Enantioselective N-Heterocyclic Carbene Catalysis via the Dienyl Acyl Azolium

Article abstract of DOI:10.1002/anie.201712604

Herein we report the enantioselective N-heterocyclic carbene catalyzed (4+2) annulation of the dienyl acyl azolium with enolates. The reaction exploits readily accessible acyl fluorides and TMS enol ethers to give a range of highly enantio- and diastereo-enriched cyclohexenes (most >97:3 er and >20:1 dr). The reaction was found to require high nucleophilicity NHC catalysts with mechanistic studies supporting a stepwise 1,6-addition/β-lactonization.

Full text of DOI:10.1002/anie.201712604

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
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Accepted Article
Title: Enantioselective N-heterocyclic carbene (NHC) catalysis via the
dienyl acyl azolium
Authors: Rachel M. Gillard, Jared E. M. Fernando, and David Lupton
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201712604
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10.1002/anie.201712604
Angewandte Chemie International Edition
DOI: 10.1002/anie.201((will be filled in by the editorial staff))
NHC catalysis
Enantioselective N-heterocyclic carbene (NHC) catalysis via the dienyl
acyl azolium**
Rachel M. Gillard, Jared E. M. Fernando and David W. Lupton*
Abstract: Herein we report the enantioselective N-heterocyclic
carbene catalyzed (4 + 2) annulation of the dienyl acyl azolium with
Established in imminium
catalysis.
Many enantioselective
reactions.
Established in acyl
azolium catalysis.
Many enantioselective
cascades.
enolates. The reaction exploits readily accessible acyl fluorides and
TMS enol ethers to give a range of highly enantio- and diastereo-
enriched cyclohexenes (most > 97:3 er and >20:1 dr). The reaction
was found to require high nucleophilicity NHC catalysts with
N
NHC
O
1
Herein
Established in imminium
catalysis.
A number of
mechanistic
studies
supporting
a
stepwise
1,6-
One report.
No enantioselective
reactions.
addition/b-lactonization.
enantioselective reactions.
N
O
NHC
2
3
N-Heterocyclic carbenes (NHC) enable diverse transformations
via normal and reverse polarity intermediates.1 In 2006, formation
and esterification of the a,b-unsaturated acyl azolium (1) was
discovered.2 Subsequent studies demonstrating its use in a broad
range of transformations1l,2-5 generally involving (3 + n)3 or (2 + n)4
annulations to provide sp3-rich materials in excellent yield and with
high enantiopurity.
CO2Et
10 mol% IMes•HCl,
10 mol% Cs2CO3,
200 mol% Ox.,
THF, rt
CO2Et
H3COC
H3C
H3COC
(1)
Ph
O
plus >30 other
examples
H3C
Ph
4
H
O
Ph
10 mol% IPr•HCl,
10 mol% KOtBu,
Cl2C6H4, Δ
While acyl azolium 1 has received significant attention, very
little has been directed to the chemistry of higher unsaturated
homologs,6a,b such as the dienyl acyl azolium (i.e. 2). The paucity of
chemistry involving dienyl acyl azolium 2 is striking and contrasts,
for example, iminium organocatalysis which exploits both the
a,b-unsaturated iminium and the dienyl iminium (3) in many
enantioselective tranformations.6c-g To the best of our knowledge,
the dienyl acyl azolium has only been successfully exploited once,
in Chi’s synthesis of substituted benzene derivatives 4 (eq. 1).7 In
addition we attempted to access the dienyl acyl azolium from ester 5,
however we found fragmentation was not possible and an olefin
isomerization Diels/Alder reaction gave [2.2.2]-bicyclic compounds
such as 6 (eq. 2).8 Herein, we report a new strategy for dienyl acyl
azolium formation that has enabled the discovery of an
enantioselective (4 + 2) annulation (eq. 3). The reaction allows the
highly diastereo- and enantioselective (most >97:3 er and >20:1 dr)
synthesis of polycyclic b-lactones (i.e. 7). In addition to providing a
novel approach to b-lactones9 this is the first example of
enantioselective catalysis via the dienyl acyl azolium.
