Enantioselective Synthesis of 3,5,6-Substituted Dihydropyranones and Dihydropyridinones using Isothiourea-Mediated Catalysis

Article abstract of DOI:10.1002/asia.201500907

The scope of dihydropyranone and dihydropyridinone products accessible by isothiourea-catalyzed processes has been expanded and explored through the use of 2-N-tosyliminoacrylates and 2-aroylacrylates in a Michael addition-lactonization/lactamization cascade reaction. Notably, to ensure reproducibility it is essential to use homoanhydrides as ammonium enolate precursors with 2-aroyl acrylates, while carboxylic acids can be used with 2-N-tosyliminoacrylates, delivering a range of 3,5,6-substituted dihydropyranones and dihydropyridinones with high enantioselectivity (typically >90 % ee). The derivatization of the heterocyclic core of a 3,5,6-substituted dihydropyranone through hydrogenation is also reported.

Full text of DOI:10.1002/asia.201500907

DOI: 10.1002/asia.201500907
Full Paper
Isothiourea Catalysis
Enantioselective Synthesis of 3,5,6-Substituted Dihydropyranones
and Dihydropyridinones using Isothiourea-Mediated Catalysis
Daniel G. Stark,[a] Louis C. Morrill,[a] David B. Cordes,[a] Alexandra M. Z. Slawin,[a]
Timothy J. C. O’Riordan,[b] and Andrew D. Smith*[a]
Abstract: The scope of dihydropyranone and dihydropyridi-
none products accessible by isothiourea-catalyzed processes
has been expanded and explored through the use of 2-N-to-
syliminoacrylates and 2-aroylacrylates in a Michael addition-
lactonization/lactamization cascade reaction. Notably, to
ensure reproducibility it is essential to use homoanhydrides
as ammonium enolate precursors with 2-aroyl acrylates,
while carboxylic acids can be used with 2-N-tosyliminoacry-
lates, delivering a range of 3,5,6-substituted dihydropyra-
nones and dihydropyridinones with high enantioselectivity
(typically >90% ee). The derivatization of the heterocyclic
core of a 3,5,6-substituted dihydropyranone through hydro-
genation is also reported.
Introduction
zation reactions with electron-deficient olefins using a wide
range of enolate precursors and strategies.[6] To date, intermo-
lecular reactions within these systems have typically utilized b-
substituted electron-deficient enones or a,b-unsaturated keti-
mines to form 3,4,6-substituted dihydropyranones and dihy-
dropyridinones with excellent diastereo- and enantiocontrol
(typically >90:10 d.r., >95% ee; Figure 1).
The synthesis of small, functionalized chiral heterocycles
through asymmetric catalysis remains a prominent area of re-
search in synthetic methodology. The recognition of endocyclic
enol dihydropyranones and dihydropyridinones as key constit-
uents within natural products and bioactive compounds aids
the appeal of catalytic routes to produce these molecules.[1]
Classical routes involve uncatalyzed Diels–Alder reactions and
more recently metal-catalyzed p-olefin and p-alkyne cycliza-
tions.[2] However, the current state-of-the-art methods for the
production of chiral dihydropyranones and dihydropyridinones
with high diastereo- and enantiocontrol remains the use of or-
ganocatalytically generated enolate equivalents. Typical pro-
cesses within this area have utilized N-heterocyclic carbene
(NHC)-generated azolium enolates,[3] enamine catalysis,[4] or
cinchona alkaloids[5] and isothiourea-generated ammonium
enolates in formal [4+2]-cycloaddition/Michael addition-cycli-
Within this area, following pioneering work by Romo and
co-workers,[7] our laboratory has developed an isothiourea-cat-
alyzed[8] Michael-addition cyclization protocol using bench
[a] D. G. Stark, L. C. Morrill, D. B. Cordes, A. M. Z. Slawin, Prof. A. D. Smith
School of Chemistry
University of St Andrews
North Haugh, St Andrews Fife, KY16 9ST (UK)
E-mail: ads10@st-andrews.ac.uk
[b] Dr. T. J. C. O’Riordan
Syngenta, Jealott’s Hill International Research Centre
Bracknell, Berkshire, RG42 6EY (UK)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/asia.201500907.
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Figure 1. Enantioselective synthesis of dihydropyranones and dihydropyridi-
nones – overview of the field.
