From Three‐ to Six‐Membered Heterocycles Bearing a Quaternary Stereocenter: an Asymmetric Organocatalytic Approach

The development of procedures useful to form quaternary stereocenters stands out as a highly challenging task in asymmetric synthesis. With the arrival of organocatalysis, different activation strategies became available to pursue this intriguing target, thus leading to notable advancements of the area. In this account, our achievements, spanning over a decade, on asymmetric methodologies to access novel three‐, five‐, six‐membered heterocycles, including spiro compounds bearing quaternary stereocenters, will be highlighted. The Michael addition reaction has been often exploited to trigger cascade reactions, using organocatalysts mostly derived from Cinchona alkaloids, and operating under non‐covalent activation of the reagents. Further manipulations of the enantioenriched heterocycles, attested them as useful compounds to prepare functionalized building blocks.


Introduction
In the area of asymmetric catalysis, the formation of quaternary carbon stereocenters represents the most challenging goal to achieve both in acyclic or cyclic molecules and of increasing difficulty when targeting spirocyclic compounds. [1] Indeed, when developing a new asymmetric catalytic method to install tertiary stereocenters, the final experiments to assess the "higher and added" value of the protocol focus on forging a quaternary one with the same efficiency.
The great interest in the development of new methodologies able to address this issue is related to the significant presence of quaternary carbon stereocenters in several natural products, often having fascinating architectures and different biological activities. [2] Among them, polycyclic alkaloids, terpenes and polyketides can be found, exemplified by the diterpene (À )-totaradiol that exhibits antimicrobial properties, [3] thiolactomycin isolated from Nocardia sp. which shows antibacterial and antiparasitical activities. [4] Unsurprisingly, Nature forges charming molecules of high complexity, such as the antidepressant and anti-cancer (+)-hyperforin, [5] embedding multiple quaternary carbon stereocenters (Figure 1).
Drugs of everyday life such as the anesthetic (R)-ketamine [6] or conversely the orphan drug spirocyclic ranirestat, [7] used for the treatment of diabetic neuropathy, contain quaternary stereocenters, whose absolute configuration is relevant for the bioactivity (Figure 1). [8] Moreover, the sterically congested nature of drugs, containing quaternary stereocenters, positively affects their metabolic stability and selectivity, which are parameters important for the success in clinical trials. [9] Most of the natural products, agrochemicals or pharmaceutically active compounds embed in their chiral structure N-, S-and O-based heterocyclic fragments of different size. [10] Hence, over the years, organic chemists spent intensive efforts to devising new asymmetric methods to prepare them, historically based on metal catalysis and later widened by organocatalysis.
The latter tool offers different possibilities to activate the reagents [11] and it demonstrated to be a suitable platform to easily accomplish, under simple conditions, cascade reactions for the stereoselective synthesis of a large number of heterocyclic compounds. [12] The covalent activation of aliphatic or α,β-unsaturated aldehydes and ketones, via covalent enamine or iminium ion formation with the amine based catalysts, the so called aminocatalysis, took the stage in the last decades, showing high versatility and most of all, notable level of stereocontrol in the αand β-functionalization of aldehydes and ketones. [13] Non-covalent activation of the reagents, does not rely on well-structured intermediates which enable to forsee the stereochemical outcome of the process. A set of interactions such as hydrogen bonding, ionic, dipolar, π-π, CH-π interactions and Van der Waals forces are involved in the catalysis. [11] Although in this case results are not easily predictable, countless examples have demonstrated up to now the fruitful cooperation of the H-bonding donor groups (thiourea, urea, squaramide, hydroxyl) and the basic tertiary and secondary amine moieties, in the activation of the electrophile and nucleophile. [14] As part of our research interests in asymmetric organocatalysis, which dates back to 2005, [15] more recently we embarked on the development of new methodologies to prepare heterocyclic and acyclic compounds bearing quaternary stereocenters. For an organic chemist working in asymmetric catalysis, this topic has always been of great fascination and an exciting synthetic challenge where trying your hand at making a contribution.
Specifically, simple organocatalysts derived from Cinchona alkaloids or readily available chiral diamines were synthesized and proved to be successful in different processes. Being available a vast space open for investigation of basic organic reactions to use in cascade sequences, we envisaged the construction of three-, five-and six-membered O-, N-and sulfur-containing heterocycles, taking advantage of the simultaneous non-covalent activation of both reagents by small chiral organic molecules. The Michael reaction has been often chosen as key and versatile transformation to construct the quaternary stereocenter and as a first step to trigger the heterocycle assembly under mild conditions. Our efforts to elucidate the stereochemical outcome of the processes and selected elaborations of the products to synthesize functionalised building blocks will be also highlighted.
In this account, the results achieved over the last decade will be illustrated, subdividing the manuscript according to the heterocycle ring size, with the exception of spirocyclic compounds grouped under the same section.

