Brønsted Base‐Catalyzed Enantioselective α‐Functionalization of Carbonyl Compounds Involving π‐Extended Enolates

Chiral Brønsted base (BB) catalyzed asymmetric transformations constitute an important tool for synthesis. A meaningful fraction of these transformations proceeds through transiently generated enolate intermediates, which display quite versatile reactivity against a variety of electrophiles. Some years ago, our group became interested in developing BB‐catalyzed asymmetric reactions of enolizable carbonyl substrates that involve π‐extended enolates in which, besides control of reaction diastereo and enantioselectivity, the site‐selectivity control is an additional issue in most cases. In the examples covered in this account the opportunities deployed, and the challenges posed, by these methods are illustrated, with a focus on the generation of quaternary carbon stereocenters. In the way, new bifunctional BB catalysts as well as achiral templates were developed that may find further applications.


Introduction
Enolizable carbonyl compounds encompass a large variety of substructures, both cyclic and acyclic, and functional groups.Deprotonation of enolizable carbonyl compounds by Brønsted bases (BB) constitutes a major entry to enolates, which upon in situ coupling with, or addition to, an electrophilic reaction partner may lead to molecules with increasing structural and stereochemical complexity. [1]In this context, soft enolization procedures relying on the use of weak chiral organobases, particularly tertiary amines bearing one or more hydrogenbonding (HB) donor groups attached, have been investigated extensively, enabling the development of catalyst-controlled enantioselective addition reaction of active enolizable carbonyl compounds to a range of suitable electrophiles. [2]The overwhelming majority of reported examples involve enolizable carbonyl substrates having attached at Cα an additional heteroatom-based functional group.This requirement, while considerably narrows the pool of substrates available for this type of catalytic activation, is ascribed to two main factors: (i) the necessity of threshold Cα carbon acidity of the pronucleophilic substrate for weak base-promoted deprotonation, [3] and (ii) the advantages of two-point catalyst coordination as critical element of transition state rigidification for attaining practical conversion and efficient chirality transfer. [4]ecently, new catalyst systems based on chiral stronger Brønsted bases (sBB) capable of deprotonating, inter alia, simple enolizable carbonyl compounds have appeared. [5]ereas the sBB approach may help to surmount the problem (i), the development of methods based on this approach progresses with paucity.In order to expand the chemical space accessible for asymmetric BB/HB bifunctional catalysis, exploring enolizable pronucleophiles incorporating either cyclic or acyclic chain unsaturation in the close vicinity of the carbonyl group bears particular interest.The presence of a double C=C (or triple C � C) bond nearby the carbonyl in the enolizable substrate might not only facilitate deprotonation (increasing acidity) but might also modify critically the reactivity of the transiently formed enolate species, opening new opportunities for exploration.
Structures A-D depicted in Figure 1 represent various patterns of unsaturated enolizable carbonyl compounds.Deprotonation of these pronucleophiles by a base, as first step of a catalytic process, may render reactive species A'-D' capable of reacting with suitable electrophiles giving access to a variety of synthetically useful building-blocks.Some time ago, our group became interested in studying asymmetric BB-catalyzed CÀ C bond forming reactions involving various classes of πextended enolates of cyclic and acyclic chain structure, e. g. structures A'-D', as transient species.Especial attention was paid to the stereocontrolled formation of new tetrasubstituted carbon stereocenters, which remain a hot subject in asymmet-ric catalysis. [6]In this personal account, we present our findings in this area, embracing from the development of improved BB/HB type catalysts and new reaction regioselectivity preferences to new opportunities for sequential, one-pot multibond forming catalytic processes.These studies ultimately provided new catalytic and enantioselective entries to access some molecular scaffolds relevant to medicinal chemistry, inter alia, 2-oxindoles, thiazolones, imidazolones, (thio)hydantoins, barbiturates, N-alkyl α-amino acids, and o-pyridyl acetonitriles, often bearing a quaternary carbon stereocenter.

BB-Catalyzed α-Functionalization of Unsaturated Lactam Heterocycles
Five-membered lactam heterocycles are widespread substructures within natural products, bioactive ingredients and advanced synthetic materials.A logical construction of such heterocycles with tridimensional architecture in enantioselective manner consists of the stereocontrolled α-functionalization of the enolizable parent lactam.As shown in Figure 2, partially unsaturated lactams bearing an additional O, S or N heteroatom in the ring may undergo deprotonation by weakly basic catalysts, such as tertiary amines, driven by the aromatic character of the formed enolate I-1.Then coupling with an electrophilic reagent would install the new group at Cα while generating a quaternary carbon stereocenter.Many catalytic methods have been reported for the α-functionalization of these heterocycles, including addition methods based on chiral Brønsted base catalysts.However, when α-substituted substrates are employed, enantioface discrimination across the trisubstituted enolate becomes challenging.To this end, the protonated catalyst must fit perfectly and interact simultaneously with the allegedly formed enolate and the approaching electrophile through multiple H-bonds mainly.

