Alkylidene Meldrum's Acids as Platforms for the Vinylogous Synthesis of Dihydropyranones

Article abstract of DOI:10.1002/anie.202014489

Upon Br?nsted base organocatalysis, ketone-derived alkylidene Meldrum's acids proved to be competent vinylogous platforms able to undergo a formal (4+2) cycloaddition reaction with dihydro-2,3-furandione, providing an unprecedented route to 3,6-dihydropyran-2-ones as spiro[4.5]decane derivatives with up to 98 % ee thanks to the commercially available Takemoto catalyst. Preliminary investigation showed that this reaction could be extended to other activated ketones, establishing these alkylidene Meldrum's acids as a novel C4-synthon in the vinylogous series.

Full text of DOI:10.1002/anie.202014489

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How to cite: Angew. Chem. Int. Ed. 2021, 60, 11110–11114
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doi.org/10.1002/anie.202014489
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Cycloadditions
Alkylidene Meldrumꢀs Acids as Platforms for the Vinylogous Synthesis
of Dihydropyranones
Stꢀphane Wittmann+, Thomas Martzel+, Cong Thanh Pham Truong, Martial Toffano,
Sylvain Oudeyer, Rꢀgis Guillot, Chloꢀe Bournaud, Vincent Gandon, Jean-FranÅois Briꢁre,* and
Giang Vo-Thanh*
Abstract: Upon Brønsted base organocatalysis, ketone-derived
alkylidene Meldrumꢂs acids proved to be competent vinylo-
gous platforms able to undergo a formal (4 + 2) cycloaddition
reaction with dihydro-2,3-furandione, providing an unprece-
dented route to 3,6-dihydropyran-2-ones as spiro[4.5]decane
derivatives with up to 98% ee thanks to the commercially
available Takemoto catalyst. Preliminary investigation showed
that this reaction could be extended to other activated ketones,
establishing these alkylidene Meldrumꢂs acids as a novel C4-
synthon in the vinylogous series.
T
he principle of vinylogy, as remarkably illuminated by
Fuson in 1935,[1] allows the remote functionalization of
a given functional group thanks to the propagation of
electronic effects through a conjugated unsaturated backbone
(Scheme 1A). More recently, synthetic chemists have tackled
the more challenging regio- and enantioselective bond-
forming events at remote positions of various electron-
withdrawing groups by means of metal or organic catalysts.[2,3]
This methodology was especially illustrated by the groups of
Jørgensen, Deng and Chen during the pioneering organo-
catalytic direct d-functionalization of a,a-dicyanoolefin plat-
forms.[4] The marked versatility of this vinylogous strategy has
witnessed several achievements encompassing the use of
various substrates suited for direct organocatalytic activation
sequences.[2,3] Upon the initiatives of Peters and Ye,[5,6] the
catalytic vinylogous transformation of crotonyl-based plat-
forms, such as a,b-unsaturated acid chlorides, opened an
avenue to the elaboration of 5,6-dihydropyran-2-ones
1 (Scheme 1A), a heterocyclic core-structure found in
Scheme 1. Novel organocatalytic vinylogous synthesis of dihydropyran-
2-ones.
numerous bioactive compounds.[2,3] By means of chiral N-
Heterocyclic Carbenes (NHC) or amines (R3N, Scheme
1A),[7,8] efficient (4 + 2) annulation reactions were subse-
quently carried out with ketone derivatives and provided
thereby the corresponding oxygen-heterocycles 1 with the
control of a congested tetrasubstituted stereocenter, even
embedded into highly valuable spiro architectures.[9] Never-
theless, to the best of our knowledge, this strategy has
exclusively led to 5,6-dihydropyran-2-ones 1, with a conju-
=
gated carbon-carbon double bond to the C O group (via C4
synthon 2). In consequence, the development of novel
platforms expanding the scope of this valuable vinylogous
methodology is still of high interest.