Epoxides and Aziridines
The asymmetric epoxidation of alkenes is considered one of the fundamental processes in academia, where to address the efficiency of new catalytic systems, as well as the most straightforward reaction to prepare oxiranes. [16] Over the decades, enantioenriched epoxides have proved to be highly versatile intermediates to access, after ring-opening, a plethora of valuable compounds and building blocks in a stereodefined manner, including ligands, natural products, drugs and agrochemicals. [17] The repertoire of the procedures has now become rich and the relevance of asymmetric epoxidation of alkenes has been one of the reactions recognized in 2001 Nobel prize assigned to Sharpless. However, despite the impressive advances in this area, further studies are needed, because of the relatively limited general methods available for the asymmetric epoxidation of alkenes with different substitution patterns and E/Z-geometry.
The preparation of terminal epoxides bearing a quaternary stereocenter still represents a formidable challenge in this regard. [18] Terminal of epoxides are likely among the most useful for synthetic applications, thanks to the ring-opening process occurring with complete regioselectivity. In consideration of the lack of procedures for the enantioselective epoxidation of terminal electron-poor alkenes, having two electron-withdrawing groups, we speculated that readily available Cinchona alkaloids derived ureas or thioureas would have been suitable promoter to catalyze this process (Scheme 1). [19] We capitalized on the knowledge that this popular class of bifunctional organocatalysts had been successfully used in Michael reactions for enantioselective carbon-carbon bond forming reaction with 1,3-dicarbonyl compounds, such as malonates in the pivotal work reported by Takemoto. [20] However, when we started this investigation, their use as organocatalysts in asymmetric oxidations was unknown. We were encouraged to pursue this ambitious goal by the results previously achieved in the Weitz-Scheffer type enantioselective epoxidation of α,β-unsaturated ketones and derivatives thereof catalysed by α,α'-diaryl prolinols. [15,21] Alessandra Lattanzi graduated in chemistry and earned her PhD from "La Sapienza" University (Rome). She has been visiting scientist in the groups of Prof. V. K. Aggarwal (Sheffield, 1999(Sheffield, -2000 and Dr. N. E. Leadbeater (London, 2001). After working as Assistant Professor at University of Salerno, in 2005, she became Associate Professor and in 2019 she was appointed Full Professor of Organic Chemistry. Her research interests include asymmetric organocatalysis focused on the development of green methodologies to access synthetic intermediates and bioactive heterocyclic compounds through cascade routes, the development of stereoselective metal-and organocatalysed oxidations and molecular chirality.
Investigations on this reaction supported that they acted as general acid-base catalysts, rather than via covalent aminocatalysis. [22] The quinine-derived thiourea was thought to be able to deprotonate the alkyl hydroperoxide to the corresponding peroxyanion, useful to initiate the oxa-Michael addition on the highly reactive acceptor. Then, prochiral peroxyenolate, hydrogen-bonded by the thiourea group in a chiral environment, would have given rise to the epoxide in enantiomerically enriched form through preferential ringclosure.
When working at room temperature with 5 mol% loading of the quinine-derived thiourea (eQNT) or in some examples hydroquinine-derived thiourea, α-aroyl and acyl N-substituted acrylamides 1 proved to be competent alkenes to rapidly afford the epoxides 2 in good to excellent yields and ee values. α-Benzoyl acrylates and carbamoyl acrylates, although being less reactive, afforded the epoxides with good enantioselectivity. However, the presence of a tertiary amide group in the alkene, almost suppressed the conversion. Finally, the 2-alkylidene-1,3-dione proved to be a poor substrate for the reaction. The data showed the crucial role exerted by the secondary amide portion in preorganization and activation of the reagent, likely via intramolecular H-bonding of the NÀ H bond with the vicinal carbonyl group. Remarkably, competitive polymerization of the highly reactive Michael acceptor was not detected, thanks to the mild conditions adopted. This represents a critical point for the outcome of the reaction, taking into account the readiness of these alkenes to polymerize, a process at times observed during their purification. Synthetically useful building blocks have been conveniently prepared through one-pot sequential synthesis of highly functionalized hydroxy thioether, thanks to the regiospecific ring-opening of the epoxide intermediate. The versatility of this class of oxiranes was also demonstrated in a stepwise process from the enantioenriched epoxide to satisfactorily yield the β-amino-α-hydroxy-acid derivative. The latter class of compounds are recurrent motives present in a large variety of natural products such as in the well-known natural-source cancer drug Taxol®. [23] Concurrently, we extended this approach to the enantioselective synthesis of challenging terminal aziridines, bearing a quaternary stereocenter. [24] In this setting, an enantioselective aza-Michael initiated ring-closure reaction of α-acyl acrylates with a N-tosyloxy tert-butyl carbamate was found to be promoted by 20 mol% of commercially available Takemoto's catalyst (Scheme 2).
In order to remove the acid by-product of the ring-closure reaction, K 2 CO 3 was added as the most effective scavenger. A variety of α-acyl acrylates was converted into the final N-Bocprotected aziridines 3 in generally high yield and good enantioselectivity.

