Enantioselective (4+2) Annulation of Donor–Acceptor Cyclobutanes by N-Heterocyclic Carbene Catalysis

Article abstract of DOI:10.1002/anie.201609330

Herein we report the enantioselective (4+2) annulation of donor–acceptor cyclobutanes and unsaturated acyl fluorides using N-heterocyclic carbene catalysis. The reaction allows a 3-step synthesis of cyclohexyl β-lactones (25 examples) in excellent chemical yield (most ≥90 %) and stereochemical integrity (all >20:1 d.r., most ≥97:3 e.r.). Mechanistic studies support ester enolate Claisen rearrangement, while derivatizations provide functionalized cyclohexenes and dihydroquinolinones.

Full text of DOI:10.1002/anie.201609330

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201609330
German Edition: DOI: 10.1002/ange.201609330
NHC Catalysis
Enantioselective (4+2) Annulation of Donor–Acceptor Cyclobutanes
by N-Heterocyclic Carbene Catalysis
Alison Levens, Adam Ametovski, and David W. Lupton*
Abstract: Herein we report the enantioselective (4+2) annu-
lation of donor–acceptor cyclobutanes and unsaturated acyl
fluorides using N-heterocyclic carbene catalysis. The reaction
allows a 3-step synthesis of cyclohexyl b-lactones (25 exam-
ples) in excellent chemical yield (most ꢀ 90%) and stereo-
chemical integrity (all > 20:1 d.r., most ꢀ 97:3 e.r.). Mecha-
nistic studies support ester enolate Claisen rearrangement,
while derivatizations provide functionalized cyclohexenes and
dihydroquinolinones.
R
elease of ring-strain provides a powerful driving force for
reaction discovery. Perhaps nowhere is this more evident than
in the ring-opening annulation of vicinal donor–acceptor
(DA) cyclopropanes.[1] Interestingly, while analogous DA-
cyclobutanes (i.e. 1) possess similar strain energy, their
application in organic synthesis is significantly more limited
(Scheme 1).[2] For example, only within the last decade have
studies building on the pioneering work of Saigo[3] delivered
general Lewis acid catalyzed approaches to the (4+2)
annulation of DA-cyclobutanes [Eq. (1)].[4] These reactions
define a concise route to tetrahydropyrans, piperidines and
cyclohexanes (2) with excellent diastereoselectivity. Despite
important advances in catalysis with DA-cyclobutanes, to the
best of our knowledge, enantioselective variants of the (4+2)
annulation are yet to be discovered. Indeed the only example
of enantioselective catalysis using DA-cyclobutanes was
reported last year by Xie and Tang with the Lewis acid
catalyzed (4+3) annulation of nitrone 3 to afford oxazepane 4
[Eq. (2)].[5] Previously, we have had success with the annula-
tion of DA cyclopropanes to give enantioenriched cyclo-
pentanes [Eq. (3)].[6] Based on these experiences, we envi-
sioned a Lewis base approach to enable the first enantiose-
lective (4+2) annulation of DA-cyclobutanes.
The challenge with enantioselective Lewis acid catalysis
using DA-cyclobutanes likely relates to oxocarbenium ion
formation from the 1,4-ylide intermediate.[7] Such a scenario
allows bond formation remote to the catalyst, thereby limiting
chirality transfer [Eq. (1)]. In contrast, a dual activation Lewis
base approach would concurrently activate both coupling
partners (i.e. I and II), covalently linking the catalyst to the p-
system. Their subsequent union in a stepwise (4+2) annula-
tion[8] (I + II!6) should proceed with enantioselective bond
construction [Eq. (4)]. Mechanistically related (4+2) annula-
Scheme 1. Background.
tions exploiting non-cyclobutane substrates have been real-
ized by Romo and Studer, although in both cases only a single
example was reported.[9] More generally, dual activation
strategies to enable enantioselective catalysis have been
reported by ourselves and others using electron rich pyr-
idyl,[10] isothiourea[11] and N-heterocyclic carbene (NHC)[12]
catalysts. Herein we communicate the enantioselective (4+2)
annulation of DA cyclobutanes using a Lewis base approach,
which provides a range of enantioenriched cyclohexyl b-
lactones[13] (25 examples, most ꢀ 97:3 e.r.).
