Cyclic Allylic Alcohols Research Articles

Pd(0)-Catalyzed Asymmetric Intramolecular Grignard-Type Reaction of Vinyl Iodide-Carbonyl.

The insertion of carbonyl into C(sp2)-Pd(II) σ-bond (Grignard-type addition) was not established until the 1990s. While this elemental reaction has been well explored since then, its application in Pd(0) asymmetric catalysis remain elusive. Herein, we report the Pd(0)-catalyzed asymmetric intramolecular Grignard-type reaction of vinyl iodide-carbonyl in the presence of HCO2H additive, affording cyclic allylic alcohol with good to excellent enantioselectivity and diastereoselectivity. Mechanistic studies suggested that besides serving as an efficient reductant, HCO2H is also capable of facilitating protonation of the involved secondary alkoxyl-Pd(II), thus completely suppressing the β-H elimination. Moreover, no KIE was found in the competing reaction between vinyl iodide-aldehyde and 1-deuterated one, demonstrating the facile step of aldehyde insertion.

Transformation of the pheromone 3‐methyl‐2‐cyclohexen‐1‐ol in the presence of [RuClCp (PTA)2] and [RuCp (OH2)(PTA)2]CF3SO3

The catalytic conversion of the substituted cyclic allylic alcohol 3‐methyl‐2‐cyclohexen‐1‐ol was studied in the presence of the metal complexes [RuClCp (PTA)2] (1) and [RuCp (OH2)(PTA)2]CF3SO3 (2) (PTA = 1,3,5‐triaza‐7‐phosphaadamantane) in different media such as water, methanol, and biphasic water/cyclohexane. Slight changes of the reaction conditions led to the isomerization to 3‐methylcyclohexanone, oxidation to 3‐methyl‐2‐cyclohexenone, or 1,3‐transposition to 1‐methyl‐2‐cyclohexen‐1‐ol. The 1,3‐transposition and oxidation reactions took place in water, and the selective formation of the isomerization product was achieved in freshly dried methanol, or biphasic water/cyclohexane mixture, achieving the highest TON values known to date. Furthermore, the reactivity of 3‐methyl‐2‐cyclohexen‐1‐ol in water was also investigated in the absence of a catalyst, revealing the formation of the 1,3‐transpostion product 1‐methyl‐2‐cyclohexen‐1‐ol and the etherification product 1‐methyl‐3‐(3‐methyl‐2‐cyclohexen‐1‐yl)oxycyclohexene. Finally, key mechanistic aspects of the different reaction pathways were enlightened by NMR spectroscopy.

Preparation of Spirocyclic Vinylic Carbonates from Allylic Alcohols.

We present the synthesis of exo- and endo-spirovinylethylene carbonates, starting from various cyclic allylic alcohols. This one-pot cascade reaction to the spirocyclic scaffold was optimized using a design of experiments approach. The introduction of spirovinylethylene carbonates broadens the scope of using these in catalytic applications and provides an easy synthetic entry into spirocyclic scaffolds of various ring sizes.

Synthesis of Neocannabinoids Using Controlled Friedel-Crafts Reactions.

A one-step transformation to produce 8,9-dihydrocannabidiol (H2CBD) and related "neocannabinoids" via controlled Friedel-Crafts reactions is reported. Experimental and computational studies probing the mechanism of neocannabinoid synthesis from cyclic allylic alcohol and substituted resorcinol reaction partners provide understanding of the kinetic and thermodynamic factors driving regioselectivity for the reaction. Herein, we present the reaction scope for neocannabinoid synthesis including the production of both normal and abnormal isomers under both kinetic and thermodynamic control. Discovery and optimization of this one-step protocol between various allylic alcohols and resorcinol derivatives are discussed and supported with density functional theory calculations.

Ru complexes containingN‐methyl‐1,3,5‐triaza‐7‐phosphaadamantane (mPTA) as catalysts for the isomerization of 2‐cyclohexen‐1‐ol

The complex [RuCp(H2O‐κO)(mPTA)2](CF3SO3)3·MeOH (4·MeOH) was synthesized and characterized by spectroscopic techniques and its crystal structure determined by single‐crystal X‐ray diffraction (mPTA = N‐methyl‐1,3,5‐triaza‐7‐phosphaadamantane). The catalytic activity of4for the redox isomerization of 2‐cyclohexen‐1‐ol into cyclohexanone was studied in water, methanol/water, and biphasic systems, reaching the highest conversion rate in biphasic water/cyclohexane (1:1) at pH 1.7 and under N2. The aqueous phase containing4was recycled up to 7 consecutive runs, reaching a total turnover number (TON) of 471 without significant losses of catalyst. Therefore, this reaction is a unique procedure for the isomerization of cyclic allylic alcohols without metal contamination of the product. The catalytic reaction mechanism was studied by nuclear magnetic resonance (NMR), showing that the reaction probably proceeds through the formation of an intermediate in which the substrate is η2‐coordinated to the metal.

