Intramolecular Aldol Cyclization Research Articles

Synthesis of the [6-6-7-5-5] Pentacyclic Core of Calyciphylline N.

A new approach for the concise 11-step synthesis of the [6-6-7-5-5] BCDEF pentacyclic core of calyciphylline N is described. A type II [5 + 2] cycloaddition was employed to construct the strained BCD skeleton, which encompasses the challenging bicyclo[2.2.2] and bicyclo[4.3.1] ring systems. With a regio- and diastereoselective Lu's [3 + 2] cycloaddition, followed by intramolecular aldol cyclization and elimination, the desired [5-5]-fused EF ring system has been successfully installed, resulting in the complete carbocyclic skeleton of calyciphylline N.

Synthesis of A-B-C-ring Tricyclic Core of iso-Merrilactone A

A desymmetrization approach for the synthesis of the A-B-C tricycle intermediate of iso-merrilactone A was described. The key steps of this synthesis to efficiently access the tetracyclic Illicium sesquiterpenes core included an intramolecular aldol cyclization and an oxidative lactonization reaction. A novel Au catalyzed hydrolytic cyclorearrangement cascade reaction was explored in the initial stage.

Reinvestigation of synthesis of halo-substituted 3-phenyl-1-(2-pyridyl)-2-propen-1-ones (azachalcones). A tandem reaction for formation of penta-substituted cyclohexanols

A systematic study of the synthesis of halo-substituted azachalcones was conducted. During the reaction course, we obtained not only the target azachalcones, but also penta-substituted cyclohexanols, which are seldom reported in the literatures. The formation of penta-substituted cyclohexanols was dependent on equivalents of base used and reaction time. Their formation followed a tandem reaction: Claisen-Schmidt condensation, three Michael reactions, retro-aldol reaction, and intramolecular aldol cyclization.

Metal Coordination Controlled and Bifunctional H‐Bonded Catalysis in Stereoselective Intramolecular Aldol Cyclizations toward Carbocyclic Tertiary β‐Ketols

The principle of bifunctional catalysis is shown in the highly regio‐ and stereoselective intramolecular aldolization of 2‐methyl‐1,3‐cyclopentanedione, C2‐substituted with a methyl ethyl ketone group, to provide [3.2.1]‐bicyclooctanol diones in the presence of catalytic amounts of either LiBr and 1,8‐diazabicyclo[5.4.0]undec‐7‐ene (DBU), or 1,5,7‐triazabicyclo[4.4.0]dec‐5‐ene (TBD). Mechanistic investigations corroborated by DFT calculations show that LiBr engages in a bifunctional coordination of two carbonyl moieties and leads to the preorganization of the reactive enolate intermediate for a base‐mediated intramolecular aldol cyclization. On the other hand, TBD catalysis of the triketone substrate proceeds through a bifunctional H‐bonded mechanism to give the same aldol product as the major diastereomer. The LiBr and TBD‐catalyzed highly stereocontrolled intramolecular aldol cyclizations can be extended to other di‐ and triketones to give carbocyclic and carbobicyclic products as single diastereomers.

Rhodium Carbenoid Initiated O-H Insertion/Aldol/Oxy-Cope Cascade for the Stereoselective Synthesis of Functionalized Oxacycles.

A novel diazo-cascade approach has been developed for the synthesis of nine-membered oxacycles utilizing readily accessible β-hydroxy vinyl ketones and vinyl diazo esters. The Rh(II)-catalyzed cascade reaction begins with carbene O-H insertion followed by an intramolecular aldol cyclization to provide a substituted tetrahydrofuran intermediate that undergoes an oxy-Cope rearrangement to provide functionalized nine-membered oxacycles with complete stereoselectivity.

ChemInform Abstract: Total Synthesis of Isodaphlongamine H: A Possible Biogenetic Conundrum.

Herein we describe the first synthetic efforts toward the total synthesis of isodaphlongamine H, a calyciphylline B-type alkaloid. The strategy employs a chemoenzymatic process for the preparation of a functionalized cyclopentanol with a quaternary center. This molecule is elaborated to form an enantiopure 1-aza-perhydrocyclopentalene core, representing rings A and E of all calyciphylline B-type alkaloids. Further transformations involve the formation of a cyclic enaminone, 1,4-conjugate addition with a cyclopentenyl subunit, and intramolecular aldol cyclization to achieve a pentacyclic intermediate, ultimately forming isodaphlongamine H in a total of 24 steps from the commercially available compound 2-carbethoxycyclopentanone. Isodaphlongamine H exhibits promising inhibitory activity against a panel of human cancer cell lines.

Total Synthesis of Isodaphlongamine H: A Possible Biogenetic Conundrum.

