# N-Heterocyclic Carbene-Catalyzed Generation of Homoenolates: Efficient Asymmetric Synthesis of Dispirocyclopentanones by Direct Annulation of Enals and Isoindigos

Zhiwei Jiang, Martial Toffano, Régis Guillot, Chloée Bournaud, Giang Vo-Thanh

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Zhiwei Jiang, Martial Toffano, Régis Guillot, Chloée Bournaud, Giang Vo-Thanh. N-Heterocyclic Carbene-Catalyzed Generation of Homoenolates: Efficient Asymmetric Synthesis of Dispirocyclopentanones by Direct Annulation of Enals and Isoindigos. Catalysts, 2026, 16 (2), pp.138. 10.3390/catal16020138. [hal-05523376](https://hal.science/hal-05523376v1)

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Article

# N-Heterocyclic Carbene-Catalyzed Generation of Homoenolates: Efficient Asymmetric Synthesis of Dispirocyclopentanones by Direct Annulation of Enals and Isoindigos

Zhiwei Jiang, Martial Toffano ID, Régis Guillot ID, Chloée Bournaud * and Giang Vo-Thanh *ID

Institut de Chimie Moléculaire et des Matériaux d'Orsay, CNRS UMR 8182, Université Paris-Saclay, 91405 Orsay, Cedex, France; jiangzhiwei@hotmail.com (Z.J.); martial.toffano@universite-paris-saclay.fr (M.T.); regis.guillot@universite-paris-saclay.fr (R.G.)

* Correspondence: chloee.bournaud@universite-paris-saclay.fr (C.B.); giang.vo-thanh@universite-paris-saclay.fr (G.V.-T.)

## Abstract

A highly efficient asymmetric (3+2) annulation between enals and isoindigos was achieved via the N-heterocyclic carbene-catalyzed addition of homoenolates to activated tetrasubstituted C=C double bonds. The protocol provided straightforward access to enantiomerically enriched dispirocyclopentanone bisoxindoles (up to 97% ee) with three contiguous stereocenters, two of which are highly congested vicinal all-carbon quaternary centers.

**Keywords:** N-heterocyclic carbene; isoindigos; dispirocyclopentanones

## 1. Introduction

The discovery of new enantioselective catalytic methods for carbon-carbon bond formation remains a formidable challenge for chemists seeking to develop efficient and sustainable chemical processes for the synthesis of natural products or molecules with therapeutic interests. Among these methods, the direct formation of enolates and their synthetic equivalents under mild reaction conditions is still of high interest. Catalytically generated homoenolate intermediates, resulting from the addition of chiral N-heterocyclic carbenes (NHCs) to α,β-unsaturated aldehydes, enabled asymmetric (3+2) annulation with electrophilic disubstituted (Scheme 1A) and trisubstituted (Scheme 1B) C=C double bonds. This yielded functionalized cyclopentanones bearing two contiguous stereogenic carbon centers with good yields and high enantioselectivities, as reported in the literature (Scheme 1) [1–9].

<figure><img src="image_2.png" /><figcaption>**Scheme 1.** Asymmetric synthesis of cyclopentanones with vicinal carbon stereocenters [3,8].</figcaption></figure>

<figure><img src="image_3.png" /></figure>

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Academic Editors: Pierre Vogel, Kendall N. Houk and Carlos Vila