α-Functionalization of Thiazolones, Oxazolones, Azlactones and 2-Oxindoles
First study in this area from our laboratory dealt with the catalytic conjugate addition of α-substituted 5H-thiazol-4-ones to nitroolefins.5H-thiazol-4-ones may be viewed as surrogates of α-mercapto carboxylic acids and the enantioselective construction of these frameworks bearing a tetrasubstituted stereogenic center remains problematic. [7]In our hands, the reaction catalyzed by common urea-and thiourea-tertiary amine bifunctional catalysts [8] proceeded slowly at À 60 °C and with diastero-and enantioselectivities from low to moderate.Inspired by the discovery of ureidopeptides as designed synthetic peptidomimetics in which a peptide bond is replaced with the ureido group, [9] it was wondered whether the additional NH moiety in the ureido-aminals C1 would impart better catalytic efficiency than the parent ureas and thioureas.In this catalyst modification, an additional stereocenter is also incorporated as another element of structural tuning.The ureido-aminals such as C1/C2 are easy to prepare from the corresponding N-protected amino acid through Curtius rearrangement and ulterior coupling of the resulting isocyanate with a chiral amine.Gratifyingly, the above addition reaction in the presence of these newly designed bifunctional catalysts proceeded comparatively faster and with higher stereoselectivity (Scheme 1). [10]Screening of various carbamate residues and chiral amine units led to identify C1 as the optimum catalyst  for the above reaction, affording product 4 Aa in 80 % yield, 93 : 7 diastereomeric ratio and 80 % ee for the major isomer.Importantly, the nature of the Ar group linked to the 5Hthiazol-4-one C 2 has an impact on the reaction outcome.Thus the reaction using quinolyl-substituted thiazolone 1D resulted the most reactive and selective, affording adduct 4 Da in 93 % yield, 95 : 5 diastereomeric ratio and 96 % ee.This catalytic addition reaction was extensible to 5H-thiazol-4-ones bearing ethyl or larger alkyl substituents at Cα, and a range of aryl nitroolefins were well tolerated.This reactivity pattern was extensible to the addition of 1 to diazocompounds, yielding the corresponding α-hydrazination adducts 5 in high yields and somehow attenuated enantioseletivity.Treatment of adducts 4 with 6 N HCl in dioxane at 45 °C and subsequently with 2 N NaOH afforded the corresponding α-mercapto carboxylic amides, such as 6.
In connection to BB-catalyzed methodologies the realization of the Michael-type addition to acrylic systems, including acrylates, acrylamides, alkyl-vinyl ketones and acrolein, progresses slowly as compared with the addition to more reactive Michael acceptors such as nitroolefins and doubly activated systems. [11]In this context we introduced α'-hydroxy enones as an effective bidentate acrylic surrogate that may engage in Hbonding networks with the catalyst. [12]Since the ketol moiety in adducts may be easily converted into ester, alkyl ketone and aldehyde functions equally, the process would represent formally a uniform approach to addition to various acrylic systems.Among the useful nucleophilic reaction partners, πextended enolates derivable from some heterocyclic lactams proved suitable in the presence of various types of chiral BB catalysts.For instance, the addition of α-aryl 2-oxindoles [13] 7 to α'-hydroxy enone 8 proceeded smoothly in the presence of 20 mol% (DHQD)PYR (C3) to afford quaternary carbonbearing Michael adducts 10 in high yields and enantioselectivities (Scheme 2).Under these conditions, the enantioselectivity of the addition reaction of α-alkyl 2-oxindoles other than αmethyl to enone 8 was significantly lower.Fortunately, high selectivities were obtained when the gem-dibenzyl analog 9 was employed instead.Ulterior oxidative cleavage of the ketol moiety allowed access to the corresponding carboxylic acids (NaIO 4 ), aldehydes (BH 3 then NaIO 4 ) and ketones (R'MgBr then NaIO 4 ), respectively.For instance, treatment of 10 Cb with NaIO 4 afforded acid 12 in 94 %, which could be transformed into esermethole 13, a (À )-physostigmine precursor, in 78 % over three steps and 90 % ee.
Enantioselective, catalytic conjugate additions of transiently generated π-extended enolates derived from related heterocyclic lactams and lactones, i. e. oxazolones, thiazolones and azlactones, [14] were also feasible.However, for optimum results with these enolizable heterocycles adjustment of the α-oxy enone template and/or the chiral BB catalyst was necessary.In particular, the addition of these enolizable heterocycles to the O-silyl protected analog 15 proceeded with higher enantioselectivity than the additions to the parent hydroxy enone 8 usually.As shown in Scheme 3, α-substituted thiazolones 1 A and oxazolones 14 reacted with 15 smoothly in dichloromethane at room temperature in the presence of squaramide C5 [15] to afford, after in situ desilylation with HF, adducts 16 and 17 in yields in the range 67-86 % and 88-98 % ee, respectively.Similarly, azlactones 20 afforded adducts 21 in good yields and enantioselectivity with C4 [16] as optimum catalyst.Oxazolones 14 also participated in the reaction with β-aryl substituted hydroxyenones 18 with generation of adjacent tertiary/quaternary stereogenic centers [6g] in good selectivity.The reaction involving the β-alkyl substituted hydroxyenone congeners 17 of 18 was unproductive.The high variability of the reaction outcomes depending on the particular combination of above donor/acceptor substrate combinations suggests that strong steric interactions may operate during the reactants approaching.