Copper-Catalyzed Enantioselective 1,2-Reduction of Cycloalkenones.

We report an asymmetric 1,2-reduction of cyclic α,β-unsaturated ketones to access various enantiomerically enriched cyclic allylic alcohols under mild conditions, catalyzed by in situ generated copper hydride ligated with (R)-DTBM-C3*-TunePhos. α-Brominated cycloalkenones were reduced with excellent enantioselectivities of up to 98% ee, while substrates that were without α-substituents were reduced chemoselectively, with moderate enantioselectivities.

Stereospecific Overman Rearrangement of Substituted Cyclic Vinyl Bromides: Access to Fully Substituted α-Amino Ketones.

A versatile thermal Overman rearrangement of enantioenriched, cyclic allylic alcohols providing tertiary allylic amines has been developed. The vinyl bromide used to control enantioselectivity in a preceding CBS reduction is utilized as a synthetic handle for the preparation of tertiary α-amino ketones and related derivatives in an asymmetric fashion.

Synthesis of oxazolidinone from enantiomerically enriched allylic alcohols and determination of their molecular docking and biologic activities

Enantioselective synthesis of functionalized cyclic allylic alcohols via kinetic resolution in transesterifcation with different lipase enzymes has been developed. The influence of the enzymes and temperature activity was studied. By determination of ideal reaction conditions, byproduct formation is minimized; this made it possible to prepare enantiomerically enriched allylic alcohols in high ee's and good yields. Enantiomerically enriched allylic alcohols were used for enantiomerically enriched oxazolidinone synthesis. Using benzoate as a leaving group means that 1 mol % of potassium osmate is necessary and can be obtained high yields 98%. Inhibitory activities of enantiomerically enriched oxazolidinones (8, 10 and 12) were tested against human carbonic anhydrase I and II isoenzymes (hCA I and hCA II), acetylcholinesterase (AChE), and α-glycosidase (α-Gly) enzymes. These enantiomerically enriched oxazolidinones derivatives had Ki values in the range of 11.6 ± 2.1–66.4 ± 22.7 nM for hCA I, 34.1 ± 6.7–45.2 ± 12.9 nM for hCA II, 16.5 ± 2.9 to 35.6 ± 13.9 for AChE, and 22.3 ± 6.0–70.9 ± 9.9 nM for α-glycosidase enzyme. Moreover, they had high binding affinity with −5.767, −6.568, −9.014, and −8.563 kcal/mol for hCA I, hCA II, AChE and α-glycosidase enzyme, respectively. These results strongly supported the promising nature of the enantiomerically enriched oxazolidinones as selective hCA, AChE, and α-glycosidase inhibitors. Overall, due to these derivatives’ inhibitory potential on the tested enzymes, they are promising drug candidates for the treatment of diseases like glaucoma, leukemia, epilepsy; Alzheimer’s disease; type-2 diabetes mellitus that are associated with high enzymatic activity of CA, AChE, and α-glycosidase.

Lewis Acids Promoted 3 + 2 Cycloaddition of Oxaziridines and Cyclic Allylic Alcohols through Carbonyl Imine Intermediates.

Syntheses of isoxazolidines through the carbonyl imine intermediates are currently limited to monosubstituted olefin substrates. Herein, we reported syntheses of novel bicyclic isoxazolidine-containing compounds through 1,3-dipolar cycloaddition reactions using cyclic allylic alcohols as substrates, which proved challenging in previous reports. Generally, the reaction yields range from good to high, and the reaction substrates tolerate various functional groups, including the cyclopropyl and amine groups. Mechanistic studies suggest that an allylic cation and a carbonyl imine intermediate are involved and responsible for the observed stereochemistry and diastereoselectivity.

Enantiospecific Total Syntheses of (+)-Hapalindole H and (-)-12-epi-Hapalindole U.

Enantiospecific total syntheses of (+)-hapalindole H and (-)-12-epi-hapalindole U as well as the formal syntheses of (+)-hapalindole Q and (+)-12-epi-fischerindole U isothiocyanate have been described. Key steps of our approach feature expedient, highly regio- and diastereoselective Lewis acid catalyzed Friedel-Crafts reaction of indole with cyclic allylic alcohols and intramolecular reductive Heck reaction. Efficiency of the synthetic route also relies on an alkynyl aluminate complex driven regioselective nucleophilic epoxide opening from a sterically hindered site.

Protecting group free enantiospecific total syntheses of structurally diverse natural products of the tetrahydrocannabinoid family.