Ph
O
(2)
O
Ph
O
5
O
O
O
not
observed
6
Ph
O
NHC
O
R2
R1(O)C
R3
R2
R4
R5
R1(O)C
R3
R4
cat. NHC
(3)
R5
OTMS
22 examples
O
most >97:3 er
most >20:1 dr
45-91% yield
F
O
8
7
9
O
Figure 1.
To avoid the olefin isomerization observed with ester 5 we
envisioned using acyl fluorides (i.e. 8), substrates suited to the
generation of unsaturated Lewis base adducts.10 In addition, deletion
of the d-substituent to favor 1,6-addition, and eliminate olefin
isomerization, was deemed desirable. Thus, reaction discovery
commenced with dienyl acyl fluoride 8a, prepared from
cyclohexanone in four-steps,11 and TMS enol ether 9a, prepared
from benzyl acetoacetate in one. Their coupling was expected to
provide products bearing three contiguous stereocentres including a
quaternary carbon thereby reducing the likelihood of aromatization.
When attempted with triazolylidene A in THF, b-lactone 7a formed
with modest yield, while the more nucleophilic IMes NHC B1 gave
the same product as a single diasteroisomer (>20:1 dr) and in 74%
yield (Table 1, entries 1 and 2). Using IPr (B2) a 15% yield of
lactone 7a with little diastereoselectivity was observed (Table 1,
entry 3). The outcome with IMes B1 was not improved using
alternate solvents (Table 1, entries 4-6). Development of the
enantioselective variant commenced by examining the impact of the
N-substituent on reaction outcome (Table 1, entries 7-9). These
studies demonstrated that more nucleophilic NHCs, which
[*]
Ms. Rachel M. Gillard, Mr. Jared E. M. Fernando and
Professor David W. Lupton*
School of Chemistry, Monash University
Clayton 3800, Victoria, AUSTRALIA
Fax: (+) 61 3 9905 4597
E-mail: david.lupton@monash.edu
[**] The authors thank the Australian Research Council through the
Discovery program (DP150101522) for financial support and
Dr Craig Forsyth (Monash University) for X-ray crystallography.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201xxxxxx.
1
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10.1002/anie.201712604
Angewandte Chemie International Edition
catalysed annulations.4a Pleasingly in this study acylic dienyl acyl
fluoride 8d (R4 = H; R5 = CH3) could be employed to give
cyclohexene 7l in 96:4 er and with acceptable yield. Next, changes
to the R3-group were examined to produce tricyclic b-lactones
bearing alkyne (7m–o), alkene (7p and q), aromatic (7r and s), and
a,b-unsaturated ester (7t) functionality. In all cases the
enantioselectivity remained high with most products obtained in
≥98:2 enantiomeric ratio. In the case of alkyne 7m X-ray
crystalographic analysis was performed to determine absolute
stereochemistry.15a As highlighted in the optimization, substrates in
which R2 ¹ H allow construction of a challenging quaternary carbon
with high enantioselectivity (>99:1 er), although poor
diastereoselectivity and yield (Table 1, entry 9). This was further
demonstrated with benzyl b-lactone 7u prepared in 97:3 er, but as a
1:1 mixture of diastereoisomers. In contrast, cyclic TMS enol ethers
gave quaternary carbon containing compounds, i.e. tetracycle 7v,
with excellent yield (91%) and diastereoselectivity (>20:1),
although modest enantioselectivity (69:31 er). This could be
improved using catalyst F2 at 0 °C, with b-lactone 7v formed in
81:19 er. These conditions were suitable for the synthesis of 7w and
x which formed with similar enantioselectivity and yield. The later
additionally bear ortho-disubstitution, were necessary (i.e. C4 and
5).12,13 Of these catalyst C514 was preferred giving b-lactone 7c in a
>99:1 enantiomeric ratio, albeit with poor diastereoselectivity and
yield (Table 1, entry 9). Examining the 2,6-(CH3O)2C6H3 substituent
on indanol (D) and pyrrolidine scaffolds (E1 and 2) failed to
improve the outcome, while desmethyl morpholinone catalysts
bearing either a 2,6-(CH3O)2C6H3 (F1) or Mes (F2) N-substituent
gave similar outcomes (Table 1, entries 10-14). Although the
optimal conditions (Table 1, entries 9 and 14) retain limitations in
preparing 7c this proved to be an outlier with all other b-lactones
formed in this study isolated in good yield with excellent enantio-,
and diasteropurity (vide infra).