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Enantioenriched aziridines are valuable intermediates to synthesize nonproteinogenic α,α-disubstituted α-amino acid esters, important scaffolds in drug discovery and bioorganic chemistry. [25] An efficient reaction carried out on a model compound with TBAF, enabled the preparation of the corresponding protecting group free aziridine, en-route to the functionalised α-amino acid ester.
In the asymmetric epoxidation of electron-poor alkenes a great focus has been paid on E-chalcones and more generally α,β-unsaturated ketones, likely recognized as typical substrates to assess the performance of novel catalytic systems. For the nucleophilic epoxidation of alkenes bearing two electronwithdrawing groups and α,β-unsaturated esters a limited number of stereoselective methodologies has been reported, especially for the latter type, which behave as scarcely activated Michael acceptors. [26] However, the corresponding epoxides, known as glycidic esters, have found interesting applications as building blocks upon ring-opening reactions, in drug and natural products synthesis. [27] In 2017, we developed a first asymmetric epoxidation of trisubstituted E-α-cyano α,β-unsaturated esters 4, using a newly synthesized multifunctional Cinchona alkaloid-derived thiourea, bearing a chiral diamine portion (Scheme 3). [28] Surprisingly, simple quinine or quinidine derived thioureas, useful for the epoxidation reported in Scheme 1, proved to be only modest promoters. With a view to improve the process, a panel of catalysts embedding additional chiral units, including readily available β-aminoalcohols or β-diamines, were synthesized. Indeed, a sterically hindered chiral portion, installed in the quinidine derived scaffold and the presence of a primary amino group able to provide additional H-bonding interactions with the reagents, greatly helped to achieve satisfactory stereocontrol. Different aryl substituted epoxides 5 were isolated in excellent yield, complete diastereoselectivity and fairly good ee values. Interestingly, the ortho-substituted epoxide was formed with almost comparable enantioselectivity and aliphatic substituents were also tolerated. The presence of electron-withdrawing groups on epoxides 5 offered the opportunity of interesting manipulations. A model enantioenriched epoxide was subjected to a variety of common functional group transformations to yield with conserved enantiopurity, difficult to prepare by alternative methods

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building blocks, including optically active electron-poor epoxy alcohol, diol ester or amide and terminal epoxy ester. The latter has been used as key compound for the synthesis of Bicalutamide-like molecules, which showed activity toward prostate cancer cell lines. [29] Although a DFT study was not performed, the synthesis and application of multifunctionalized Cinchona alkaloid-derived thioureas provided helpful hints on the impact of either matching and mismatching effects and the nature of the H-bonding group present in the chiral βamino alcohol or β-diamine backbone inserted. Unexpectedly, the NH 2 group showed to be of crucial importance with respect to a typical OH group in tuning the enantioselectivity. This result might be ascribed to a better engagement of the NH 2 moiety in establishing H-bonding network with the EWG groups present in the alkene, favouring a well-organized transition state.

