Intermolecular oxonium ylide mediated synthesis of medium-sized oxacycles

Detailed in this account are our efforts toward efficient oxacycle syntheses. Two complementary approaches are discussed, with both employing chemoselective allyl ether activation and rearrangement as the key step. Vinyl substituted oxiranes and oxetanes provide a single step access to dihydropyrans and tetrahydrooxepines. Oxiranes proved to be poor substrates, while oxetanes were slightly better. An alternative approach using substituted allyl ethers proved successful and addressed the limitations encountered in the ring expansions.     

Novel "protecting group-dependent" alkylation-RCM strategy to medium-sized oxacycles: first total synthesis of --isoprelaurefucin

[reaction: see text] A novel "protecting group-dependent" alkylation strategy was developed for complementary diastereoselective syntheses of alpha,alpha'-syn- and alpha,alpha'-anti-bis-alkenes 2 and 3, which represent ring-closing metathesis (RCM) substrates for medium-sized oxacycles. This principle has been applied to a stereoselective and concise total synthesis of (-)-isoprelaurefucin (4) in 14 steps in 12% overall yield from known epoxide 8.     

The furan approach to oxacycles: synthesis of medium-size 2,3-disubstituted oxacycles

We describe an efficient new approach for the synthesis of medium-size oxacycles that is based on the oxidation of a furan ring with singlet oxygen followed by an intramolecular Michael addition. This present study enlarges the scope of the furan approach strategy for the synthesis of oxepanes.     

Enantioselective synthesis of functionalized 3,4-dihydropyran derivatives organocatalyzed by a novel fluorinated-diphenylprolinolether

A novel fluorinated diarylprolinol silyl ether catalyst have been designed and it successfully applicated in the first asymmetric Michael addition-cyclization reaction between 1,3-dicarbonyl compounds with α,β-unsaturated aldehydes at room temperature. The products were isolated in good yields with high diastereoselectivities and enantioselectivities.     

Enantioselective approach to functionalized quinolizidines: synthesis of (+)-julandine and (+)-cryptopleurine

An efficient synthesis of functionalized quinolizidines was developed from an enantiomerically enriched γ-nitroketone, which is easily prepared by an organocatalytic ketone-nitroalkene Michael addition. Oxidative ring expansion of the nitroketone followed by reductive ring-opening leads to a suitably functionalized nitrodiol which is an intermediate to the title compounds.     

Asymmetric modular synthesis of highly functionalized medium-sized carbocycles and lactones via ring-closing metathesis of sulfoximine-substituted trienes

A modular asymmetric synthesis of medium-sized carbocycles and lactones has been developed that affords highly substituted 7-, 9-, and 11-membered rings. The key steps are (1) the highly diastereoselective synthesis of sulfoximine-substituted homoallylic alcohols from allylic sulfoximines and unsaturated as well as saturated aldehydes, (2) an E-stereoselective alkylation and hydroxyalkylation of sulfoximine-substituted alkenyllithium derivatives, (3) the esterification of sulfoximine-substituted homoallylic alcohols, and (4) the ring-closing metathesis reaction of sulfoximine-substituted trienes with the ruthenium catalyst 8. Two examples for the further synthetic elaboration of the sulfoximine-substituted carbocycles are provided. The selective cleavage of the tert-butyldimethylsilyl group of 12 in the presence of the triethylsilyl group afforded the allylic alcohol 18 which was oxidized to enone 19. A cross-coupling reaction of the sulfoximine-substituted carbocycle 9 with LiCuMe2 furnished the methyl-substituted derivative 20.     

Enantioselective organocatalytic oxidation of functionalized sterically hindered disulfides

[structure: see text]. The first study on enantioselective oxidation of functionalized sterically hindered disulfides is reported. This study shows that the Shi organocatalytic system using carbohydrate-derived ketone with oxone is superior to the Ellman-Bolm vanadium catalyst in terms of chemical yield and enantioselectivity. Whereas the latter system afforded mostly racemic thiosulfinates in low to moderate yields, the former one afforded thiosulfinates with up to 96% ee.     

