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A direct and asymmetric triisopropylsilyltrifluoromethanesulfonate (TIPSOTf) mediated aldol reaction of N-azidoacetyl-1,3-thiazolidine-2-thione with aromatic aldehydes catalyzed by a chiral nickel(II)-Tol-BINAP complex has been developed (BINAP=2,2'-bis(diphenylphosphino)-1,1'-binaphthyl). The catalytic protocol gives the corresponding anti α-azido-β-silyloxy adducts with outstanding stereocontrol and in high yields. Theoretical calculations account for the stereochemical outcome of the reaction and lay the foundations for a mechanistic model. In turn, the easy removal of the thiazolidinethione yields a wide array of enantiomerically pure derivatives in a straightforward and efficient manner. Such a noteworthy character of the heterocyclic scaffold together with the appropriate manipulation of the azido group open a new route to the synthesis of di- and tripeptide blocks containing a β-aryl-β-hydroxy-α-amino acid.

Herein, the asymmetric synthesis of umuravumbolide (1) is described. The new approach features highly stereoselective transformations (dr ≥ 95:5) to install both stereocenters and the Z olefin, which involve a new radical alkylation, an Ando olefination, and a Krische allylation on a Z allylic alcohol, not reported before. The application of such successful reactions, together with the limited use of protecting groups and concession steps, makes it possible to complete the synthesis in 10 steps, resulting in a 39% overall yield from chiral N-acyl oxazolidinone 2.

Here, we present a new stereoselective alkylation of titanium(IV) enolates of chiral N-acyl oxazolidinones with tert-butyl peresters from Cα-branched aliphatic carboxylic acids, which proceeds through the decarboxylation of the peresters and the subsequent formation of alkyl radicals to produce the alkylated adducts with an excellent diastereoselectivity. Theoretical calculations account for the observed reactivity and the outstanding stereocontrol. Importantly, the resultant compounds can be easily converted into ligands for asymmetric and catalytic transformations.

A direct and asymmetric aldol reaction of N‐acyl thiazinanethiones with aromatic aldehydes catalyzed by chiral nickel(II) complexes is reported. The reaction gives the corresponding O‐TIPS‐protected anti‐aldol adducts in high yields and with remarkable stereocontrol and atom economy. Furthermore, the straightforward removal of the achiral scaffold provides enantiomerically pure intermediates of synthetic interest, which involve precursors for anti‐α‐amino‐β‐hydroxy and α,β‐dihydroxy carboxylic derivatives. Theoretical calculations explain the observed high stereocontrol., Appropriate and simultaneous activation of robust and easy to handle [Tol‐BINAP]NiCl2 and aromatic aldehydes with TIPSOTf orchestrates a direct, asymmetric, and catalytic aldol reaction of a wide array of N‐acyl‐1,3‐thiazinane‐2‐thiones. This method enables the corresponding TIPS‐protected anti aldol adducts to be obtained in a highly efficient and atom economical manner.

[EN]Here, we present a new stereoselective alkylation of titanium(IV) enolates of chiral N-acyl oxazolidinones with tert-butyl peresters from Calpha-branched aliphatic carboxylic acids, which proceeds through the decarboxylation of the peresters and the subsequent formation of alkyl radicals to produce the alkylated adducts with an excellent diastereoselectivity. Theoretical calculations account for the observed reactivity and the outstanding stereocontrol. Importantly, the resultant compounds can be easily converted into ligands for asymmetric and catalytic transformations. We acknowledge financial support from the Spanish Ministerio de Ciencia, e Innovación (MCIN)/Agencia Estatal de Investigación (AEI)/Fondo Europeo de Desarrollo Regional (FEDER, UE) (Grant No. PGC2018-094311-B-I00 and Grant No. PID2019-110008GB-I00), the Generalitat de Catalunya (2017SGR 271), and SGIker (UPV/EHU) for providing human and computational resources. Furthermore, a doctorate studentship to M.P.-P. (FPU, MINU) is acknowledged.