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stable carboxylic acids as starting materials that has been ap-
plied to the synthesis of a variety of heterocycles.[9] Following
our previous report on the synthesis of di-, tri-, and tetra-sub-
stituted pyridines using 2-N-tosyliminoacrylates, we considered
using b-unsubstituted Michael acceptors (2-N-tosyliminoacry-
lates and 2-aroylacrylates) in enantioselective isothiourea-cata-
lyzed Michael addition-cyclization cascades to generate 3,5,6-
trisubstituted dihydropyranones and dihydropyridinones con-
taining a single stereocenter (Figure 2).[10] To the best of our
knowledge, only limited precedent with such b-unsubstituted
acrylate acceptors in organocatalytic [4+2]-cycloaddition type
processes have been reported.[11]
Scheme 1. Initial results of the Michael addition-lactonization. [a] Syringe
pump addition of 1 (0.25m in CH2Cl2) over 2 h.
À788C gave the desired dihydropyranone 6 in a good yield of
80% but with 0% ee. Attempted optimization through syringe
pump addition of Michael acceptor 1 (0.25m in CH2Cl2) gave
marginal improvement with typical enantioselectivities of ap-
proximately 20% ee observed with isothiourea catalyst 4
(Scheme 1).
To investigate the lack of enantiocontrol using 4-bromo-
phenyl acetic acid 5 in this process the feasibility of a competi-
tive base-mediated racemic reaction process was probed.
Direct treatment of 4-bromophenyl acetic acid 5 with pivaloyl
chloride and iPr2NEt, followed by addition of 2-aroylacrylate
1 without the inclusion of the isothiourea Lewis base yielded
dihydropyranone 6 in an isolated yield of 52%. This is consis-
tent with a significant base-mediated reaction under these
conditions presumably enhanced by the high reactivity of the
2-aroylacrylate (Scheme 2).[13]
Figure 2. Enantioselective synthesis of dihydropyranones and dihydropyridi-
nones – this work.
At the onset of these investigations the highly reactive
nature of b-unsubstituted 2-N-tosylimino- and 2-aroylacrylates,
and the assumed relative rate of a competitive racemic base-
promoted background reaction, were envisioned as problems
to overcome to obtain high enantioselectivity in these reac-
tions. In this study, the scope and limitations of this approach
are investigated and explored, with the key finding being the
necessity to use homoanhydrides as ammonium enolate pre-
cursors with 2-aroylacrylates, while carboxylic acids can be
used with 2-N-tosyliminoacrylates.
Results and Discussion
Michael Addition-Lactonization using 2-Aroylacrylates; Opti-
mization and Generality
Scheme 2. Control experiment.
Preliminary studies began with optimization of the isothiourea-
catalyzed Michael addition-lactonization using 2-aroylacrylate
1 and phenylacetic acid 2 as a model system.[12] Employing in
situ mixed anhydride formation using pivaloyl chloride and
Alternative reaction conditions were explored to prepare the
target products with reproducibly high enantioselectivity. We
have previously demonstrated the use of homoanhydrides as
alternative ammonium enolate precursors to carboxylic acids,
with one advantage of this approach being the reduced levels
of added organic base necessary for catalysis in comparison to
the in situ mixed anhydride approach.[9g] The use of homoan-
hydride 7 as the enolate precursor offered a major break-
through in this system, delivering products with high and re-
producible levels of enantioselectivity under optimized reac-
tion conditions (Table 1).
phenylacetic acid
2 with 2-aroylacrylate 1 catalyzed by
(+)-BTM (benzotetramisole) 4 (5 mol%) at À788C after 1 h af-
forded dihydropyranone 3 in an excellent yield of 79% and
93% ee (Scheme 1). However, disappointingly this method did
not prove general when applied to subsequent substrates. In
all cases the desired dihydropyranone products were formed
in typically excellent yield but with no enantiocontrol. For ex-
ample, treatment of 4-bromophenyl acetic acid 5 and 2-aroyla-
crylate 1 with iPr2NEt, pivaloyl chloride, and (+)-BTM 4 at
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Table 1. Optimization studies of the Michael addition-lactonization.
Table 2. Substrate scope of the Michael addition-lactonization.
Entry
Lewis base
[mol%]
T [8C]
t [h]
Base
Yield
[%][a]
ee
[%][b]
1
2
3
4
5
6
7
8[d]
8 (5)
9 (5)
4 (5)
4 (5)
4 (5)
4 (5)
4 (5)
4 (5)
rt
rt
rt
À78
À78
À78
À78
À78
0.2
0.2
0.2
1
1
1
iPr2NEt
iPr2NEt
iPr2NEt
iPr2NEt
Et3N
Cs2CO3
Na2CO3
iPr2NEt
81
80
88
88
85
58
81
88
46
78[c]
88
91
0
57
83
70
1
2
[a] Yield of isolated product. [b] Determined by chiral HPLC analysis.
