The Diarylprolinol Silyl Ethers: After 20 Years Still Opening New Doors in Asymmetric Catalysis

ABSTRACT

A new chapter starts now. Since its discovery in 2005, the diarylprolinol silyl ether catalytic concept has emerged as a general and reliable aminocatalytic tool for the synthesis of enantioenriched molecules. Recently its combination with emerging technologies, as well as its application in more complex molecular systems has opened new avenues for novel enantioenriched scaffolds. In this review, we will highlight these recent developments, unfolding five primary categories that define new horizons in the use of diarylprolinol silyl ethers: Photochemical‐, electrochemical‐, dual‐catalytic transformations, higher‐order cycloadditions and applications in total synthesis of complex natural products.

Catalysis Rules! The year 2025 marks the 20^th anniversary of diarylprolinol silyl ethers in asymmetric organocatalysis. During the first decade after their discovery, these catalysts have been established as one of the most versatile tools in aminocatalysis. Although now considered mature, recent years have witnessed renewed innovation. We outlined these developments, demonstrating that this remains a rapidly evolving field.

1. Introduction

In nature, many systems reach full maturity only after 20 years—from oak trees that begin to bear fruits, to coral reefs that stabilize into complex ecosystems. Humans themselves typically complete their physical maturation around the age of 20, reaching a phase of full capability and resilience.

Twenty years after their discovery, the diarylprolinol silyl ether organocatalysts have reached a level of maturity that does not mark an endpoint, but rather a new chapter from which new transformations continue to emerge. This review highlights the recent directions in asymmetric catalysis in which the diarylprolinol silyl ethers have played a pivotal role, further expanding the landscape of aminocatalysis.

Organocatalysis represents one of the major pillars of asymmetric catalysis along with enzymatic‐ and transition‐metal catalysis [1, 2]. The success of this field arises largely from the ability to design new enantioselective transformations in a conceptually straightforward manner, through the application of generic modes of activation [3, 4]. The catalytic generation of enamines and iminium ions, as transient covalent intermediates, through the condensation of chiral amines with carbonyl compounds, is defined as aminocatalysis [5]. From an historical perspective, the first examples involving enamine catalysis were independently reported by Weichert and Hajos in 1971 [6, 7], while Yamaguchi demonstrated the first organocatalytic iminium‐ion‐mediated transformation in 1993 (Figure 1A) [8]. The field gained momentum at the turn of the millennium, when the groups of List, Lerner, and Barbas III, and MacMillan independently introduced breakthrough aminocatalytic asymmetric transformations—an enamine‐mediated aldol reaction and an iminium‐ion‐mediated Diels–Alder reaction, respectively [9, 10].

FIGURE 1.

(A) Historical lineup of enamine and iminium‐ion catalysis. (B) Classical activation modes using diarylprolinol silyl ethers in enamine and iminium‐ion catalysis. (C) New horizons in diarylprolinol silyl ether catalysis.

Among the numerous chiral amines introduced since then, the diarylprolinol silyl ethers, disclosed in 2005, rapidly distinguished themselves as exceptionally reliable and broadly applicable chiral organocatalysts. That year, our research group and the Hayashi group independently reported the use of diarylprolinol silyl ethers as catalysts for the activation of aldehydes via chiral enamine intermediates, specifically in the α‐sulfenylation of aldehydes and the Michael addition of aldehydes to nitroalkenes, respectively [11, 12]. A few months later, the first application of the catalyst in iminium‐ion catalysis was reported by our group in the stereoselective epoxidation of α,β‐unsaturated aldehydes [13]. Since then, the research community has developed a myriad of aminocatalyzed transformations, establishing covalent activation of aldehydes as a reliable tool for generating new bonds and stereocenters at both the α‐ and β‐positions [14, 15].

In enamine catalysis, the chiral aminocatalyst condenses with an aldehyde giving rise to an enamine intermediate, resulting in an increase of the HOMO energy compared to the substrate enol‐tautomer and, thereby, higher nucleophilicity (HOMO‐raising activation). The enamine can now react in an enantioselective fashion with different electrophiles affording α‐functionalized aldehydes (Figure 1B, left). In contrast, in iminium‐ion catalysis, the condensation of the aminocatalyst with an α,β‐unsaturated aldehyde gives rise to an iminium‐ion intermediate featuring a reduced LUMO energy and improved electrophilicity, if compared to the starting α,β‐unsaturated aldehyde (LUMO‐lowering activation). The iminium‐ion intermediate allows for the enantioselective β‐functionalization with suitable nucleophilic species (Figure 1B, right).

The high enantioselectivity observed in aminocatalytic transformations is attributable to the well‐defined geometry of the covalently bound catalyst–substrate intermediates. Both in the case of enamine and iminium‐ion intermediates, the exocyclic group of the pyrrolidine moiety provides the steric bias responsible for the reliable enantioselectivity, due to the predictable facial discrimination of the transient intermediate in aminocatalytic transformations [16, 17]. These activation concepts extend to more complex intermediates, such as dienamines [18, 19], trienamines [20, 21], and tetraenamines [22], as well as vinylogous and bis‐vinylogous iminium ions [23, 24, 25], now considered classic modes of organocatalytic activation.

During the first decade after its discovery, diarylprolinol silyl ether has established itself as one of the most reliable catalytic tools in aminocatalysis, allowing for novel and unprecedented reactions in asymmetric catalysis—an impact reflected in the extensive body of articles, reviews, and perspectives devoted to it [26, 27, 28, 29, 30, 31]. Although now considered fully mature, recent years have witnessed renewed innovation. The classical activation modes have been integrated with emerging technologies such as photo‐ and electrochemistry. Their synergistic use with other systems, and application to increasingly complex substrates, such as higher‐order cycloadditions have further expanded their synthetic utility. These developments opened novel reaction concepts generating previously unachievable bond‐connections and demonstrate that this is a rapidly evolving field.

This review does not aim to provide a comprehensive overview of all existing transformations involving diarylprolinol silyl ethers. Instead, it offers a glance at the most innovative and recent developments enabled by the strategic use of this catalytic platform (Figure 1C). We have identified five primary categories that define new horizons in the use of diarylprolinol silyl ethers: Photochemical‐ and electrochemical transformations, dual catalytic systems, higher‐order cycloadditions, and application in total synthesis of complex natural products. Beyond these categories, some selected additional examples involving classical aminocatalytic activation modes will also be presented.

2. Photochemical Transformations

Catalytic enantioselective radical reactions have experienced tremendous growth over the past decade [32], largely driven by the continuous advances in light‐mediated strategies that enable radical generation under mild reaction conditions [33]. Among these, photoredox catalysis has emerged as the most widely used approach for producing radicals in a controlled and efficient manner [34, 35, 36].

The pioneering work of most recent photoredox catalysis can be attributed to MacMillan, who in 2008 applied the concept of photoexcitation of ruthenium‐based polypyridyl catalyst to promote an organocatalyzed, and enantioselective, radical α‐alkylation of aldehydes [37]. This seminal work demonstrated that radical reactivity could be effectively merged with enamine organocatalytic activation to achieve not only high levels of enantioselectivity, but also paving the way to new avenues of performing radical reactions.

Over the last years, a wide range of organocatalytic and enantioselective radical transformations have been developed, with diarylprolinol silyl ether catalysts playing a central role [38]. The unique properties of this class of organocatalysts emerge from their versatility in enabling different photochemical activation modes depending on the decoration of the diarylprolinol silyl ether scaffold. In the following we will unfold these different activation modes and their applications.

In 2015 Melchiorre et al. introduced an innovative concept concerning the exploitation of the redox properties of organocatalytic enamines in their excited state (Scheme 1) [39]. Upon visible light excitation, enamine I*, formed from aldehyde 1 and diarylprolinol silyl ether C1, becomes a potent photoreductant, capable of generating radical II and bromide, through reductive cleavage of the C─Br bond in bromomalonate 2. Next, another equivalent of ground state enamine I can trap II in a stereoselectively fashion, affording α‐amino radical III. Later mechanistic investigations revealed that the reaction proceeds through a radical chain propagation pathway [40]. This pathway involves an atom transfer radical addition in which III abstracts a bromine atom from 2, thereby generating radical II and producing α‐bromo amine intermediate IV. Elimination of bromide affords the iminium‐ion intermediate V which, by hydrolysis, furnished the α‐alkylated aldehydes 3.

SCHEME 1.

Photochemical α‐alkylation of aldehydes 1 with bromo‐malonates 2.

The authors demonstrated the generality of the transformation providing a series of α‐alkylated aldehydes 3 in high yields and enantioselectivity (Scheme 1). Both secondary and tertiary bromomalonates 2 proved viable radical precursors, as well as different substituent patterns in 1. It should also be noted that this strategy was extended to achieve the enantioselective γ‐functionalization of α,β‐unsaturated aldehydes via dienamine catalysis, and, later, to the development of a photocatalytic α‐sulfenylation of aldehydes applying C1 as catalyst [41].

The Melchiorre group also established the first light‐driven radical method based on diarylprolinol silyl ether scaffold within the chemistry of electron donor–acceptor (EDA) complexes (Scheme 2) [42]. When an electron‐deficient alkyl bromide 4 was combined with a chiral enamine I generated from catalyst C2, the initial colorless reaction mixture turned bright yellow. This observation was attributed to the generation of an EDA complex VI, arising from orbitals sharing between the enamine I and 4. A key feature of this complex is a shift of transfer‐band absorption to a longer wavelength, enabling excitation using visible light.

SCHEME 2.

Photochemical α‐alkylation of aldehydes 1 with alkyl bromides 4.

Upon excitation, the EDA complex VI undergoes single‐electron transfer (SET) leading to the generation of a radical anion, which then evolves into radical VII (Scheme 2). Another molecule of enamine I is trapped in a stereoselectively manner by VII, leading to α‐amino radical VIII. The authors demonstrated the reaction proceeds through a chain propagation mechanism, where VIII is oxidized by another molecule of alkyl bromide radical precursor 4. Hydrolysis of IX afforded enantioenriched α‐alkylated aldehydes 5. The method displayed a scope tolerating strongly electron‐deficient benzyl bromides and a wide set of phenacyl bromides 4 reacting with various aldehydes 1 and furnishing 5 in high yields and enantioselectivities. Notably, the strategy also enabled transformations of α‐phenylpentenal as dienamine precursors.

An alternative approach integrates the oxidation of diarylprolinol silyl ether‐derived enamines by an external photocatalyst, as shown by MacMillan for the α‐alkylation of aldehydes 1 with styrenes 6 (Scheme 3) [43].

SCHEME 3.

Top: Photochemical α‐alkylation of aldehydes 1 with styrenes 6. Bottom: Photochemical α‐alkylation of aldehydes 1 with [1,1,1]propellane 9.

A series of α‐alkylated aldehydes 8 was obtained in good to high yields and excellent enantioselectivity across a broad range of reaction partners, including β‐ substituted and β,β‐disubstituted aldehydes, electron‐rich‐ and electron‐poor styrenes, as well as heteroaryl olefins (Scheme 3). An intramolecular variant of the transformation was also reported, enabled by an imidazolidinone‐type organocatalyst. The authors utilized a triple catalytic process involving organocatalyst C1, an iridium photocatalyst and a thiophenol‐based hydrogen atom transfer (HAT) catalyst 7. The enamine I is oxidized by the photoexcited *Ir(III) to generating a α‐iminyl radical cation X, which then undergoes addition to 6 to form radical intermediate XI. A reductive HAT of this radical affords, after hydrolysis of iminium ion XII, the enantioenriched α‐alkylated aldehyde 8 while liberating C1. The catalytic cycle is closed by oxidation of the photocatalyst by the thiyl radical derived from 7.

