Enantioselective N-Heterocyclic Carbene Catalyzed Diene Regenerative (4 + 2) Annulation

Article abstract of DOI:10.1021/acs.orglett.5b02693

An enantioselective N-heterocyclic carbene (NHC)-catalyzed diene regenerative (4 + 2) annulation has been achieved through the use of highly nucleophilic morpholinone-derived catalysts. The reaction proceeds with good to excellent yields, high enantiosele

Full text of DOI:10.1021/acs.orglett.5b02693

Letter
pubs.acs.org/OrgLett
Enantioselective N‑Heterocyclic Carbene Catalyzed Diene
Regenerative (4 + 2) Annulation
Alison Levens, Changhe Zhang, Lisa Candish, Craig M. Forsyth, and David W. Lupton*
School of Chemistry, Monash University, Clayton 3800, Australia
S
* Supporting Information
ABSTRACT: An enantioselective N-heterocyclic carbene (NHC)-
catalyzed diene regenerative (4 + 2) annulation has been achieved
through the use of highly nucleophilic morpholinone-derived
catalysts. The reaction proceeds with good to excellent yields, high
enantioselectivity (most >92% ee), and good diastereoselectivity
(most >7:1). The generality of the reaction is high, with 19 examples
reported. The utility of the products has been examined with
subsequent derivatization in Diels−Alder reactions using electron-poor dienophiles. Furthermore, interception of the proposed
β-lactone intermediate has been achieved, allowing the synthesis of compounds bearing four contiguous stereocenters with high
levels of enantio- and diastereoselectivity.
ore than 80 years ago, Diels and Alder reported the
M
double (4 + 2) cycloaddition between maleic anhydride
and 2-pyranone 1. Following an initial Diels−Alder reaction,
decarboxylation regenerates diene intermediate 2 that reacts in a
subsequent (4 + 2) cycloaddition (eq 1).1a While one-pot diene
regenerative cascades (as in eq 1) have seen limited application,
stepwise and enantioselective versions have enduring signifi-
cance in target-focused synthesis.2,3
In 2011, our group reported the diene regenerative (4 + 2)
annulation of acyl fluorides (i.e., 4) and silyl dienol ethers (i.e., 5)
(eq 2).4a This N-heterocyclic carbene (NHC)-catalyzed5,6
transformation is orthogonal to pyranone (4 + 2) additions
providing regioisomeric diene products (i.e., 7 cf. 2). While the
reaction is highly diastereoselective (>20:1 dr), challenges
accessing the α,β-unsaturated acyl azolium7 and competing O-
acylation precluded discovery of the enantioselective variant,
while restricting reaction scope. To resolve these limitations,
established homochiral NHCs, BAC carbenes (A),8 imidazolium
NHCs (B,9a C,9b and E10), and imidazoliumide NHC (D)11 have
been examined over the last 5 years and found wanting in the
synthesis of 8 (Figure 1).12
Figure 1. Background.
isomerization (i.e., 9). While reaction discovery with F1 was not
possible, it was using the highly nucleophilic catalyst F2.15,16
Herein, we report studies that have allowed discovery of the
enantioselective NHC-catalyzed diene regenerative (4 + 2)
annulation. The reaction has broad scope (>19 examples), high
enantioselectivity (most >92% ee), and good diastereoselectivity
(most >7:1 dr). Derivatization of the dienyl products (i.e., 10)
through subsequent Diels−Alder reactions and interception of
the β-lactone intermediate are described.
Recently, we reported the (4 + 2) annulation4c of trienyl esters
using t-butyl morpholinone catalyst F1.13 While this reaction
provides novel β-lactone products, olefin isomerization
precluded diene regeneration.14 Due to the utility of diene
regenerative reactions,1−3 we wished to overcome this limitation.