Table 1. Selected Optimizations
R1
20 mol% cat. A–F,
solvent,
rt, 18 h
EtO2C
H3C
EtO2C
H3C
R1
R2
R2
R2
(4)
R2
OTMS
F
O
Table 2. Scope of the (4 + 2) annulationa-c
O
O
9a, R1 = Bn
b, R1 = CH2COCH3
8a, R2 = H
b, R2 = CH3
7a, R1 = Bn, R2 = H
b, R1 = CH2COCH3, R2 = H
c, R1 = CH2COCH3, R2 = CH3
R2
H3CO
R1(O)C
R3
R4
20 mol% cat. C5•HBF4,
20 mol% KHMDS,
THF, rt, 1-3 h
O
N
O
R4
N
N
R1(O)C
R2
N
H3C
H3C
R3
N
N
N
N
N
N
N
N
N
Mes
Ar
(5)
R5
R3
OTMS
Bn
Bn
F1, Ar =
2,6-(CH3O)2C6H3
F2,
R5
O
H3CO
A
C1, R3 = C6F5
C2, R3 = t-Bu
D
O
7c-x
all >20:1 dr except as noted
F
O
H3CO
9
8
C3, R3 = 4-CH3OC6H4
C4, R3 = Mes
N
N
N
N
Ar = Mes
H
Ph
H
C5, R3 = 2,6-(CH3O)2C6H3
Ar
H
Ar
R1OC
H3C
R1OC
R1OC
H3C
R4
H3CO
B1 Ar = Mes
B2 Ar = 2,6-(iPr)2C6H3
E1, R4 = H
E2, R4 = Ph
H3C
CH3
CH3
O
O
O
O
O
entry
cata
9/8
solvent
yieldb
drc
erd
O
7j, R1 = OEt, 72%, 99:1 er
k, R1 = OBn, 72%, 98:2 er
i, R1 = OtBu, 68%, 96:4 er
7d, R1 = OEt, 55%, 97:3 er 7h, R1 = OEt, 55%, 95:5 er
1c
2
A
a/a
THF
THF
THF
48
74
15
3:1
-
-
-
e, R1 = OBn, 71%, 98:2 er
f, R1 = Ph, 67%, >99:1 er
g, R1 = 4-CH3OC6H4, 75%, >99:1 er
B1
B2
"
"
>20:1
2:1
H
H
3
EtO2C
BnO2C
H3C
4
B1
"
"
DMF
C6H5CH3
dioxane
THF
11
60
54
-
2:1
19:1
19:1
-
-
CH3
5
"
-
O
O
6
"
"
-
O
O
7l, 45%, 96:4 erd
7
C1-3
C4
C5
D
b/a
-
7m, 77%, 97:3 er
EtO2C
H
H
H
8
"
THF
32
47
20
32
35
35
30
3:1
2:1
97:3
7:3
6:1
3:1
6:1
88:12
>99:1
98:2
81:19
63:37
91:9
96:4
EtO2C
EtO2C
9
b/b
THF
CH3
CH3
10
11
12
13
14
"
"
"
"
"
THF
O
n
O
O
E1
E2
F1
F2
THF
O
O
O
THF
7n, 76%, 92:8 er
7o, 66%, 93:7 er
7p, n=1, 63%, 98:2 er
q, n=2, 75%, 98:2 er
THF
C(O)CH3
H
H
THF
EtO2C
H3C
EtO2C
EtO2C
[a] NHCs generated with KHMDS [b] Isolated yield of 7 [c] Diastereomeric ratio
by 1H-NMR analysis [d] er determined by HPLC over chiral stationary phases.
