Intramolecular Aldol Reaction Research Articles

Iodine‐Catalyzed Annulations of 2‐Amino Carbonyls for Diverse 1‐Azaxanthones, Quinolines, and Naphthyridines

AbstractAn efficient and facile iodine‐catalyzed reaction of 2‐amino carbonyls with β‐enamino esters or β‐enaminones affords 1‐azaxanthones, quinolines, and naphthyridines in good to excellent yields. This novel catalytic [4+2] annulation reaction proceeds through a cascade I2‐activation, Michael addition, intramolecular aldol reaction, and aromatization.

Total Synthesis of ent-Callilongisin B.

The first enantioselective total synthesis of tricyclic diterpenoid callilongisin B, which was isolated from Callicarpa longissima, has been achieved. The synthetic method includes a diastereoselective 1,4-addition and Hosomi-Sakurai allylation followed by Wacker oxidation, intramolecular aldol reaction to construct a six-membered ring, and oxidative dearomatization accompanied by diastereoselective δ-lactonization.

Asymmetric Synthesis of Functionalized 9-Methyldecalins Using a Diphenylprolinol-Silyl-Ether-Mediated Domino Michael/Aldol Reaction.

Substituted 9-methyldecalin derivatives containing an all carbon quaternary chiral center were synthesized with excellent enantioselectivity via an organocatalyst-mediated domino reaction. The first reaction is a diphenylprolinol silyl ether-mediated Michael reaction, and the second reaction is an intramolecular aldol reaction. The enantiomerically pure catalyst is involved in both reactions.

Biomimetic Total Synthesis of Enterocin

AbstractThe first chemical total synthesis of the highly oxygenated polyketide enterocin has been accomplished. The key step of the synthesis was a late‐stage biomimetic reaction cascade involving two intramolecular aldol reactions in which each step proceeded in 52 % yield (averaged) and which established four of the seven stereogenic centers. The pivotal precursor for the cascade reaction was assembled from three readily available building blocks. A chiral dithioacetal with two stereogenic centers originating from L‐arabinose represented the core fragment to both ends of which the other building blocks were attached by aldol reactions. The remaining stereogenic center was installed by Davis oxygenation immediately prior to the key step.

Biomimetic Total Synthesis of Enterocin.

The first chemical total synthesis of the highly oxygenated polyketide enterocin has been accomplished. The key step of the synthesis was a late‐stage biomimetic reaction cascade involving two intramolecular aldol reactions in which each step proceeded in 52 % yield (averaged) and which established four of the seven stereogenic centers. The pivotal precursor for the cascade reaction was assembled from three readily available building blocks. A chiral dithioacetal with two stereogenic centers originating from L‐arabinose represented the core fragment to both ends of which the other building blocks were attached by aldol reactions. The remaining stereogenic center was installed by Davis oxygenation immediately prior to the key step.

Oxidative Functionalization of Trinor-18α-olean-17(22)-ene Derivatives. Annulation of the E-Ring by an Intramolecular Aldol Reaction.

cis-Dihydroxylation of trinor-18α-olean-17(22)-ene 2 with osmium tetroxide led to diol 9. Its cleavage with lead tetraacetate gave tetracyclic ketoaldehyde 10. By comparison, the ozonation of trinor-18α-olean-17(22)-ene 2 in the presence of p-toluenesulfonic acid gave the corresponding ketoacetal 12. Both products were subjected to an intramolecular aldol reaction under the acidic conditions and yielded unusual triterpenes bearing a bicyclo[4.3.1]decane fragment (22). Further manipulation of the protective groups afforded compounds useful in triterpene synthesis, especially in the preparation of potentially biologically active saponins based on a tetracyclic terpene core.

Synthesis of the Core Structure of Palhinine A

AbstractWe present a strategy to the core structure of the alkaloid palhinine A passing through a 2,5‐difunctionalized cyclohexenone. This enone was prepared by a domino Michael/aldol condensation sequence. An allylation reaction on the cyclohexenone followed by oxy‐Cope rearrangement introduced an allyl group at C3. After the generation of an aldehyde function on the terminus of the C5 substituent, an intramolecular aldol reaction led to a bicyclo[2.2.2]octanone. The five‐membered ring of the core structure could be established by an intramolecular nitrile oxide‐alkene [3+2]‐cycloaddition. Prior to this key transformation, the keto function was converted to an alkene and the allyl group to an oxime.