Central to this would be the use of substrates less prone to olefin
Received: September 16, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b02693
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Studies commenced with triene 9a. When exposed to IMes
NHC (G), the (4 + 2) annulation reaction was achieved (Table
1, entry 1). While the crude residue contained both diene 10a
and β-lactone precursor (vide infra), following silica gel
chromatography, decarboxylation allowed diene 10a to be
isolated in 76% yield. To develop the enantioselective variant,
N-t-butyl NHC F1, N-4-methoxyphenyl F3, and N-phenyl
catalyst F4 were examined. Although F1 and F3 failed to provide
10a, catalyst F4 gave the expected product with excellent
diastereoselectivity (>20:1 dr) and modest enantioselectivity
(Table 1, entries 2−4). Changing to N-Mes F5 (Table 1, entry 5)
failed to improve the enantioselectivity; however, N-2,6-
dimethoxyphenyl F2, while moderately more enantioselective
at room temperature (result not shown), allowed conversion at
lower temperatures, providing diene 10a in 87% isolated yield
and 65% ee after 30 min (Table 1, entry 6). In contrast, at this
temperature, the reaction with catalyst N-Mes F5 took 16 h to
provide 10a in 46% yield and 55% ee (Table 1, entry 7). The N-
2,6-diisopropylphenyl NHC F6 also allowed low-temperature
reactions, however with less enantioselectivity (Table 1, entry 8),
while pentafluorophenyl NHC F7 was inactive (Table 1, entry
9). The N-phenyl and N-2,6-dimethoxyphenyl substituents were
then appended to an indanol scaffold; however, catalyst H1 was
inactive, and H2 failed to improve the selectivity (Table 1, entries
10 and 11). Similarly, performing the reaction with catalyst F2 in
toluene had little effect on the enantioselectivity (Table 1, entries
12). Although the enantioselectivity with this substrate (9a) was
modest, this is the outlier, with other substrates (vide infra)
reacting with excellent enantioselectivity (most >92% ee) under
the optimized conditions (Table 1, entry 6).
The generality of the reaction was initially examined with the
preparation of a series of dienyl decalans (10a−d) from
substrates with electronically dissimilar cinnamate functionality
(9a−d) (Figure 2). Electron-rich cinnamates reacted with higher
enantioselectivity (9c and d: 78 and 84% ee) than electron-poor
derivatives (9b, 67% ee); however, this was achieved at the
expense of diastereoselectivity. While similar enantioselectivity
was obtained with ring-expanded dienes (i.e., 10e), non-
annulated substrates reacted with significantly increased
enantioselectivity. Thus, dimethyl cyclohexadienes derived
from neutral (i.e., 9f), electron-poor (i.e., 9g), and electron-
rich cinnamates (9h−j) formed with excellent enantioselectivity
(93, 95, 92, 94, and 95% ee), although diastereoselectivity ranged
from 3:1 to 5:1. Similarly, furan 10k and indole 10l were
prepared in 95 and 92% ee. Longer alkyl substituents at R1 and R2
generally improved enantio- and diastereoselectivity. Thus,
dienes 10m−q bearing an ethyl chain at R1 formed with a
enantioselectivity similar to that of the dimethyl variants (94, 95,
91, 90, and 94% ee); however, the diastereoselectivity was
enhanced. Furthermore, substitution with n-propyl and ethyl
groups gave cyclohexadienes 10r and s in 90 and 99% ee and 12:1
and 20:1 dr, respectively. Unfortunately, and as with other related
reactions, the use of β-alkyl α,β-unsaturated esters led to only
traces of the expected product.