Herein we describe the first synthetic efforts toward the total synthesis of isodaphlongamine H, a calyciphylline B-type alkaloid. The strategy employs a chemoenzymatic process for the preparation of a functionalized cyclopentanol with a quaternary center. This molecule is elaborated to form an enantiopure 1-aza-perhydrocyclopentalene core, representing rings A and E of all calyciphylline B-type alkaloids. Further transformations involve the formation of a cyclic enaminone, 1,4-conjugate addition with a cyclopentenyl subunit, and intramolecular aldol cyclization to achieve a pentacyclic intermediate, ultimately forming isodaphlongamine H in a total of 24 steps from the commercially available compound 2-carbethoxycyclopentanone. Isodaphlongamine H exhibits promising inhibitory activity against a panel of human cancer cell lines.

Total Synthesis of Isodaphlongamine H: A Possible Biogenetic Conundrum

AbstractHerein we describe the first synthetic efforts toward the total synthesis of isodaphlongamine H, a calyciphylline B‐type alkaloid. The strategy employs a chemoenzymatic process for the preparation of a functionalized cyclopentanol with a quaternary center. This molecule is elaborated to form an enantiopure 1‐aza‐perhydrocyclopentalene core, representing rings A and E of all calyciphylline B‐type alkaloids. Further transformations involve the formation of a cyclic enaminone, 1,4‐conjugate addition with a cyclopentenyl subunit, and intramolecular aldol cyclization to achieve a pentacyclic intermediate, ultimately forming isodaphlongamine H in a total of 24 steps from the commercially available compound 2‐carbethoxycyclopentanone. Isodaphlongamine H exhibits promising inhibitory activity against a panel of human cancer cell lines.

Expression, purification and crystallization of a plant polyketide cyclase from Cannabis sativa.

Plant polyketides are a structurally diverse family of natural products. In the biosynthesis of plant polyketides, the construction of the carbocyclic scaffold is a key step in diversifying the polyketide structure. Olivetolic acid cyclase (OAC) from Cannabis sativa L. is the only known plant polyketide cyclase that catalyzes the C2-C7 intramolecular aldol cyclization of linear pentyl tetra-β-ketide-CoA to generate olivetolic acid in the biosynthesis of cannabinoids. The enzyme is also thought to belong to the dimeric α+β barrel (DABB) protein family. However, because of a lack of functional analysis of other plant DABB proteins and low sequence identity with the functionally distinct bacterial DABB proteins, the catalytic mechanism of OAC has remained unclear. To clarify the intimate catalytic mechanism of OAC, the enzyme was overexpressed in Escherichia coli and crystallized using the vapour-diffusion method. The crystals diffracted X-rays to 1.40 Å resolution and belonged to space group P3121 or P3221, with unit-cell parameters a = b = 47.3, c = 176.0 Å. Further crystallographic analysis will provide valuable insights into the structure-function relationship and catalytic mechanism of OAC.

Nitrogen-containing 1,5-diketones based on N-Boc-piperidin-4-one, synthesis, intramolecular cyclization, and reaction with o-phenylenediamine

Reactions of N-Boc-piperidin-4-one with aromatic aldehydes afforded nitrogen-containing 1,5-diketones in the form of products of intramolecular aldol cyclization, like aza derivatives of tricyclo[7.3.1.02,7]-tridecanone system underlying naturally occurring limonoids. With o-phenylenediamine they enter into a domino-reaction leading to the formation of hydrobenzimidazo[2,1-e]acridine structure. N-Boc-piperidin-4-one in Michael reaction with diarylidenecyclohexanones forms 1,5-diketones undergoing cyclization into hydroxypyran structure.

Asymmetric Total Synthesis of (-)-Kravanhin B.

The first asymmetric total synthesis of kravanhin B has been accomplished with a linear reaction sequence of 13 steps starting from (R)-(-)-carvone. The synthesis features an intramolecular aldol cyclization to construct the desired cis-fused decalin skeleton and an acid-catalyzed dehydration and olefin isomerization to install the γ-butenolide ring.

Synthetic Study on Naphthospironone A: Construction of Benzobicyclo[3.2.1]octene Skeleton with Oxaspirocycle.

In connection with the total synthesis of naphthospironone A, a model study has revealed a promising approach to construct a benzobicyclo[3.2.1]octene skeleton possessing an oxaspirocycle by employing an intramolecular aldol cyclization.

ChemInform Abstract: Annulation Reactions of Allenyl Esters: An Approach to Bicyclic Diones and Medium‐Sized Rings.

AbstractThe addition of allenyl esters (II) to α‐sulfonyl cycloalkanes (I) leads to lactones (III), which are converted into desired bicyclic diones (IV) by a reductive intramolecular aldol cyclization and a subsequent oxidation.

The first asymmetric total synthesis of lycoposerramine-R.

The first asymmetric total synthesis of lycoposerramine-R, a Lycopodium alkaloid possessing a novel skeleton, was accomplished by a strategy featuring the stereoselective intramolecular aldol cyclization giving a cis-fused 5/6 bicyclic skeleton and a new method for the construction of the pyridone ring via the aza-Wittig reaction.

