Enantioselective synthesis of 2,3-disubstituted: Trans -2,3-dihydrobenzofurans using a Br?nsted base/thiourea bifunctional catalyst

Article abstract of DOI:10.1039/c6ob01326k

The diastereo- and enantioselective synthesis of 2,3-disubstituted trans-2,3-dihydrobenzofuran derivatives (15 examples, up to 96 : 4 dr, 95 : 5 er) via intramolecular Michael addition has been developed using keto-enone substrates and a bifunctional tertiary amine-thiourea catalyst. This methodology was extended to include non-activated ketone pro-nucleophiles for the synthesis of 2,3-disubstituted indane and 3,4-disubstituted tetrahydrofuran derivatives.

Full text of DOI:10.1039/c6ob01326k

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Enantioselective synthesis of 2,3-disubstituted
trans-2,3-dihydrobenzofurans using a Brønsted
base/thiourea bifunctional catalyst†
Cite this: DOI: 10.1039/c6ob01326k
Diego-Javier Barrios Antúnez, Mark D. Greenhalgh, Charlene Fallan,
Alexandra M. Z. Slawin and Andrew D. Smith*
The diastereo- and enantioselective synthesis of 2,3-disubstituted trans-2,3-dihydrobenzofuran deriva-
tives (15 examples, up to 96 : 4 dr, 95 : 5 er) via intramolecular Michael addition has been developed using
keto–enone substrates and a bifunctional tertiary amine–thiourea catalyst. This methodology was
extended to include non-activated ketone pro-nucleophiles for the synthesis of 2,3-disubstituted indane
and 3,4-disubstituted tetrahydrofuran derivatives.
Received 20th June 2016,
Accepted 30th June 2016
DOI: 10.1039/c6ob01326k
www.rsc.org/obc
Introduction
Substituted dihydrobenzofurans form the core structure in a
variety of natural products, pharmaceuticals and bio-active
compounds.1 The biological activities ascribed to such mole-
cules has inspired the development of a plethora of synthetic
strategies for the preparation of this core motif.2 Methods for
the diastereo- and enantioselective synthesis of these com-
pounds are still relatively limited however, and traditionally
rely upon the use of transition metal catalysts.2,3 In recent
years the use of enantioselective organocatalytic methods for
the synthesis of 2,3-disubstituted 2,3-dihydrobenzofurans has
been investigated by a number of groups.4 As part of our on-
going development of Lewis base catalysis for the enantio-
selective synthesis of heterocycles,5 we have reported the use
of isothiourea and cinchona alkaloid catalysts for the stereo-
divergent synthesis of 2,3-dihydrobenzofurans and tetrahydro-
furans (Scheme 1a).6 Using enone acid substrates, cis-
disubstituted products were obtained using (S)-(−)-tetramisole
[up to 99 : 1 dr (cis : trans), 99 : 1 er], whilst the trans-products
could be obtained using a quinidine-derived catalyst [up to
85 : 15 dr (trans : cis), 99 : 1 er]. Jørgensen and co-workers, as
well as Wang and Zhou, independently reported the use of
enamine catalysis for the synthesis of disubstituted dihydro-
benzofurans using intramolecular Michael addition reactions
(Scheme 1b).7 Using a primary amine analogue of quinidine,
Scheme 1 Organocatalytic enantioselective synthesis of 2,3-dihydro-
benzofurans using intramolecular Michael additions.
EaStCHEM, School of Chemistry, University of St Andrews, North Haugh,
St Andrews, KY16 9ST, UK. E-mail: ads10@st-andrews.ac.uk
†Electronic supplementary information (ESI) available: Experimental pro-
cedures; product characterisation data; copies of NMR (1H, 13C, 19F, 31P) and
HPLC traces;21 X-ray crystallographic data file for compound 20. CCDC 1469161.
For ESI and crystallographic data in CIF or other electronic format see DOI:
10.1039/c6ob01326k
Jørgensen reported moderate to good diastereoselectivity and
excellent enantioselectivity for the synthesis of cis-2,3-di-
substituted dihydrobenzofurans [up to 83 : 17 dr (cis : trans),
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Table 1 Reaction optimisation: initial catalyst screena
Scheme 2 Brønsted base/hydrogen bonding catalytic approach to the
enantioselective synthesis of 2,3-dihydrobenzofurans.