CH3
CH3
n
O
O
O
O
O
O
EtO2C
7r, n=1, 65%, 99:1 er
s, n=2, 68%, 98:2 er
7c, 47%, 2:1 dr, >99:1 er
7t, 51%, 98:2 er
Reaction generality was examined with fourteen TMS enol
ethers of 1,3-diketones or b-ketoesters 9 and four dienyl acyl
fluorides 8 (Table 2). TMS enol ethers of ethyl, benzyl and t-butyl
Ph
CO2Et
CO2Et
EtO2C
CH3
CH3
H3C
O
CH3
CH3
b-ketoesters when R2
=
H
produced six cyclohexyl,
O
n
O
dimethylcyclohexyl and cycloheptyl fused b-lactones (7d, e and h–
k) in good yields. TMS enol ethers of 1,3-diketones were also viable
giving ketone containing b-lactones 7f and g both in >99:1 er and
good yield. In all eight examples high enantiopurity (≥95:5
enantiomeric ratio) with complete diastereoselectivity was observed
(>20:1 dr). Indeed, whilst studying generality 20 of the 22 examples
formed as single diastereoisomers. The s-cis enforcing annulation
(i.e. annulation across R4 and R5) has been essential in related NHC
O
O
7v, 91%, 69:31 er
73%, 81:19 ere
O
7u, 55%, 1:1 dr, 97:3 er
7w, n = 1, 61%, 76:24 ere
x, n = 2, 68%, 81:19 ere
[a] Isolated yield [b] Diastereomeric ratio by 1H-NMR analysis [c] er determined
by HPLC over chiral stationary phases [d] reaction heated to reflux [e] 20 mol%
F2 at 0 °C.
2
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10.1002/anie.201712604
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b-lactone 7c contains a pendant methyl ketone, that could have
delivered a (4 + 3) adduct. Failure to observed this product is likely
due to a more rapid 6-exo-trig cyclization (cf. 7-exo-trig) of the acyl
azolium enolate intermediate analogous to 14. To overcome this
kinetic bias, and expand the scope of chemistry accessible via dienyl
acyl azolium 2, trifluoro methyl ketone 9d was prepared. Pleasingly
this produced cycloheptane 15 however, despite significant
optimization, the yield remained poor (eq. 10).
product contains a tetracyclic ring system reminiscent of the
yonarolide and scabrolide natural products16 and is assembled in a
concise 4-step sequence from commercial materials.
Simple enolates have been sparingly exploited in NHC catalysed
reactions of acyl azolium.3a When the (4 + 2) annulation was
examined with the TMS enol ether of acetone (i.e. 10) and dienyl
acyl fluoride 8b a Claisen-condensation/(4 + 2) annulation provided
11 in 96:4 er (Scheme 1, eq. 6). This result suggests that the
d-position of the dienyl acyl azolium is less electrophilic than the
b-position of the related a,b-unsaturated acyl azolium, thus Claisen
condensation is kinetically more favourable than 1,6-addition.
The b-lactone products in this study were expected to have
moderate stability due to the presence of unsaturated functionality
likely to stabilise the biradicaloid transition state of
decarboxylation.17 Consistent with this prediction, it was found that
decarboxylation occurred when the b-lactones were heated at reflux
in dimethylformamide. While quaternary carbon containing
compounds (i.e. 7a) gave the expected diene (see SI) substrates
lacking this functionality (i.e. 7d) gave mixtures of olefin containing
products. However, when the decarboxylation was performed in the
presence of maleic anhydride a 92% yield of [2.2.2]-bicycle 1215b
was obtained, as a 4:1 mixture of the separable endo and exo
isomers, indicating that the Diels-Alder reaction is more facile than
olefin isomerization. As a consequence of the relatively high
stability of the b-lactone b-hydroxy amide 13 could be prepared in
98% yield and >99:1 enantiomeric ratio by simple ring-opening with
benzylamine.
