our previous NHC-me-
(3R,4R) (Figure 1). All other syn-dihydropyranone-phos- diated [4+2] cycloaddition methodology,16 although the
phonates within this series derived from γ-aryl-β,γ-unsat- reason for this change is not clear. Interestingly, under
urated-α-ketophosphonates were therefore assigned as these conditions, ketene dimerisation was not observed.12
(3R,4R) by analogy.22
The catalyst and base screen summarised in Table 1 re-
vealed that Et3N is a competent base for this NHC-medi-
ated process (Table 1, entry 2). Encouraged by this result,
we investigated the NHC-mediated formal [4+2] cycload-
dition between arylacetyl chlorides 18a–d and α-keto-
phosphonate 3a through in situ ketene generation25 using
an organic base. Table 5 shows the results for this NHC-
mediated formal [4+2] cycloaddition with arylacetyl chlo-
ride 18 as a ketene precursor using Me2EtN as the base.26
For comparison, the corresponding yields for the two-step
process in which the ketene was isolated and purified is
also given. Dihydropyranone-phosphonates 4 and 7–9
were formed in equivalent levels of diastereoselectivity
and enantioselectivity compared with the corresponding
products synthesised from isolated ketene.27 An improve-
ment in overall yield (compared with the two-step proce-
dure) for dihydropyranones 7–9 was generally observed.
Dihydropyranone-phosphonate 9a, synthesised from eth-
yl-(4-bromophenyl)ketene generation in situ, resulted in
high diastereo- and enantioselectivity (>98:2 dr, syn/anti;
99% ee, syn). These results are far superior compared with
the corresponding product synthesised from the isolated
ketene (71:29 dr, syn/anti; 90% ee, syn; Table 2, entry 6)
and, at present, the reason for this improved level of stereo-
selectivity is unclear.28
Figure 1 Representation of the single crystal X-ray structure of syn-
dihydropyranone-phosphonate 13a
Extension of the substrate scope to include γ-methyl-β,γ-
unsaturated α-ketophosphonate 3e under these conditions
led to the preferential formation of side-product 17 (Table
4).23 As a result, reduced conversion to the desired [4+2]
cycloaddition product 16 was obtained. To prevent the
formation of 17, a brief reoptimisation was investigated.
Control experiments in the absence of ketene indicated
that formation of 17 is both NHC- and base-catalysed. To
circumvent this problem, dropwise addition of phospho-
nate 3e to a solution of the ketene, NHC precatalyst 1 and
Cs2CO3 inhibited the formation of side-product 17, allow-
ing dihydropyranone-phosphonate 16 to be isolated in
71% yield as a mixture of diastereoisomers (20:80 dr,
syn/anti) and with excellent levels of enantioselectivity
(71% ee, anti; 90% ee, syn; Table 4). The relative config-
uration of the major anti-diastereoisomer of dihydropyra-
none-phosphonate 16b was assigned on the basis of NOE
experiments.24 The observed switch in diastereoselectivi-
The absolute configuration of the [4+2] adducts with α-
ketophosphonates is consistent with that previously re-
ported employing α-ketocarboxylate series,16 therefore
we assume that they are formed through a similar mecha-
nistic pathway (Scheme 2). Deprotonation of precatalyst
1 to generate NHC 19, followed by addition to the ketene
anti to the ketene aryl substituent29 will generate azolium
enolate 20. Irreversible asymmetric Michael addition un-
der kinetic control, followed by lactonisation will form
Table 4 Reoptimisation of γ-Methyl-β,γ-Unsaturated α-Ketophosphonate
N
N
N
Ph
BF4
Ph
Ph
O
O
OTBS
Et
O
Ph
MeO
MeO
P
1 (10 mol%)
O
O
+
OMe
OMe
OMe
OMe
Cs2CO3 (9 mol%)
Me
P
Me
P
PhMe, r.t., 16 h
Ph
Et
O
O
O
2a
(anti)-16b
17
OMe
(2.4 equiv)
Me
P
OMe
3e
O
Dropwise addition
Product ratio 16/17
dr 16 (syn/anti)a
% ee (syn, anti)b
Yield (%)c
ketene 2a
40:60
>98:2
20:80
20:80
–
–
acceptor 3e
90, 71
71
a Determined by 1H and 31P NMR spectroscopic analysis of the unpurified reaction mixture.
b Determined by chiral HPLC analysis.
c Isolated yield of both diastereoisomers.