α-Functionalization of Imidazolones
In subsequent work we focused on the enolizable lactam heterocycles 22.These structures, 2-thio substituted 1Himidazol-4(5H)-ones, may be viewed as masked forms of αamino acid derivatives, [17] in general, and (thio)hydantoins, [18] in particular, both relevant substructures among biologically active compounds.Despite this potential, to the best of our knowledge these pronucleophiles were unprecedented in asymmetric catalytic transformations.Heterocycles 22 can be prepared in gram-scale in two steps from the respective thiohydantoins.As shown in Scheme 4, soft deprotonation of 22 upon exposure to Rawal's chiral tertiary amine catalyst C6 [19] and subsequent reaction with active Michael acceptors like nitroolefins was feasible, giving rise to adducts 23 smoothly (CH 2 Cl 2 , RT or À 20 °C). [20]It is noticeable that, regardless the nature of the R 1 group in the π-extended enolate intermediate I-2 I-1, adducts from the α-carbon reaction were observed exclusively.In related heterocyclic systems, particularly azlactones, substrate-dependent regiodivergent αand γaddition product formation has been reported. [21]While various alkyl groups at sulfur other than benzyl, such as methyl and ethyl, were also well tolerated in 22, the chemical yield of the catalytic reaction diminished slightly.Alkyl-substituted nitroolefins were also tolerated but, as expected, the yields and especially selectivity with these acceptors decreased.Imidazolones with various substituents at both the C 5 and N 1 position were equally competent, including bicyclic ones leading to adducts 23 n and 23 o.Using catalyst C5 similar levels of stereoselectivity was attained, but in favor of the opposite enantiomer.
To explain the observed reaction outcomes we proposed a Papai-type [22] transition state model TS1 (Figure 3) in which the extended enolate and the incoming nitroolefin would approach through their Re/Re faces.In support of this TS model, we found that the chemical shift of the ortho-ArH in the catalyst is considerably affected (Δδ = + 0.11 ppm) by addition of 1 equivalent of imidazolone 22 a (R 1 ,R 2 : Me, R 3 : Bn), whereas it remains unaffected by addition of nitrostyrene 2 (R 4 : Ph).This observation also suggests that the polarized aromatic ortho protons in this type of catalysts contribute to TS stabilization.However, the alternative, Takemoto-type [23] approach as in TS2 could not be fully discarded.
Further studies [24] demonstrated that not only the N-alkyl/ aryl derivatives 22 A but also the related N-acyl imidazolones 22 B and the isomeric 30 (Figure 4) were effective enolizable pronucleophiles for the BB-catalyzed addition reactions, and that the pool of suitable electrophilic partners could be broadened to other Michael acceptors and aldehydes.However, it was necessary to find the best fitting bifunctional catalyst for each substrate combination.For example, as indicated in Scheme 6, newly developed catalyst C7, bearing a tethered amide unit capable for an additional H-bonding interaction, [8m] was more active than the parent catalysts C5 or C6 in promoting the addition of 22 B to nitroolefins.Thus, while the C5-catalyzed addition of 22 B (R 1 : Bn; R 2 : COPh) to β-nitrostyrene at room temperature required 16 hours for full conversion, the same reaction in the presence of C7 was over in 4 hours, both providing the corresponding adduct 31