Later, Anderson et al. applied this concept to the enantioselective synthesis of α‐chiral bicyclo[1.1.1]pentanes 10 from aldehydes 1 and [1,1,1]propellane 9 (Scheme 3, bottom) [44].

The ability of organocatalytic enamines to trap radicals has recently been exploited by Chang et al. in the development of an enantioselective α‐amidation of aldehydes using the synergistic action of diarylprolinol silyl ether C1 and FeCl₃ as catalysts (Scheme 4) [45].

SCHEME 4.

Photochemical α‐amidation of aldehydes 1 with dioxazolones 11.

The key step involves a visible‐light driven ligand‐to‐metal charge transfer to generate the active Fe(II)Cl₃ ⁻ species from Fe(III)Cl₄ ⁻, which activates dioxazolones 11 to form an iron‐acylnitrenoid radical XIII via a decarboxylative process (Scheme 4). This radical is stereoselectively trapped by the in situ generated enamine I, to give the α‐amino radical intermediate XIV. An intramolecular oxidative SET affords iminium ion XV, which upon hydrolysis furnishes α‐amido aldeydes 12, regenerating both the organo‐ and metal‐based catalysts. The method displayed a broad scope, efficiently delivering a wide set of 12 with excellent enantioselectivity, employing aliphatic, aromatic, and heteroaryl‐substituted aldehydes and dioxazolones. Notably, the protocol is amenable to the late‐stage functionalization of aldehydes derived from drugs such as chlorambucil, oxaprozin, and D‐α‐tocopherol succinate.

In 2017, Pericàs et al. exploited visible‐light photoredox catalysis in an enantioselective cross‐dehydrogenative coupling of aldehydes 1 with xanthenes 13, using diarylprolinol silyl ether C1 (Scheme 5) [46].

SCHEME 5.

Photochemical α‐alkylation of aldehydes 1 with xanthenes 13.

An array of alkylated alcohols (after reduction) 14, bearing one or two stereocenters, was obtained in moderate to high yields and with excellent enantioselectivity using a range of aliphatic aldehydes, as well as substituted xanthenes (or thioxanthene), including benzo‐fused ones (Scheme 5). Diastereoselectivity was generally higher for xanthenes substituted at the C1‐position. Experiments and DFT studies revealed a dual catalytic mechanism, composed of photoredox‐ and organocatalytic cycles. The Ru‐photocatalyst is oxidatively quenched by BrCCl₃, generating a CCl₃ radical, which engages in the rate‐determining HAT with 13 affording radical XVII. The calculations indicated that the addition of carbocation XVIII to enamine I, leading to iminium ion XVI, is energetically more favorable than the corresponding pathway involving radical XVII. The authors proposed that the oxidation enabling the radical‐polar crossover might occur through reduction of Ru(III), thereby closing the photoredox cycle (i), although a radical chain process in which XVII is directly oxidized by another equivalent of BrCCl₃ could not be excluded (ii). Finally, hydrolysis of XVI furnishes the enantioenriched 14, regenerating C1.

Beyond the ability of the excited state organocatalytic dienamines to act as a photoreductants to bromomalonates or engage in EDA with electron‐poor benzyl or phenacyl bromides [41, 42], Mechiorre et al. in 2022 disclosed a general enantioselective γ‐alkylation of α,β‐unsaturated aldehydes 15 by merging dienamine‐ and dithiocarbamate (DTC) catalysis [47], using difficult‐to‐reduce alkyl chlorides 16 as radical precursors (Scheme 6) [48]. A library of γ‐alkylated enals 18 was obtained in good yields and enantioselectivities using phenacyl chloride, aliphatic α‐chloro ketones, and benzyl chlorides as radical precursors 16, and 15 embedding different substituents with various electronic‐ and steric properties. Quantum‐yield measurements supported a closed catalytic cycle in which diarylprolinol silyl ether C3 and an indole‐based DTC catalyst 17 cooperate to form enantioenriched 18. The photoactive intermediate XXII is generated through an S_N2 substitution of 16 by catalyst 17. Blue‐light excitation of XXII triggers homolytic cleavage, furnishing the thiyl‐radical XXIII and the carbon‐centered radical VII. This radical is then enantioselectively trapped by dienamine XIX, generated by condensation of 15 with C3, exclusively at the remote γ‐carbon. Turnover of 17 is given by a single‐electron oxidation of the resulting α‐amino radical XX. Finally, hydrolysis of iminium ion XXI delivers 18 and regenerates catalyst C3. Interestingly, the use of linear pentenal or hepta‐2,4‐dienal (as trienamine precursor) afforded exclusively γ‐ or ε‐functionalized products, respectively, even though as racemates. It is worth mentioning that the same group combined DTC catalysis with enamine catalysis for the enantioselective α‐alkylation of aldehydes using diarylprolinol silyl ether as catalyst [47].

SCHEME 6.

Photochemical γ‐alkylation of α,β‐unsaturated aldehydes 15 with alkyl halides 16.

Later, the same group reported a photochemical, enantioselective γ‐perfluoroalkylation of α‐branched α,β‐unsaturated aldehydes 15 (Scheme 7) [49]. The use of chiral diarylprolinol silyl ether C4 generates the corresponding dienamine XXIV, which forms photoactive EDA complex XXV with perfluoroalkyl iodide 19. Under blue light irradiation, this complex undergoes SET affording radical XXVI, which is trapped by another molecule of XXIV in a regio‐ and stereoselective fashion. Quantum yield measurement indicated the operation of a radical chain process, in which the ensuing α‐amino radical XXVII regenerates radical XXVI via a SET event, or through abstraction of an iodine atom from 19 via an atom transfer radical addition. Final hydrolysis of the iminium ion XXVIII affords the γ‐perfluoroalkyled enal 20, while regenerating C4. The generality of this γ‐regioselective perfluoroalkylation was demonstrated by the formation of 20 in moderate to high yields and generally good enantioselectivities, using α‐aryl 15 and 16 of different perfluoroalkyl chain lengths, including CF₃, α‐difluoro esters, and sulfonyl fluorides.

SCHEME 7.

Photochemical γ‐perfluoroalkylation of α,β‐unsaturated aldehydes 15 with alkyl halides 19.

Building on their earlier discovery that organocatalytic enamines can operate as strong reductants in their photoexcited state, the Melchiorre group proposed that photoexcited iminium ion XXIX* could instead serve as a potent oxidant, enabling single‐electron oxidation of electron‐rich benzyl silane 22 to generate reactive open‐shell intermediates. This concept was applied to develop an enantioselective radical β‐benzylation of α,β‐unsaturated aldehydes 21 (Scheme 8) [50]. Condensation of diarylprolinol silyl ether C5 with 21 generates iminium ion XXIX which can absorb light reaching its excited state XXIX*. Single‐electron oxidation of 22 by XXIX* enables generation of radical cation XXX, which spontaneously releases trimethylsilyl cation. The resulting radical XXXII undergoes a stereocontrolled radical–radical coupling with the chiral β‐enaminyl radical XXXI, affording enamine XXXIII. This species, upon isomerization and hydrolysis, furnishes mainly β‐benzylated aldehydes 23, while regenerating catalyst C5. A characteristic feature of this study is the catalyst design: installation of gem‐difluoride substituents at the C4‐position of the diarylprolinol silyl ether scaffold increases its oxidation potential, preventing catalyst degradation by the excited iminium ion and thereby enabling higher efficiency, while increasing enantioselectivity by utilizing the bulkier TDS (thexyldimethylsilyl) group.

SCHEME 8.

Photochemical β‐alkylation of α,β‐unsaturated aldehydes 21 with benzyl silane 22.

This strategy allowed for access to β‐functionalized aldehydes 23 in moderate to good yields and high enantioselectivities using an array of cinnamaldehydes and benzyl‐ or heteroaryl‐silanes, including a product with two vicinal stereocenters, even though with low diastereoselectivity (Scheme 8). Furthermore, α‐silyl thioethers, α‐silyl amines, and α‐silyl ethers were also found to engage in the photochemical reaction with comparable results. The strategy was subsequently extended to enantioselective biradical coupling‐based β‐functionalizations of iminium ions using diarylprolinol silyl ether catalysts [51, 52, 53, 54, 55, 56].

An example involving a photochemical cascade process that merges the photoexcitation of iminium ions with the ground‐state reactivity of enamines should be mentioned [53]. This directly converts α,β‐unsaturated aldehydes 21 and cyclopropanols 24 into cyclopentanols 25 in good yields and with excellent stereoselectivity in the presence of diarylprolinol silyl ether C6 (Scheme 9). Cyclopropanols 24 with linear or branched aliphatic‐, benzylic‐, and heterocyclic substituents, as well as spirocyclic variants, were well tolerated. Diverse β‐aryl substitution patterns were amenable within 21, while β‐alkyl fragments inhibited the reaction. The authors proposed a catalytic cycle where 24 undergoes SET oxidation by the excited iminium ion XXIX* to form unstable oxycyclopropyl radical cation XXXIV, which rapidly ring‐opens to give XXXV. This species engages in a stereoselective radical–radical coupling with the β‐enaminyl radical XXXI, furnishing the ground‐state enamine XXXVI, which subsequently is involved in an intramolecular aldol cyclization to deliver the highly diastereo‐ and enantioenriched 25 bearing three contiguous stereocenters.

SCHEME 9.

Photochemical annulation between α,β‐unsaturated aldehydes 21 and cyclopropanols 24.

In 2022, Alemán et al. disclosed an alternative strategy to generate β‐enaminyl radicals from organocatalytic iminium‐ion intermediates. They demonstrated that the electron–donor character of gem‐difluoride sulfinates 26 enables formation of an EDA complex XXXVII with iminium ion XXIX, obtained from condensation of diarylprolinol silyl ether C6 with α,β‐unsaturated aldehydes 21, thereby allowing for an enantioselective β‐difluoroalkylation of 21 (Scheme 10) [57]. Under visible‐light irradiation, excitation of complex XXXVII triggers a SET event that simultaneously furnishes β‐enaminyl radical XXXI and a gem‐difluoride radical XXXVIII (after SO₂ extrusion). A subsequent stereoselective radical–radical coupling followed by catalyst‐regenerating hydrolysis affords the β‐difluoroalkylated aldehydes 27.

SCHEME 10.

Photochemical β‐difluoroalkylation of α,β‐unsaturated aldehydes 21 with sulfinates 26.

The applicability of the protocol was ascertained using a number of different substrates allowing for the access to β‐difluoroalkylated aldehydes 27 in moderate to high yields and generally high enantioselectivities (Scheme 10). First, various substitution patterns in the aromatic or hetero‐aromatic moiety of α,β‐unsaturated aldehydes 21 proved viable. The successful utilization of non‐substituted, aryl‐, heteroaryl‐, and CF₂‐alkyl sulfinates 26 further expanded the generality of the protocol.

More recently, another example of an EDA complex derived from an iminium ion of type XXIX enabling enantioselective β‐functionalization of α,β‐unsaturated aldehydes was reported by Quintavalla et al. [58].

