# Recent advances of asymmetric catalytic transformations of alkylidene Meldrum's acid derivatives

Hélène Beucher, Vincent Levacher, Sylvain Oudeyer, Jean-François Brière

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Hélène Beucher, Vincent Levacher, Sylvain Oudeyer, Jean-François Brière. Recent advances of asymmetric catalytic transformations of alkylidene Meldrum's acid derivatives. Chemical Communications, 2025, 61, pp.6555. 10.1039/x0xx00000x. hal-05049778

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Submitted on 28 Apr 2025

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# Recent advances of asymmetric catalytic transformations of alkylidene Meldrum's acid derivatives

Hélène Beucher,ª Vincent Levacher,ª Sylvain Oudeyer,ª and Jean-François Brière *ª

Received 00th January 20xx,
Accepted 00th January 20xx

DOI: 10.1039/x0xx00000x

Amongst the electron-deficient alkene derivatives, as molecular platforms widely used in organic synthesis, the readily available alkylidene Meldrum's acid derivatives hold a unique place due to the high electrophilicity and chemical versatility of the 1,3-dioxan-4,6-dione moiety. This short review intends to give an overview of recent advances in the asymmetric catalytic transformation of alkylidene Meldrum's acids into valuable chiral heterocycles, evolving from seminal investigations into C-C bond construction from the alkene moiety, to more recent enantioselective C-N and C-S bond formation, vinylogous processes, and the exploitation of the reactivity of the 1,3-dioxan-4,6-dione moiety's reactivity to develop efficient annulation sequences.

## Introduction

The chemical transformation of electron-deficient alkene derivatives, as versatile molecular platforms, is a widely used synthetic approach by organic chemists to build valuable C(sp³)-rich molecules useful in pharmaceutical chemistry, bio-conjugation approach, material science, etc. (Scheme 1). The investigation of the reactivity of the C-C double bonds encompassed the achievement of (hetero)-Michael reactions,¹ annulation and cycloaddition sequences,² to name the most famous synthetic tactics, especially following modern developments in sustainable catalysis and asymmetric synthesis. The variation of the chemical properties of the electron-poor alkene skeleton led the chemists to get insight into several kind of electron-withdrawing (EWG) moieties both as a modulation lever of the conjugated unsaturation and to allow downstream functional group manipulation.

In that context, the alkylidene Meldrum's acid (AMA) derivatives hold a unique place owing to their unique properties (Scheme 1).³ The AMA architecture possesses a significant capability to undergo 1,4-nucleophilic conjugate addition reactions as quantified by Mayr' parameters (E = -9.15), showing that AMA is 10¹¹ times more electrophilic than the corresponding ethyl malonate analogue **1** (E = -20.22).⁴ This remarkable reactivity is, on the one hand, due to the significant stability of the 1,3-dioxan-4,6-dione derived anion MA⁻ (actually Meldrum's acid (MA) is known to be very acidic - pKₐ = 4.8 in water), being conversely a moderately reactive nucleophile N = 13.91.³a, ³b, ⁴ On the other hand, from a kinetic point of view, the specific boat conformation of the native MA structure, a topology also found within the AMA, leads to minimal changes of conformation and a good orbital overlapping securing an energy cost efficiency during the course of the 1,4-conjugate addition reaction to AMA.³a, ³b Accordingly, facile Carbon-Carbon or Carbon-Heteroatom bond constructions are expected during Michael or annulation reactions, although the great stability (and conversely the moderate reactivity) of the formed 1,3-dioxan-4,6-dione

derived anion intermediate MA⁻ has to be taken into account during the overall process.³a, ³b

<figure><img src="image_2.png" /></figure>

Electrophilic (E) and Nucleophilic (N)
Mayr's parameters,
and acidity (MA → MA)

* E: -20.55 (1) • E: -9.15 (AMA), for ☉ = Ph

* N: 13.91 (MA) • N: 20.22 (diethyl malonate)

* pKₐ (H₂O): 4.8 (MA) • pKₐ: 12.9 (diethyl malonate)

<caption>**Scheme 1.** Alkylidenes Meldrum's acid (AMA) derivatives and their properties.</caption>

Subsequent to the C-C double bond transformation, substituted MA derivatives are formed, acting as versatile molecular platforms with unique reactivity compared to malonates (Scheme 2). This stems from the enhance electrophilicity of the carbonyl group of the dioxan-4,6-dione ring. This increased electrophilicity promotes the addition of a wide variety of nucleophiles (Nu' ), typically followed by a two-steps sequence, i.e., fragmentation and decarboxylation reactions (-Me₂CO, -CO₂). In addition, an abundant literature highlights the significant synthetic opportunities offered by the thermal decomposition of Meldrum's acid derivatives.³a, ⁵ For example, disubstituted MA fragments into disubstituted ketenes around 200 °C, while the mono-substituted MA undergoes a retro-Diels-Alder cycloaddition in its enolate form MA⁻ to give highly reactive acylketene species (taking place around 100 °C).³a, ⁵

<figure><img src="image_3.png" /><figcaption>**Scheme 2.** Reactivity of 1,3-dioxan-4,6-dione structure.</figcaption></figure>

<footnote>ª CNRS, INSA Rouen Normandie, Univ Rouen Normandie, Univ Caen Normandie, ENSICAEN, Institut CARMeN UMR 6064, F-76000 Rouen, France.</footnote>

<footnote>† Footnotes relating to the title and/or authors should appear here. Supplementary Information available: [details of any supplementary information available should be included here]. See DOI: 10.1039/x0xx00000x</footnote>
A specific asset which favoured these achievements (a key factor that has greatly contributed to these advances) is the seminal development of robust procedures to prepare alkylidene Meldrum's acid derivatives, by means of the cheap and commercially available **MA**, either from aldehydes or ketones by several groups.⁶ Many **AMA** flanked by a terminal aromatic ring or a sterically hindered aliphatic branched moiety on the alkene are stable enough to be isolated and stored for a while. However, more reactive **AMA** derivatives, featuring a less hindered and often unbranched aliphatic group, tend to be unstable and are best prepared *in situ* for immediate use in subsequent transformations, ideally under multicomponent reaction (MCR) conditions.

