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The asymmetric allylic alkylation of benzofuran-3(2H)-ones with nitroallylic acetates has been achieved employing a bifunctional thiourea organocatalyst via SN2′ substitution. A series of 2,2-disubstituted benzofuranones bearing adjacent tetrasubstituted and tertiary stereocenters have been synthesized with moderate to good yields and very good stereoselectivities.

A new strategy for the N-heterocyclic carbene catalyzed asymmetric synthesis of cyclopentene-fused tetrahydroquinoline derivatives has been developed. The one-pot organocatalytic domino protocol allows a direct entry to the characteristic cyclopenta[c]tetrahydroquinoline core of many alkaloids and some potential drugs employing readily available quinolinone and enal substrates in good domino yields and stereoselectivities.

A highly diastereo- and enantiostereoselective synthesis of bicyclic dihydropyranothiazoles combining a thiazole and δ-lactone skeleton via NHC-catalyzed [4+2] annulation of 5-alkenylthiazolones and α-chloroaldehydes has been developed. The heterocyclic products are formed via azolium enolate intermediates in good yields with high diastereo- and enantistereoselectivities.

The electrophilic reactivity of a series of novel pyrazole-4,5-dione derivatives in the organocatalytic Friedel–Crafts reaction with various substituted indoles has been tested. The disclosed procedure catalyzed by a cinchona alkaloid derivative allows the conjugation of two very important aza-heterocyclic scaffolds to generate a new class of indolylpyrazolones bearing a tetrasubstituted stereocenter in excellent yields (up to 99%) and with enantioselectivities of up to 94:6 er.

An efficient method for the synthesis of malononitrile-substituted­ diarylmethines through 1,6-conjugate addition of para-quinone­ methides with masked acyl cyanide (MAC) reagents has been developed. Under mild conditions, the scalable reaction occurs in good to excellent yields providing a straightforward access to a series of malononitrile-substituted diarylmethines. The synthetic utility of this protocol has been demonstrated in the synthesis of bioactive compounds.

The enantioselective vinylogous Henry reaction of 3,5-dimethyl-4-nitroisoxazole with trifluoromethyl ketones employing a bifunctional squaramide organocatalyst has been developed. A series of isoxazole bearing trifluoromethyl-substituted tertiary alcohols, 2-substituted (R)-1,1,1-trifluoro-3-(3-methyl-4-nitroisoxazol-5-yl)propan-2-ols, were obtained under these mild reaction conditions in good yields and moderate to good enantioselectivities

A highly diastereo- and enantioselective Mannich reaction of N-acetylindolin-3-ones with isatin N-Boc ketimines to form 2,3′-connected bis-indolinones is developed employing a low loading of a readily available bifunctional thiourea catalyst. The asymmetric synthesis connects two indolinones via a vic-diamine unit and generates two neighboring stereocenters.

An N-heterocyclic carbene (NHC)-catalyzed asymmetric [4+2] annulation of (E)-2-benzoyl-3-phenylacrylonitriles with α-chloroaldehydes has been developed. The protocol leads to 5-cyano-substituted dihydropyranones in good to excellent yields with excellent diastereo- and enantioselectivities (up to 93% yield, >20:1 d.r. and 99% ee).

A new synthetic strategy for the asymmetric synthesis of five-membered spiropyrazolones via N-heterocyclic carbene-catalyzed [3+2] annulations employing enals and unsaturated pyrazolones as substrates has been developed. The new protocol allows the flexible variation of all four substituents of the pharmaceutically important spiropyrazolones in moderate to very good yields and in most cases with excellent diastereoselectivities and good to excellent enantioselectivities.

A one-pot synthesis of 1-substituted 1H-isochromenes employing various 2-alkynyl-benzaldehydes and ketones as substrates under a combination of Bronsted acid and silver catalysis has been developed. The isochromenes, which are present as important heterocyclic core structures in many bioactive and natural compounds, are obtained in medium to excellent yields with diastereomeric ratios of up to 9:1. A first enantioselective variant has also been tested.

Synthesis : journal of synthetic organic chemistry 48(19), 3207-3216(2016). doi:10.1055/s-0035-1561468, Published by Thieme, Stuttgart [u.a.]