Total synthesis of 3-epi-(+)-lycoricidine from Garner aldehyde via intramolecular aldol cyclization

A highly efficient total synthesis of 3-epi-(+)-lycoricidine has been described for the first time from easily available (S)-Garner aldehyde with an overall yield of 7% in 20 steps. Stereoselective nucleophilic addition, Sharpless asymmetric dihydroxylation, Dess–Martin periodinane oxidation, intramolecular aldol cyclization, and Luche reduction are the salient features of this approach.

Annulation reactions of allenyl esters: an approach to bicyclic diones and medium-sized rings.

A flexible approach to construct sterically congested bicyclo-alkenedione frameworks is reported. Under the action of potassium carbonate, α-sulphonyl cycloalkanones are added to functionalized allenyl esters, leading to a lactone intermediate that is subsequently reduced to initiate an intramolecular aldol cyclization to [3.2.1], [3.3.1], and [4.3.1] bicycles. Oxidation then affords bicyclic diones in good three-step yields. Under exceptionally mild conditions, these bicycles are converted to highly functionalized medium-sized rings through a Grob-type fragmentation.

Asymmetric reductive aldol-type reaction with carbonyl compounds using dialkyl tartrate as a chiral ligand.

An asymmetric reductive aldol-type reaction of α,β-unsaturated esters with carbonyl compounds using Rh catalyst and Et2Zn was investigated. A chiral zinc complex from α,β-unsaturated ester was easily generated as the key intermediate from Et2Zn and Wilkinson's catalyst with diisopropyl L-(+)-tartrate to give a variety of enantioenriched β-hydroxy esters. The reaction was also applied to the intramolecular reductive aldol cyclization.

ChemInform Abstract: Sequential Norrish Type II Photoelimination and Intramolecular Aldol Cyclization of α‐Diketones: Synthesis of Polyhydroxylated Cyclopentitols by Ring Contraction of Hexopyranose Carbohydrate Derivatives.

The excitation of the innermost carbonyl of nono-2,3-diulose derivatives by irradiation with visible-light initiates a sequential Norrish typeII photoelimination and aldol cyclization process that finally gives polyfunctionalized cyclopentitols. The rearrangement has been confirmed by the isolation of stable acyclic photoenol intermediates that can be independently cyclized by a thermal 5-(enolexo)-exo-trig uncatalyzed aldol reaction with high diastereoselectivity. In this last step, the large deuterium kinetic isotope effect found for the 1,5-hydrogen atom transfer seems to indicate that the aldol reaction runs through a concerted pericyclic mechanism. Owing to the ready availability of pyranose sugars of various configurations, this protocol has been used to study the influence of pyranose ring-substituents on the diastereoselectivity of the aldol cyclization reaction. In contrast with other pyranose ring contraction methodologies no transition-metal reagents are needed and the sequential rearrangement occurs simply by using visible light and moderate heating (0 to 60 degrees C).

Sequential Norrish Type II Photoelimination and Intramolecular Aldol Cyclization of α‐Diketones: Synthesis of Polyhydroxylated Cyclopentitols by Ring Contraction of Hexopyranose Carbohydrate Derivatives

The excitation of the innermost carbonyl of nono-2,3-diulose derivatives by irradiation with visible-light initiates a sequential Norrish type II photoelimination and aldol cyclization process that finally gives polyfunctionalized cyclopentitols. The rearrangement has been confirmed by the isolation of stable acyclic photoenol intermediates that can be independently cyclized by a thermal 5-(enolexo)-exo-trig uncatalyzed aldol reaction with high diastereoselectivity. In this last step, the large deuterium kinetic isotope effect found for the 1,5-hydrogen atom transfer seems to indicate that the aldol reaction runs through a concerted pericyclic mechanism. Owing to the ready availability of pyranose sugars of various configurations, this protocol has been used to study the influence of pyranose ring-substituents on the diastereoselectivity of the aldol cyclization reaction. In contrast with other pyranose ring contraction methodologies no transition-metal reagents are needed and the sequential rearrangement occurs simply by using visible light and moderate heating (0 to 60 °C).

Enantioselective Total Synthesis of (+)-Reserpine

A catalytic, enantioselective synthesis of (+)-reserpine is reported. The route features a highly diastereoselective, chiral catalyst-controlled formal aza-Diels-Alder reaction between a 6-methoxytryptamine-derived dihydro-β-carboline and an enantioenriched α-substituted enone to form a key tetracyclic intermediate. This approach addresses the challenge of setting the C3 stereogenic center by using catalyst control. Elaboration of the tetracycle to (+)-reserpine includes an intramolecular aldol cyclization and a highly diastereoselective hydrogenation of a sterically hindered enoate.