<figure><img src="image_4.png" /><figcaption>**Scheme 3.** Emerging developments of Alkylidenes Meldrum's acid (AMA) derivatives in catalytic synthesis of chiral heterocycles.</figcaption></figure>

Despite their unique characteristics, the catalytic and enantioselective transformations of **AMA** only emerged in the literature in the 2000s, both with metal-based catalysis and organocatalysis in action.³ Ever since, several elegant asymmetric Michael reactions, annulation or cycloaddition protocols have steadily appeared, allowing to build various chiral molecules based, however and essentially, on key stereoselective C-C bond formation, as testified by dedicated reviews in that field (Scheme 3).³ It is unnecessary to insist on the importance of exploring the three-dimensional (3D) chemical space of C(sp³)-rich medicinally relevant molecules, especially chiral heterocycles, since it has been established that “escaping from the flatland” increases the chances of success in developing new drug candidates.⁷ This paradigm shift has also fostered and accelerated the development of novel catalytic, especially asymmetric, transformations that convert versatile molecular platforms such as **AMA** derivatives into 3D-heterocyclic skeletons.

This review does not intend to be exhaustive, but rather to give an overview of the recent developments in the asymmetric catalytic transformation of **AMA** that open up new avenues for the construction of chiral heterocycles going beyond the historically interesting but somewhat limited Michael or annulation reactions based on the C-C bond formation taking place onto the alkene moiety. In that vein, new catalytic transformations that markedly expand the utility of **AMA** as molecular platforms will be discussed such as C-Heteroatom bond formation, addition-cyclocondensation sequences and

vinylogous chemistry, including the achievements of our groups (Scheme 3). A literature context will be provided for clarity purposes in order to give an historical and peripheral view of the realizations within this domain of organic synthesis. Readers interested in using Meldrum's acid derivatives as versatile building blocks in organic synthesis are encouraged to consult insightful reviews that cover this dynamic field of research.³,⁸

## 1,4-Addition-Cyclocondensation

In this session, the **AMA** will behave as either a C3 or a C3-O synths (Figure 1), with regard to the incoming reactant.

<figure><img src="image_5.png" /><figcaption>**Fig. 1.** Alkylidenes Meldrum's acid (AMA) as C3 or C3-O synths.</figcaption></figure>

### Domino Aza-Michael-cyclocondensation

While elegant catalytic enantioselective 1,4-conjugate additions,⁹ or cycloaddition reactions¹⁰ involving the C-C double bond of **AMA** emerged in the beginning of 2000s,³ these processes involved essentially a key C-C bond construction in the stereoselective step. In contrast, achieving enantioselective Carbon-Heteroatom bond formation holds an additional challenge due to a likely more equilibrated 1,4-addition process.

In 2014 (Scheme 4), our group developed a smooth asymmetric synthesis of original diazabicyclo[3.3.0]octane-2,8-diones 3 by simply mixing pyrazolidinone 2, aldehydes and Meldrum's acid (MA) in the presence of (DHQ)₂PHAL as organocatalyst (15 mol%) with good enantiomeric excesses (ee) up to 92%.¹¹ This so-called organocatalyzed multicomponent Knoevenagel-Michael-Cyclocondensation (KMC)⁸f reaction benefits from (1) the *in situ* formation of the highly reactive **AMA**, likely through a Knoevenagel condensation catalyzed by 2, allowing to use both aliphatic (branched and linear) and aromatic aldehydes. Then, (2) the transient **AMA** is rapidly consumed by an unprecedented organocatalyzed enantioselective aza-Michael reaction mediated by (DHQ)₂PHAL catalyst, whereby the irreversibility of the C-N bond construction was secured by the subsequent cyclocondensation (loss of acetone). Finally, this MCR was concluded by a decarboxylative-protonation sequence (loss of CO₂) that regenerates thereby the organocatalyst R₃N* and highlight a use of **AMA** as a C3-synthon in soft conditions. As things stand, the proton transfer mechanism after the aza-Michael step remains uncertain, but the acidity of the cyclic hydrazine nucleophile might be key for the process to occur as acyclic hydrazines were unsuccessful partners. However, it has been demonstrated that six-membered ring pyridazinones can act as nucleophiles in the multicomponent KMC reaction, leading to the formation of diazabicyclo[4.3.0]nonane-2,7-diones, albeit in a diastereoselective fashion.¹²
<figure><img src="image_6.png" /><figcaption>**Scheme 4.** Multicomponent KMC reaction through a key aza-Michael step.</figcaption></figure>

The multicomponent KMC reaction was extrapolated to the aza-Michael reaction (C-N bond formation) involving hydroxylamine,¹³ and amidine derivatives¹⁴ towards the construction of chiral isoxazolidinones and dihydropyrimidin-4-ones, respectively, in both racemic and diastereoselective manners. In 2020, we uncovered the possibility to use readily available hydroxamic acids **4** derived from naturally occurring chiral α-amino acids (α-AA) as bis-nucleophiles. This approach paved the way to new isoxazolidin-5-ones **5** as masked α,β-dipeptides (vide infra), with some possessing a homologous (hβ) proteinogenic α-AA derived moiety (Scheme 5).¹⁵ Although the diastereoselectivity of the base-promoted MCR was mostly controlled by substrate **4**, it was observed a match effect with (DHQ)₂PHAL as organocatalyst, leading to improved diastereoisomeric ratios (dr ranging from 75:25 to 95:5) and higher yields. Worthy of note, the major diastereoisomer could be separated by silica gel column chromatography. The isoxazolidinone part, as a masked β-AA, underwent facile N-O bond hydrogenolysis or ring-opening reactions upon the nucleophilic addition of another α-AA. This strategy allowed the diversity-oriented synthesis of various α,β-dipeptides **6**, respectively, with high diastereoisomeric ratio.