In addition to allowing the construction of two new σ-bonds
and two stereogenic centers, the diene regenerative (4 + 2)
annulation enables subsequent (4 + 2) annulations. Thus, a two-
step process involving NHC-catalyzed (4 + 2) annulation,
Table 1. Selected Optimization Studies
d
temp (°C)/time
yield
b
ee
a
c
entry cat.
solvent
(h)
(%)
dr
(%)
1
2
G
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
toluene
−78→rt/1
Δ/16
rt/5
76
>20:1
e
F1
F3
F4
F5
F2
F5
F6
F7
NR
e
3
NR
4
rt/5
42
90
87
46
61
>20:1
>20:1
>20:1
>20:1
>20:1
55
53
65
55
62
5
rt/5
6
0/0.5
0/16
0/5
7
8
e
9
rt/5
NR
e
10
11
12
H1
H2
F2
rt/5
NR
0/5
79
87
9:1
63
59
0/5
>20:1
a
Generated in situ from the salt with KHMDS; see Supporting
b
Information. Isolated yield following flash column chromatography.
Figure 2. Scope of the enantioselective (4 + 2) annulation. aAll
diastereoisomers were isolated by flash column chromatography, with a
c
Determined by 1H NMR analysis of the unpurified residue.
d
b
Determined by HPLC on chiral stationary phases; see Supporting
combined yield of both. Enantioselectivity was determined by HPLC
e
Information. No reaction.
on chiral stationary phases. cMinor diastereoisomer.
B
DOI: 10.1021/acs.orglett.5b02693
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
followed by a Diels−Alder reaction, can be devised to rapidly
generate structural and stereochemical complexity. Demonstrat-
ing this strategy, prochiral trienyl esters 9o and r were elaborated
to [2.2.2]-bicyclooctanes 11o and 12r, bearing six contiguous
stereocenters as a single diastereoisomer, in 90% ee and good
overall yield and enantiomeric excess (Scheme 1).
Scheme 2. Diastereoselectivity and Plausible Mechanism
Derivatization via the β-lactone intermediate was examined.
The chemoselective reduction of the β-lactone intermediate 13
providing diol 14c, which following single-crystal analysis,
allowed absolute and relative stereochemistry to be deter-
mined.17 In contrast to the non-enantioselective (4 + 2)
annulation, which proceeds via an endo pretransition state
reminiscent of a Diels−Alder reaction to give a trans arrangement
of substituents, the cis product was formed. Similarly, diols 14k
and q were prepared via β-lactones 13k and q with high levels of
stereochemical purity. Finally, β-lactone intermediate 13 was
cleaved with ethanol to afford diester 15c, bearing four
contiguous stereocenters, without significant erosion in stereo-
chemical purity.
Scheme 1. Derivatization
rapidly undergoes vinylogous Michael addition. Thus, a
mechanism can be proposed in which fragmentation of the
enol ester substrate (i.e., 9f) gives α,β-unsaturated acyl azolium I
and dienolate II. Previous computational studies have shown that
the acyl unit is twisted from the plane of the triazolium ring,13
thereby projecting away from the benzyl group. Approach of the
dienolate to the diene is blocked by the N-substituent, forcing an
exo-type approach from the opposite aspect of the Michael
acceptor. These unite in an enantio- and diastereoselective
vinylogous Michael addition to afford acyl azolium enolate III,
which undergoes lactonization via IV to yield a β-lactone
intermediate that decarboxylates to provide the cyclohexadiene
products (i.e., 10f).
1,3-Dienes are significant motifs in chemical synthesis, in large
part due to their capacity to engage in the Diels−Alder reaction.
Herein, we have developed a new diene regenerative reaction
that allows the facile synthesis of enantio- and diastereoenriched
cyclohexadienes. The strategy provides dienes that are
regiosiomeric to those provided by pyranone strategies and
hence creates new opportunities in complex target synthesis. The
application of the dienyl products in subsequent Diels−Alder
reactions has been demonstrated, allowing the synthesis of
[2.2.2]-bicyclooctanes containing six contiguous stereocenters
and four new σ-bonds as a single diastereomer and in 90% ee.
