Stereocontrolled Introduction Research Articles

Collective Syntheses of Corynanthe Alkaloids Based on a Chirality-Tunable Structure Unit.

A novel strategy based on a common intermediate bearing a chirality-tunable structure unit for the collective syntheses of corynantheine-type and heteroyohimbine-type alkaloids has been developed. Key transformations of the synthetic strategy are a sequential nucleophilic C-N bond formation/Mannich-type cyclization to construct the highly functional C/D rings, a stereocontrolled introduction of the C15 and C20 chiral centers based on the chirality-tunable structure unit, and an amine-directed addition of Me3Al to construct the C18 methyl group.

Synthesis of Naphthaleman Family Utilizing Regiocontrolled Benzannulation: Unique Molecules Composed of Multisubstituted Naphthalenes.

The naphthaleman family, a set of uniquely designed visual molecular structures comprising multisubstituted naphthalenes, was synthesized utilizing regiocontrolled benzannulation as a key step. The naphthaleman family possesses a common naphthalene body with a head comprising the 3,4-methylenedioxy group, symmetrical or unsymmetrical right and left arms, and two alkynyl legs. The synthesis involves six C–C bond-forming reaction sequences. (i) syn-Stereoselective gem-dichlorocyclopropanation of methyl angelate (86%). (ii) Acylation with ArMgBr (three examples, 60–91% yield). (iii) Stereocontrolled introduction of the 3,4-methylenedioxyphenyl group (three examples, 67–92% yield). (iv) Crucial regiocontrolled benzannulation to construct a common body segment (71–73% yield). (v) Two Suzuki–Miyaura cross-couplings to install the right or left arms (first-stage route: four examples, 77–93% and second-stage route: four examples, 42–90% yield). (vi) Double alkynylation to insert two legs (first-stage route: four examples, 61–77% yield and second-stage route: sole example, 83% yield). The four core members were produced through both first-stage and second-stage routes, with the second-stage approach demonstrating superiority over the first-stage approach. One of the members was alternatively synthesized by switching the installation order of the right and left arms, and identical twin members were produced by high-performance liquid chromatography chiral separation. The most stable conformations of two naphthaleman family members were calculated by Spartan software.

A convenient synthesis of branched-chain nucleoside isothiocyanates via aza-Claisen rearrangement

Stereocontrolled introduction of a nitrogen atom at either C-2′ or C-3′ positions of nucleosides derived from uridine, 4-N-benzoylcytidine and adenosine was investigated. An efficient and rapid procedure was employed for creating new chiral centers at C-2′ and C-3′ positions using [3,3]-sigmatropic aza-Claisen rearrangement of allyl thiocyanates under conventional and microwave conditions. Structure of isothiocyanate products was confirmed by 1-D and 2-D NMR spectral analyses including selective 1H 1-D-NOE experiments.

ChemInform Abstract: Mechanistic, Crystallographic, and Computational Studies on the Catalytic, Enantioselective Sulfenofunctionalization of Alkenes.

The stereocontrolled introduction of vicinal heteroatomic substituents into organic molecules is one of the most powerful ways of adding value and function. Although many methods exist for the introduction of oxygen- and nitrogen-containing substituents, the number of stereocontrolled methods for the introduction of sulfur-containing substituents pales by comparison. Previous reports from our laboratories have described sulfenofunctionalizations of alkenes that construct carbon-sulfur bonds vicinal to carbon-oxygen, carbon-nitrogen or carbon-carbon bonds with high levels of diastereospecificity and enantioselectivity. This process is enabled by the concept of Lewis-base activation of Lewis acids, which provides activation of Group 16 electrophiles. To provide a foundation for the expansion of substrate scope and improved selectivities, we have undertaken a comprehensive study of the catalytically active species. Insights gleaned from kinetic, crystallographic and computational methods have led to the introduction of a new family of sulfenylating agents that provide significantly enhanced selectivities.

Mechanistic, crystallographic, and computational studies on the catalytic, enantioselective sulfenofunctionalization of alkenes.