Tetrahydrothiophenes
The development of asymmetric organocatalysis fostered a great expansion of cascade reactions, which are well-suited for the synthesis of cyclic and heterocyclic compounds endowed with multiple stereocenters. Indeed, we have assisted to an explosion of one-pot stereoselective processes by coupling key reactions for carbon-carbon and carbon-heteroatom bond formations. [30] Cascade processes attracted a lot of attention in consideration of the great advantages over the stepwise synthesis in terms of being cost and time effective as well as more environmentally sustainable. Moreover, excellent diastereo-and enantiocontrol has been generally observed in the installation of multiple chiral centers. In this respect, spectacular stereocontrol has been observed in the final cyclic compounds even when installing up to six stereocenters. [31] Among the five-membered rings, optically pure tetrahydrothiophenes constitute the structural core encountered in vital molecules such as biotin, or important motives in medicinal chemistry, building blocks, ligands and organocatalysts. [32] One of the straightforward routes to prepare tetrahydrothiophenes includes a cascade coupling of two Michael reactions using a 4-mercapto-2-butenoate and a proper electron-poor alkene. At the outset of this study, a few organocatalytic reports based on this approach included Eenals [33] and E-nitroalkenes [34] as the acceptors, which provided the tetrahydrothiophene heterocycles with tertiary stereocenters.
We envisioned that stereodefined trisubstituted electronpoor alkenes could have been suitable acceptors to install one all-carbon quaternary sterocenter (Scheme 4). [35] Readily available E-α-cyano-α,β-unsaturated ketones 6 demonstrated to be successful Michael acceptor for the double Michael cascade process with E-tert-butyl 4-mercapto-2butenoate 7 catalysed at room temperature by a simple amino thiourea, easily synthesized by our group from a commercially available diamine. The diastereoselectivity was generally satisfactory, although somewhat dependent on the substitution pattern of the starting Michael acceptor. However, the major diastereoisomer of the tetrahydrothiophenes was recovered with excellent ee values.
The cascade reaction proved to be intriguing with respect to the elucidation of the stereochemical outcome. We demonstrated that the stereoselectivity was completely regulated by a dynamic kinetic resolution (DKR), occurring via a retro-sulfa Michael/sulfa-Michael/Michael process. When the racemic mixture of a diastereoisomeric adduct 9 (dr 1/1) was treated under the usual conditions with the organocatalyst, the heterocycle was obtained with comparable diastereoisomeric ratio and 98 % ee. A one-pot synthesis, starting directly from commercially available reagents, conveniently yielded the heterocyclic compound with only slightly reduced stereoselectivity.

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large range of biological activities. [36] Specifically, paraconic acids, bearing a carboxylic acid moiety at the β-position, act as a relevant class of heterocycles endowed with antitumor and antibiotic activities. [37] In this respect, few asymmetric routes suitable to install a quaternary stereocenter at β-position have been developed in stepwise manner, likely due to the challenging control of the stereocenter position, located far from more easily controllable αand γ-positions.
In 2014, we conceived a straightforward organocatalytic aldol/lactonization cascade sequence to access β,β-disubstituted γ-butyrolactones 11 from acylated succinic esters 10 and formaldehyde (Scheme 5). [38] In the designed plan, the first aldol reaction, where the quaternary stereocenter is installed, represents a significant challenge, given the highly reactive nature and symmetric structure of formaldehyde as an electrophile. Indeed, efforts were required to obtain modified Cinchona alkaloid amines, which served to prepare the bifunctional organocatalyst and the optimization of the reaction conditions. Finally, a dihydroquinine derived squaramide catalysed the process at only 3 mol% loading under mild conditions in the presence of additives. A different array of substitution pattern on the phenyl ring of the aroyl residue and heteroaromatic moiety were tolerated, achieving the formation of the paraconic acid Scheme 6. Diastereodivergent and enantioselective epoxidation of unsaturated pyrazolones catalysed by amine-derived thioureas.

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derivatives in high yields and good ee values (up to 88 % ee).
The ortho-substitution proved to be more problematic and a decreased level of enantioncontrol was observed. The sequence has been also applied for the synthesis of γ-butyrolactones bearing alkyl groups. This class of optically enriched paraconic acid esters could be transformed, via a two-step process, in difficult to access β-(hydroxyalkyl)-γ-butyrolactones, bearing contiguous tertiary and quaternary stereocenters with fairly good diastereoisomeric ratio, while maintaining the enantioselectivity.