99 : 1 er].7a Wang and Zhou found that a bifunctional primary
amine–squaramide catalyst provided complementary access to
trans-dihydrobenzofurans with excellent diastereo- and
enantioselectivity [up to 97 : 3 dr (trans : cis), 99 : 1 er].7b
Although a range of substitution patterns on the benzofuran
core were demonstrated, these enamine-catalysed methodo-
logies were limited to aryl-substituted enone Michael acceptors
and unhindered alkyl-substituted α-aryloxy ketone donors
(R2 = Me, one example of Et, Scheme 1b).
Time
(h)
Conv.b
(%)
drb
(trans : cis)
erc
(R,R : S,S)
Entry
Catalyst
1d
2d
3d
4
5
6
3
4
5
6
7
8
48
16
18
96
24
100
58
75
93
7
95 : 5
35 : 65
68 : 32
78 : 22
78.5 : 21.5
n.d.e
78 : 22
62 : 38
93 : 7
62 : 38
83 : 17
To extend the range of methodologies available for the
stereoselective synthesis of dihydrobenzofurans, we sought to
develop alternative methods for the cyclisation of α-aryloxy-
substituted ketone derivatives containing a pendant enone
Michael acceptor (Scheme 2). Specifically, the use of α-aryloxy-
120
86
68 : 32
a Conditions: 1 (0.044 mmol), catalyst (10 mol%), CH2Cl2 (0.044 M),
substituted acetophenone derivatives with both aryl and alkyl- r.t. b Measured by 1H NMR spectroscopy. c Measured by chiral HPLC
(major diastereoisomer). d i-Pr2NEt (0.044 mmol) added. e Not
substituted Michael acceptors were targeted in order to
provide product architectures currently inaccessible by organo-
determined.
catalytic methods. Herein we report the development of a
Brønsted base catalytic approach for the diastereo- and
enantioselective synthesis of trans-2,3-disubstituted 2,3-di-
the bifunctional catalyst framework by using cinchona alka-
loid-derived thiourea 7 12 and Jacobsen’s amide-substituted
hydrobenzofurans. This approach was found to be most
thiourea 8 13 gave inferior conversions and levels of stereo-
effective when combined in concert with hydrogen bonding
control (entries 5 and 6). Based on the promising diastereo-
catalysis. The wider applicability of the methodology is also
and enantioselectivities obtained, further optimisation was
demonstrated through extension to the synthesis of tetrahydro-
undertaken using guanidine
3 and bifunctional tertiary
furan and indane core structures.
amine–thiourea 6 (Tables 2 and 3).
The effect of temperature on stereocontrol was first investi-
gated using guanidine 3 (Table 2, entries 1–3). It was found
that improved enantioselectivity was obtained at lower reaction
temperatures, with −20 °C giving the best combination of
Results and discussion
Reaction optimisation
Initial studies focused on the use a selection of Brønsted bases enantioselectivity and reactivity (entry 2). A solvent screen
for the cyclisation of keto–enone 1 (Table 1). This substrate identified 1,2-dichloroethane as optimal, with much shorter
could be easily prepared in two steps from salicylic aldehyde reaction times providing full conversion and comparable levels
and represented a substrate class which was not amenable to of stereocontrol (entries 4–6). A base screen showed that the
cyclisation using the organocatalytic methods previously tertiary amine i-Pr2NEt gave the highest enantioselectivity
reported by ourselves,6 Jørgensen,7a and Wang and Zhou.7b (entry 6). The use of a secondary amine (i-Pr2NH) resulted in
Pleasingly, the use of C2-symmetric guanidine 3 8 provided lower conversion and stereocontrol (entry 7), whilst the use of
trans-dihydrobenzofuran 2 in high yield and with excellent an amidine (DBU) or inorganic base (Cs2CO3) gave trans-
diastereoselectivity, albeit with only modest enantioselectivity dihydrobenzofuran 2 as a racemate (entries 8 and 9). These results
(entry 1). The use of alternative Brønsted base catalysts 4 9 and may be explained by a competitive racemic background reac-
5 10 gave trans-dihydrobenzofuran 2 with improved enantio- tion, as in the absence of catalyst 3 both DBU and Cs2CO3 gave
selectivity, but with relatively low diastereoselectivity (entries full conversion to trans-dihydrobenzofuran 2 in the same reac-
2 and 3). Takemoto’s bifunctional tertiary amine–thiourea cata- tion time. An analogous control reaction using i-Pr2NEt in the
lyst 6 11 provided trans-dihydrobenzofuran 2 with promising absence of catalyst 3 resulted in just 4% conversion in 91 h,
levels of diastereo- and enantiocontrol (entry 4). Variation of indicating that the rate of racemic background reaction was
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Table 2 Reaction optimisation using C2-symmetric guanidine 3a
Entry
Temp. (°C)
Solvent
Base
Time (h)
Conv.b (%)
drb (trans : cis)
erc (R,R : S,S)
1
2
3
4
5
6
7
r.t.