An efficient and unprecedented [4+3] cycloaddition between in situ generated aza-o-quinone methides and azomethine imines via an aza-Michael/aminalization sequence has been developed. The scalable protocol allows to expeditiously assemble a valuable heterocyclic system incorporating tetrahydroisoquinoline and benzotriazepine scaffolds in good to excellent yields under mild conditions.

The asymmetric synthesis of tetrahydropyridines employing a normal electron-demanding aza-Diels–Alder reaction has been developed. The [4+2] cycloaddition of ethyl glyoxylate imine with aryl-substituted 2-silyloxy-1,3-butadienes is catalyzed by 5 mol% of a BINOL-derived phosphoric acid and in general leads to good yields and ee values with good to excellent diastereoselectivities. The cycloadducts can be further converted into the corresponding piperidinones, which are important pipecolic acid derivatives.

A highly diastereo- and enantioselective domino Michael/Henry reaction of 1-acetylindolin-3-ones with o-formyl-(E)-β-nitrostyrenes catalyzed by low loading of a quinine-derived amine-squaramide provides the corresponding indolin-3-one derivatives bearing four adjacent stereogenic centers in good to high yields and with excellent stereoselectivities., Graphical Abstract

Synthesis : journal of synthetic organic chemistry 46(9), 1261-1269 (2014). doi:10.1055/s-0033-1340826, Published by Thieme, Stuttgart

In this review, recent works on metal-catalyzed asymmetric Mannich, aza-Henry and vinylogous Mannich reactions are described. The asymmetric Mannich reaction is one of the most powerful methodologies among the carbon–carbon bond-forming reactions, and provides direct access to a wide range of optically active natural products with useful biological properties. 1 Introduction 2 Catalytic Asymmetric Mannich Reactions 2.1 BINOL Ligands 2.2 BINAP Ligands 2.3 Bisoxazoline Ligands 2.4 Pyridine Bisoxazoline Ligands 2.5 Diamine Ligands 2.6 P,N-Ligands 2.7 P,S-Ligands 2.8 P,P-Ligands 2.9 N,N-Ligands 2.10 Miscellaneous 3 Asymmetric Aza-Henry Reactions 3.1 BINOL Ligands 3.2 Bisoxazoline Ligands 3.3 N,N-Ligands 3.4 Miscellaneous 4 Asymmetric Vinylogous Mannich Reactions 5 Conclusion

The enantioselective synthesis of 2-alkylated pyrroles via Michael addition of pyrroles to α,β-unsaturated ketones employing cinchona alkaloid-derived primary amines as organocatalysts is described. Good to excellent yields (78–99%) and good to very good enantioselectivities (75–93% ee) are obtained. With this protocol highly enantioenriched C-alkylated pyrroles can be synthesized easily, thus facilitating their possible application in medicinal chemistry.

The diastereo- and enantioselective synthesis of 3-acetyl-4-hydroxyisochroman-1-ones via an intramolecular trans-selective aldol reaction employing proline-type organocatalysts is described. Good yields (64–88%) and high stereoselectivities (87 to >95% de, 84–99% ee) are obtained, thus potentially enabling, for example, a new direct entry to carbazolelactone alkaloid natural products.

Synargentolide A was synthesized in 11 steps starting from the commercially available 2,2-dimethyl-1,3-dioxan-5-one, employing the SAMP/RAMP-methodology via an α,α′-bis-alkylation to generate the first two stereogenic centers with virtually complete asymmetric induction (de, ee >99%). After the asymmetric synthesis of the triol fragment of the molecule, the δ-lactone moiety was constructed using an asymmetric allylation, esterification, and ring-closing metathesis sequence.