P e r s o n a l A c c o u n t T H E C H E M I C A L R E C O R D
in 97 % and 98 % ee as essentially single diastereomer.The reaction catalyzed by C7 proved to be quite general, providing various N-acyl derivatives 31 in yields above 70 % for most entries, d.r. up to > 98 : 2 and very high enantioselectivity (Scheme 6).Aliphatic nitroolefins also led to high selectivities, but eroded isolated yields (R : i Bu 53 %, R : n Pr 40 %) under these conditions.
In this context enones 32 demonstrated to be competent electrophilic reaction partners and the corresponding adducts 33 were obtained in high yields and very high enantioselectivity, with few exceptions (Scheme 6).
As noted above, N 3 -substituted 2-benzylthioimidazolones 30 A could also be functionalized by BB/HB-catalyzed addition reactions to electrophiles.However, the behavior of these heterocycles was electrophile-dependent.Thus, with nitroolefins the α-addition adducts 34 were obtained cleanly and for most examples in high yields, diastereo-and enantioselectivities (Scheme 7).However, when reacted with vinyl ketones 32 two divergent reaction pathways were observed producing, respectively, the 5-addition products 35 and the 3-addition products 36.Configuration of products 36 was not determined and that of products 35 was assigned by assuming a uniform reaction mechanism.Attempts to favor either reaction pathway were unsuccessful and, regardless the type of mono-or bifunctional BB catalysts and the reaction temperature, a quasi-equimolar ratio of both regioisomeric products was formed in the studied cases.Formation of regioisomeric mixtures was previously reported in BB-catalyzed addition reactions involving azlactones as the nucleophile. [21]n the aforementioned examples readily accessible and partially unsaturated 2-benzylthio imidazolones 22 and 30 showed to be quite active and selective in BB/HB-catalyzed addition reactions.In sharp contrast, the related saturated heterocyclic (thio)hydantoin pronucleophiles shown in Scheme 8 displayed comparatively poorer reactivity and/or selectivity.For example, it was reported [25] that the basecatalyzed reaction of thiohydantoin 37 with nitroolefins led to complex reaction mixtures.In our hand, the similar reaction of the N 3 -and N 1 -substituted thiohydantoins 38 and 40 afforded the corresponding α-addition adducts 39 and 41, respectively, but with poor diastereoselectivity or/and enantioselectivity.Finally, both mono-and dibenzoylated compounds 42 and 43 proved to be unreactive under the present catalytic conditions.
The BB-catalyzed addition reaction of these enolizable imidazolidones could be extended to additional electrophiles, including aldehydes (aldol-type reaction) and vinyl sulfones (Michael-type addition), provided that "reactive forms" of these latter species were employed. [26]For example, imidazolidones 30 A could reacted with 2-formyl pyridine N-oxides 44 to afford the corresponding aldol adducts 45 bearing adjacent tri-and tetrasubstituted carbon stereocenters in high diastereoand enantioselectivity (Scheme 9). [27]Among several BB catalyst, the amide-squaramide C9 led to the highest selectivity.This catalytic reaction showed to be quite general for differently substituted imidazolones 30 A and aldehydes 44.Once again, the free amide NH group in C9 proved to be crucial for attaining effective catalysis and stereoselectivity, as the reaction using the N-methyl analog led to poor results.Very recently, we studied the behaviour of these enolizable lactam heterocycles 22 and 30 in the additions to vinyl sulfones using the same type of chiral BB catalyst systems. [28]It was found that in reactions involving even the most reactive unsubstituted vinyl bis(sulfone) 47, both reactivity and selectivity are strongly dependent on the structure of the heterocyclic pronucleophile.As Scheme 10 shows, while C4catalyzed reaction of 47 with azlactone 20 A proceeded fast, the reaction enantioselectivity was suboptimal.The enantiocontrol of the addition reaction involving imidazolone 30 Aa was even worse.More striking, when using imidazolones 22 B radically different reactivities were observed depending on the nature of N 1 substituent.While the N-acetyl derivative (R 2 : COMe) was totally unreactive in CH 2 Cl 2 at 0 °C, the corresponding N-benzoyl derivative reacted smoothly to give rise product 50 a in 95 % conversion after 24 hours and a 88 % ee.This divergent behavior was tentatively attributed to increased carbon acidity of the benzoyl derivative as compared to the acetyl derivative, with pK a estimates, respectively, of 15 and 16 (according to Grzybowski's method) or 19.71 vs 21.15 (using Jaguar pK a module29 in DMSO as implemented in Schrodinger 2021-0130 program suite).These conditions were applied to other α-alkyl and α-heteroalkyl substituted 2benzylthioimidazoles 22 B which nicely provided the corresponding adducts 50 in very high enantioselectivity.
As expected, the corresponding β-substituted vinyl sulfones 51 proved to be much more challenging acceptors due to attenuated reactivity.All attempted reactions with varying catalysts and conditions led to recovery of unmodified starting materials.Then we decided to investigate the cyclic ("rigidified") congeners 52, which according to Mayr kinetic measurements are roughly one order of magnitude more electrophilic than the acyclic congeners. [29]Gratifyingly, the reaction of 22 B with 52 in the presence of 10 mol% squaramide catalyst C9 proceeded smoothly even at 0 °C to afford adducts 53 in moderate to good yields, essentially complete diastereoselectivity and usually very high enantioselectivity (Scheme 11).Among other applications, the bis(sulfone) moiety of adducts could be reductively removed in the presence of magnesium metal. [30]to achieve the formal α-alkylation products, e. g. 54 from 53 a, which are difficult to prepare otherwise.

α-Functionalization of Barbituric Acid Surrogates
Barbituric acid derivatives have found applications as therapeutic agents as well as functional materials, and thousands of 5,5disubstituted barbiturates have been synthesized and selected for clinical trials. [31]However, the great majority are racemic, even though pharmacological profile is known to be configuration-dependent.One reason contributing to this situation might be the lack of enantioselective methods to access the cyclic 1,3-diimide substructure with in-ring chirality, [32] which may be related to the pseudosymmetric structure of the resulting enolate intermediate I-52 (Scheme 12).By analogy with what we previously found concerning the reactivity of enolizable five-member lactam heterocycles, it was reasoned that chiral BB catalysis may be well suited for deprotonating the corresponding unsaturated alkylthio-substituted pronucleophiles 55.The allegedly formed extended enolate intermediate I-63 would display enhanced dissymmetry as compared with I-52.
We started by preparing 2-benzylthio-4,6-dioxopyrimidines 55 in one step from the corresponding thio-barbiturates.Gratifyingly, the reaction between 55 A (Scheme 13) and vinyl aryl ketones could be catalyzed by bifunctional BB/HB catalysts. [33]Among the catalysts screened, the squaramidetriarylmethanol C10 and its O-silyl ether C11 provided the best selectivity, with the former being more active.Adducts 57 were obtained in good yields and enantioselectivities from high to excellent.α'-Silyloxy enone 15 was also a competent Michael acceptor in these catalytic additions.Given the easy with which the ketol group in adducts 58 can be transformed into carboxylic acid and aldehyde functions, this protocol enables access to products formally derived from the conjugate addition to acrylic esters and acrolein.Complementing these addition reactions, the coupling between 55 A and Morita-Baylis-Hillmann-type bromides 59 was also possible in the presence of K 2 CO 3 as the acid scavenger, leading to the allylic alkylation products 60 in good yields and enantioselectivities from moderate to extremely high.The synthetic potential of thus obtained adducts was illustrated by the conversion of 60 (R 1 : allyl) into spiranic 61 through a ring-closing metathesis reaction catalyzed by Grubbs catalyst in CH 2 Cl 2 at room temperature and ulterior acid hydrolysis in dioxane/water.