[*] Dr. S. Wittmann,[+] C. T. Pham Truong, Dr. M. Toffano, Dr. R. Guillot,
Dr. C. Bournaud, Prof. V. Gandon, Prof. G. Vo-Thanh
Institut de Chimie Molꢀculaire et des Matꢀriaux d’Orsay, CNRS UMR
8182, Universitꢀ Paris Saclay
In that vein, we started to investigate the alkylidene
Meldrumꢀs acid derivatives 3, as an original platform in
vinylogous series (Scheme 1B). These compounds are stable
and readily available in one-step by the condensation reaction
between Meldrumꢀs acid and ketones.[10] With regard to the
remarkable high acidity of the 2,2-dimethyl-1,3-dioxan-4,6-
dione, namely Meldrumꢀs acid (pKa = 4.8 in water),[11] we
anticipated a facile deprotonation of the distant methyl group
of 3, so that the formation of the enolate 6 with a g-
nucleophilic site would occur,[12] following the principle of
vinylogy. Then, taking advantage of the marked electrophilic
properties of carbonyl moieties of the 1,3-dioxan-4,6-dione
backbone, the platform 3 was expected to be capable of
undergoing a formal (4 + 2) cycloaddition with ketones
91405 Orsay Cedex (France)
E-mail: giang.vo-thanh@universite-paris-saclay.fr
Dr. T. Martzel,[+] Dr. S. Oudeyer, Dr. J.-F. Briꢁre
Normandie Univ, UNIROUEN, INSA Rouen, CNRS, COBRA
76000 Rouen (France)
E-mail: jean-francois.briere@insa-rouen.fr
Prof. V. Gandon
Laboratoire de Chimie Molꢀculaire (LCM), CNRS UMR 9168, Ecole
Polytechnique, Institut Polytechnique de Paris
route de Saclay, 91128 Palaiseau cedex (France)
[+] These authors contributed equally to this work.
Supporting information and the ORCID identification numbers for
some of the authors of this article can be found under:
https://doi.org/10.1002/anie.202014489.
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through a domino aldol/cyclocondensation reaction towards
Et3N for 24 hours. Then, we assume that 1aa (thermodynamic
the construction of dihydropyran-2-one. We are pleased to
report on the alkylidene Meldrumꢀs acid derivatives 3 as
a novel precursor in enantioselective vinylogous transforma-
tions upon Brønsted base organocatalysis. The exquisite
reactivity of platform 3 allows an unprecedented entry to
non-racemic 3,6-dihydropyran-2-ones 5, having a non-con-
jugated carbon-carbon double bond (via synthon 6’ instead of
2) which, accordingly, extends the chemical space in the
dihydropyran-2-one heterocyclic series.
product) is mainly originated from the kinetic product 5aa
during this domino sequence, whose outcome depends on
both the strength of the base and the stability and/or acidity of
the intermediates. Accordingly, alkylidene Meldrumꢀs acid
derivative 3a proved to be an original and versatile vinylo-
gous platform, while affording an unprecedented pathway to
original 3,6-dihydropyran-2-ones 5. Furthermore, the useful-
ness of these products was demonstrated through the
stereoselective epoxidation reaction which took place regio-
À
This project began by the exploration of alkylidene
Meldrumꢀs acid 3 reactivity as a potentially vinylogous
platform (Scheme 2). To our delight, the model benzylidene
Meldrumꢀs acid 3a and dihydro-4,4-dimethyl-2,3-furandione
selectively without C C double bond migration (7, 74%).
Then, we embarked towards the development of an organo-
catalytic enantioselective version.
Various Cinchona-derived organocatalysts (see SI for full
details) were first assessed for the transformation of the
dihydro-4,4-dimethyl-2,3-furandione 4a to 3,6-dihydropyran-
2-ones 5aa (Scheme 3). The bifunctional thiourea organo-
catalyst A2 (60% yield, 88% ee) proved to be more effective
Scheme 2. Alkylidene Meldrum’s acid 3a as an original vinylogous
platform. Yields correspond to the yield of isolated product after
column chromatography, and the ratio of isomers (1:5) was deter-
mined by 1H NMR analysis of the crude product. [a] In THF (0.2 M);
only traces of 5a- was observed. [b] In CH2Cl2 (0.4 M).
Scheme 3. Towards an enantioselective process. Reaction conditions:
3a (0.15 mmol), ketone 4a (1 equiv), catalyst (20 mol%) in the given
solvent (0.5 M) at 208C for 24 hours. Yields correspond to the yield of
isolated product after column chromatography, enantiomeric excess
(ee) determined by chiral HPLC, and the ratio of isomers (5aa:1aa)
was determined by 1H NMR analysis of the crude product. [a] 94:6
(5aa:1aa) was measured.
4a as electrophile led straightforwardly to the formation of
virtually novel spiro 5,6-dihydropyran-2-ones 1aa in the
presence of 20 mol% of DBU as a base (unoptimized
conditions).[13] This smooth domino sequence could be
applied to an array of diketones 4b–e to afford the
corresponding 5,6-dihydropyran-2-ones 1ab–1ae derivatives
as major products in yields ranging from 47% to 72%.