Spiro Heterocycles
Spiro heterocycles are well-represented motifs in nature, often encountered in drug development. [39] Their skeletal rigidity, dictated by two rings connected by one carbon atom, provides them with peculiar properties such as conformational restrictions, which can affect the rich variety of biological activities showed by these compounds. Moreover, they have been applied in asymmetric catalysis either as ligands or organic promoters. [40] Among them, spiroepoxides displayed important biological activities, such as the angiogenesis inhibitor luminacin D [41] and analogs or the antimicrobial natural product fumagillin. [42] The stereoselective routes to prepare spiro-oxiranes are limited and the asymmetric epoxidation of suitable alkenes can serve as one of the most straightforward and useful transformation to access these compounds.
Pyrazolones are often embedded as substructure of many biologically active compounds, including in spiro heterocyclic compounds. [43] Surprisingly, before we started our investigation, only protocols for the racemic synthesis of spiropyrazolone epoxides were present in the literature. Interestingly, from the (Z)-α,β-unsaturated pyrazolones when using the NaOH/ H 2 O 2 system, the trans-spiroepoxides were prevalently obtained. [44] These data suggested that the diastereocontrol of the Weitz-Scheffer epoxidation, at the ring-closure step of the peroxy enolate intermediate, could have been modulated by the action of a bifunctional organocatalyst. Consequently, we envisaged an attracting possibility to develop organocatalytic systems able to provide both diastereoisomers of the spiroepoxides in enantioenriched form.
In 2017, we succeded in developing a diastereodivergent and enantioselective epoxidation by using two readily available organocatalysts, starting from (Z)-α,β-unsaturated pyrazolones 12, working under different reaction conditions (Scheme 6). [45] Acceptable trans-diastereoselectivity for the spiroepoxides was observed, when using 10 mol% of the 1,2-di-1-naphthyl amino-derived thiourea, synthesized by our group, in toluene at À 20°C. The oxiranes 13 were efficiently obtained in high yields and ee values, irrespective of the substitution pattern of the phenyl moiety or the presence of heteroaromatic groups, with the exception of the ortho-substitued epoxide. Satisfactory results have been achieved when the R 2 group was replaced with different alkyl moieties.
To prepare the cis-spiroepoxides 14, the quinidine-derived thiourea was selected as the best catalyst to perform the reaction in trifluoromethyl toluene at room temperature. The diastereoselectivity generally exceeded the 80/20 ratio and the products 14 were recovered in high yield and excellent enantioselectivity. A preliminary investigation was carried out on highly challenging and less reactive symmetrically β,β'substituted alkylidene pyrazolone, whose final epoxide bears