BB-Catalyzed Functionalization of β-Tetralones
and Related Benzo-Fused Cycloalkanones β-Tetralones have been employed profusely as starting scaffold for the synthesis of polycyclic carbon structures with various biological activities. [34]Asymmetric functionalization of βtetralones via prior transformation into a chiral enamine is already established. [35]In contrast, catalyst-controlled direct methods for the enantioselective α or α'-functionalization are rare.With β-tetralones and related benzo-fused cyclic ketones, full control of the two possible ketone enolization sites becomes an issue.We anticipated that the fused aromatic ring in β-tetralones might induce preferential enolization at Cα rather than C α' , while increasing the carbon acidity as to be feasible for weak base, i. e. tertiary amine catalyst, induced deprotonation (Figure 5).However, the above predictions were uncertain given the precedents in the literature.Thus, while BB-catalyzed αfunctionalization of α-substituted cyclopentanone is reported to proceed satisfactorily, the same process appeared unpractical with α-substituted cyclohexanones. [36]We were delighted to observe that α-substituted β-tetralones 62 reacted smoothly with nitroolefins in the presence of 10 mol% squaramidetertiary amine catalysts in CH 2 Cl 2 at room temperature (Scheme 14).The α-addition adducts 63 were obtained exclusively and as a single diastereomer. [37]The reactions using catalyst C12 proceeded with ee's up to 99 %.Interestingly, the α-unsubstituted β-tetralone 62 (R 2 : H) also reacted cleanly in the presence of 2 mol% catalyst C4 or C12 to provide the monoaddition adduct 64 only.With the exception of the 2furyl substituted β-tetralone, which led to equimolar mixture of diastereomers, the remaining examples were isolated with dr higher than 4 : 1 and perfect enantiocontrol of both isomers.These adducts were prone to base-promoted epimerization, which may explain the moderate diastereoselectivity. Nevertheless, the process could be applied to related benzo-fused cycloalkanones successfully providing a route to diverse substructures, such as 65-67.In the case of starting from a benzo-fused cyclic diketone, adduct 68 was isolated as a result of a sequential, catalytic Michael-nitroaldol process.
The structural diversity of polycyclic products within reach by applying this technology is considerably broad as examples depicted compounds 69-75 in Scheme 15 show, all affordable from the corresponding adduct 63 or 64 through conventional chemistry in one or maximum two synthetic steps.

BB-Catalyzed Functionalization of 2-Pyridyl Acetates and Acetonitriles
o-Substituted pyridine frameworks are among the most commonly used nitrogen heterocycles in FDA approved pharmaceuticals. [38]Development of catalytic, enantioselective routes to access pyridines and related azaarenes with a quaternary carbon substituent at ortho position is therefore of practical relevance.α-Deprotonation of o-substituted acyl pyridines may lead to mixtures of E-and Z-configured enolates D' aza-A' (Figure 6), making enantiocontrol of reactions proceeding through these intermediates difficult.In contrast, the corresponding nitriles (2-pyridyl acetonitriles) would skip such a complication.In addition, nitrile is a versatile functional group for many synthetic purposes.However, the αcarbon acidity of nitriles is relatively low. [39]In order to overcome this shortcoming, we decided to use the corresponding pyridine N-oxides instead, which should be comparatively more acidic and thus more active substrates for BB-catalyzed α-functionalization.Moreover, the N-oxide group may provide an additional site for catalyst coordination, and be reductively converted into the parent pyridine if desired.Our initial attempts using o-cyanomethylpyridine and enone 8 as an active Michael acceptor in the presence of various typical BB/HB bifunctional catalysts led to very low conversions and selectivities, even using 20 mol% catalyst loading.The reactivity increased considerably by using the corresponding N-oxide derivative 76 and after 2 days at 40 °C conversions near 90 % were achieved with typical squaramidetertiary amine catalysts.Then we decided to test the related squaramides bearing an alkyl-aryl silyl group appendage, e. g.C13, speculating with the possibility of Si … O stabilizing interactions in the substrate-catalyst complex.With this latter catalyst total conversion was reached in about 24 h at 40 °C.Further optimization of reaction conditions allowed to obtain enantioselectivities above 90 % by running the reaction at RT or 0 °C, with 10 mol catalyst loading with still acceptable reaction times.As Scheme 16 illustrates, the catalytic reaction tolerates a variety of 2-pyridyl acetonitrile N-oxides 76 bearing Cl, Br or Me substituents at the pyridine ring and either electron-poor or electron-rich aryl substituents at Cα. Substrates with alkyl substituents at Cα were also tolerated, but gave poorer conversion and selectivity.Eventually, the related pyrazine N-oxides 77 were also competent pronucleophiles.Importantly, among various additional transformations of thus obtained adducts, the N-oxide product could be transformed into the corresponding parent pyridine by treatment with (Bpin) 2 in warm acetonitrile in yields typically in the 75-80 % range. [40]everal control experiments were carried out to quantify the effect on the reactivity and/or enantioselectivity of: (i) the substrate o-, m-and p-substitution pattern, (ii) using the Noxide analogs as compared to the parent pyridines, and (iii) the noncatalyzed vs. the catalyzed reaction.As the data in Figure 7 show, the N-oxide group and its ortho-relationship to the cyanoalkyl substituent are key for optimal reaction outcome.As a general trend, for the three positional isomers ortho, meta and para, the corresponding pyridine N-oxide showed to be more reactive than the parent pyridine in both the catalyzed and uncatalyzed reactions.In fact, among the six experiments involving cyanoalkylpyridines, only that using p-cyanoalkylpyridine in the presence of C13 provided practical conversion after 24 h, leading to racemic product.Equally important is the position of the N-oxide group relative to the cyanoalkyl substituent on the ring.Among the three cyanoalkylpyridine N-oxides, the meta and para isomers showed to be inherently  more reactive than the ortho isomer, also in the presence of cat C13, although both led to essentially racemic product.In contrast, the ortho isomer led to 92 % ee.Under similar conditions and using the triphenylsilyl analog C14 as optimum catalyst, the α-hydrazination reaction leading to adducts 79 could be carried out satisfactorily.Further investigations showed that the N-oxides of 2azaaryl acetate esters 80 are also competent pronucleophiles and their BB-catalyzed α-functionalization could be successfully applied. [41]In this latter case (Scheme 17), however, the silyl group-bearing catalysts, e. g.C13, proved suboptimal.In particular, the Mannich-type addition reaction of acetate esters 80 with N-Boc and N-Cbz aldimines 81 was best performed using urea-aminal catalysts, e. g.C15, and products 82 were formed in very good yields and excellent diastereo-and enantioselectivity.The catalytic addition reaction involving isatin-derived imines as active ketimines, did also work well to provide adducts like 83 a and 83 b, although with attenuated enantioselectivity.