<figure><img src="image_7.png" /><figcaption>**Scheme 5.** Diversity oriented synthesis of α,β-dipeptides.</figcaption></figure>

The development of a catalytic enantioselective multicomponent KMC reaction with achiral hydroxamic acids turned out to be challenging due to a marked background reaction starting from carbamate derived compound such as **7a** (Scheme 6).¹⁶ However, hydroxamic acid components **7b-c**, especially those featuring a sterically hindered amide possessing a di-*iso*-propylamine moiety, turned out to be competent to promote the formation of the corresponding isoxazolidinones **8** with 85% ee (with **7c**). The benzhydryl-derived cupreine **9**, specifically developed as a bifunctional organocatalyst for this reaction, achieved good enantioselectivities up to 89% ee. After the N-O bond hydrogenolysis, the resulting β³-amino acid displays a salient feature. Upon heating at 130 °C, the sterically hindered twisted di-*iso*-propylurea moiety is converted into the corresponding methylcarbamate in the presence of methanol, likely through the formation of an isocyanate intermediate.¹⁶

<figure><img src="image_8.png" /><figcaption>**Scheme 6.** Organocatalyzed enantioselective synthesis of isoxazolidinones.</figcaption></figure>

As long as the mechanism is concerned (Scheme 7), it is believed that cupreine **9** promotes at first the Knoevenagel condensation between **MA** and the aldehyde, leading to the formation of **AMA** followed by the aza-Michael reaction. It is supposed that both the quinuclidine and phenol moieties of the bifunctional cupreine **9** orchestrated the *re*-face approach of the hydroxamic acid nucleophile through hydrogen bonding events to allow C-N bond formation and subsequent cyclocondensation to yield carboxylate intermediate **10**. Importantly, during previous investigation of the cyclization process of a Meldrum's acid derivative flanked by an hydroxylamine motif, it was demonstrated by DFT computational study that the organocatalyst plays a crucial role in promoting this type of cyclocondensation through a proton shuttle event.¹⁷ Finally, the decarboxylative-protonation sequence takes place to give **8a**, and the organocatalyst **9** is regenerated en route to another catalytic cycle.
<figure><img src="image_9.png" /><figcaption>**Scheme 7.** Proposed catalytic cycle for the multicomponent KMC reaction with a urea-type hydroxamic acid.</figcaption></figure>

In order to both determine the absolute configuration of isoxazolidinone **8c** and demonstrate the usefulness of this building block, a synthesis of known β-amino acid **13** was undertaken (Scheme 8). After an uneventfully N-O hydrogenolysis and esterification sequence, furnishing the ring-opened product **11** in 94% yield, the author could benefit from the specific reactivity of the sterically hindered urea.¹⁸ Upon heating in the presence of benzyl alcohol, the transient isocyanate **12** formation is supposed thanks to the labile nature of the diisopropylamine moiety. This reactive intermediate **12** is trapped by BnOH in order to provide a synthesis of the corresponding N-Cbz protected β-amino acid **13**, with very little racemization event.

<figure><img src="image_10.png" /><figcaption>**Scheme 8.** Towards the synthesis of a β-amino acid.</figcaption></figure>

### Domino Michael-cyclocondensation (addition to C=O function)

Although the first enantioselective catalytic Michael reactions to **AMA** appeared in the literature at the beginning of the 2000s,³ the pioneering investigation of Feng and Zhang in 2012 demonstrated the possibility to performing a domino Michael-type Friedel-Crafts alkylation/cyclization of phenol derivatives to **AMA** under enantioselective conditions with the Takemoto's catalyst.¹⁹ This achievement thereby expanded thereby the use of alkylidene Meldrum's acids as a C3 synthon to a broader range of nucleophiles. On the other hand, List and later Bhat reported on the multicomponent Knoevenagel-

Michael reaction of ketones to **AMA** under aminocatalysis conditions.⁹a, ²⁰

The first example of a multicomponent reaction involving a tandem Knoevenagel-Michael-Lactonization sequence was reported in 2017 by the group of Bhat, leading to the synthesis of enantiopure γ-butyrolactones **15** from **MA** and α-hydroxyketone **14** (Scheme 9).²¹

<figure><img src="image_11.png" /></figure>

### Selected examples

<figure><img src="image_12.png" /></figure>

* with Me

**15a** (*R* = *H*), 78%, 94% ee, 2.5:1 dr
75%, 94% ee (gram scale)

**15b** (*R* = 4-F), 82%, 99% ee, 1.7:1 dr

**15c** (*R* = 2-NO₂), 51% 86% ee, 20:1 dr

* with n-Pr

**15d** (*R* = *H*), 64%, 90% ee, 1.1:1 drᵇ

* with Ph

**15e** (*R* = 2-NO₂), 59%, 61% ee, 3:1 drᵇ

b10 mol% **epi-NH₂-QN** and 20 mol% TFA

<figure><img src="image_13.png" /></figure>

* with Me

**15f**, 64%, 90% ee, 1.1:1 dr

<figure><img src="image_14.png" /></figure>

* with Ph

**15g**, 62%, 70% ee, 20.1 drᵇ

<caption>**Scheme 9.** Organocatalyzed synthesis of γ-butyrolactone through a tandem Knoevenagel-Michael-Lactonization sequence.</caption>