H
EtO2C
TMSO
H
As in Table 1,
entry 9
EtO2C
H3C
(9)
CH3
O
8a
Z-9c
(from Z-9c)
H
F
O
7d, 57% yield,
>20:1 dr, 97:3 er
(from 9c)
7d, 55% yield,
>20:1 dr, 97:3 er
EtO2C
O
1,6-addition
H3C
O
H
O
EtO2C
H3C
NHC
H
EtO2C
H3C
O
O
NHC
O
H
14
EtO2C
E-7d
O
H3C
O
concerted
(4 + 2) annulation
NHC
O
O
CF3
O
CH3
20 mol% B1•HCl
20 mol% KHMDS,
THF, Δ, 14 h
EtO2C
EtO2C
H3C
(10)
CH3
CH3
CH3
CH3
8b
F3C
OTMS
F
O
O
15,10% yield,
>20:1 dr
9d
O
Scheme 2. Mechanistic studies and (4 + 3) annulation.
H3C
TMSO
CH3
As in
Table 1,
entry 9
H3C
H
10
O
H3C
(6)
CH3
CH3
8b
CH3
CH3
Studies reported herein exploit the dienyl acyl azolium in an
enantioselective (4 + 2) annulations with enolates. As with the lower
homolog (the a,b-unsaturated acyl azolium) good outcomes can be
achieved with enolates of b-ketoesters and 1,3-diketones.3
Pleasingly these are highly abundant materials. The transformation
gives rise to a diverse range of bi-, tri-, and tetracyclic b-lactones
with high stereochemical purity and yield. In addition to the
significant potential of this reaction to deliver enantioenriched
building blocks for synthesis these studies demonstrate the first
enantioselective reaction of the dienyl acyl azolium. Preliminary
studies have demonstrated the viability of a (4 + 3) annulation,
however the dienyl acyl azolium could be exploited in a host of
alternate reactions by appropriate selection of the coupling partner.
O
11,
68%, >20:1 dr,
96:4 er
F
O
O
H
EtO2C
Maleic anhydride,
toluene 110 °C, 15 h
EtO2C
H3C
(7)
H3C
O
O
O
7d
O
O
12,
92% yield, 4:1 endo:exo, 97:3 er
H
H
BnNH2, THF, 50 °C,
24 h
EtO2C
EtO2C
(8)
O
HO
Bn
7m
O
N
O
Received: ((will be filled in by the editorial staff))
H
13, 98%, >20:1 dr, >99:1 er
Published online on ((will be filled in by the editorial staff))
Scheme 1. Reaction of TMS enol ether of acetone (10) and b-lactone stability.
Keywords: enantioselective catalysis • N-heterocyclic carbene •
dienyl acyl azolium • 1,6-addition • b-lactonization•
Mechanistically a stepwise or concerted annulation is potentially
viable. To probe these scenarios Z-9c was prepared and reacted with
acyl fluoride 8a under the standard conditions (Scheme 2, eq. 9). In
a concerted reaction Z-9c should give E-7d. In the event the product
of this reaction was 7d, with similar yield, and identical
stereoselectivity to its formation from 9c. Thus, the reaction likely
proceeds via 1,6-addition to give acyl azolium enolate 14 which
[1] For selected reviews, on general NHC catalysis see: (a) D. Enders,
O. Niemeier, A. Henseler, Chem. Rev. 2007, 107, 5606–5655; (b)
M. N. Hopkinson, C. Richter, M. Schedler, F. Glorius, Nature 2014,
510, 485–496; (c) D. M. Flanigan, F. Romanov-Michailidis, N. A.
White, T. Rovis, Chem. Rev. 2015, 115, 9307–9387. For
homoenolate chemistry see: (d) V. Nair, R. S. Menon, A. T. Biju, C.