Synlett 2013, 24, 1243–1249
© Georg Thieme Verlag Stuttgart · New York

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[4+2] Cycloaddition of Alkylarylketenes
1247
Table 5 Ketene Generation In Situ and Subsequent [4+2] Cycloaddition
N
N
N
Ph
BF4
Ph
Ph
O
O
Et
Et
Ar
OTBS
Ar
O
Cl
Et
1 (10 mol%)
O
O
OMe
OMe
OMe
OMe
+
Me2EtN (3.5–6 equiv)
Et2O, 0 °C to r.t., 16 h
Ph
P
Ph
P
Ar
O
O
O
OMe
(syn)-4,7a–9a
(anti)-4,7b–9b
18a–d
(2.5–3.5 equiv)
Ph
P
OMe
3a
O
Entry
Ar
Product (a/b)
dr (syn/anti)a
% ee (syn)b
Yield (%)c
1
2
3
4
Ph
4
7
8
9
63:37
65:35
71:29
>98:2
93
92
93
99
24 (60)
47 (22)
27 (14)
54 (36)
4-FC6H4
4-ClC6H4
4-BrC6H4
a Determined by 1H and 31P NMR spectroscopic analysis of the unpurified reaction mixture.
b Determined by chiral HPLC analysis.
c Isolated yield of both diastereoisomers; yield in parenthesis corresponds to overall yield over two-step procedure.
zwitterionic intermediate 21, which delivers dihydropyra- enantioselectivity for the major syn-diastereoisomer (up
none phosphonate 22 and regenerates NHC 19.
to 98% ee). A γ-methyl α-ketophosphonate provides a
switch in diastereoselectivity with the anti-diastereoiso-
mer formed preferentially (20:80 dr, syn/anti), in good
yield and enantioselectivity (71% ee, anti; 90% ee, syn).
Ketene generation in situ from the corresponding arylace-
tyl chloride gave dihydropyranone-phosphonate with
comparable levels of stereocontrol and, in most examples,
improved isolated yields.
N
N
N
Ph
BF4
TBSO
Ph
Ph
1
O
R
Cs2CO3
Ar1
Ar2
O
O
P(O)(OMe)2
N
22
Acknowledgment
N
N
Ph
TBSO
Ph
Ar1
R
We thank the Royal Society for a University Research Fellowships
(A.D.S.), the EPSRC and Pfizer (CASE funding for S.M.L.) and the
EU (C.F. and J.E.T.) for funding, as well as the European Research
Council under the European Union’s Seventh Framework Program-
me (FP7/2007-2013) ERC grant agreement No. 279850. We also
thank the EPSRC National Mass Spectrometry Service Centre
(Swansea).
19
Ph
2
N
N
N
O
N
N
N
TBSO
Ph
Ph
Ph
R
TBSO
Ph
O
Ph
R
Ph
O
P(O)(OMe)2
Ar1
21
Ar1
20
Ar2
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnuIpofoiprmntgirStanoIuifpog
O
m
t
iornat
Ar2
P(O)(OMe)2
3
References and Notes
Scheme 2 Proposed mechanism of NHC-mediated formal [4+2] cy-
cloaddition
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Synlett 2013, 24, 1243–1249

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(16) Leckie, S. M.; Brown, T. B.; Pryde, D.; Lébl, T.; Slawin, A.
M. Z.; Smith, A. D. Org. Biomol. Chem. 2013, 11, 3230.
(17) For recent examples of β,γ-unsaturated α-ketophosphonates
in asymmetric catalysis, see: (a) Jiang, H.; Paixão, M. W.;
Monge, D.; Jørgensen, K. A. J. Am. Chem. Soc. 2010, 132,
2775. (b) Bachu, P.; Akiyama, T. Chem. Commun. 2010, 46,
4112. (c) Liu, T.; Wang, Y.; Wu, G.; Song, H.; Zhou, Z.;
Tang, C. J. Org. Chem. 2011, 76, 4119.
(18) Shie, J.-J.; Fang, J.-M.; Lai, P.-T.; Wen, W.-H.; Wang, S.-
Y.; Cheng, Y.-S. E.; Tsai, K.-C.; Yang, A.-S.; Wong, C.-H.