Preliminary studies focused on DA-cyclobutanes bearing
a single ester. While some opening and annulation occurred,
these substrates are less reactive than their cyclopropyl
analogs. To address this, the more reactive malonate derived
DA-cyclobutane 1a was targeted.[14] Gratifyingly, in the
presence of acyl fluoride 5a a trace of b-lactone 6a was
observed with Fuꢀs pyridyl catalyst, although isothiourea B
gave no product (Table 1, entries 1 and 2). In contrast,
NHC[15] C1 gave cyclohexyl b-lactone 6a in 18% yield as
a 67:33 ratio of enantiomers (Table 1, entry 3). Alternate
[*] A. Levens, A. Ametovski, Prof. D. W. Lupton
School of Chemistry, Monash University
Clayton 3800, Victoria (Australia)
E-mail: david.lupton@monash.edu
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/anie.201609330.
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Table 1: Selected optimizations.
Table 2: Scope.
Entry
Ar
R2
6
Yield e.r.[c]
[%][b]
1
2
3
4
4-BrC6H4
C6H5
Et
Et
Et
Et
Et
Et
Et
b
c
a
d
d
e
f
g
h
i
80
86
93
100
73
90
97
93
83
84
86
88
92:8
95:5
96:4
97:3
96:4
99:1
99:1
96:4
98:2
98:2
94:6
99:1
4-CH3C6H4
4-CH3OC6H4
4-CH3OC6H4
2,4-(CH3O)2C6H3
4-(CH3)2NC6H4
5[d]
6
Entry Cat.[a] T [8C] Solvent/Time
Yield [%][b] d.r.[c]
e.r.[d]
7
8
9
10
11
12
1
2
A
B
C1
C2-5
C6
D
rt THF/12 h
rt THF/12 h
rt THF/12 h
rt THF/12 h
rt THF/12 h
rt THF/12 h
rt THF/12 h
ꢁ78 THF/12 h
trace
–
18
trace
44
40
31
62
59
21
–
–
–
–
3,4,5-(CH3O)3C6H2 Et
3-Ts-indolyl
4-CH3OC6H4
4-CH3OC6H4
4-CH3OC6H4
Et
3[e]
4[e]
5[e]
6[e]
7[e]
8
>20:1 67:33
–
CH3
i-Pr
allyl
–
j
k
>20:1 96:4
>20:1 15:85
>20:1 78:22
>20:1 92:8
>20:1 97:3
>20:1 93:7
>20:1 92:8
>20:1 96:4
>20:1 96:4
>20:1 96:4
E
13
14
15
4-(CH3)2NC6H4
2,4-(CH3O)2C6H3
2-CH3OC6H4
Et
Et
CH3
l
m
n
90
83
87
96:4
97:3
97:3
C6
C6
C6
C6
C6
C6[f]
C6[g]
9
D
D
D
D
D
D
THF/12 h
10
11
12
13
14
toluene/11 h
DMF/13 h
1:9 DMF:THF/12 h 73
1:9 DMF:THF/2 h 93
1:9 DMF:THF/2 h 93
86
16
17
18
4-CH3OC6H4
2,4-(CH3O)2C6H3
2-BnN(CH3)C6H4
Et
Et
Et
o
p
q
93
100
98
97:3
99:1
99:1
[a] NHCs generated with KHMDS [b] Isolated yield. [c] Diastereomeric
ratio by H-NMR analysis. [d] Enantiomeric ratio by HPLC over chiral
stationary phases. [e] 20 mol% catalyst. [f] KBF4 and HMDS free, see
experimental section. [g] 10 mol% HMDS, KBF4 free.