In the presence of the *epi*-amino quinine catalyst **epi-NH₂-QN**, the reaction proceeded smoothly to afford a wide array of functionalized γ-butyrolactones **15** as a mixture of *trans/cis* diastereoisomers (up to 20:1 dr in favor of the *trans* isomer) in good yields and high enantioselectivities up to 99% ee. Practically speaking, while the reaction was performed at room temperature, a heating period (65 °C) was required to allow the decarboxylation event of the carboxylic acid intermediate that originated from the cyclo-condensation onto the dioxan-4,6-dione ring (*vide infra*). It is worthy of note that at the onset of the study, **D-proline** was used as a catalyst, but it afforded a low level of diastereo- and enantioselectivity. Regarding the scope of the reaction, the reaction proceeded smoothly with aromatic aldehydes to give products **15a-d** whatever the electronic nature of the substituent *R* on the aromatic ring, and the reaction can be scaled up to a gram scale without any drop in yield or enantioselectivity. Generally speaking, the reaction seems not to be significantly affected by the steric or electronic environment. However, a limitation was found with derivatives flanked by an *ortho*-nitroaryl moiety giving product **15e** with a reduced 61% ee. On the other hand, heteroaromatic aldehydes also provided high level of enantioselectivity (**15f**, 90% ee). More interestingly, aliphatic aldehydes such as valeraldehyde were also easily converted into the corresponding lactone **15g**, albeit in modest yield and enantioselectivity. Nevertheless, 10 mol% of *epi-NH₂-QN* along with 20 mol% of TFA were required to ensure complete conversion.
The authors shed light on the reaction mechanism by implementing DFT calculations (Scheme 10). This computational investigation showed that the Z-enamine intermediates is more stable than the E-enamine thanks to an intramolecular hydrogen bonding interaction. This enamine intermediate was then involved in the (4+2)-hetero-Diels-Alder cycloaddition as a dienophile in the presence of the *in situ* formed **AMA** as a diene to furnish **16**. Elucidation of the transition state (TS) demonstrated a favored approach involving the *si*-face of the dienophile and the *si*-face of the diene as the lowest TS, which accounts for the high stereoselectivity experimentally observed. Then, upon hydrolysis, a condensation process occurs with the loss of a molecule of acetone, giving rise to the carboxylic intermediate **17**, which undergoes a decarboxylation event towards the formation of **15a**.

<figure><img src="image_15.png" /><figcaption>**Scheme 10.** Computational investigation of the a tandem Knoevenagel-Michael-Lactonization sequence.</figcaption></figure>

In complement to previous racemic or non-catalytic approaches using the Acceptor-Donor properties of **AMA** through (4+2) cycloaddition,²² Lin et al. reported on an organocatalytic domino asymmetric (3+2) cycloaddition-annulation reaction between **AMA** and the *in situ* formed azomethine ylides originating from imines **18**, for the construction of chromeno[4,3-b]pyrrolidine **19** based on the Acceptor-Donor-Acceptor (ADA) capability of the **AMA** (Scheme 11).²³ Among all the catalysts screened, the *epi*-amino thiourea quinine (*epi-TU-QN*) provided the highest levels of enantiomeric excess. Under standard conditions (i.e., 1 mol% *epi-TU-QN* in THF at 30 °C), several chromeno[4,3-b]pyrrolidines **19** were isolated in yields ranging from 51 to 97% and with an excellent level of enantioinduction (88-99% ee) as a single diastereoisomer except for sporadic examples. Regarding the **AMA** substitution, aromatic, heteroaromatic and aliphatic pendants are well tolerated (**19a-e**), best result being obtained with the 4-MeO-phenyl substituent providing the cycloaddition product **19b** in 97% isolated yield and perfect 99% ee. As far as the imine partner **18** is concerned, three points of diversity were successfully evaluated to furnish the corresponding products **19f-19i**, highlighting the generality of this approach as long as a malonate moiety is present.

<figure><img src="image_16.png" /><figcaption>**Selected examples (dr > 20:1 unless specified)**</figcaption></figure>

<table><caption>**Scheme 11.** Organocatalyzed synthesis of chromeno[4,3-b]pyrrolidines through a an asymmetric (3+2) cycloaddition-annulation sequence.</caption><thead><tr><th>With</th><th>5-Br</th><th>CO<sub>2</sub>Et</th><th>R = Et</th><th>With</th><th>Ph</th></tr></thead><tbody><tr><td>19a</td><td>(C<sub>6</sub>H<sub>5</sub>), 93%, 99% ee</td><td></td><td></td><td>19f</td><td>(H, CO<sub>2</sub>Et, R = Et), 82%, 99% ee</td></tr><tr><td>19b</td><td>(4-MeOC<sub>6</sub>H<sub>4</sub>), 97%, 99% ee</td><td></td><td></td><td>19g</td><td>(5-Br, CO<sub>2</sub>Me, R = Me), 92%, 96% ee</td></tr><tr><td>19c</td><td>(2-ClC<sub>6</sub>H<sub>4</sub>), 51%, 95% ee, 5:1 dr</td><td></td><td></td><td>19h</td><td>(5-Br, Ph, R = Et), no reaction</td></tr><tr><td>19d</td><td>(2-thienyl), 95%, 99% ee</td><td></td><td></td><td>19i</td><td>(5-Br, H, R = Et), no reaction</td></tr><tr><td>19e</td><td>(c-hexyl), 52%, 99% ee</td><td></td><td></td><td></td><td></td></tr></tbody></table>