[c] (S)-enantiomer obtained. [d] Syringe pump addition of 1 (0.25m in
CH2Cl2) over 2 h.
Homoanhydride 7 and 2-aroylacrylate 1 were used as
a model system for reaction optimization. Lewis base screening
showed 5 mol% (+)-BTM 4 to be optimal, forming product 6
in 88% yield and excellent 91% ee at À788C (Table 1, entry 4).
The nature of the base used in this process also proved key to
high enantioselectivity, as Et3N gave the product in 85% yield,
but in racemic form, consistent with a competitive base-cata-
lyzed background reaction (Table 1, entry 5). The inorganic
base Cs2CO3 gave 6 in poor yield and ee, whereas Na2CO3
proved moderately successful, and yielded 6 in 81% yield and
83% ee (Table 1, entries 6 and 7). Syringe pump-addition of Mi-
chael acceptor 1 in CH2Cl2 over 2 h gave no improvement, and
formed 6 in 70% ee (Table 1, entry 8).
genated aromatics can be installed at the 6-position to afford
17 in 61% yield but with moderate 68% ee. Finally, the naph-
thyl substituent was employed and afforded 18 in 71% yield
and 86% ee. The absolute configuration of 12 was confirmed
by X-ray diffraction with all other examples assigned by analo-
gy (Figure 3).[16]
With optimized reaction conditions in hand, the scope of
this reaction process was evaluated (Table 2).[14] The use of a ho-
moanhydride containing an electron-donating 4-MeOC6H4 sub-
stituent was tolerated and gave 10 in 83% yield and 91% ee,
while 4-substituted halogenated aromatics could also be instal-
led in high yield and ee (products 6 and 11). Pleasingly, sterical-
ly demanding enolate precursors such as the 1-naphthyl and
o-tolyl homoanhydrides could be applied, producing 12 in an
excellent yield of 81% and 97% ee and 13 in 81% yield with
moderate 50% ee. Assessing the scope of aroyl acrylate Mi-
chael acceptors, the electron-rich 4-MeOC6H4 aryl unit was in-
corporated in 14 and isolated in 79% yield and 91% ee. Dihy-
dropyranone 15 was synthesized in 65% yield and 81% ee,
however, in this case Na2CO3 was required as the base to
obtain good enantioselectivity.[15] Furthermore, 4-methoxy-
phenyl acetic anhydride was explored with heteroaryl groups
such as 2-furyl, and gave 16 in 61% yield and 99% ee. Halo-
Following the development of this procedure for the synthe-
sis of 3,5,6-substituted dihydropyranones, the utility and fur-
ther elaboration of these products was explored. The isothiour-
ea-catalyzed Michael addition-lactonization could be readily
carried out on a reasonable laboratory scale (4.27 mmol),
thereby providing 1.27 g of 10 in 87% ee. Dihydropyranone 10
Figure 3. Molecular representation of X-ray structure 12.
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tion process, the method was extended to explore the struc-
turally related dihydropyridinone motif. Initial investigations
began with optimization using 2-N-tosyliminoacrylate 21 and
carboxylic acid 2. Treatment of 2 with pivaloyl chloride and
iPr2NEt followed by subsequent addition of Michael acceptor
21 and HyperBTM 8 (10 mol%) in CH2Cl2 at room temperature
gave dihydropyridinone 22 in 60% yield and 80% ee after
30 min (Table 3, entry 1). A screen of isothiourea catalysts re-
vealed (À)-tetramisole 9 to be optimum, providing dihydropyr-
idinone 22 in 62% yield and 84% ee (Table 3, entry 2). Lower-
ing the reaction temperature to À788C gave 22 in a 74% yield
and an improved 91% ee (Table 3, entry 5). The reaction was
sensitive to solvent choice in terms of both conversion and
enantioselectivity. For example, THF gives a poor 40% yield of
22 in 86% ee (Table 3, entry 7), while MeCN at À308C provides
22 in 70% yield but in racemic form (Table 3, entry 8). Finally,
the catalyst loading for 9 could be lowered to 5 mol% without
compromising the yield or ee (Table 3, entry 9).