1
19
20
4-(CH3)2NC6H4
2,4-(CH3O)2C6H3
Et
Et
r
s
88
81
93:7
90:10
21
22
4-(CH3)2NC6H4
2,4-(CH3O)2C6H3
Et
Et
t
u
98
99
97:3
98:2
morpholine catalysts C2–C5 bearing various N-substituents[16]
were not viable (Table 1, entry 4), however t-butyl NHC C6
gave a 44% yield of enantioenriched b-lactone 6a (96:4 e.r.)
as a single diastereoisomer (> 20:1 d.r.) (Table 1, entry 5).
Indanol and pyrrolidine t-butyl catalysts D and E were viable,
albeit less enantioselective (Table 1, entries 6 and 7). Enan-
tioselectivity was poorer at lower temperature, while it
increased when heated to reflux (97:3 e.r.) (Table 1, entries 8
and 9). The reaction tolerated toluene and DMF, with the
later increasing yield but decreasing enantioselectivity
(Table 1, entries 10 and 11). A compromise between yield
and enantioselectivity was realized, with a 1:9 DMF/THF
mixture providing b-lactone 6a in 73% yield and 96:4 e.r.
(Table 1, entry 12). Finally a “salt”[17] and HMDS-free version
of the reaction increased the yield to 93% without affecting
enantioselectivity (Table 1, entry 13). Reintroduction of
HMDS had no impact on the reaction (Table 1, entry 14),
thus removal of KBF4 is key to this improvement (see below).
Reaction generality was examined with the coupling of
unsaturated acyl fluorides 5 and DA-cyclobutanes 1. While
electron poor, neutral, and rich acyl fluorides reacted with
good yields (ꢀ 80%), enantioselectivity was sensitive to b-
aryl electronics. Thus, substrates containing the 4-BrC6H4
group gave b-lactone 6b in 92:8 e.r. (Table 2, entry 1), while
electron rich 2,4-(CH3O)2C6H3 and 4-(CH3)2NC6H4 gave 6e
and 6 f in 99:1 e.r. (Table 2, entries 6 and 7). The reaction
23
24
4-CH3OC6H4
2,4-(CH3O)2C6H3
Et
Et
v
w
94
80
98:2
98:2
25
26
4-CH3OC6H4
2,4-(CH3O)2C6H3
Et
Et
x
y
75
91
98:2
99:1
[a] Determined by 1H-NMR analysis of crude residue. [b] Isolated yield.
[c] Enantiomeric ratio by HPLC over chiral stationary phases. [d] 3 mol%
C6.
tolerated N-heterocycles with indole-containing b-lactone 6h
prepared in 83% yield and 98:2 e.r. (Table 2, entry 9).
Unfortunately, b-alkyl acyl fluorides were not compatible
with the reaction, potentially due to acyl azolium dienolate
formation as developed by Chi and others with related
substrates.[18] Variation of the ester was examined with
methyl, isopropyl, and allyl esters (6i, 6j and 6k) prepared
with excellent enantiopurity (98:2, 94:6 and 99:1 e.r.)
2
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(Table 2, entries 10–12). The later was analyzed by single-
crystal X-ray diffraction to determine absolute stereochem-
istry.[19] Absence of substitution about the cyclobutane was
tolerated with cyclohexyl b-lactones 6l, 6m and 6n prepared
in ꢀ 96:4 e.r. (Table 1, entries 13–15). Similarly dimethyl DA-
cyclobutane gave b-lactones 6o, 6p and 6q in excellent yield
and enantiopurity (97:3, 99:1 and 99:1 e.r.) (Table 1,
entries 16–18). The synthesis of spirocyclic cyclobutanes 6r
and 6s occurred with decreased enantioselectivity, 93:7 and
90:10 respectively, (Table 2, entries 19 and 20) while cyclo-
pentyl, heptyl, and octyl b-lactones 6t–6y all formed in ꢀ 97:3
e.r. (Table 2, entries 21–26). Finally, a vinylogous variant of
the reaction was possible using TBS ether 1l and acyl fluoride
5d to give d-lactone 6z [Eq. (7)]. NHC-catalyzed approaches
to related products have recently been report by Studer, Ye
and Chi, all with high enantioselectivity.[20] While the syn-
thesis of 6z was viable with IMes, suitable chiral catalysts are
yet to be identified, presumably due to the enhanced stability
of the TBS (cf. TMS) requiring more nucleophilic catalysts.
