Stereocontrolled Aldol-Like Reactions Involving Oxocarbenium Intermediates

Abstract

Oxocarbenium cations are key intermediates for the stereocontrolled construction of carbon–carbon bonds. In particular, we have developed a wide range of stereoselective aldol-like processes that take advantage of the high reactivity of the oxocarbenium species arising from acetals, glycals, and orthoesters with metal enolates. This Account describes the development and optimization of such processes, together with other significant contributions, with a particular emphasis on their application to the synthesis of natural products.

1 Introduction

2 Substrate-Controlled Processes

2.1 Additions to Acyclic Acetals

2.2 Additions to Cyclic Acetals

3 Chiral-Auxiliary-Based Processes

3.1 Additions to Acyclic Acetals

3.2 Additions to Cyclic Acetals and Glycals

4 Chiral-Catalysis-Based Processes

4.1 Organocatalysis

4.2 Metal Catalysis

5 Conclusions

Biographical Sketches

Oriol Galeote was born in 1997 in Barcelona. He received his degree in chemistry from the University of Barcelona in 2019, and joined the group of Ernesto Nicolás to work on the preparation of protected peptides on solid phase for convergent synthesis. Subsequently, he pursued a master’s in organic chemistry at the same university, where he worked with Professors Fèlix Urpí and Pedro Romea on the study of direct asymmetric aldol reactions catalyzed by chiral Ni(II) complexes. Since 2021, he has been studying for his Ph.D., which focuses on the development of new direct, catalytic, and asymmetric C–C bond-forming reactions catalyzed by chiral metal complexes. During this period, he also completed an internship at the Max Planck Institut für Kohlenforschung, where he worked under the guidance of Prof. Benjamin List on organocatalyzed asymmetric Mannich additions.

Stuart C. D. Kennington was born in Cambridgeshire, UK, in 1992 and studied chemistry at the University of Warwick, obtaining his MChem in 2015. He then moved to the University of Barcelona, joining the group of Professors Fèlix Urpí and Pedro Romea to study for his Ph.D. in organic chemistry which he completed in 2020. After spending a year in the pharmaceutical industry in R&D focusing on the development and synthesis of HPAPI products, he moved to his current two-year position as a visiting lecturer at the University of Girona. He is currently conducting his postdoctoral investigations in the group of Dr. Anna Pla and Professor Anna Roglans at the University of Girona and the IQCC. His research focuses on new carbon–carbon bond-forming reactions catalyzed by chiral metal complexes, predominately nickel, and centered mainly on alkylation, aldol-type addition, and cycloaddition reactions. The application of these methodologies to the synthesis of biologically active molecules is also of great interest to him.

Miguel Mellado-Hidalgo was born in 1996 in Barcelona. He received his chemistry degree from the University of Barcelona in 2018. He subsequently pursued his master’s in organic chemistry at the same University, joining the group of Professors Fèlix Urpí and Pedro Romea to develop direct and asymmetric aldol reactions from thioimides catalyzed by chiral nickel(II) complexes. Since 2020, he has been carrying out his Ph.D. in the same group, focusing his research on developing new catalytic and asymmetric C–C bond-forming reactions with acetals and aldehydes, and their application to the synthesis of peptide-like fragments, small natural products, and biologically active compounds.

Anna M. Costa studied chemistry at the University of Barcelona, where she earned her Ph.D. in 1999 under the supervision of Professor Jaume Vilarrasa for her studies on synthetic organic chemistry. After a postdoctoral stay in the laboratories of Professor Patrick J. Walsh at the University of Pennsylvania (2000–2001) working on asymmetric catalysis, she returned to the University of Barcelona in 2001, becoming an associate professor in 2007. Her current research activity focuses on the development of new stereoselective processes and their application to the total synthesis of biologically active natural products.

Pedro Romea completed his B.Sc. in chemistry at the University of Barcelona and then undertook his Ph.D. studies from 1987 to 1991 under the supervision of Professor Jaume Vilarrasa at the same institute. He subsequently joined the group of Professor Ian Paterson at the University of Cambridge (UK), where he participated in the total synthesis of oleandolide. He then returned to the University of Barcelona, where he became an associate professor and later a full professor in 2020. His research interests have focused on the development of new synthetic methodologies and their application to the stereoselective synthesis of naturally occurring molecular structures.

Fèlix Urpí received his B.Sc. in chemistry at the University of Barcelona and completed his Ph.D. studies in 1988 under the guidance of Professor Jaume Vilarrasa at the same institute. He then worked as a NATO postdoctoral research associate in titanium enolate chemistry with Professor David A. Evans at Harvard University in Cambridge, Massachusetts (USA). He then moved back to the University of Barcelona, becoming an associate professor in 1991. Since 2017, he has held a chair as a Full Professor in Organic Chemistry at the same institute. His research interests have focused on the development of new synthetic methodologies and their application to the stereoselective synthesis of naturally occurring molecular structures.

Introduction

Oxocarbenium cations are instrumental intermediates in carbohydrate chemistry and, in a broad sense, are key synthons for the synthesis of furan or pyran rings.[2] Notwithstanding, they have been scarcely exploited in stereoselective carbon–carbon bond-forming reactions. The lack of asymmetric methods based on the addition of d² synthons to acetals in aldol-like processes is particularly surprising since Mukaiyama established early that silyl enol ethers and ketene silyl acetals, from ketones and esters respectively, reacted with dialkyl acetals and trimethyl orthoformate in the presence of TiCl₄ to yield the corresponding β-alkoxy derivatives without elimination of the alcohol.[3] [4] Noyori made a significant leap forward in disclosing that reactions of silyl enol ethers with dimethyl acetals catalyzed by TMSOTf provided racemic mixtures of the corresponding syn β-methoxy carbonyl compounds in good yields,[5] presumably through open transition states in which both electrostatic and steric interactions favor the relative syn configuration (Scheme [1]).[6] Further findings by Heathcock, Denmark, and Sammakia confirmed the pathway, although an alternative S_N2 mechanism was not definitely discarded in sterically unhindered acetals.[7]

Parallel to such contributions, Evans’ report of a straightforward procedure for the formation of titanium(IV) enolates from the corresponding carbonyl precursors using the appropriate combination of a titanium(IV) Lewis acid and a tertiary amine turned out to be crucial for the development of stereoselective transformations evolving through S_N1-like pathways.[8] Indeed, recognizing that the titanium enolates from chiral N-acyl oxazolidinones underwent stereocontrolled additions to acetals, orthoesters, and certain substrates with predisposition towards S_N1 reactivity paved the way for further advances (Scheme [1]).[9]

The abovementioned precedents and the structural similarity of oxocarbenium cations and Lewis acid activated aldehydes (Figure [1]), seemed to herald a successful future for all of those intermediates in asymmetric aldol reactions.[10] Surprisingly, this has not been the case and the chemistry of oxocarbenium intermediates derived from acetals remains, in a sense, underdeveloped.[11]

Taking into account these insights and other recent advances in the stereoselective aldol arena,[12] [13] we describe in this Account asymmetric aldol-like additions to acetals, glycals, orthoesters, and silyl-activated aldehydes proceeding through open transition states, with a particular emphasis on our own contributions based on the use of metal enolates. From a broader point of view, evidence presented across this Account suggests that all the species shown in Figure [1], including acyclic and cyclic oxocarbenium cations, may play a remarkable role in stereocontrolled carbon–carbon bond-forming reactions.

Substrate-Controlled Processes

Additions to Acyclic Acetals

The first reports on the stereocontrolled Lewis acid mediated addition of silyl enol ethers to acetals revolved around intramolecular transformations. The construction of the bicyclo[5.1.0]octane substructure, common to several sesquiterpenes, was a case in point. Indeed, treatment of silyl enol ether 1 with TiCl₄ led to extensive degradation, but, following exhaustive experimentation, it was finally found that a mild Lewis acid such as ZnCl₂ promoted the smooth closure of the cycle to give a 92:8 mixture of bicyclic ketones from which the desired trans diastereomer 2 was isolated in a 54% yield (Scheme [2]).[14] Despite such a successful example, it was necessary to wait for Szimoniak and Moïse’s report on the coupling of enantiomerically pure silyl enol ether 3 and benzaldehyde dimethyl acetal, leading to syn β-methoxy ketone 4, to demonstrate that the intermolecular Mukaiyama aldol reaction with acetals could also become a synthetically useful method for the stereoselective construction of carbon–carbon bonds (Scheme [2]).[15] Alternatively, Rychnovsky placed the stereocontrolling elements on the electrophilic partner, so the enantiomerically pure oxocarbenium intermediate from α-acetoxy ether 5 containing an α-(trimethylsilyl)benzyl group could be trapped by enol silane 6 to give methyl ketone 7 as a single diastereomer (dr 40:1) with an impressive 95% yield (Scheme [2]).[16] The key to understanding such extraordinary π-facial selectivity lies in the rigid conformation of the resultant α-silyl oxocarbenium ion I in which a bulky TMS group determines the approach of the nucleophile (Scheme [2]).

In turn, Funk showed that the intramolecular addition of the titanium enolate from the β-keto ester to the diethyl acetal in 8 delivered β-ethoxy cyclohexanone 9 as a single diastereomer in a high yield (Scheme [3]).[17] In this context and using the Evans method for the formation of titanium enolates, Keck described that the intermolecular reaction of the titanium enolate from chiral ketone 10 with dimethyl acetal 11 allowed for the forging of the advanced intermediate 12 as a single stereoisomer in a 52% yield, from which the total synthesis of rhizoxin D was accomplished (Scheme [3]).[18]

Beyond the results themselves, the transformations represented in Schemes 2 and 3 highlight the crucial role of oxocarbenium intermediates in aldol-like processes and suggested a promising role for dialkyl acetals in stereoselective carbon–carbon bond-forming reactions. Unfortunately, a lack of comprehensive studies have hampered further advances.

Additions to Cyclic Acetals

The theoretical model for nucleophilic additions to cyclic acetals is rooted in conformational grounds. Following preliminary findings by Kishi on the synthesis of C-glycosides,[19] Woerpel established that the stereochemical outcome of the nucleophilic additions to six-membered-ring oxocarbenium intermediates can be understood by considering both the conformational preferences of the cation and the changes associated with its conversion into a tetrahydropyran ring.[20] On the basis that a pseudoaxial trajectory maximizes the overlap of the nucleophile HOMO with the oxocarbenium cation LUMO of the half-chair conformation II represented in Scheme [4], the approach to the upper π-face at C2 leads to the twisted boat conformation III, less stable than the chair-like conformation IV resulting from attack of the nucleophile on the opposite π-face of II. Therefore, the bottom π-face attack finally becomes the most favored. Bearing in mind that the major half-chair conformation depends on the configuration of the C3–C6 stereocenters, these consequently determine the stereochemical outcome of any nucleophilic addition.[20] [21] A related analysis has been applied to the oxocarbenium intermediates from five-membered rings.[22]

Such a conceptual framework was key to account for the outcome of glycosylation reactions.[2] [23] In particular, this was applied to Mukaiyama-like C-glycosylation reactions in the stereoselective construction of tetrahydropyran rings, commonly embedded in a variety of natural products.[24] For instance, studies towards the total synthesis of phorboxazole A reported by Smith involved the addition of acetaldehyde-derived silyl enol ether 14 to 4,6-cis disubstituted acetal 13 to afford 2,6-trans tetrahydropyran ring 15 as a single stereoisomer in a 72% yield (Scheme [5]).[24b] Paterson followed a similar approach to access 2,6-trans tetrahydropyran 18 from acetal 16 and more elaborated enolsilane 17 with complete stereocontrol and a 43% yield en route to swinholide A (Scheme [5]).[24a] Presumably, both reactions evolve through transition state V in which all the substituents are placed at pseudoequatorial positions. Interestingly, Woerpel demonstrated that a through-space effect stabilizes the pseudoaxial conformation of a C5 alkoxy-substituted oxocarbenium cation, VI in Scheme [5], and accounts for the conversion of C5-benzyloxy acetal 19 into 2,5-trans tetrahydropyran 21 with remarkable diastereoselectivity (Scheme [5]).[20]

Since the configuration of the stereocenters and the electronic character of the substituents determine the stereochemical outcome of these Mukaiyama C-glycosylations, it should come as no surprise that some examples do not match the outstanding diastereoselectivities described in Scheme [5]. This was the case for acetate 22, reported by Carda and Marco (Scheme [6]), the glycosylation of which with 23 en route to aspergilide B delivered the 2,6-trans pyran ring 24 with a 55% yield but in a moderate diastereomeric ratio (dr 72:28).[25] Furthermore, the control of the configuration of the exocyclic Cα stereocenter turns out to be tremendously complicated and reactions usually lead to complex mixtures. For instance, studies completed by Heathcock during the synthesis of the C29–C44 fragment of spongistatin 1 revealed that the C-glycosylation of 25 with silyl enol ether 26 afforded a mixture of tetrahydropyrans 27–30 in high yields (Scheme [6]).[26] Treatment of the crude reaction mixture with NaHMDS led to a 2:1 mixture of 29 and 30, and 29 was further converted into the desired 2,6-cis tetrahydropyran 30 following three equilibration cycles using KOH/MeOH with a final overall yield of 79% (Scheme [6]).