Scheme 3. Derivatization of dihydropyranone 10.
could be transformed into pyranone 19 through a substrate
controlled Pd/C-catalyzed hydrogenation to afford product 19
in 60% yield with >95:5 d.r. (Scheme 3). Pyranone 19 was fur-
ther derivatized by a reductive ring-opening, providing triol 20
in 88% yield and high diastereoselectivity. Nuclear Overhauser
effect (NOE) experiments confirmed the relative configuration
of 19, however, the ee determination of 19 or triol 20 by chiral
HPLC or GC was not possible in our hands.[17]
The generality of this process was next examined using (À)-
tetramisole 9 (5 mol%) as the Lewis base. Initially 2-N-tosylimi-
noacrylate 21 was treated with a range of commercially avail-
Table 4. Substrate scope of the Michael addition-lactamization.
Michael Addition-Lactamization using 2-N-tosyliminoacry-
lates; Optimization and Generality
Following the successful synthesis of dihydropyranones
through an isothiourea-catalyzed Michael addition-lactoniza-
Table 3. Optimization studies of the Michael addition-lactamization.
Entry
Lewis base
[mol%]
T [8C]
t [h]
Solvent
Yield
[%][a]
ee
[%][b]
1
2
3
4
5
6
7
8
9
8 (10)
9 (10)
4 (10)
8 (10)
9 (10)
4 (10)
9 (10)
9 (10)
9 (5)
rt
rt
rt
À78
À78
À78
À78
À30
À78
0.5
0.5
0.5
16
16
16
16
16
16
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
THF
60
62
60
71
74
70
40
70
74
80[c]
84
80[c]
86[c]
91
85[c]
86
0
91
MeCN
CH2Cl2
[a] Yield of isolated product. [b] Determined by chiral HPLC analysis.
[a] 4.17 mmol scale.
[c] (R)-enantiomer obtained.
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able carboxylic acids under the previously optimized reaction
conditions (Table 4). However, some examples gave poor con-
version of the desired dihydropyridinone products even after
extended reaction times at À788C. Therefore, a more general
procedure was developed by allowing the reaction to warm
over 16 h from À788C to room temperature, giving full conver-
sion of the Michael acceptor with a range of acetic acids.[18]
Electron-rich aromatic substituents such as 4-MeOC6H4 and 4-
Me2NC6H4 are tolerated and desired products 23 and 24 are af-
forded in good yields of 76% and 71% with excellent 95%
and 94% ee, respectively. Electron-deficient aryl units were also
tolerated, and the CF3-bearing dihydropyridinone 25 was iso-
lated in 73% yield and 93% ee. 3-Tolylacetic acid produced di-
hydropyridinone 26 in 69% yield and high 95% ee. Halogen-
substituted aryl substituents could also be incorporated, giving
product 27 in 61% yield, albeit a reduced 71% ee was ob-
tained. Pleasingly, heteroaryl groups were tolerated and deliv-
ered dihydropyridinone 28 in 65% yield and excellent 90% ee.
Next, the scope of 2-N-tosyliminoacrylate Michael acceptors
was explored. Unfortunately, only electron-rich aryl units could
be included at the 6-position of the dihydropyridinone prod-
ucts owing to a limitation in the synthesis of the 2-N-tosylimi-
noacrylates.[19] For example, the 4-MeOC6H4 aryl group could
be included to give product 29 in 63% yield and 98% ee. Also,
4-tolyl and 3,5-xylyl groups were well tolerated and afforded
the corresponding products 30 and 31 in 60% yield, 97% ee
and 59% yield and 90% ee, respectively. Finally, 2-naphthyl
substitution was possible, 32 was formed in 69% yield and
91% ee. This Michael addition-lactamization method was also
performed on reasonable laboratory scale (4.17 mmol), thus
providing 1.30 g of 22 with excellent 99% ee. The absolute
configuration of 25 was determined by X-ray diffraction, with
all other products assigned by analogy (Figure 4).[20]
Figure 5. Proposed catalytic cycle.
by lactamization/lactonization, provides the corresponding het-
erocyclic products 35 and releases the catalyst.
Conclusions
In conclusion, the isothiourea-catalyzed Michael-addition lac-
tamization/lactonization of 2-[aryl(tosylimino)methyl]acrylate or
2-aroylacrylates from arylacetic acids or homoanhydrides, re-
spectively, produces stereodefined 3,5,6-substituted dihydro-
pyridinones or dihydropyranones in high yield and enantiose-
lectivity. Using these products to provide further complex
chiral building blocks has been demonstrated through the use
of hydrogenation or ring-opening processes. Further studies
within our laboratory are focused towards the continued de-
velopment of isothioureas and other Lewis bases in catalysis.