The stereocontrolled introduction of vicinal heteroatomic substituents into organic molecules is one of the most powerful ways of adding value and function. Although many methods exist for the introduction of oxygen- and nitrogen-containing substituents, the number of stereocontrolled methods for the introduction of sulfur-containing substituents pales by comparison. Previous reports from our laboratories have described sulfenofunctionalizations of alkenes that construct carbon-sulfur bonds vicinal to carbon-oxygen, carbon-nitrogen or carbon-carbon bonds with high levels of diastereospecificity and enantioselectivity. This process is enabled by the concept of Lewis-base activation of Lewis acids, which provides activation of Group 16 electrophiles. To provide a foundation for the expansion of substrate scope and improved selectivities, we have undertaken a comprehensive study of the catalytically active species. Insights gleaned from kinetic, crystallographic and computational methods have led to the introduction of a new family of sulfenylating agents that provide significantly enhanced selectivities.

Regio- and Diastereoselective Cu-Mediated Trifluoromethylation of Functionalized Alkenes

α- and β-substituted N,N-diethylacrylamides undergo copper-mediated direct β-trifluoromethylation. The amide moiety acts as a directing group for the regio- and the stereo-controlled introduction of the trifluoromethyl group. The reaction is carried out under acidic conditions in the presence of Umemoto's reagent. This method does not require prefunctionalized substrates and delivers excellent stereoselectivity.

ChemInform Abstract: Regio‐ and Stereocontrolled Introduction of Secondary Alkyl Groups to Electron‐Deficient Arenes Through Copper‐Catalyzed Allylic Alkylation.

AbstractIn the title reaction allylic substrates with a carbonate or acetate leaving group instead of the phosphate group are not reactive.

Regio‐ and Stereocontrolled Introduction of Secondary Alkyl Groups to Electron‐Deficient Arenes through Copper‐Catalyzed Allylic Alkylation

Regio‐ and Stereocontrolled Introduction of Secondary Alkyl Groups to Electron‐Deficient Arenes through Copper‐Catalyzed Allylic Alkylation

Regio‐ and Stereocontrolled Introduction of Secondary Alkyl Groups to Electron‐Deficient Arenes through Copper‐Catalyzed Allylic Alkylation

Copper-catalyzed allylic alkylation of azoles, a pyridine N-oxide, and fluoroarenes with secondary allylic phosphates proceeded under mild reaction conditions with excellent γ-E-selectivity. The reactions with enantioenriched allylic phosphates proceeded with 1,3-anti stereoselectivity to generate an allylic stereogenic center at the position α to the aromatic ring.

ChemInform Abstract: Stereoselective Conjugate Addition Reactions to Phenylglycinol‐Derived, Unsaturated Oxazolopiperidone Lactams.

AbstractReview: 40 refs.

Stereoselective Conjugate Addition Reactions to Phenylglycinol‐Derived, Unsaturated Oxazolopiperidone Lactams

Phenylglycinol-derived, unsaturated oxazolopiperidone lactams are extremely useful building blocks that undergo stereoselective conjugate addition reactions with organocuprates, enolates, and sulfur-stabilized anions, allowing the stereocontrolled introduction of substituents at the piperidine 4-position. The factors governing the exo- or endo-facial selectivity are discussed. The methodology can be used for the preparation of a variety of enantiopure piperidines, including pharmaceuticals, alkaloids precursors, piperidine-fused derivatives, as well as complex piperidine-containing natural products.

Single- and double-chained truncated jaspine B analogues: asymmetric synthesis, biological evaluation and theoretical study of an unexpected 5-endo-dig process

An optimized synthesis of jaspine B analogues bearing an n-octyl or a p-fluorophenethyl lipophilic appendage was developed. Key to the approach was the use of acetylenic nucleophiles for the stereocontrolled introduction of the side chain and the implementation of a novel cyclization procedure to build the tetrahydrofuran ring. Three N-substituted amine or amide derivatives were also accessed. The biological activity of these four jaspine B analogues was shown to strongly depend on the nature of both the N-substituent and the aliphatic moiety connected to the tetrahydrofuran ring. Gratifyingly, the truncated jaspine B derivative proved to be a pro-apoptotic inhibitor of the conversion of ceramide into sphingomyelin. Finally, the efficient formation of a fused bis-furan derivative according to a 5-endo-dig process was observed under saponification conditions. On the basis of a theoretical study, a mechanistic pathway was delineated highlighting the Lewis acidity of the K+ ion as the driving force for this transformation in a strongly alkaline medium.

