Application of the chiral base desymmetrisation of imides to the synthesis of the alkaloid jamtine and the antidepressant paroxetine

The synthesis of the alkaloid jamtine and the antidepressant paroxetine have been addressed by a strategy involving asymmetric desymmetrisation of prochiral imides by a chiral lithium amide base. A short reaction sequence, starting with a cyclohexane fused succinimide, led to the structures originally reported for the alkaloid jamtine and its derived N-oxide. The structures synthesised are shown not to correspond with those originally reported. A second sequence involves desymmetrisation of a 4-arylglutarimide, and provides a short enantioselective synthesis of the drug substance paroxetine.     

Asymmetric synthesis of the erythrinan alkaloid system using a chiral lithium amide base desymmetrisation as the key step

A new asymmetric approach to the erythrinan alkaloid system is described, which involves chiral base desymmetrisation of a ring fused imide and a 6-exo-trig radical cyclisation as the key steps.     

Asymmetric total synthesis of dendrobatid alkaloid 251F

The dendrobatid alkaloid (-)-251F was synthesized. The key steps of the synthesis were (1) an asymmetric Diels-Alder reaction to establish four of the necessary stereocenters in the target, (2) a ring-opening/ring-closing metathesis reaction to establish a key [3.3.0] bicyclic intermediate, and (3) an intramolecular Schmidt reaction.     

Enantioselective epoxidation by the chiral auxiliary approach: Asymmetric total synthesis of (+)-Ambrisentan

Enantioselective and a highly concise total synthesis of Ambrisentan are described. The chiral auxiliary controlled enantioselective epoxidation (Azerad protocol), photochemical regioselective epoxide opening, and base mediated ester hydrolysis reactions are the key reactions.     

Asymmetric synthesis of (+)-lentiginosine using a chiral aziridine based approach

The synthesis of the indolizidine alkaloid, (+)-lentiginosine, is described. A key feature of the preparative route is the efficient and stereoselective construction of a dihydroxylated pyrrolidine via Sharpless asymmetric dihydroxylation of an aziridine-enoate, which was prepared from commercially available 1-(S)-α-methylbenzylaziridine-2-methanol. In addition, a regioselective aziridine-to-pyrrolidinone ring expansion process followed by a Wittig olefination was employed to construct a late stage pyrrolidine intermediate that was transformed into (+)-lentiginosine.     

Asymmetric total synthesis of a pentacyclic lycopodium alkaloid: huperzine-q

Right on Q: The first asymmetric total synthesis of (-)-huperzine-Q, which possesses six stereogenic centers and a spiroaminal moiety, has been achieved in 19 steps and 16.4?% overall yield. This synthesis involved a novel stereoselective Pauson-Khand reaction, a vinyl Claisen rearrangement, and a biomimetic spiroaminal formation. TBDPS=tert-butyldiphenylsilyl.     

Asymmetric catalytic synthesis of the proposed structure of trocheliophorolide B

A concise catalytic asymmetric synthesis of the proposed structure of trocheliophorolide B is reported. The synthetic sequence notably features an asymmetric acetaldehyde alkynylation, a Ru-catalyzed alder-ene reaction, and a Zn-ProPhenol ynone aldol condensation. Comparison with the reported data suggests a misassignment of the natural product structure.     

Asymmetric total synthesis of (20S)-Camptothecin using a chiral auxiliary strategy

An asymmetric eight-step total synthesis of (20S)-camptothecin, starting from the known compound tert-butyl (2-chloroquinolin-3-yl)methylcarbamate, is described. A Heck reaction followed by an intramolecular Michael addition to form the C-ring provides the first key step in this synthesis. The construction of the 20(S) chiral center relies on a chiral auxiliary-mediated Michael addition using (2R,5R)-2-tert-butyl-5-ethyl-1,3-dioxolan-4-one as the auxiliary.     

A short diastereoselective synthesis of the putative alkaloid jamtine,using a tandem pummerer/mannich cyclization sequence

Treatment of 2-phenylhex-5-enal with benzylamine followed by sequential reaction with ethylthioacetyl chloride and sodium periodate oxidation afforded a E/Z mixture of alpha-sulfinylamides. As anticipated from a 4pi-conrotatory mechanism, cyclization of each olefin afforded fused isoquinoline lactams as single diastereomers epimeric at the ethylthio position without any cross contamination. Some preliminary studies were directed toward the synthesis of mesembrine using a 3,4-dimethoxy aryl group. In this case, the Z-enamide prefers to undergo electrophilic aromatic substitution to give a substituted azepinone as the preferred product in 87% yield. In contrast, the E-enamide isomer provided the desired hydroindolone. The convergency and stereochemical control associated with the tandem Pummerer /Mannich cyclization make it particularly suited for the assembly of jamtine, a tetrahydroisoquinoline alkaloid reputed for its therapeutic properties. The key step in the synthesis involves a domino thionium/N-acyliminium ion cyclization to provide the tricyclic ring skeleton 27a as the major diastereomer. Deprotonation of 27a with NaH gave 28a, which contains the fully assembled skeleton of jamtine. Completion of the synthesis entailed installation of the double bond and reduction of the lactam. Oxidation of a synthetic sample of jamtine with MCPBA afforded the corresponding N-oxide, which does not match the spectral data reported in the literature for this alkaloid. Our synthetic efforts raise the possibility of a revision of the earlier assignment.     