Received: 19 December 2025

Revised: 30 December 2025

Accepted: 29 January 2026

Published: 2 February 2026

**Copyright:** © 2026 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the [Creative Commons Attribution (CC BY) license](https://creativecommons.org/licenses/by/4.0/).
Apart from the asymmetric synthesis of cyclopentanones containing a quaternary carbon stereocenter from activated di- and trisubstituted alkenes, the preparation of multi-substituted cyclopentanones with two vicinal quaternary carbon stereocenters from the direct annulation of activated tetrasubstituted alkenes and enals, catalyzed by NHC-generated homoenolates, has never been disclosed. To the best of our knowledge, there has been only one report of an NHC-catalyzed asymmetric reaction between enals and malononitrile-derived oxindole used as an activated tetrasubstituted alkene. This reaction led to the formation of 3,3-disubstituted oxindole bearing vicinal tertiary-quaternary stereocenters as a non-annulative coupling product instead of the expected cyclopentanone adduct (Scheme 2A) [10]. In this project, we propose using activated tetrasubstituted alkenes, such as isoindigo derivatives, as novel reaction partners with enals in chiral NHC-catalyzed homoenolate reactions. This is achieved through a conjugate addition-cyclization sequence to afford enantiomerically enriched multi-substituted cyclopentanones with three contiguous stereocenters, two of which are highly congested adjacent all-carbon quaternary stereogenic centers (Scheme 2B).

<figure><img src="image_4.png" /><figcaption>(B) NHC-catalyzed (3+2) annulation of enals and activated tetrasubstituted alkenes: multisubstituted cyclopentanones (this work)</figcaption></figure>

<figure><img src="image_5.png" /></figure>

**Scheme 2.** Asymmetric addition of homoenolate to activated tetrasubstituted alkenes [10].

Isoindigo, which bears two oxindole moieties, is an isomer of the well-known dye indigo and acts as an electron-deficient tetrasubstituted alkene. This compound is a potential building block for the synthesis of chiral dispiro-oxindoles, which have emerged as a fascinating framework that defines the typical structural core of many pharmaceuticals and bioactive natural products [11–21], such as antifungal agents [22], antimicrobial agents [23], anticancer agents [24], and antitumor agents [25]. Few organocatalytic asymmetric reactions involving isoindigos have been reported. Using chiral phosphines [26], or amines [27], efficient (3+2) annulation reactions of isoindigos were subsequently carried out with alkenoates or 1,4-dithiane-2,5-ol. These protocols provided a straightforward way for the highly efficient asymmetric construction of oxindole-based dispirocyclic motifs featuring two vicinal all-carbon quaternary centers. More recently, Wang and co-workers employed amino acid-derived bifunctional phosphonium salts as phase-transfer catalysts to conduct highly regio- and stereoselective (4+2) annulation reactions between electron-deficient allenes and isoindigos. This approach led to the construction of oxindole-based spiro-4H-pyran core frameworks bearing a quaternary carbon stereocenter [28]. Unfortunately, during the course of this work, a very similar approach to ours was reported [29]. To our knowledge, no NHC-catalyzed reaction using isoindigo as a reagent has been reported to date, apart from this work.
## 2. Results and Discussions

In continuation of our interest in asymmetric organocatalysis [30–34], and NHC-catalyzed generation of homoenolates [35], we envisioned that the one-step assembly of cyclopentanone-fused dispiro-oxindoles with two adjacent spiro-quaternary centers could be achieved by direct coupling of enals with indigoid compounds, such as indigo or isoindigo derivatives (Scheme 3) [36,37]. Conversely, the presence of two indolinone moieties connected by a C=C double bond implies a high electronic deficit in the tetra-substituted alkene core. This electronic characteristic may provide sufficient activation for the C=C double bond, which is typically considered internally buried. Moreover, the planar indolinone structures may be less sterically demanding than other complex substrates, making the otherwise extremely difficult nucleophilic addition process feasible. We therefore decided to examine the reaction of these tetrasubstituted alkenes with enals, catalyzed by chiral NHC, hoping that a variety of valuable enantioenriched substituted dispirocyclopentanones might be accessible from this homoenolate annulation reaction.

<figure><img src="image_6.png" /><figcaption>**Scheme 3.** Design plan of asymmetric (3+2) annulations via NHC-catalyzed addition of homoenolate intermediates to indigo or isoindigo derivatives.</figcaption></figure>

In that vein, we started our study by examining the potential homoenolate annulation of enal **1a** and indigo derivative **2a** using triazolium NHC pre-catalyst **4a** in the presence of DBU in toluene. However, when the reaction was performed under these conditions, only a trace of the expected homoenolate-derived cycloadduct **3a** was detected. Instead, a large amount of diester **5a** was obtained (36% yield, Scheme 4), and its structure was confirmed by X-ray diffraction analysis. A control experiment was conducted under the same conditions but in the absence of NHC pre-catalyst **4a**, and no reaction was observed. This observation confirms that the NHC pre-catalyst **4a** is essential for activating the substrate and facilitating the formation of diester **5a**, though the desired homoenolate or acyl azolium intermediate leading to **3a** appears to be undergoing an alternative reaction pathway (see Supporting Information for full details).