CH2Cl2
CH2Cl2
CH2Cl2
PhMe
i-Pr2NEt
i-Pr2NEt
i-Pr2NEt
i-Pr2NEt
i-Pr2NEt
i-Pr2NEt
i-Pr2NH
DBU
48
60
96
60
16
16
16
16
16
16
115
100
100
100
100
23
95
65
97
98
0
91
95 : 5
94 : 6
93 : 7
95 : 5
90 : 10
94 : 6
93 : 7
97 : 3
96 : 4
—
35 : 65
21.5 : 78.5
21.5 : 78.5
33.5 : 66.5
42 : 58
21.5 : 78.5
38.5 : 61.5
50 : 50
−20 → r.t.
−78 → r.t.
−20 → r.t.
−20 → r.t.
−20 → r.t.
−20 → r.t.
−20 → r.t.
−20 → r.t.
−20 → r.t.
−20
EtOAc
(ClCH2)2
(ClCH2)2
(ClCH2)2
(ClCH2)2
(ClCH2)2
(ClCH2)2
8d
9d
10
11
Cs2CO3
—
i-Pr2NEt
51 : 49
—
17.5 : 82.5
93 : 7
a Conditions: 1 (0.044 mmol), catalyst (10 mol%), solvent (0.044 M). b Measured by 1H NMR spectroscopy. c Measured by chiral HPLC (major dia-
stereoisomer). d Same conversion and dr obtained under the same reaction conditions in the absence of catalyst 3.
Table 3 Reaction optimisation using Takemoto’s tertiary amine/thiourea bifunctional catalyst 6a
Entry
Catalyst loading (mol%)
Temp. (°C)
Solvent
Time (h)
Conv.b (%)
drb (trans : cis)
erc (R,R : S,S)
1
2
3
4
5
6
7
8
20
20
20
20
20
20
20
20
20
5
r.t.
r.t.
r.t.
r.t.
r.t.
0
10
35
50
50
50
80
50
CH2Cl2
EtOAc
Dioxane
THF
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
96
96
72
72
96
48
96
18
18
42
72
20
144
93
35
9
28
100
13
93 : 7
94 : 6
71 : 29
71 : 29
94 : 6
99 : 1
91 : 9
93 : 7
94 : 6
94 : 6
96 : 4
96 : 4
65 : 35
78 : 22
86 : 14
87.5 : 12.5
78.5 : 21.5
88 : 12
65.5 : 34.5
84 : 16
92 : 8
92 : 8
95 : 5
92.5 : 7.5
87 : 13
50 : 50
53
89
9
97
10d
11
12
13f
92 (83)e
97
2.5
2.5
20
88
53
1
a Conditions: 1 (0.044 mmol), catalyst (2.5–20 mol%), solvent (0.044 M). b Measured by H NMR spectroscopy. c Measured by chiral HPLC (major
diastereoisomer). d Performed on 0.26 mmol scale, reaction concentration = 0.086 M. e Isolated yield. f 9 used in place of 1.
insignificant using this base. Interestingly, in the absence of using guanidine 3, attention was focussed on reaction optimi-
an auxiliary base no reaction took place, despite the overall sation using Takemoto’s catalyst 6.