Microwave-assisted synthesis of medium-sized heterocycles

The development of new strategies for synthesis of medium-sized heterocycles has remained a highly attractive but challenging proposition. In the last few years, the application of microwave irradiation has greatly facilitated the construction of such heterocyclic ring systems through a myriad of different synthetic approaches. This feature article illustrates the progress made in the microwave-assisted synthesis of medium-sized heterocycles with an emphasis on examples describing the use of a dedicated microwave synthesizer.     

Enantioselective organocatalyzed cascade reactions to highly functionalized quinolizidines

An organocatalyzed one-pot Michael addition-Pictet-Spengler sequence of β-ketoamides and α,β-unsaturated aldehydes was developed, which provided access to highly substituted indolo[2,3-α]quinolizidines and benzo[α]quinolizidines in moderate to good yields and good to excellent enantioselectivities. For aromatic α,β-unsaturated aldehydes 1a-j products 10a-r containing a stable enol configuration were obtained.     

Enantioselective synthesis of chromenes

A concise approach for the synthesis of optically active chromenes is reported. The process described herein involves, as the key steps, a Sharpless-epoxidation, a selective deoxygenation, and a ring-closing metathesis.     

Enantioselective total synthesis of octalactin a using asymmetric aldol reactions and a rapid lactonization to form a medium-sized ring

Octalactin A, an antitumor agent containing an eight-membered lactone moiety, has been stereoselectively prepared by means of enantioselective aldol reactions of selected silyl enolates with achiral aldehydes, promoted by a chiral Sn(II) complex. The medium-sized lactone part was effectively constructed by way of a new and rapid mixed-anhydride lactonization using 2-methyl-6-nitrobenzoic anhydride (MNBA) with a catalytic amount of 4-(dimethylamino)pyridine (DMAP) or 4-(dimethylamino)pyridine 1-oxide (DMAPO). The use of only 5 mol % of DMAP or 2 mol % of DMAPO rapidly promoted formation of the medium-sized ring of the octalactin, demonstrating the remarkable efficiency of the new lactonization protocol.     

Enantioselective synthesis of alpha-aminopropargylphosphonates

α-Aminopropargylphosphonates have been synthesized for the first time in good yields and enantiomeric excesses (up to 81% ee) by using a copper(I)-pybox complex as the catalyst.     

Enantioselective synthesis of ansa-zirconocenes

The reaction of the chiral chelated bis-amide complex Zr{(2R,4R)-PhNCHMeCH2CHMeNPh}Cl2(THF)2 (R,R-7) with lithium ansa-bis-indenyl reagents Li2[SBI](Et2O) (8a, SBI = (1-indenyl)2SiMe2) or Li2[EBI](Et2O) (8b, EBI = 1,2-(1-indenyl)2ethane) in THF affords the corresponding ansa-zirconocenes S,S-(SBI)Zr{(2R,4R)-PhNCHMeCH2CHMeNPh} (S,S,R,R-9a) or S,S-(EBI)Zr{(2R,4R)-PhNCHMeCH2CHMeNPh} (S,S,R,R-9b) in >95% isolated yield and >99% enantiomeric excess. Compound 9b was converted to the corresponding enantiomerically pure dichloride S,S-(EBI)ZrCl2 (S,S-10b) in 91% isolated yield by reaction with HCl in Et2O. The chiral diamine (2R,4R)-HPhNCHMeCH2CHMeNHPh (R,R-5) was recovered from this reaction.     

Enantioselective synthesis of silanol

An enantioselective nucleophilic substitution reaction of achiral dialkoxysilane has been developed. The reaction proceeds with efficient stereocontrol on the silicon chirality center to give the enantioenriched silyl ether, which can be converted to the silanol without loss of enantiopurity. We have analyzed the steric course of the reaction by using DFT calculations and propose a transition state model to explain the observed enantioselectivity.     

Enantioselective synthesis of aminobenzazepinones

Enantioselective synthesis of constrained trans-aminobenzazepinone utilizing palladium-mediated Jeffery-Heck reaction and rhodium(II) catalyzed asymmetric hydrogenation as key steps are described. Diverse functional groups such as alkyl, aryl, basic or amino acid moieties were introduced with minimal racemization.