Peterson Olefination Research Articles

Non-Ionic Peterson-Type Olefination Reactivity and its Use in a Silicon-Promoted Carbonyl-Carbonyl Cross Coupling Reaction.

The [2+2] cycloaddition reaction between the Si=C double bond of adamantylsilene and the carbonyl group of aliphatic, aromatic or acetylenic ketones and aldehydes is demonstrated. The product of this reaction that is central to a non-ionic version of the Peterson olefination is an unusual four-membered 1,2-silaoxetane heterocycle that was characterized spectroscopically and crystallographically. In the presence of SiO2, the silaoxetane undergoes retro-cycloaddition with the formation of alkene products. As the [2+2] cycloaddition proceeds without the necessity of any base, enolizable ketones can be converted into olefins. In addition, it is shown that the adamantylsilene can be produced in situ by a sila-Peterson reaction, providing valuable input for the development of a new one-pot silicon-based reductive carbonyl-carbonyl cross coupling methodology.

Design and Synthesis of Out/Out, Out/In, and In/In Epoxides in Polycyclic Cage Frameworks

AbstractWe report a useful synthetic approach to assemble in/in epoxide, in/out epoxide, and out/out epoxide in cage systems using the Corey–Chaykovsky reaction and the Peterson olefination as key steps. In this regard, a variety of pentacycloundecane (PCUD) based cage compounds containing oxirane rings with diverse stereochemical disposition were synthesized via a simple synthetic sequence. Five cage diones were used for this purpose, and the starting cage diones were prepared with easily accessible starting materials such as 1,4-hydroquinone derivatives and cyclopentadiene. Here, we have used the Diels–Alder (DA) reaction, a [2+2] photocycloaddition, the Corey–Chaykovsky reaction, and the Peterson olefination as crucial steps to prepare the target molecules.

Non‐Ionic Peterson‐type Olefination Reactivity and its Use in a Silicon‐promoted Carbonyl‐Carbonyl Cross Coupling Reaction

The [2+2] cycloaddition reaction between the Si=C double bond of adamantylsilene and the carbonyl group of aliphatic, aromatic or acetylenic ketones and aldehydes is demonstrated. The product of this reaction that is central to a non‐ionic version of the Peterson olefination is an unusual four‐membered 1,2‐silaoxetane heterocycle that was characterized spectroscopically and crystallographically. In the presence of SiO2, the silaoxetane undergoes retro‐cycloaddition with the formation of alkene products. As the [2+2] cycloaddition proceeds without the necessity of any base, enolizable ketones can be converted into olefins. In addition, it is shown that the adamantylsilene can be produced in situ by a sila‐Peterson reaction, providing valuable input for the development of a new one‐pot silicon‐based reductive carbonyl‐carbonyl cross coupling methodology.

Modular Assembly of Six‐Membered Carbocyclic Spirooxindoles via Peterson Olefination/Michael Addition/C(sp3) Arylation Cascade

Comprehensive SummaryConcise assembly of spirooxindoles is of great significance but a challenging task in modern organic synthesis. Described herein is an unusual base‐promoted [4+2] spiroannulation of rarely used isatin‐derived β‐silylcarbinols with o‐halogen aromatic ketones, which enables rapid and modular synthesis of six‐membered carbocyclic spirooxindoles in high yields with excellent functional group tolerance (> 50 examples). Mechanistic experiments revealed that this reaction involved a Peterson olefination, Michael addition and intramolecular C(sp3) arylation cascade. The variegated synthetic derivatization of target products and successful construction of bioactive molecules further illustrate the synthetic potential in spirooxindole‐related drug discovery.