Surprisingly, in the course of these processes, we also
detected minor amounts of the non-conjugated 3,6-dihydro-
pyran-2-ones 5. By means of triethylamine as a softer
organocatalyst in dichloromethane, the outcome of the
reaction was essentially balanced towards the construction
of 3,6-dihydropyran-2-one isomers 5aa–ad with yields ranging
from 54–72%, except for the more reactive keto-ester 4e
giving the known 5,6-dihydropyran-2-ones 1ae in good 82%
yield.[7a] The structure of the novel compound 5aa was fully
proven especially by X-Ray single crystal diffraction.[14]
Interestingly, the 3,6-dihydropyran-2-one product 5aa iso-
merized into the conjugated isomer 1aa in the presence of
than the native quinine A1 (36% yield, 55% ee and reverse
enantioselectivity) or the sulfonamide derivatives A3 (24%,
47% ee) both in terms of yields and ee. This marked outcome
with regard to bifunctional-topology was also observed with
organocatalysts A4—A6, having a cyclohexanediamine back-
bone, albeit lower yields were measured probably due to the
sterically hindered piperidine moiety. Nevertheless, the
squaramide derived catalyst A6 provided 91% ee in 36%
yield. Importantly, in this series, the catalyst A5 having an
amide functional group led to inverse enantioselectivity (30%
ee) in comparison to thiourea or squaramide analogues A4
and A6, showing the key importance of the hydrogen bonding
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Table 1: Scope and limitations.[a]
donor moiety. To our delight, the less encumber catalysts A7–
A8, having a dimethylamine moiety, furnished the 3,6-
dihydropyran-2-ones 5aa with improved 64–75% yields and
up to 93% ee for the original Takemoto catalyst A8.
Interestingly, the catalysts A7–A8 possessing
a NMe2
Brønsted base display a reverse influence of the NH-hydro-
gen bonding donor part onto ee as the thiourea derivative A8
led to better ee than the squaramide A7 in the contrary to
piperidine derivatives A4 and A6; then a subtle cooperation
between the two functionalities of the catalyst is set for this
new transformation (3a to 5aa). An optimization of reaction
conditions with catalyst A8 showed that toluene furnished
improved ee (94%) and yields (89%) albeit with the
formation of a small amount of 5,6-dihydropyran-2-ones 1a.
Nonetheless, the selectivity between isomers 5aa:1aa was in
favor of the 3,6-dihydropyran-2-ones 5aa (> 98/2 5aa:1aa) at
108C, obtained in 77% isolated yield and excellent 96% ee,
while lower temperature (08C) led to a drop of yield (38%).
Having these conditions in hands, the substrate scope was
addressed (Table 1). Increasing the reaction time to 40 hours
allowed the formation of the expected product 5aa in 89%
yield while keeping an excellent enantiomeric excess of 96%
ee, even on 1 mmol scale (85%, 95% ee). A series of
alkylidene Meldrumꢀs acid derivatives 3b–3j were engaged
into a vinylogous transformation of dihydro-4,4-dimethyl-2,3-
furandione 4a into 3,6-dihydropyran-2-ones 5ba–5ja as
major products with yields between 61–79% and ee values
ranging from 76% to 98%. The alkylidene Meldrumꢀs acid
flanked by a 4-CF3C6H4 moiety led to the corresponding 3,6-
dihydropyran-2-ones 5ka with an excellent 92% ee but
a moderate yield of 33% (42% of conversion). The con-
version could be improved (> 90% of conversion) after 90 h
of reaction but a lower ratio of 5ka:1ka (74:26) was
measured. In this series, product 5la obtained from the
Meldrumꢀs acid derivative 3l, having a 2-chlorophenyl
moiety, proved to be more challenging (Table 1). Then, only
77% of conversion after 90 hours at 108C was measured
giving product 5la in moderate 63% isolated yield and 56%
ee. In order to further probe the structure/activity relation-
ship, one can consider that alkylidene Meldrumꢀs acid flanked
by two methyl group is still able to be involved into this aldol
process, albeit lower reaction rate (67% of conversion) and
selectivity (5ma:1ma 83:17) was observed giving 5ma in 53%
yield and 73% ee. On the other hand, the original product
5na, having a versatile styrenyl group, was synthesized easily
in 91% ee and 88% yield from the corresponding dienyl
