Search

A palladium-catalyzed cycloisomerization of carbamimidothioates with the formation of a quaternary carbon and a sulfide is described. The use of (IPr)Pd(allyl)Cl (CX21), K3 PO4 , and Me-C(OTBS)=NTBS in refluxing xylenes was optimal, and the methoxycarbonyl group was the most suitable substituent for the nitrogen atom of the carbamimidothioate. Phenyl and alkyl groups can be used as tethers for carbamimidothioates, and alkyl and aryl carbamimidothioates can undergo Pd-catalyzed cycloisomerization in high yields. [ABSTRACT FROM AUTHOR]

A Pd-catalyzed carbothiolation using thioesters, with the formation of a quaternary carbon, is described. Carbothiolation using thioesters was problematic due to a direct-coupling side reaction that produced a sulfide, but this side reaction was successfully suppressed by an appropriate selection of the thioester and the reaction conditions. In the preparation of chroman or coumaran derivatives by this method, the reaction using S -phenyl 4-methoxybenzenecarbothioate Pd(PPh3)4 , and Cs2 CO3 at 100 °C in toluene afforded the desired products in good yields (77–92%). The carbothiolation reaction also proceeded with esters of alkanethiols in higher yields (56–93%) than those obtained from the previously reported carbothiolation using triisopropylsilyl (TIPS) thioethers (12–63%). The developed Pd-catalyzed carbothiolation is applicable in the preparation of a wide range of products, including a tetralin derivative and an indoline derivative. The Pd-catalyzed carbothiolation using thioesters was found to be comparable with a previously reported carbothiolation using TIPS thioethers in terms of the yield and substrate scope, and to be a superior alternative owing to the stability and lower cost of thioesters. [ABSTRACT FROM AUTHOR]

This article traces the development of synthetic routes toward 1-indanones containing a β-quaternary carbon center. The recent advancement in the regio- and chemoselective formal (4+1) carbocyclization of chalcones with internal alkynes via rhodium(III) catalysis for the synthesis of 1-indanones is highlighted. [ABSTRACT FROM AUTHOR]

Here, we have successfully achieved the addition of difluoroacetate radicals to 2‐aryl‐3H‐indol‐3‐ones, enabling various difluoroalkylations of C2‐tetrasubstituted 2‐aryl indolin‐3‐ones in a highly efficient and economical manner. It is worth mentioning that these difluoroalkylation compounds can be easily transformed into various derivatives under mild reaction conditions. Control experiments suggest the involvement of ethyl difluoroacetate radical species in the reaction. [ABSTRACT FROM AUTHOR]

This article presents a new method for synthesizing α-quaternary carbaldehydes through the chemoselective House-Meinwald rearrangement of trisubstituted epoxides. The authors used Brønsted acids as catalysts and identified optimal reaction conditions. The method allows for the synthesis of various carbaldehydes and has been validated for stereospecific reactions. The authors suggest that this method could be useful in the total synthesis of natural products. [Extracted from the article]

This study presents the synthesis of analogues of bioactive Amaryllidaceae alkaloids that contain a five‐membered ring C and a quaternary carbon centre. The synthesis was carried out in a divergent manner, starting from a common intermediate, keto aldehyde 1 a. This intermediate was obtained by oxidative cleavage of a carbocyclic ring present in the previously synthesised tetracyclic compounds. Subsequent closure of a new heterocyclic ring B using different methods led to products with structural cores found in naturally occurring alkaloids such as pretazettine, tazettine or macronine. In addition, an analogue of egonine was prepared from the same intermediate. Our approach thus provides access to multiple structural types of potentially bioactive molecules. [ABSTRACT FROM AUTHOR]

A practical method for the preparation of quaternary and tertiary allyl‐substituted heteroarenes by site‐selective couplings of heteroaryl nitriles and allylic nucleophiles is disclosed. Transformations utilize readily accessible stable reagents, proceed in the presence of a Lewis base activator, and undergo aryl‐C(sp3) quaternary and tertiary carbon formation with high γ‐selectivity (up to >98 : 2 γ : α). [ABSTRACT FROM AUTHOR]