It was demonstrated that the thiourea moiety of the bifunctional **epi-TU-QN** catalyst was crucial for the stereoselectivity outcome as the native quinine organocatalyst provided the cycloaddition product **19** in almost the same isolated yield but as a racemate. Accordingly, regarding the mechanism (Scheme 11), it was proposed that after the deprotonation of imine **18** by the Brønsted base **epi-TU-QN**, the resulting activated **azomethine ylide** intermediate was guided by the tertiary ammonium cation part of the catalyst **epi-TU-QN-H⁺** while the **AMA** was well-oriented thanks to hydrogen bonding interactions. This dual activation model ensures the approach of the *si*-face of the **azomethine ylide** toward the *re*-face of the **AMA**, leading to a high level of stereocontrol. Then, after the (3+2) cycloaddition event, a highly stereoselective cyclization takes place upon the regioselective addition of the phenol nucleophile to one of the two carbonyl functions of the 1,3-dioxan-4,6-dione structure, ultimately providing the annulated adduct **19** with a *cis* configuration.

### Domino Michael-Cyclocondensation (addition of the C=O function)

The enantioselective and catalytic 1,4-conjugate alkynylation addition to **AMA** were pioneered by the groups of Carreira and Fillion upon the catalytic influence of chiral copper and rhodium complexes.⁹c,²⁴ The subsequent intramolecular addition of the oxygen for the 1,3-dioxan-4,6-dione C=O functional group to the alkyne pendant was demonstrated in order to build a butyrolactone via a 5-*exo*-dig cyclization.²⁴a,²⁵ This general principle was further extended by the group of Aponick to the enantioselective orthogonal tandem catalyzed synthesis of δ-lactones **21** thanks to a 6-*endo*-dig cyclization event starting from **AMA** and alkyne **20** (Scheme 12).²⁶
<figure><img src="image_17.png" /><figcaption>**Scheme 12.** Synthesis of δ-lactones via an enantioselective Cu/Ag orthogonal tandem catalytic process.</figcaption></figure>

By using a mixture of Cul (5 mol%) and AgOAc (6.5 mol%) in the presence of **(S)-Me-Stack-Phos** (6.5 mol%) as a ligand for both metals, δ-lactones **21** were obtained in good to excellent yields (52-93%) and excellent enantiomeric excesses (88-99% ee). The reaction conditions proved to be versatile tolerating a wide array of substituents both on the **AMA** (aryl, heteroaryl) or on the alkyne **20** (aryl, alkyl or alkenyl) without altering the level of enantioselectivity. Regarding the mechanism, the difference in regioselectivity of the cyclisation was attributed to the use of ligated copper catalyst instead of Ag(I) salts reported by Fillion.²⁵ Several control experiments allowed the authors to propose a mechanism where the ligated Cu(I) complex (**CuOAc•L**\*) acts as a catalyst for the enantioselective alkynylation of **AMA**, whereas the **AgOAc•L**\* complex generated in small amount *in situ* (i.e. 1.5 mol% alongside the precipitation of AgI) is predominantly responsible for the a 6-endo-dig cyclization, namely the heterofunctionalization step, following overall an orthogonal tandem catalysis approach.

<figure><img src="image_18.png" /><figcaption>**Scheme 13.** Application to the elaboration of a bio-active ingredient.</figcaption></figure>

The authors took advantage of the readily available dihydropyranone **21g** by this tandem strategy to synthesis the corresponding saturated lactone 22 upon palladium promoted hydrogenation conditions (Scheme 13).²⁶ This lactone is claimed as an intermediate for the elaboration of a platelet aggregation inhibitor molecule.

<figure><img src="image_19.png" /><figcaption>**Scheme 14.** Enantioselective ammonium ylide mediated one-pot synthesis of γ-butyrolactones.</figcaption></figure>

While the racemic synthesis of γ-butyrolactones from **AMA** and arsonium ylides was reported by several groups,²⁷ the use of stoichiometric amounts of toxic arsenic compounds severely hampered the wide application of this approach. The use of non-toxic ammonium ylides by the group of Liang afforded a practical solution to this issue.²⁸ Nevertheless, no catalytic or asymmetric strategies were reported in the literature. More recently, the group of Worgull and Pietruszka reported on the enantioselective organocatalyzed synthesis of γ-butyrolactones **24** and **25** starting from **AMA** and α-bromo acetophenone derivatives **23** (Scheme 14).²⁹ The authors observed the formation of two different products either **24** or **25** depending upon the reaction conditions. First of all, when water (5 equiv) was used, in the presence of the O-benzyl cinchonidine **Bn-CD** as a chiral organocatalyst (20 mol%), lactones **25** were obtained in low to modest isolated yields (20-94%) along with variable level of enantioselectivity (24-94% ee) for a large variety of **AMA** bearing aromatic or heteroaromatic substituents and for α-bromo acetophenone derivatives **23** bearing diversely substituted aromatic pendants. Generally speaking, best results were obtained with the electron rich functional group on **AMA**. It is worthy of note that in the absence of the Bn substituent at the C9 position of the catalyst **Bn-CD**, no conversion was observed. Moreover, for some examples, the use of β-ICD instead of **Bn-CD** catalyst significantly improved the yields but at the expense of the enantioselectivity (for instance 24%, 66% ee with **Bn-CD** vs 75%, 60% ee with β-ICD for compound **20c**). This improvement was attributed to the more nucleophilic
character of β-ICD allowing to shorten the reaction time and thus avoiding the decomposition events under the reaction conditions (i.e., 60 °C). The replacement of water additive (5 equiv) by a mixture of t-BuOH/H₂O (4:0.5 equiv) resulted in the formation of the lactone 25 bearing an ester at the α-position of the carbonyl group. However, the reaction turned out to be less general and enantioselective. While in this original sequence the AMA can be considered as a C2 synthon along with the cyclopropanation step, after the rearrangement a homologated sequence could be considered overall.