Unfortunately, no alternative procedures based on substrate-controlled reactions using metal enolates have been disclosed and the flaws pointed out in Scheme [6] remain unsolved.

Chiral-Auxiliary-Based Processes

Additions to Acyclic Acetals

Despite the successful examples based on substrate-controlled reactions described in Schemes 2 and 3, at the beginning of the present century no general methods for the asymmetric synthesis of α-alkyl-β-alkoxy carbonyl compounds exploiting the reactivity of oxocarbenium intermediates were available. Instead, the approaches towards those targets relied on a two-step sequence, which involved (i) a stereoselective aldol reaction, followed by (ii) the O-alkylation of the resultant aldol product. In this context, considering that the second step is often troublesome and the benefits arising from a single-step process, we launched a project aiming to develop an efficient method for the stereoselective synthesis of α-alkyl-β-alkoxy carboxyl motifs through the Lewis acid mediated intermolecular addition of chiral titanium enolates to acetals. Building on the Evans protocol for the straightforward formation of highly reactive titanium enolates and being aware of the crucial role played by the chiral auxiliary, we initially assessed the reactions of the titanium enolates from the valine-derived imides and thioimides shown in Scheme [7] with the dimethyl acetal of benzaldehyde in the presence of BF₃·OEt₂.[27]

The results summarized in Scheme [7] demonstrated the feasibility of our approach and the crucial role of the exocyclic sulfur atom for the stereocontrolled carbon–carbon bond-forming reaction. Having established the synthetic utility of titanium enolates from chiral thioimides, we next focused our attention on the influence of the C4 group of thiazolidinethiones on the diastereoselectivity. With this in mind, we examined the addition of the titanium enolates formed from the N-propanoyl thiazolidinethiones shown in Scheme [8] to the dimethyl acetal of benzaldehyde in the presence of 1 equivalent of BF₃·OEt₂. Not surprisingly, the steric hindrance of the substituent at C4 was crucial and thioimides possessing a bulky isopropyl or tert-butyl group at that position ended up being the most appropriate. Given the similar diastereoselectivity provided by both thioimides, due to the higher yield achieved, starting material availability, and the ease of separating the major diastereomer product, the valine-derived thiazolidinethione (R: i-Pr in Scheme [8]) was chosen as the most suitable platform from which to carry out further studies.[27]

To our pleasure, the reaction of the titanium enolate of valine-derived thioimide 31 with dimethyl acetals from aromatic and α,β-unsaturated aldehydes in the presence of 1 equivalent of BF₃·OEt₂ at –78 °C proceeded with remarkable stereocontrol and pure anti adducts 31a–f were isolated in high yields (Eq 1 in Scheme [9]).[28] In turn, less reactive acetals from electronically poor aromatic aldehydes or aliphatic aldehydes required a stronger Lewis acid, such as SnCl₄, and sometimes a higher temperature (–20 °C) to provide the corresponding anti α-methyl-β-alkoxy adducts 31g–j in moderate to high yields and high diastereoselectivities (Eq 1 in Scheme [9]).

This chemistry was successfully exported to dibenzyl acetals (Eq 2 in Scheme [9]).[29] Indeed, the anti α-methyl-β-benzyloxy adducts 31k–r, which can be viewed as traditionally protected aldol adducts, were obtained in a single step with high yields and diastereomeric ratios of up to 96:4. Interestingly, double stereodifferentiating reactions with chiral dibenzyl acetals derived from (R)- and (S)-3-tert-butyldiphenylsilyloxy-2-methylpropanal gave the corresponding adducts 31q and 31r with different diastereoselectivities. The mismatched pair involves the (R) acetal, the reaction of which produced the anti-Felkin adduct 31q with poor diastereoselectivity (dr 66:34). Conversely, the matched pair from the (S) acetal produced the Felkin adduct 31r as a single diastereomer (dr 99:1) in a yield of 71%.

The remarkable stereocontrol and high yields of most of these reactions and the relatively easy purification of the resultant mixtures enables the isolation of significant amounts of the anti diastereomers. Furthermore, the straightforward removal of the chiral thiazolidinethione gives access to a wide array of enantiomerically pure α-alkyl-β-alkoxy derivatives, which have been used for the total synthesis of a variety of natural products.[30] Indeed, Goswami took advantage of the reaction of phenylalanine-derived thioimide 32 with dimethyl acetal 33 to obtain the β-methoxy adduct 34 with a high yield and an excellent diastereoselectivity on a multigram scale; further treatment of 34 with DIBAL-H gave aldehyde 35, which was subsequently converted into aldol 36 en route to carolacton (Scheme [10]).[30e] In addition, Crimmins demonstrated the broad scope of the overall transformation using thioimide 37 possessing a longer acyl chain, and dibenzyl acetal 38 to prepare the anti adduct 39, which was reduced with LiBH₄ to the enantiomerically pure alcohol 40, an intermediate in the synthesis of aldingenin B (Scheme [10]).[30b]

The chiral thiazolidinethione can also be removed under non-reducing conditions as in the total synthesis of the antibacterial polyketide thailandamide lactone shown in Scheme [11]. Indeed, the SnCl₄-mediated addition of the titanium enolate of 32 to dimethyl acetal 41 on a multigram scale produced anti adduct 42 in a stereocontrolled manner (dr 95:5, 89% yield); then, treatment of 42 with lithium hydroperoxide furnished enantiomerically pure β-methoxy carboxylic acid 43 containing an ester group in a high yield.[30f] Following the addition of the titanium enolate of valine-derived thioimide 31 to dimethyl acetal 44, Chakraborty chose a lithiated dimethyl methylphosphonate to remove the chiral auxiliary of adduct 45, obtaining β-keto phosphonate 46 in a 92% yield, designed to undergo a Horner–Wadsworth–Emmons (HWE) olefination in an advanced step towards the synthesis of the monomeric unit of the macrolide rhizopodin (Scheme [11]).[30c]

An S_N1-like mechanism accounts for the stereochemical outcome of the former reactions. Indeed, treatment of dialkyl acetals from aromatic or α,β-unsaturated aldehydes with BF₃·OEt₂ produces the corresponding conjugated oxocarbenium cation.[28] In turn, less stable counterparts arising from electronically poor aromatic or aliphatic aldehydes need a stronger Lewis acid. Once generated, the oxocarbenium intermediate, acting as the electrophilic partner, approaches the less hindered Si π-face of the chelated titanium enolate VII and the reaction proceeds through the open transition state VIII (Scheme [12]), which determines the R configuration of the α-stereocenter. In turn, the main anti diastereomer arises through an antiperiplanar arrangement in VIII favored by stereoelectronic and steric considerations. Importantly, the results with the chiral dibenzyl acetals in Scheme [9] support such an S_N1-like mechanism as they can be explained according to the Felkin–Anh model in which the carbon–carbon bond is formed through the addition of the nucleophile to a double carbon–oxygen bond.[29]

Following the success in the abovementioned transformations with propanoyl-like substrates, the challenging acetate version was also assessed. A case in point reported by Smith involves a boron enolate of N-acetyl thiazolidinethione 47 developed by Sammakia[31a] in a BF₃-mediated addition to dimethyl acetal 48 (Scheme [13]). The reaction proceeds through an open transition state to deliver the β-methoxy derivative 49 in 54% yield with good diastereoselectivity (dr 80:20). The adduct 49 was then easily converted into aldehyde 50, an advanced intermediate towards hennoxazole A (Scheme [13]).[31b] Other examples based on titanium enolates have also been described.[32] For instance, Nicolaou employed the titanium enolate from valine-derived thioimide 51 in the BF₃-mediated addition to α,β-γ,δ-unsaturated dimethyl acetal 52 to obtain 53 in a 67% yield. Interestingly, the chiral scaffold was displaced by methyl serinate hydrochloride 54 under mild conditions to furnish β-methoxy amide 55, which was converted into key intermediate 56 towards disorazole A₁ (Scheme [13]).[32e]

An interesting example that demonstrates the utility of such stereoselective methods involves the synthesis of a fragment of debromoaplysiatoxin by combining the addition of titanium enolates from N-propanoyl and N-acetyl thiazolidinethiones to acyclic dialkyl acetals.[33] The synthetic sequence commenced with the reaction of the titanium enolate from valine-derived N-acetyl thiazolidinethione ent-51 with 3-benzyloxybenzaldehyde dimethyl acetal in the presence of BF₃·OEt₂ to give β-methoxy thioimide 57 in an 82% yield (Scheme [14]). Removal of the chiral auxiliary under reducing conditions afforded enantiomerically pure alcohol 58 in an 87% yield, which was further converted into dibenzyl acetal 59. Next, SnCl₄-mediated coupling of 59 with the titanium enolate of N-propanoyl thiazolidinethione 31 allowed for the isolation of the Felkin anti aldol adduct 60 in 74% yield with outstanding diastereoselectivity (dr > 98:2). Eventually, the chiral heterocycle was displaced by simple stirring of 60 in methanol with catalytic DMAP at room temperature to deliver, in a 95% yield, enantiomerically pure ester 61 as a potential precursor for debromoaplysiatoxin (Scheme [14]).

Remarkably, the method tolerated the introduction of an oxygenated substituent at the Cα position of the acyl group (Eq 3 in Scheme [15]).[34] [35] As a result of a thorough scrutiny of the Cα alcohol protecting group, we found that α-pivaloyloxy thioimide 62 was particularly suitable for such a glycolate aldol reaction. As shown in Scheme [15], dimethyl acetals of aromatic and α,β-unsaturated aldehydes reacted with the titanium enolate of 62 in the presence of BF₃·OEt₂ at –78 °C, whereas dialkyl acetals from aliphatic aldehydes, less likely to generate the necessary oxocarbenium intermediate, required SnCl₄ and a higher temperature (Scheme [15]). Under these conditions, thioimide 62 reacted with a wide range of dimethyl and dibenzyl acetals to give the anti aldol products 62a–l in high yields and excellent diastereomeric ratios (Scheme [15]).

Dimethyl ketals from methyl ketones could also undergo similar transformations (Eq 4 in Scheme [16]).[36] These substrates turned out to be less reactive than those from aldehydes and required the use of SnCl₄ at –20 °C. Under these conditions, dimethyl ketals from alkyl methyl ketones (ka–kf) provided anti adducts 31ka–kf, possessing a β-quaternary stereocenter, in high yields and diastereomeric ratios, whereas their counterparts from aryl and α,β-unsaturated ketones (kg and kh, respectively) gave low yields or complex mixtures (Scheme [16]).