Asymmetric total synthesis of the indole alkaloid cyclopiazonic acid and first structure-activity data

The indole alkaloid α-cyclopiazonic acid (CPA) is one of the few known inhibitors of sarco(endo)plasmic reticulum Ca²⁺-ATPase (SERCA) besides the terpenoids thapsigargin and artemisinin. We report here the first asymmetric total synthesis of cyclopiazonic acid by a modification of the Knight synthesis, currently the most efficient route to CPA. First structure-activity data of CPA derivatives and stereoisomers are presented and will be discussed in connection with the published crystal structures of CPA-SERCA complexes.     

Stereoselective total synthesis of the proposed structure of 2-epibotcinolide

[Structure: see text] The total synthesis of pseudo 2-epibotcinolide (1b) through several featured synthetic approaches has been attained. First, the chiral linear precursors of the nine-membered ring compound is stereoselectively constructed by the asymmetric aldol reaction for producing beta-hydroxy ester units. Second, the key cyclization reaction to form the nine-membered lactone moiety is efficiently achieved by the extremely facile and powerful mixed-anhydride method promoted by 2-methyl-6-nitrobenzoic anhydride (MNBA) with basic promoters.     

Asymmetric synthesis of alkaloids using polyfunctionalized chiral building blocks

Enantiopure N‐sulfinyl‐δ‐amino‐β‐ketoesters and isoquinolones, prepared from sulfinimines (N‐sulfinyl imines) are a new class of polyfunctionalized chiral building blocks. These building blocks provide easy access to enantiomerically pure, functionalized piperidines and tetrahydroisoquinolines with a minimum of chemical manipulation and protecting‐group chemistry. © 2002 Wiley Periodicals, Inc. Heteroatom Chem 13:486–492, 2002; Published online in Wiley Interscience (www.interscience.wiley.com). DOI 10.1002/hc.10090     

Asymmetric approach towards the total synthesis of (+)-actinopyllic acid

This paper describes our efforts towards the asymmetric total synthesis of (+)-actinophyllic acid. Starting from the chiral oxazolidinone 9, an azocino [4,3-b]indolyl intermediate (5) possessing the A/B/C ring system and the C16 quaternary stereogenic center of actinophyllic acid has been synthesized. Key steps include a LHMDS-promoted condensation to establish the critical C2–C16 bond and a successive four-step transformation to assemble the eight-membered C-ring of the target molecule.     

Asymmetric total synthesis of reported structure of eudistomidin B, an indole alkaloid isolated from a marine tunicate

Eudistomidin B, isolated from a marine tunicate, was originally assigned a tetrahydro-β-carboline structure with a 2-p-tolylethanamine residue. Asymmetric total synthesis of the reported structure of natural product, which features an intramolecular diastereoselective Pictet-Spengler cyclization, suggests that the reported structure of the natural product needs to be revised.     

Asymmetric synthesis of chiral oxindoles using isatin as starting material

Asymmetric synthesis plays an important role in the synthesis of therapeutics and natural products. Asymmetric oxindoles with a stereogenic quaternary carbon center are extensively present in various natural products and biologically active compounds. Several methods such as employing chiral auxiliaries or chiral catalysts were developed for asymmetric synthesis of spirooxindoles or 3,3-disubtituted oxindoles. In this review, we make a detailed overview of the latest developments in the use of isatin as starting material for the asymmetric synthesis of spirooxindoles and 3,3-disubstituted oxindoles during the period from 2015 to 2017.     

Enantioselective total synthesis of the proposed structure of macrolide iriomoteolide-1b

An enantioselective total synthesis of the proposed structure of macrolide iriomoteolide-1b has been achieved by a convergent protocol, which was featured by an enantioselective organocatalytic transfer hydrogenation of enal, a Julia-Kocienski olefination to establish the C15-C16 E-olefin moiety, a Kulinkovich reaction associated with cyclopropyl-allyl rearrangement to produce allyl stannane and ytterbium triflate and carboxylic acid promoted allylation between allyl stannane and aldehyde with tertiary alcohol at the α-position. The construction of macrolide 2 was realized by the successful implementation of RCM utilizing 5 mol % Grubbs’s second generation catalyst at room temperature with E-isomer as a single product.     

A chemoenzymatic total synthesis of the structure assigned to the alkaloid (+)-montabuphine

An enantioselective synthesis of the structure, 3, assigned to the alkaloid (+)-montabuphine has been achieved using the readily available metabolite 4 as starting material. A comparison of the physical and spectral data recorded on compound 3 with those reported for (+)-montabuphine suggests that they are different compounds.     

A total synthesis of the alkaloid deplancheine

The indole alkaloid deplancheine (1) has been synthesised utilising a Witting reaction on the octahydro[2,3-a]quinolizin-2-one (2) itself available in four synthetic steps from readily available materials.     

Asymmetric aza-Mannich reactions of sulfinimines: scope and application to the total synthesis of a bromopyrrole alkaloid

[reaction: see text] An asymmetric intermolecular aza variant of the Mannich reaction is reported utilizing chiral sulfinimine anions as the nucleophile and N-sulfonyl aldimines as the electrophilic component. A wide range of nucleophiles and electrophiles are tolerated by the reaction conditions, delivering the condensation products in good to excellent yield with a high degree of stereocontrol. Application of this methodology to the total synthesis of a natural product is reported.