Iain Coldham

Asymmetric deprotonation of N-boc piperidine: react IR monitoring and mechanistic aspects.

The high yielding asymmetric deprotonation trapping of N-Boc piperidine is successfully realized using s-BuLi and a (+)-sparteine surrogate. Monitoring of the lithiation by in situ React IR allowed the direct observation of a prelithiation complex.

An Experimental and in Situ IR Spectroscopic Study of the Lithiation–Substitution of N-Boc-2-phenylpyrrolidine and -piperidine: Controlling the Formation of Quaternary Stereocenters

A general and enantioselective synthesis of 2-substituted 2-phenylpyrrolidines and -piperidines, an important class of pharmaceutically relevant compounds that contain a quaternary stereocenter, has been developed. The approach involves lithiation-substitution of enantioenriched N-Boc-2-phenylpyrrolidine or -piperidine (prepared by asymmetric Negishi arylation or catalytic asymmetric reduction, respectively). The combined use of synthetic experiments and in situ IR spectroscopic monitoring allowed optimum lithiation conditions to be identified: n-BuLi in THF at -50 °C for 5-30 min. Monitoring of the lithiation using in situ IR spectroscopy indicated that the rotation of the tert-butoxycarbonyl (Boc) group is slower in a 2-lithiated pyrrolidine than a 2-lithiated piperidine; low yields for the lithiation-substitution of N-Boc-2-phenylpyrrolidine at -78 °C can be ascribed to this slow rotation. For N-Boc-2-phenylpyrrolidine and -piperidine, the barriers to rotation of the Boc group were determined using density functional theory calculations and variable-temperature (1)H NMR spectroscopy. For the pyrrolidine, the half-life (t(1/2)) for rotation of the Boc group was found to be ∼10 h at -78 °C and ∼3.5 min at -50 °C. In contrast, for the piperidine, t(1/2) was determined to be ∼4 s at -78 °C.

Cascade cyclization, dipolar cycloaddition to bridged tricyclic amines related to the Daphniphyllum alkaloids.

A tandem one-pot reaction of an aldehyde with a primary amine involving condensation and then cyclization (N-alkylation), followed by intramolecular dipolar cycloaddition of the resulting nitrone or azomethine ylide, provides a synthesis of bridged tricyclic amines. The reaction was most successful using hydroxylamine, and when the dipolarophile was an unsaturated ester, subsequent reduction of the N-O bond and cyclization to the lactam provided the core ring system of the yuzurimine, daphnilactone B, and bukittinggine type Daphniphyllum alkaloids.

Stereoselective formation of fused tricyclic amines from acyclic aldehydes by a cascade process involving condensation, cyclization, and dipolar cycloaddition.

The preparation of tricyclic amines from acyclic precursors is described using a cascade of tandem reactions involving condensation of an aldehyde with a primary amine, cyclization (with displacement of a halide), and then in situ deprotonation or decarboxylation to give an azomethine ylide or nitrone followed by intramolecular dipolar cycloaddition. The methodology is straightforward, and the aldehyde precursors are prepared easily and quickly in high yield using nitrile alkylations followed by DIBAL-H reduction. The relative ease of reaction of various substrates with different tether lengths between the aldehyde and the halide or dipolarophile has been studied. Several primary amines including simple amino acids such as glycine, alanine, and phenylalanine and derivatives such as glycine ethyl ester and also hydroxylamine have been investigated. High yields are obtained in the formation of different tricyclic ring sizes; the dipolar cycloaddition necessarily creates a five-membered ring, and we have investigated the formation of five- and six-membered rings for the other two new ring sizes. In all cases, yields are high (except when using glycine when the tether to the terminal alkene dipolarophile leads to a six-membered ring), and most efficient is the formation of the tricyclic product in which all five-membered rings are formed. Examples with an alkyne as the dipolarophile were also successful. In all the reactions studied, the products are formed with complete regioselectivity and remarkably with complete stereoselectivity. The key step involves the formation of three new rings and potentially up to four new stereocenters in a single transformation. The power of the chemistry was demonstrated by the synthesis of the core ring systems of the alkaloids (+/-)-scandine and (+/-)-myrioneurinol and the total syntheses of the alkaloids (+/-)-aspidospermine, (+/-)-quebrachamine, and (+/-)-aspidospermidine.