Central to the development of this reaction was the use of the
highly electron-rich N-2,6-dimethoxy aryl morpholinone catalyst
F2. In previous (4 + 2) annulations, we found this catalyst to be
too reactive, leading to poor yields and various side reactions. In
the context of this reaction, however, the enhanced reactivity
allows its application at lower temperatures, delivering a highly
enantioselective reaction. The utility of the enantioselective
NHC-catalyzed diene regenerative (4 + 2) annulation is
The variable diastereoselectivity of the reaction is striking and
may be due to a lack of selectivity in the vinylogous Michael
addition or epimerization following completion of the reaction.
To examine these scenarios, the diastereoselectivity of the
formation of 10e was monitored and found to vary little over the
reaction course (eq 6). In addition, when the enantiopurity of the
minor diastereoisomer of 10h was determined, it was found to be
significantly different from that of the major diastereoisomer
(Figure 2, 60 cf. 92% ee), a result inconsistent with an
epimerization pathway. Next, the fragmentation was examined
with a crossover experiment involving substrates 9b and e.
Although no crossover was observed (eq 7), we believe that
fragmentation occurs, but this yields a tight ion pair, which
C
DOI: 10.1021/acs.orglett.5b02693
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
recent comprehensive review of NHC organocatalysis, see: (l) Flanigan,
D. F.; Romanov-Michailidis, F.; White, N. A.; Rovis, T. Chem. Rev. 2015,
115, 9307.
significant, and we are conducting ongoing studies focused on
the application of this reaction in multistep synthesis.
(6) For related NHC-catalyzed approaches to aromatic compounds,
see: (a) Zhu, T.; Zheng, P.; Mou, C.; Yang, S.; Song, B.-A.; Chi, Y. R.
Nat. Commun. 2014, 5, 5027. (b) Zhu, T.; Mou, C.; Li, B.; Smetankova,
M.; Song, B.-A.; Chi, Y. R. J. Am. Chem. Soc. 2015, 137, 5658.
(7) For a review discussing the challenges of n−π* activation with ester
substrates, see: Candish, L.; Nakano, Y.; Lupton, D. W. Synthesis 2014,
46, 1823.
(8) BAC A donated by Professor Gravel (University of Saskatchewan);
for recent applications, see: (a) Wilde, M. M. D.; Gravel, M. Org. Lett.
2014, 16, 5308. (b) Wilde, M. M. D.; Gravel, M. Angew. Chem., Int. Ed.
2013, 52, 12651.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.5b02693.
■
S
Experimental procedures and H and 13C NMR of new
materials (PDF)
1
AUTHOR INFORMATION
Corresponding Author
■
(9) For NHC B, see: (a) Glorius, F.; Altenhoff, G.; Goddard, R.;
Lehmann, C. Chem. Commun. 2002, 2704. For NHC C, see: (b) Wuertz,
*E-mail: david.lupton@monash.edu.
S.; Lohre, C.; Frohlich, R.; Bergander, K.; Glorius, F. J. Am. Chem. Soc.
2009, 131, 8344.
(10) NHC E was donated by Professor Jonathan Morris (University of
̈
Notes
The authors declare no competing financial interest.
New South Wales).
(11) For NHC D, see: Seiders, T. J.; Ward, D. W.; Grubbs, R. H. Org.
Lett. 2001, 3, 3225.
(12) In all cases, starting materials were recovered unchanged.
(13) Candish, L.; Forsyth, C. M.; Lupton, D. W. Angew. Chem., Int. Ed.
2013, 52, 9149 and references therein.
ACKNOWLEDGMENTS
■
The authors acknowledge financial support from the Australian
Research Council through the Discovery (DP150101522) and
Future Fellowship (FT110100319) programs.
(14) Unsaturation flanking β-lactones promoted decarboxylation; see
ref 4b and references therein.
(15) For studies quantifying the Lewis basicity and nucleophilicity of
various NHCs, see: (a) Maji, B.; Breugst, M.; Mayr, H. Angew. Chem., Int.
Ed. 2011, 50, 6915. For an early application of the 2,6-dimethoxy
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D
DOI: 10.1021/acs.orglett.5b02693
Org. Lett. XXXX, XXX, XXX−XXX