Having established a method based on the reaction of titanium enolates from different chiral thioimides with a broad range of acetals, our attention then focused on parallel transformations requiring only substoichiometric amounts of Lewis acids to prepare the metal enolates. Inspired by the Evans report described in Scheme [43] and findings by Sodeoka (see below) on the in situ preparation of nickel(II) triflate complexes, we developed a direct and highly diastereoselective reaction of valine-derived thioimide 31 with substrates prone to produce cationic intermediates catalyzed by tiny amounts of an achiral nickel(II) complex. Indeed, direct reactions of 31 with trimethyl orthoformate and benzhydryl methyl ethers gave a single diastereomer of the adducts 63 and 64 (Scheme [17]).[37]

The nickel(II)-mediated addition of a chiral thioimide to trimethyl orthoformate was the first step of a concise sequence towards the C9–C19 fragment of peloruside A, in which the reaction of a chiral N-acetyl thiazolidinethione with an acetal also plays a crucial role (Scheme [18]).[38] Indeed, the gram-scale and direct reaction of the valine-derived N-butanoyl thiazolidinethione 65 with trimethyl orthoformate catalyzed by commercially available (Me₃P)₂NiCl₂ provided acetal 66 as a single diastereomer. Removal of the chiral auxiliary and protection of the resultant alcohol led to acetal 67. Finally, acidic treatment of 67 followed by a Still–Gennari olefination gave enantiomerically pure (Z)-α,β-unsaturated ester 68 in an 80% overall yield. This intermediate was converted into acetal 69, which underwent a stereocontrolled addition with the titanium enolate from ent-51 to give adduct 70 fairly efficiently (dr 88:12 and a 58% four-step yield). Finally, treatment of 70 with DIBALH afforded the expected aldehyde, which was immediately submitted to a Mukaiyama aldol reaction with ketene silyl acetal 71 to provide the enantiomerically pure C9–C19 fragment 72 (Scheme [18]).

Efforts to apply such a nickel-catalyzed reaction of thioimide 31 to acetals proved unsuccessful and mixtures of the syn and anti adducts were usually isolated with poor stereocontrol. Better results were obtained from α-pivaloyloxy and α-azidoacetyl thiazolidinethiones, 62 and 73 respectively.[39] Particularly, the latter substrate turned out to be a stunning platform to gain access to α-amino-β-hydroxy acids in a highly efficient manner.[39b] Indeed, reactions of thioimide 73 with aromatic acetals produced anti α-azido-β-alkoxy adducts with noteworthy stereocontrol (Eq 5 in Scheme [19]). The reaction was applied to methyl, allyl, and benzyl acetals and produced the corresponding products with similar yields and diastereomeric ratios. However, it was rather sensitive to the electronic character of the substituents, so benzaldehyde and 4-chlorobenzaldehyde dimethyl acetals required higher loadings of the nickel(II) complex to achieve adducts 73f and 73g, respectively, with moderate to low yields (Scheme [19]).

The proposed mechanism to account for these catalytic transformations is represented in Scheme [20].[39b] A feature worth highlighting is the twofold role of TESOTf. Initially, TESOTf converts the commercially available and easy to handle (Me₃P)₂NiCl₂ into the more reactive (Me₃P)₂Ni(OTf)₂. Next, this new nickel(II) species coordinates to the thioimide to form complex IX in which the acidity of the Cα-H has been enhanced enough to be removed by 2,6-lutidine (B in Scheme [20]) leading to nickel(II) enolate X, the nucleophilic partner of the reaction. In parallel, reaction of TESOTf with the dialkyl acetal gives the oxocarbenium intermediate XI, namely the electrophilic partner, which adds to X through open transition state XII. Once the carbon–carbon bond is formed, the resultant complex XIII releases the final adduct and the nickel(II) catalyst, ready to start a new cycle (Scheme [20]).

The simplicity of the experimental procedure and the easy manipulation of the resultant adducts make this catalytic reaction an appealing entry for creating non-proteinogenic α-amino-β-hydroxy acids that are present in many biologically active cyclopeptides and depsipeptides. The synthesis of tripeptide 74, structurally close to a fragment of vancomycin, is a case in point (Scheme [21]).[40] Indeed, reaction of thioimide 73 with 4-benzyloxybenzaldehyde diallyl acetal in the presence of 5 mol% of (Me₃P)₂NiCl₂ furnished a crude mixture containing a single diastereomer (dr > 95:5), from which pure anti aldol product 75 was isolated in 76% yield. Displacement of the chiral auxiliary with tert-butyl l-asparaginate hydrochloride took place smoothly and dipeptide 76 was obtained (90%, dr > 95:5). Next, reduction of the azido group followed by a standard coupling of the resultant amine with N-Fmoc-N-methyl-l-leucine, and a terminal amine deprotection delivered tripeptide 74 ready for further coupling (Scheme [21]).

Aiming to expand the scope of the direct and catalytic reaction of thioimide 73, we assessed the use of other acetals. Unfortunately, acetals from aliphatic aldehydes turned out to be unsuitable, but the cobalt-derived propargylic counterparts met the challenge and proceeded with extraordinary stereocontrol (Eq 6 in Scheme [22]). Indeed, reaction of a plethora of cobalt propargylaldehyde diethyl acetals provided single diastereomers (dr > 97:3) of the aldol adducts 73h–o in good yields (62–76%) with the only exception being 73h (Scheme [22]).[39b] Since removal of the cobalt releases a carbon–carbon triple bond, such an approach may give access to a variety of enantiomerically pure derivatives.

Chiral auxiliaries have also been employed in stereoselective vinylogous Mukaiyama aldol reactions (VMAR) of acyclic acetals.[41] Hosokawa reported that chiral vinyl ketene silyl N,O-acetals 77 and 78, with or without a methyl group at the C2 position respectively, reacted with dimethyl and dibenzyl acetals from aliphatic, α,β-unsaturated, and aromatic aldehydes to give protected polyketide syn motifs 77a–g and 78a–g in high yields with an amazing remote asymmetric induction (Eq 7 and Eq 8 in Scheme [23]).[42]

The π-facial discrimination hinges on the chiral auxiliary and the syn configuration arises from different approaches of the oxocarbenium intermediate to C4. The transition states to account for such a stereochemical outcome (see Scheme [23]) confirm the key role of the oxocarbenium intermediates.

Extension of this chemistry to acetate-type reactions was successfully completed by Liu.[43] In particular, the gram-scale addition of E-vinyl ketene silyl N,O-acetal 79 to dimethyl acetal 80 furnished the δ-methoxy derivative 81 with excellent stereocontrol in a high yield, which demonstrated the synthetic utility of these methods (Scheme [24]). In turn, the chiral auxiliary was displaced using the classical procedure to yield carboxylic acid 82, an advanced intermediate towards the depsipeptide nannocystin Ax (Scheme [24]).

Additions to Cyclic Acetals and Glycals

The number of stereoselective additions of chiral metal enolates to oxocarbenium intermediates from cyclic acetals is scarce. Pilli pioneered this field when in 2000 he described the use of chiral titanium enolates for the stereoselective synthesis of 2,5-disubstituted tetrahydrofurans. In particular, titanium enolates from N-propanoyl-1,3-oxazolidin-2-ones 83 and ent-83 reacted with lactol 84, derived from (S)-glutamic acid, to yield 2,5-trans tetrahydrofurans 85a and 85b (Scheme [25]).[44]

Lessons learned from these reactions were manifold, since (i) they proved that chiral titanium enolates could participate in stereoselective additions to cyclic oxocarbenium intermediates, (ii) the configuration of C2 at the furan ring was mainly controlled by that of C5, and (iii) the configuration of the Cα stereocenter was basically controlled by the chiral auxiliary.

With these ideas in mind, and taking advantage of our own experience on intermolecular reactions with acyclic acetals (see Scheme [9]), we envisaged that titanium enolates from valine-derived thioimides might undergo stereocontrolled Lewis acid mediated additions to cyclic oxocarbenium intermediates derived from glycals to furnish the corresponding dihydropyrans with significant control of the configuration of both the C2 and Cα stereocenters. The results confirmed our hypothesis, and three out of the four potential stereoisomers were prepared with remarkable diastereoselectivity (Scheme [26]).[45a]

Indeed, SnCl₄-mediated addition of the titanium enolates from thioimide 31 to a wide range of glycals gave the 2,6-trans pyrans 31ga–gg (Eq 9 in Scheme [27]). The 2,6-trans configuration of the resultant pyran turned out to be independent of the C6 substituent and the protecting groups at R¹ and R², with the best yields being those from C6 non-ester-protected glycals ge, gf, and gg. Furthermore, the chiral auxiliary of 31 imparted absolute control of the R configuration of the Cα stereocenter.

The stereochemical outcomes of the parallel reactions of ent-31 were a little more complicated (Eq 10 in Scheme [27]). The S configuration of the Cα stereocenter also hinged on that of the chiral thiazolidinethione heterocycle, as in the R series. However, the major diastereomer depended in this case on the group at C6: ester protecting groups of the alcohol at C6 gave the 2,6-cis pyrans ent-31ga–gd with high to excellent stereocontrol of the C2 configuration, while similar reactions with silyl protecting groups, as in ent-31ge and ent-31gf, provided the 2,6-trans pyrans as a single diastereomer. The same trans trend was observed for deoxyglucal gg.

In summary, the stereochemical outcome of the C-glycosylation reactions involving titanium enolates from 31 (or ent-31) hinges on both the chiral auxiliary and the structure of the glycal compound. The configuration of Cα was closely associated to the chiral auxiliary employed (31 or ent-31), whereas that of C2 depends on the glycal and, particularly, on the R¹ group at C6. In short, non-oxygenated R¹ groups (R¹: Me) or silyl-protected hydroxylated groups (R¹: CH₂OTBS) consistently produced the corresponding 2,6-trans pyrans, but ester-protected hydroxylated groups (R¹: CH₂OAc or CH₂OBz) provided 2,6-trans or 2,6-cis pyrans depending on the chiral auxiliary employed. The impact of the R² groups was less important and had only a limited influence on the configuration of the main diastereomer.[45]

These details were crucial for the use of such a C-glycosylation in the synthesis of natural products. A representative example can be found in the approach to the C1–C17 fragment of the polyether salinomycin (Scheme [28]).[46] In accordance with the observed trends, the SnCl₄-mediated addition of the titanium enolate from 65 to pseudoglycal 86 gave a crude mixture containing a single diastereomer (dr > 97:3 by ¹H NMR) of 2,6-trans pyran 87 from which pure ester 88 was isolated, after displacement of the chiral auxiliary, as an enantiomerically pure intermediate in a 75% two-step yield. Further manipulation of 88 yielded the C1–C17 fragment 89 of salinomycin (Scheme [28]).

In turn, Leighton and Krische demonstrated that the abovementioned C-glycosylation method could also be used with cyclic acetals. Leighton first reported the successful use of titanium enolates from ent-31 for the stereoselective addition to cyclic acetal 90 en route to zincophorin methyl ester (Scheme [29]).[47a] Indeed, the initial sequence involved the reaction of acetal 90 containing different protected alcohols to yield the 2,6-trans tetrahydropyran 91 as a single diastereomer. Next, methanolysis of 91 quantitatively gave methyl ester 92 from which zincophorin methyl ester was finally prepared. Further studies showed that related acetal 93 consistently reproduced the stereochemical outcome of the glycosylation with TES protecting groups (Scheme [29]). Finally, the most efficient approach took advantage of the addition to a small fragment 95 possessing a non-protected ketone (Scheme [29]).[47b] All together, these transformations prove the feasibility of the C-glycosylation of cyclic acetals using titanium enolates and the outstanding control on the configuration of both the Cα and the C2 stereocenters provided that the structural requirements are met. As for glycals, the configuration of Cα hinges on the chiral auxiliary employed, while the C6-alkyl group of the oxocarbenium intermediate determines that of the C2 stereocenter and the trans relative configuration of the tetrahydropyran.

Krische also employed this method for his asymmetric synthesis of the zincophorin methyl ester (Scheme [30]).[48] Amazingly, a late-step C-glycosylation involving the titanium enolate from ent-31 and the fully elaborated acetal 97 containing an unprotected alcohol at C13 gave the expected 2,6-trans tetrahydropyran 98 as a single diastereomer. Subsequent treatment of 98 with methanol led to the desired zincophorin methyl ester with a 37% two-step yield (Scheme [30]).

