Acyclic Allylic Alcohols Research Articles

1,3-Alkyl Transposition in Allylic Alcohols Enabled by Proton-Coupled Electron Transfer.

A method is described for the isomerization of acyclic allylic alcohols into β-functionalized ketones via 1,3-alkyl transposition. This reaction proceeds via light-driven proton-coupled electron transfer (PCET) activation of the O-H bond in the allylic alcohol substrate, followed by C-C β-scission of the resulting alkoxy radical. The transient alkyl radical and enone acceptor generated in the scission event subsequently recombine via radical conjugate addition to deliver β-functionalized ketone products. A variety of allylic alcohol substrates bearing alkyl and acyl migratory groups were successfully accommodated. Insights from mechanistic studies led to a modified reaction protocol that improves reaction performance for challenging substrates.

1,3‐Alkyl Transposition in Allylic Alcohols Enabled by Proton‐Coupled Electron Transfer

AbstractA method is described for the isomerization of acyclic allylic alcohols into β‐functionalized ketones via 1,3‐alkyl transposition. This reaction proceeds via light‐driven proton‐coupled electron transfer (PCET) activation of the O−H bond in the allylic alcohol substrate, followed by C−C β‐scission of the resulting alkoxy radical. The transient alkyl radical and enone acceptor generated in the scission event subsequently recombine via radical conjugate addition to deliver β‐functionalized ketone products. A variety of allylic alcohol substrates bearing alkyl and acyl migratory groups were successfully accommodated. Insights from mechanistic studies led to a modified reaction protocol that improves reaction performance for challenging substrates.

Synthesis of 1,3‐Amino Alcohols by Hydroxy‐Directed Aziridination and Aziridine Hydrosilylation

AbstractWe describe an approach to N‐tosyl 1,3‐amino alcohols that consists of a diastereoselective aziridination reaction of acyclic allylic alcohols and an unprecedented regioselective hydrosilylation of α‐hydroxy aziridines. The products contain up to three contiguous stereocenters. Computational studies outline key aspects of the aziridination mechanism, which is different and more intricate than anticipated.

Synthesis of 1,3-Amino Alcohols by Hydroxy-Directed Aziridination and Aziridine Hydrosilylation.

We describe an approach to N-tosyl 1,3-amino alcohols that consists of a diastereoselective aziridination reaction of acyclic allylic alcohols and an unprecedented regioselective hydrosilylation of α-hydroxy aziridines. The products contain up to three contiguous stereocenters. Computational studies outline key aspects of the aziridination mechanism, which is different and more intricate than anticipated.

Chemoselective and stereoselective lithium carbenoid mediated cyclopropanation of acyclic allylic alcohols.

The reaction of geraniol with different lithium carbenoids generated from n-BuLi and the corresponding dihaloalkane has been evaluated. The reaction occurs in a chemo and stereoselective manner, which is consistent with a directing effect from the oxygen of the allylic moiety. Furthermore, a set of polyenes containing allylic hydroxyl or ether groups were chemoselectively and stereoselectively converted into the corresponding gem-dimethylcyclopropanes in one single step in moderate to good yields mediated by a lithium carbenoid generated in situ by the reaction of n-BuLi and 2,2-dibromopropane.

Diastereoselective osmium-catalyzed vicinal oxyamination of acyclic allylic alcohol derivatives.

The osmium-catalyzed oxyamination of chiral acyclic allylic alcohol derivatives bearing mono- and 1,1-di-substituted double bonds with benzyl N-(4-tosyloxy)carbamate proceeds with high regioselectivity and moderate levels of diastereoselectivity favoring the anti product. The observed stereoselectivity shows a clear and systematic trend with anti:syn ratios increasing in line with the size of substituent at both the allylic stereocenter and double bond α-carbon. The stereoinduction is in accord with the sense of diastereoselectivity predicted by Kishi's empirical rule and a previously reported transition state model for the osmium-catalyzed dihydroxylation of allylic alcohol derivatives. In contrast, allylic alcohol derivatives bearing trisubstituted double bonds show low or no reactivity in the oxyamination reaction affording the syn product in low yield in the cases examined.