R. Sinu, R. R. Paul, A. Jose, V. Sreekumar, Chem. Soc. Rev. 2011,
40, 5336–5346; (e) R. S. Menon, A. T. Biju, V. Nair, Beilstein J.
Org. Chem. 2016, 12, 444–461. For acyl azolium enolates see: (f) J.
Douglas, G. Churchill, A. D. Smith, Synthesis 2012, 44, 2295–2309.
undergoes rotation prior to
b-lactonization.17 The likelihood of
introduces the possibility for alternate (4 + n) reactions. For example
a
pseudo-concerted aldol
a
stepwise mechanism
3
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10.1002/anie.201712604
Angewandte Chemie International Edition
T. Naicker, P. H. Poulsen, K. A. Jørgensen, J. Am. Chem. Soc. 2013,
135, 8063-8070; (e) X. Tian, P. Melchiorre, Angew. Chem. Int. Ed.
2013, 52, 5360-5363 (f) J. Wang, S.-G. Chem, B.-F. Sun, G.-Q. Lin,
Y. J. Shang, Chem. Eur. J. 2013, 19, 2539
For cascade catalysis see: (g) A. Grossmann, D. Enders, Angew.
Chem. Int. Ed. 2012, 51, 314–325. For acyl anion chemistry see: (h)
X. Bugaut, F. Glorius, Chem. Soc. Rev. 2012, 41, 3511–3522. For
applications in total synthesis see: (i) J. Izquierdo, G. E. Hutson, D.
T. Cohen, K. A. Scheidt, Angew. Chem. Int. Ed. 2012, 51, 11686–
11698. For acyl anion free catalysis see: (j) S. J. Ryan, L. Candish,
D. W. Lupton, Chem. Soc. Rev. 2013, 42, 4906–4917. For acyl
azolium catalysis: (k) S. De Sarkar, A. Biswas, R. C. Samanta, A.
Studer, Chem. Eur. J. 2013, 19, 4664–4678; (l) C. Zhang, J. F.
Hooper, D. W. Lupton, ACS Catalysis 2017, 7, 2583-2596. For
reactions with esters see: (m) P. Chauhan, D. Enders, Angew. Chem.
Int. Ed. 2014, 53, 1485–1487. For cooperative catalysis see: (n) M.
H. Wang, K. A. Scheidt, Angew. Chem. Int. Ed. 2016, 5, 424-429.
[2] For selected esterifications of the a,b-unsaturated acyl azolium see:
(a) K. Zeitler, Org. Lett. 2006, 8, 637–640; (b) B. E. Maki, A. Chan,
E. M. Phillips, K. A. Scheidt, Org. Lett. 2007, 9, 371–374.
[7] T. Zhu, C. Mou, B. Li, M. Smetankova, B.-A. Song, Y. R. Chi, J.
Am. Chem. Soc. 2015, 137, 5658–5661.
[8] M. Kowalczyk, D. W. Lupton, Angew. Chem. Int. Ed. 2014,
53, 5314-5317. ꢀ
[9] For selected examples of the enantioselective synthesis
of b-lactones: (a) G. S. Cortez, R. L. Tennyson, D. Romo, J. Am.
Chem. Soc. 2001, 123, 7945-7946; (b) C. Zhu, X. Shen, S. G.
Nelson, J. Am. Chem. Soc. 2004, 126, 5352-5353; (c) J. E. Wilson,
G. C. Fu, Angew. Chem. Int. Ed. 2004, 43, 6358-6360; (d) L. He, H.
Lv, Y.-R. Zhang, S. Ye, J. Org. Chem. 2008, 73, 8101-8103; (e) C.
A. Leverett, V. C. Purohit, D. Romo, Angew. Chem. Int. Ed. 2010,
49, 9479-9483. For reviews: (f) H. W. Yang, D. Romo, Tetrahedron
1999, 55, 6403-6434; (g) C. Schneider, Angew. Chem. Int. Ed. 2002,
41, 744-746; (h) V. C. Purohit, A. S. Matla, D. Romo, Heterocycles
2008, 76, 949-979.