All these examples indicate that chiral titanium enolates can participate in highly stereoselective additions to cyclic oxocarbenium intermediates from lactols, acetals, pseudoglycals, and glycals with excellent control of the configuration of both the Cα and the C2 stereocenters.[45]

Chiral-Catalysis-Based Processes

The increasing need for efficient processes adapted to the conditions dictated by atom economy[49] and green chemistry[50] has triggered the development of a wide range of catalytic transformations. In particular, the feasibility of oxocarbenium cations as electrophilic intermediates in asymmetric, direct, and catalytic aldol reactions has been convincingly demonstrated in some amazing transformations.

The challenge of generating the oxocarbenium intermediates in the presence of the nucleophilic partner has promoted the blossoming of new activation modes.[51] Common approaches rely on the removal of a leaving group from an oxygenated position promoted by the solvent, a catalyst, or an additive (route A in Scheme [31]), but other strategies based on the activation of a carbonyl compound with a silyl triflate (route B in Scheme [31]), or the selective oxidation of benzylic ethers (route C in Scheme [31]) also came onto the scene and opened appealing opportunities for the generation of oxocarbenium cations.

In this context, the examples below prove that both small chiral molecules and metal complexes are suitable tools to perform catalytic and asymmetric reactions evolving through oxocarbenium cations, with a stark difference between acyclic and cyclic substrates.[12] [52]

Organocatalysis

A milestone in the field was the use of chiral hydrogen-bond donors to catalyze enantioselective Mukaiyama additions to acetals, as reported by Jacobsen. Indeed, the reaction of a variety of enolsilanes with dibenzyl acetals from bromobenzaldehydes in the presence of 10 mol% of squaramide 99 and TBSOTf gave the corresponding β-benzyloxy carbonyl compounds 100–103 in excellent yields and enantioselectivities (Eq 11 in Scheme [32]).[53]

This new mode of action relies on the generation of oxocarbenium intermediates promoted by a silyl triflate–chiral squaramide combination XV (Scheme [33]).

The key point is the greater reactivity of silyl triflates through association with a chiral squaramide XIV which enables the formation of the required electrophilic oxocarbenium cation from a stable acetal (Route A in Scheme [31]). The resultant oxocarbenium/squaramide–triflate ionic pair XVI is then trapped by the nucleophilic enolsilane to provide the corresponding β-benzyloxy carbonyl compound XVII in a highly stereocontrolled manner.

Rather than using an ionizing method to transform acetals into the desired oxocarbenium species (Route A in Scheme [31]), a completely different strategy consists of the activation of a carbonyl compound with a silyl triflate followed by the reaction with a nucleophile (Route B in Scheme [31]). If the silyl group remains in the final product, differences between both routes simply lie on the substituent, carbon or silicon, in the resultant aldol product, but a common mechanism could be operative in both cases. This is what List reported in a seminal article, in which challenging aldol reactions of a wide range of aldehydes with acetaldehyde enolsilanes catalyzed by 0.5–1 mol% of imidodiphosphorimidates, or IDPi, 104a–c led to aldol products 105–111 in high yields and enantioselectivities (Eq 12 in Scheme [34]).[54] As proof of the utility of this method, the antidepressant (S)-duloxetine was synthesized through a concise sequence based on a gram-scale aldol reaction of 2-thiophenecarbaldehyde with enolsilane 14 catalyzed by 0.5 mol% of 104c, delivering quantitatively the protected aldol 112 as a single enantiomer (Scheme [34]).

The reaction is suggested to commence with the in situ silylation of the IDPi (H–X in Scheme [35]). The resultant silylated species XVIII, the actual catalyst, is very reactive and easily interacts with the aldehyde to give rise to the oxocarbenium-like intermediate XIX, which undergoes an irreversible reaction with the enolsilane to yield the protected aldol XX (Scheme [35]).[55]

This method was further applied to Mukaiyama reactions of the TBS ketene acetal from methyl acetate with methyl ketones catalyzed by IDPi 104d to afford enantioenriched β-methyl-β-silyloxy propanoates 113–118 with high yields (Eq 13 in Scheme [36]).[56] As proof of the synthetic potential of the method, a 2 g scale reaction of (E)-4-phenyl-3-buten-2-one was successfully completed with an extremely low loading of catalyst 104d to furnish the protected aldol adduct 117 in an 88% yield (Scheme [36]).

Parallel to these studies, Mukaiyama C-glycosylations of cyclic oxocarbenium intermediates have also attracted much attention. In a pioneering study, Jacobsen used chiral thiourea 119 as a hydrogen-bond donor organocatalyst to carry out highly enantioselective reactions of symmetric tetrasubstituted silyl ketene acetals with chloroisochromans to give enantioenriched tetrahydropyrans 120–123 in high yields (Eq 14 in Scheme [37]).[57] Despite its limited scope, this method unveiled a new model of catalysis based on anion abstraction. The mechanistic hypothesis, consistent with an oxocarbenium-chloride thiourea complex as the reactive electrophilic species (Scheme [37]), guided the rational design of a bis-thiourea catalyst with enhanced activity.

A totally different reaction involving prochiral cyclic oxocarbenium ions was reported by Lou and Liu.[58] On this occasion, the cationic intermediate arises from the selective DDQ oxidation of cyclic benzylic ethers (see Route C in Scheme [31]) or thioethers, whereas the nucleophilic partner is a chiral E-enamine from the MacMillan amine 124 (Eq 15 in Scheme [38]). Standard reduction of the resultant mixtures gave isochroman alcohols 125–128 with moderate to good diastereoselectivity and high enantiocontrol. Isothiocroman and phthalan ether were also suitable substrates and furnished alcohols 129 and 130 with similar results; it is also important to note that the acyclic benzyl methyl ether shown in Scheme [38] did not yield the desired alcohol 131 and benzaldehyde was isolated as the major product instead. Further evidence suggested that the triflate oxocarbenium complex was the real electrophilic species.

Finally, a groundbreaking report by List described the reaction of oxygen-containing heterocycles from readily accessible lactol acetates with enolsilanes catalyzed by imidodiphosphorimidates (Eq 16 in Scheme [39]).[59] The remarkable acidic character of IDPi enables them to participate in silylium-based asymmetric counteranion-directed catalysis through the conversion of a wide range of lactols into non-stabilized cyclic oxocarbenium intermediates. Furthermore, the confined active site of IDPi 104e allows for an efficient π-facial discrimination of sterically and electronically unbiased oxocarbenium intermediates and provides the corresponding enantioenriched C-glycosides 132–140 in high yields (Scheme [39]).

A significant extension of this procedure involves the IDPi-catalyzed synthesis of five- and six-membered oxygenated heterocycles from dicarbonyl compounds. The mechanistic idea behind such an approach is highlighted in Scheme [40] for the asymmetric construction of a tetrahydrofuran heterocycle from a 4-ketoaldehyde catalyzed by an IDPi. As previously indicated (see Scheme [35]), treatment of the IDPi with a silyl ketene acetal produces the real catalytic species XVIII. This silylium catalyst then coordinates to the less sterically hindered aldehyde to produce an activated intermediate XXI, which undergoes a ring closure to give cyclic oxocarbenium XXII. Finally, Mukaiyama addition of the silyl ketene acetal to XXII affords the substituted tetrahydrofuran XXIII and regenerates the catalytic species XVIII. Once again, the π-facial discrimination of the C=O bond of XXII hinges on the counteranion of the IDPi.

The cyclic acetal in XXII (Scheme [40]) enabled further transformations based on substitution of the silyloxy group via additional oxocarbenium intermediates. Indeed, Mukaiyama reactions of 4- and 5-ketoaldehydes with ketene silyl acetals catalyzed by IDPi 104f and treatment of the resultant cyclic acetals with appropriate nucleophiles under acidic conditions gave a variety of highly decorated five- or six-membered oxygenated heterocycles 141–149 (Eq 17 in Scheme [41]).[60] The use of Et₃SiH furnished enantioenriched 2,2-disubstituted heterocycles 141–146, whereas parallel reactions with carbon nucleophiles stereoselectively provided 2,2,5-trisubstituted tetrahydrofurans 147–149 in high yields (Scheme [41]).

Interestingly, submission of the cyclic acetal intermediate 150 to a new Mukaiyama glycosylation catalyzed by IDPi ent-104e or 104e led to the selective formation of either the cis or trans 2,2,5-trisubstituted tetrahydrofurans, 151 or 152 respectively, overcoming the intrinsic bias imparted by the substrate (Scheme [42]).[60]

The results of all these processes demonstrate that organocatalysts cover a wide range of aldol-like reactions proceeding through acyclic or cyclic oxocarbenium intermediates. All of them, apart from that reported by Liu, rely on Mukaiyama reactions and provide excellent control of the configuration of the Cβ stereocenter. Nevertheless, the challenge of stereoselectively installing a Cα stereocenter has only been addressed by Lou and Liu’s procedure[58] with moderate success and thus remains unmet.

Metal Catalysis

Chiral metal catalysts have also been used in stereoselective reactions involving oxocarbenium intermediates. Evans first showed, in a groundbreaking study, that achiral N-acyl-1,3-thiazolidine-2-thiones reacted with trimethyl orthoformate in the presence of BF₃·OEt₂, 2,6-lutidine, and 5 mol% of chiral nickel(II) complex 153, [(S)-Tol-BINAP]Ni(OTf)₂, to give chiral 3,3-dimethoxy adducts 154–161 with notable stereocontrol (Eq 18 in Scheme [43]).[61] Saturated alkyl-substituted substrates provided the desired compounds in lower yields than the related allyl or benzyl counterparts; furthermore, the reaction tolerated a phenyl and an oxygenated substituent at Cα to deliver the corresponding products, 160 and 161 respectively, in high yields and enantioselectivities (Scheme [43]).

The proposed mechanism is outlined in Scheme [44]. Basically, the coordination of the chiral nickel(II) triflate and the N-acyl thiazolidinethione XXIV gives rise to XXV, in which the increased acidity of Cα-H enables 2,6-lutidine to form the Z-enolate XXVI. This then reacts with the oxocarbenium intermediate, generated in situ from the reaction of trimethyl orthoformate and BF₃·OEt₂, to give XXVII. Finally, dissociation of the nickel(II) complex regenerates the catalyst and furnishes the desired product XXVIII (Scheme [44]).

As mentioned before (see Scheme [17]), this study and further findings by Sodeoka[62] were the basis for a project aiming to develop direct carbon–carbon bond-forming reactions catalyzed by nickel(II) complexes through cationic intermediates. With the first results of these studies, we established that direct reactions of N-acyl-1,3-thiazinane-2-thiones with cationic electrophiles, formed according to Route A in Scheme [31], catalyzed by tiny amounts of a chiral nickel(II) complex 162, [(R)-DTBM-SEGPHOS]NiCl₂, in the presence of TESOTf and 2,6-lutidine delivered adducts 163–167 possessing a single stereocenter at Cα with amazing stereocontrol (Eq 19 in Scheme [45]).[63] Interestingly, azidoacetyl thiazolidinethione 168 turned out to be an impressive starting material to perform such transformations (Scheme [45]). Indeed, the reaction with trimethyl orthoformate catalyzed by [(S)-Tol-BINAP]NiCl₂ (169) and treatment of the resultant adduct with benzyl amine produced enantiomerically enriched (ee 96%) amide 170 in an 88% yield, from which the total synthesis of the antiepileptic agent lacosamide was completed in a few steps.[64]

The successful installation of the Cα stereocenter in so many processes encouraged us to tackle further challenges. In particular, we envisaged that the appropriate silyl triflate activation of an aldehyde might lead to an oxocarbenium-like intermediate (Route B in Scheme [31]) able to react with simultaneously generated nickel enolates to provide the corresponding silyl-protected aldol products and thus selectively introduce two new stereocenters. Following a thorough assessment of the experimental conditions, it was finally established that TIPSOTf-mediated reactions of N-acyl-1,3-thiazinane-2-thiones with aromatic aldehydes catalyzed by 2–10 mol% of [(R)-Tol-BINAP]NiCl₂ ( ent-169) allowed for the isolation of enantiomerically pure (ee 90–99%) anti aldol products 171–182 in high yields (Eq 20 in Scheme [46]).[65]