Lewis acid mediated substrate-controlled reactions of the titanium(IV) enolates of chiral α-benzyloxy ketones with conjugated nitroalkenes give 2,4-anti-4,5-syn Michael adducts in good yields and diastereomeric ratios. The supplementary Lewis acid plays a key role in the outcome of these transformations, probably as a consequence of the formation of dimetallic enolates that increase the reactivity of the enolate and direct the approach of the nitroalkene. Importantly, the most appropriate Lewis acid depends on the electrophilic partner: TiCl4 is the most suitable Lewis acid for β-aryl-nitroalkenes, whereas the best results for β-alkyl-nitroalkenes are obtained with SnCl4. Finally, the nitro group of the resultant compounds can be converted into the corresponding amine, oxime, and nitrile groups under mild conditions, which permits the synthesis of a variety of enantiomerically pure derivatives in excellent yields.

A direct and highly enantioselective reaction of N-azidoacetyl-1,3-thiazolidine-2-thione with trimethyl orthoformate catalyzed by Tol-BINAPNiCl2 in the presence of TESOTf and 2,6-lutidine is reported. The heterocyclic scaffold can be easily removed by addition of a wide array of amines to give the corresponding enantiomerically pure 2-azido-3,3-dimethoxypropanamides in high yields. Appropriate manipulation of the N-benzyl amide derivative provides an efficient access to the antiepileptic agent lacosamide through a new enantioselective C-C bond-forming process. DFT computational studies uncover clues for the understanding of the remarkable stereocontrol of the addition of a nickel(II) enolate to a putative oxocarbenium intermediate from trimethyl orthoformate.

Simple treatment of chiral titanium(IV) enolates with diacyl peroxides produces highly diastereoselective decarboxylative alkylations to efficiently deliver the corresponding adducts, most of which are not accessible through any of the current alkylating procedures. Such an unprecedented alkylation proceeds through an SET process that triggers the decomposition of the peroxide into a carbon-centered radical that finally combines with the resulting Cα radical. The procedure has been applied to the enantioselective synthesis of arundic acid.

Chiral α-hydroxy ketones are valuable platforms from which highly stereoselective substrate-controlled aldol reactions may be performed. The suitable choice of the hydroxyl protecting group and the enolization conditions produce aldol adducts that can be easily manipulated to give a variety of enantiomerically pure compounds. Moreover, such aldol reactions often play a crucial role in the coupling of elaborate fragments in advanced steps of the synthesis of natural products. Together, these features confer to the α-hydroxy ketones a prominent position among the chiral substrates that are capable of providing highly asymmetric transformations. 1 Introduction 2 Pioneering Contributions 3 Boron-Mediated Aldol Reactions from α-Hydroxy Ethyl Ketones 4 Titanium-Mediated Aldol Reactions from α-Hydroxy Ethyl Ketones 5 Other Aldol Reactions from α-Hydroxy Ethyl Ketones 6 Aldol Reactions from α-Hydroxy Methyl Ketones 7 Conclusions

A concise synthesis of the C9-C19 fragment of peloruside A that is both highly stereoselective and efficient is described. Achieving an overall yield of 23% over 14 steps, this synthesis not only is high yielding but also involves four chromatography steps. This approach is based on the addition of metal enolates of chiral auxiliary scaffolds generated by either catalytic or stoichiometric amounts of nickel(II) or titanium(IV) Lewis acids.

A wide array of new N-acyl thiazinanethiones are employed in a number of direct and enantioselective carbon-carbon bond forming reactions catalyzed by nickel(II) complexes. The electrophilic species are mostly prepared in situ from ortho esters, methyl ethers, acetals, and ketals, which makes the overall process highly efficient and experimentally straightforward. Theoretical calculations indicate that the reactions pro-ceed through an open transition state in a SN1-like mechanism. The utility of this novel procedure has been demonstrated by the asymmetric preparation of syntheti-cally useful intermediates and the total synthesis of pe-peromin D.

A comprehensive analysis of the influence of the chiral auxiliary on the α-aminoxylation of titanium(iv) enolates with TEMPO indicated that (S) 4-tert-butyl-1-oxazolidine-2-thione is the most appropriate scaffold to provide a single diastereomer in high yields for a variety of substrates, which converts such a radical reaction into a highly chemo- and stereoselective oxidation.

