An N-acyliminium cyclization approach to a total synthesis of (+)-cylindricine C

[reaction: see text] Details of problems and solutions encountered during the development of an enantioselective total synthesis of (+)-cylindricine C are described here. The total synthesis itself was accomplished in 8 steps, featuring an N-acyliminium cyclization strategy, the seldom-used Wharton rearrangement, and a key epimerization at C5.     

Practical solid-phase parallel synthesis of Delta(5)-2-oxopiperazines via N-acyliminium ion cyclization

A practical solid-phase strategy for the synthesis of Delta(5)-2-oxopiperazines via N-acyliminium ion cyclization has been developed. A key step in the library synthesis is tandem acidolytic cleavage with subsequent in situ iminium formation, followed by stable enamide transformation. This approach is exemplified by the preparation of a 192-member pilot library using bromoacetal resins without further purification.     

A novel synthesis of (di)-benzazocinones via an endocyclic N-acyliminium ion cyclisation

The triflic acid-mediated endocyclic N-acyliminium ion cyclisation provides a facile synthesis of (di)-benzazocinones. On reduction of the 10-phenyl derivative, an unusually non-polar tertiary alkylamine was obtained.     

A formal total synthesis of (+/-)-cephalotaxine using sequential N-acyliminium ion reactions

[reaction: see text] Novel synthesis of cephalotaxine 1 based on tertiary N-acyliminium ion chemistry starting from alkynylamide 2 was achieved. The key steps include the preparation of pyrroloisoquinoline 4 from alkynylamide 2, the ring expansion of pyrroloisoquinoline 4 to pyrrolobenzazepine 12, and the construction of cyclopentapyrrolobenzazepine ring system 6, all of which are derived from N-acyliminium ion intermediates.     

Total synthesis of (+)-isoschizandrin utilizing a samarium(II) iodide-promoted 8-endo ketyl-olefin cyclization

The 13-step synthesis of (+)-isoschizandrin reported herein features a samarium(II) iodide-promoted 8-endo ketyl-olefin coupling to assemble the eight-membered ring present in the target concomitantly with the required functionality and stereochemistry. In constructing (+)-isoschizandrin as a single atropisomer, the synthesis utilizes a kinetic resolution of a seven-membered lactone using a CBS-oxazaborolidine.     

Stereoselective total syntheses of the racemic form and the natural enantiomer of the marine alkaloid lepadiformine via a novel N-acyliminium ion/allylsilane spirocyclization strategy

Stereoselective total syntheses of the racemic form and the natural enantiomer of the tricyclic marine alkaloid lepadiformine (6) have been accomplished using a novel intramolecular spirocyclization of an N-acyliminium ion with an allylsilane to form the A/C rings as the key step. Introduction of the hydroxymethyl group at C-13 of the racemic spirocycle 11 was achieved using our methodology for oxidative radical-based remote functionalization of o-aminobenzamides, followed by copper-catalyzed addition of Grignard reagent 16 to the N-acyliminium ion intermediate derived from 15. Subsequent Tamao oxidation of silane 17 then afforded the requisite hydroxymethyl compound 19, which was converted to the dimethyl acetal 25 via hydroformylation followed by aldehyde protection. Hydrolysis of the benzamide moiety of 25 and subsequent protection of the primary alcohol gave amino acetal 27. The synthesis was concluded from 27 by a four-step procedure: acid-catalyzed ring closure, amino nitrile formation, introduction of the hexyl chain by a Grignard reaction to an iminium salt, and removal of the O-benzyl protecting group to give (+/-)-lepadiformine (6). The enantioselective total synthesis of 6 started from known optically pure bromide 37, derived from (S)-pyroglutamic acid, and followed a similar sequence involving the key spirocyclization of N-acyliminium ion 42. This synthesis has established the absolute configuration of naturally occurring lepadiformine to be 2(R),5(S),10(S),13(S).     

First total synthesis of dragmacidin A via indolylglycines

The first total synthesis of dragmacidin A has been accomplished using condensation of two indolylglycines followed by cyclization and reduction. The general and practical method for synthesis of indolylglycines via Wittig reaction, azide addition, and reduction from indolin-3-ones is also described.     

Asymmetric synthesis of 5-substituted pyrrolidinones via a chiral N-acyliminium equivalent

5-Substituted pyrrolidinones 5 were synthesized in good yields and with fair to good diastereoselectivities from the chiral non-racemic oxazolopyrrolidinone 4. Various nucleophiles including cuprates, silanes and phosphites were used. The chiral induction is thought to arise from a chelated N-acyliminium species.     