J. Am. Chem. Soc. 2011, 133, 17959.
(7) (a) Duguet, N.; Donaldson, A.; Leckie, S. M.; Douglas, J.;
Shapland, P.; Brown, T. B.; Churchill, G.; Slawin, A. M. Z.;
Smith, A. D. Tetrahedron: Asymmetry 2010, 21, 582.
(b) Duguet, N.; Donaldson, A.; Leckie, S. M.; Kallström, E.
A.; Campbell, C. D.; Shapland, P.; Brown, T. B.; Slawin, A.
M. Z.; Smith, A. D. Tetrahedron: Asymmetry 2010, 21, 601.
(c) Irgolic, K. J. In Houben-Weyl; Klamann, D., Ed.;
Thieme: Stuttgart, 1990, 4th ed., Vol. E12b, 150.
(8) (a) Campbell, C. D.; Duguet, N.; Gallagher, K. A.;
Thomson, J. E.; Lindsay, A. G.; O’Donoghue, A. C.; Smith,
A. D. Chem. Commun. 2008, 3528. (b) Campbell, C. D.;
Concellón, C.; Smith, A. D. Tetrahedron: Asymmetry 2011,
22, 797. (c) Campbell, C. D.; Collett, C. J.; Thomson, J. E.;
Slawin, A. M. Z.; Smith, A. D. Org. Biomol. Chem. 2011, 9,
4205. (d) Collett, C. J.; Massey, R. S.; Maguire, O. R.;
Batsanov, A. S.; O’Donoghue, A. C.; Smith, A. D. Chem.
Sci. 2013, 4, 1514. (e) Duguet, N.; Campbell, C. D.; Slawin,
A. M. Z.; Smith, A. D. Org. Biomol. Chem. 2008, 6, 1108.
(f) Ling, K.; Smith, A. Chem. Commun. 2011, 47, 373.
(g) Massey, R. S.; Collett, C. J.; Lindsay, A. G.; Smith, A.
D.; O’Donoghue, A. C. J. Am. Chem. Soc. 2012, 134, 20421.
(h) Thomson, J. E.; Rix, K.; Smith, A. D. Org. Lett. 2006, 8,
3785. (i) Thomson, J. E.; Campbell, C. D.; Concellón, C.;
Duguet, N.; Rix, K.; Slawin, A. M. Z.; Smith, A. D. J. Org.
Chem. 2008, 73, 2784. (j) Thomson, J. E.; Kyle, A. F.; Ling,
K. B.; Smith, S. R.; Slawin, A. M. Z.; Smith, A. D.
Tetrahedron 2010, 66, 3801. (k) Douglas, J.; Taylor, J. E.;
Churchill, G.; Slawin, A. M. Z.; Smith, A. D. J. Org. Chem.
2013, 78, 3925.
(9) Concellón, C.; Duguet, N.; Smith, A. D. Adv. Synth. Catal.
2009, 351, 3001.
(10) Douglas, J.; Ling, K. B.; Concellón, C.; Churchill, G.;
Slawin, A. M. Z.; Smith, A. D. Eur. J. Org. Chem. 2010,
5863.
(11) (a) He, L.; Lv, H.; Zhang, Y. R.; Ye, S. J. Org. Chem. 2008,
73, 8101. (b) Wang, X. N.; Shao, P. L.; Lv, H.; Ye, S. Org.
Lett. 2009, 11, 4029. (c) Zhang, Y. R.; He, L.; Wu, X.; Shao,
P. L.; Ye, S. Org. Lett. 2007, 10, 277. (d) Wang, X. N.;
Zhang, Y. Y.; Ye, S. Adv. Synth. Catal. 2010, 352, 1892.
(e) Huang, X. L.; Chen, X. Y.; Ye, S. J. Org. Chem. 2009,
74, 7585. (f) Jian, T. Y.; He, L.; Tang, C.; Ye, S. Angew.
Chem. Int. Ed. 2011, 50, 9104.
(19) Consistent with our previous series, see ref. 16.