We described in a recent work the rational improvement of an esterase from Bacillus sp. BP7 aimed at investigating the efficiency of several esterase variants for enantiomeric resolution of acetate esters of tertiary alcohols. Variant EstBP7-AGA, bearing two aminoacidic changes in the oxyanion hole, showed an excellent E > 100 enantioselectivity value towards a complex tertiary alcohol acetate (2-(4-pyridyl)-3-butyn-2-yl acetate) at low reaction temperature (4 °C). We here go further in the investigation of such esterase variant by analyzing the kinetic resolution of benzylic propargylic esters to prove that this enzyme is a powerful tool to obtain enantiomerically pure tertiary as well as secondary alcohols, provided that the structural integrity of the parent benzylic propargylic ester is maintained. Understanding the mode of action and interaction of such esterase variant with the assayed substrates will allow production of interesting pharmaceutical building blocks.

The structurally simple (Me3P)2NiCl2 complex catalyzes SN1-type alkylations of chiral N-acyl thiazolidinethiones with diarylmethyl methyl ethers and other stable carbenium cations. The former can contain a variety of functional groups and heteroatoms at the α-position. The resultant adducts are isolated as single diastereomers in high yields and can be converted into enantiomerically pure derivatives in a straightforward manner.

TiCl4-mediated aldol reactions of chiral methyl α-silyloxy ketones with a variety of aldehydes provide the corresponding 1,4-syn aldol adducts with moderate to high stereocontrol. This transformation represents a new approach to substrate-controlled acetate aldol reactions and complements the 1,4-anti asymmetric induction produced by the related α-benzyloxy ketones. This new approach could be useful in the design of more efficient syntheses of natural products.

Direct addition of a chiral N-azidoacetyl thiazolidinethione to a variety of dialkyl acetals catalyzed by a commercially available and structurally simple nickel(II) complex gives access in good yields and a highly stereocontrolled manner to anti-beta-alkoxy-alpha-azido carboxylic derivatives which, in turn, can be easily converted into a wide array of enantiomerically pure compounds.

Quantum chemical calculations have unveiled the unexpected biradical character of titanium(IV) enolates from N-acyl oxazolidinones and thiazolidinethiones. The electronic structure of these species therefore involves a valence tautomerism consisting of an equilibrium between a closed shell (formally Ti(IV) enolates) and an open shell, biradical, singlet (formally Ti(III) enolates) electronic states, whose origin is to be basically found in changes of the Ti−O distance. Spectroscopic studies of the intermediate species lend support to such a model, which also turns out to be crucial for a better understanding of the overall reactivity of titanium(IV) enolates. In this context, a thorough computational analysis of the radical addition of titanium(IV) enolates from N-acyl oxazolidinones to TEMPO has permitted us to suggest an entire mechanism, which accounts for the experimental details and the diastereoselectivity of the process. All together, this evidence highlights the relevance of biradical intermediates from titanium(IV) enolates and may be a useful contribution to the foundations of a more insightful comprehension of the structure and reactivity of titanium(IV) enolates.

Direct nickel-catalyzed alkylation of chiral N-acyl-4-isopropyl-1,3-thiazolidine-2-thiones using a commercially available nickel(II) complex, (Me3P)2NiCl2, has been developed for tropylium and trityl tetrafluoroborate salts. The reaction provides a single diastereomer of the corresponding adducts in good to high yields, which, in turn, can be easily converted into a wide array of enantiomerically pure compounds that are difficult to obtain by other asymmetric procedures.

Lipases and esterases are important biocatalysts for synthetic organic fine chemistry. An esterase from Bacillus sp. BP-7 (EstBP7) bears in its amino acid sequence a rare GGG(A)X oxyanion hole motif, where an uncommon threonine (T) is found at the third position. Detection of this pattern motivated evaluation of the ability of EstBP7 for conversion of tertiary alcohols. The enzyme was engineered in order to optimize its performance to provide important chiral building blocks: five variants with mutations in the oxyanion hole motif were created to investigate the influence on activity and enantioselectivity in the kinetic resolution of eight acetates of tertiary alcohols. Wild-type enzyme converted all esters of tertiary alcohols assayed with low enantioselectivity, whereas some of the mutants displayed significantly increased E-values. One of the mutants (EstBP7-AGA; Mut 5) showed an E >100 towards a complex tertiary alcohol acetate (2-(4-pyridyl)but-3-yn-2-yl acetate) at low reaction temperature (4 °C). Therefore, the catalytic toolbox was expanded for biocatalysis of optically pure tertiary alcohols valuable for the pharmaceutical industry.