To allow larger scale (4+2) annulations lower catalyst
loadings were examined. Pleasingly, 3 mol% C6 provided the
expected product in good yield and similar enantioselectivity
(Table 2, entry 5), allowing a 5 mmol reaction, producing
1.98 grams of b-lactone 6d in 89% yield and 95:5 e.r. (cf.
100% yield; 97:3 e.r.), to be realized [Eq. (8)] (Scheme 2).
Derivatization studies commenced with the decarboxylation
of b-lactone 6e to afford cyclohexene 7 in 94% yield and 99:1
e.r. [Eq. (9)]. Coupling b-lactone decarboxylation with decar-
boxylative allylation of diallyl malonate 6k allowed diene 8 to
be prepared as a 3:1 mixture of diastereoisomers [Eq. (10)].
Opening of the b-lactone with ethanol triggered desymmet-
rization of the malonate to afford [2.2.2]-bicyclic d-lactone 9
[Eq. (11)]. Benzylamine, under milder conditions, opened the
b-lactone to afford amide 10 in 86% isolated yield [Eq. (12)],
while chemoselective reductive opening of the b-lactone led
to formation of diol 11 in 83% yield [Eq. (13)]. Finally,
hydrogenolysis of b-lactone 6q followed by cyclization
provided quinolinone 12 in 94% yield as a 5:1 mixture of
separable diastereomers [Eq. (14)]. Relative stereochemistry,
and structural confirmation, were performed by single-crystal
X-ray analysis.[19]
Scheme 2. Scale-up and derivatization studies.
azolium[9b] in a reaction likely to proceed by either Michael
ꢁ
addition or C O bond formation followed by Claisen
rearrangement.[22] To investigate these scenarios the reaction
was performed using various bases for NHC generation
bearing different counterions [Eq. (15)]. Tellingly, the reac-
tion fails with strongly coordinating lithium and sodium bases,
which favor Michael addition of the enolate. Similarly adding
LiCl (0.5 equiv) to a reaction with Cs2CO3 causes the reaction
to fail. In contrast, potassium and cesium salts favor ionic
ꢁ
structures, and subsequent C O bond formation, giving good
yields of 6a. Further support for a [3,3]-rearrangement is
derived from the known acceleration of such reactions by
poorly coordinating counterions.[23] Thus, we propose that
ꢁ
C O bond formation gives hemiacetal V that undergoes [3,3]-
Mechanistically, the early stages of this reaction likely
involve NHC mediated defluorination–desilylation to afford
acyl azolium III and enolate IV[21] (Scheme 3). The viability of
such a process is supported by the fluoride mediated opening
of cyclobutane 1a with TBAF which gives protonated IV in
88% yield (see the Supporting Information). Unfortunately,
re-subjection of this material to the reaction conditions leads
to complex mixtures, presumably as a result of acyl anion
formation. In related work of Studer this is avoided by
exploiting the methyl ketone variant of IV and a related acyl
sigmatropic rearrangement to afford VI, which after asyn-
chronous (2+2)[24] and loss of the NHC, then delivers b-
lactone 6. A striking observation in the optimization was the
enhanced enantioselectivity at higher temperatures.
Although less common than enhancement at low temperature
it has been observed in reactions with large entropic
contributions to the diastereomeric transition state energies
in the enantiodetermining step (i.e. DDS° significant cf.