BB-Catalyzed Functionalization of Unsaturated Ketones and Thioesters via Di-and Trienolates
Upon exposure to base, enolizable carbonyl compounds displaying β,γ-chain-unsaturation may lead to formation of dienolates A', or even trienolates D' (Figure 8).Dienolates are ambidentate nucleophiles and may react through αor γcarbon, while trienolates may react even through the ɛ-carbon.This makes control of the reaction site-selectivity an issue, beyond the problems of reaction diastereo-and enantiocontrol. [42]egarding site-selectivity, the majority of catalyst-controlled asymmetric reactions of transiently generated vinylogous enolates and enolate equivalents, including dienamines, tend to proceed through Cγ. [43] This pathway implies πconjugation is preserved along the reaction coordinate.In contrast, attack from Cα would imply disruption of conjugation.Examples belonging to this latter reactivity pattern are uncommon and might require steric shielding of the γposition. [44]We found that allylic ketones and thioesters, in the presence of bifunctional BB/HB catalysts, may react through the α-position preferentially against conjugated (1,4-addition) and nonconjugated (1,2-addition) carbon electrophiles. [45]For instance, Scheme 18, the addition of allyl-alkyl ketones 84 to nitroolefins catalyzed by C17 provided the Michael-type adducts 85 as exclusive reaction products.The reaction tolerates a variety of aryl-substituted nitroolefins and ketones bearing aryl, alkyl or alkenyl side-chains all participated equally, affording adducts 85 in diastereoselectivities from moderate to excellent and high enantioselectivity.Under these conditions, neither double addition products nor epimerization were observed.A simple hydrogenation of the olefinic residue in the resulting adducts 85 allowed to access products, e. g. 86, from a formal side-selective, diastereo-and enantioselective alkylation of nonsymmetrical alkyl-alkyl ketones, a yet unsolved transformation using direct methodologies.Submitted to similar reaction conditions and type of catalysts, the corresponding allylic esters 87 A and thioesters 87 B were less selective than ketones, and mixtures of the αand γ-addition adducts 88/89 were obtained (Scheme 19, top).This deficiency could be surmounted using hydroxyketones as masked ester/aldehyde equivalents.Thus, the corresponding α'-hydroxy ketones 90 reacted with both aryl-and alkyl-substituted nitroolefins to give adducts 91 in very high selectivity.Ulterior oxidative ketol/diol scission provided an indirect access to the target ester and aldehyde α-addition products, e. g. 92-94.
It should be noted that in certain cases the nature of the bifunctional BB/HB catalyst may modulate, or even override, the substrates innate regio-selectivity trend.As the data in Scheme 20 indicate, while mixtures of both α and γ-addition products 91/95 were obtained using the thiourea/tertiary amine catalyst C18, [46] essentially perfect regioselectivity was observed using catalyst C17 instead. [47]he catalytic, enantioselective α-functionalization of αbranched allylic ketones represents an unmet challenge so far.In this type of transformation exquisite stereocontrol during formation of a new quaternary α-carbon is necessary.Moreover, inducing the intermediate dienolate to react through the α-carbon rather than the less sterically shielded γ-carbon seemed a difficult task.Initial experiments aimed at reacting the α-branched methyl ketone 96 with nitrostyrene to produce 97 (less than 25 % yield after 72 hours at RT) demonstrated the attenuated reactivity of 96 as compared with the parent αunsubstituted ketones (Scheme 21). [48]Additional control experiments showed that this limited reactivity is even more dramatic for the corresponding α-branched phenyl ketone 96 c.As expected, using reactive, sterically less demanding Michael acceptors, such as vinyl bis(sulfone) 47, some reactivity is gained, but still larger alkyl (ethyl) and aryl ketones remain unpractical, while the enantioselectivity remained poor.
We hypothesized that cyclic α-branched allylic ketones may show better reactivity and selectivity profiles in these catalytic transformations.The usually higher nucleophilicity of cyclic vs. acyclic parent substrates [49] and the less conformational disorder of the former might be key factors for threshold reactivity of cyclic systems.In addition, chirality transfer from the catalyst to the product might be secured as there is not E/Z configurational ambiguity of the intermediate dienolate in cyclic systems.Gratifyingly, the reaction between cycloalkanones 99 and vinyl bis(sulfone) 47 proceeded at 0 °C within 16 h smoothly in the presence of either catalyst C19 or C20 to give products 100 in very good yields and high enantioselectivity for most cases (Scheme 22). [48]As before, desulfonylation of adducts yielded products derived from a formal alkylation process, e. g. 102.Not only monocyclic 5, 6, 7 and 8membered cycloalkanones were compatible, but also benzofused cycloalkanones were excellent substrates for this catalytic addition affording the α-quaternary products in very high enantioselectivity.Control experiments demonstrated that both common Brønsted acid catalysts (i.e. (R)-or (S)-TRIP) and primary amine-thioureas were less efficient catalysts for this reaction.
As the examples in Scheme 23 show, these α-branched cycloalkanones may also react with nitroalkenes and formaldehyde to afford in high selectivity the corresponding 1,4-and 1,2-addition adducts 104 and 106-108, respectively, using C21 as a catalyst. [50]he most probable transition states for both Re-face and Si-face approaches in these addition reactions according to DFT calculations would be TS3 and TS4 (Figure 9).
We also studied the likelihood for catalytic, enantioselective α-functionalization of doubly unsaturated skipped ketone and thioester systems 109 and 114 which would involve trienolate formation.In initial attempts using the aryl thioester 109 and nitrostyrene as reaction partner, up to four different  products 110-113 were isolated, with the strength of the base catalyst used being determinant on product distribution (Scheme 24).Upon optimization of the catalyst and conditions, formation of cyclohexene product 113 could be maximized using C22 [19] as the initial catalyst (10 mol%) and then adding MTBD (20 mol%) to promote the isomerization/ intramolecular addition reaction cascade process. [51]nder optimized conditions, that consist of a two-step one-pot process involving first stirring of aryl thioesters 109 and nitroolefins 2 (R: aryl) in the presence of 10 mol% C22 for 24 hours at room temperature and then addition of 20 mol% MTBD and stirring for an additional 16 hours, cycloadducts 113 were isolated in good yields as single diastereomer and high enantioselectivity (Scheme 25a).Extension of this catalytic method to doubly unsaturated skipped ketones 114 was straightforward (Scheme 25b).In this case, the initially formed α-addition adducts 115 could be isolated, if desired, before subsequent MTBD-catalyzed transformation into cycloadducts 116.Interestingly, while analysis of the open-chain adducts 115 showed a mixture of diastereomers in a ratio of ca. 2 : 1, the final products 116 were isolated as essentially single diastereomers, which would be compatible with a kinetic resolution of diastereomers.
As shown in Scheme 26, the above results could be explained by assuming a concatenation of base-catalysed deprotonation-addition-isomerization events, including: (i) deprotonation of the unsaturated ketone/thioester with formation of trienolate VI, which would react with nitroolefin through Cα preferentially, (ii) isomerization of the double bonds in VII leading to conjugate diene-thioester/ketone VIII, (iii) base-promoted carbocyclization of VIII via intramolecular 1,6-addition, and (iv) base-catalyzed isomerization to conjugated cyclohexene products 113/116.
In this reaction scheme, among the four possible isomeric products in step (i), DFT calculations carried out on a model reaction correctly predict formation of VII featuring an (R)configured β-carbon as major isomer.Here, isomerization of VII to VIII (step ii) makes the actual configuration of Cα stereocenter in VII irrelevant.In addition, none of the chiral amine catalysts tested is able to promote the VII!VIII isomerization nor the subsequent conversion of VIII to IX (step iii).Instead, achiral stronger base is needed.Therefore, the carbocyclization step appears to be fully substratecontrolled.This assumption was also supported by the calculated energy barriers for the four possible nitronatedienone approaching combinations, with the re,re approach Scheme 24.Screning of basic catalysts for the reaction between doubly unsaturated thioesters 109 and nitrostyrene, and products formed.(9.6 kcal/mol barrier) lying about 2 kcal/mol lower than the other three possible approaches.Finally, isomerization of starting thioesters/ketones 109/114 into the conjugated V would be a dead-end for the system.