An organocatalytic quadruple cascade initiated by a Friedel–Crafts-type reaction is described. The (S)-diphenylprolinol trimethylsilyl ether catalyzed reaction yields highly functionalized cyclohexenecarbaldehydes bearing a 1,1-bis[4-(dialkylamino)phenyl]ethene moiety and three contiguous stereogenic centers. The reaction tolerates various functional groups and all products are obtained with very good diastereoselectivity and with virtually complete enantiomeric excess., Graphical Abstract

An efficient asymmetric synthesis of the potential antitumor agent (–)-gonioheptolide A derivatives is described. By employing an (S)-proline-catalyzed aldol reaction, the RAMP hydrazone α-alkylation methodology, and a diastereoselective reduction with zinc borohydride five stereocenters are established in the target compound. 4-epi-Methoxy-gonioheptolide A was obtained in ten steps in 15% overall yield and excellent diastereo- and enantiomeric excesses (de ≥95%, ee ≥99%).

A secondary-amine-catalyzed asymmetric Michael addition of 3-substituted N-(tert-butoxycarbonyl)oxindoles to maleimides with activation by a Bronsted base gives the corresponding products in high yields (86–98%), excellent diastereomeric ratios (dr > 99:1), and high enantiomeric excesses (86–91% ee).

An efficient two-step asymmetric synthesis of highly substituted 3-alkoxy-hexahydro-3 H -isochromenes and 3-sulfenylated hexahydro-3 H -isochromenes is described. The procedure involves an organocatalytic triple cascade reaction, followed by an intermolecular [Yb(fod) 3 ]-catalyzed inverse-electron-demand hetero-Diels–Alder reaction. Using this strategy, a total of six stereogenic centers are obtained with excellent diastereoselectivities and virtually complete enantioselectivities (>95:5 dr, >99% ee).

A one-pot thiourea-catalyzed enantioselective synthesis of polyfunctionalized 4H-chromenes via a domino Michael-hemiacetalization reaction and subsequent dehydration is reported. Starting from 2-nitrovinylphenols and β-keto esters, the new protocol affords the 4H-chromenes bearing a variety of functional groups with good to excellent yields (76-95%) and enantioselectivities ranging from 30-99% ee. Both enantiomers are available at will depending on the ephedrine or pseudoephedrine-based thiourea catalyst used.

The direct pyrrolidine-catalyzed α-sulfenylation ofaldehydes and ketones with the commercially available, very cheap chemicaltetramethylthiuram disulfide (thiram) is described. The dithiocarbamoylderivatives are obtained in good to excellent yields (47-98%).In the case of α-substituted aldehydes the protocol allowsthe generation of quaternary stereocenters. The sensibility of the α-sulfenylatedcarbonyl compounds for racemization has been investigated.

The asymmetric synthesis of the antitumor and immunostimulatory α-D-galactosyl ceramide KRN7000 using a (R)-proline-catalyzed enantioselective aldol reaction as key step is described. The title compound is synthesized in thirteen linear steps with excellent stereoselectivity (de >98%, ee = 95%) employing the commercially available substrates 1-pentadecanal, 2,2-dimethyl-1,3-dioxan-5-one, hexacosanoic acid, and D-galactose.

An efficient two-step asymmetric synthesis of highly substituted cis-configured thiadecalins and the corresponding hexahydrobenzothiophene core is described. Thiadecalin derivatives are known for their widespread biological activities, such as antimicrobial and neurotropic properties. The procedure is based on an organocatalytic triple cascade reaction followed by an intramolecular sulfa-Michael addition. In this manner six consecutive stereocentres are controlled and the target molecules are obtained in moderate yields, with virtually complete enantioselectivitiy (ee >99%) and after recystallisation in diastereomeric ratios of>97:3. The relative and absolute configuration was determined by NMR spectroscopy and X-ray structure analysis.

A microwave-assisted, organocatalytic domino Michael/Henry condensation/Michael/aldol condensation reaction has been developed. Employing acetaldehyde and nitroalkenes as substrates, this quadruple cascade allows an efficient asymmetric synthesis of trisubstituted cyclohexene carbaldehydes in moderate to good yields (25-45%) and high enantioselectivities (ee = 89 to >99%). ESI-MS measurements were carried out to support the proposed complex catalytic cycle.

An efficient asymmetric synthesis of anti-1,2-disubstituted taurine derivatives through nucleophilic addition of phenyl-methanesulfonate to various N-acylimines in the presence of l,2:5,6-di-O-isopropylidene-a-D-allofuranose as a chiral auxiliary is described. The taurine derivatives were obtained in three steps with good overall yields (36-61%) and excellent enantiomeric excesses (83-98%). The diastereomeric excesses of 15-91% could be improved to 90-98% by column chromatography or recrystallization. The relative and absolute configurations of the products were determined by means of an X-ray crystal structure analysis.