Aldol reactions of titanium enolates of lactate-derived ethyl ketone 1 with other ketones proceed in a very efficient and stereocontrolled manner provided that a further equivalent of TiCl4 is added to the reacting mixture. The scope of these reactions encompasses simple ketones such as acetone or cyclohexanone as well as other ketones that contain potential chelating groups such as pyruvate esters or α- and β-hydroxy ketones.

A total synthesis of (+)-herboxidiene/GEX 1A has been accomplished from (R)- and (S)-lactate esters in a highly efficient manner. Key steps of the synthesis involve substrate-controlled titanium-mediated aldol reactions from chiral lactate-derived ethyl ketones, an oxa-Michael cyclization, an Ireland-Claisen rearrangement, and a Suzuki coupling. Furthermore, computational studies of the oxa-Michael reaction have unveiled the dramatic influence of intramolecular hydrogen bonds on the stereochemical outcome of such cyclizations, whereas biological analyses have clearly proved the important cytoxicity of (+)-herboxidiene/GEX 1A.

The stereochemical control of aldol reactions from unsubstituted enolor enolatelike species, what are known as acetate aldol reactions, has been a matter of concern for nearly 30 years [1, 2]. Indeed, pioneering studies soon recognized that the asymmetric installation of a single stereocenter in such aldol reactions was much more demanding than the simultaneous construction of two new stereocenters in the related propionate counterparts (Scheme 1.1) [3]. This challenge, together with the ubiquitous presence of chiral β-hydroxy α-unsubstituted oxygenated structures in natural products, has motivated the development of new concepts and strategies and a large number of highly stereoselective methodologies. These involve Lewis-acid-mediated additions of enolsilane derivatives of carbonyl compounds to aldehydes (Mukaiyama aldol variant) [4, 5], a plethora of transformations that take advantage of the reactivity of boron, titanium(IV), and tin(II) enolates (metal enolates) [6], and some insightful organocatalytic approaches [7]. In spite of these accomplishments, the quest for more powerful and selective methodologies and a better understanding of their intricate mechanisms is an active area of research. Herein, we describe the most significant achievements in the field of stereoselective acetate aldol reactions based on the Lewis-acid-mediated addition of enolsilanes and metal enolates to aldehydes, with particular attention to their application to the asymmetric synthesis of natural products. Recent advances in parallel organocatalytic procedures are not discussed.

Good levels of 1,4-anti asymmetric induction are obtained in the TiCl3(i-PrO)-mediated aldol reaction of chiral α-benzyloxy methyl ketones with a wide array of aldehydes. This methodology represents a new approach to substrate-controlled acetate aldol reactions capable of providing highly functionalized fragments in a straightforward manner, which may be useful in the design of more efficient syntheses.

Chiral α-silyloxy ketones participate in highly stereoselective TiCl4-mediated aldol reactions that afford diastereomerically pure syn–syn adducts in high yield irrespective of the R1 and R2 substituents flanking the carbonyl or the silicon protecting group. Further manipulation of the resulting aldol adducts provide in a straightforward manner highly functionalized fragments that facilitate the synthesis of natural products.

Substrate-controlled titanium-mediated aldol reactions from (S)-4-benzyloxy-3-methyl-2-butanone provide satisfactory levels of 2,5-syn asymmetric induction if they are carried out in the presence of a second equivalent of TiCl(4). Such reactions give high yields and excellent diastereoselectivity with a wide array of achiral and chiral aldehydes without needing other sources of chirality. This procedure is thus of interest for the synthesis of natural products. Furthermore, spectroscopic studies and analyses of the reacting species have revealed a possible mechanism to account for the experimental results.

A sequential transformation based on the titanium-mediated aldol addition of (S)-1-bromo-3-(tert-butyldimethylsilyloxy)2-butanone, a chiral lactate-derived ketone, to tetradecanal followed by reduction of the ensuing aldolate afforded the corresponding syn-1,3-diol as a single diastereomer. Debro

A sequential transformation based on a titanium-mediated aldol reaction from chiral α-tert-butyldimethylsilyloxy ketones followed by reduction of the resultant aldolates with LiBH4 provides a straightforward access to syn-1,3-diols. These diols, containing up to three new stereocentres, can be easily isolated in high yields after a simple work-up without any additional oxidative treatment, which confers to this procedure an appealing position to prepare stereoselectively such sort of structures.