(20) Asymmetric formal [4+2] cycloaddition; Typical
procedure: To a flame-dried Schlenk flask under an
atmosphere of argon was added triazolium salt 1 (14.0 mg,
0.0245 mmol), Cs2CO3 (7.2 mg, 0.0221 mmol) and toluene
(1.5 mL), and the resultant suspension was stirred at r.t. for
30 min, then (E)-dimethyl cinnamoylphosphonate (3a; 58.8
mg, 0.245 mmol) was added as a solution in toluene (1.5
mL). As soon as the addition was complete, a solution of
ethylphenylketene 2a (86.0 mg, 0.588 mmol) in toluene (4
mL) was added over 1 h by using a syringe pump. When the
addition was complete, the solution was stirred at r.t.
overnight before concentration in vacuo to give the crude
product (63:37 dr syn/anti). Purification by column
chromatography on silica gel (petroleum ether–EtOAc,
70:30) gave a fully inseparable mixture of lactones 4a and
4b (80 mg, 84%) as a colourless solid. The syn/anti ratio was
determined by both 1H and 31P NMR spectroscopy of the
unpurified reaction mixture and the ee was determined by
chiral HPLC analysis of the purified product.
Analytical Data for the Mixture of 4a and 4b: Mp 58–
59 °C; IR (KBr): 2955 (C–H), 1769 (C=O), 1267 (P=O),
1032 (P–OMe) cm–1. 1H NMR (300 MHz, CDCl3): δ (4a) =
1.05 (t, J = 7.3 Hz, 3 H, CH2CH3), 2.26–2.44 (m, 2 H, CH2),
3.87–3.92 [m, 1 H, C(4)H], 3.90 (d, J = 2.8 Hz, 3 H, OMe),
3.94 (d, J = 2.8 Hz, 3 H, OMe), 6.50 [dd, J = 10.0, 4.8 Hz,
1 H, C(5)H], 6.66–6.69 (m, 2 H, PhH), 6.82–6.88 (m, 2 H,
PhH), 7.07–7.16 (m, 6 H, PhH); δ (4b) = 0.58 (t, J = 7.4 Hz,
3 H, CH2CH3), 1.48 [dq, J = 14.4, 7.4 Hz, 1 H, C(3)CHAHB],
1.91 (dq, J = 14.4, 7.4 Hz, 1 H, CHAHB), 3.12 (d, J =
11.3 Hz, 1 H, OMe), 3.76 (d, J = 11.3 Hz, 1 H, OMe), 4.26
[d, J = 6.8 Hz, 1 H, C(4)H], 6.60 [dd, J = 9.7, 6.8 Hz, 1 H,
C(5)H], 7.19–7.24 (m, 2 H, PhH), 7.29–7.40 (m, 8 H, PhH);
13C (75 MHz, CDCl3): δ (4a) = 9.5 (CH3), 29.0 (CH2), 50.2
[d, J = 12.7 Hz, C(4)], 53.7 (d, J = 5.7 Hz, 2 × OMe), 55.1
[C(3)], 124.0 [d, J = 19.6 Hz, C(5)], 127.0 (PhH), 127.7
(2 × Ph), 128.1 (Ph), 128.2 (Ph), 129.1 (Ph), 136.0
[C(3)Ph(1)], 136.4 [d, J = 1.0 Hz, C(4)Ph(1)], 142.2 [d, J =
234.4 Hz, C(6)], 168.4 [d, J = 8.0, C(2)]; δ (4b) = 8.2
(CH2CH3), 28.3 (CH2), 45.7 [d, J = 12.5 Hz, C(4)], 52.7 (d,
J = 4.6 Hz, OMe), 53.5 (d, J = 5.7 Hz, OMe), 54.3 [C(3)],
125.0 [d, J = 19.4 Hz, C(5)], 127.2 (Ph), 128.0 (Ph), 128.4
(Ph), 128.6 (Ph), 128.8 (Ph), 129.8 (Ph), 135.9 [d, J = 2.4 Hz,
C(4)Ph(1)], 137.7 [C(3)Ph(1)], 141.8 [d, J = 238.8 Hz,
(12) Lv, H.; Zhang, Y.-R.; Huang, X.-L.; Ye, S. Adv. Synth.
Catal. 2008, 350, 2715.
(13) Shao, P. L.; Chen, X. Y.; Ye, S. Angew. Chem. Int. Ed. 2010,
49, 8412.