Experimental Section
General procedure: Isothiourea-catalyzed Michael addition-lactoni-
zation
To a solution of requisite homoanhydride (1.25 equiv) in CH2Cl2
(0.31m in homoanhydride) at À788C was added Lewis base cata-
lyst (5 mol%) and the reaction stirred for 20 min. A solution of Mi-
chael acceptor (1.0 equiv) in CH2Cl2 (0.25m), pre-cooled to À788C,
is added followed by a solution of iPr2NEt (1.25 equiv) in CH2Cl2
(0.31m), also pre-cooled to À788C, and reaction stirred until com-
plete by TLC analysis. The reaction was quenched with HCl (1m in
H2O), extracted with CH2Cl2 (”3), dried over MgSO4, and concen-
trated under reduced pressure to give the crude residue. Products
were purified by Biotage Isolera 4 and kieselgel 60 (0.040–
0.063 mm) silica grade in the solvent system reported.
Figure 4. Molecular representation of X-ray structure 25.
Following our previous studies a proposed mechanism for
the processes described above begins with N-acylation of iso-
thiourea catalyst with either the homoanhydride (with aroyl
acrylates) or in situ formed mixed anhydride (with imino acryl-
ates) to form an acyl ammonium species 33 (Figure 5). Subse-
quent deprotonation gives (Z)-ammonium enolate 34, which is
stabilized by a proposed nO to s*CÀS interaction or favorable
electrostatic stabilization between the enolate oxygen and
sulfur atom on the catalyst framework.[21] Enantioselective Mi-
chael addition to an aroyl acrylate or imino acrylate, followed
General procedure: Isothiourea-catalyzed Michael addition-lactam-
ization
To a solution of requisite carboxylic acid (2.0 equiv) in CH2Cl2 (0.1m
in carboxylic acid) at 08C was added iPr2NEt (3.0 equiv) and pivalo-
yl chloride (3.0 equiv). The reaction was left to stir for 10 min
before being cooled to À788C at which point Lewis base catalyst
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(5 mol%), Michael acceptor (1.0 equiv), and iPr2NEt (1.0 equiv) were
added and the reaction was warmed to room temperature over
16 h. The reaction was quenched with HCl (1m in H2O), extracted
with CH2Cl2 (”3), dried over MgSO4, and concentrated under re-
duced pressure to give crude residue. Products were purified by
column chromatography in the solvent system reported.
The data underpinning the work in this manuscript can be
found at http://dx.doi.org/10.17630/6e0ad60a-ddf5-459c-bc45-
cdd80fd518b8
Acknowledgements
We thank the Royal Society for a University Research Fellow-
ship (ADS), Syngenta and EPSRC grant No. EP/K503162/
1 (DGS), and the European Research Council under the Europe-
an Union’s Seventh Framework Programme (FP7/2007–2013)
ERC Grant Agreement No. 279850, for funding. We also thank
the EPSRC UK National Mass Spectrometry Facility at Swansea
University.
[10] D. G. Stark, T. J. C. O’Riordan, A. D. Smith, Org. Lett. 2014, 16, 6496–
6499.
Keywords: dihydropyranones
enantioselective catalysis · isothioureas · Michael addition
·
dihydropyridinones
·
[11] For other examples of the use of acrylate derivatives in [4+2]-cycloaddi-
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Sun, Y. Cao, R. Wang, Angew. Chem. Int. Ed. 2012, 51, 2084–2087;
Angew. Chem. 2012, 124, 2126–2129; b) X. Jiang, L. Liu, P. Zhang, Y.
Zhong, R. Wang, Angew. Chem. Int. Ed. 2013, 52, 11329–11333; Angew.
Chem. 2013, 125, 11539–11543.
[12] 1-Phenylprop-2-en-1-one gave no conversion under the optimized reac-
tion conditions and hence the inclusion of the ester substituent was re-
quired for reactivity and conversion.
[13] Epimerization experiments were conducted with the treatment of dihy-
dropyranones, present in >90% ee, to the reaction conditions for 4 h.
These experiments showed no degradation in the ee and therefore we
excluded epimerization as a source of the reduced product enantiose-
lectivity in some cases.
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Manuscript received: August 28, 2015
Accepted Article published: October 16, 2015
Final Article published: November 12, 2015
Chem. Asian J. 2016, 11, 395 – 400
www.chemasianj.org
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