Meldrumꢀs acid 4n. Additionally, although more sterically
hindered ethyl-derivative 3o proved to be unreactive, the
cyclic-analogue, namely the indenyl-derived Meldrumꢀs acid
3p, was transformed into the corresponding tetracyclic
product 5pa in 75% ee (64% yield). Subsequently, we
wondered whether this Meldrumꢀs acid-based platform 3a
could react with other ketones, known as good starting
materials for the efficient enantioselective vinylogous syn-
thesis of 5,6-dihydropyran-2-ones 1.[7,8a–e,g–i] However, in our
case, we expected to extend the chemical diversity with the
formation of isomeric and non-racemic 3,6-dihydropyran-2-
one architectures 5. Accordingly, the transformation of
various ketones 4b, 4d, 4 f,g proceeded with moderate to
Reaction conditions: 3 (0.15 mmol), ketone 4 (1 equiv), catalyst A8
(20 mol%) in PhMe (0.5 M) at 108C. Yields correspond to the yield of
the pure major isomer 5 after column chromatography (unless otherwise
noted), enantiomeric excess (ee) determined by chiral HPLC, and the
ratio of isomers (5:1) was determined by 1H NMR analysis of the crude
product. [a] 40 hours of reaction. [b] On 1 mmol scale. [c] 90 hours of
reaction. [d] In CH2Cl2 owing to solubility issue. [e] At 208C in CH2Cl2 for
72 hours. [f] 72 hours of reaction. [g] The absolute configurations were
determined by X-ray diffraction for (R)-5aa and by comparison to
a similar structure in the literature for (R)-5ad[6] (see SI); the absolute
stereochemistry of the other products was drawn by analogy.
[h] 1.3 equivalent of alkylidene Meldrum’s acid 3a and catalyst A3 was
used instead of A8, which gave 5ab in 74% yield and 55% ee (see SI).
good yields (50–83%) in favor of the major 3,6-dihydropyran-
2-one products. However, the diketones 4b[8e] and 4d[6] were
transformed into products 5ab and 5ad in only 70% and 55%
ee, respectively. To our delight, by means of epi-tosylamide
quinine catalyst A3 instead of A8, the spiro-oxindole 5ad was
obtained with improved 87% ee. In spite of the less activated
phenyl a-keto esters 4g did not react in these conditions,[8f]
the more electrophilic para-NO2-phenyl a-keto esters 4 f
furnished the corresponding dihydropyranones 5af and 1af as
a 86:14 mixture of isomers as determined on the crude
product. However, a complete isomerization of this mixture
into the 5,6-dihydropyran-2-one product occurred during
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purification by silica gel column chromatography to afford
sition state (TS6-8 = 19.2 kcalmolÀ1) showing a complete
1af in good 76% yield and 94% ee.[15]
proton-transfer from the ammonium to the alcohol-product
8aa. The subsequent cyclization leads to the ortho-ester 9aa
along with a base-promoted proton migration. Importantly, it
was found that the alternative (4 + 2) cycloaddition reaction
(6a + 4a to 9aa) was more energetically demanding than the
nucleophilic addition of dienolate 6a to 4a (24.9 vs. 19.2 kcal
molÀ1). The subsequent fragmentation process liberates
a molecule of acetone to furnish the carboxylate 10aa.[16]
Although the detail of the formal
On the basis of preliminary set of computations with
trimethylamine as a model organocatalyst (see SI for full
details), a proposed catalytic cycle is shown in Scheme 4. First,
the deprotonation of alkylidene Meldrumꢀs acid 3a gives the
enolate 6a flanked by the H-bonded tertiary ammonium
(R3NH+). Then, the addition to the ketone-electrophile 4a
gives the adduct 8aa (enantioselective step), though a tran-
symmetry forbidden 1,3-H shift was
not easy to address from the computa-
tional point of view, it is believed that
À
a C C double bond isomerization
occurs to reveal the hemi-malonate
backbone of 11aa. This Csp3-CO2
framework is then able to undergo
a stepwise decarboxylation/tautomeri-
zation sequence (TS11-12 = À6.2 kcal
molÀ1) to eventually deliver the
kinetic product 5aa. Importantly, by
means of a stronger base or longer
reaction time an equilibration event
À
occurs leading to the C C double
bond migration of 5aa to provide the
more stable 5,6-dihydropyran-2-one
1aa having a conjugated alkene to
the carbonyl functional group (via
a formal protonation to g-position).