reaction being a proton-neutral process (entry 10). Finally, it
An initial solvent screen using Takemoto’s catalyst 6 at
was found that using an immersion cooler to maintain a more room temperature revealed toluene to be optimal, giving trans-
constant reaction temperature resulted in an improved dihydrobenzofuran 2 in full conversion and with improved
enantioselectivity of 82.5 : 17.5 er, albeit following a 115 h reac- enantioselectivity (88 : 12 er, Table 3, entry 5). Using this cata-
tion time. As satisfactory optimisation could not be achieved lyst an auxiliary base was not required in order to obtain good
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reactivity. Interestingly, whilst lowering the reaction tempera-
ture resulted in excellent diastereocontrol, the enantio-
selectivity of the reaction was significantly reduced (entries
6 and 7). In contrast, increasing the reaction temperature gave
an improvement in both enantioselectivity and conversion
(entries 8 and 9).14 Conducting the reaction at 50 °C allowed
the catalyst loading to be dropped to 5 mol%, with trans-
dihydrobenzofuran 2 isolated in 83% yield with excellent
diastereo- and enantioselectivity (94 : 6 dr, 95 : 5 er, entry 10).
The catalyst loading could be reduced to 2.5 mol% without sig-
nificant loss in diastereo- or enantiocontrol, however extended
reaction times were required for high conversion (entry 11).
Increasing the reaction temperature to 80 °C in an attempt to
improve conversion resulted in decreased enantioselectivity
(entry 12). The use of 5 mol% of Takemoto’s catalyst 6 in
toluene at 50 °C was therefore chosen as the optimal reaction
conditions (entry 10). Under these conditions, the cyclisation of
α-aryloxy methyl ketone 9, previously used by Jørgensen,7a and
Wang and Zhou,7b was investigated. This substrate was found to
react slowly and give 2,3-dihydrobenzofuran 10 as a racemate
(entry 13). This result, in combination with the successful cycli-
sation of keto–enone 1, demonstrates high complementarity
between the developed method using Brønsted base/hydrogen
bonding catalysis and the enamine catalysis methods previously
reported by Jørgensen,7a and Wang and Zhou.7b
Scheme 3 Previous reports using Takemoto’s catalyst
molecular cyclisations using carbon-based pro-nucleophiles.
6 for intra-
Table 4 Substrate scope: variation of aromatic core
Takemoto’s catalyst 6, and subsequent related derivatives,
have been used to catalyse a wide range of highly diastereo-
and enantioselective addition reactions.15 For reactions pro-
ceeding through Brønsted base/hydrogen bonding catalysis
however, in general only highly activated pro-nucleophiles
such as 1,3-dicarbonyls (pKa ≈ 7–16 in DMSO),16a,b nitro-
alkanes (pKa ≈ 12–17 in DMSO)16c,d and heterocycles which upon
deprotonation gain aromaticity, have been used. In contrast,
keto–enone 1 represents a much less-activated class of pro-
nucleophile (pKa ≈ 21 in DMSO).16e Takemoto’s catalyst 6, and
related derivatives, have been applied previously in intra-
molecular cyclisations,15 however the majority of these
examples initially involve the intermolecular reaction between
two achiral reactants to give a stereodefined intermediate,
which then undergoes cyclisation. In these processes the role
of the catalyst in the intramolecular cyclisation event is not
well defined, with the formation of further stereocenters in the
intramolecular reaction potentially proceeding under substrate
control. Examples in which Takemoto’s catalyst 6 has been
used for C–C bond forming intramolecular reactions starting
a Isolated yield. b Measured by 1H NMR spectroscopy. c Measured by
chiral HPLC (major diastereoisomer).
from achiral reactants are scarce (Scheme 3).17 It was therefore 4-, 5-, 6- or 7-position, obtained in high yield and with excel-
considered of interest to fully explore the scope of this novel lent diastereo- and enantioselectivity (Table 4). Notably, the
intramolecular cyclisation process, with a focus on examining aromatic system could be extended to give dihydronaphtho-
the use of less highly activated aryl-ketone pro-nucleophiles furan derivative 11, and the incorporation of both electron-
(pKa ≥ 20 in DMSO).
donating and electron-withdrawing substituents was well
tolerated.