<figure><img src="image_7.png" /><figcaption>**Scheme 4.** Reaction between enal **1a** and indigo derivative **2a** under chiral NHC pre-catalyst **4a**.</figcaption></figure>
Subsequently, we turned our attention to isoindigo derivatives for the first investigation. Under the same reaction conditions, the chiral NHC-catalyzed reaction of enal **1a** and Boc-isoindigo **7a** was evaluated (Scheme 5). We were very pleased to find that using 20 mol% of the chiral aminoindanol-based N-mesityl NHC pre-catalyst **4a** in the presence of DBU in toluene at room temperature, the reaction led straightforwardly to the formation of the expected dispirocyclopentanone bisoxindole **8a** in 60% yield with an excellent stereomeric ratio (25:1 dr) and an excellent enantiomeric excess (94% *ee*). It is noteworthy that this reaction proceeded in a highly chemoselective manner. The catalyst selectively generated the homoenolate equivalent from enal **1a**, facilitating its subsequent addition to the tetrasubstituted C=C double bond of **7a** to furnish the desired (3+2) annulation product **8a**.

<figure><img src="image_8.png" /><figcaption>**Scheme 5.** Reaction between enal **1a** and Boc-isoindigo **7a** under chiral NHC catalyst. Reaction conditions: **1a** (0.15 mmol), **7a** (0.1 mmol), cat. (0.02 mmol), and DBU (0.04 mmol) in toluene (2.0 mL) at 22 °C for 14 h. Yield of the isolated product after column chromatography. The dr value was determined by ¹H NMR spectroscopic analysis. The *ee* value was determined by HPLC analysis on a chiral stationary phase.</figcaption></figure>

In contrast, no trace of annulation product was detected when using isoindigo **6a** (the unprotected form) in place of Boc-indigo **7a** under the same reaction conditions (see Supplementary Materials for full details). Therefore, the Boc-protected isoindigo **7a** was chosen as a substrate for the model reaction with enal **1a** under chiral NHC catalysis for further optimization.

Some NHC-catalyst precursors were first assessed for the transformation of Boc-isoindigo **7a** to dispirocyclopentanone bisoxindole **8a** (Scheme 5). Screening of the NHC-catalyst precursors showed that the triazolium-based NHCs (**4a**, **4c**, **4e**) led to a more selective formation of the homoenolate product **8a** than the imidazolium-based NHC pre-catalysts (**4d**, **4f**). An attempt of this reaction with bifunctional imidazolium-based NHC pre-catalyst **4d** [35] gave rise to a complex mixture. Not surprisingly, the aminoindanol-derived triazolium pre-catalyst **4c** with a more electron-deficient and less bulky N-pentafluorophenyl substituent showed low reactivity and stereoselectivity for this homoenolate reaction (31% yield, >20:1 dr, 10% *ee*). As a result, catalyst screening identified the NHC N-mesityl pre-catalyst **4a** as the best choice in terms of chemo-, diastereo-, and enantioselectivity. The reaction proceeded smoothly when the loading of the NHC **4a** pre-catalyst was reduced to 15 mol% (65% yield, 25:1 dr, *ee* 94%). However, a 10 mol% catalyst loading resulted in a decrease in yield (49% yield, 18:1 dr, *ee* 94%). Encouraged by the reaction results with the commercially available NHC pre-catalyst **4a**, we decided to prepare its enantiomer **4b** (*ent-4a*) according to the general procedure reported by Bode and co-workers with slight modifications (See Supplementary Materials for details of the
synthesis of **4b**) [38,39]. Under the same reaction conditions, pre-catalyst **4b** provided the expected results. We therefore decided to use it for further investigations (Scheme 5).