Diastereotopic Group-Selective Intramolecular Aldol Reactions Initiated by Enantioselective Conjugate Silylation: Diastereodivergence Controlled by the Silicon Nucleophile

A reaction sequence consisting of enantioselective copper-catalyzed conjugate silylation and diastereotopic group-selective aldol cyclization is reported. The diastereoselectivity of the intramolec...

Stereoselective Convergent Synthesis of Carbon Skeleton of Cotylenin A Aglycone

AbstractIn this paper, the synthesis of the carbon skeleton of cotylenin A aglycone is described. The key reactions, including an intramolecular aldol reaction, an aldol coupling reaction, and a ring-closing meta­thesis, allow for the effective and stereoselective access to the carbon skeleton of cotylenin A aglycone. The stereochemistry was confirmed by single-crystal X-ray crystallographic analyses of related compounds.

Asymmetric Total Synthesis of Rumphellclovane E.

The first asymmetric total synthesis of rumphellclovane E, a clovane-type sesquiterpenoid, has been accomplished in eight steps from commercially available (R)-carvone. Key elements of the synthesis include Rh-catalyzed cyclopropanation, iron-catalyzed intramolecular reductive aldol reaction, and SmI2-mediated chemo- and diastereoselective reduction of the cyclopentanone.

Regioselectivity Umpolung in Asymmetric Diels-Alder Reaction of ortho-Formyl-Substituted Cinnamates and Dienals via Double Aminocatalysis.

The cinnamates having an ortho-formyl group can potentially form vinylogous iminium ion species under the catalysis of chiral amines, which facilitates the Diels-Alder cycloaddition reaction with the concurrently generated trienamines between dienals and amine catalysts in a regioselectivity umpolung manner. A cascade intramolecular aldol reaction was followed, finally furnishing polyhydrophenanthrene frameworks with excellent diastereo- and enantioselectivity.

Stereoselectivity Enhancement During the Generation of Three Contiguous Stereocenters in Tetrahydrothiophenes

AbstractApplication of carefully designed Cinchona alkaloid based squaramides resulted in the formation of three contiguous stereocenters in enantio‐ and diastereoselective Sulfa‐Michael/intramolecular aldol reactions cascade. Increase of the temperature to 333 K in reaction of mercaptoacetic aldehyde and various en‐ynones allowed the rise of the reaction rate while not affecting the enantioselectivity nor diastereoselectivity. Stereoselectivity was dependent on the structure of the hydrogen‐bonding unit, thus revealing the importance of weak interactions in the formation of the multifunctional tetrahydrothiophenes. Kohn‐Sham Density Functional Theory results suggest that a perfect fit of the electrophile and squaramide via tailored (+)N−H hydrogen bonding and π–π stacking interactions were the main factors of the chirality transfer.

Concise Total Synthesis of Tronocarpine.

A concise total synthesis of tronocarpine, a chippiine-type indole alkaloid, was accomplished. The key feature of this total synthesis is a one-pot construction of the pentacyclic skeleton containing an azabicyclo[3.3.1]nonane core by tandem cyclization from an indole derivative with all carbon side chains and functional groups. This tandem cyclization consists of α,β-unsaturated aldehyde formation, intramolecular aldol reaction, six-membered lactamization, azide reduction, and seven-membered lactamization. The stereochemical outcome in this tandem cyclization is controlled by the stereocenter at the C14 position. This strategy can be utilized to synthesize other chippiine-type alkaloids with azabicyclo[3.3.1]nonane skeletons.

Concise Total Synthesis of Tronocarpine

AbstractA concise total synthesis of tronocarpine, a chippiine‐type indole alkaloid, was accomplished. The key feature of this total synthesis is a one‐pot construction of the pentacyclic skeleton containing an azabicyclo[3.3.1]nonane core by tandem cyclization from an indole derivative with all carbon side chains and functional groups. This tandem cyclization consists of α,β‐unsaturated aldehyde formation, intramolecular aldol reaction, six‐membered lactamization, azide reduction, and seven‐membered lactamization. The stereochemical outcome in this tandem cyclization is controlled by the stereocenter at the C14 position. This strategy can be utilized to synthesize other chippiine‐type alkaloids with azabicyclo[3.3.1]nonane skeletons.

Total Syntheses of (±)-Melicolones A and B.