Reaction scope and limitations
Variation of the Michael acceptor and the pro-nucleophilic
An extensive investigation of the substrate scope and limit- groups of the substrates was then investigated (Table 5). The
ations of this methodology was next investigated (Tables 4, 5, addition of electron-donating substituents (NMe2, OMe, Me) to
and Scheme 4). Variation of the aromatic core was well toler- the Michael acceptor gave trans-dihydrobenzofurans 16, 17,
ated, with cyclised products 11–15 bearing substitution in the and 18 in high yield and with excellent diastereo- and enantio-
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Table 5 Substrate scope: Michael acceptor and pro-nucleophile scope
required a higher catalyst loading and longer reaction time
than that of 1, consistent with the lower pKa expected for the
α-protons. The use of an acyclic substrate without an aromatic
tether 27 was also investigated, with 3,4-disubstituted tetra-
hydrofuran 28 obtained in good yield and stereocontrol. To the
best of our knowledge, the use of such pro-nucleophiles has
not been reported previously using bifunctional tertiary
amine–thiourea catalysts.
Scheme 4 Substrate scope: non-activated ketone pro-nucleophiles.
a Isolated yield. b Measured by 1H NMR spectroscopy. c Measured by
chiral HPLC (major diastereoisomer). d Yield of major diastereoisomer.
The relative and absolute configuration within the major
diastereoisomer of tert-butyl-substituted 2,3-dihydrobenzo-
furan 20 was confirmed by single crystal X-ray analysis.18 The
absolute configuration of the remaining products were
assigned by analogy. Based upon the absolute configuration of
the product it is possible to propose a tentative rationale for
the stereochemical outcome of the reaction (Fig. 1). The mecha-
nism of reactions promoted by bifunctional tertiary amine–
thiourea catalysts have been studied experimentally and theore-
tically by a number of groups.19 Based on these works, it is
assumed that the carbonyl of the pro-nucleophile binds to the
thiourea, enhancing the acidity of the α-proton, and enabling
deprotonation by the proximal tertiary amine to give a (Z)-
enolate with subsequent stereodetermining C–C bond for-
mation. The pre-transition state assembly for this step may be
characterised by the thiourea binding the oxyanion of the
enolate, with the ammonium ion hydrogen bonding to the
enone (Fig. 1, TS1†).19c,e–g,i,j An alternative plausible pre-tran-
a Isolated yield. b Measured by 1H NMR spectroscopy. c Measured by
chiral HPLC (major diastereoisomer). d 20 mol% 6 used.
control. Slightly extended reaction times were required in
these cases, which may be rationalised by the lower electrophi-
licity of the Michael acceptor. In line with this proposal, sub-
stitution of the Michael acceptor with an electron-withdrawing
substituent (CF3) gave cyclised product 19 in a shorter reaction
time, but with similarly high levels of diastereo- and enantio-
control. Alkyl-substituted Michael acceptors were also toler-
ated. tert-Butyl-substituted trans-dihydrobenzofuran 20 was
obtained in high yield and with excellent levels of stereo-
control, whilst methyl-substitution gave trans-dihydrobenzofuran
21 with only moderate diastereo- and enantioselectivity. Struc-
tural variation of the pro-nucleophilic ketone was also investi-
gated, with both electron-donating and -withdrawing groups
well tolerated. trans-Dihydrobenzofurans 22 and 23 were
obtained in high yield and with excellent diastereo- and
enantioselectivity, however the incorporation of a thiophenyl
moiety resulted in lower levels of stereocontrol.
Having demonstrated the synthesis of a range of dihydro-
benzofurans, the generality of the methodology was investi-
gated through the use of substrates in which the pro-
nucleophile was a simple unsubstituted ketone (pKa ≈ 24–25
in DMSO,16e,f Scheme 4). Using 25, an analogue of keto–enone
1 in which the oxygen linker was replaced with an all carbon
tether, led to the formation of indane 26 in good yield, albeit
with slightly lower levels of stereocontrol. This cyclisation
Fig. 1 Proposed models for the pre-transition state assembly.