Synlett 2013, 24, 1243–1249
© Georg Thieme Verlag Stuttgart · New York

CLUSTER
C(6)], 170.4 [d, J = 8.1 Hz, C(2)]; HRMS (NSI+): m/z
[4+2] Cycloaddition of Alkylarylketenes
1249
(27) Asymmetric formal [4+2] cycloaddition with ketene
generation in situ; Typical procedure: To a flame-dried
Schlenk flask under an atmosphere of argon and at 0 °C, was
added sequentially 2-phenylbutanoyl chloride (112 mg,
0.613 mmol) as a solution in toluene (1.5 mL), (E)-dimethyl
cinnamoylphosphonate (3a; 58.8 mg, 0.245 mmol) as a
solution in toluene (1.5 mL) and triazolium salt 1 (14.0 mg,
0.0245 mmol) as a solid. Finally, dimethylethylamine
(93 μL, 0.858 mmol) was added in one portion and the
reaction mixture warmed to r.t. overnight before
[M+H]+ calcd for C21H24O5P+: 387.1356; found: 387.1364
(+2.4 ppm). Chiral HPLC (Chiralpak OD-H; 5% IPA–
hexane; flowrate: 1 mL min–1; 220 nm): tR = 25.9 (4b minor),
29.5 (3R,4R), 35.3 (3S,4S), 43.2 (4b major) min; 93% ee
syn, 29% ee anti.
For a full list of unreactive ketenes screened in this process
see the Supporting Information.
(21) When para-halogen substituted alkylarylketenes were
employed, the anti-diastereoisomer was not isolated after
purification. In all of the examples presented in Table 2,
resonances consistent with the presence of both syn- and
concentration in vacuo to give the crude product (63:37 dr
syn/anti). Purification by column chromatography on silica
gel (petroleum ether–EtOAc, 70:30) gave a fully inseparable
mixture of lactones 4a and 4b (23 mg, 24%) as a colourless
solid with spectroscopic data as described in ref. 20. The
syn/anti ratio was determined by both 1H and 31P NMR
spectroscopy of the unpurified reaction mixture and the ee
was determined by chiral HPLC analysis of the purified
product. Chiral HPLC (Chiralpak OD-H; 5% IPA–hexane;
flowrate 1 mL min–1; 220 nm): tR = 26.0 (4b minor), 30.7
(3R,4R), 36.2 (3S,4S), 42.8 (4b major) min; 98% ee syn,
37% ee anti.
anti-diastereoisomers are clearly visible by both 1H and 31
NMR spectroscopic analysis of the unpurified reaction
mixture. However, following purification, the anti-
P
diastereoisomer was no longer visible in any of the isolated
fractions and the yield given is for the recovered syn-
diastereoisomer only. The reasons for this remain unclear.
(22) Dihydropyranone phosphonate 13a was characterised by
single-crystal X-ray diffraction. Crystallographic data is
available free of charge from the Cambridge
Crystallographic Data Centre, www.ccdc.ac.uk/data-
request/cif, as CCDC 930998.
(28) A control experiment in which isolated and purified ketene
was used in the NHC-mediated formal [4+2] cycloaddition
with phosphonates 3a and Me2EtN gave similar results to
those with Cs2CO3 reported in Table 2, entry 6. See the
Supporting Information for full details.
(29) (a) Baigrie, L. M.; Seiklay, H. R.; Tidwell, T. T. J. Am.
Chem. Soc. 1985, 107, 5391. (b) Cannizzaro, C. E.;
Strassner, T.; Houk, K. N. J. Am. Chem. Soc. 2001, 123,
2668. (c) Cannizzaro, C. E.; Houk, K. N. J. Am. Chem. Soc.
2004, 126, 10992.
(23) The formation of product 17 has recently been described
through a Lewis acid mediated transformation, and
presumably arises from a bimolecular reaction of the α,β-
ketophosphonate starting material, see: Sun, Y.-W.; Zhu, P.-
L.; Xu, Q.; Shi, M. Tetrahedron 2012, 68, 9924.
(24) See Supporting Information for details.
(25) For a recent example of ketene formation in situ in catalysis,
see: Rasik, C.; Brown, M. J. Am. Chem. Soc. 2013, 135,
1673.
(26) Me2EtN was preferred over Et3N because it did not require
distillation over CaH2 prior to use.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 1243–1249