Interestingly, when the reaction was carried out in the presence of additional 4 Å
molecular sieves (MS), the desired product **8a** was formed in an improved yield of 79%
while maintaining the 94% *ee*, albeit with a slightly decreased diastereoselectivity (12:1 dr).
Subsequently, under the standard conditions with 4 Å MS, various other parameters such
as solvents, bases, and additives were screened (See Supplementary Materials for full
details). The best results were ultimately obtained when the reaction was performed in
*m*-xylene with a combination of DBU (30 mol%), chiral NHC pre-catalyst **4b** (15 mol%),
and 4 Å MS at room temperature for 14 h. Under these optimized conditions, the optically
active dispirocyclopentanone bisoxindole **8a** was isolated in 92% yield, with excellent
diastereoselectivity and enantioselectivity (14:1 dr and 94% *ee*, respectively).

With these optimized conditions in hands, the scope of the reaction with respect to
enals was investigated (Scheme 6). In all cases, the reactions proceeded with excellent
stereoselectivities, and the products **8a–i** were isolated in good yields with over 90% optical
purities. Specifically, the β-aryl enals bearing either electron-donating (e.g., 4-MeOC₆H₄)
or electron-withdrawing (e.g., 4-FC₆H₄) substituents reacted smoothly with Boc-isoindigo
**7a**. Products **8a–c** were thus obtained in 82–92% yields, showing good diastereoselectivities
(10:1–14:1 dr) and excellent enantioselectivities (93–94% *ee*). Additionally, both the (Z) and
(E) isomers of cinnamaldehyde afforded the same product **8b** with a comparable yield
and stereoselectivity. This outcome is possibly due to isomerization occurring during the
formation of the homoenolate intermediate. The reaction with β-2-furylenal proceeded
smoothly, giving **8d** in 85% yield with 12:1 dr and 96% *ee*. Furthermore, even with sterically
hindered naphthyl or piperonyl groups, the reactions proceeded efficiently, leading to the
corresponding products **8e–f** in 87–90% yields with 14:1–17:1 dr and 93–94% *ee* values.
Notably, the extension of this asymmetric transformation to a β-alkyl-substituted enal
was also successful and afforded cycloadduct **8g** in 62% yield with 8:1 dr and 92% *ee*.
Furthermore, 2,4-dienals (R¹ = propenyl, styryl) also worked well for the reaction, providing
the corresponding annulation products **8h–i** in 65–73% yields with 7:1–8:1 dr and 91–97% *ee*
values, respectively. Finally, enal **1j** bearing an ester moiety (R¹ = CO₂Et) was tested, but
only a trace of optically active product was detected. However, this reaction proceeded
effectively in the presence of the achiral triazolium **4e**, leading to the racemic cycloadduct
**8j** in 66% yield with excellent diastereoselectivity (>20:1 dr).

Next, we studied the generality of this asymmetric reaction by investigating various
oxindole-derived isoindigos. As shown in Scheme 7, symmetric Boc-isoindigos bear-
ing substituents at different positions of the oxindole aryl rings (R² = 5-Cl, 6-Br, 7-Cl)
were well tolerated, affording products **8k–m** in good yields (72–84%) with excellent di-
astereoselectivities (19:1 to >20:1 dr), and good to excellent enantioselectivies (81–92% *ee*).
Moreover, symmetric Boc-isoindigos with both electron-donating (R² = 5-CH₃) and electron-
withdrawing (R² = 5-F) substituents at the C5-position of the oxindole aryl rings worked
well. These provided products **8n–o** in high yields (89–98%) with excellent diastereo- and
enantioselectivities (18:1 to >20:1 dr, 92–93% *ee*). Evaluation of the N-protective groups
(R³) showed that all N-Boc-, N-Ac-, N-Bn-, and N-Me-substituted isoindigos were tolerated
without apparent change in the enantioselectivities for this asymmetric transformation
of **8a**, **8p–r**. Unfortunately, the use of bipyrazolone **7x** as an electrophilic tetrasubstituted
alkene resulted in a complex mixture where no starting material or desired product could
be detected. Similarly, malononitrile-derived oxindole **7y** failed to react with enal **1a**. To our
delight, the reaction between *p*-methoxycinnamaldehyde **1a** and N-Boc isoindigo **7a** was
successfully carried out at a 1 mmol scale, affording the dispirocyclopentanone bisoxindole
**8a** in 88% yield without erosion of the stereoselectivity (14:1 dr, 94% *ee*).
<figure><img src="image_9.png" /><figcaption>**Scheme 6.** Reaction between enals **1a–j** and Boc-isoindigo **7a** under chiral NHC pre-catalyst **4b**.</figcaption></figure>