In conclusion, we have shown that
ketone derived alkylidene Meldrumꢀs
acids 3 are novel C4-synthon capable
of being engage into a vinylogous
formal (4 + 2) cycloaddition reaction
with reactive ketones to furnish an
unprecedented route to 3,6-dihydro-
pyran-2-ones 5 upon Brønsted base
catalytic conditions. By means of the
commercially available bifunctional
Takemoto organocatalyst up to 98%
ee were obtained, especially for orig-
inal spiro compound 3,6-dihydro-
pyran-2-ones 5. The exploitation of
this novel and readily available vinyl-
ogous platform in enantioselective
transformations and the use of original
products obtained thereby is currently
under investigation.
Acknowledgements
We are grateful to the Charm3At-
SynOrg Interlabex for a post-doctoral
fellowship to S.W., the CNRS (UMR
8182) and the University Paris Saclay
for financial support. We also thank
Scheme 4. Proposed mechanism based on DFT calculations. [a] The computed free energies
(DG298) of intermediates and transition states (TS) are given in kcalmolÀ1 in brackets with Me3N
as catalyst (selected distances in ꢂ).
Emilie Kolodziej for technical assis-
tance with the HPLC analysis. This
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Shi, C. Zhao, L. Ding, S. Jiang, L. Yang, G. Zhong, Chem.
Commun. 2018, 54, 1567 – 1570.
work has been partially supported by INSA Rouen Nor-
mandy, University of Rouen Normandy, the Centre National
de la Recherche Scientifique (CNRS), EFRD, and Labex
SynOrg (ANR-11-LABX-0029), and by Region Normandie
(CRUNCh network). V.G. thanks Ecole Polytechnique and
the CINES (project A0070810977) for computational resour-
ces.
[8] For selected examples of Brønsted base organocatalyzed enan-
tioselective syntheses of 5,6-dihydropyran-2-one, see: a) C.
Cassani, P. Melchiorre, Org. Lett. 2012, 14, 5590 – 5593; b) T.-P.
Gao, J.-B. Lin, X.-Q. Hu, P.-F. Xu, Chem. Commun. 2014, 50,
8934 – 8936; c) T.-Z. Li, Y. Jiang, Y.-Q. Guan, F. Sha, X.-Y. Wu,
Chem. Commun. 2014, 50, 10790 – 10792; d) J.-L. Han, C.-H.
Chang, Chem. Commun. 2016, 52, 2322 – 2325; e) Y. Jiang, J.-H.
Fu, T.-Z. Li, F. Sha, X.-Y. Wu, Org. Biomol. Chem. 2016, 14,
6435 – 6441; f) T.-P. Gao, D. Liu, J.-B. Lin, X.-Q. Hu, Z.-Y. Wang,
P.-F. Xu, Org. Chem. Front. 2016, 3, 598 – 602; g) J.-L. Han, Y.-D.
Tsai, C.-H. Chang, Adv. Synth. Catal. 2017, 359, 4043 – 4049; h) S.
Crotti, N. Di Iorio, A. Mazzanti, P. Righi, G. Bencivenni, J. Org.
Chem. 2018, 83, 12440 – 12448; i) Z.-G. Zhang, J.-H. Fu, F. Sha,
X.-Y. Wu, Tetrahedron 2018, 74, 3557 – 3563.
Conflict of interest
The authors declare no conflict of interest.
Keywords: asymmetric synthesis · dihydropyranones ·
[9] E. Chupakhin, O. Babich, A. Prosekov, L. Asyakina, M.
Krasavin, Molecules 2019, 24, 4165.
Meldrum’s acid · organocatalysis · vinylogy
[10] G. Baxter, R. Brown, Aust. J. Chem. 1975, 28, 1551 – 1557.
[11] For reviews on catalytic transformations of Meldrumꢀs acid
derivatives, see: a) A. M. Dumas, E. Fillion, Acc. Chem. Res.
2010, 43, 440 – 454; b) E. Pair, T. Cadart, V. Levacher, J.-F.
Briꢁre, ChemCatChem 2016, 8, 1882 – 1890.
[12] For pioneering dimerization of alkylidene Meldrumꢀs acids and
discussion of their acidity, see: a) J. Leitich, P. Schuster, A. Eitel,
Tetrahedron 1967, 23, 2221 – 2227; b) P. Schuster, A. Stephen,
O. E. Polansky, F. Wessely, Monatsh. Chem. 1968, 99, 1246 –
1276; c) R. Akuꢂ-Gꢂdu, H. El-Hafidi, B. Rigo, D. Couturier, J.
Heterocycl. Chem. 2006, 43, 365 – 369.