Optical pharmaceutical important compounds which bring CF2H to mimic the role of –SH were synthesized through the asymmetric S‐Michael addition reaction in the presence of quinine–a derived squaramide catalyst. Various sulfhydryl compounds including Benzyl mercaptan, phenthiol, alkyl thiophenol, mercaptoacetate, methyl 3‐mercaptoacrylate, and 1,4‐dithiane‐2,5‐diol were tested. The broad substrate scope, good functional group tolerance, and easy derivatization make this synthesis method very attractive. [ABSTRACT FROM AUTHOR]

In this personal account, our recent developments on the asymmetric synthesis of a quaternary carbon stereogenic center by organocatalysis using a primary amino acid and its salt as a catalyst are described in three chapters: (1) conjugate addition to nitroalkenes and vinyl ketones, (2) nucleophilic addition to π‐allyl palladium complexes, and (3) nucleophilic substitution reactions with allyl and propargyl halides. By these methods, asymmetric α‐allylation of α‐branched aldehydes and ketones smoothly proceeded to give γ‐nitroaldehydes, ketoaldehydes, α‐allylated aldehydes, and α‐allylated β‐ketoesters possessing a quaternary carbon stereogenic center in good yields with high enantioselectivities. [ABSTRACT FROM AUTHOR]

A practical method for the efficient and enantioselective preparation of versatile ketones and aldehydes that contain an α‐quaternary stereocenter is described. Reactions utilize simple carboxylic acid or ester starting materials, a monodentate chiral phosphine, and afford a variety of aryl, alkenyl, alkynyl, and alkyl‐substituted ketone and aldehyde products in 25–94 % yield and 90 : 10 to >99 : 1 enantiomeric ratio. Reactions proceed by acyl substitution with in situ formed chiral allylic nucleophiles, and display selectivity and conversion dependence on a protic additive. The utility of the approach is demonstrated through several product transformations. [ABSTRACT FROM AUTHOR]

Aldehydes constitute a main class of organic compounds widely applied in synthesis. As such, catalyst-controlled enantioselective α-functionalization of aldehydes has attracted great interest over the years. In this context, α-branched aldehydes are especially challenging substrates because of reactivity and selectivity issues. Firstly, the transient trisubstituted enamines and enolates resulting upon treatment with an aminocatalyst or a base, respectively, would exhibit attenuated reactivity; secondly, mixtures of E- and Z-configured enamines/enolates may be formed; and third, effective face-discrimination on such trisubstituted sp2 carbon intermediates by the incoming electrophilic reagent is not trivial. Despite these issues, in the last 15 years, several catalytic approaches for the α-functionalization of prostereogenic α-branched aldehydes that proceed in useful yields and diastereo- and enantioselectivity have been uncovered. Developments include both organocatalytic and metal-catalyzed approaches as well as dual catalysis strategies for forging new carbon–carbon and carbon–heteroatom (C-O, N, S, F, Cl, Br, ...) bond formation at Cα of the starting aldehyde. In this review, some key early contributions to the field are presented, but focus is on the most recent methods, mainly covering the literature from year 2014 onward. [ABSTRACT FROM AUTHOR]

A Pd‐catalyzed decarboxylative approach for the construction of 2‐allyl‐2,2‐diarylacetaldehydes via dearomative umpolung strategy is reported. The reaction is applicable to a number of cyclic carbonates or allylic acetates featuring with different functional groups. These reactions could be performed in a gram‐scale but without loss of the reaction efficiency. The control experiments suggest that the reaction proceeds though a palladium catalyzed dearomative decarboxylation step followed by an umpolung nucleophilic attack. [ABSTRACT FROM AUTHOR]