<figure><img src="image_10.png" /><figcaption>**Scheme 7.** Reaction between enal **1a** and isoindigo **7a,k-r** under chiral NHC pre-catalyst **4b**. Reaction conditions: **1a** (0.15 mmol), **7** (0.1 mmol), **4b** (0.015 mmol), DBU (0.03 mmol), and 50 mg of 4 Å molecular sieves in m-xylene (2.0 mL) at room temperature for 14 h. Yield of the isolated product. *dr* are determined by ¹H NMR spectroscopic analysis. *ee* are determined by chiral HPLC analysis. [a] Reaction was carried out on 1.0 mmol, 20 mol% **4b** was used, 24 h.</figcaption></figure>
The absolute configuration of **8r** was assigned as (*R*,*R*,*R*) by X-ray crystallographic analysis (Figure 1).

<figure><img src="image_11.png" /><figcaption>**Figure 1.** X-ray crystallography of **8r**.</figcaption></figure>

Given the excellent results obtained with isoindigos containing two identical oxindole moieties, we wondered whether unsymmetric isoindigos, which are constructed from different oxindole subunits, could potentially be used in the annulation reaction. This prospect is truly exciting. Indeed, we have envisioned that the use of unsymmetric isoindigos could create intriguing regioisomers of the annulation products bearing two structurally similar oxindole units. However, the reaction of unsymmetric isoindigos faces more challenges. Besides reactivity, diastereoselectivity, and enantioselectivity, the regioselective addition of enal-derived homoenolates to activated C=C double bonds has to be carefully considered.

Initially, *N*-Boc-protected unsymmetric isoindigo **7z**, featuring a 5-Cl substituent on one of the oxindole aryl rings, was tested for the asymmetric reaction of enal **1a**. Three complex products were isolated from this reaction: one was a single isomer, while the other two were mixtures of multiple isomers. It was therefore very difficult to identify the structure of these products (See Supplementary Materials for full details). We consequently decided to study the annulation of enals and unsymmetric *N*-benzyl isoindigos in the hope that this change would lead to solid *N*-benzyl oxindoles that are more easily characterized by X-ray analysis.

Therefore, *N*-Bn-protected unsymmetric isoindigo **7s** was synthesized and subjected to an NHC **4b**-promoted asymmetric (3+2) annulation reaction with enal **1a** under standard reaction conditions (Scheme 8). Three products were isolated from this reaction: one major product along with two minor products. Importantly, all of these isolated compounds were identified by X-ray crystal structure analysis (See Supplementary Materials for full details). The expected (3+2) annulation product **8s** was formed in good yield (87%) with very high regioselectivity (18:1 regioisomeric ratio) and excellent diastereoselectivity (>20:1 dr), albeit with slightly decreased enantioselectivity (70% *ee* for the major regioisomer). The regioselective formation of **8s** could be explained by the presence of both 5-Cl and 7-Cl groups on one of the oxindole aryl rings of **7s**. This substitution makes the C3-carbon more electron-deficient than the C3'-carbon, thus favoring the nucleophilic attack of the enal-derived homoenolate at the C3-position.
<figure><img src="image_12.png" /><figcaption>**Scheme 8.** Reaction between enal **1a** and N-Bn-unsymmetric isoindigo **7s–u** under chiral NHC pre-catalyst **4b**. Reaction conditions: **1a** (0.15 mmol), **7s–u** (0.1 mmol), **4b** (0.015 mmol), DBU (0.03 mmol), and 50 mg of 4 Å molecular sieves in m-xylene (2.0 mL) at room temperature for 14 h. Yield of the isolated product. *dr* are determined by ¹H NMR spectroscopic analysis. *ee* are determined by chiral HPLC analysis. Regioisomer ratios (*rr*) are determined by ¹H NMR spectroscopic analysis.</figcaption></figure>