The reaction is compatible with double and triple carbon–carbon bonds, halides, ethers, and ester groups, and allows for the isolation of pure (2S,3R) anti diastereomers in yields ranging from 60 to 80%. Aldehydes containing electron-poor aromatic rings usually require higher loadings of the catalyst and longer reaction times. In turn, the reaction features a remarkable stereocontrol as the diastereoselectivity is usually larger than 80:20, and the enantioselectivity is predominantly over 97% (Scheme [46]).[65]

These excellent results motivated our interest in expanding such chemistry to other substrates. We were particularly keen to apply it to the azidoacetyl thiazolidinethione 168 to gain access to non-proteinogenic α-amino acids, as we had previously achieved using chiral auxiliaries (see Schemes 19–21). To our pleasure, the TIPS-mediated aldol reaction of 168 with aromatic aldehydes, catalyzed by 2–6 mol% of nickel complex 169 produced a single enantiomer (ee 99%) of the protected anti aldol products 168a–i in diastereoselectivities normally higher than dr 93:7 and in yields of up to 95% (Eq 21 in Scheme [47]).[66] In particular, the reaction with benzaldehyde catalyzed by 4 mol% of ent-169 furnished enantiomerically pure anti aldol ent-168c (dr 93:7, ee 99%) in an 89% yield through a mechanism like that represented in Scheme [20]. Displacement of the thiazolidinethione with H-Pro-Ot-Bu led quantitatively to 183, and appropriate manipulation of the azido group, followed by a further coupling with Fmoc-Asn-OH and standard removal of the Fmoc group from the resulting product afforded tripeptide 185 containing a β-hydroxy phenylalanine residue (Scheme [47]).[66]

The direct reaction of oxocarbenium intermediates from acyclic dimethyl acetals was also exploited by Liu to gain access to anti α-alkyl or α-aryl-β-methoxy thioimides (Eq 22 in Scheme [48]).[67] Indeed, the addition of N-acyl oxazolidinethiones to dimethyl acetals activated by BF₃·OEt₂ and catalyzed by 10 mol% of the chiral nickel triflate 153 provided mixtures of aldol adducts in high overall yields, from which the anti stereoisomers 186–194 were mainly obtained with remarkable enantioselectivities (ee 88–99%). Unfortunately, the synthetic applications of this method may be restricted by the low diastereoselectivities (dr anti/syn ≈ 60:40) observed in most of the examples.

The mechanism proposed to account for such results is represented in Scheme [49]. As for similar processes, the chiral nickel triflate initially coordinates to the arylacetyl oxazolidinethione XXIX to yield XXX, which can be smoothly converted into chelated nickel enolate XXXI. Next, the crucial carbon–carbon bond-forming step involves the reaction of XXXI with oxocarbenium XXXII, generated from benzaldehyde dimethyl acetal and BF₃·OEt₂, to produce XXXIV. Interestingly, the authors suggest that the base may reversibly interact with oxocarbenium XXXII to give pyridinium complex XXXIII, which can be viewed as a weak electrophilic reservoir of XXXII. Finally, regeneration of the nickel catalyst from XXXIV releases the final anti aldol product XXXV.[67]

In this context and aiming to gain access to protected syn aldol compounds, we carefully analyzed the direct asymmetric reaction of thioimides with acetals catalyzed by chiral nickel complexes. As a result, we established that the reaction of a wide range of N-acyl oxazinanethiones with dialkyl acetals from aromatic aldehydes activated by TMSOTf and catalyzed by 2–5 mol% of [(R)-DTBM-SEGPHOS]NiCl₂ (162) allowed for the isolation of enantiomerically pure (most ee values are ≥97%) syn α-alkyl-β-alkoxy thioimides 195–207 with noteworthy diastereoselectivity (dr > 80:20) and yields of 62–82% (Eq 23 in Scheme [50]).[68] In particular, methyl, allyl, and benzyl acetals can be used interchangeably (compare 195–197), while para-, meta-, and ortho-isomers (compare 199–201) all provide similar results. Furthermore, the reaction was highly chemoselective and significant stereocontrol was achieved for compounds containing alkenes, alkynes, and ester functional groups for R; even an α-benzyloxy group was tolerated and the corresponding α,β-dioxygenated adduct 207 (dr 68:32, ee 95%) was isolated in 47% yield (Scheme [50]).

Such a method complements, to a certain extent, that described in Scheme [46] and 47, making the synthesis of any of the potential protected aldol products at will possible through the adequate choice of the scaffold (thiazinanethione versus oxazinanethione), the electrophile (aldehyde versus acetal), and the catalyst (Tol-BINAP versus DTBM-SEGPHOS).

Following a substantially different approach, Scheidt opened a valuable route to the stereoselective synthesis of oxygenated heterocycles based on the intramolecular cross-dehydrogenative coupling of β-keto-δ-alkoxy esters. This new process combines the catalytic generation of a copper(II) enolate and the oxidative conversion of an ether into a transient oxocarbenium electrophile to access, through a stereoselective carbon–carbon bond-forming reaction, substituted tetrahydropyranones (Eq 24 in Scheme [51]).[69] In detail, the mechanism of such a transformation relies on the intramolecular reaction of a chelated and chiral enolate from a relatively acidic β-ketoester and the copper(II) bisoxazoline 208 with an oxocarbenium cation arising from the oxidation of an allylic or benzylic ether with DDQ (for a related example, see Scheme [38]). The resultant tetrahydropyranones are isolated in good to high yields as the sole trans diastereomers 209–214 (dr ≥ 95:5) with reasonable enantioselectivities (Scheme [51]).

In a similar scenario and facing the limited scope of the abovementioned method, Liu recently developed a catalytic coupling of saturated ethers with thioimides. This one-pot transformation involves the initial copper(I)-mediated oxidation of an acyclic or cyclic ether and subsequent reaction of the resultant acetal with a nickel enolate catalytically generated from a thioimide and chiral nickel(II) triflates 215 or 220. In particular, oxidation of acyclic ethers in the presence of benzoic acid provided activated acetals, which were then treated with BF₃·OEt₂, 2,4,6-collidine, and 10 mol% of [(S)-MeO-BIPHEP]Ni(OTf)₂ (Eq 25 in Scheme [52]).[70]

This one-pot process yielded the syn and anti β-alkoxy adducts 216–219 as equimolar diastereomeric mixtures in which the configuration of the Cα stereocenter was controlled (ee 80–95%) by the chiral catalyst. In turn, parallel reactions with cyclic ethers catalyzed by chiral nickel(II) triflates 215 or 220 were also examined (Eq 26 in Scheme [52]).[70] These turned out to be successful and C-glycosides 222–229 were obtained in good to high overall yields and remarkable enantioselectivities (ee 92–98%) but with moderate diastereoselectivities (dr ≈ 2:1). The reaction was notably restricted to arylacetyl and β,γ-unsaturated thioimides since submission of N-butanoyl thiazolidinethione to the same experimental conditions did not produce the expected compound 221 (Scheme [52]).

The process is postulated to evolve through an oxocarbenium intermediate, as represented in Scheme [53] for the coupling of the N-phenylacetyl thiazolidinethione and tetrahydrofuran. Indeed, the cyclic ether THF undergoes a regioselective oxidation to provide acetal XXXVI, which is subsequently converted into the crucial cyclic oxocarbenium XXXVII by treatment with BF₃·OEt₂. Importantly, the base may partially capture the highly reactive oxocarbenium cation to form complex XXXVIII, which acts as an electrophilic reservoir for the catalytic cycle. Once formed, XXXVII can react with the chelated nickel enolate XXXIX in the carbon–carbon bond-forming step that determines the configuration of the two new stereocenters in the resultant complex XL, which finally releases C-glycoside XLI (Scheme [53]).

As for organocatalysis, the examples summarized in this section show the synthetic ability of chiral nickel and copper complexes to catalyze aldol reactions proceeding through oxocarbenium intermediates. In retrospect, the reactions involving the simultaneous installation of two new stereocenters achieve significant stereocontrol, but methods with broader scope that include cyclic acetals are still required.

Conclusions

Nowadays, oxocarbenium cations arising from a wide range of substrates hold a strategic position in aldol-like processes leading to β-alkoxy carbonylic compounds. As we have sought to demonstrate throughout this Account, treatment of acyclic and cyclic acetals, glycals, and orthoesters with appropriate Lewis acids as well as the activation of aldehydes and ketones with silyl triflates give rise to highly reactive oxocarbenium intermediates that react with d² synthons, namely enolsilanes, metal enolates, or enamines, to forge new carbon–carbon bonds with remarkable stereocontrol. Recent contributions taking advantage of catalytic transformations have joined more classical examples based on stoichiometric grounds to significantly increase the utility of such methods and to place aldol-like asymmetric transformations proceeding through S_N1-like mechanisms in a privileged position to attain the stereoselective synthesis of natural products.

Conflict of Interest

The authors declare no conflict of interest.

• References

• 1 New address: Department of Chemistry, Faculty of Sciences, Universitat de Girona, Carrer Maria Aurèlia Capmany 69, 17003 Girona, Catalonia, Spain.
• 2a Adero PO, Amarasekara H, Wen P, Bohé L, Crich D. Chem. Rev. 2018; 108: 8242
  CrossrefPubMedSearch in Google Scholar
• 2b Franconetti A, Ardá A, Asensio JL, Blériot Y, Thibaudeau S, Jiménez-Barbero J. Acc. Chem. Res. 2021; 54: 2552
  CrossrefPubMedSearch in Google Scholar
• 3 Mukaiyama T, Hayashi M. Chem. Lett. 1974; 3: 15
  CrossrefPubMedSearch in Google Scholar
• 4 Saigo K, Osaki M, Mukaiyama T. Chem. Lett. 1976; 5: 769
  CrossrefSearch in Google Scholar
• 5 Murata S, Suzuki M, Noyori R. J. Am. Chem. Soc. 1980; 102: 3248
  CrossrefSearch in Google Scholar
• 6 Murata S, Suzuki M, Noyori R. Tetrahedron 1988; 44: 4259
  CrossrefSearch in Google Scholar
• 7a Mori I, Ishihara K, Flippin LA, Nozaki K, Yamamoto H, Bartlett PA, Heathcock CH. J. Org. Chem. 1990; 55: 6107
  CrossrefSearch in Google Scholar
• 7b Denmark SE, Almstead NG. J. Am. Chem. Soc. 1991; 113: 8089
  CrossrefSearch in Google Scholar
• 7c Denmark SE, Almstead NG. J. Org. Chem. 1991; 56: 6458
  CrossrefSearch in Google Scholar
• 7d Sammakia T, Smith RS. J. Am. Chem. Soc. 1992; 114: 10998
  CrossrefSearch in Google Scholar
• 7e Sammakia T, Smith RS. J. Am. Chem. Soc. 1994; 116: 7915
  CrossrefSearch in Google Scholar
• 8 Evans DA, Urpí F, Somers TC, Clark JS, Bilodeau MT. J. Am. Chem. Soc. 1990; 112: 8215
  CrossrefSearch in Google Scholar
• 9 Ciez D, Palasz A, Trzewik B. Eur. J. Org. Chem. 2016; 1476
  Crossref
• 10a Elian M, Chen MM. L, Mingos MP, Hoffmann R. Inorg. Chem. 1976; 15: 1148
  CrossrefSearch in Google Scholar
• 10b Hoffmann R. Angew. Chem., Int. Ed. Engl. 1982; 21: 711
  CrossrefSearch in Google Scholar
• 11a Mukaiyama T, Murakami M. Synthesis 1987; 1043
  Thieme Connect
• 11b Fujioka H. Chem. Pharm. Bull. 2020; 68: 907
  CrossrefPubMedSearch in Google Scholar
• 12a Trost BM, Brindle CS. Chem. Soc. Rev. 2010; 39: 1600
  CrossrefPubMedSearch in Google Scholar
• 12b Yamashita Y, Yasukawa T, Yoo W.-J, Kitanosono T, Kobayashi S. Chem. Soc. Rev. 2018; 47: 4388
  CrossrefPubMedSearch in Google Scholar
• 12c Trost BM, Hung C.-I, Mata G. Angew. Chem. Int. Ed. 2020; 59: 4240
  CrossrefPubMedSearch in Google Scholar
• 13a In Modern Methods in Stereoselective Aldol Reactions. Mahrwald R. Wiley-VCH; Weinheim: 2013
  Search in Google Scholar
• 13b Kennington SC. D, Costa AM, Romea P, Urpí F. Diastereoselective Aldol Reactions. In Reference Module in Chemistry, Molecular Sciences, and Chemical Engineering. Elsevier; Amsterdam: 2022.
  CrossrefSearch in Google Scholar
• 14 Taylor MD, Minaskanian G, Winzenberg KN, Santone P, Smith AB. III. J. Org. Chem. 1982; 47: 3960
  CrossrefSearch in Google Scholar
• 15 Lefranc H, Szymoniak J, Delas C, Moïse C. Tetrahedron Lett. 1999; 40: 1123
  CrossrefSearch in Google Scholar
• 16 Rychnovsky SD, Cossrow J. Org. Lett. 2003; 5: 2367
  CrossrefPubMedSearch in Google Scholar
• 17 Funk RL, Fitzgerald JF, Olmstead TA, Para KS, Wos JA. J. Am. Chem. Soc. 1993; 115: 8849
  CrossrefSearch in Google Scholar
• 18 Keck GE, Wager CA, Wager TT, Savin KA, Covel JA, McLaws MD, Krishnamurthy D, Cee VJ. Angew. Chem. Int. Ed. 2001; 40: 231
  CrossrefPubMedSearch in Google Scholar
• 19 Lewis MD, Cha JK, Kishi Y. J. Am. Chem. Soc. 1982; 104: 4976
  CrossrefPubMedSearch in Google Scholar
• 20a Ayala L, Lucero CG, Romero JA. C, Tabacco SA, Woerpel KA. J. Am. Chem. Soc. 2003; 125: 15521
  CrossrefPubMedSearch in Google Scholar
• 20b Chamberland S, Ziller JW, Woerpel KA. J. Am. Chem. Soc. 2005; 127: 5322
  CrossrefPubMedSearch in Google Scholar
• 21 For recent theoretical calculations, see: Remmerswaal WA, Hansen T, Hamlin TA, Codée JD. C. Chem. Eur. J. 2023; 29: e202203490
  CrossrefPubMedSearch in Google Scholar
• 22a Smith DM, Tran MB, Woerpel KA. J. Am. Chem. Soc. 2003; 125: 14149
  CrossrefPubMedSearch in Google Scholar
• 22b Larsen CH, Ridgway BH, Shaw JT, Smith DM, Woerpel KA. J. Am. Chem. Soc. 2005; 127: 10879
  CrossrefPubMedSearch in Google Scholar