A simple, highly diastereoselective, Lewis acid catalyzed Friedel-Crafts coupling of a cyclic allylic alcohol with resorcinol derivatives has been developed. The method was applied for the enantiospecific total syntheses of structurally diverse natural products such as machaeriol-D, Δ(8)-THC, Δ(9)-THC, epi-perrottetinene and their analogues. Synthesis of both natural products and their enantiomers has been achieved with high atom economy, in a protecting group free manner and in less than 6 steps, the longest linear sequence, in a very good overall yield starting from R-(+) and S-(-)-limonene.

ChemInform Abstract: 1,n‐Rearrangement of Allylic Alcohols Promoted by Hot Water: Application to the Synthesis of Navenone B, a Polyene Natural Product.

AbstractThe 1,n‐rearrangement of acyclic and cyclic allylic alcohols under aqueous conditions represents a novel method for the synthesis of various β,γ‐unsaturated alcohols.

ChemInform Abstract: Hydrogen Bond Directed Epoxidation: Diastereoselective Olefinic Oxidation of Allylic Alcohols and Amines

AbstractReview: [26 refs.

ChemInform Abstract: Enzyme‐ and Ruthenium‐Catalyzed Dynamic Kinetic Resolution of Functionalized Cyclic Allylic Alcohols.

ChemInform Abstract: Enzyme‐ and Ruthenium‐Catalyzed Dynamic Kinetic Resolution of Functionalized Cyclic Allylic Alcohols.

Hydrogen bond directed epoxidation: diastereoselective olefinic oxidation of allylic alcohols and amines.

This article compares the diastereoselective epoxidation of acyclic and cyclic allylic alcohols, with the chemo- and diastereoselective olefinic oxidation of a range of acyclic and cyclic allylic amines. The diastereoselectivity in these systems is compared and a discussion about the origin of this high diastereocontrol is also presented. The ammonium directed epoxidation methodology has been extended to more complex substrates and representative applications of this protocol in natural product synthesis are also summarised.

Enzyme- and Ruthenium-Catalyzed Dynamic Kinetic Resolution of Functionalized Cyclic Allylic Alcohols

Enantioselective synthesis of functionalized cyclic allylic alcohols via dynamic kinetic resolution has been developed. Cyclopentadienylruthenium catalysts were used for the racemization, and lipase PS-IM or CALB was employed for the resolution. By optimization of the reaction conditions the formation of the enone byproduct was minimized, making it possible to prepare a range of optically active functionalized allylic alcohols in good yields and high ee's.

ChemInform Abstract: Transition‐Metal‐Catalyzed Cyclization of Alkynals via Oxametallacycle Intermediates

AbstractReview: Ni, Rh, Ru, Ti; 82 refs.

Transition‐Metal‐Catalyzed Cyclization of Alkynals via Oxametallacycle Intermediates

AbstractThe transition‐metal‐catalyzed cyclization of alkynals viaoxametallacycle intermediates is a useful method for thestereoselective synthesis of cyclic allylic alcohol derivatives. The reductive cyclization reactions are catalyzed by titanium and nickel complexes using organosilanes, organoboranes, and organozincs as reducing agents. The alkylative, arylative, and alkenylative cyclization reactions are catalyzed by nickel complexes using organozincs and alkenylzirconiums. On the other hand, the recently developed rhodium‐catalyzed reductive cyclization reactions of alkynals allow using dihydrogen as a reducing agent without the use of organometalloid and organometallic reagents. Furthermore, very recently, the rhodium‐catalyzed acylative cyclization reactions of alkynals were accomplished by using aldehydes and acyl phosphonates as acylating reagents. Importantly, the use of the rhodium catalysts realized the enantioselective cyclization reactions of alkynals with excellent levels of enantioselection.

Catalytic, Asymmetric, Bromine-Induced Semipinacol Rearrangements at Unactivated Double Bonds

A new catalyst system for the enantioselective bromine-induced semipinacol rearrangement of cyclic allylic alcohols is described. Using the commercially available (DHQD)2Pyr catalyst the products containing an all-carbon quaternary chiral centre can be obtained in good yield and high enantioselectivity.

Enzymatic resolution of racemic secondary cyclic allylic alcohols

The resolutions of five racemic cyclic alcohols: 6,6-dimethylcyclohex-2-en-1-ol (±)- 5, 4,4-dimethylcyclohex-2-en-1-ol (±)- 7, 5,5-dimethylcyclohex-2-en-1-ol (±)- 11 and isomeric trans-(±)- 13 and cis-piperitols (±)- 14 are presented. They were resolved by enzymatic esterification with vinyl esters or by enzymatic hydrolysis of their racemic esters in phosphate buffer. The following lipases were used as biocatalysts: Novozyme 435 ( Candida antarctica), Amano PS ( Burkholderia cepacia) and lipase from Candida cylindracea. All isomers of alcohols were obtained with at least 96% ee.