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sition state assembly would involve the thiourea moiety hydro-
gen bonding to the enone, with the enolate forming an ion
pair with the ammonium (Fig. 1, TS2†).11,19d,h Both pre-tran-
sition state assemblies would predict addition of the Re-face of
the (Z)-enolate to the Re-face of the enone to give the observed
(2R,3R)-configuration.20
P. T. Franke, L. T. Nielsen, K. Daasbjerg and
K. A. Jørgensen, Angew. Chem., Int. Ed., 2010, 49, 129;
(d) Ł. Albrecht, L. K. Ransborg, V. Lauridsen, M. Overgaard
and K. A. Jørgensen, Angew. Chem., Int. Ed., 2011, 50,
12496; (e) A. Lu, K. Hu, Y. Wang, H. Song, Z. Zhou, J. Fang
and C. Tang, J. Org. Chem., 2012, 77, 6208; (f) M. M. Calter
and N. Li, Org. Lett., 2011, 13, 3686; (g) C. Jarava-Barrera,
F. Esteban, C. Navarro-Ranninger, A. Parra and J. Alemán,
Chem. Commun., 2013, 49, 2001; (h) X.-X. Sun, H.-H. Zhang,
G.-H. Li, L. Meng and F. Shi, Chem. Commun., 2016, 52,
2968.
5 For selected recent examples see: (a) C. Simal, T. Lebl,
A. M. Z. Slawin and A. D. Smith, Angew. Chem., Int. Ed.,
2012, 51, 3653; (b) E. R. T. Robinson, C. Fallan, C. Simal,
A. M. Z. Slawin and A. D. Smith, Chem. Sci., 2013, 4, 2193;
(c) D. Belmessieri, D. B. Cordes, A. M. Z. Slawin and
A. D. Smith, Org. Lett., 2013, 15, 3472; (d) L. C. Morrill,
J. Douglas, T. Lebl, A. M. Z. Slawin, D. J. Fox and
A. D. Smith, Chem. Sci., 2013, 4, 4146; (e) S. R. Smith,
C. Fallan, J. E. Taylor, R. McLennan, D. S. B. Daniels,
L. C. Morrill, A. M. Z. Slawin and A. D. Smith, Chem. – Eur.
J., 2015, 21, 10530; (f) A. T. Davies, A. M. Z. Slawin and
A. D. Smith, Chem. – Eur. J., 2015, 21, 18944.
Conclusion
In conclusion, the catalytic enantioselective synthesis of trans-
2,3-disubstituted dihydrobenzofurans from readily-available
salicylic aldehyde derivatives has been achieved using a bifunc-
tional tertiary amine–thiourea catalyst 6. This method provided
a range of dihydrobenzofuran derivatives in high yield with
generally good to high diastereo- and enantiocontrol (up to
96 : 4 dr and 95 : 5 er). The generality of the method was high-
lighted by extension to the synthesis of disubstituted 2,3-
indane, and 3,4-tetrahydrofuran substructures. Ongoing work
in this laboratory is focused on further applications of organo-
catalysis for the asymmetric synthesis of biologically-active
compounds.
6 (a) D. Belmessieri, L. C. Morrill, C. Simal, A. M. Z. Slawin
and A. D. Smith, J. Am. Chem. Soc., 2011, 133, 2714;
(b) D. Belmessieri, A. de la Houpliere, E. D. D. Calder,
J. E. Taylor and A. D. Smith, Chem. – Eur. J., 2014, 20, 9762.
7 (a) J. Christensen, Ł. Albrecht and K. A. Jørgensen, Chem. –
Asian J., 2013, 8, 648; (b) Y. Liu, A. Lu, K. Hu, Y. Wang,
H. Song, Z. Zhou and C. Tang, Eur. J. Org. Chem., 2013, 4836.
8 (a) E. J. Corey and M. J. Grogan, Org. Lett., 1999, 1, 157;
(b) W. Ye, D. Leow, S. L. M. Goh, C.-T. Tan, C.-H. Chian and
C.-H. Tan, Tetrahedron Lett., 2006, 47, 1007.
Acknowledgements
The research leading to these results (D.-J. B. A.; C. F.) has
received funding from the ERC under the European Union’s
Seventh Framework Programme (FP7/2007–2013)/ERC grant
agreement no 279850. ADS thanks the Royal Society for a
Wolfson Research Merit Award. We also thank the EPSRC UK
National Mass Spectrometry Facility at Swansea University.