For recent reviews on glycosylation reactions, see:
• 23a Yang Y, Yu B. Chem. Rev. 2017; 117: 12281
  CrossrefPubMedSearch in Google Scholar
• 23b Kinfe HH. Org. Biomol. Chem. 2019; 17: 4153
  CrossrefPubMedSearch in Google Scholar

See, for instance:
• 24a Paterson I, Cumming JG, Ward RA, Lamboley S. Tetrahedron 1995; 51: 9393
  CrossrefSearch in Google Scholar
• 24b Smith AB. III, Minbiole KP, Verhoest PR, Schelhaas M. J. Am. Chem. Soc. 2001; 122: 10942
  CrossrefPubMedSearch in Google Scholar
• 24c Vitale JP, Wolckenhauer SA, Do NM, Rychnovsky SD. Org. Lett. 2005; 7: 3255
  CrossrefPubMedSearch in Google Scholar
• 25 Díaz-Oltra S, Angulo-Pachón CA, Murga J, Falomir E, Carda M, Marco JA. Chem. Eur. J. 2011; 17: 675
  CrossrefPubMedSearch in Google Scholar
• 26 Wallace GA, Scott RW, Heathcock CH. J. Org. Chem. 2000; 65: 4145
  CrossrefPubMedSearch in Google Scholar
• 27 Baiget J, Cosp A, Gálvez E, Gómez-Pinal L, Romea P, Urpí F. Tetrahedron 2008; 64: 5637
  CrossrefSearch in Google Scholar
• 28a Cosp A, Romea P, Talavera P, Urpí F, Vilarrasa J, Font-Bardia M, Solans X. Org. Lett. 2001; 3: 615
  CrossrefPubMedSearch in Google Scholar
• 28b Gálvez E, Romea P, Urpí F. Org. Synth. 2009; 86: 81
  CrossrefSearch in Google Scholar
• 29a Cosp A, Larrosa I, Vilasís I, Romea P, Urpí F, Vilarrasa J. Synlett 2003; 1109
• 29b Gálvez E, Parelló R, Romea P, Urpí F. Synlett 2008; 2951
• 30a Crimmins MT, Dechert A.-MR. Org. Lett. 2009; 11: 1635
  CrossrefPubMedSearch in Google Scholar
• 30b Crimmins MT, Hughes CO. Org. Lett. 2012; 14: 2168
  CrossrefPubMedSearch in Google Scholar
• 30c Pulukuri KK, Chakraborty TK. Org. Lett. 2012; 14: 2858
  CrossrefPubMedSearch in Google Scholar
• 30d Liu H.-M, Chang C.-Y, Lai Y.-C, Yang M.-D, Chang C.-Y. Tetrahedron: Asymmetry 2014; 25: 187
  CrossrefSearch in Google Scholar
• 30e Kuilya TK, Goswami RK. Org. Lett. 2017; 19: 2366
  CrossrefPubMedSearch in Google Scholar
• 30f Sharma H, Mondal J, Ghosh AK, Pal RR, Goswami RK. Chem. Sci. 2022; 13: 13403
  CrossrefPubMedSearch in Google Scholar
• 31a Zhang Y, Sammakia T. Org. Lett. 2004; 6: 3139
  CrossrefPubMedSearch in Google Scholar
• 31b Smith TE, Kuo W.-H, Bock VD, Rolzen JL, Balskus EP, Theberge AB. Org. Lett. 2007; 9: 1153
  CrossrefPubMedSearch in Google Scholar
• 32a Cosp A, Romea P, Urpí F, Vilarrasa J. Tetrahedron Lett. 2001; 42: 4629
  CrossrefSearch in Google Scholar
• 32b Chakraborty TK, Pulukuri KK, Sreekanth M. Tetrahedron Lett. 2010; 51: 6444
  CrossrefSearch in Google Scholar
• 32c Hidgson DM, Man S. Chem. Eur. J. 2011; 17: 9731
  CrossrefPubMedSearch in Google Scholar
• 32d Gajula PK, Sharma S, Ampapathi RS, Chakarborty TK. Org. Biomol. Chem. 2013; 11: 257
  CrossrefPubMedSearch in Google Scholar
• 32e Nicolaou KC, Bellavance G, Buchman M, Pulukuri KK. J. Am. Chem. Soc. 2017; 139: 16636
  Search in Google Scholar
• 33 Cosp A, Llàcer E, Romea P, Urpí F. Tetrahedron Lett. 2006; 47: 5819
  CrossrefPubMedSearch in Google Scholar
• 34 Baiget J, Caba M, Gálvez E, Romea P, Urpí F, Font-Bardia M. J. Org. Chem. 2012; 77: 8809
  CrossrefPubMedSearch in Google Scholar
• 35 For a review on stereoselective aldol reactions of glycolic acid and derivatives, see: Engesser T, Brückner R. Synthesis 2017; 51: 1715
  CrossrefPubMedSearch in Google Scholar
• 36 Checa B, Gálvez E, Parelló R, Sau M, Romea P, Urpí F, Font-Bardia M, Solans X. Org. Lett. 2009; 11: 2193
  CrossrefPubMedSearch in Google Scholar
• 37a Romo JM, Gálvez E, Nubiola I, Romea P, Urpí F, Kindred M. Adv. Synth. Catal. 2013; 355: 2781
  CrossrefSearch in Google Scholar
• 37b Fernández-Valparis J, Romo JM, Romea P, Urpí F, Kowalski H, Font-Bardia M. Org. Lett. 2015; 17: 3540
  CrossrefPubMedSearch in Google Scholar
• 37c Kennington SC. D, Ferré M, Romo JM, Romea P, Urpí F, Font-Bardia M. J. Org. Chem. 2017; 82: 6426
  CrossrefPubMedSearch in Google Scholar
• 38 Kennington SC. D, Romo JM, Romea P, Urpí F. Org. Lett. 2016; 18: 3018
  CrossrefPubMedSearch in Google Scholar
• 39a Romo JM, Romea P, Urpí F. Eur. J. Org. Chem. 2019; 6296
  Crossref
• 39b Fernández-Valparís J, Romea P, Urpí F, Font-Bardia M. Org. Lett. 2017; 19: 6400
  CrossrefPubMedSearch in Google Scholar
• 40 Fernández-Valparís J, Romea P, Urpí F. Eur. J. Org. Chem. 2019; 2745
  Crossref