The construction of the successive stereogenic centers, including an all-carbon quaternary stereogenic center, of ent -kauranoid through an oxidative dearomatization/1,2-shift cascade is described. The developed cascade reaction of a substrate bearing a trans -2-(p -methoxyphenyl)vinyl group as the migrating group afforded the desired product in 83% yield. The 1,2-shift in the cascade is strongly affected by a stereoelectronic effect. The X-ray crystal structure of a compound bearing four successive stereogenic centers in the fused-ring moiety of ent -kauranoid diterpene, which was prepared by the oxidative dearomatization/1,2-shift cascade and subsequent stereoselective transformations, is also reported. [ABSTRACT FROM AUTHOR]

Preparation of skipped dienes with a quaternary carbon center at the C‐3 position remains a synthetic challenge. We report here an iridium‐catalyzed formal addition of tertiary sp3 C−H bond to alkyne for the facile preparation of skipped dienes. The tertiary allylic C−H bond is cleaved regioselectively, at the site of which a new C−C bond is formed. Enantioselective construction of acyclic quaternary carbon stereocenters is also demonstrated. [ABSTRACT FROM AUTHOR]

Aldehydes constitute a main class of organic compounds widely applied in synthesis. As such, catalyst-controlled enantioselective α-functionalization of aldehydes has attracted great interest over the years. In this context, α-branched aldehydes are especially challenging substrates because of reactivity and selectivity issues. Firstly, the transient trisubstituted enamines and enolates resulting upon treatment with an aminocatalyst or a base, respectively, would exhibit attenuated reactivity; secondly, mixtures of E- and Z-configured enamines/enolates may be formed; and third, effective face-discrimination on such trisubstituted sp2 carbon intermediates by the incoming electrophilic reagent is not trivial. Despite these issues, in the last 15 years, several catalytic approaches for the α-functionalization of prostereogenic α-branched aldehydes that proceed in useful yields and diastereo- and enantioselectivity have been uncovered. Developments include both organocatalytic and metal-catalyzed approaches as well as dual catalysis strategies for forging new carbon–carbon and carbon–heteroatom (C-O, N, S, F, Cl, Br, …) bond formation at Cα of the starting aldehyde. In this review, some key early contributions to the field are presented, but focus is on the most recent methods, mainly covering the literature from year 2014 onward.

Bicyclo[2.2.2]octane derivatives possessing a quaternary bridgehead carbon were synthesized with excellent diastereoselectivity in nearly optically pure form by diphenylprolinol silyl ether mediated domino Michael/Michael reaction of α,β‐unsaturated aldehyde and cyclohex‐2‐en‐1‐one bearing an electron‐withdrawing group at the 3‐position. Carbonitrile, alkoxycarbonyl, and sulfonyl substituents were successfully employed as a suitable electron‐withdrawing group at the 3‐position of cyclohex‐2‐en‐1‐one. [ABSTRACT FROM AUTHOR]

A Co‐catalyzed enantioselective desymmetric [2+2+2] cycloaddition for synthesis of pyridines with all‐carbon quaternary carbon centers has been developed. The regio‐ and enantioselectivities are controlled by the inherent nature of terminal alkynes and the substituents on the bisoxazolinephosphine ligands. Pyridines with 5‐substitutents could be obtained with >20:1 regioselectivity and up to 94 % ee when terminal alkyl, alkenyl or silyl alkynes and DTBM/Ph‐based NPN* ligand L6 were used. Terminal aryl alkynes and Ph/Bn‐based ligand L4 leads to formation of pyridines with 6‐substitutents in up to 99 % ee. [ABSTRACT FROM AUTHOR]

In this work, we report a facile access to a 3,3-disubstituted isoindolinone by means of Krapcho decarboxylation reaction of the respective substituted dimethyl malonate derivative. Good isolated yields were obtained under mild reaction conditions.

In this work we report a facile access to a 3,3-disubstituted isobenzofuranone by tandem addition/cyclization reaction to methyl 2-acetylbenzoate in the presence of dimethyl malonate, under basic conditions.