Intermolecular Enantioselective Heck–Matsuda Arylations of Acyclic Olefins: Application to the Synthesis of β-Aryl-γ-lactones and β-Aryl Aldehydes

We describe herein a synthetically useful method for the enantioselective intermolecular Heck-Matsuda arylation of acyclic allylic alcohols. Aryldiazonium tetrafluoroborates were applied as arylating agents in the presence of Pd(TFA)2 and a chiral, commercially available, bisoxazoline ligand. The methodology is straightforward, robust, scalable up to a few grams, and of broad scope allowing the synthesis of a range of β-aryl-carbonyl compounds in good to high enantioselectivities and yields. This new enantioselective Heck-Matsuda arylation allowed the synthesis of β-aryl-γ-lactones and β-aryl aldehydes, which play a vital role as key intermediates in the synthesis of the biologically active compounds, such as (R)-baclofen, (R)-rolipram, (S)-curcumene, (S)-dehydrocurcumene, and (S)-tumerone.

ChemInform Abstract: Substrate-Controlled Diastereoselectivities in Catalyzed and Uncatalyzed Hydroboration of Acyclic Allylic Alcohol Derivatives: Secondary Orbital Effects Involving dπ-pπ Interactions.

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Bisabolyl-Derived Sesquiterpenes from Tobacco 5-Epi-aristolochene Synthase-Catalyzed Cyclization of (2Z,6E)-Farnesyl Diphosphate

We report the structures and stereochemistry of seven bisabolyl-derived sesquiterpenes arising from an unprecedented 1,6-cyclization (cisoid pathway) efficiently catalyzed by tobacco 5-epi-aristolochene synthase (TEAS). The use of (2Z,6E)-farnesyl diphosphate as an alternate substrate for recombinant TEAS resulted in a robust enzymatic cyclization to an array of products derived exclusively (>/=99.5%) from the cisoid pathway, whereas these same products account for ca. 2.5% of the total hydrocarbons obtained using (2E,6E)-farnesyl diphosphate. Chromatographic fractionations of extracts from preparative incubations with the 2Z,6E substrate afforded, in addition to the acyclic allylic alcohols (2Z,6E)-farnesol (6.7%) and nerolidol (3.6%), five cyclic sesquiterpene hydrocarbons and two cyclic sesquiterpene alcohols: (+)-2-epi-prezizaene (44%), (-)-alpha-cedrene (21.5%), (R)-(-)-beta-curcumene (15.5%), alpha-acoradiene (3.9%), 4-epi-alpha-acoradiene (1.3%), and equal amounts of alpha-bisabolol (1.8%) and epi-alpha-bisalolol (1.8%). The structures, stereochemistry, and enantiopurities were established by comprehensive spectroscopic analyses, optical rotations, chemical correlations with known sesquiterpenes, comparisons with literature data, and GC analyses. The major product, (+)-2-epi-prezizaene, is structurally related to the naturally occurring tricyclic alcohol, jinkohol (2-epi-prezizaan-7beta-ol). Cisoid cyclization pathways are proposed by which all five sesquiterpene hydrocarbons are derived from a common (7R)-beta-bisabolyl(+)/pyrophosphate(-) ion pair intermediate. The implications of the "cisoid" catalytic activity of TEAS are discussed.

Synthesis of Substituted Allylic Sulfonamides from β-Alkoxy Aziridines and Organolithium Reagents

The scope and limitations of the organolithium-mediated conversion of (3-methoxy N-tosyl aziridines derived from acyclic allylic alcohols into substituted allylic sulfonamides are described.