S/R
DDH°S/R).[25] Although further studies are needed to fully
appreciate this interesting observation it seems probable that
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Scheme 3. Mechanistic studies.
reaction volume is gained in the conversion of V to VI that
allows the DDS° term to make a significant contribution to
the overall activation energy.
Donor–acceptor cyclobutanes are exceptional substrates
for reaction design. Beyond documented ring-strain, they are
readily accessible, with all substrates prepared in 2 steps.
Thus, the enantioselective (4+2) annulation allows a 3-step
synthesis of densely functionalized cyclohexyl b-lactones. This
sequence compares favorably to the state-of-the-art in
enantioselective b-lactone synthesis.[13] The ability of this
reaction to rapidly deliver molecular complexity is currently
being examined as a vehicle to drive studies in total synthesis
and medicinal chemistry.
[7] In references [4a,b,5a], the oxocarbenium ion is discussed to
account for the role of aldehyde electronics on reaction out-
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[8] For examples of all-carbon NHC catalyzed (4+2) annulations
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cyclobutenones: g) B.-S. Li, Y. Wang, Z. Jin, P. Zheng, R.
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Acknowledgements
The authors thank the Australian Research Council through
the Discovery (DP150101522) and Future Fellowship
(FT110100319) programs for financial support and Drꢀs
Craig Forsyth (Monash University) and Jamie Hicks
(Monash University) for X-ray crystallography.
[9] a) G. Liu, M. E. Shirley, K. N. Van, R. L. McFarlin, D. Romo,
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Keywords: cyclohexanes · donor–acceptor cyclobutanes ·
enantioselective catalysis · N-heterocyclic carbenes ·
organocatalysis
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4
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[13] For selected examples of enantioselective b-lactone synthesis:
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[19] Single crystal X-ray analysis of b-lactone 6k using CuK radiation
for absolute stereochemistry (CCDC 1494651), relative stereo-
chemistry and structure of 12 (CCDC 1500815). These data can
be obtained free of charge from The Cambridge Crystallo-
graphic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
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145.
[14] For studies on DA-cyclobutane synthesis see: a) E. Canales, E. J.
Corey, J. Am. Chem. Soc. 2007, 129, 12686; b) S. Mangelinckx, B.
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[21] S. J. Ryan, A. Stasch, M. N. Paddon-Row, D. W. Lupton, J. Org.
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A. Biswas, R. C. Samanta, A. Studer, Chem. Eur. J. 2013, 19,
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Flanigan, F. Romanov-Michailidis, N. A. White, T. Rovis, Chem.
Rev. 2015, 115, 9307.
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Samanta, B. Maji, S. De Sarkar, K. Bergander, R. Frçhlich, C.
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[23] D. A. Evans, A. M. Golob, J. Am. Chem. Soc. 1975, 97, 4765.
[24] For computational studies on b-lactonization by (2+2) see:
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b) D. E. A. Raup, B. Cardinal-David, D. Holte, K. A. Scheidt,
Received: September 23, 2016
Revised: October 31, 2016
Published online: && &&, &&&&
Angew. Chem. Int. Ed. 2016, 55, 1 – 6
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

Angewandte
Communications
Chemie
Communications
NHC Catalysis
A. Levens, A. Ametovski,
D. W. Lupton*
&&&& — &&&&
Enantioselective (4+2) Annulation of
Donor–Acceptor Cyclobutanes by N-
Heterocyclic Carbene Catalysis
Feeling a little strained? The enantio-
selective (4+2) annulation of donor–
acceptor cyclobutanes with unsaturated
acyl fluorides using N-heterocyclic car-
bene (NHC) catalysis has been discov-
ered. The reaction provides a 3-step entry
to cyclohexyl b-lactones (25 examples) in
excellent chemical yield (most ꢀ90%)
and stereochemical integrity (all >20:1
d.r., most ꢀ97:3 e.r.).
6
www.angewandte.org
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2016, 55, 1 – 6
These are not the final page numbers!