A novel semipinacol rearrangement using dibromocyclopropanes as sources of carbocations was developed. Heating dibromocyclopropanes bearing a 1-hydroxyalkyl group with silver perchlorate and 2,6-lutidine induced cleavage of the cyclopropane ring to form allyl cations, which underwent 1,2- shift of a substituent at the α-position of the hydroxy group to give β,γ-unsaturated carbonyl compounds having a quaternary carbon at the α-position. Because the products have convertible functional groups such as bromo, vinyl, and formyl groups, the method is expected to be applicable to the synthesis of various molecules. [ABSTRACT FROM AUTHOR]

A method has been developed for the α-tertiary alkylation of zirconium enolates of N -(arylacetyl)oxazolidinones. This reaction directly installs an all-carbon quaternary center vicinal to a benzylic tertiary carbon in a highly diastereoselective manner. [ABSTRACT FROM AUTHOR]

Palladium‐catalyzed asymmetric [4+5] annulation of ortho‐quinone methides (o‐QMs) with substituted vinylethylene carbonates (VECs) is described for the first time, giving a novel enantioselective approach to chiral nine‐membered benzoheterocycles. Based on this designed [4+5] annulation, an unprecedented silica gel‐promoted tandem rearrangement reaction featuring a unique asymmetric aromatic Claisen rearrangement is explored at room temperature, offering a new method for asymmetric construction of all‐carbon quaternary stereocenters embedded in chiral functionalized homoallylic alcohols. [ABSTRACT FROM AUTHOR]

We disclose our synthetic studies on bilobalide, which features a Diels–Alder reaction of a cyclic anhydride to form two contiguous quaternary carbon centers, desymmetrization of a symmetric diol, and construction of a cyclic acetal under acidic conditions with inversion of configuration at an allylic position. [ABSTRACT FROM AUTHOR]

N-Substituted succinimides having different alkyl groups were prepared by the reaction of N-substituted maleimide with aldehydes. A two-component catalyst system composed of an amino acid (l-isoleucine) and a base (KOH) was used to facilitate reaction of the α-hydrogen-containing aldehyde with N-substituted maleimide. With 20 mol % catalyst/cocatalyst, good results in term of the reaction time and yield (892-99%) of products containing contiguous quaternary and tertiary stereogenic centers were obtained. The CHN elemental analyses of N-substituted succinimides indicated appreciable purity. Structural assessment of the synthesized N-substituted succinimides was carried out by 1H and 13C NMR spectroscopy. The products exhibited excellent antioxidant and mild antimicrobial activities. [ABSTRACT FROM AUTHOR]

A TBAB‐mediated radical 5‐exo‐trig ipso‐cyclization of N‐aryl‐2‐arylbenzamide is described herein for the synthesis of spiro[cyclohexane‐1,1′‐isoindoline]‐2,5‐diene‐3′,4‐dione. The transformation proceeds regioselectively and provides the final products with high efficiency and a broad reaction scope. Mechanism studies show the use of TBAB as an additive is pivotal for the reaction. In the process, para‐bromination of N‐aryl group, 5‐exo‐tri ipso‐cyclization of N‐aryl‐2‐arylbenzamide nitrogen radical and sequential aromatization is involved. [ABSTRACT FROM AUTHOR]

Short gram‐scale asymmetric syntheses of asperazine, pestalazine A, and their unnatural congeners thereof, have been achieved in ≈10 steps by using readily accessible starting materials. The nickel‐catalyzed reductive coupling protocol was utilized as a key step for the direct construction of C3asp3−C7′sp2 bond furnishing the diaryl‐substituted quaternary carbon centers with remarkable steric hindrance. The streamlined access to this core structure of heterodimeric tryptophans under the mild reaction conditions, makes this strategy hold a great promise in the concise synthesis of other relevant oligomeric pyrroloindoline alkaloids with unique C3a−C7′ linkages. Highly efficient syntheses of bioactive alkaloids (+)‐asperazine and (+)‐pestalazine A were realized by means of Ni‐catalyzed reductive coupling between 7‐iodotryptophan and 3‐chlorocyclotryptophan derivatives. This key reaction secured the construction of C3a−C7′ bond and the associated sterically congested all‐carbon quaternary stereocenter in a single step. [ABSTRACT FROM AUTHOR]