[10]For selected examples of nucleophilic catalysis with acyl fluorides
see: 3(a), 4(a-c), (a) E. Bappert, P. Müller, G. C. Fu, Chem.
Commun. 2006, 2604-2606; (b) T. Poisson, V. Dalla, C. Papamicaël,
G. Dupas, F. Marsais, V. Levacher, Synlett. 2007, 3, 381-386; (c) P.
A. Woods, L. C. Morrill, T. Lebl, A. M. Z. Slawin, R. A. Bragg, A.
D. Smith Org. Lett. 2010, 12, 2660-2663.
[11] (a) R. J. K. Taylor, Synthesis 1977, 566-567; (b) G. Pousse, F. Le
Cavelier, L. Humphreys, J. Rouden, J. Blanchett, Org. Lett. 2010,
12, 3582-3585.
[12] For a discussion on the impact of the N-substituent see: A. Levens,
F. An, M. Breugst, H. Mayr, D. W. Lupton, Org. Lett. 2016, 18,
3566–3569, and references therein.
[13] For selected examples of the impact of the N-substituent on
reaction outcome: (a) M. S. Kerr, J. Read de Alaniz, T. Rovis, J.
Am. Chem. Soc. 2002, 124, 10298-10299; (b) J. Read de Alaniz, T.
Rovis, J. Am. Chem. Soc. 2005, 127, 6284-6289; (c) C. J. Collett, R.
S. Massey, O. R. Maguire, A. S. Batsanov, A. C. O’Donoghue, A.
D. Smith, Chem. Sci. 2013, 4, 1514-1522;
[14] For the N-2,6-(CH3O)2C6H3 group: (a) F. Liu, X. Bugaut, M.
Schedler, R. Fröhlich, F. Glorius, Angew. Chem. Int. Ed. 2011, 50,
12626-12630; (b) M. Schedler, D.-S. Wang, F. Glorius, Angew.
Chem. Int. Ed. 2013, 52, 2585-2589.
[15] (a) Single crystal X-ray analysis of b-lactone 7j using CuK
radiation for absolute stereochemistry (CCDC 1589642). These data
can be obtained free of charge from The Cambridge
Crystallographic Data Centre. (b) Single crystal X-ray analysis of
Diels-Alder adduct 12 was used to confirm relative stereochemistry
(CCDC 1818971).
[16] (a) J. H. Sheu, A. F. Ahmed, R.-T. Shiue, C.-F. Dai, Y.-H. Kuo, J.
Nat. Prod. 2002, 65, 1904-1908; (b) S.-Y. Cheng, C.-T. Chuang, Z.-
H. Wen, S.-K. Wang, S.-F. Chiou, C.-H. Hsu, C.-F. Dai, C.-Y. Duh,
Bioorganic Med. Chem. 2010, 18, 3379-3386.
[17] For mechanistic studies examining b-lactonization see: S. J. Ryan,
A. Stasch, M. N. Paddon-Row, D. W. Lupton, J. Org. Chem. 2012,
77, 1113-1124.
[3] For selected (3 + n) reactions: (a) S. J. Ryan, L. Candish, D. W.
Lupton, J. Am. Chem. Soc. 2009, 131, 14176–14177; (b) S. De
Sarkar, A. Studer, Angew. Chem. Int. Ed. 2010, 49, 9266–9269; (c) J.
Kaeobamrung, J. Mahatthananchai, P. Zheng, J. W. Bode, J. Am.
Chem. Soc. 2010, 132, 8810–8812; (d) F.-G. Sun, L.-H. Sun, S. Ye,
Adv. Synth. Cat. 2011, 353, 3134–3138; (e) J. Mo, L. Shen, Y. R.
Chi, Angew. Chem. Int. Ed. 2013, 52, 8588–8591; (f) X. Wu, B. Liu,
Y. Zhang, M. Jeret, H. Wang, P. Zheng, S. Yang, B.-A. Song, Y. R.
Chi, Angew. Chem. Int. Ed. 2016, 55, 12280–12284; (g) S. R. Yetra,
S. Mondal, S. Mukherjee, R. G. Gonnade, A. T. Biju, Angew. Chem.
Int. Ed. 2016, 55, 268–272.
