Direct Vinylogous Aldol Reaction Research Articles

Synthesis and Evaluation of N-Diaminophosphoryl Aminothioureas as Bifunctional Catalysts for Vinylogous Aldol Reactions of Isatins and 2(3H)-Furanones.

The organocatalytic asymmetric direct vinylogous aldol reaction of N-methylisatins 1 and γ-butenolides 2 to provide 3-hydroxy-2-oxindole derivatives 3 was investigated. A series of N-diaminophosphoryl aminothiourea catalysts 4 was synthesized, and their utility for the stereoselective formation of 3 was examined.

Development of Green Asymmetric Organocatalytic Synthesis

Organocatalysts, which are less toxic than metal catalysis, as well as inexpensive, environmentally benign, and stable against moisture and oxygen compared to metal-based catalysts, have received considerable attention for being efficient and clean catalysts. With respect to green chemistry, the development of organocatalysis is a significant research subject for a sustainable society. This article reviews studies on the development of novel organocatalysts and the reactions achieved from using them. Focusing on the push-pull ethylene moiety, in which two electron-withdrawing groups (EWGs) were introduced, we proposed that the vinylogous amide proton (N-H) will lead to the design of organocatalysts. We have developed the diaminomethylenemalononitrile (DMM) organocatalysts, which are push-pull ethylenes having two cyano groups as EWGs, and proved that they are effective for highly stereoselective hydrophosphonylation with aldehydes. The catalytic ability of the DMM organocatalyst was demonstrated in the development of the first asymmetric hydrophosphonylation of ketones using organocatalysts. The DMM organocatalyst can be applied to the selective 1,4-addition asymmetric hydrophosphonylation of enones. In addition, we designed and synthesized novel organocatalysts bearing squaramide-sulfonamide motif as multiple hydrogen bond donors. Squaramide-sulfonamide organocatalysts efficiently catalyzed the asymmetric direct vinylogous aldol reactions of furan-2(5H)-one with aldehydes. Successively, we achieved the synthesis of γ,γ-disubstituted-δ-hydroxy-γ-butenolide via asymmetric direct vinylogous aldol reaction of furanone derivatives using the squaramide-sulfonamide organocatalysts.

Catalytic enantioselective synthesis of chiral 4-hydroxy 4′-substituted pyrazolones by the vinylogous aldol reaction of pyrazole-4,5-diones with 3-alkylidene-2-oxindoles

Here, a bifunctional quinine-derived benzamide catalyzed direct enantioselective vinylogous aldol reaction between 3-alkylidene-2-oxindoles and pyrazole-4,5-diones has been developed.

Synthesis of Chiral γ,γ-Disubstituted γ-Butenolides via Direct Vinylogous Aldol Reaction of Substituted Furanone Derivatives with Aldehydes.

An organocatalyzed method for synthesizing chiral γ,γ-disubstituted γ-butenolides via direct vinylogous aldol reactions of γ-substituted β,γ-butenolides with aldehydes is reported. This reaction is catalyzed by a squaramide-sulfonamide organocatalyst to afford a range of anti-aldol adducts possessing vicinal quaternary and tertiary stereocenters with high to excellent enantioselectivities (reaching 95% ee). This is the first report of a successful stereoselective direct vinylogous aldol reaction of aldehydes with γ-substituted β,γ-butenolides.

1,5,7-Triazabicylodec-5-ene-Promoted Direct Vinylogous Aldol Reaction for the Synthesis of 3-Hydroxy-2-oxoindole Derivatives

A simple and efficient method has been developed for the synthesis of 3-hydroxy-2-oxoindole derivatives through a direct vinylogous aldol reaction of allylic esters with isatins, catalyzed by 1,5,7-triazabicyclodec-5-ene. This method affords a variety of 3-hydroxy-2-oxoindole derivatives in moderate to excellent yields with high regioselectivities. An asymmetric version of this reaction catalyzed by Corey’s chiral guanidine proceeded with moderate enantioselectivity. The protocol can also be used to synthesize isatin spiro ethers.

Correction to "Asymmetric Synthesis of α,β-Unsaturated δ-Lactones through Copper(I)-Catalyzed Direct Vinylogous Aldol Reaction".

Correction to "Asymmetric Synthesis of α,β-Unsaturated δ-Lactones through Copper(I)-Catalyzed Direct Vinylogous Aldol Reaction".