The use of electron‐rich β‐enaminyl radicals XXXI proved crucial for addressing the long‐standing challenge of elusive stereoselective conjugate cyanation of α,β‐unsaturated aldehydes 21 (Scheme 11). A stereoselective method, in which the cooperative action of diarylprolinol silyl ether C5 and a visible‐light‐activated photoredox catalyst 29 was disclosed, enabling this unprecedented disconnection with β‐enaminyl radical XXXI being generated by reduction of the corresponding iminium ion XXIX by the external photocatalyst [59]. Upon excitation, photocatalyst 29 is quenched by dihydropyridine 30, affording 29^•– , which then reduces iminium ion XXIX (formed by condensation of diarylprolinol silyl ether C5 and α,β‐unsaturated aldehyde 21) to deliver the chiral β‐enaminyl radical XXXI. This transient species intercepts TsCN 28 with high regio‐ and stereoselectivity. The ensuing radical XXXIX undergoes β‐fragmentation to form enamine XL, while releasing a tosyl radical. Hydrolysis of XL provides β‐cyanoaldehydes 31, regenerating catalyst C5.

SCHEME 11.

Top: Photochemical β‐cyanation of α,β‐unsaturated aldehydes 21 with TsCN 28. Bottom: Photochemical β‐alkylation of α,β‐unsaturated aldehydes 21 with acrylates 33.

The method tolerates a range of aliphatic β‐substituents on α,β‐unsaturated aldehydes 21, including branched or alkene‐/alkyne‐tethered chains, as well as β‐aryl groups, efficiently affording β‐cyanoaldehydes 31 with full β‐regioselectivity and high enantioselectivity (Scheme 11). Biorelevant residues can also be employed, as demonstrated by the reaction of an α,β‐unsaturated aldehydes derived from deoxycholic acid. Under slightly modified conditions, this strategy could also be applied to the stereoselective β‐addition of acrylates 33, affording the corresponding β‐alkylated aldehydes 34 in good to high yields and enantioselectivity, albeit with modest diastereocontrol (Scheme 11, bottom).

The organocatalytic generated iminium ion XXIX, derived from diarylprolinol silyl ether C6, can participate in Giese‐type acyl‐radical additions, enabling the synthesis of chiral 1,4‐dicarbonyl compounds 36 as presented by Melchiorre et al. in 2019 (Scheme 12) [60].

SCHEME 12.

Photochemical β‐acylation of α,β‐unsaturated aldehydes 21 with dihydropyridines 35.

Visible‐light excitation of 4‐acyl‐1,4‐dihydropyridine 35 generates acyl radical XLI, which is intercepted by the ground‐state iminium ion XXIX. The resulting intermediate XLII undergoes a HAT with a second molecule of 35, furnishing iminium ion XLIII. Hydrolysis of XLIII then delivers the enantioenriched 1,4‐dicarbonyl 36 and regenerates catalyst C6. The scope of the acyl radical conjugate addition tolerates a variety of radical precursors 35 embedding aromatic, heteroaryl, and alkyl groups, efficiently furnishing 36 with moderate to good enantioselectivity. Variously β‐aryl‐ and β‐alkyl‐substituted α,β‐unsaturated aldehydes 21 also proved suitable.

Independently, Yu et al. reported a similar transformation employing catalyst C6 along with a Ru‐photocatalyst and α‐ketoacids as acyl radical precursors [61]. The utility of the iminium ion as radical traps in enantioselective Giese‐type additions was expanded by the Melchiorre group, particularly in combination with an external acridinium‐based photocatalyst, to achieve the enantioselective β‐alkylation of β‐aryl‐ or β‐alkyl‐substituted α,β‐unsaturated aldehydes [62], and the stereoselective synthesis of 1,7‐dicarbonyl compounds [63].

In 2017, Melchiorre et al. reported a light‐driven β‐benzylation of α,β‐unsaturated aldehydes 21 (Scheme 13) [64]. Irradiation of 2‐alkyl benzophenones 37 with 365 nm light triggers a 1,5‐HAT event to generate ortho‐quinomethane photoenol XLIV, which undergoes a vinylogous Michael addition to iminium ion XXIX to furnish intermediate XLV. While the use of diphenylphosporic acid as co‐catalyst was required to improve the conversion of the transformation, utilization of the diarylprolinol silyl ether C7 provided the β‐benzylated aldehydes 38 in moderate to good yields and with high enantioselectivity. Several β‐alkyl‐ and β‐aryl substituted 21 proved viable, as well as acyclic‐ and cyclic 37, adorned with various substituent patterns.

SCHEME 13.

Photochemical β‐benzylation of α,β‐unsaturated aldehydes 21 with benzophenones 37. DPP = diphenylphosphoric acid.

As shown by some of the examples discussed above, the photochemistry of iminium ions generated from α,β‐unsaturated aldehydes and diarylprolinol silyl ether catalysts has enabled a wide range of enantioselective transformations. These processes rely on the singlet excited state (S₁) of the iminium‐ion intermediate. In 2020, Bach et al. enabled the triplet excited state (T₁) reactivity of stochiometric chiral iminium ion salts 39, prepared from α,β‐unsaturated aldehydes 21 and diarylprolinol silyl ether salt C8, in a Ru‐catalyzed, intermolecular [2+2] photocycloaddition with olefins 40 to afford cyclobutanes 41 with moderate to high diasteroselectivity and high enantioselectivity after alkaline hydrolysis (Scheme 14) [65].

SCHEME 14.

Top: Photochemical [2+2] cycloaddition between stochiometric iminium ions 39 and olefins 40. Bottom: Catalytic variant.

The reaction proved compatibility with various iminium ions 39, tolerating diversely substituted aryl groups, as well as a number of conjugated olefins 40 (Scheme 14). Mechanistic studies revealed that visible‐light excitation of the Ru‐photocatalyst triggers a triplet‐energy transfer to the iminium salt, which then reacts with the olefin to form the 1,4‐diradical intermediate XLVI. After intersystem crossing (ISC), this intermediate undergoes the subsequent C–C bond‐forming step. Despite the inherent challenges posed by this system, careful optimization of the reaction conditions enabled the authors to develop two catalytic variants of the transformation involving cinnamaldehyde and dimethyl butadiene (utilizing catalysts C5 or C9), which furnished cyclobutane 42 in moderate yield and with good enantioselectivity (Scheme 14, bottom).

To summarize, the photochemical reactivity of enamines and iminium ions generated from diarylprolinol silyl ether catalyst can be rationalized as follows. In the first scenario, a photoinduced SET involves the organocatalytic intermediate, either as an enamine or an iminium ion, enabling radical generation by direct excitation or EDA‐complex formation/excitation. In a complementary mode, light is used to generate radical species from external precursors through a direct excitation manifold or by mediation of a metal‐ or organic‐based photocatalyst or a DTC catalyst. These radicals are then typically trapped by ground‐state enamines or iminium ions in stereoselective C─C bond‐forming events, typically following a Giese‐type reaction, or engaged in radical–radical couplings with α‐iminyl radical cations (from enamines) or β‐enaminyl radicals (from iminium ions). Finally, less‐common activation pathways have also been disclosed, including energy‐transfer activation of stochiometric iminium ions to access triplet‐state reactivity, as well as polar photochemical processes in which light serves to generate electrophilic or nucleophilic partners that react with organocatalytic intermediates following a two‐electron‐logic pathway.

3. Electrochemical Transformations

Recent years have witnessed a renaissance of organic electrosynthesis as a sustainable strategy for constructing complex molecular architectures [66, 67]. Within this landscape, enantioselective electrochemical methods have emerged as increasingly powerful tools. Although electrochemistry has already demonstrated successful synergy with asymmetric metal catalysis [68] and biocatalysis [69], its combination with asymmetric aminocatalysis is still in its infancy [70, 71].

In 2009 the Jang's group reported a seminal enantioselective radical α‐oxamination of aldehydes, in which a radical–radical coupling between TEMPO and a α‐iminyl radical cation—generated from electrochemical oxidation of an organocatalytic enamine—is the key step [72]. The following year, our group introduced a distinct concept, demonstrating that electricity could be used to generate a transient electrophilic Michael acceptor through the anodic oxidation of a tosyl para‐hydroxy aniline, which then reacted stereoselectively with an organocatalytic enamine [73]. Notably, in both seminal studies, the enamine intermediates were derived from diarylprolinol silyl ether catalysts. Although several reports over the past decade have merged electrochemistry with enamine catalysis [74], it is only in the last couple of years that diarylprolinol silyl ether catalysts have been strategically applied to these systems to advance the seminal concepts.

In 2024, Dell'Amico et al. reported an enantioselective electrochemical α‐alkylation of aldehydes 1, exploiting the anodic oxidation of enamine I generated from catalyst C1 (Scheme 15) [75].

SCHEME 15.

Top: Electrochemical α‐alkylation of aldehydes 1 with silyl enol ethers 43. Bottom: α‐allylation of aldehydes 1 with allyl silanes 47 and intramolecular variant.

The enamine I is oxidized at the anode to form the corresponding α‐iminyl radical cation X, which is then stereoselectively trapped by silylenol ether 43 to furnish radical cation XLVII (Scheme 15). A subsequent oxidation step affords intermediate XLVIII, whose hydrolysis delivers α‐alkylated aldehydes 44. The electrochemical circuit is closed by cathodic hydrogen evolution. Mechanistic experiments and DFT calculations indicated the importance of 4,4′‐bisanisole acting as a radical shuttle, mitigating the rise of the cell potential over time, thereby preventing decomposition of C1, while simultaneously facilitating the oxidation of enamine I to X. This electrochemical method proved tolerant to variation of both substrates, enabling access to a panel of 44 in moderate to high yields and generally with high enantioselectivity. The authors extended the methodology to an enantioselective α‐allylation of aldehydes using allyl silanes 47. This transformation was adapted to an intramolecular variant using aldehydes 45, providing cycloadducts 46 with excellent diastereoselectivity and high enantioselectivity.

An example of electrochemical in situ generation of electrophiles was accomplished in the same year by Xu et al., that designed an ad hoc bifunctional catalyst C10 to enable a stereoselective α‐alkylation of aldehydes 1 with phenols 49 (Scheme 16) [76].

SCHEME 16.

Electrochemical α‐alkylation of aldehydes 1 with phenols 49.

The novelty lay in the strategic incorporation of a morpholine redox‐mediator moiety into the diarylprolinol scaffold. Catalyst C10 thus covered a double function in the system: it generates the reactive enamine I while acting as a redox mediator (Scheme 16). Indeed, the anodically oxidized form of C10 (XLIX) efficiently promotes the oxidation of phenol 49 to radical L, which is further oxidized at the anode to generate the electrophilic para‐quinone methide LI. This species is engaged in a stereoselective Michael addition with enamine I, furnishing iminium ion LII, which upon hydrolysis yields the α‐alkylated aldehyde 50. The addition of HFIP proved crucial, both for activating intermediate LI and for increasing the diastereoselectivity by improving face selectivity of the catalyst in the transition state. The authors experimentally confirmed that using the two components separately—that is, a simplified C4‐substituted diarylprolinol silyl ether catalyst and N‐methyl morpholine—resulted in much lower yield. The scope of the transformation was broad, providing 50 in good yields and with excellent diastereo‐ and enantiocontrol. Notably, both symmetrical and non‐symmetrical 2,4,6‐substituted phenols 49 were suitable, as well as aldehydes derived from biorelevant scaffolds such as pregabalin and estrone. Although this transformation could be achieved under classical polar conditions in comparable efficiency and stereoselectivity, as previously reported [77], this electrochemical approach circumvents the need to synthesize difficult‐to‐make para‐quinone methides LI.