[4] For selected (2 + n) reactions: (a) S. J. Ryan, L. Candish, D. W.
Lupton, J. Am. Chem. Soc. 2011, 133, 4694–4697; (b) L. Candish, D.
W. Lupton, J. Am. Chem. Soc. 2013, 135, 58–61; (c) L. Candish, A.
Levens, D. W. Lupton, J. Am. Chem. Soc. 2014, 136, 14397–14400;
(d) S. Bera, R. C. Samanta, C. G. Daniliuc, A. Studer, Angew. Chem.
Int. Ed. 2014, 53, 9622–9626; (e) S. Mondal, S. R. Yetra, A. Patra,
S. S. Kunte, R. G. Gonnade, A. T. Biju, Chem. Commun. 2014, 50,
14539–14542; (f) S. Bera, C. G. Daniliuc, A. Studer, Org. Lett.
2015, 17, 4940–4943; (g) Z.-Q. Liang, D.-L. Wang, H.-M. Zhang, S.
Ye, Org. Lett. 2015, 17, 5140–5143; (h) G. Zhang, W. Xu, J. Liu, D.
K. Das, S. Yang, S. Perveen, H. Zhang, X. Li, X. Fang, Chem.
Commun. 2017, DOI: 10.1039/C7CC08680F
[5] Selected g-addition reactions see: (a) J. Mo, X. Chen, Y. R. Chi, J.
Am. Chem. Soc. 2012, 134, 8810–8813; (b) X. Chen, S. Yang, B.-A.
Song, Y. R. Chi, Angew. Chem. Int. Ed. 2013, 52, 11134–11137; (c)
C. Yao, Z. Xiao, R. Liu, T. Li, W. Jiao, C. Yu, Chem. Eur. J. 2013,
19, 456–459; (d) M. Wang, Z. Huang, J. Xu, Y. R. Chi, J. Am.
Chem. Soc. 2014, 136, 1214–1217; (e) T. Zhu, P. Zheng, C. Mou, S.
Yang, B.-A. Song, Y. R. Chi, Nat. Commun. 2014, 5, 5027(1-6)
[6] For reviews see: (a) S. E. Denmark, J. R. Heemstra, G. L. Beutner,
Angew. Chem. Int. Ed. 2005, 44, 4682-4698. For an introduction to
dienyl iminium catalysis see: (b) d) M. J. Lear, Y. Hayashi
ChemCatChem 2013, 5, 3499-3501. For pioneering studies: (c) M.
Harmata, S. K. Ghosh, X. Hong, S. Wacharasindhu, P. Kirchhoefer,
J. Am. Chem. Soc. 2003, 125, 2058; (d) L. Dell’Amico, Ł. Albrecht,
4
This article is protected by copyright. All rights reserved.

10.1002/anie.201712604
Angewandte Chemie International Edition
CH3
N
H3C
O
NHC =
NHC Catalysis
Bn
H
EtO2C
H3C
EtO2C
H3C
N
N
Rachel M. Gillard, Jared E. M. Fernando
and David W. Lupton* __________
Page – Page
OCH3
OTMS
F
O
73% yield,
H3CO
O
>20:1 dr, 99:1 er
plus 21 other
examples.
O
-TMSF
EtO2C
H3C
Enantioselective N-heterocyclic carbene
(NHC) catalysis via the dienyl acyl
azoliums.
O
NHC
dienyl acyl azolium
O
1,6-Addition of enolates into the dienyl acyl azolium followed by b-lactonization
provides a diverse array of polycyclic b-lactones. The reaction proceeds with high
enantioselectivity, diastereoselectivity and good yields and represents the first
example of enantioselective catalysis using the dienyl acyl azolium, the higher
homolog of the a,b-unsaturated acyl azolium.
5
This article is protected by copyright. All rights reserved.