The asymmetric Michael addition of aromatic heterocyclic aldehydes to arylidenemalonates catalyzed by N-heterocyclic carbenes is described. The ketomalonates are obtained in 84-98% yields and moderate to good enantioselectivities (30-78% ee). The enantiomeric excesses could be improved to excellent levels of up to 99% ee after a single recrystallization.

The asymmetric synthesis of jaspine B (pachastrissamine) using a (R)-proline-catalyzed enantioselective aldol reaction as key step is described. Jaspine B was synthesized from the commercially available and inexpensive 1-pentadecanal and the dihydroxyacetone equivalent 2,2-dimethyl-1,3-dioxan-5-one in nine steps, good overall yield (23.6%) and excellent stereoselectivity (de >98%, ee = 95%).

A versatile and efficient route to both enantiomers of 4′-quaternary 2′-deoxy-3′- and -4′- EPI-β- C- and - N-nucleosides is described. The asymmetric synthesis involves the SAMP/RAMP--hydrazone α-alkylation methodology and diastereoselective nucleophilic 1,2-additions. Manipulation of the substituents in the anomeric position leads to the thermodynamically more stable β-anomers of excellent diastereo- and enantiomeric purity (

The synthesis of all four possible stereoisomers of enantiopure and diastereomerically pure or highly enriched α-branched [2.2]paracyclophanylalkylamines is described. Key step is the nucleophilic 1,2-addition of alkyllithium reagents to hydrazones of 4-formyl[2.2]paracyclophane derived from the chiral auxiliaries SAMP/RAMP and RAMBO/SAMBO via chromatographic epimer separation. Reductive N-N bond cleavage of the resulting hydrazines, followed by treatment with benzyloxycarbonyl chloride afforded the N-Cbz-protected diastereo- and enantiopure (de, ee ÷ 99%) or diastereomerically enriched (de = 89-96%) title amines.

An efficient route to α-phenyl-γ-hetero (O, S, Se, Cl)-substituted isopropyl sulfonates via S N 2-ring opening of γ-sultones, easily available by asymmetric synthesis from chiral lithiated sulfonates, is described. The title compounds are obtained in very good overall yields of 65-86% over three steps and excellent diastereo- and enantiomeric excesses (de = 94-96%, ee ≥ 98%).

Numerous asymmetric methods have been developed over the past 30 years to effect the Michael reaction of sulfur donors and Michael acceptors. Many of these stoichiometric and catalytic methods are complementary to one another, each having a certain range of substrate tolerance. Organocatalysis has a place at the origin of this field in the discovery of cinchona alkaloid catalyzed sulfa--Michael reactions. At the same time, it is involved in the current state-of-the-art as several elegant tandem processes that employ secondary amine catalysts and involve initial sulfa-Michael additions have been developed.

The asymmetric synthesis of ( S, S)- and ( R, R)-2-methylthreitol was carried out, starting from the SAMP or RAMP hydrazone of 2,2-dimethyl-1,3-dioxan-5-one. The protocol involves an enantioselective α-alkylation as a key step. The second stereogenic center was installed by either nucleophilic 1,2-addition or diastereo-selective epoxidation with bis(acetylacetonato)oxovanadium(IV) [VO(acac) 2 ] as catalyst. The title compounds were obtained in excellent diastereo- and enantiomeric excesses (≥98% de, 98% ee) and in good overall yields (40-61%).

An efficient biomimetic C 3 +C n entry to amino sugars and derivatives via a direct asymmetric organocatalytic Mannich methodology employing 2,2-dimethyl-l,3-dioxan-5-one as a dihydroxyacetone phosphate equivalent and N-PMP or N-Boc protected imines has been developed. The Mannich bases were obtained in high diastereo- and enantiomeric excesses (78% to >99% de, 81-98% ee) and were further elaborated using diastereoselective reduction protocols, as well as via diastereoselective direct reductive amination reactions.