The first total syntheses of (±)-melicolones A and B, which have a unique and densely functionalized framework derived from a rearranged prenylated acetophenone, were accomplished in 12.3% combined overall yield. The concise and divergent synthesis of these two natural products, which were isolated in racemic form, was achieved in a longest linear sequence requiring only 9 steps (11 total steps) and 8 isolated intermediates using commercially available starting materials. This approach, which might enable access to all tetracyclic melicolones, features the highly regioselective (16:1) and diastereoselective (15:1) dipolar cycloaddition of a carbonyl ylide generated by the unusual cyclization of a rhodium carbene with the carbonyl oxygen atom of an aliphatic aldehyde. This cycloaddition proceeds with dominant steric control to give a highly functionalized oxabicycloheptane core. Stereoselective enolate alkylation led to a prenylated intermediate that underwent an intramolecular aldol reaction to give the penultimate tricyclic intermediate. Tandem epoxidation of the pendant prenyl group followed by a regioselective, acid-catalyzed cyclization delivered (±)-melicolones A and B.

Total Synthesis of Liangshanone

AbstractThe first total synthesis of liangshanone, a hexacyclic ent‐kaurane diterpenoid alkaloid, has been completed. Its intricate cagelike framework was assembled through several key transformations, including an oxidative dearomatization/Diels–Alder (OD/DA) cycloaddition sequence, a tandem alkene cleavage/Mannich cyclization, a Robinson‐type annulation, and an intramolecular aldol reaction. Notably, an organocatalytic enantioselective α‐hydroxymethylation process allowed the preparation of an enantiomerically enriched tricyclic intermediate that should enable asymmetric access to the target natural product.

Total Synthesis of Liangshanone

The first total synthesis of liangshanone, a hexacyclic ent-kaurane diterpenoid alkaloid, has been completed. Its intricate cagelike framework was assembled through several key transformations, including an oxidative dearomatization/Diels-Alder (OD/DA) cycloaddition sequence, a tandem alkene cleavage/Mannich cyclization, a Robinson-type annulation, and an intramolecular aldol reaction. Notably, an organocatalytic enantioselective α-hydroxymethylation process allowed the preparation of an enantiomerically enriched tricyclic intermediate that should enable asymmetric access to the target natural product.

Record-Breaking Steric Crowding in Trialkylamines Prepared by Oxidative Ring Opening

AbstractEpoxidation of olefinic heterocyclic amines and subsequent acid-catalyzed hydrolysis or alternatively the direct dihydroxylation with the help of osmium tetroxide led to diols, which underwent ring cleavage in the presence of lead tetraacetate to give 3-isopropyl-2,2,4,4-tetramethyl-3-azahexanedial and 3-tert-butyl-2,2,4,4-tetramethyl-3-azapentanedial. Whereas the former dialdehyde is a highly unstable model compound because of a rapid intramolecular aldol reaction, the latter product proves to be isolable at room temperature. Furthermore, this compound is the first open-chain tri-tert-alkylamine establishing in a new record of steric crowding in tertiary amines. Strong tendencies to a Hofmann-like elimination reaction or to ring-closing reactions were observed when the aldehyde units of 3-tert-butyl-2,2,4,4-tetramethyl-3-azapentanedial were transformed into other functionalities, since both types of reactions led to a significantly decrease of the steric stress.

One‐pot, Direct Synthesis of 3‐Hydroxy‐3‐aryl‐1‐indanones and their 2‐Benzylidene Derivatives from 2‐Alkynylbenzophenones

AbstractA rapid and efficient one‐pot strategy for the synthesis of 3‐hydroxy‐3‐aryl‐1‐indanones, directly from the corresponding 2‐alkynylbezophenones via a sequential carbonyl directed regioselective hydration followed by an intramolecular Aldol reaction has been reported. Further this strategy has also been extended for the efficient conversion of these 3‐hydroxy‐3‐aryl‐1‐indanone units into biologically important 2‐benzylidene‐3‐hydroxy‐3‐aryl‐1‐indanone derivatives, employing an intermolecular Aldol condensation reaction, both in a stepwise manner as well as one pot strategy. The process exhibits very good substrate scope and high reaction yields under mild reaction conditions.

Enantioselective Total Synthesis of Chondrosterins I and J by Catalytic Asymmetric Intramolecular Aldol Reaction Using Chiral Diamine Catalyst

The first enantioselective total synthesis of chondrosterins I and J was accomplished. The synthetic method focuses on an intramolecular aldol reaction through catalytic asymmetric desymmetrization using chiral diamine catalyst. An intensive investigation of this reaction improved the enantiomeric excess up to 92 % ee. In addition, stereoselective reduction of the ketone moiety efficiently converted chondrosterin I to chondrosterin J.