<figure><img src="image_20.png" /><figcaption>**Scheme 15.** Mechanistic proposal.</figcaption></figure>

From a mechanistic point of view (Scheme 15), the **AMA** undergoes a conjugated addition of the *in situ* generated **ammonium enolate** intermediate, formed upon the addition of **R<sub>3</sub>N*<sup>+</sup>** amine to α-bromoketone **23** in the presence of K<sub>2</sub>CO<sub>3</sub>, to afford, after cyclization, the spirocyclopropane intermediate **26**. The three-membered ring **21** then undergoes a Cloke-Wilson rearrangement giving rise to the formation of a transient benzylic carbocation **27** which is trapped by the oxygen of the **MA** moiety to form the cyclized product **28**. Then, two scenarios can occur, depending upon the reaction conditions. In the presence of water, product **24** is obtained by hydrolysis, loss of acetone and decarboxylation. On the other hand, in the presence of alcohol/water mixture, product **25** is obtained after addition of the alcohol nucleophile followed by a fragmentation (- Me<sub>2</sub>CO) protonation sequence.

Having shown that this ammonium ylide strategy allowed the synthesis of lactone **24a** in 94% ee, the authors performed a Baeyer-Villiger transformation of the acetyl moiety into the corresponding ester **29** in 56% yield (Scheme 16). Then, a simple saponification gave rise to the formation of a 2-substituted paraconic acid derivative **30** (98%, 94% ee), a family of naturally occurring lactones which are also known as precursors of valuable furofuran compounds.

<figure><img src="image_21.png" /><figcaption>**Scheme 16.** Application to the synthesis of a paraconic acid derivative.</figcaption></figure>

## Vinylogous chemistry

In this session, the **AMA** will behave as a C2, C4 or a C5 synths (Figure 2), with regard to the incoming reactant.

<figure><img src="image_22.png" /></figure>

<figure><img src="image_23.png" /><figcaption>**Fig. 2.** Alkylidenes Meldrum's acid (AMA) as C3 or C4 synths.</figcaption></figure>

### Vinylogous Aldolisation

The principle of vinylogy relates to the remote functionalization of a functional group (FG) separated by a conjugated unsaturated backbone, allowing the propagation of electronic effects of the FG. Highlighted in 1935 by Fuson,³⁰ this synthetic approach found a myriad of applications in organic synthesis, together with important developments in asymmetric catalysis, despite the remote stereocontrol of the bond-forming event remaining a challenging task.³¹ However, only a handful of racemic investigations tended to show that this type of reactivity might be exploited with **AMA**.³²

In 2021, the groups of Vo-Thanh and Brière reasoned that the deprotonation of the ketone derived alkylidene Meldrum's acid **KAMA** into anion **KAMA**⁻ may occur with a soft trialkylamine organobase (**R<sub>3</sub>N*<sup>+</sup>**, Scheme 17).³³ This hypothesis was based on the low pK<sub>a</sub> value of the corresponding **MA** (pK<sub>a</sub> = 4.8 in water) and hence the high stability of the corresponding enolate **MA**⁻ in association with a vinylogous phenomenon (Scheme 17). Furthermore, the cyclic nature of the 1,3-dioxan-4,6-dione structure should guide the chiral **R<sub>3</sub>N*<sup>-</sup>-H** close to the γ-position to be functionalized to facilitate the asymmetric induction. Thanks to the **Takemoto catalyst** a straightforward addition to activated ketones **31** followed by a domino cyclocondensation sequence, (i.e. a formal (4+2) cycloaddition) took place with ee ranging from 56 to 96% for products **32**. Most
interestingly, the formation of the unexpected 3,6-dihydropyran-2-ones **32** (with an unconjugated C-C double bond) instead of the thermodynamically more stable and predictable 5,6-dihydropyran-2-ones **33** (with an enone moiety, *vide infra*) was observed with soft bases. This unique issue allowed to prepare a series of original spiro-heterocycles **32a-32e** by means of the commercially available **Takemoto catalyst**, albeit in the case of oxindole derivatives such as **32d** better results were obtained with **epi-tosylaminoquinine (epi-TsNH2-QN)** derived alkaloid as catalyst.

<figure><img src="image_24.png" /></figure>

Selected examples

<figure><img src="image_25.png" /><figcaption>**32a** (*R* = Ph), 89%, 96% ee</figcaption></figure>

<figure><img src="image_26.png" /><figcaption>**32b** (*R* = (*E*)-PhCHCH), 88%, 91% ee</figcaption></figure>

<figure><img src="image_27.png" /><figcaption>**32c** (*R* = Me), 53%, 73% ee
(17% of 5,6-dihydropyran-2-ones)</figcaption></figure>

<caption>**32d**, 51%, 87% ee
(epi-TsNH2-QN cat.)</caption>

<caption>**32e**, 83%, 70% ee</caption>

**Scheme 17.** KAMA as new platforms in vinylogous catalysis.

A preliminary DFT computational study suggested a catalytic cycle initiated by an **aldolization** reaction after deprotonation of the **KAMA** by the organocatalyst **R<sub>3</sub>N (Me<sub>3</sub>N)** taken for DFT calculation), followed by a **cyclization** and a **fragmentation** leading to a carboxylate intermediate (Scheme 18).³³ While the transition states could not be ascertained at that stage, it is believed that a tautomerization (**1,3-H shift**) generates a Csp³ at Cα to allow a regioselective **decarboxylative-protonation** sequence (at Cα) giving rise to the formation of product **32a**.