9 Z. Yu, X. Liu, L. Zhou, L. Lin and X. Feng, Angew. Chem.,
Int. Ed., 2009, 48, 5195.
References
1 (a) A. Goel, A. Kumar and A. Raghuvanshi, Chem. Rev., 10 J. S. Bandar and T. H. Lambert, J. Am. Chem. Soc., 2012,
2013, 113, 1614; (b) M. Saleem, H. J. Kim, M. S. Ali and 134, 5552.
Y. S. Lee, Nat. Prod. Rep., 2005, 22, 696; (c) R. S. Ward, Nat. 11 (a) T. Okino, Y. Hoashi and Y. Takemoto, J. Am. Chem. Soc.,
Prod. Rep., 1999, 16, 75; (d) P. Proksch and E. Rodriguez,
Phytochemistry, 1983, 22, 2335.
2003, 125, 12672; (b) T. Okino, Y. Hoashi, T. Furukawa,
X. Xu and Y. Takemoto, J. Am. Chem. Soc., 2005, 127, 119.
2 For reviews see: (a) T. D. Sheppard, J. Chem. Res., 2011, 35, 12 (a) B. Vakulya, S. Varga, A. Csámpai and T. Soós, Org. Lett.,
377; (b) F. Bertolini and M. Pineschi, Org. Prep. Proced. Int.,
2009, 41, 385.
2005, 7, 1967; (b) S. H. McCooey and S. J. Connon, Angew.
Chem., Int. Ed., 2005, 44, 6367.
3 For selected recent examples see: (a) L. Pauli, R. Tannert, 13 D. E. Fuerst and E. N. Jacobsen, J. Am. Chem. Soc., 2005,
R. Schiel and A. Pfaltz, Chem. – Eur. J., 2015, 21, 1482; 127, 8964.
(b) H. Cong and G. C. Fu, J. Am. Chem. Soc., 2014, 136, 14 This temperature dependence may indicate that the
3788; (c) T. Shibuta, S. Sato, M. Shibuya, N. Kanoh,
T. Taniguchi, K. Monde and Y. Iwabuchi, Heterocycles,
2014, 89, 631; (d) H. Wang, G. Li, K. M. Engle, J.-Q. Yu and
H. M. L. Davies, J. Am. Chem. Soc., 2013, 135, 6774;
(e) N. Ortega, S. Urban, B. Beiring and F. Glorius, Angew.
Chem., Int. Ed., 2012, 51, 1710.
enantioselectivity of the reaction is entropy-controlled, see:
(a) H. Buschmann, H.-D. Scharf, N. Hoffmann and
P. Esser, Angew. Chem., Int. Ed. Engl., 1991, 30, 477;
(b) Y. Inoue, T. Yokoyama, N. Yamasaki and A. Tai, Nature,
1997, 341, 225; (c) J. Otera, K. Sakamoto, T. Tsukamoto and
A. Orita, Tetrahedron Lett., 1998, 39, 3201; (d) Y. Sohtome,
B. Shin, N. Horitsugi, R. Takagi, K. Noguchi and
K. Nagasawa, Angew. Chem., Int. Ed., 2010, 49, 7299.
4 For selected examples see: (a) D. Enders, O. Niemeier and
L. Straver, Synlett, 2006, 3399; (b) J. Alemán, S. Cabrera,
E. Maerten, J. Overgaard and K. A. Jørgensen, Angew. 15 For reviews see: (a) G. Jakab and P. R. Schreiner, in Compre-
Chem., Int. Ed., 2007, 46, 5520; (c) K. L. Jensen,
hensive Enantioselective Organocatalysis: Catalysts, Reactions,
Org. Biomol. Chem.
This journal is © The Royal Society of Chemistry 2016

View Article Online
Organic & Biomolecular Chemistry
Paper
and Applications, ed. P. I. Dalko, Wiley-VCH, Weinheim, 19 For reviews see: (a) P. H.-Y. Cheong, C. Y. Legault,
2013, vol. 2, ch. 12, pp. 315–341; (b) Y. Takemoto, Chem.