Concomitantly, the group of Pan developed an enantioselective electrochemical cross‐dehydrogenative coupling reaction between dibenzylic substrates 13 and aldehydes 1 using catalyst C1 (Scheme 17) [78]. Cyclic voltammetry and radical‐clock experiments support a mechanism initiated by the anodic oxidation of 13 to generate radical XVII. Analogously to the photochemical variant previously reported by Pericàs [45], the corresponding dibenzylic electrophilic cation XVIII arises from a radical‐polar crossover step. In this case, the oxidation of radical XVII to XVIII occurs at the Pt‐anode. This carbocation is then enantioselectively intercepted at the α‐position of enamine I, thereby delivering α‐alkylated aldehyde 51, after hydrolysis of iminium ion XVI, in variable yields and with high diastereo‐ and enantioselectivitity. The methodology exhibited broad applicability and excellent stereocontrol, tolerating a range of radical precursors such as xanthenes, methylacridines, and electron‐rich diarylmethanes. A variety of aldehydes, including the naturally occurring citronellal, were also compatible. The authors further demonstrated the electrochemical coupling of 1 with cycloheptatriene 52, providing the corresponding chiral adducts 53 in high enantioselectivity (Scheme 17, bottom).

SCHEME 17.

Top: Electrochemical α‐alkylation of aldehydes 1 dibenzylic substrates 13. Bottom: Electrochemical α‐alkylation of aldehydes 1 with cycloheptatriene 52.

The combination of electrochemistry with aminocatalytic intermediates can also be extended to dienamine catalysis, as recently demonstrated by Albrecht et al. in the development of an eliminative, enantioselective Diels–Alder reaction between hydroquinones 55 and α,β‐unsaturated aldehydes 54, in the presence of catalyst C11 (Scheme 18) [79]. Although the scope of hydroquinone 55 proved relatively narrow, a range of cyclic and acyclic 54 bearing diverse substitution patterns were well tolerated, thereby enabling access to polycyclic adducts 56 featuring different ring‐fusions in moderate to high yields and with high diastereo‐ and enentioselectivity. A sequential reaction pathway was proposed, in which an initial anodic oxidation of 55 generates the corresponding electrophilic quinone LIII, which then undergoes a stereoselective Michael addition at the γ‐position of the organocatalytically generated dienamine LIV, forming zwitterionic intermediate LV. Subsequent intramolecular cyclization affords LVI, which readily eliminates the catalyst furnishing cycloadduct 56. Based on previous DFT studies of a previous related process [80], it was suggested that this transformation proceeds via an endo‐selective, step‐wise cycloaddition.

SCHEME 18.

Electrochemical [4+2] cycloadditions between α,β‐unsaturated aldehydes 54 and hydroquinones 55.

So far, a unique example involving an organocatalytic iminium‐ion intermediate in asymmetric electrochemistry was recently reported by Ošeka et al. (Scheme 19) [81]. It was shown that an electrochemical enantioselective cyclopropanation of α,β‐unsaturated aldehydes 21 with malonates or oxindoles 57 could be achieved through a C11‐promoted electro‐organocatalytic cascade process. A panel of cyclopropane‐carbaldehydes 58 was obtained in moderate to good yields, with generally good diastereoselectivity and excellent enantioselectivity. A range of β‐aryl‐substituted 21 proved suitable, as did various 57 as nucleophiles, thereby enabling access even to oxindole‐based enantioenriched spirocycles. The authors proposed that condensation of C11 with 21 generates iminium ion XXIX, which first undergoes a stereoselective Michael addition with 57 to furnish enamine LVII. Concurrently, anodic oxidation of iodide forms electrophilic iodonium, that reacts at the α‐position of enamine LVII. The incipient iminium ion LVIII next undergoes an intramolecular nucleophilic substitution, regenerating iodide in the electrocatalytic cycle and forming the cyclopropane ring within LIX. Final hydrolysis releases 58, while regenerating catalyst C11.

SCHEME 19.

Electrochemical cyclopropanation of α,β‐unsaturated aldehydes 21 with malonates or oxindoles 57.

4. Dual Catalytic Transformations

In contrast to a catalytic system involving only a single catalyst to activate the nucleophile or electrophile in a single catalytic cycle, in synergistic dual catalysis two catalysts controlling two individual cycles work in synergy to form a new bond. Each of the two catalysts serve to activate the nucleophile and electrophile concurrently, thus reducing the HOMO–LUMO gap, enabling otherwise unfeasible or ineffective transformations [82, 83, 84]. The feasibility of combining aminocatalysis and transition metal catalysis was first demonstrated by the group of Córdova in 2006 when subjecting α‐enolizable aldehydes to allyl acetate in the presence of pyrrolidine and Pd(PPh₃)₄ to facilitate a racemic α‐allylation [85].

This work was later expanded by Carreira et al. in 2013 when disclosing the fully stereodivergent α‐allylation of α‐branched aldehydes with allylic alcohols by a synergistic iridium and primary cinchona alkaloid aminocatalyst system [86]. Thus, the aldehyde is activated by an aminocatalyst through enamine catalysis, while the allylic alcohol is concurrently activated by a chiral iridium catalyst to generate a π‐allyl complex, each controlling the configuration of one of the two stereocenters in the product. Shortly after, Carreira et al. expanded the methodology to function with diarylprolinol silyl ether catalysts for aldehydes that are not α‐branched [87, 88]. Since then, the field has expanded significantly with dual catalytic protocols involving the diarylprolinol silyl ether class of catalysts in concert with various transition metal‐ and Lewis acid‐based systems. This chapter will focus mostly on the application of transition metals and Lewis acids in concert with aminocatalysis to highlight recent key examples to access otherwise unattainable scaffolds.

The influence of Carreira's original system remains visible on the field to this day. One recent example was disclosed by the group of Zi involving the stereodivergent hydroalkylation of α‐enolizable aldehydes 1 with 1,3‐dienes 59 to access both the syn‐ and anti‐configured coupling products 60 and 61, respectively, in moderate to high yield and overall good to excellent stereocontrol (Scheme 20) [89]. The protocol leading to the syn‐configured 60 was more selective than the anti‐protocol. The developed protocol is amenable to various aliphatic 1 and 59 carrying aromatic or olefinic substituents; however, aliphatic substituents were not tolerated. DFT calculations showed that the in situ generated chiral palladium complex LXI is first protonated to generate PdH species LXII, whose insertion into 59 from the Si‐face generates Pd‐π‐allyl complex LXIII. Stereoselective nucleophilic attack by enamine I affords iminium ion LX when L1 was applied, which after hydrolysis of the catalyst provides 60. The authors demonstrated that the protocol could even be applied to dienamine catalysis.

SCHEME 20.

Pd‐catalyzed stereodivergent hydroalkylation of aldehydes 1 with 1,3‐dienes 59.

Multiple similar transformations hinging on chiral palladium‐ or iridium‐π‐allyl complexes in combination with the diarylprolinol silyl ether catalysts have been reported in the last decade, such as the α‐allylation of various uncommon enamine precursors [87, 90, 91, 92, 93], and in aminocatalytic cascade reactions [94, 95, 96]. It is worth noting that an α‐allylation without relying on the utilization of transition metals was accomplished by Hall et al. exploiting boronic acids in a synergistic system with aminocatalysis [97]. In this protocol the boronic acid serves to dehydrate the substrate allylic alcohol and generate a reactive carbocation intermediate capable of reacting with the in situ generated enamine.

Despite the appearance of photochemical alternatives, aminocatalytic SOMO activation [98, 99] has recently been utilized in combination with a copper‐mediated enantioselective α‐azidation of α‐branched aldehydes 62 (Scheme 21) [100]. The method was amenable toward both cyclic‐ and acyclic α‐branched aldehydes carrying an aromatic moiety and afforded α‐azidoaldehydes 65 in moderate to high yields and high to excellent enantioselectivity. The catalytic cycle is initiated by the condensation of C14 to 62 forming enamine LXIV, which after SET by the sacrificial oxidant 64 generates α‐iminyl radical cation LXV. Concomitantly, the Cu(I) complex LXVII interacts with TMSN₃ 63 to generate LXVIII, which after SET affords the active Cu(II)‐N₃ species LXIX. It was then proposed, that the open‐shell intermediate LXV can be sequestered by the Cu(II)‐N₃ species LXIX via an outer‐sphere ligand transfer step to generate LXVI, and subsequently 65 after aminocatalyst hydrolysis. Intriguingly, the utilization of chirality pairing between the aminocatalyst and ligand is essential to achieving high enantioselectivity.

SCHEME 21.

Cu‐catalyzed α‐azidation of α‐branched aldehydes 62 with TMSN₃ 63.

The combination of aminocatalysis with redox‐active transition metals has enabled the α‐functionalization of alcohol substrates via a transient aldehyde intermediate through borrowing hydrogen relay catalysis [101]. This is shown in the work of Zhao et al. detailing the α‐alkylation of aliphatic and aromatic alcohols 66 by nitrostyrenes 67 catalyzed by diarylprolinol silyl ether C11 and iridium complex 68 (Scheme 22) [102].

SCHEME 22.

Ir‐catalyzed α‐functionalization of alcohols 66 with nitrosyrenes 67.

This protocol notably provided improved diastereocontrol compared to starting from the corresponding aldehydes (15:1 vs. 1.7:1 d.r.), hypothesized to originate from the suppression of the product aldehyde (LXXIII) epimerization, and enabled the direct functionalization of simple alcohols in overall good to excellent yield and selectivity (Scheme 22). The proposed mechanism commences by a two‐electron oxidation of alcohol 66 to generate aldehyde LXX by iridium complex 68 forming LXXI. After condensation of C11 to generate enamine I, the stereoselective Michael addition to nitrostyrene 67 proceeds to generate iminium ion LXXII. After hydrolysis of the aminocatalyst and two‐electron reduction by LXXI, Michael adduct 69 is formed while regenerating both catalysts. The transformation was also feasible for vinyl sulfone electrophiles.

In the past decade borrowing‐hydrogen catalysis has been combined with aminocatalysis on multiple occasions primarily for the in situ generation of α,β‐unsaturated aldehydes from allylic alcohols engaged in iminium‐ion catalysis [103, 104, 105].

A stereoselective oxidative homo‐ and hetero‐γ‐coupling of in situ generated dienamines mediated by a catalytic amount of Cu(II) with atmospheric oxygen serving as a terminal oxidant was developed as outlined in Scheme 23 [106].

SCHEME 23.

Cu‐catalyzed oxidative homo‐ and hetero‐γ‐coupling of α,β‐unsaturated aldehydes 54 and 54′.

The protocol was amenable to α,β‐unsaturated aldehydes 54 and 54′ carrying both cyclic and acyclic aliphatic γ‐substituents and aromatic substituents on the β‐position to afford the coupled adducts 70 in good to high yield and stereoselectivity (Scheme 23). The proposed catalytic cycle is initiated by the condensation of ent‐C11 onto 54 and 54′ affording dienamines LIV and LIV′ which upon SET oxidation by Cu(II) generates radical cations LXXIV and LXXIV′. To complete the oxidative coupling, LXXIV couples with LXXIV′ or LIV′ to generate 70 after catalyst hydrolysis (for simplicity shown only for LXXIV′). To regenerate Cu(II), the Cu(I) formed in the SET step is reoxidized by atmospheric oxygen.