Good levels of 1,4-syn asymmetric induction are obtained in the TiCl4-mediated aldol reaction of methyl α-silyloxy ketones with achiral aldehydes. Such methodology represents a new approach to the substrate-controlled acetate aldol reaction, which can be useful to design more efficient syntheses of natural products.

Both α- and β-C-glycosides can be prepared by SnCl 4 -mediated addition of titanium enolates from N-acetylthiazolidinethiones to glycals. Subsequent removal of the chiral auxiliary provides enantiomerically pure fragments that are useful for the synthesis of natural products.

A route to fluvirucinins B(2-5) (the common aglycon of fluvirucins B(2)-B(5), Sch 38518, and Sch 39185) is reported for the first time. A ring-closing metathesis (RCM) generated the C6-C7 double bond, which by catalytic hydrogenation (in toluene) gave the desired epimer with a 9:1 diastereoselection. Azide 8a and carboxylic acid 5 came from ethyl-branched fragments C9-C13 (CHO at C9) and C1-C5 via an asymmetric allylation of the former and a cross metathesis (CM) followed by a ketone methylenation (with 20 mol % of DMF as a sacrificial additive) of the latter.

2,2'-Dipyridyl diselenide (PySeSePy) is the catalyst or activator of choice for the direct reaction of carboxylic acids with azides and trimethylphosphine at room temperature. The mechanism of the process, which is not an aza-Wittig reaction, has been elucidated.

Dialkyl acetals containing other functional groups can participate in stereoselective coupling reactions with chiral titanium enolates. Such an approach provides the protected γ-amino acid present in bistramides and FR252921 in a highly efficient manner.

Titanium enolates from chiral N-propanoyl-1,3-thiazolidine-2-thiones containing bulky substituents at C4 turned out to be excellent platforms to get highly stereocontrolled cross-coupling reactions with acetals. Related oxazolidinethiones also afforded good results, but the corresponding oxazolidinones resulted completely unselective for such reactions, which proves that an exocyclic C S bond is essential to attain a synthetically useful stereocontrol.

The structurally simple (Me3P)2NiCl2 complex catalyzes SN1-type alkylations of chiral N-acyl thiazolidinethiones with diarylmethyl methyl ethers and other stable carbenium cations. The former can contain a variety of functional groups and heteroatoms at the α-position. The resultant adducts are isolated as single diastereomers in high yields and can be converted into enantiomerically pure derivatives in a straightforward manner.

Substrate-controlled Michael additions of the titanium(IV) enolate of lactate-derived ketone 1 to acyclic α,β-unsaturated ketones in the presence of a Lewis acid (TiCl4 or SnCl4) provide the corresponding 2,4-anti-4,5-anti dicarbonyl compounds in good yields and excellent diastereomeric ratios. Likely, the nucleophilic species involved in such additions are bimetallic enolates that may add to enones through cyclic transition states. Finally, further studies indicate that a structurally related β-benzyloxy chiral ketone can also participate in such stereocontrolled conjugate additions.

Titanium-mediated aldol reactions based on (S)-2-tert-butyldimethylsilyloxy-3-pentanone, a lactate-derived chiral ketone, provide the corresponding 2,4-syn-4,5-syn adducts in high yields and diastereomeric ratios with a wide array of achiral and chiral aldehydes. Furthermore, spectroscopic studies of intermediates involved in the process have permitted to propose a mechanism that accounts for the experimental results.

Selective hydrogenolysis of benzyl ethers can be achieved by the appropriate choice of the catalyst, solvent, and concentration, which facilitates the design of O-benzyl based protecting group strategies for the synthesis of natural products.

A highly stereoselective synthesis of the C9–C21 fragment of debromoaplysiatoxin and oscillatoxins A and D has been devised. This new approach relies on the cross coupling of titanium enolates from N -acyl-1,3-thiazolidine-2-thiones and dialkyl acetals and the selective hydrogenolysis of O -benzyl protecting groups.