Asymmetric Synthesis of α,β-Unsaturated δ-Lactones through Copper(I)-Catalyzed Direct Vinylogous Aldol Reaction

A simple methodology for the asymmetric synthesis of chiral α,β-unsaturated δ-lactones was achieved by copper(I)-catalyzed direct vinylogous aldol reaction (DVAR) of β,γ-unsaturated esters and various aldehydes, including aromatic aldehydes, heteroaromatic aldehydes, α,β-unsaturated aldehydes, and aliphatic aldehydes. For aromatic and heteroaromatic aldehydes, a one-pot reaction consisting of DVAR, isomerization of the unsaturated carbon-carbon double bond from ( E)-form to ( Z)-form, and subsequent intramolecular transesterification was required to get the lactones in moderate to high yields with high enantioselectivity. For α,β-unsaturated and aliphatic aldehydes, the DVAR proceeded directly to afford the lactones in moderate yields with high enantioselectivity. In the DVAR, various functional groups were well tolerated. Moreover, the methodology was nicely applicable to the aldehyde group distributed in natural products, derivatives of natural product, and derivatives of drug molecules (atomoxetine and naproxen). The mechanism studies revealed that α-addition was reversible and not favored, which accounted for the excellent regioselectivity in the DVAR. The copper(I)-dienolate species generated through deprotonation was proposed to form an equilibrium with an allylcopper(I) species, which reacted with aldehydes to afford the DVAR products through a catalytic asymmetric allylation of aldehydes. Finally, the robustness of the present reaction was demonstrated by a gram-scale reaction, and the utility of the present methodology was showcased by the formal asymmetric synthesis of ezetimibe and fostriecin.

Theoretical Investigation on Direct Vinylogous Aldol Reaction of Isatin Catalyzed by Chiral-N, N'-dioxide Sc(III) Complex

The mechanism and enantio- as well as diastereo-selectivity of asymmetric direct aldol reaction of isatin with α-angelica lactone catalyzed by chiral N, N'-dioxide-Sc(OTf)3 were studied at the B3LYP(SMD, THF)/6-31G(d,p) level. The calculations indicated that the reaction occurred along stepwise mechanism, that is, CC bond formation followed by H-transfer from α-angelica lactone to carbonyl group of isatin. The H-transfer step was predicted to be the rate-determining step(RDS), with the energy barrier of 23.3 ∼ 26.2 kcal mol−1 for four stereoisomeric products. The ortho-isopropyl groups of amide in ligand blocked the reacting site from re-face of isatin and induced the re-face of α-angelica lactone to approach to the si-face of isatin, leading to the predominant product with 3S, 2′S-configuration. In this asymmetric catalysis, the interaction energy term (ΔEint), especially stabilizing orbital energy (ΔEoi) and electrostatic energy (ΔVelstat), were the main contributors to the enantioselectivity of the reaction, while the activation strain energy (ΔEstrain) of α-angelica substrate enhanced the diastereodifferentiation of the two competing pathways, contributing to high diastereomeric ratio (d.r.). The turnover frequency (TOF) along the favorable si-face pathway was predicted to be 2.76 × 10−21 s−1, with the rate constant of k(T) = 7.5 × 10−2 exp(-108390/RT) dm3 mol−1 s−1 over 258.15 K ∼ 358.15 K temperature range. These results provided explanation for the good reactivity as well as excellent asymmetric induction of chiral N, N'-dioxide-Sc(OTf)3 in direct aldol reaction of isatin.

Catalytic Asymmetric Direct Vinylogous Aldol Reaction of Isatins with β,γ-Unsaturated Butenolides.

A direct asymmetric vinylogous aldol reaction of nonactivated natural α-angelica lactone to isatins has been developed. With a N,N'-dioxide-Sc(OTf)3 complex as catalyst, a variety of δ-hydroxy butenolides bearing congested adjacent tetrasubstituted stereocenters were obtained in good yields with high diastereoselectivities and excellent enantioselectivities. Besides, a possible transition state was proposed to explain the origin of the asymmetric induction.

Synthesis of (–)-Muricatacin and (–)-(R,R)-L-Factor Involving an Organocatalytic Direct Vinylogous Aldol Reaction

Concise syntheses of the polyketide natural product (–)-muricatacin and (–)-(R,R)-L-factor (natural product enantiomer) were achieved in four steps by employing an organocatalytic asymmetric direct vinylogous aldol reaction of γ-crotonolactone and suitable aliphatic aldehydes as the key step.

New Developments in Chiral Cooperative Ion Pairing Organocatalysis by Means of Ammonium Oxyanions and Fluorides: From Protonation to Deprotonation Reactions.

This personal account summarizes our contribution to the ion pairing organocatalysis mainly by use of chiral quaternary or tertiary ammonium fluorides, aryloxides and carboxylates. Starting from an experimental observation, we were able to develop several approaches for the enantioselective protonation of silyl enolates and enol esters giving rise to chiral carbonyl compounds bearing a stereogenic center at the α-position. Moving from protonation to deprotonation reactions, chiral ammonium ion pair catalysts were successfully applied to several asymmetric transformations such as an Henry reaction or a direct vinylogous aldol reaction to cite a few. An outlook of further possible developments in this field of research will also be discussed.