Synergistic amino‐ and palladium‐catalyzed systems have not only been employed in allylations, but also in for example, an asymmetric Michael/Conia‐ene cascade reaction (Scheme 24) [107]. In this work, Veselý et al. developed a methodology to access spirocyclic pyrazolones 72 in moderate to high yield and stereoselectivity from α,β‐unsaturated aldehydes 21. The reaction was tolerant to both aromatic, aliphatic, and ester functionalities on 21. For pyrazolones 71, both aromatic substituent were suitable in R² and R³, while aliphatic substituents were only viable for R³. The mechanism was suggested to proceed through an initial Michael addition onto the in situ generated iminium ion XXIX to afford intermediate LXXV upon complexation with Pd(0). The palladium mediated Conia‐ene reaction then proceeds to accomplish formation of LXXVI, which after hydrolysis and palladium release produces 72, while regenerating the aminocatalyst.

SCHEME 24.

Pd‐catalyzed Michael/Conia‐ene cascade reaction between α,β‐unsaturated aldehydes 21 and pyrazolones 71.

A synergistic strategy combining aminocatalytic iminium‐ion activation of aryl‐ and heteroaryl‐bearing α,β‐unsaturated aldehydes 21 with Lewis‐acid activation of substituted alkyl quinolines 73 was applied in 2017, enabling the access to both mono‐ and double‐addition adducts 74 in good to excellent yields and stereochemical outcomes (Scheme 25, only double addition shown) [108]. It was proposed that InCl₃ first coordinates to the quinoline nitrogen to form LXXX, rendering the methyl proton more acidic, thereby facilitating the formation of intermediate LXXXI. Next, LXXXI attacks the in situ generated iminium ion XXIX to generate intermediate LXXVII. A second deprotonation leads to LXXVIII which can react with a second entity of XXIX to generate LXXIX. After intramolecular aldol condensation, hydrolysis of the aminocatalyst and decomplexation of the Lewis acid, 74 is formed and both catalytic entities are regenerated.

SCHEME 25.

In‐catalyzed annulation between α,β‐unsaturated aldehydes 21 and alkyl quinolines 73.

Bicyclo[1.1.0]butanes (BCBs) are a class of strained rings that have garnered considerable attention in recent years [109, 110] due to their potential application for generating three‐dimensional scaffolds, valuable as bioisosteres within the “Escape from Flatland” paradigm [111, 112, 113]. The first usage of BCBs in combination with aminocatalysis was recently reported by our group utilizing a Lewis acid to synergistically activate BCBs 75 for a formal [2+2] cycloaddition with in situ generated iminium ions to generate highly functionalized bicyclo[2.1.1]hexanes (BCHs) 76 in moderate to high yield and enantioselectivity invariably as a single diastereoisomer (Scheme 26) [114].

SCHEME 26.

Top: Yb‐catalyzed [2+2] cycloadditions between α,β‐unsaturated aldehydes 21 and BCBs 75. Bottom: Brønsted‐acid catalyzed variant.

The strategy could tolerate various α,β‐unsaturated aldehydes 21 bearing both aromatic and carbonyl substituents, but not aliphatic ones, and BCBs 75 carrying a variety of R²‐substituents, however electron‐deficient R³‐substituents were not tolerated (Scheme 26). After condensation of C15 onto 21 to generate iminium ion XXIX, it was proposed that Yb(III) activates 75 to generate a zwitterionic intermediate LXXXII that can participate in a stereoselective nucleophilic attack on XXIX to afford LXXXIII. After ring‐closure and hydrolysis of the aminocatalyst, BCH 76 is released and the catalytic cycle can repeat.

Shortly after, it was shown by Xu et al. that a Brønsted acid and thiourea could likewise activate BCB 75 in a synergistic manner, enabling similar reactivity to afford BCHs 76 in good to high yield and excellent selectivity (Scheme 26, bottom) [115]. While the scope is narrower, the same limitation toward the substituent of α,β‐unsaturated aldehydes 21 and BCB 75 was observed. It is worth noting that it was found that the more sterically encumbered catalyst C5 could furnish an even higher degree of enantioinduction.

Additionally, it was showcased by the group of Feng et al. that vinyl‐BCBs 77 could be activated by palladium, enabling the formal [2+2] cycloaddition with aminocatalytically generated iminium ions to afford BCHs 78 in good to high yield and excellent stereocontrol (Scheme 27) [116].

SCHEME 27.

Pd‐catalyzed [2+2] cycloadditions between α,β‐unsaturated aldehydes 21 and BCBs 77.

The reaction tolerated aromatic α,β‐unsaturated aldehydes 21 but did not allow aliphatic substituents (Scheme 27). The vinyl‐BCBs 77 were amenable to ketone functionalities, however, did not allow esters, sulfones or the installation of bulk on the vinyl group. The mechanism is reminiscent of the previous example, the difference lying in the activation of 77. It was proposed that 77 undergoes oxidative addition with Pd(0) generating the zwitterionic π‐allyl‐palladium intermediate LXXXV, which can then undergo 1,4‐addition to iminium ion XXIX to generate LXXXVI. Intramolecular allylic substitution generates intermediate LXXXVII while liberating Pd(0). Hydrolysis of LXXXVII liberates product 78 and aminocatalyst C11. It is worth noting that synergistic aminocatalytic and palladium mediated systems exploiting vinyl‐substituted strained rings have previously been reported for vinyl‐cyclopropanes [117, 118, 119] and vinyl‐aziridines [120].

Recently, a stereodivergent protocol exploiting a synergistic amino‐ and Lewis base–catalyst system was reported by the group of Lee for the Michael addition of aryl acetic acid esters 79 to aromatic α,β‐unsaturated aldehydes 21, selectively enabling access to the anti‐ and syn‐configured adducts, 80 and 81, respectively, in good to high yield and stereochemical outcomes (Scheme 28) [121]. While both protocols offered access to either product isomers in high stereochemical fidelity, generally the diastereoselectivity was higher for 80 (anti) compared to the syn‐isomer. The proposed catalytic cycle starts with a condensation of ent‐C1 to 21, providing iminium ion XXIX. Simultaneously, benzotetramisole (R)‐82 undergoes acyl substitution to the aryl acetic acid ester 79 to generate intermediate LXXXVIII. Upon deprotonation of LXXXVIII, the enolate LXXXIX is unveiled and undergoes nucleophilic attack to XXIX. Upon hydrolysis of the aminocatalyst, and acyl substitution by the aryloxide, anti‐adduct 80 is released and both organocatalysts regenerated. It was also shown that the adducts could be further functionalized by an aminocatalytic α‐fluorination, either after isolation or one‐pot, forging a total of three contiguous stereocenters with excellent stereoselectivity.

SCHEME 28.

Benzotetramisole‐catalyzed stereodivergent Michael addition of aryl acetic acid esters 79 to α,β‐unsaturated aldehydes 21.

The same authors also accomplished a stereodivergent Michael addition between α,β‐unsaturated aldehydes and α‐fluoro azaaryl acetamides relying on a chiral Lewis acid complex to activate and direct the enolate precursor in combination with iminium‐ion activation, accessing all four possible stereoisomers with high chemical fidelity [122].

A synergistic concept exploiting the 1,5‐HAT of a formed α‐iminyl radical to enable the generation of enantioenriched axially chiral heterobiaryls 85 in moderate to good yields and enantioselectivitity was described (Scheme 29) [123]. The reaction was built on the non‐enantioselective protocol for cinnamaldehyde derivatives reported in the same paper. Hence, the authors utilized napthyl‐derived α,β‐unsaturated aldehydes 83 embedding an ester or ether ortho‐substituent with oxime esters 84 amenable for both electron‐rich and ‐poor aryl substituents. In the proposed mechanism C16 first condenses to 83 to generate iminium ion XC. Simultaneously, a SET reduction of 84 proceeds to afford iminyl radical XCI, while oxidizing Fe(II) to Fe(III). Next, XCI undergoes 1,3‐HAT to form α‐carbon radical XCII which engages in conjugate addition with XC affording XCIII. Subsequent 1,5‐HAT generates the tertiary radical XCIV, followed by homolytic aromatic substitution providing XCV. SET oxidation by Fe(III) and tautomerization leads to XCVI, which by an intramolecular cyclization and aminocatalyst elimination generates centrally chiral intermediate XCVII and regenerates the aminocatalyst. Upon two sequential single‐electron oxidations, atropoisomer 85 is generated through a central‐to‐axial chirality conversion.

SCHEME 29.

Fe‐catalyzed atroposelective annulation between α,β‐unsaturated aldehydes 83 and oxime esters 84.

In 2024, the synergistic Mn(I)‐ and aminocatalytic enantioselective C(sp² )─C(sp³ ) bond formation to generate skipped dienes 88 from dienals 86 and alkenyl boronic acids 87 in good to high yields and high enantioselectivity was presented (Scheme 30) [124]. The methodology was tolerant for 86 carrying aromatic or styrenyl residues, while 87 can accommodate both aromatic and aliphatic substituents. The proposed mechanistic cycle is initiated by the condensation of C17 to 86 to generate vinylogous iminium ion XCVIII. Simultaneously, the dimeric manganese source undergoes transmetallation with 87 to generate a HOMO‐raised alkenylmanganese species XCIX. Migratory insertion into the C─[Mn] bond of XCIX leads to intermediate C, which after demetallation and tautomerization forms iminium ion CII. Hydrolysis regenerates the aminocatalyst and liberates the skipped diene 88. Intriguingly, the propensity for the 1,4‐ over 1,6‐hydroalkenylation was investigated by DFT calculations indicating that while both pathways are thermodynamically feasible, a kinetic bias toward the 1,4‐addition is present.

SCHEME 30.

Mn‐catalyzed β‐alkenylation of dienals 86 with alkenyl boronic acids 87.

Although synergistic catalytic protocols are the most common, examples have been reported involving sequential procedures to generate complex product scaffolds. Enders et al. presented a quadruple component cascade followed by a sequential Lewis acid‐mediated hetero‐inverse electron‐demand Diels–Alder reaction (IEDDA) to be feasible in a one‐pot procedure (Scheme 31) [125].

SCHEME 31.

Yb‐catalyzed, multi‐component cascade annulation of acrolein 89, alcohols 90 and nitrostyrenes 67.

The transformation is commenced by the condensation of ent‐C11 to acrolein 89 to generate iminium ion CIII, which is susceptible to an oxa‐Michael addition from alcohol 90 to generate enamine intermediate CIV (Scheme 31). Upon Michael addition of enamine CIV to nitroolefin 67 followed by hydrolysis of the aminocatalyst, the nucleophilic intermediate CV is formed. Upon Michael addition of CV to another equivalent of CIII, intermediate CVI is generated, which upon intramolecular aldol condensation forms the isolable intermediate CVII after hydrolysis of the aminocatalyst. Upon subjection of CVII to Yb(III), either one‐pot or after isolation, a Lewis acid‐mediated stereospecific hetero‐IEDDA reaction (CVIII) proceeds to generate the complex tricyclic cycloadduct 91. While the yields were modest, credit should be given, as the overall process is a highly elaborate and stereoselective multicomponent reaction from commercial or easily accessible substrates.

While marking perhaps the most prominent example of sequential catalysis based on aminocatalysis in the last decade, other examples involving Lewis acids [126, 127] and N‐heterocyclic carbene catalysis [128] have also been reported.