Based on the configuration of products **8** determined by X-ray analysis, a plausible mechanism for the NHC-catalyzed asymmetric (3+2) annulation of enals with isoindigos is suggested in Scheme **9**. First, addition of the in situ-generated chiral NHC **4b** to enal **1** gives the corresponding conjugated Breslow intermediate **A**. The subsequent addition to the structurally congested activated C=C double bond in isoindigo **7** apparently favors the less hindered β-attack. Michael addition of the NHC-bound homoenolate **A** from the back face of the bulky chiral aminoindanol moiety to the isoindigo **7** may be driven by an intermolecular hydrogen-bonding interaction between the homoenolate and the Michael acceptor. This interaction is presented in the favored pre-transition state assembly **B**. This proposed reaction model for stereoinduction may contribute to the observed stereochemistry of the major product **8**. Conversely, the reaction would lead to the formation of a minor diastereoisomer via the transition state **C**. Following carbon–carbon bond formation, a tautomerization process occurs, giving rise to acyl azolium **D**. This intermediate then presumably undergoes C-acylation to furnish the dispirocyclopentanone **8** and regenerate the NHC organocatalyst **4b** for the next catalytic cycle.

<figure><img src="image_13.png" /><figcaption>**Scheme 9.** Proposed mechanism for the NHC-catalyzed asymmetric reaction of enals with isoindigos. ‡: transition State.</figcaption></figure>

**3. Conclusions**

In conclusion, we have shown that the chemoselective generation of homoenolates from simple enals leads to highly efficient asymmetric (3+2) annulation reactions with
isoindigos. This methodology produces enantiomerically enriched dispirocyclopentanone bisoxindoles featuring three contiguous stereocenters, two of which are highly congested vicinal all-carbon quaternary centers. β-(hetero)aryl, β-alkenyl, and β-alkyl enals all performed well in these rarely explored annulation reactions. Furthermore, by using isoindigos bearing two identical oxindole moieties as electrophilic tetrasubstituted alkenes, various challenging dispirocyclic bisoxindole skeletons were efficiently constructed in good yields and excellent stereoselectivities. Moreover, the protocol also provides a regioselective-controlled approach to access structurally distinct dispirocyclic molecules with two different oxindole moieties, which are derived from the corresponding unsymmetric isoindigo precursors. We hope that this direct functionalization can provide an alternative and concise strategy for the synthesis of dispirooxindole-based alkaloids and pharmaceutical molecules.

**Supplementary Materials:** The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/catal16020138/s1. References [27,39–53] are cited in the Supplementary Materials.

**Author Contributions:** Conceptualization, G.V.-T.; Methodology, Z.J. and M.T.; Formal analysis, Z.J., M.T. and R.G.; Investigation, M.T. and C.B.; Writing—original draft, G.V.-T.; Writing—review & editing, G.V.-T.; Supervision, C.B. and G.V.-T.; Project administration, G.V.-T. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research received no external funding.

**Data Availability Statement:** The original contributions presented in this study are included in the article/Supplementary Materials. Further inquiries can be directed to the corresponding author(s).

**Acknowledgments:** We are grateful to the 'Chinese Government' (China Scholarship Council, CSC) for a fellowship to Z. Jiang, and to the CNRS (UMR 8182) and University Paris-Saclay for financial support.

**Conflicts of Interest:** The authors declare no conflicts of interest.

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