Pharm. Bull., 2010, 58, 593; (c) S. J. Connon, Chem.
Commun., 2008, 2499; (d) W.-Y. Siau and J. Wang, Catal. Sci.
Technol., 2011, 1, 1298; (e) H. Xuehui, M. Zhiwei, W. Jianling
and L. Hongmin, Chin. J. Org. Chem., 2014, 34, 1509.
J. M. Um, N. Çelebi-Ölçüm and K. N. Houk, Chem. Rev.,
2011, 111, 5042; (b) Z. Zhang and P. R. Schreiner, Chem.
Soc. Rev., 2009, 38, 1187. For selected examples see:
(c) A. Hamza, G. Schubert, T. Soós and I. Pápai, J. Am.
Chem. Soc., 2006, 128, 13151; (d) S. J. Zuend and
E. N. Jacobsen, J. Am. Chem. Soc., 2007, 129, 15872;
(e) B. T. Tan, Y. Lu, X. Zeng, P. J. Chua and G. Zhong, Org.
Lett., 2010, 12, 2682; (f) R. Manzano, J. M. Andrés,
R. Álvarez, M. D. Muruzábal, Á. R. de Lera and R. Pedrosa,
Chem. – Eur. J., 2011, 17, 5931; (g) X.-F. Wang, L. Peng,
J. An, C. Li, Q.-Q. Yang, L.-Q. Lu, F.-L. Gu and W.-J. Xiao,
Chem. – Eur. J., 2011, 17, 6484; (h) C. Reiter, S. López-
Molina, B. Schmid, C. Neiss, A. Görling and S. B. Tsogoeva,
ChemCatChem, 2014, 6, 1324; (i) T. Azuma, Y. Kobayashi,
K. Sakata, T. Sasamori, N. Tokitoh and Y. Takemoto, J. Org.
Chem., 2014, 79, 1805; ( j) A. Quintard, D. Cheshmedzhieva,
M. M. Sanchez Duque, A. Gaudel-Siri, J.-V. Naubron,
Y. Génisson, J.-C. Plaquevent, X. Bagaut, J. Rodriguez and
T. Constantieux, Chem. – Eur. J., 2015, 21, 778.
16 (a) W. N. Olmstead and F. G. Bordwell, J. Org. Chem., 1980,
45, 3299; (b) E. M. Arnett, S. G. Maroldo, S. L. Schilling and
J. A. Harrelson, J. Am. Chem. Soc., 1984, 106, 6759;
(c) W. S. Matthews, J. E. Bares, J. E. Bartmess,
F. G. Bordwell, F. J. Cornforth, G. E. Drucker, Z. Margolin,
R. J. McCallum, G. J. McCollum and N. R. Vanier, J. Am.
Chem. Soc., 1975, 97, 7006; (d) F. G. Bordwell, J. E. Bares,
J. E. Bartmess, G. J. McCollum, M. Van Der Puy,
N. R. Vanier and W. S. Matthews, J. Org. Chem., 1977, 42,
321; (e) F. G. Bordwell, M. Van Der Puy and N. R. Vanier,
J. Org. Chem., 1976, 41, 1885; (f) F. G. Bordwell and
J. A. Harrelson Jr., Can. J. Chem., 1990, 68, 1714.
17 For catalyst-controlled C–C bond-forming cyclisations
using bifunctional tertiary amine/thiourea catalysts see:
(a) W. J. Nodes, D. R. Nutt, A. M. Chippindale and 20 Based upon previous computational work it would be
A. J. A. Cobb, J. Am. Chem. Soc., 2009, 131, 16016; (b) Q. Gu
and S.-L. You, Org. Lett., 2011, 13, 5192; (c) S. Sakamoto,
T. Inokuma and Y. Takemoto, Org. Lett., 2011, 13, 6374.
expected that these two assemblies may be similar in
energy, and therefore further discrimination at this time is
not possible.
18 CCDC 1469161 contains the supplementary crystallo- 21 The data underpinning this research can be found at DOI:
graphic data for compound 20.
10.17630/e2138b18-be8d-4632-8f92-6c1391a4d058.
This journal is © The Royal Society of Chemistry 2016
Org. Biomol. Chem.