5. Higher‐Order Cycloadditions

Cycloadditions involving more than 6π‐electrons are termed higher‐order cycloadditions (HOCs). The feasibility of thermal HOCs was already postulated as early as the Woodward and Hoffmann papers detailing the selectivity rules of pericyclic reactions based on orbital symmetry considerations [129, 130]. One year after its prediction, the first [6+4] cycloaddition was experimentally accomplished independently by the groups of Cookson and Itô detailing the reaction between tropone and cyclopentadiene [131, 132]. Classically, HOCs were notorious for affording poor yields and periselectivities; however, since the increased application of catalytic systems, several highly selective methods have been developed [133, 134, 135, 136].

The first enantioselective intermolecular organocatalytic protocols were reported serendipitously in 2017 by our group and Chen et al., and since then the field has undergone a renaissance [137, 138]. In particular, the application of aminocatalysis in the development of new enantioselective HOCs has been exploited, often applying aminocatalytic species containing 10π‐electrons or more.

One of the earliest publications regarding aminocatalytic HOCs utilizing the diarylprolinol silyl ether catalyst ent‐C7 was disclosed in 2018, presenting the [10+4] cycloaddition between indenecarbaldehydes 92 and electron‐deficient dienes 93 (Scheme 32) [139]. This cycloaddition afforded dihydroazulenes 94 in moderate to excellent yields and enantioselectivity invariably as single diastereoisomers. Multiple substitution patterns on 92 were tolerated, while various electron‐withdrawing groups on 93 were amenable. DFT calculations showed that the stereoinduction originates from a kinetic preference toward cyclic polyenamine intermediate CIX over other competing conformation. This was further corroborated by the beneficial effect of removing moisture by adding molecular sieves as hydrolysis back to the substrates is minimized. Intermediate CIX can then undergo a step‐wise [10+4] cycloaddition to generate CXI, which, after elimination of the catalyst, releases 94.

SCHEME 32.

[10+4] Cycloaddition between indenecarbaldehydes 92 and dienes 93.

It was also demonstrated that aminocatalytically generated aza‐ and diazafulvenes could react as electron‐rich 6π‐components in stereoselective [6+2] and [6+4] cycloadditions of pyrrole carbaldehydes 95 with nitroolefins 67 and electron‐deficient dienes, respectively. However, only the [6+2] cycloaddition utilized a diarylprolinol silyl ether catalyst, therefore the [6+4] cycloaddition will not be discussed herein. The catalytic cycle is initiated by the aminocatalytic formation of azafulvene intermediate CXII from 95 and ent‐C7 (Scheme 33) [140]. DFT calculations showed that CXII engages in a non‐selective addition to 67 to generate both enantiomers of intermediate CXIII. However, only the (R)‐configured intermediate CXIII can proceed as suggested by the calculated transition state barrier for the second‐bond formation being nearly 10 kcal mol⁻¹ lower in energy than the (S)‐configured CXIII, therefore ensuring the selective generation of intermediate CXIV. Upon catalyst elimination, CXV is generated, which upon treatment with a nucleophile can provide 96. The cycloadducts 96 were formed in moderate to good yields and high enantioselectivity. The [6+2] cycloaddition was amenable to pyrrole carbaldehydes carrying various substitution patterns. Multiple nucleophiles can be employed such as hydride, thiols, and indole; however, treatment with a nucleophile was not required and can be stopped by isolation of CXV.

SCHEME 33.

[6+2] Cycloaddition between pyrrole carbaldehydes 95 and nitrostyrenes 67.

In 2020, the stereoselective [10+2] cycloaddition to afford chiral tetrahydrocyclopenta[a]indenes 98 in low to good yields and moderate to excellent stereocontrol was achieved by applying catalyst C7 (Scheme 34) [141]. This was accomplished in a dual catalytic fashion where C7 simultaneously activates both the α,β‐unsaturated aldehyde 21 and homologated indenecarbaldehyde 97, as revealed by the presence of a significant non‐linear effect. Indenecarbaldehydes 97 bearing a variety of substitution patterns could be employed, as did 21 carrying both aliphatic‐, aromatic‐, and unsaturated substituents. Upon aminocatalytic activation of 97 and 21 to generate CXVI and XXIX, the step‐wise [10+2] cycloaddition proceeds furnishing CXVIII, which releases 98 upon hydrolysis of the catalysts. The step‐wise mechanism was further corroborated by the isolation of an intermediate after the first bond formation (intermediate CXVII after hydrolysis of the aminocatalysts). It was also found through DFT calculations, that the cycloaddition operates through a Curtin–Hammett scenario where the possible stereoisomers of CXVII are in equilibrium enabling only the isomer capable of inducing the final stereochemistry to proceed through the ring‐closure generating CXVIII.

SCHEME 34.

[10+2] Cycloaddition between homologated indenecarbaldehydes 97 and α,β‐unsaturated aldehydes 21.

The diarylprolinol silyl ether was shown to control the HOCs between 2‐trifluoromethanesulfonate tropone 99 and various vinylogous enamine species (Scheme 35) [142]. It was demonstrated as a proof‐of‐concept that 99 could undergo an unprecedented [10+6] HOC with homologated indenecarbaldehydes 97 in the presence of C7, followed by an unprecedented ring‐contracting Favorskii‐like rearrangement to afford cycloadducts 100 with high peri‐ and stereoselectivity. Although, the reaction was accomplished in low yield, it allowed for the formation of complex cycloadducts with high stereoselectivity. The mechanism of the transformation was investigated in detail by DFT calculations but will not be discussed in detail herein.

SCHEME 35.

Top: [10+6] Cycloaddition between homologated indenecarbaldehydes 97 and 2‐trifluoromethanesulfonate tropone 99. Bottom: [6+4] Cycloaddition between dienals 101 and 99.

The catalytic cycle in Scheme 35 begins with the condensation of catalyst C7 to the homologated indenecarbaldehydes 97 to generate vinylogous enamine CXVI, which then undergoes a step‐wise [10+6] cycloaddition with 2‐trifluoromethanesulfonate tropone 99 to generate transient cycloadduct CXX. Upon rearrangement and hydrolysis of C7 cycloadduct 100 is formed. Furthermore, it was shown that 99 could undergo a similar cascade reaction with dienals 101 operating through a trienamine catalyzed [6+4] cycloaddition followed by an equivalent Favorskii‐like rearrangement to generate 102 in high peri‐ and stereoselectivity and moderate yields. Only aromatic substituents on the dienal 101 could facilitate the rearrangement (Scheme 35, bottom).

In 2019, the group of Albrecht disclosed an aminocatalytic [8+2] cycloaddition between tropothione 104 and α,β‐unsaturated aldehydes 103, having one or more aliphatic and aromatic β‐substituents, enabled by iminium‐ion catalysis to stereoselectively generate chiral tetrahydrothiophenes 105 in good to high yield and generally excellent stereocontrol (Scheme 36) [143]. Pivotal for the success of this strategy was the incorporation of a sulfur atom into the tropone core, rendering the otherwise electron‐deficient 8π‐component instead electron‐rich. In the proposed mechanism, C1 first condenses to 103 to generate iminium ion XXIX. Subsequently, the stereoselective [8+2] cycloaddition proceeds generating CXXII, which after catalyst hydrolysis liberates 105. The diastereocontrol arises from the desymetrization of 104 via an approach between the prochiral faces of 104 and XXIX during the cycloaddition to minimize steric interactions with the exocyclic group of C1.

SCHEME 36.

[8+2] Cycloaddition between α,β‐unsaturated aldehydes 103 and tropothione 104.

In 2021, an efficient synthesis of chiral cycl[3.2.2]azines 108 in a highly stereoselective manner in moderate to high yields based on the use of diarylprolinol silyl ether was disclosed (Scheme 37) [144]. This was accomplished by the utilization of (E)‐3‐benzylidene‐3H‐pyrrolizines 107, embedding aromatic substituents, in conjunction with α,β‐unsaturated aldehydes 106 catalyzed by C1 through an iminium‐ion mediated step‐wise [8+2] cycloaddition. The α,β‐unsaturated aldehydes were tolerant toward a variety of substitution patterns, including aliphatic and aromatic groups. After condensation of C1 to 106, the iminium ion XXIX undergoes a step‐wise [8+2] cycloaddition with 107 affording intermediate CXXIV, which after hydrolysis liberates cycl[3.2.2]azine 108 and regenerates the catalyst.

SCHEME 37.

[8+2] Cycloaddition between α,β‐unsaturated aldehydes 106 and benzylidene pyrrolizines 107.

6. Total Synthesis

Within the last decade aminocatalytic strategies based on diarylprolinol silyl ethers as catalysts have been exploited on multiple occasions for the total syntheses of complex natural compounds [30]. As this review will not contain a comprehensive examination of all total syntheses utilizing this class of catalysts in one or more of its synthetic steps, some selected examples involving a key aminocatalytic step will be discussed.

One impressive accomplishments of aminocatalysis in total synthesis over the last decade was disclosed by the group of Lu in 2024 detailing the synthesis of (‐)‐bipolarolide D (Scheme 38) [145]. In this synthesis, the key step involved an aminocatalytic intramolecular [6+2] HOC between an enamine and pentafulvene motif, inspired by the first reported intramolecular aminocatalytic HOC showcased by Hayashi et al. in 2011 [146]. By slight modification of Hayashi's original conditions, the authors could successfully access 110 in 77% yield and 98% ee from 109 in a one‐pot [6+2] HOC and ketal hydrolysis procedure. Ultimately, this allowed for the first enantioselective synthesis of (‐)‐bipolarolide D in 1.2% yield over 13 steps.

SCHEME 38.

Intramolecular [6+2] cycloaddition in the total synthesis of (‐)‐bipolarolide D.

Dual catalytic α‐allylations have been utilized as a key step to introduce chiral information at an early stage in multiple total syntheses over the past decade [147, 148]. A recent example was presented by the group of Yang for the total synthesis of (‐)‐daphenylline (Scheme 39) [149]. Their total synthesis was initiated by the formation of chiral aldehyde 113 from propanal 111 and phenyl vinyl carbinol 112 following a modification of the Ir/aminocatalyst synergistic system developed by Carreira [86, 87, 88]. Aldehyde 113 was accessed in 75% yield, 6:1 d.r. and >99% ee after optimization of the acid additive. Access to this key intermediate enabled the enantioselective total synthesis of (‐)‐daphenylline in 14 steps.

SCHEME 39.

Ir‐catalyzed α‐allylation in the total synthesis of (‐)‐daphenylline.

Recently, the group of Burton developed an aminocatalytic enantioselective aza‐Michael/aldol cascade for the synthesis of dihydroquinolines 116 in 89% yield and greater than 98% ee (Scheme 40). The dihydroquinoline synthesis proved compatible with other substitution patterns of aromatic α‐ketoesters 115 and cinnamaldehyde derivatives 114 with high yields and excellent selectivity throughout the presented scope. This subsequently allowed for the total synthesis of sealutomicin C in 16 steps as the longest linear sequence [150]. An intramolecular cyclization of an aryllithium onto a γ‐lactone is featured as a second key step.

SCHEME 40.

Aza‐Michael/aldol cascade in the total synthesis of sealutomicin C.