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two vicinal quaternary stereocenters. The reaction performed at À 20°C delivered the spiroepoxide 15 in good yield and an encouraging ee value. It is useful to compare this data with the epoxidation reported in Scheme 1. Similarly to that case, a prochiral peroxyenolate was involved in the ring-closure step, where the face-selectivity would regulate the enantiocontrol of process at the spiro (α)-carbon. Accordingly, further improvement of the asymmetric induction represents here a hard task, involving a fine tuning of catalyst's nature and reaction conditions. Only rare examples of highly enantioselective Weitz-Scheffer epoxidations to oxiranes bearing a β-quaternary stereocenter have been reported, as an indication of a similarly highly challenging process. [46] The DFT study of the process showed the crucial role played by the secondary amine moiety of the 1,2-di-1-naphthyl amino-derived thiourea. The NÀ H bond served to establish additional H-bonding interaction, beside the ones provided by the thiourea group with the carbonyl oxygen of the alkene, thus assuring a well-organized transition state. The oxa-Michael reaction, was found to be the enantioselectivity and rate-determining step. A relatively low energetic barrier was calculated for the rotation about the CÀ C-CÀ O dihedral angle of the firstly formed peroxyenolate, to give a more energetically The good ability of the α,β-unsaturated pyrazolones 12 to serve as Michael acceptors, prompted us to investigate a double cascade sulfa-Michael-Michael organocatalyzed process using 4-mercapto-2-butenoates, likewise the one illustrated in Scheme 4. [47] The designed cascade sequence would have yielded a library of novel hybrid spirocyclic scaffolds, namely spiro[pyrazolone-4,3'-tetrahydrothiophenes], incorporating the important bioactive pyrazolone and tetrahydrothiophene units (Scheme 7).
The targeted spiro compounds 16, bearing three contiguous stereocenters, one being an all-carbon quaternary, have been prepared using the same amino thiourea catalyst reported in Scheme 4, working at room temperature in Et 2 O. Fairly good level of diastereoselectivity and ee values for the major diastereoisomer of the spirocyclic product were generally observed.
We proposed a catalytic cycle for the cascade process, where the bifunctional organocatalyst would easily deprotonate the 4-mercapto-2-butenoate, whereas the α,β-unsaturated pyrazolone would be hydrogen-bonding engaged with the thiourea group to form a ternary pre-reactive complex. Then, the thiolate would attack the si-face of the Michael acceptor to give the (S)-configured adduct. The adduct enolate engaged in a network of H-bonding interactions with the organocatalyst would preferentially attack the re-face of the enoate to afford the (5R, 6S, 9R)-configured product.
In 2019, we further extended the investigation on cascade reactions with a view to construct new hydrid spiro heterocyclic compounds incorporating the pyrazolone framework and a six-membered ring architecture. We became interested in this target, due to the relevant place this class of spiroheterocycles occupies in medicinal chemistry. [48] Among the different routes previously developed to prepare spirocyclic cyclohexane-pyrazolone derivatives, we envisioned a strategy based on vinylogous Michael/cyclization cascade reaction of α,β-unsaturated pyrazolones with α,α-dicyanoalkylidenes, where an all-carbon quaternary spirocenter could have been installed (Scheme 8). The latter have been scarcely used in asymmetric cascade reactions to prepare spirocyclic compounds of different nature. [49] However, in the examples reported, compounds of type 19 were usually obtained, which are the tautomers of firstly formed imines 18.
The optimization stage allowed us to select Takemoto's catalyst as the most efficient promoter to work at room temperature. When using 2-(3,4-dihydronaphthalen-1(2H)ylidene) malononitrile, high conversion to the unexpected pyrazolone fused spirocyclohexenimines with poor diastereocontrol was observed, although both diastereoisomers proved to be highly enantioenriched.
Interestingly, α,α-dicyanoalkylidene derived from acyclic 2naphthyl methyl ketone afforded the corresponding pyrazolone fused spirocyclohexenimine with excellent diastereocontrol and ee value. Again, when using a branched α,α-dicyanoalkylidene derived from 1,2-diphenylethan-1-one, a poor diastereocontrol was detected, with the diastereoisomeric spirocyclohexenimines showing 60 % ee and 94 % ee. After demonstrating that the process can be scaled up, in the hydrolytic elaboration of model enantioenriched 18 a and 18 a' products, a different outcome was observed. Interestingly, for the generally most prevalent diastereoisomer 18 a product 20, bearing the free carbonyl compound was obtained, whereas a tautomerization to product 20' occurred, when treating compound 18 a' under the same conditions. Compounds of type 20 are difficult to access intermediates [50] and structurally resemble polycyclic βoxoalkenenitriles, which displayed strong inhibition of enzyme 5α-reductase. [51] At the end of this section, where α,β-unsaturated pyrazolones 12 have been illustrated as Michael acceptors, it is interesting to note how the structure of the organocatalysts played a crucial role in governing the stereoselectivity. Indeed, catalysts deriving from simple 1,2-diamine cores rather than from Cinchona alkaloids, performed at best in different cascade processes. The presence of the secondary amine group, instead of the tertiary one present in Takemoto's catalyst, often proved to be beneficial for the stereocontrol. This can be likely ascribed to the ability to reinforce the H-bonding network with the reagents and furnish better proton transfer assistance within the transition states, as pointed out for the epoxidation illustrated in Scheme 6.

Conclusions
Over the last years, we have been involved in the asymmetric synthesis of new heterocycles of different ring size including spirocyclic compounds, bearing a quaternary stereocenter. Some of them proved to be useful building blocks to achieve other products of interest and difficult to prepare by alternative routes, as demonstrated with epoxides reported in Schemes 1 and 3. The cascade combinations of Michael and aldol reactions allowed us to expand the panel of compounds from tetrahydrothiophenes and lactones to hybrid scaffolds embedding key heterocyclic units at the spirocenter. To achieve this goal, readily available bifunctional organic molecules have been used, as an indication that the simplest catalyst can be often the best one. Typical promoters, based on Cinchona alkaloids or 1,2-diamines, proved to be suitable for expanding their catalytic abilities beyond the initial boundaries displayed in non-covalent organocatalysis. With the help of DFT calculations, we have learnt more on the plausible mode of reagents activation and how the incorporation of other chiral units can be exploited to fine tuning the stereocontrol. Although the

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installation of quaternary stereocenters is not an easy path to walk, but rather climbing a ladder to the top, the acquired knowledge, helpful integration with theoretical calculations and eventual combination with other activation strategies will guide us toward future investigations.