[13] The presence of this substructure was reported in a naturally
occurring product with an inhibitory activity against ubiquitin-
specific protease 7: N. Tanokashira, S. Kukita, H. Kato, T.
Nehira, E. D. Angkouw, R. E. P. Mangindaan, N. J. de Voogd, S.
Tsukamoto, Tetrahedron 2016, 72, 5530 – 5540.
[1] R. C. Fuson, Chem. Rev. 1935, 16, 1 – 27.
[2] For leading reviews on indirect vinylogous catalytic processes,
see: a) S. E. Denmark, J. R. Heemstra, Jr., G. L. Beutner,
Angew. Chem. Int. Ed. 2005, 44, 4682 – 4698; Angew. Chem.
2005, 117, 4760 – 4777; b) G. Casiraghi, L. Battistini, C. Curti, G.
Rassu, F. Zanardi, Chem. Rev. 2011, 111, 3076 – 3154.
[3] For selected reviews on direct vinylogous aldol processes, see:
a) S. V. Pansare, E. K. Paul, Chem. Eur. J. 2011, 17, 8770 – 8779;
b) V. Bisai, Synthesis 2012, 44, 1453 – 1463; c) I. D. Jurberg, I.
Chatterjee, R. Tannert, P. Melchiorre, Chem. Commun. 2013, 49,
4869 – 4883; d) X.-Y. Chen, Q. Liu, P. Chauhan, D. Enders,
Angew. Chem. Int. Ed. 2018, 57, 3862 – 3873; Angew. Chem.
2018, 130, 3924 – 3935; e) R. Dalpozzo, R. Mancuso, Synthesis
2018, 50, 2463 – 2472; f) H. Li, L. Yin, Tetrahedron Lett. 2018, 59,
4121 – 4135.
[4] a) T. B. Poulsen, C. Alemparte, K. A. Jørgensen, J. Am. Chem.
Soc. 2005, 127, 11614 – 11615; b) D. Xue, Y.-C. Chen, Q.-W.
Wang, L.-F. Cun, J. Zhu, J.-G. Deng, Org. Lett. 2005, 7, 5293 –
5296; c) A. J. Grenning, Synlett 2017, 28, 633 – 639.
[5] a) P. S. Tiseni, R. Peters, Angew. Chem. Int. Ed. 2007, 46, 5325 –
5328; Angew. Chem. 2007, 119, 5419 – 5422; b) P. S. Tiseni, R.
Peters, Org. Lett. 2008, 10, 2019 – 2022; c) P. S. Tiseni, R. Peters,
Chem. Eur. J. 2010, 16, 2503 – 2517.
[14] CCDC 1998088, 1998089 and 1992496 contain the supplemen-
tary crystallographic data for compound (+ /À)-1aa, (+ /À)-5aa
and (R)-5aa.
[15] The vinylogous addition of 3a successfully provided acyclic
trifluoroacetophenone (67% yield and 93% ee) and para-CN-
phenyl a-keto ethyl ester (50% yield and 82% ee) but led to the
corresponding 5,6-dihydropyran-2-ones 1 due to isomerization
after a prolonged reaction time and purification by silica gel
column chromatography.
[16] In the presence of tetramethylguanidine, an intermediate like
10aa, as a guanidinium carboxylate salt, precipitated out of the
solution to provide a crystal suitable for X-ray diffraction
analysis (see SI).
[6] L.-T. Shen, P.-L. Shao, S. Ye, Adv. Synth. Catal. 2011, 353, 1943 –
1948.
[7] For selected examples of NHC organocatalyzed enantioselective
syntheses of 5,6-dihydropyran-2-one, see: a) J. Mo, X. Chen,
Y. R. Chi, J. Am. Chem. Soc. 2012, 134, 8810 – 8813; b) Z. Xiao,
C. Yu, T. Li, X.-S. Wang, C. Yao, Org. Lett. 2014, 16, 3632 – 3635;
c) Y. Lin, L. Yang, Y. Deng, G. Zhong, Chem. Commun. 2015, 51,
8330 – 8333; d) Y. Que, T. Li, C. Yu, X.-S. Wang, C. Yao, J. Org.
Chem. 2015, 80, 3289 – 3294; e) X. Rong, H. Yao, W. Xia, Y. Du,
Y. Zhou, H. Liu, ACS Comb. Sci. 2016, 18, 220 – 224; f) J. Yan, K.
Manuscript received: October 29, 2020
Accepted manuscript online: March 5, 2021
Version of record online: April 6, 2021
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