Recently, Hayashi et al. accomplished a highly pot‐efficient total synthesis of (‐)‐quinine in 14% total yield utilizing a key multicomponent aminocatalytic step to build part of the core of the quinuclidine motif (Scheme 41) [151]. The first of five one‐pot procedures involves a three component Michael/aza‐Henry cascade catalyzed by C11. The multicomponent cascade reaction was initiated by the aminocatalytic Michael addition between the enamine generated from aldehyde 117 and nitroolefin 118 to form intermediate 119. Upon addition of imine precursor 120 and DBU to the same pot, the aza‐Henry/hemiaminalization cascade proceeded to form piperidine 121, which after elimination of the nitro group by DBU, generated tetrahydropyridine 122 in 66% yield and excellent stereoselectivity as the C2‐isomer is inconsequential since the hydroxy group is subsequently reductively removed. As the quinoline motif was installed late, Hayashi et al. also showed that installation of a bromine in the C2′‐position enabled access to multiple (‐)‐quinine derivatives.

SCHEME 41.

Multicomponent Michael/aza‐Henry cascade in the total synthesis of (‐)‐quinine.

In 2020, the group of Hayashi accomplished the seven step, one‐pot synthesis of Corey's lactone leveraging an aminocatalytic Michael/Michael cascade to introduce the stereochemical information (Scheme 42) [152]. This was achieved using acrylate 124 and α,β‐unsaturated aldehyde 123 to generate cyclopentanone 125 in the presence of ent‐C11 in the first step of the multi‐step one‐pot protocol. This enabled the synthesis of Corey's lactone in 50% overall yield as a single stereoisomer. Furthermore, the authors demonstrated that the Michael/Michael cascade to generate cyclopentanone motifs was also feasible for different α,β‐unsaturated aldehydes, including cinnamaldehyde derivatives.

SCHEME 42.

Michael/Michael cascade in the total synthesis of Corey's lactone.

The total synthesis of the unnatural isomer of quinine, (+)‐quinine, as well as (‐)‐9‐epi‐quinine, was accomplished by the group of Ishikawa (Scheme 43) [153]. Cornerstone to this was a formal aza‐[3+3] annulation catalyzed by only 0.5 mol% of C19 to trigger the annulation between α,β‐unsaturated aldehyde 126 and thiomalonamate 127. The resulting cyano Δ‐thiolactam 128 was afforded in high yield as a mixture of three diastereoisomers; however, treatment with MeOH and DBU afforded imidate 129 in 79% yield, 3:1 d.r. and 94% ee of each diastereoisomer. This ultimately enabled the synthesis of both (+)‐quinine and (‐)‐9‐epi‐quinine in 16% overall yield as a 1.1:1 mixture, although importantly, it was demonstrated that the two quinine isomers could efficiently be interconverted by a Mitsunobu reaction.

SCHEME 43.

Aza‐[3+3] annulation in the total synthesis of (+)‐quinine and (‐)‐9‐epi‐quinine.

Nicolaou et al. utilized a biomimetic intramolecular aminocatalytic oxa‐Michael reaction to diastereodivergently access highly functionalized dihydropyrans, which could further be hydrogenated to tetrahydropyrans, thereby proving pivotal in the total synthesis of thailanstatin A (Scheme 44) [154]. When dienal 130 was subjected to C1 dihydropyran 131 was accessed as a single diastereoisomer in 77% yield. Should ent‐C1 instead be utilized the C11‐epimer 11‐epi‐131 was afforded as a single diastereoisomer in 64% yield. Hydrogenation of dihydropyran 131 by Pd/C under H₂ atmosphere generated tetrahydropyran 132 in 54% over three steps. Replacing Pd/C with Ir(Py)(PCy₃)(COD)BARF, the C12‐epimer 12‐epi‐132 was accessed in 85% overall yield. Finally, thailanstatin A was obtained by a nine step longest linear sequence. Later, the group of Nicolaou demonstrated that this strategy could be applied to generate multiple analogous and assessed their antitumor potency against multiple cell lines [155].

SCHEME 44.

Intramolecular oxa‐Michael in the total synthesis of thailanstatin A.

The group of Hayashi applied C11 to introduce stereochemical information in the pot‐efficient total synthesis of estradiol methyl ether in 15% overall yield over 15 steps in only five reaction vessels (Scheme 45) [156]. The total synthesis was initiated by the aminocatalytic Michael/aldol cascade between α,β‐unsaturated aldehyde 133 and nitroalkane 134 to generate bicyclo[4.3.0]nonane 135 in 89%, >20:1 d.r. and >99% ee. It should be noted that this intermediate need not be isolated in the total synthesis of estradiol methyl ether and could be carried through a three step, one‐pot procedure to afford intermediate 136 in 78% yield. Furthermore, it was also demonstrated that the initial Michael/aldol cascade was general and could amend different cinnamaldehydes in high yield and with excellent stereochemical outcome.

SCHEME 45.

Michael/aldol cascade in the total synthesis of estradiol methyl ether.

7. Miscellaneous

Beyond the novel activation modes unlocked through the combination of diarylprolinol silyl ether catalysts with emerging technologies such as photo‐ and electrochemistry, their synergy with metal catalysis, their application in higher‐order cycloadditions, and their practical utility in enabling key steps of total syntheses, recent years have also experienced the continued application of classic aminocatalytic activation manifolds. Traditional activation modes, such as enamine, dienamine, trienamine, and iminium‐ion catalysis have remained fundamental for developing new enantioselective transformations—particularly within aminocatalyzed cycloaddition reactions—providing access to novel, chiral, cyclic chemotypes, as well as bio‐relevant polycyclic scaffolds [29]. These advances underscore how the diarylprolinol silyl ether family persists as an evergreen and powerful platform for expanding accessible three‐dimensional chemical space. In this chapter, we will highlight some recent and relevant contributions, providing an overview of how classical organocatalytic activation modes have enabled novel enantioselective cycloaddition or annulation reactivity, through unprecedented mechanistic pathways.

In 2016, a three‐component, one‐pot cascade process combining enamine and vinylogous iminium‐ion catalysis to enable a sequential IEDDA reaction between aldehydes 1, 1′ and oxadendralenes 137, catalyzed by C11 was unveiled (Scheme 46) [126]. This strategy furnished a series of optically active tetrahydroisochromenes 138 in moderate to good yields and invariably with full enantioselectivity, with the diastereoselectivity depending on whether aldehyde 1 was prochiral, and on the use of C11 vs. ent‐C11 in the second step.

SCHEME 46.

Top: Multicomponent, cascade between aldehydes 1, 1′ and dienal 137. Bottom: Eu‐catalyzed variant using vinyl ethers 139. fod = 6,6,7,7,8,8,8‐heptafluoro‐2,2‐dimethyl‐3,5‐octanedionate.

The transformation relies on dual activation of both reacting partners by two molecules of the same catalyst (Scheme 46). Activation of oxadendralene 137 by C11 generates a vinylogous iminium ion CXXV, which undergoes a regioselective 1,6‐addition with enamine I, formed from aldehyde 1 and a second molecule of C11. The resulting intermediate CXXVI engages in an intramolecular cyclization to form cyclic oxadendralenic intermediate CXXVII, which acts as the dienophile in a subsequent enamine‐mediated hetero‐IEDDA reaction. Use of ent‐ C11 in this second cycloaddition leads to an exo‐transition state via (E‐s‐trans) conformation of sterically demanding aldehydes, thereby enhancing diastereoselectivity. Within the same study, it was also demonstrated that intermediate CXXVII could be used in combination with Eu(fod)₂ as a Lewis acid to promote a hetero‐IEDDA reaction with vinyl ethers 139, affording tetrahydroisochromenes 140 bearing five contiguous stereocenters with excellent enantioselectivity.

A distinctive example at the interface of organic methodological and computational chemistry involving diarylprolinol silyl ether catalysis was presented in 2020 (Scheme 47). Here, the first stereoselective photochemical [1,3]‐sigmatropic silyl shift of an allylsilane was disclosed [157]. In this investigation an organocatalytic enantioselective cascade annulation between 3‐methylcrotonaldehyde 141 and oxadendralene 142, catalyzed by ent‐ C11, enabled the formation of a chiral enantiopure silyl‐o‐isotoluene 144 (Scheme 47). The reaction proceeds through a dual aminocatalytic activation, involving formation of a dienamine CXXIX and a rare cross‐iminium‐ion CXXX, followed by a stereoselective conjugate addition, intramolecular aldol cyclization, and dehydration to furnish Z‐s‐cis‐configured silyl‐o‐isotoluene 144. Subsequently, UV irradiation promoted an unprecedented photochemical [1,3]‐silyl shift, delivering enantioenriched benzylsilane 143 with only minimal erosion of stereochemical integrity. CASSCF, DFT, and TD‐DFT computational studies revealed that the photochemical rearrangement proceeds via photoexcitation to a singlet excited state, followed by ultrafast internal conversion through a silyl/allyl conical intersection (CI). The excited‐state surface becomes degenerate with the ground‐state surface in a product‐like geometry, directing the system toward formation of the [1,3]‐silyl‐shifted benzylsilane 143. Moreover, control experiments employing radical traps, triplet sensitizers, and triplet quenchers were consistent with a non‐radical, singlet excited‐state pathway governed by a conical intersection.

SCHEME 47.

Top: Photochemical [1,3]‐sigmatropic silyl shift of allylsilane 144. Bottom: Silyl/allyl conical intersection of 144.

In 2020, Zanardi et al. reported an aminocatalytic cross‐[4+2] cycloaddition between 6‐methyluracil‐5‐carbaldehydes 145 and α,β‐unsaturated aldehydes 21, enabling the enantioselective synthesis of dihydroquinazoline‐2,4‐diones 146 catalyzed by ent‐C11 (Scheme 48) [158]. A series of cycloadducts 146 were obtained in moderate to high yields with high enantioselectivity. Substituent variation at the N1‐ and N3‐positions of 145 was well tolerated.

SCHEME 48.

Top: [4+2] cycloaddition between 6‐methyluracil‐5‐carbaldehydes 145 and α,β‐unsaturated aldehydes 21. Bottom: Double [4+2] cycloaddition variant.

Mechanistic investigations and DFT calculations revealed a dual catalytic activation mode in which both reaction partners 6‐methyluracil‐5‐carbaldehydes 145 and α,β‐unsaturated aldehydes 21 are simultaneously activated by two molecules of ent‐ C11, forming the corresponding uracil‐based dienamine ortho‐quinodimethane CXXXV and iminium ion XXIX, respectively (Scheme 48). Dihydroquinazoline‐2,4‐dione 146 arose from a step‐wise, eliminative [4+2] cycloaddition initiated by a vinylogous Michael addition between dienamine CXXXV and iminium ion XXIX, generating CXXXVI. This intermediate undergoes an intramolecular cyclization to furnish bicyclic species CXXXVII, which readily evolves into the iminium ion CXXXVIII via elimination of one catalyst molecule. Subsequent hydrolysis releases the second equivalent of ent‐ C11 to furnish 146. The methodology was further extended to the synthesis of uracil‐fused bicyclo[2.2.2]octanes 147. When the reaction was performed using an excess of 21 in the presence of benzoic acid, a double [4+2] cycloaddition took place, affording enantiopure 147. Under these conditions, isomerization of intermediate CXXXVIII into the corresponding trienamine ortho‐quinodimethane CXXXIX is favored, enabling a subsequent cycloaddition with a second molecule of chiral iminium ion XXIX, thereby leading to the tricyclic framework within 147 (Scheme 48, bottom).

SCHEME 49.

Multicomponent [4+2] cycloaddition between α,β‐unsaturated aldehydes 148 and acetals 149.

Beyond this example, the use of diarylprolinol silyl ether catalysts has recently enabled the stereoselective synthesis of further novel polycyclic chemotypes exploiting heterocyclic ortho‐quinodimethane intermediates in [4+2]‐cycloadditions [159, 160, 161].