A One-Pot Tandem Strategy in Catalytic Asymmetric Vinylogous Aldol Reaction of Homoallylic Alcohols

Reported is a rationally-designed one-pot sequential strategy that allows homoallylic alcohols to be employed in a catalytic, asymmetric, direct vinylogous aldol reaction with a series of activated acyclic ketones, including trifluoromethyl ketones, γ-ketoesters, and α-keto phosphonates, in high yields (up to 95%) with excellent regio- and enantio-selectivity (up to 99% ee). This modular combination, including Jones oxidation and asymmetric organocatalysis, has satisfactory compatibility and reliability even at a 20 mmol scale, albeit without intermediary purification.

ChemInform Abstract: Highly Diastereoselective Vinylogous Mukaiyama Aldol Reaction of Isatins with 2‐(Trimethylsilyloxy)furans Catalyzed by Quinine.

AbstractA number of δ‐hydroxyalkylbutenolide oxindoles (III) are obtained with high diastereoselectivity by quinine‐catalyzed direct vinylogous Mukaiyama aldol reaction of N‐unsubstituted and N‐alkyl‐isatins with 2‐(trimethylsilyloxy)furans.

ChemInform Abstract: Direct Asymmetric Vinylogous Aldol Reaction of Allyl Ketones with Isatins: Divergent Synthesis of 3‐Hydroxy‐2‐oxindole Derivatives.

AbstractThe first highly enantioselective direct vinylogous aldol reaction between allyl aryl ketones and isatins is developed using a L‐valine derived bifunctional amino‐thiourea catalyst.

Synthesis of (+)-Febrifugine and a Formal Synthesis of (+)-Halofuginone Employing an Organocatalytic Direct Vinylogous Aldol Reaction

The enantioselective organocatalytic direct vinylogous aldol reaction of γ-crotonolactone and a suitable aldehyde was utilized in the synthesis of a functionalized γ-butenolide. The γ-butenolide (aldol product) was stereoselectively converted into a 5-aminoalkyl butyrolactone, which isomerized to the key 2,3-disubstituted piperidinone, a common intermediate to (+)-febrifugine and (+)-halofuginone.

Direct Asymmetric Vinylogous Aldol Reaction of Allyl Ketones with Isatins: Divergent Synthesis of 3‐Hydroxy‐2‐Oxindole Derivatives

The first highly enantioselective direct vinylogous aldol reaction between allyl aryl ketones and isatins is developed using a L-valine derived bifunctional amino-thiourea catalyst.

ChemInform Abstract: Asymmetric Vinylogous Aldol Reaction via H‐Bond‐Directing Dienamine Catalysis.

AbstractThe presented new enantioselective direct vinylogous aldol reaction of cyclohexenone with various α‐keto esters uses the bifunctional primary amine‐thiourea catalyst ATU.

Chiral Quaternary Ammonium Aryloxide/N,O‐Bis(trimethyl‐ silyl)acetamide Combination as Efficient Organocatalytic System for the Direct Vinylogous Aldol Reaction of (5H)‐Furan‐2‐one Derivatives

AbstractA chiral quaternary ammonium amide was generated in situ from N,O‐bis(trimethylsilyl)acetamide (BSA) as non‐nucleophilic Brønsted base precursor and the combination of chiral quaternary ammonium halide/sodium aryloxide as chiral Lewis base. This system was applied to an anti‐selective organocatalytic direct vinylogous aldol (ODVA) reaction of (5H)‐furan‐2‐one derivatives with aldehydes. Several 5‐(1′‐hydroxy)‐γ‐butenolides were obtained in good diastereomeric ratios (up to 95/5) and excellent enantioselectivities (up to 94%) with both aliphatic or (hetero)aromatic aldehydes, so providing a rare example of general and efficient conditions for the ODVA reaction.

Asymmetric Vinylogous Aldol Reaction via H-Bond-Directing Dienamine Catalysis

The enantioselective direct vinylogous aldol reaction of 3-methyl 2-cyclohexen-1-one with α-keto esters has been developed. The key to success was the design of a bifunctional primary amine-thiourea catalyst that can combine H-bond-directing activation and dienamine catalysis. The simultaneous dual activation of the two reacting partners results in high reactivity while securing high levels of stereocontrol.

Direct Catalytic Enantioselective Vinylogous Aldol Reaction of α-Branched Enals with Isatins

The direct vinylogous aldol reaction of α-substituted α,β-unsaturated aldehydes with isatins is described. The chemistry provides easy access to valuable 3-substituted 3-hydroxyoxindole derivatives with high stereocontrol and perfect γ-site selectivity. Preliminary mechanistic studies suggest that, depending on the nature of the α-branched enal substituents, two divergent reaction mechanisms can be operating, leading to different products and stereochemical outcomes.