Generation of N-acyliminium ions via intramolecular conjugate addition reactions: a strategy for the total synthesis of nakadomarin A

[reaction: see text] The rapid construction of the tetracyclic core ring system of nakadomarin A via a tandem enecarbamate Michael addition/N-acyliminium ion cyclization is described.     

Silicon-assisted synthesis of bridged azabicyclic systems via N-acyliminium intermediates

Intramolecular acid-mediated reactions of 2-propynyl- and allylsilanes with five- and six-membered cyclic N-acyliminium ion precursors lead to bridged azabicyclic compounds (Table I). Neat formic acid is the reaction medium of choice in most cases. The cyclization reactions take place with complete regioselectivity. 2-Propynylsilanes are more reactive than allylsilanes. An ordinary olefin reacts poorly. The cyclization products can be useful for the synthesis of γ- and δ-amino acids and derivatives.     

Concise asymmetric total synthesis of lycopodine and flabelliformine via cascade cyclization reaction

The shortest asymmetric total synthesis of lycopodine (3) and the first asymmetric total synthesis of flabelliformine (4) were accomplished by a strategy that features a cascade cyclization of linear substrate (5) to construct tetracyclic structure (6).     

Concise total synthesis of antiarrhythmic drug dronedarone via a conjugate addition followed intramolecular heck cyclization

A concise, scalable, and an efficient total synthesis for dronedarone ( 2 ) was described using conjugate addition followed by intramolecular Heck cyclization. The other key reaction includes selective reduction of nitro functionality and addition of lithiated terminal alkyne to the aldehyde. The overall yield of this approach is 44% in six steps.     

Solid-phase synthesis of pyrroloisoquinolines via the intramolecular N-acyliminium Pictet-Spengler reaction

In the present investigation, solid-phase routes toward 1,5,6,10b-tetrahydro-2H-pyrrolo[2,1-a]isoquinolin-3-ones via the intramolecular N-acyliminium Pictet-Spengler reaction are established. Peptide aldehydes generated from their parent N-Boc 1,3-oxazines by acidic reaction conditions undergo intramolecular condensation reactions with the amide N of a solid-supported peptide backbone, thus forming a 1:1 epimeric mixture of a cyclic 5-hydroxylactam, which in turn is in equilibrium with the corresponding intermediate N-acyliminium ion. Provided appropriate acidic reaction conditions, a second ring may be appended via Pictet-Spengler cyclization from the aromatic ring of a neighboring phenylalanine derivative in the peptide sequence. The aromatic substitution pattern of the nucleophilic benzene ring of the phenylalanine derivative and the nature of the acidic reaction media are critically important for the course of the reaction, and both Lewis and Br?nsted acids may be employed to effect the cyclization process. This intramolecular reaction is under strict control of stereoselectivity, and only a single stereoisomer is detected in the crude products. A range of mono-, di-, and trisubstituted phenylalanines with diverse sets of electron-donating and electron-withdrawing substituents, pyrene, and naphthalenes have successfully been brought within the scope of the reaction, thus providing a unique scaffold for combinatorial library synthesis.     

Synthesis of novel pyrimidine fused 8-membered heterocycles via iminium ion cyclization reactions

Novel tricyclic pyrimidine-fused 8-membered heterocycles were prepared by an iminium ion cyclization using pyrimidinediamine systems with electron-rich aromatic rings.     

Total synthesis of (+/-)-jamtine using a thionium/N-acyliminium ion cascade

[reaction: see text] The first total synthesis of (+/-)-jamtine (4), a tetrahydroisoquinoline alkaloid reputed for its therapeutic properties, is described. The key step involves a tandem thionium/N-acyliminium ion cyclization from enamido sulfoxide 13. The cascade process takes place with high diastereoselectivity and in excellent yield.     

Highly regioselective synthesis of indene derivatives including an allene functional group via Pd/C-catalyzed cyclization reaction in air

Indene derivatives including an allene functional group are readily prepared in moderate to excellent yields with high regioselectivity under very mild reaction conditions by the Pd/C-catalyzed reaction of propargylic compounds. The resulting products can be further elaborated using Pd-catalyzed annulation reactions.     

First stereoselective total synthesis of decarestrictine O via RCM protocol

A convergent first stereoselective total synthesis of decarestrictine O via RCM protocol starting from 1,3-propanediol and propylene oxide is reported.