Recently, we reported an organocatalytic asymmetric multicomponent cascade based on dienamine catalysis, integrating a [4+2] cycloaddition, a nucleophilic addition, and a ring‐opening event into a single transformation. The unprecedented application of isobenzopyrylium ions CXLI in asymmetric catalysis, in combination with α,β‐unsaturated aldehydes 148 and catalyst C6 in the presence of excess water, enabled access to chiral tetrahydronaphthols 150 bearing four contiguous stereocenters (Scheme 49) [162]. The cycloadducts 150 were obtained in good to high yields, with high diastereoselectivity, and excellent enantioselectivity. The reaction exhibited a broad substrate scope, tolerating a range of β‐alkyl‐ and β‐aryl‐substituted 148, as well as aryl‐ and heteroaryl‐substituted acetals 149. Interestingly, selected compounds were evaluated in U‐2OS cancer cells, where they induced clear morphological changes. Mechanistic insights were obtained through a combination of oxygen‐18‐labeling studies and DFT calculations. These studies supported a scenario in which intermediate CXLI is generated via expulsion of the isopropoxide leaving group from 149. The electrophilic species CXLI is then intercepted at the γ‐position of dienamine CXL, formed from C6 and 148, forging the initial C─C bond and delivering intermediate CXLII. Subsequent ring closure affords oxonium ion CXLIII, which undergoes nucleophilic addition of water at the carbonyl to generate protonated hemiacetal CXLIV. A sequence of proton transfer, C─O bond cleavage, and hydrolysis ultimately furnishes product 150, while regenerating catalyst C6.

In 2022, Mukherjee et al. reported the first application of diarylprolinol silyl ether catalysis to the de novo construction of chiral arenes through a desymmetrizing oxidative [4+2] cycloaddition. The protocol, based on catalyst C20, enabled the reaction of α,β‐unsaturated aldehydes 151 with meso‐cyclohexenediones 152 which, under aerobic conditions, provided access to enantioenriched, centrally chiral unfunctionalized arenes 153 (Scheme 50) [163]. The transformation proved remarkably general with respect to substitution patterns on both coupling partners. Substituents at the α‐, β‐, or γ‐positions of 151, as well as cyclic analogous, were all suitable substrates, and meso‐quinones 152 fused to rings of different sizes consistently delivered the corresponding 153 with high enantioselectivity. The versatility of the method allowed the synthesis of a range of fused polycyclic architectures, which were shown to be amenable to further synthetic elaboration. The transformation proceeds through a stereoselective, endo‐selective [4+2] cycloaddition between dienamine CXLV and meso‐cyclohexenedione 152, affording intermediate CXLVI, which undergoes facile elimination of catalyst C20. The resulting cyclohexadiene CXLVII is then converted, via aerobic and stereoablative oxidation, into the enantioenriched arene 153.

SCHEME 50.

Desymmetrizing oxidative [4+2] cycloaddition between α,β‐unsaturated aldehydes 151 and meso‐cyclohexenediones 152.

Notably, the same group later extended this strategic concept by employing alkoxy‐directed dienamine catalysis with the same catalyst C20, enabling the stereoselective synthesis of benzo‐[3]‐ladderanol [164].

A notable example exploiting trienamine catalysis for the construction of chiral polycyclic architectures was reported in 2021 [165]. This work introduced the strategic integration of the halogen or pseudo‐halogen effect—that is, the presence of a halogen or pseudo‐halogen substituent in one of the cycloaddition partners to enhance endo‐selectivity in the cycloaddition—to promote a diarylprolinol silyl ether–catalyzed Diels–Alder reaction. This approach enabled the stereoselective synthesis of norcarenes 156 (Scheme 51). A panel of dienals 154 and electron‐poor α‐(pseudo‐)halogenated enones 155 were successfully engaged in the presence of catalyst C20. DFT calculations unveiled the mechanism of the transformation, which is initiated by condensation of C20 with 154 to generate trienamine CXLVIII, which undergoes a step‐wise and highly endo‐selective cycloaddition with 155 to afford enamine intermediate CXLIX. This species is involved in a cascade sequence by an intramolecular nucleophilic substitution at the leaving group (OTf, or Br), thereby forging the cyclopropane ring embedded in the final norcarene adduct 156. Using this protocol, a range of norcarene derivatives were isolated in generally high yields and excellent enantioselectivity, invariably as single diastereoisomers. Notably, modulation of the ring size of the pseudo‐halogenated enone, possible benzofusion, and the use of diverse acyclic and cyclic trienals—including heteroatom‐tethered variants—enabled access to a collection of previously unexplored, enantioenriched polycyclic scaffolds.

SCHEME 51.

[4+2] Cyloaddition/S_N2 cascade between dienals 154 and α‐(pseudo‐)halogenated enones 155.

Turning to LUMO‐lowering iminium‐ion catalysis applied to the enantioselective synthesis of complex polycyclic architectures, a notable example was recently reported by Hayashi et al. In this study, the authors disclosed a diarylprolinol silyl ether–catalyzed domino reaction between α,β‐unsaturated aldehydes 21 and 2,2‐(cyclohexane‐1,4‐diylidene)dimalononitrile or 2‐(4‐oxocyclohexylidene)malononitrile pronucleophiles 157, catalyzed by C19 (Scheme 52) [166]. This transformation represented the first enantioselective entry to noradamantane‐based scaffolds 158, which were obtained with excellent enantioselectivity and moderate to good diastereocontrol (Scheme 52). The protocol proved broadly applicable to a variety of substituted 21. The domino reaction is initiated by a Michael addition of 157 to iminium ion XXIX, in situ generated from 21 and C19, furnishing syn‐CL. Due to the strong electron‐withdrawing character of the methylene malononitrile moiety, this intermediate undergoes facile epimerization, establishing an equilibrium between syn‐CL and anti‐CL. The anti‐diastereoisomer is the only one geometrically allowed to undergo a subsequent intramolecular cyclization—either a Michael addition (when X = C(CN)₂) or an aldol reaction (when X = O)—to generate iminium ion CLI. Hydrolysis of this intermediate provides aldehyde CLII, whose conformation enables a final intramolecular addition to the aldehyde carbonyl group, ultimately forging the enantioenriched noradamantane core embedded in 158.

SCHEME 52.

Michael/epimerization/Michael (or aldol)/1,2‐addition between α,β‐unsaturated aldehydes 21 and alkylidene malononitriles 157.

Diarylprolinol silyl ether catalysis has also recently found application in the construction of highly strained spirocyclic architectures. In 2020, Xu et al. reported a general organocatalytic enantioselective strategy for the synthesis of spiro[2,3]hexane frameworks 160 from α,β‐unsaturated aldehydes 21 and methylenecyclopropanes 159 (Scheme 53) [167]. A key element of this approach was the use of an electron‐deficient, gem‐difluoro‐substituted catalyst C6, which condenses with 21 to generate iminium ion XXIX. Subsequently, Michael addition of 159 to the β‐position of iminium ion XXIX affords cationic enamine intermediate CLIII. This species undergoes an enamine‐mediated ring‐expansion rearrangement, in which opening of the cyclopropane ring leads to formation of a four‐membered ring, while concomitantly generating a new cyclopropane moiety within iminium ion CLIV. Hydrolysis of this intermediate regenerates catalyst C6 and delivers the enantioenriched spiro[2,3]hexane product 160.

SCHEME 53.

Michael addition/ring expansion/cyclization cascade between α,β‐unsaturated aldehydes 21 and methylenecyclopropanes 159.

DFT calculations showed that the electrophilic addition of enamine to cyclopropyl cation and rearrangement to the four‐membered ring within CLIII occur in a concerted fashion. Moreover, NMR characterization of iminium ions derived from different diarylprolinol silyl ether catalysts revealed that the iminium ion formed from C6 was more electrophilic, accounting for the reactivity observed. Regarding substrate scope, a range of α,β‐unsaturated aldehydes 21 with various electronic and steric properties, as well as diaryl‐substituted methylenecyclopropanes 159, were well tolerated. Notably, the methodology could also be extended to access a novel chiral dispiro[2.1.5⁵.1³]undecane motif in high enantioselectivity, albeit in low yield.

Some further diarylprolinol silyl ether‐catalyzed rearrangements have been recently reported by the group of Christmann [168] and Vicario [169].

8. Conclusion and Outlooks

A distinctive feature of diarylprolinol silyl ethers is the leading role they have played in shaping the evolution of asymmetric aminocatalysis over the past two decades. In this review, we have presented recent advances to highlight new directions in the use of this catalytic platform within the landscape of modern asymmetric organocatalysis.

We have described how classic aminocatalytic activation modes have been combined with photochemistry, thereby unveiling novel activation mode patterns, where the generation of diarylprolinol silyl ether‐tethered intermediates allow for the challenging stereochemical control over open‐shell one‐electron reactivity. Furthermore, recent applications in electrochemistry have been summarized, providing insight into an emerging field that we expect will flourish in the future. The long‐standing synergy with metal catalysis is continuously expanding. Selected examples have been provided, in which various metal‐activated intermediates facilitate novel reactions merged with classic organocatalytic intermediates. We have shown representative examples of enantioselective higher‐order cycloadditions enabled using diarylprolinol silyl ether catalysts to access enantioenriched, complex polycyclic molecular architectures in few synthetic steps. We further described how the maturity of this catalytic platform has manifested in its use within key steps of total synthesis of natural products. Finally, relevant examples employing classical organocatalytic intermediates in novel cycloaddition reactions through unprecedented mechanisms, enabling enantioselective access to new cyclic chemotypes, have been illustrated.

Overall, these reports exemplify the privileged role that diarylprolinol silyl ethers have played over the last decade in disclosing new concepts that have expanded the scope of organocatalysis beyond classical activation modes. We expect further advances in the use of this catalyst class, particularly through the expansion of classical concepts enabled by their integration with emerging technologies and by the creation of increasing molecular complexity in a stereoselective fashion: A new chapter starts now.

Conflicts of Interest

The authors declare no conflicts of interest.

Biographies

Enrico Marcantonio: completed his M.Sc. at the University of Bologna (Italy). Shortly after, he joined the University of Parma (Italy), where he earned his Ph.D. title (Doctor Europaeus degree) in 2023 under the supervision of Prof. Franca Zanardi. In 2021, he spent a research period in the group of Prof. Paolo Melchiorre at ICIQ (Spain). He is currently a postdoctoral researcher with Prof. Karl Anker Jørgensen at Aarhus University (Denmark). His research focuses on the investigation of new enantioselective organocatalytic transformations.

René Slot Bitsch: received his M.Sc. at Aarhus University (Denmark). In 2025 he received his Ph.D. from Aarhus University (Denmark) under the supervision of Prof. Karl Anker Jørgensen. He is currently a postdoctoral researcher in the same group. His research interests are the development and application of new asymmetric organocatalytic transformations.

Karl Anker Jørgensen: received his Ph.D. from Aarhus University in 1984. He was a postdoctoral researcher with Roald Hoffmann at Cornell University (1985). In 1985, he became Assistant Professor at Aarhus University, and in 1992, he was promoted to Professor. His research interests are the development, understanding, and application of asymmetric catalysis, mainly in the field of organocatalysis.

Marcantonio E., Bitsch R. S., and Jørgensen K. A., Angewandte Chemie International Edition. 65, no. 11 (2026): e26146, 10.1002/anie.202526146

Data Availability Statement

Data sharing is not applicable to this article as no new data were created or analyzed in this study.