BB-Catalyzed Functionalization of Conjugated Ynones
Enolizable alkynyl ketones (conjugated ynones) represent a distinguished subset of ketones with some unique reactivity profile in BB catalyzed transformations.In contrast to the previous examples which involve linearly extended di(tri)enolates, deprotonation of alkynyl ketones B would produce crossed π-systems B'/B'' (Figure 10).We and others [52] have observed that the alkynyl moiety in these systems, while facilitating enolate formation, influences the reactivity trends of transiently formed (di)enolates as well as the stability of the resulting adducts.
For example, allylic ynones showed to react with nitroolefins under the presence of bifunctional BB/HB catalysts following diverting pathways that depend on the substitution pattern on the olefinic residue.Thus (Scheme 27), simple allyl ynones 117 A invariably yielded the corresponding α-addition/ isomerization adducts 118, with C4 being the best catalysts. [45]n contrast, the β-methylsubstituted congeners 117 B provided the α-addition adducts 119 without ulterior isomerization, regardless the catalyst employed.Finally, the γ-substituted ynones 117 C provided a mixture of both types of products, the ratio of which is catalyst-dependent.With the new catalyst C23 the α-addition product could be isolated in high enantioselectivity as a mixture of diastereomers. [53]he activation effect imparted by the alkynyl sidearm on the ketones α-reactivity goes beyond allylic ynones.Thus, we found that arylmethyl ynones 122 and alkoxymethyl ynones 123 both display gained reactivity as compared with the parent alkyl or aryl ketones in BB-catalyzed transformations. [53]For example, Scheme 28, the reaction with nitroolefins at room temperature using 10 mol% catalyst C17, C22 or C23 afforded the respective addition products 124 and 125 in isolated yields from moderate to very high and useful stereoselectivities.In sharp contrast, under these conditions simple arylmethyl or alkoxymethyl ketones are completely unreactive.
Importantly, the alkyne moiety in the resulting adducts is a versatile platform for further chemical elaboration.As illustrated in Scheme 29, this aspect could be capitalized via intramolecular carbofunctionalizations of species X to construct polycyclic structures like XI.For example, applying Larock's ipso-halocyclisation [54] to adduct 124 a the spirocycle 126 was furnished in 86 % yield.Then trimethylamine promoted intramolecular Michael reaction afforded product 127 in 72 % yield.Similarly, heating adduct 124 b at 65 °C in the presence of copper(II) triflate, according to the method of