Stereoselective Synthesis of Furans by the Pd‐Catalyzed Oshima—Utimoto Reaction.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Peroxy Acid Epoxidation of Acyclic Allylic Alcohols. Competition between s-trans and s-cis Peroxy Acid Conformers

[Reaction: see text]. RB3LYP calculations, reported here, indicate that peroxy acid s-cis conformer is more stable than its s-trans counterpart, in agreement with experimental data. Difference in stability is the highest in the gas phase, but it falls considerably on going from the gas phase to moderately polar solvent. In the case of peroxy formic acid, the enthalpy (free energy) difference is about 3.4 (2.5) kcal/mol, respectively, in the gas phase but decreases to 1.2 (0.6) kcal/mol in dichloromethane solution. Introduction of an alkyl or aryl substituent on the peroxy acid, that is, on passing to peroxy acetic, peroxy benzoic (PBA), and m-chloroperoxy benzoic acid (MCPBA), adds a further significant (1.0-1.5 kcal/mol) favor to the s-cis isomer. RB3LYP/6-31+G(2d,p) calculations on the epoxidation of 2-propenol with peroxy formic and peroxy benzoic acids, respectively, suggest that the less stable peroxy acid s-trans conformer can compete with the more stable s-cis form in epoxidation reaction of these substrates. Transition structures arising from s-trans peroxy acids ("trans" TSs) retain both the well-established, for "cis" TS, perpendicular orientation of the O-H peroxy acid bond relative to the C=C bond and the one-step oxirane ring formation. These TSs collapse to the final epoxide via a 1,2-H shift at variance with the 1,4-H transfer of the classical Bartlett's "cis" mechanism. The "trans" reaction pathways have a higher barrier in the gas phase than the "cis" reaction channels, but in moderately polar solvents they become competitive. In fact, the "trans" TSs are always significantly more stabilized than their "cis" counterparts by solvation effects. Calculations also suggest that going from peroxy formic to peroxy benzoic acid should slightly disfavor the "trans" route relative to the "cis" one, reflecting, in an attenuated way, the decrease in the peroxy acid s-trans/s-cis conformer ratio. The predicted behavior for MCPBA parallels that of PBA acid.

Stereoselective Synthesis of Furans by the Pd-Catalyzed Oshima−Utimoto Reaction

[reaction: see text]. The Pd-catalyzed coupling of acyclic allylic alcohols with vinyl ethers was examined and found to proceed with 2.5-10 mol % of catalyst and to provide cyclic acetals with good stereoselection. The reaction is tolerant of a number of functional groups and can be used to generate quaternary centers in a stereoselective fashion.

Radical Cyclization of Haloacetals: The Ueno—Stork Reaction

AbstractFor Abstract see ChemInform Abstract in Full Text.

Radical Cyclization of Haloacetals: The Ueno-Stork Reaction

The formation of the C-C bond using radical cyclization of haloacetals (Ueno-Stork reaction) has proven to be an extremely efficient method to access γ-lactones and related compounds. This reaction is also highly attractive for the regio- and stereoselective introduction of side chains to cyclic and acyclic allylic alcohols. It has been used as a key step in many natural product syntheses and has proven to be particularly efficient for the stereoselective generation of quaternary carbon centers. This review focuses on the different methods available to carry out this radical cyclization, as well as on the stereochemical aspect of the reaction and its applications in total synthesis.

A Silicon Tether Approach for Addition of Functionalized Radicals to Chiral α‐Hydroxyhydrazones: Diastereoselective Additions of Hydroxymethyl and Vinyl Synthons.

AbstractFor Abstract see ChemInform Abstract in Full Text.

A silicon tether approach for addition of functionalized radicals to chiral alpha-hydroxyhydrazones: diastereoselective additions of hydroxymethyl and vinyl synthons.

Stereocontrolled additions of hydroxymethyl and vinyl groups to chiral alpha-hydroxyhydrazones can be achieved by radical cyclizations using bromomethyl or vinyl radical precursors tethered via a temporary silicon connection. Tin-mediated 5-exo radical cyclization of alpha-hydroxyhydrazones using a silicon-tethered bromomethyl group, followed by oxidative removal of the tether, provides anti-2-hydrazino 1,3-diols in good yield. Tandem thiyl radical addition-cyclization of alpha-hydroxyhydrazones using a silicon-tethered vinyl group, followed by treatment with potassium fluoride, affords acyclic allylic anti-hydrazino alcohols in good yield. The thiyl addition-cyclization method has been successfully extended to the use of alpha,beta-dihydroxyhydrazones without prior protection or hydroxyl differentiation. Diastereoselection in both reaction types increases with increasing A values of the appended groups, consistent with prediction by the Beckwith-Houk model for stereocontrol in 5-hexenyl radical cyclizations.