Total Synthesis of the Guangnanmycin A Alcohol

AbstractGuangnanmycin A is a recently discovered congener of the well‐known antitumor drug lead leinamycin; its macrolactam ring, however, is even more strained than that of the parent compound. The first synthetic foray towards this challenging target is reported, which relies on molybdenum‐catalyzed macrocyclization by ring closing alkyne metathesis (RCAM) followed by ruthenium‐catalyzed redox isomerization of the propargyl alcohol thus formed; the resulting enone enabled the introduction of the yet missing exo‐methylene group by a modified Peterson olefination. The signature disulfide moiety of guangnanmycin A was installed by strain‐driven thia‐Michael addition followed by conversion of the thioether thus formed into an unsymmetric disulfide with the aid of (methylthio)dimethylsulfonium tetrafluoroborate and MeSSMe. While this sequence furnished racemic guangnanmycin A alcohol in good overall yield, the final oxidation to the corresponding acid failed, most likely because of the exceptional sensitivity of the strained scaffold.

Total Synthesis of the Guangnanmycin A Alcohol.

Guangnanmycin A is a recently discovered congener of the well-known antitumor drug lead leinamycin; its macrolactam ring, however, is even more strained than that of the parent compound. The first synthetic foray towards this challenging target is reported, which relies on molybdenum-catalyzed macrocyclization by ring closing alkyne metathesis (RCAM) followed by ruthenium-catalyzed redox isomerization of the propargyl alcohol thus formed; the resulting enone enabled the introduction of the yet missing exo-methylene group by a modified Peterson olefination. The signature disulfide moiety of guangnanmycin A was installed by strain-driven thia-Michael addition followed by conversion of the thioether thus formed into an unsymmetric disulfide with the aid of (methylthio)dimethylsulfonium tetrafluoroborate and MeSSMe. While this sequence furnished racemic guangnanmycin A alcohol in good overall yield, the final oxidation to the corresponding acid failed, most likely because of the exceptional sensitivity of the strained scaffold.

Harnessing the Peterson Reaction for the Stereospecific Synthesis of Z-Vinyl Ethers.

Vinyl ethers are valuable synthetic intermediates which are also found as natural products, including aflatoxins, rifamycins and plasmalogens. The latter are ubiquitous phospholipids in human cells and contain a vinyl ether moiety with specifically Z configuration. Although numerous methods are available for synthesis of vinyl ethers, there is a lack of methods for obtaining Z isomers of molecules of the type RCH=CHOR' that are applicable to plasmalogens. A variant of the Peterson reaction is described that generates such molecules with very high stereoselectivity (Z/E ratio: 99 : 1). (R,R)/(S,S)-1-alkoxy-2-hydroxyalkylsilanes were synthesized from 1-trimethylsilylalkynes by a sequence of reduction with di-isobutylaluminium hydride to a (Z)-1-trimethylsilylalkene, epoxidation of the alkene to a 2-trimethylsilyl-3-substituted epoxide and regioselective, boron-trifluoride catalyzed ring-opening of the epoxide by reaction with an alcohol. Conversion of the (R,R)/(S,S)-1-alkoxy-2-hydroxyalkylsilanes to vinyl ethers (RCH=CHOR') was achieved under basic conditions as in a standard Peterson reaction. However, near exclusive formation of a Z vinyl ether was only achieved when the reaction was performed using potassium hydride in the non-polar solvent α,α,α-trifluorotoluene, more polar solvents giving increasing amounts of the E isomer. The sequence described embraces a variety of substituents and precursors, proceeds in overall high yield and is readily scalable.

Divergent Synthesis of Skeletally Distinct Arboridinine and Arborisidine.

A divergent synthesis of skeletally distinct arboridinine and arborisidine was achieved. The central divergent strategy was inspired by the divergent biosynthetic cyclization mode of arboridinine and arborisidine and their hidden topological connection. The branch point was reached through a Michael and Mannich cascade process. A site-selective intramolecular Mannich reaction was developed to construct the tetracyclic core of arboridinine, while a site-selective intramolecular α-amination of ketone was used to access the tetracyclic core of arborisidine. A strategic Peterson olefination through intramolecular nucleophile delivery was able to set up the exocyclic olefin of arboridinine.