From a single α‐silylated carbinol intermediate, easily accessible by carbometallation of cyclopropenes, various scaffolds featuring a quaternary carbon stereocenter could be obtained selectively. The selectivity towards these different products was achieved by either changing the experimental conditions or the nature of the organometallic species involved. From a single α‐silylated carbinol intermediate, easily accessible by carbometallation of cyclopropenes, various scaffolds featuring a quaternary carbon stereocenter could be obtained selectively. The selectivity towards these different products was achieved by either changing the experimental conditions or the nature of the organometallic species involved. [ABSTRACT FROM AUTHOR]

A procedure for the a-arylation of a,a-disubstituted esters and ketones to generate quaternary carbon centers is described. The developed protocol is operationally simple and employs an air- and moisture-stable dinuclear Pd(I) complex [Pd(µ-I)(Pt-Bu3)]2 to mediate selective a-arylation of aromatic C-I/Br bonds in the presence of aromatic C-Cl and/or C-OTf sites. [ABSTRACT FROM AUTHOR]

Efficient construction of quaternary carbon centers represents one of the most challenging goals in organic synthesis, and it has drawn tremendous research interest from organic chemist community. The past decade has witnessed a significant advancement of direct C−H functionalization, which delivers various synthetic tools for assembling structurally diversified architectures with the advantage of step‐ and atom‐economy, operational simplicity, and readily available substrates. In this Minireview, synthetic methods based on transition‐metal‐catalyzed C−H functionalization as efficient tools for the construction of quaternary carbon centers are summarized. C−H activation to make quaternary carbons: Transition‐metal‐catalyzed C−H activation offers an intriguing strategy for construction of quaternary carbon centers in a highly atom‐ and step‐economic manner with molecular complexity, which is highlighted in this Minireview. [ABSTRACT FROM AUTHOR]

The cationic AuI‐catalyzed cyclization of highly substituted enynes has been shown to provide cyclopentenones with up to two contiguous, all‐carbon atom quaternary centers in a diastereospecific process. In the more challenging examples in which two contiguous quaternary centers are formed during cyclization, the essential role of a ethoxycarbonyl group to control the reaction outcome has been demonstrated. The less challenging examples that lead to a single quaternary center in the ring require no activation by aryl or by electron withdrawing groups. [ABSTRACT FROM AUTHOR]

Allylic substitution of secondary γ,γ-disubstituted allylic picolinates with ArMgBr-based copper reagents was applied to the synthesis of LY426965. Reduction of ( R )-6-(PMB-oxy)-3-hexyn-2-ol of 93% ee (PMB =  p -MeOC 6 H 4 CH 2 ) using Red-Al gave ( R , Z )-4-iodo-5-(PMB-oxy)hex-3-en-2-ol, which was later converted to the Me-substituted allylic picolinate by Pd-catalyzed coupling with MeZnI followed by esterification with picolinic acid. Allylic substitution with PhMgBr/Cu(acac) 2 proceeded with high anti S N 2′ selectivity (99%). Ozonolysis, addition of c -Hex-MgBr to the resulting aldehyde, and reductive amination with the piperazine derivative afforded LY426965. [ABSTRACT FROM AUTHOR]

In the present study, the key secondary allylic picolinate was synthesized via Pd(PPh3)4-catalyzed coupling of the TBS ether of (R,Z)- 4-iodo-5-methylhex-3-en-2-ol with allyl-MgBr. Allylic substitution of the picolinate with the copper reagent derived from 3,4- (MeO)2C6H3MgBr and Cu(acac)2 in a 2:1 ratio afforded the anti SN2' product with complete chirality transfer and 91% regioselectivity. Synthetic manipulation of the olefin moiety led to the nitrile group, generating the intermediate for the synthesis of (S)-verapamil. [ABSTRACT FROM AUTHOR]