Highly Selective Palladium‐Catalyzed Kinetic Resolution and Enantioselective Substitution of Racemic Allylic Carbonates with Sulfur Nucleophiles: Asymmetric Synthesis of Allylic Sulfides, Allylic Sulfones, and Allylic Alcohols.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Highly selective palladium catalyzed kinetic resolution and enantioselective substitution of racemic allylic carbonates with sulfur nucleophiles: asymmetric synthesis of allylic sulfides, allylic sulfones, and allylic alcohols.

We describe the highly selective palladium catalyzed kinetic resolutions of the racemic cyclic allylic carbonates rac-1 a-c and racemic acyclic allylic carbonates rac-3 aa and rac-3 ba through reaction with tert-butylsulfinate, tolylsulfinate, phenylsulfinate anions and 2-pyrimidinethiol by using N,N'-(1R,2R)-1,2-cyclohexanediylbis[2-(diphenylphosphino)-benzamide] (BPA) as ligand. Selectivities are expressed in yields and ee values of recovered substrate and product and in selectivity factors S. The reaction of the cyclohexenyl carbonate 1 a (>/=99 % ee) with 2-pyrimidinethiol in the presence of BPA was shown to exhibit, under the conditions used, an overall pseudo-zero order kinetics in regard to the allylic substrate. Also described are the highly selective palladium catalyzed asymmetric syntheses of the cyclic and acyclic allylic tert-butylsulfones 2 aa, 2 b, 2 c, 2 d and 4 a-c, respectively, and of the cyclic and acyclic allylic 2-pyrimidyl-, 2-pyridyl-, and 4-chlorophenylsulfides 5 aa, 5 b, 5 ab, 6 aa-ac, 6 ba and 6 bb, respectively, from the corresponding racemic carbonates and sulfinate anions and thiols, respectively, in the presence of BPA. Synthesis of the E-configured allylic sulfides 6 aa, 6 ab, 6 ac and 6 bb was accompanied by the formation of minor amounts of the corresponding Z isomers. The analogous synthesis of allylic tert-butylsulfides from allylic carbonates and tert-butylthiol by using BPA could not be achieved. Reaction of the cyclopentenyl esters rac-1 da and rac-1 db with 2-pyrimidinethiol gave the allylic sulfide 5 c having only a low ee value. Similar results were obtained in the case of the reaction of the cyclohexenyl carbonate rac-1 a and of the acyclic carbonates rac-3 aa and rac-3 ba with 2-pyridinethiol and lead to the formation of the sulfides 5 ab, 6 ab, and 6 bb, respectively. The low ee values may be ascribed to the operating of a "memory effect", that is, both enantiomers of the substrate give the substitution product with different enantioselectivities. However, in the reaction of the racemic carbonate rac-1 a as well as of the highly enriched enantiomers 1 a (>/=99 % ee) and ent-1 a (>/=99 % ee) with 2-pyrimidinethiol the ee values of the substrates and the substitution product remained constant until complete conversion. Similar results were obtained in the reaction of the cyclic carbonates rac-1 a, ent-1 a (>/=99 % ee) and ent-1 c (>/=99 % ee) with lithium tert-butylsulfinate. Thus, in the case of rac-1 a and 2-pyrimidinthiol and tert-butylsulfinate anion as nucleophiles the enantioselectivity of the substitution step is, under the conditions used, independent of the chirality of the substrate; this shows that no "memory effect" is operating in this case. Hydrolysis of the carbonates ent-1 a-c, ent-3 aa and ent-3 ba, which were obtained through kinetic resolution, afforded the enantiomerically highly enriched cyclic allylic alcohols 9 a-c (>/=99 % ee) and acyclic allylic alcohols 10 a (>/=99 % ee) and 10 b (99 % ee), respectively.

Simmons—Smith Cyclopropanation Reaction

AbstractFor Abstract see ChemInform Abstract in Full Text.