For reviews on vinylogous Mukaiyama aldol reactions, see:
• 41a Kalesse M, Cordes M, Symkenberg G, Lu H.-H. Nat. Prod. Rep. 2014; 31: 563
  CrossrefPubMedSearch in Google Scholar
• 41b Cordes M, Kalesse M. Molecules 2019; 24: 3040
  CrossrefPubMedSearch in Google Scholar
• 41c Curti C, Battistini L, Sartori A, Zanardi F. Chem. Rev. 2020; 120: 2448
  CrossrefPubMedSearch in Google Scholar
• 42a Tsukada H, Mukaeda Y, Hosokawa S. Org. Lett. 2013; 15: 678
  CrossrefPubMedSearch in Google Scholar
• 42b Sagawa N, Moriya H, Hosokawa S. Org. Lett. 2017; 19: 250
  CrossrefPubMedSearch in Google Scholar
• 43 Zhang Y.-H, Liu R, Liu B. Chem. Commun. 2017; 53: 5549
  CrossrefPubMedSearch in Google Scholar
• 44 Pilli RA, Riatto VB, Vencato I. Org. Lett. 2000; 2: 53
  CrossrefPubMedSearch in Google Scholar
• 45a Larrosa I, Romea P, Urpí F, Balsells D, Vilarrasa J, Font-Bardia M, Solans X. Org. Lett. 2002; 4: 4651
  CrossrefPubMedSearch in Google Scholar
• 45b Gálvez E, Larrosa I, Romea P, Urpí F. Synlett 2009; 2982
• 45c Gálvez E, Sau M, Romea P, Urpí F, Font-Bardia M. Tetrahedron Lett. 2013; 54: 1467
  CrossrefSearch in Google Scholar
• 46 Larrosa I, Romea P, Urpí F. Org. Lett. 2006; 8: 527
  CrossrefPubMedSearch in Google Scholar
• 47a Harrison TJ, Ho S, Leighton JL. J. Am. Chem. Soc. 2011; 133: 7308
  CrossrefPubMedSearch in Google Scholar
• 47b Chen L.-A, Ashley MA, Leighton JL. J. Am. Chem. Soc. 2017; 139: 4568
  CrossrefPubMedSearch in Google Scholar
• 48 Kasun ZA, Gao X, Lipinski RM, Krische MJ. J. Am. Chem. Soc. 2015; 137: 8900
  CrossrefPubMedSearch in Google Scholar
• 49a Trost BM. Science 1991; 254: 1471
  CrossrefPubMedSearch in Google Scholar
• 49b Trost BM. Angew. Chem., Int. Ed. Engl. 1995; 34: 259
  CrossrefSearch in Google Scholar
• 50a Anastas PT, Kirchhoff MM. Acc. Chem. Res. 2002; 35: 686
  CrossrefPubMedSearch in Google Scholar
• 50b Lipshutz BH. J. Org. Chem. 2017; 82: 2806
  CrossrefPubMedSearch in Google Scholar
• 51 MacMillan DW. C. Nature 2008; 455: 304
  CrossrefPubMedSearch in Google Scholar
• 52 For a review on organocatalytic approaches, see: Lei C.-W, Mu B.-S, Zhou F, Yu J.-S, Zhou Y, Zhou J. Chem. Commun. 2021; 57: 9178
  CrossrefPubMedSearch in Google Scholar
• 53 Banik SM, Levina A, Hyde AM, Jacobsen EN. Science 2017; 358: 761
  CrossrefPubMedSearch in Google Scholar
• 54 Schreyer L, Kaib PS. J, Wakchaure VN, Obradors C, Properzi R, Lee S, List B. Science 2018; 362: 216
  CrossrefPubMedSearch in Google Scholar
• 55 For a review on IDPis catalysis, see: Schreyer L, Properzi R, List B. Angew. Chem. Int. Ed. 2019; 58: 12761
  CrossrefPubMedSearch in Google Scholar
• 56 Bae HY, Höfler D, Kaib PS. J, Kasaplar P, De CK, Döhring A, Lee S, Kaupmees K, Leito I, List B. Nat. Chem. 2018; 10: 888
  CrossrefPubMedSearch in Google Scholar
• 57a Reisman SE, Doyle AG, Jacobsen EN. J. Am. Chem. Soc. 2008; 130: 7198
  CrossrefPubMedSearch in Google Scholar
• 57b Ford DD, Lehnherr D, Kennedy CR, Jacobsen EN. J. Am. Chem. Soc. 2016; 138: 78605
  Search in Google Scholar
• 57c Kennedy CR, Lehnherr D, Rajapaksa NS, Ford DD, Park Y, Jacobsen EN. J. Am. Chem. Soc. 2016; 138: 13525
  CrossrefPubMedSearch in Google Scholar
• 58 Meng Z, Sun S, Yuan H, Lou H, Liu L. Angew. Chem. Int. Ed. 2014; 53: 543
  CrossrefPubMedSearch in Google Scholar
• 59 Lee S, Kaib PS. J, List B. J. Am. Chem. Soc. 2017; 139: 2156
  CrossrefPubMedSearch in Google Scholar
• 60 Lee S, Bae HY, List B. Angew. Chem. Int. Ed. 2018; 57: 12162
  CrossrefPubMedSearch in Google Scholar
• 61 Evans DA, Thomson RJ. J. Am. Chem. Soc. 2005; 127: 10506
  CrossrefPubMedSearch in Google Scholar
• 62 Suzuki T, Hamashima M, Sodeoka M. Angew. Chem. Int. Ed. 2007; 46: 5435
  CrossrefPubMedSearch in Google Scholar
• 63 Kennington SC. D, Taylor AJ, Romea P, Urpí F, Aullón G, Font-Bardia M, Ferré L, Rodrigalvarez J. Org. Lett. 2019; 21: 305
  CrossrefPubMedSearch in Google Scholar
• 64 Teloxa SF, Kennington SC. D, Camats M, Romea P, Urpí F, Aullón G, Font-Bardia M. Chem. Eur. J. 2020; 21: 11540
  CrossrefPubMedSearch in Google Scholar
• 65 Kennington SC. D, Teloxa SF, Mellado-Hidalgo M, Galeote O, Puddu S, Bellido M, Romea P, Urpí F, Aullón G, Font-Bardia M. Angew. Chem. Int. Ed. 2021; 60: 15307
  CrossrefPubMedSearch in Google Scholar
• 66 Teloxa SF, Mellado-Hidalgo M, Kennington SC. D, Romea P, Urpí F, Aullón G, Font-Bardia M. Chem. Eur. J. 2022; 28: e202200671
  CrossrefPubMedSearch in Google Scholar
• 67 Ye P, Liu X, Wang G, Liu L. Chin. Chem. Lett. 2021; 32: 1237
  CrossrefPubMedSearch in Google Scholar
• 68 Mellado-Hidalgo M, Romero-Cavagnaro EA, Nageswaran S, Puddu S, Kennington SC. D, Costa AM, Romea P, Urpí F, Aullón G, Font-Bardia M. Org. Lett. 2023; 25: 659
  CrossrefPubMedSearch in Google Scholar
• 69 Lee A, Betori RC, Crane EA, Scheidt KA. J. Am. Chem. Soc. 2018; 140: 6212
  CrossrefPubMedSearch in Google Scholar
• 70 Wang G, Xin X, Wang Z, Lu G, Ma Y, Liu L. Nat. Commun. 2019; 10: 559
  CrossrefPubMedSearch in Google Scholar

Corresponding Authors

Publication History

Received: 19 September 2023

Accepted after revision: 29 September 2023

Accepted Manuscript online:
29 September 2023

Article published online:
17 November 2023

© 2023. Thieme. All rights reserved

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

• References

• 1 New address: Department of Chemistry, Faculty of Sciences, Universitat de Girona, Carrer Maria Aurèlia Capmany 69, 17003 Girona, Catalonia, Spain.
• 2a Adero PO, Amarasekara H, Wen P, Bohé L, Crich D. Chem. Rev. 2018; 108: 8242
  CrossrefPubMedSearch in Google Scholar
• 2b Franconetti A, Ardá A, Asensio JL, Blériot Y, Thibaudeau S, Jiménez-Barbero J. Acc. Chem. Res. 2021; 54: 2552
  CrossrefPubMedSearch in Google Scholar
• 3 Mukaiyama T, Hayashi M. Chem. Lett. 1974; 3: 15
  CrossrefPubMedSearch in Google Scholar
• 4 Saigo K, Osaki M, Mukaiyama T. Chem. Lett. 1976; 5: 769
  CrossrefSearch in Google Scholar
• 5 Murata S, Suzuki M, Noyori R. J. Am. Chem. Soc. 1980; 102: 3248
  CrossrefSearch in Google Scholar
• 6 Murata S, Suzuki M, Noyori R. Tetrahedron 1988; 44: 4259
  CrossrefSearch in Google Scholar
• 7a Mori I, Ishihara K, Flippin LA, Nozaki K, Yamamoto H, Bartlett PA, Heathcock CH. J. Org. Chem. 1990; 55: 6107
  CrossrefSearch in Google Scholar
• 7b Denmark SE, Almstead NG. J. Am. Chem. Soc. 1991; 113: 8089
  CrossrefSearch in Google Scholar
• 7c Denmark SE, Almstead NG. J. Org. Chem. 1991; 56: 6458
  CrossrefSearch in Google Scholar
• 7d Sammakia T, Smith RS. J. Am. Chem. Soc. 1992; 114: 10998
  CrossrefSearch in Google Scholar
• 7e Sammakia T, Smith RS. J. Am. Chem. Soc. 1994; 116: 7915
  CrossrefSearch in Google Scholar
• 8 Evans DA, Urpí F, Somers TC, Clark JS, Bilodeau MT. J. Am. Chem. Soc. 1990; 112: 8215
  CrossrefSearch in Google Scholar
• 9 Ciez D, Palasz A, Trzewik B. Eur. J. Org. Chem. 2016; 1476
  Crossref
• 10a Elian M, Chen MM. L, Mingos MP, Hoffmann R. Inorg. Chem. 1976; 15: 1148
  CrossrefSearch in Google Scholar
• 10b Hoffmann R. Angew. Chem., Int. Ed. Engl. 1982; 21: 711
  CrossrefSearch in Google Scholar
• 11a Mukaiyama T, Murakami M. Synthesis 1987; 1043
  Thieme Connect
• 11b Fujioka H. Chem. Pharm. Bull. 2020; 68: 907
  CrossrefPubMedSearch in Google Scholar
• 12a Trost BM, Brindle CS. Chem. Soc. Rev. 2010; 39: 1600
  CrossrefPubMedSearch in Google Scholar
• 12b Yamashita Y, Yasukawa T, Yoo W.-J, Kitanosono T, Kobayashi S. Chem. Soc. Rev. 2018; 47: 4388
  CrossrefPubMedSearch in Google Scholar
• 12c Trost BM, Hung C.-I, Mata G. Angew. Chem. Int. Ed. 2020; 59: 4240
  CrossrefPubMedSearch in Google Scholar
• 13a In Modern Methods in Stereoselective Aldol Reactions. Mahrwald R. Wiley-VCH; Weinheim: 2013
  Search in Google Scholar
• 13b Kennington SC. D, Costa AM, Romea P, Urpí F. Diastereoselective Aldol Reactions. In Reference Module in Chemistry, Molecular Sciences, and Chemical Engineering. Elsevier; Amsterdam: 2022.
  CrossrefSearch in Google Scholar
• 14 Taylor MD, Minaskanian G, Winzenberg KN, Santone P, Smith AB. III. J. Org. Chem. 1982; 47: 3960
  CrossrefSearch in Google Scholar
• 15 Lefranc H, Szymoniak J, Delas C, Moïse C. Tetrahedron Lett. 1999; 40: 1123
  CrossrefSearch in Google Scholar
• 16 Rychnovsky SD, Cossrow J. Org. Lett. 2003; 5: 2367
  CrossrefPubMedSearch in Google Scholar
• 17 Funk RL, Fitzgerald JF, Olmstead TA, Para KS, Wos JA. J. Am. Chem. Soc. 1993; 115: 8849
  CrossrefSearch in Google Scholar
• 18 Keck GE, Wager CA, Wager TT, Savin KA, Covel JA, McLaws MD, Krishnamurthy D, Cee VJ. Angew. Chem. Int. Ed. 2001; 40: 231
  CrossrefPubMedSearch in Google Scholar
• 19 Lewis MD, Cha JK, Kishi Y. J. Am. Chem. Soc. 1982; 104: 4976
  CrossrefPubMedSearch in Google Scholar
• 20a Ayala L, Lucero CG, Romero JA. C, Tabacco SA, Woerpel KA. J. Am. Chem. Soc. 2003; 125: 15521
  CrossrefPubMedSearch in Google Scholar
• 20b Chamberland S, Ziller JW, Woerpel KA. J. Am. Chem. Soc. 2005; 127: 5322
  CrossrefPubMedSearch in Google Scholar
• 21 For recent theoretical calculations, see: Remmerswaal WA, Hansen T, Hamlin TA, Codée JD. C. Chem. Eur. J. 2023; 29: e202203490
  CrossrefPubMedSearch in Google Scholar
• 22a Smith DM, Tran MB, Woerpel KA. J. Am. Chem. Soc. 2003; 125: 14149
  CrossrefPubMedSearch in Google Scholar
• 22b Larsen CH, Ridgway BH, Shaw JT, Smith DM, Woerpel KA. J. Am. Chem. Soc. 2005; 127: 10879
  CrossrefPubMedSearch in Google Scholar

For recent reviews on glycosylation reactions, see:
• 23a Yang Y, Yu B. Chem. Rev. 2017; 117: 12281
  CrossrefPubMedSearch in Google Scholar
• 23b Kinfe HH. Org. Biomol. Chem. 2019; 17: 4153
  CrossrefPubMedSearch in Google Scholar