<figure><img src="image_28.png" /><figcaption>**Scheme 18.** DFT investigation – proposed catalytic cycle.</figcaption></figure>

In the aforementioned vinylogous processes, the obtained 3,6-dihydropyran-2-ones **32** turned out to be the kinetic products, which isomerized into the more stable 5,6-dihydropyran-2-one derivatives **33** under slightly forced conditions.³³ Toffano nicely exploited this phenomenon in order to develop an unprecedented auto tandem catalytic synthesis of the unsaturated lactones **33** (Scheme 19).³⁴ The authors observed that **(DHQ)<sub>2</sub>PHAL** organocatalyst promoted the addition of **KAMA** to lactam **31a** to afford the product **32a** in favor of the *S*-enantiomer. Then, the same catalyst selectively promoted *in situ* the subsequent 1,3-proton shift under kinetic resolution conditions namely by mediating a selective deprotonation event of the (*S*)-precursor **32a** into the enantioenriched (*S*)-product **33a** in excellent 98% ee. This sequence furnished the corresponding 5,6-dihydropyran-2-one derivatives **33a-f** with very high enantioselectivity, while a few sterically hindered precursors such as **33g** proved to be reluctant to undergo the isomerization event.
<figure><img src="image_29.png" /></figure>

<figure><img src="image_30.png" /></figure>

<figure><img src="image_31.png" /><figcaption>**Scheme 19.** Catalytic enantioselective synthesis of 5,6-dihydropyran-2-ones.</figcaption></figure>

Later on, Vo-Thanh and Toffano extended this auto tandem vinylogous principle to a triple cascade allowing the diastereoselective synthesis of bis-lactone derivatives albeit in a racemic fashion.³⁵

### Vinylogous alkylidene Meldrum's acids as 1,3-dienes

Vinylogous **AMA** (VAMA), namely containing a 1,3-diene pendant, have only recently been involved into asymmetric 1,6-addition reactions, or remote related processes. Fillion's seminal investigation in 2006 showed that **VAMA** underwent a 1,6-conjugate addition with up to 84% ee in the presence of dialkylzinc as nucleophiles and a chiral copper complex.³⁶ A sterically hindered *iso*-propyl group at the C4-position was shown to prevent a competitive 1,4-conjugate addition.

Zhang and coworkers have thereafter expanded the scope of asymmetric 1,6-conjugate addition on **VAMA** by using arylboronic acids as reagents under palladium catalysis (Scheme 20).³⁷ Only **Pyrox**-type chiral ligands were competent to promote the reaction. Further optimization to obtain the product in high enantioselectivity led to the development of a new **Pyrox** structure bearing an extended *para*-(t-Bu)aryl pendant. The obtention of the (*R*)-enantiomer was assessed by X-ray crystallography, and it was proposed that the asymmetric induction aroused from the *Re*-face approach of the Pd-complex considering that the extended arylated-diene part of **VAMA** was lying away from the bulky functionalized oxazoline ring (Scheme 20, transition state). While the range of arylboronic acids was limited to phenyl and tolyl derivatives, the reaction was rather insensitive to the substitution pattern on the aryl group at position C6, with EWG and EDG in *ortho*, *meta*- and *para*-positions well tolerated (34a-e). Precursors with an alkyl group could also be used (34f), although at the expense of a lower enantioselectivity of 63%.

<figure><img src="image_32.png" /></figure>

<figure><img src="image_33.png" /><figcaption>**Scheme 20.** Pd-catalyzed asymmetric addition of arylboronic acids to **VAMA**.</figcaption></figure>

**Selected examples with Ar = Ph**

<figure><img src="image_34.png" /></figure>

The groups of Chen³⁸ and Enders³⁹ independently reported (4+2) cycloaddition reactions, that involved the remote functionalization of **VAMA** as starting material (single example for each) to deliver cyclic-products **35** and **36** in good to excellent enantioselectivity, with the **MA** motif remaining intact (Scheme 21). In the first case (Scheme 21a), a **trienamine** mode of activation was implemented for the annulation process involving 2,4-dienal thanks to a chiral **prolinol** derived organocatalyst.³⁸ In these conditions, an excellent γ,δ regioselectivity and *exo*-control of the formal Diels-Alder reaction led to product **35** in 97% ee and 19:1 dr. This result was assigned to the steric effect of substituent at Cγ by analogy to the outcome obtained with similar malononitrile derived substrates. In the latter case (Scheme 21b), *N*-Heterocyclic Carbene (**NHC**) based catalysis, originated from the deprotonation of the corresponding chiral **triazolium** pre-catalyst, was exploited.³⁹ Then, the Breslow intermediate **37** was formed upon the addition of the **NHC** to the aldehyde, and subsequently oxidized by bisquinone into vinylogous ammonium-enolate **38** able to undergo a regio- and stereoselective (4+2) cycloaddition (80% ee and 20:1 dr) with the **VAMA** platform.
<figure><img src="image_35.png" /></figure>

<figure><img src="image_36.png" /></figure>

<figure><img src="image_37.png" /></figure>

<figure><img src="image_38.png" /></figure>

<figure><img src="image_39.png" /><figcaption>**Scheme 21.** (4+2) cycloaddition reactions with VAMA.</figcaption></figure>