Asymmetric Substitutions of 2‐Lithiated N‐Boc‐piperidine and N‐Boc‐azepine by Dynamic Resolution

Proton abstraction of N-tert-butoxycarbonyl-piperidine (N-Boc-piperidine) with sBuLi and TMEDA provides a racemic organolithium that can be resolved using a chiral ligand. The enantiomeric organolithiums can interconvert so that a dynamic resolution occurs. Two mechanisms for promoting enantioselectivity in the products are possible. Slow addition of an electrophile such as trimethylsilyl chloride allows dynamic resolution under kinetic control (DKR). This process occurs with high enantioselectivity and is successful by catalysis with substoichiometric chiral ligand (catalytic dynamic kinetic resolution). Alternatively, the two enantiomers of this organolithium can be resolved under thermodynamic control with good enantioselectivity (dynamic thermodynamic resolution, DTR). The best ligands found are based on chiral diamino-alkoxides. Using DTR, a variety of electrophiles can be used to provide an asymmetric synthesis of enantiomerically enriched 2-substituted piperidines, including (after Boc deprotection) the alkaloid (+)-beta-conhydrine. The chemistry was extended, albeit with lower yields, to the corresponding 2-substituted seven-membered azepine ring derivatives.

Synthesis of the Core Ring System of the Yuzurimine-Type Daphniphyllum Alkaloids by Cascade Condensation, Cyclization, Cycloaddition Chemistry

Addition of hydroxylamine to substituted 4-chlorobutanals gives intermediate nitrones that undergo tandem cyclization and then intramolecular dipolar cycloaddition to give the core ring system of the yuzurimine-type natural products. Ring-opening of the isoxazolidines gives amino alcohols that can be converted to 1,3-oxazines, representing the tetracyclic core of alkaloids such as daphcalycic acid and daphcalycine.

Synthesis of 2-Arylpiperidines by Palladium Couplings of Aryl Bromides with Organozinc Species Derived from Deprotonation of N-Boc-Piperidine

The organolithium species derived from proton abstraction of N-Boc-piperidine with s-BuLi and TMEDA can be transmetalated to the organozinc reagent, and this organometallic species can be coupled directly with aryl bromides in a Negishi-type reaction using palladium catalysis with the ligand tri-tert-butylphosphine (t-Bu3P-HBF4). The chemistry was applied to a very short synthesis of the alkaloid anabasine.

Ring expansion of aziridines to piperidines using the aza-wittig rearrangement

Abstract A one-pot, two-step synthesis of unsaturated piperidines from 2-keto aziridines is reported, Treatment of a range of 2-keto aziridines with two equivalents of a phosphonium ylide generates intermediate vinyl aziridines which rearrange by a [2,3]-sigmatropic shift to create a new carbon-carbon bond with concomitant ring opening of the aziridines to give the unsaturated piperidines. This three- to six-membered ring expansion allows the synthesis of N -unsubstituted piperidines and pipecolic acid derivatives.

Synthesis of 1,1-Disubstituted Tetrahydroisoquinolines by Lithiation and Substitution, with in Situ IR Spectroscopy and Configurational Stability Studies

Lithiation of N-Boc-1-phenyltetrahydroisoquinolines was optimized by in situ IR spectroscopy. The kinetics for rotation of the carbamate group and for the enantiomerization of the organolithium were determined. The organolithium is configurationally stable at low temperature, and the asymmetric synthesis of 1,1-disubstituted tetrahydroisoquinolines can be achieved with high yields and high enantiomer ratios. The chemistry was applied to the preparation of FR115427 and provides a way to recycle the undesired enantiomer in the synthesis of solifenacin.

Synthesis of fused tricyclic amines from enolizable acyclic aldehydes by cyclization then dipolar cycloaddition cascade: synthesis of myrioxazine A.

A tandem one-pot reaction involving a condensation, then cyclization (N-alkylation), followed by an azomethine ylide or nitrone dipolar cycloaddition allows a synthesis of tricyclic amines from acyclic enolizable aldehydes. The reaction was unsuccessful using amino acids or esters but was successful with (tributylstannyl)methylamine or hydroxylamine. One of the products was converted in two steps to the alkaloid (+/-)-myrioxazine A. The chemistry also provides a formal synthesis of the antimalarial alkaloids myrionidine and schoberine.