Triflimide-Catalyzed Peterson Olefinations

Key words Peterson olefination - Brønsted acid - silyl alcohols - alkynols - enynes - alkenes

Brønsted Acid Catalyzed Peterson Olefinations.

A mild and facile Peterson olefination has been developed employing low catalyst loading of the Brønsted acid HNTf2. The reactions are typically performed at room temperature, with the reaction tolerant to a range of useful functionalities. Furthermore, we have extended this methodology to the synthesis of enynes.

Synthesis of Resolvin D6 and the Silyl Ether of the Resolvin E2 Methyl Ester via trans-Enynyl Alcohols

Two trans-enynyl alcohol intermediates corresponding to the C1–C8 and C13–C22 parts of resolvin D6 (RvD6) were prepared through the Hudrlik–Peterson reaction of the TMS-substituted trans-epoxy alcohols with TMS-acetylide and subsequent TMS-desilylation. These intermediates were coupled with a 1,4-dihalo-2-butyne derivative under copper catalysis, and the resulting acetylene was reduced with Zn(Cu/Ag) to afford the TBS ether of RvD6 methyl ester. Desilylation with TBAF yielded the γ-lactone of RvD6, which was hydrolyzed to RvD6. The total yield of RvD6 was 1.9% in 19 steps from (3-trimethylsilyl)propargyl alcohol. The TBS ether of RvE2 methyl ester was also synthesized.

The Hudrlik–Peterson Reaction of Secondary cis-TMS-Epoxy Alcohols and its Application to the Synthesis of the Fatty Acid Intermediates

As an extension of the study on the Hudrlik–Peterson reaction of trans-TMS-epoxy alcohols with lithium acetylides, four cis-TMS-epoxy alcohols possessing different alkyl substituents were subjected to the reaction with TMS-acetylide. The reaction completed in 1 h at 0 °C to afford cis-enynyl alcohols in good yields. The results indicated that cis-TMS-epoxy alcohols had higher reactivity than the trans-isomers. Anions derived from 1-heptyne and phenylacetylene participated in the reaction as well. The reaction was applied to optically active cis-TMS-epoxy alcohols, and the resulting enynyl alcohols were transformed to the synthetic intermediates of protectin D1, maresin 1, resolvin E1, and leukotriene B4.

Stereoselective One-Pot Deconjugation, Aldol, and Stabilized Peterson Olefination of α-Trialkylsilyl-β-alkyl-α,β-Unsaturated Esters.

A stereoselective reaction process including a one-pot deconjugation, aldol, and stabilized Peterson olefination of α-trialkylsilyl-β-alkyl-α,β-unsaturated esters coupled with aliphatic aldehydes is described. This sequential procedure afforded tri-and disubstituted conjugated diene ester products with dr values of 12-20:1 for the newly established alkene moieties in modest to good isolated yields.

Tandem Peterson olefination and chemoselective asymmetric hydrogenation of β-hydroxy silanes.

Here, we report the first Ir-N,P complex catalyzed tandem Peterson olefination and asymmetric hydrogenation of β-hydroxy silanes. This reaction resulted in the formation of chiral alkanes in high isolated yields (up to 99%) and excellent enantioselectivity (up to 99% ee) under mild conditions. Modification of the reaction conditions provides a choice to transform either an olefin or the β-hydroxy silane in a chemoselective manner. Additionally, based on this method, an expedient enantioselective synthesis of (S)-(+)-α-curcumene, from a simple ketone, was accomplished in two steps with 75% overall yield and 95% ee.

Novel Synthesis of Trisubstituted Olefins for the Preparation of the C16-C30 Fragment of Dolabelide C.

A silicon-tether ring-closing metathesis strategy is reported for the synthesis of trisubstituted olefins flanked by allylic or homoallylic alcohols, which are difficult to obtain by classical ring-closing or cross-metathesis reactions. In addition, a novel Peterson olefination reaction has been developed for the preparation of the allyldimethylsilane precursors, which are versatile synthetic intermediates. This method was then applied to the synthesis of the C16-C30 fragment of dolabelide C.