Recently, our group disclosed a stereoselective organocatalytic domino 1,6-sulfa-Michael-aldol-cyclocondensation reaction on VAMA using mercapto benzaldehyde as nucleophile 39 (Scheme 22).⁴⁰ At first, racemic conditions were developed with quinuclidine as organocatalyst under basic biphasic liquid/liquid conditions permitted to trigger the vinylogous sulfa-Michael process and the control of three-contiguous stereocenters, along with the subsequent formal (4+2) annulation, to eventually deliver one major diastereoisomer 41 (essentially >92:8 dr). Upon addition of the thiol moiety on the likely more stable *s-trans* VAMA, the mechanism was postulated to proceed through a formal (4+2) cycloaddition as previously described with KAMA (Scheme 14),³³ except that after the cyclization/fragmentation events (-Me₂CO), no decarboxylation was observed and the carboxylic acid derivative 40 could also be isolated. This specific feature probably aroused from geometric constraint in the tricyclic core, retarding the C-C double bond shift. Overall, the VAMA behaves as a C5-synthone. The reaction proved to be rather insensitive to the electronic nature and steric hinderance of the aryl at position C6 (41a-d). Aryl (like Ph 41e), as well as Me (41f) and *iso-propyl* (41g) groups were also well-tolerated at position C4, although, as an exception, the *iso-propyl*-functionalized derivatives led to a drop in dr of 74:25. Most importantly, one example of enantioselective approach was successfully reported using Takemoto catalyst (*R*₃N*) and cesium carbonate as a solid base in toluene to deliver product 41e in 75% yield and 75% ee, while surprisingly the diastereoselectivity decreased to 81:19. A mismatch between the chiral catalyst

induction and the substrate-controlled diastereoselective (4+2) cycloaddition was hypothesized to explain this issue.

<figure><img src="image_40.png" /></figure>

<figure><img src="image_41.png" /></figure>

### Selected examples

<figure><img src="image_42.png" /></figure>

* 41a (R = *p*-NO₂), 80%, 93:7 dr

* 41b (R = *p*-OMe), 80%, 92:8 dr

* 41c (R = *m*-OMe), 75%, 92:8 dr

* 41d (R = *o*-Me), 77%, 92:8 dr

<figure><img src="image_43.png" /></figure>

<figure><img src="image_44.png" /></figure>

<figure><img src="image_45.png" /></figure>

<figure><img src="image_46.png" /></figure>

<figure><img src="image_47.png" /></figure>

### Enantioselective approach towards 5e

* *R*₃N* (20 mol%), Na₂CO₃, PhMe/NaClₐ₅t, rt, 2 h
  56%, 79:21 dr, 74% ee (after TMSCHN₂ treatment)

* *R*₃N* (20 mol%), Cs₂CO₃ solid, PhMe, rt, 2 h
  75%, 81:19 dr, 75% ee (after TMSCHN₂ treatment)

<caption>**Scheme 22.** Domino Vinylogous sulfa-Michael-Aldol-Cyclocondensation reaction.</caption>

Shortly after, we extended this vinylogous Michael-Aldol cyclocondensation to aza-derivatives using α-ketoamides 42 as bifunctional nucleophiles under slightly basic conditions (Cs₂CO₃ as a base) delivering pyrano[2,3-c]pyrrole products 43, with excellent diastereoselectivity (> 95:5 dr) albeit in a racemic fashion (Scheme 23).⁴¹ Nevertheless, a preliminary enantioselective screening needs to be pointed out, as the corresponding product 43a could be obtained in 16% ee using Waser's catalyst as chiral quaternary ammonium salt under phase-transfer catalytic solid/liquid conditions.

<figure><img src="image_48.png" /></figure>

### Enantioselective approach towards 10a

<figure><img src="image_49.png" /><figcaption>**Scheme 23.** Domino Vinylogous aza-Michael-Aldol-Cyclocondensation reaction.</figcaption></figure>

## Conclusions

Over the years, alkylidene Meldrum's acid derivatives have proven to be versatile building blocks in catalytic asymmetric synthesis, due to their high electrophilicity and chemical versatility of the 1,3-dioxan-4,6-dione moiety. These platforms can be used as isolable entities or formed *in situ* through
efficient multicomponent reactions, which enable the construction of a large range of molecules. While inspiring seminal contributions in this field were principally focused on C-C bond formation at the alkene moiety, this review highlights recent advances in C-N and C-S bond formation in an enantioselective fashion. It also reports on vinylogous processes and the exploitation of the versatile reactivity of the 1,3-dioxan-4,6-dione moiety to develop efficient annulation sequences, opening routes to valuable 3D-enantioenriched heterocycles. Overall, this review intends to highlight new dimensions in the use of alkylidene Meldrum's acid as a versatile molecular platform in organic synthesis. Importantly, a lot of alternative approaches remain to be explored, e.g., involving other enantioselective C-Heteroatom bond formation (C-O, C-S, etc.), pathways towards a broader family of chiral heterocycles with larger ring sizes, and the use of radical-based processes, to name a few.

## Conflicts of interest

There are no conflicts to declare.

## Data availability

No primary research results, software or code have been included and no new data were generated or analysed as part of this review.

## Acknowledgements

This work has been partially supported by University of Rouen Normandy, INSA Rouen Normandy, the Centre National de la Recherche Scientifique (CNRS), European Regional Development Fund (ERDF), Région Normandie, Labex SynOrg (ANR-11-LABX-0029), Carnot Institute I2C, the graduate school for research XL-Chem (ANR-18-EURE-0020 XL CHEM). This research was also supported by the French National Research Agency (ANR) as part of the ANR-16-CE07-0011-01 project OMaChem. The authors would like to warmly thank the (post)doctoral students at CARMEN laboratory (ex-COBRA, Heterocycles team) for their involvement and for making all this work possible!

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