See, for instance:
• 24a Paterson I, Cumming JG, Ward RA, Lamboley S. Tetrahedron 1995; 51: 9393
  CrossrefSearch in Google Scholar
• 24b Smith AB. III, Minbiole KP, Verhoest PR, Schelhaas M. J. Am. Chem. Soc. 2001; 122: 10942
  CrossrefPubMedSearch in Google Scholar
• 24c Vitale JP, Wolckenhauer SA, Do NM, Rychnovsky SD. Org. Lett. 2005; 7: 3255
  CrossrefPubMedSearch in Google Scholar
• 25 Díaz-Oltra S, Angulo-Pachón CA, Murga J, Falomir E, Carda M, Marco JA. Chem. Eur. J. 2011; 17: 675
  CrossrefPubMedSearch in Google Scholar
• 26 Wallace GA, Scott RW, Heathcock CH. J. Org. Chem. 2000; 65: 4145
  CrossrefPubMedSearch in Google Scholar
• 27 Baiget J, Cosp A, Gálvez E, Gómez-Pinal L, Romea P, Urpí F. Tetrahedron 2008; 64: 5637
  CrossrefSearch in Google Scholar
• 28a Cosp A, Romea P, Talavera P, Urpí F, Vilarrasa J, Font-Bardia M, Solans X. Org. Lett. 2001; 3: 615
  CrossrefPubMedSearch in Google Scholar
• 28b Gálvez E, Romea P, Urpí F. Org. Synth. 2009; 86: 81
  CrossrefSearch in Google Scholar
• 29a Cosp A, Larrosa I, Vilasís I, Romea P, Urpí F, Vilarrasa J. Synlett 2003; 1109
• 29b Gálvez E, Parelló R, Romea P, Urpí F. Synlett 2008; 2951
• 30a Crimmins MT, Dechert A.-MR. Org. Lett. 2009; 11: 1635
  CrossrefPubMedSearch in Google Scholar
• 30b Crimmins MT, Hughes CO. Org. Lett. 2012; 14: 2168
  CrossrefPubMedSearch in Google Scholar
• 30c Pulukuri KK, Chakraborty TK. Org. Lett. 2012; 14: 2858
  CrossrefPubMedSearch in Google Scholar
• 30d Liu H.-M, Chang C.-Y, Lai Y.-C, Yang M.-D, Chang C.-Y. Tetrahedron: Asymmetry 2014; 25: 187
  CrossrefSearch in Google Scholar
• 30e Kuilya TK, Goswami RK. Org. Lett. 2017; 19: 2366
  CrossrefPubMedSearch in Google Scholar
• 30f Sharma H, Mondal J, Ghosh AK, Pal RR, Goswami RK. Chem. Sci. 2022; 13: 13403
  CrossrefPubMedSearch in Google Scholar
• 31a Zhang Y, Sammakia T. Org. Lett. 2004; 6: 3139
  CrossrefPubMedSearch in Google Scholar
• 31b Smith TE, Kuo W.-H, Bock VD, Rolzen JL, Balskus EP, Theberge AB. Org. Lett. 2007; 9: 1153
  CrossrefPubMedSearch in Google Scholar
• 32a Cosp A, Romea P, Urpí F, Vilarrasa J. Tetrahedron Lett. 2001; 42: 4629
  CrossrefSearch in Google Scholar
• 32b Chakraborty TK, Pulukuri KK, Sreekanth M. Tetrahedron Lett. 2010; 51: 6444
  CrossrefSearch in Google Scholar
• 32c Hidgson DM, Man S. Chem. Eur. J. 2011; 17: 9731
  CrossrefPubMedSearch in Google Scholar
• 32d Gajula PK, Sharma S, Ampapathi RS, Chakarborty TK. Org. Biomol. Chem. 2013; 11: 257
  CrossrefPubMedSearch in Google Scholar
• 32e Nicolaou KC, Bellavance G, Buchman M, Pulukuri KK. J. Am. Chem. Soc. 2017; 139: 16636
  Search in Google Scholar
• 33 Cosp A, Llàcer E, Romea P, Urpí F. Tetrahedron Lett. 2006; 47: 5819
  CrossrefPubMedSearch in Google Scholar
• 34 Baiget J, Caba M, Gálvez E, Romea P, Urpí F, Font-Bardia M. J. Org. Chem. 2012; 77: 8809
  CrossrefPubMedSearch in Google Scholar
• 35 For a review on stereoselective aldol reactions of glycolic acid and derivatives, see: Engesser T, Brückner R. Synthesis 2017; 51: 1715
  CrossrefPubMedSearch in Google Scholar
• 36 Checa B, Gálvez E, Parelló R, Sau M, Romea P, Urpí F, Font-Bardia M, Solans X. Org. Lett. 2009; 11: 2193
  CrossrefPubMedSearch in Google Scholar
• 37a Romo JM, Gálvez E, Nubiola I, Romea P, Urpí F, Kindred M. Adv. Synth. Catal. 2013; 355: 2781
  CrossrefSearch in Google Scholar
• 37b Fernández-Valparis J, Romo JM, Romea P, Urpí F, Kowalski H, Font-Bardia M. Org. Lett. 2015; 17: 3540
  CrossrefPubMedSearch in Google Scholar
• 37c Kennington SC. D, Ferré M, Romo JM, Romea P, Urpí F, Font-Bardia M. J. Org. Chem. 2017; 82: 6426
  CrossrefPubMedSearch in Google Scholar
• 38 Kennington SC. D, Romo JM, Romea P, Urpí F. Org. Lett. 2016; 18: 3018
  CrossrefPubMedSearch in Google Scholar
• 39a Romo JM, Romea P, Urpí F. Eur. J. Org. Chem. 2019; 6296
  Crossref
• 39b Fernández-Valparís J, Romea P, Urpí F, Font-Bardia M. Org. Lett. 2017; 19: 6400
  CrossrefPubMedSearch in Google Scholar
• 40 Fernández-Valparís J, Romea P, Urpí F. Eur. J. Org. Chem. 2019; 2745
  Crossref

For reviews on vinylogous Mukaiyama aldol reactions, see:
• 41a Kalesse M, Cordes M, Symkenberg G, Lu H.-H. Nat. Prod. Rep. 2014; 31: 563
  CrossrefPubMedSearch in Google Scholar
• 41b Cordes M, Kalesse M. Molecules 2019; 24: 3040
  CrossrefPubMedSearch in Google Scholar
• 41c Curti C, Battistini L, Sartori A, Zanardi F. Chem. Rev. 2020; 120: 2448
  CrossrefPubMedSearch in Google Scholar
• 42a Tsukada H, Mukaeda Y, Hosokawa S. Org. Lett. 2013; 15: 678
  CrossrefPubMedSearch in Google Scholar
• 42b Sagawa N, Moriya H, Hosokawa S. Org. Lett. 2017; 19: 250
  CrossrefPubMedSearch in Google Scholar
• 43 Zhang Y.-H, Liu R, Liu B. Chem. Commun. 2017; 53: 5549
  CrossrefPubMedSearch in Google Scholar
• 44 Pilli RA, Riatto VB, Vencato I. Org. Lett. 2000; 2: 53
  CrossrefPubMedSearch in Google Scholar
• 45a Larrosa I, Romea P, Urpí F, Balsells D, Vilarrasa J, Font-Bardia M, Solans X. Org. Lett. 2002; 4: 4651
  CrossrefPubMedSearch in Google Scholar
• 45b Gálvez E, Larrosa I, Romea P, Urpí F. Synlett 2009; 2982
• 45c Gálvez E, Sau M, Romea P, Urpí F, Font-Bardia M. Tetrahedron Lett. 2013; 54: 1467
  CrossrefSearch in Google Scholar
• 46 Larrosa I, Romea P, Urpí F. Org. Lett. 2006; 8: 527
  CrossrefPubMedSearch in Google Scholar
• 47a Harrison TJ, Ho S, Leighton JL. J. Am. Chem. Soc. 2011; 133: 7308
  CrossrefPubMedSearch in Google Scholar
• 47b Chen L.-A, Ashley MA, Leighton JL. J. Am. Chem. Soc. 2017; 139: 4568
  CrossrefPubMedSearch in Google Scholar
• 48 Kasun ZA, Gao X, Lipinski RM, Krische MJ. J. Am. Chem. Soc. 2015; 137: 8900
  CrossrefPubMedSearch in Google Scholar
• 49a Trost BM. Science 1991; 254: 1471
  CrossrefPubMedSearch in Google Scholar
• 49b Trost BM. Angew. Chem., Int. Ed. Engl. 1995; 34: 259
  CrossrefSearch in Google Scholar
• 50a Anastas PT, Kirchhoff MM. Acc. Chem. Res. 2002; 35: 686
  CrossrefPubMedSearch in Google Scholar
• 50b Lipshutz BH. J. Org. Chem. 2017; 82: 2806
  CrossrefPubMedSearch in Google Scholar
• 51 MacMillan DW. C. Nature 2008; 455: 304
  CrossrefPubMedSearch in Google Scholar
• 52 For a review on organocatalytic approaches, see: Lei C.-W, Mu B.-S, Zhou F, Yu J.-S, Zhou Y, Zhou J. Chem. Commun. 2021; 57: 9178
  CrossrefPubMedSearch in Google Scholar
• 53 Banik SM, Levina A, Hyde AM, Jacobsen EN. Science 2017; 358: 761
  CrossrefPubMedSearch in Google Scholar
• 54 Schreyer L, Kaib PS. J, Wakchaure VN, Obradors C, Properzi R, Lee S, List B. Science 2018; 362: 216
  CrossrefPubMedSearch in Google Scholar
• 55 For a review on IDPis catalysis, see: Schreyer L, Properzi R, List B. Angew. Chem. Int. Ed. 2019; 58: 12761
  CrossrefPubMedSearch in Google Scholar
• 56 Bae HY, Höfler D, Kaib PS. J, Kasaplar P, De CK, Döhring A, Lee S, Kaupmees K, Leito I, List B. Nat. Chem. 2018; 10: 888
  CrossrefPubMedSearch in Google Scholar
• 57a Reisman SE, Doyle AG, Jacobsen EN. J. Am. Chem. Soc. 2008; 130: 7198
  CrossrefPubMedSearch in Google Scholar
• 57b Ford DD, Lehnherr D, Kennedy CR, Jacobsen EN. J. Am. Chem. Soc. 2016; 138: 78605
  Search in Google Scholar
• 57c Kennedy CR, Lehnherr D, Rajapaksa NS, Ford DD, Park Y, Jacobsen EN. J. Am. Chem. Soc. 2016; 138: 13525
  CrossrefPubMedSearch in Google Scholar
• 58 Meng Z, Sun S, Yuan H, Lou H, Liu L. Angew. Chem. Int. Ed. 2014; 53: 543
  CrossrefPubMedSearch in Google Scholar
• 59 Lee S, Kaib PS. J, List B. J. Am. Chem. Soc. 2017; 139: 2156
  CrossrefPubMedSearch in Google Scholar
• 60 Lee S, Bae HY, List B. Angew. Chem. Int. Ed. 2018; 57: 12162
  CrossrefPubMedSearch in Google Scholar
• 61 Evans DA, Thomson RJ. J. Am. Chem. Soc. 2005; 127: 10506
  CrossrefPubMedSearch in Google Scholar
• 62 Suzuki T, Hamashima M, Sodeoka M. Angew. Chem. Int. Ed. 2007; 46: 5435
  CrossrefPubMedSearch in Google Scholar
• 63 Kennington SC. D, Taylor AJ, Romea P, Urpí F, Aullón G, Font-Bardia M, Ferré L, Rodrigalvarez J. Org. Lett. 2019; 21: 305
  CrossrefPubMedSearch in Google Scholar
• 64 Teloxa SF, Kennington SC. D, Camats M, Romea P, Urpí F, Aullón G, Font-Bardia M. Chem. Eur. J. 2020; 21: 11540
  CrossrefPubMedSearch in Google Scholar
• 65 Kennington SC. D, Teloxa SF, Mellado-Hidalgo M, Galeote O, Puddu S, Bellido M, Romea P, Urpí F, Aullón G, Font-Bardia M. Angew. Chem. Int. Ed. 2021; 60: 15307
  CrossrefPubMedSearch in Google Scholar
• 66 Teloxa SF, Mellado-Hidalgo M, Kennington SC. D, Romea P, Urpí F, Aullón G, Font-Bardia M. Chem. Eur. J. 2022; 28: e202200671
  CrossrefPubMedSearch in Google Scholar
• 67 Ye P, Liu X, Wang G, Liu L. Chin. Chem. Lett. 2021; 32: 1237
  CrossrefPubMedSearch in Google Scholar
• 68 Mellado-Hidalgo M, Romero-Cavagnaro EA, Nageswaran S, Puddu S, Kennington SC. D, Costa AM, Romea P, Urpí F, Aullón G, Font-Bardia M. Org. Lett. 2023; 25: 659
  CrossrefPubMedSearch in Google Scholar
• 69 Lee A, Betori RC, Crane EA, Scheidt KA. J. Am. Chem. Soc. 2018; 140: 6212
  CrossrefPubMedSearch in Google Scholar
• 70 Wang G, Xin X, Wang Z, Lu G, Ma Y, Liu L. Nat. Commun. 2019; 10: 559
  CrossrefPubMedSearch in Google Scholar