Total Synthesis of Pactamycin

Lest we forget: 50 years after pactamycin was first isolated from a fermentation broth of Streptomyces pactum var pactum, this highly functionalized aminocyclopentitol natural product has finally succumbed to total synthesis. The modular and stereocontrolled introduction of functional groups should lead to the synthesis of less toxic congeners that maintain the antibacterial and cytotoxic activities.

Diastereoselective Synthesis of Lincosamine Precursors

AbstractThe stereoselective syntheses of the four aminodiol precursors of the diastereomers of lincosamine are reported. The procedure is based on the initial two‐carbon elongationof 1,2;3,4‐di‐O‐isopropylidene‐α‐D‐galactohexodialdo‐1,5‐pyranose, followed by the stereocontrolled introduction of the amino group by nucleophilic amination. Two complementary approaches have been investigated and compared: The first one is the direct transformation of α‐chloroglycidic ester into β‐amino‐α‐keto ester. The second strategy is a three‐step synthesis that is based on the treatment of the β‐iodo‐α‐keto ester with dibenzylamine. Subsequent reduction of the β‐amino‐α‐keto ester provides the pure D‐erythro, L‐threo, L‐erythro, and D‐threo aminodiols after chromatographic purification. Further classical transformations afford the N‐acetyl derivatives, which are key precursors of the lincosamine diastereomers.

A short practical approach to 24 R,25-dihydroxyvitamin D 3

A synthesis of the vitamin D 3 metabolite 24 R,25-dihydroxyvitamin D 3 ( 1) by Lythgoe's Wittig–Horner approach is described. The key step of the synthesis is the stereocontrolled introduction of the 24-hydroxyl group by a palladium(0)-induced [3,3]-sigmatropic rearrangement on a 22 R-allylic acetate ( 7).

A unified approach to the tedanolides: total synthesis of (+)-13-deoxytedanolide.

A unified approach for the construction of the potent marine antitumor agents (+)-tedanolide (1) and (+)-13-deoxytedanolide (2) is described. Highlights of the synthetic strategy include the development of a versatile bifunctional dithiane-vinyl iodide linchpin, the unorthodox use of the Evans-Tishchenko reaction, and a late-stage high-risk stereocontrolled introduction of the C(18,19) epoxide to achieve a total synthesis of (+)-13-deoxytedanolide (2).

Divergent and stereocontrolled synthesis of the enamide side chains of oximidines I/II/III, salicylihalamides A/B, lobatamides A/D, and CJ-12,950.

[reaction: see text] A unified strategy for the divergent and stereocontrolled introduction of the (E)- and (Z)-enamide side-chains of oximidines I, II, and III, salicylihalamides A and B, lobatamides A and D, and CJ-12,950 is detailed. The synthesis relied on the copper-promoted C-N coupling of (E)- and (Z)-vinyl iodides with a protected maleimide hemiaminal followed by deprotection and reaction of the resulting (E)- or (Z)-enelactam hemiaminals with O-methylhydroxylamine or propylidenetriphenylphosphorane.

Toward the Enantioselective Total Synthesis of Lyngbyatoxin A: On the Stereocontrolled Introduction of the Quaternary Stereogenic Center.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Toward the enantioselective total synthesis of lyngbyatoxin A: on the stereocontrolled introduction of the quaternary stereogenic centre

This paper deals with an approach to the enantioselective total synthesis of Lyngbyatoxin A, with focus on the stereocontrolled introduction of the quaternary stereogenic centre. The key step in the synthesis involves an enantiospecific Lewis-acid mediated rearrangement of chiral vinyl epoxides carrying a 7-substituted indole moiety.

Studies toward the total synthesis of hibarimicinone. Progress on the assembly of the AB- and GH-ring systems

Studies directed towards the synthesis of the AB- and GH-ring systems of hibarimicinone are described. The synthesis of tetralin 3 was accomplished in three steps (43% overall yield) from benzoquinone and resolved using a Lipase-mediated resolution to >92% ee. Key reactions developed en route to the AB/GH ring systems of hibarimicinone include a dimethyl dioxirane oxidation for stereocontrolled introduction of the C(14) and C(14′) hydroxyl groups and the stereoselective addition of a n-propylcerium dichloride to ketone 13 to give diol 15 .