[structure: see text]. A convergent and module-based strategy for the asymmetric synthesis of the western hemisphere (C1-C17 fragment) of salinomycin has been devised. This new synthetic approach relies on highly stereoselective C-glycosidation and aldol processes.

The Negishi coupling between a chiral C3 synthon and an iodoalkene arising from 3-butyn-1-ol, which gave the C3–C9 fragment of amphidinolide Y, was the starting point of a formal total synthesis of this marine natural product. By means of Sharpless ADH and TADDOL-mediated crotylation, the full western fragment (C1–C11) was obtained, which was coupled with the eastern fragment (3-hydroxyoxolane derivative). The penultimate step (ring-closing metathesis, with G-II, H–G-II, or Nitro-Grela reagents, under several conditions) posed great difficulties. The cyclization was achieved with 15c (7,9-bis- O -TES) and 15d (7- O -TES, 9- O -TBS); more than stoichiometric amounts of the H–G-II Ru complex were required for complete conversion.

Reactions of ( E )- and ( Z )-ketoximes with trialkylphosphines and diphenyl disulfide (PhSSPh) have been compared to gain insight into the mechanisms involved and their potential applications. N -Sulfenylimine isomers and ketimines have been spectroscopically characterised. Both the E and Z isomers of erythromycin A oxime, when treated with Bu 3 P and PhSSPh (1:4:8 ratio), give the same N -phenylsulfenyl ketimine (of configuration E ) as the major compound, whereas with Bu 3 P or Me 3 P and PySeSePy (1:8:4 ratio) afford the imine in good yield. Clarithromycin oxime behaves similarly.

Stereoselectivity of the titanium-mediated aldol process based on ( S )-2-benzyloxy-3-pentanone, 1 , is dramatically modified by the presence of a Lewis acid. Among the Lewis acids surveyed, TiCl 4 has given access to the corresponding 2,4- anti -4,5- syn aldol adducts with the highest diastereomeric ratios. The excellent stereocontrol exerted by the aforementioned ketone has been demonstrated in double asymmetric reactions involving chiral α-methyl-β-OTBDPS aldehydes.

Highly stereoselective titanium-mediated aldol additions of ethyl ketones derived from lactic acid to α-methyl-β-OTBDPS chiral aldehydes are documented. One of these double stereodifferentiating processes represents the key step of a straightforward and efficient synthetic approach to the C1-C6 fragment of erythronolides.

Addition of the chiral titanium enolate arising from 1 to dibenzyl acetals gives access to anti-b-benzyloxy-a-methyl carbox- ylic adducts in good yields and with diastereomeric ratios up to 99:1. These adducts can be easily converted into a plethora of enan- tiopure protected derivatives. Aldol reaction nowadays constitutes one of the most pow- erful tools for the carbon-carbon bond formation, 1 giving easy access to a-alkyl-b-hydroxy oxygenated moieties present in the molecular architecture of a vast array of nat- ural products. 2 Taking into account that (i) in spite of re- cent advances, the stereoselective construction of anti aldol units is still one of the remaining challenges, 3 and that (ii) the protection of the hydroxyl group of the result- ing aldol adducts is usually required, any methodology able to provide stereoselectively protected anti aldol ad- ducts in a single step would be highly desirable. In this context, we have recently reported that the Lewis acid me- diated cross-coupling reaction of a wide range of dimethyl acetals with the titanium enolate arising from (S)-4-iso- propyl-N-propanoyl-1,3-thiazolidine-2-thione (1) fur- nishes efficiently enantiopure anti-b-methoxy-a-methyl adducts. 4 On the basis of these results, we envisaged that the use of appropriate acetals might lead to a broader va- riety of b-alkoxy-a-methyl carboxylic derivatives, which, in turn, could be considered as protected aldol synthons. Herein, we wish to report that the reaction of the titanium enolate of 1 and dibenzyl acetals affords stereoselectively anti-b-benzyloxy-a-methyl adducts that can be trans- formed into a large number of enantiopure derivatives. Initially, we examined the reaction of 1 with diallyl and dibenzyl acetals derived from benzaldehyde and isobu- tyraldehyde, 5,6 which could afford aldol adducts with eas