P e r s o n a l A c c o u n t T H E C H E M I C A L R E C O R D
Taylor and Unsworth, [55] led to the spirocycle 128 (81 %), which allowed easy transformation into tricycle 129 in 69 % isolated yield.The resulting tricyclic carbon skeletons of 127 and 129 resemble the core structure present in homodimericin A, a structurally intricate compound whose enantioselective chemical synthesis is still pending.

Conclusions
Catalyst-controlled direct, asymmetric α-functionalization of enolizable substrates is a powerful strategy to access synthetically relevant building-blocks in enantioenriched form.Among the several activation strategies, methods based on Brønsted base catalyst-promoted deprotonation of the carbonyl pronucleophile has proven mild and practical.In this context, enolizable substrates incorporating a chain-unsaturation nearby the carbonyl group result especially attractive because the adducts resulting from their addition to, or coupling with, an electrophilic reagent will display additional carbon-carbon double or triple bonds available for ulterior synthetic manipulation.In the past recent years, our group has investigated how to exploit these opportunities to expand the chemical space of enantioenriched building-block available, with a focus on the generation of quaternary carbon stereocenters.During this exercise several difficulties were encountered concerning either the lack of threshold reactivity, insufficient stereoselectivity or chemo-and site-selectivity complications.In general, we found that enolization of many types of "benzylic" and allylic (skipped) ketones and thioesters, including ynones and α-branched examples, is feasible using bifunctional tertiary amine/HB donor catalysts, and that they may react with a sort of electrophilic reaction partners, including nitroolefins, vinyl sulfones, enones, aldehydes, imines or diazocompounds leading to products in high chemo-, site-, diastereo-and enantioselectivities in most cases.Eventually, an unexpected tandem process to afford isomerically pure tetrasubstituted cyclohexene compounds was uncovered.In this context, it was also found that heterocyclic lactams, including newly designed alkylthiosubstituted imidazolones and pyrimidinediones, may work as efficient masked forms of (thio)hydantoins, α-amino amides and barbituric acid derivatives, allowing new enantioselective entries to the respective target compounds bearing a quaternary α-stereocenter.In our experience, each reaction development required careful screening of both the optimum reaction conditions and organocatalyst.Given the variety of substrates, both nucleophilic and electrophilic, and reaction types explored, there was no universal bifunctional catalyst identified.Instead, well-established or even commercial (thio)urea-and squaramide-based aminocatalysts were sufficient occasionally.In other instances, new catalysts were developed that incorporate either additional H-bond donor sites (ureido-aminals, NH amides, phenols), enhanced steric constrains (tertiary carbinol ethers), a trialkylsilyl side-arm or combinations of these designing elements.In several of the examples illustrated, additional insights on the activation mechanisms and the course of reaction site-and stereoselectivity were investigated by means of computational methods.Finally, while this investigation has provided a variety of new procedures to access synthetically relevant building-blocks in enantioenriched form through operationally simple protocols, new or not-so-well understood problems as well as yet unmet challenges were also uncovered that will deserve further efforts in the area.

Claudio
Palomo studied Chemistry at the Instituto Químico de Sarria, in Barcelona, where he received his Chemical Engineering Degree in 1975.He obtained his Licenciatura in Chemistry in 1979 at the University of Barcelona and his Ph.D. in 1983 at the University of the Basque Country under the supervision of Prof. R. Mestres.In 1989 he was promoted to Professor and in 1991 he joined Prof. H. Rapoport at the University of California at Berkeley as a visiting professor.His current interests are in the area of asymmetric catalysis.Mikel Oiarbide obtained his PhD from the University of the Basque Country UPV/EHU (Spain) in 1991 working with Prof. C. Palomo and J.M. Aizpurua on tributyltin hydride mediated transformations.He then spent two years as a PDRA with Prof. H. Rapoport at UC Berkeley (USA) working on the synthesis of Nglycosides pentostatin and coformycin.In 1994, he took up a tenure position at UPV/EHU and was promoted to Professor in 2003.

Figure 3 .
Figure 3. Plausible TS models and selected 1 H NMR data.

Figure 7 .
Figure 7.Comparison of various o-, m-, and p-substituted pyridinylacetonitriles vs. their N-oxide analogues for the noncatalyzed and catalyzed reactions.Adapted from ref.[40]Copyright (2016), with permission from American Chemical Society.

Figure 9 .
Figure 9.The less energetic TS for the addition of allylic cyclohexanone to vinyl bis(sulfone) and the δ O-H hydrogen-bond distances.