Total Synthesis of the Reported Structure of Stresgenin B Enabled by the Diastereoselective Cyanation of an Oxocarbenium.

We report the first total synthesis of the reported structure of the heat shock protein expression inhibitor stresgenin B. The synthesis features (1) diastereoselective cyanation of an oxocarbenium intermediate en route to the synthetically challenging α-amido dioxolane, (2) Pd-catalyzed hydration of an unstable nitrile, and (3) late-stage Au-catalyzed Meyer-Schuster rearrangement or Ce-mediated Peterson olefination to furnish the exocyclic α,β-unsaturated ester. Our synthetic endeavors allowed us to conclude that the structure of stresgenin B requires revision.

Synthesis of 8-Oxabicyclo[3.2.1]octanes by TiCl4-Mediated Reactions of 3-Alkoxycyclobutanones and Allenylsilanes

1-Substituted allenylsilanes reacted with 3-alkoxycyclobutanones in the presence of TiCl4 to afford 8-oxabicyclo[3.2.1]octan-3-ones stereoselectively. Nucleophilic attack of allenylsilanes to a 1,4-zwitterionic intermediate formed from 3-alkoxycyclobutanones and TiCl4­ followed by 1,2-silyl migration, five-membered cyclization with an alkoxy group, and seven-membered cyclization of titanium enolate was proposed. Deuteration and one-pot Peterson olefination suggested that alkyl titanium species were formed after cyclization to 8-oxabi­cyclo[3.2.1]octane skeletons.

Enantioselective Synthesis of Thailanstatin A Methyl Ester and Evaluation of in Vitro Splicing Inhibition.

Thailanstatin A has been isolated recently from the fermentation broth of B. thailandensis MSMB43. We describe here an enantioselective convergent synthesis of thailanstatin A methyl ester and evaluation of its splicing activity. Synthesis of both highly functionalized tetrahydropyran rings were carried out from commercially available tri- O-acetyl-d-glucal as the key starting material. Our convergent synthesis involved the synthesis of both tetrahydropyran fragments in a highly stereoselective manner. The fragments were then coupled using cross-metathesis as the key step. The synthesis of the diene subunit included a highly stereoselective Claisen rearrangement, a Cu(I)-mediated conjugate addition of MeLi to set the C-14 methyl stereochemistry, a reductive amination reaction to install the C16-amine functionality, and a Wittig olefination reaction to incorporate the diene unit. The epoxy alcohol subunit was synthesized by a highly selective anomeric allylation, a Peterson olefination, and a vanadium catalyzed epoxidation that installed the epoxide stereoselectively. Cross-metathesis of the olefins provided the methyl ester derivative of thailanstatin A. We have carried out in vitro splicing studies of the methyl ester derivative, which proved to be a potent inhibitor of the spliceosome.

Studies toward the Synthesis of Iriomoteolide-2a: Construction of the C(6)-C(28) Fragment.

The synthesis of an appropriately functionalized advanced C(6-28) fragment (3) of the marine macrolide iriomoteolide-2a (1) has been achieved in a highly efficient manner. The C(6)-C(18) fragment of 1 is prepared via a radical cyclization of a vinyl ether intermediate and palladium-promoted hydrostannylation/iodination. Paterson aldol reaction and Peterson olefination are used to construct the C(19)-C(28) fragment. The union of the C(6)-C(18) and C(19)-C(28) fragments is accomplished via a Suzuki-Miyaura coupling reaction.

Design and synthesis of N–acetylglucosamine derived 5a-carbasugar analogues as glycosidase inhibitors

An efficient synthesis of new six-membered carbasugars in both L-form and D-form starting from N–acetylglucosamine is described. The key synthetic steps involved regioselective protection and deprotection, Ferrier carbocyclization, Peterson olefination, hydroboration and stereoselective epoxidation followed by regioselective epoxide ring opening reactions. These six-membered carbasugars showed moderate glycosidase inhibitory activity and one of the compounds was found selective towards β-galactosidase inhibitory activity.