The ability to affect asymmetric reduction of heterocyclic β-aminoacrylates 1 (n = 1–3) has been assessed with pyrrolidine and piperidone variants generating the corresponding N-heterocyclic β2-amino acids 3b and 5b with high enantioselectivity (≥97% ee) using a Rh/WALPHOS catalyst combination. The use of the carboxylic acid substrate was essential; the corresponding esters do undergo reduction but led to racemic products. The seven-ring azepanone variant (as the carboxylic acid 9b) underwent reduction, but only a minimal level of asymmetric induction was observed.

Expedient routes to three classes of novel spiro-fused pyrrolidine, piperidine, and indoline heterocycle scaffolds are described. These three-dimensional frameworks, which conform to the “rule of three”, are suitably protected to allow for site-selective manipulation and functionalization. Different modes of substrate control were explored, which allow for good to excellent levels of diastereoselectivity and dispense with the need for additional chiral reagents or catalysts. The concepts developed were applied in short, formal syntheses of (±)-coerulescine and (±)-horsfiline.

When combined with an appropriate nucleophilic component, 1,2- and 1,3-cyclic sulfamidates function as versatile precursors to a range of substituted and enantiopure heterocyclic classes. Functionalised enolates provide a direct entry to C-3 functionalised lactams, as exemplified by total syntheses of (−)-aphanorphine, (+)-laccarin and (−)-paroxetine. Heteroatom nucleophiles, such as thiol esters, amino esters and bromo phenols, provide concise access to a range of enantiomerically pure thiomorpholine, piperazine and benzofused heterocyclic scaffolds. The latter methodology enables a facile synthesis of the antibacteriocidal agent levofloxacin.

The electrophilic C−H palladation and Heck-type alkenylation of the tetrahydro[1,2-a]pyrimidine scaffold leads to exclusive formation of the C(7) adducts, and this palladium-catalyzed process is applicable to a broad range of alkenyl components. Mechanistic studies suggest that palladation is selective for C(7), and there was no evidence for C(9) metalation; the latter corresponds to the pathway observed previously with N-methylpyridone.

Nucleophilic cleavage of enantiomerically pure 1,2-cyclic sulfamidates with phenol, aniline, and thiophenol nucleophiles, followed by a Mitsunobu reaction, including use of a o-quinomethide variant of this process, provides an entry to substituted 1,4-tetrahydrobenzoxazepines, benzothiazepines, and benzodiazepines. Application of this methodology to 1,3-cyclic sulfamidates affords a parallel entry to the analogous substituted 1,5-benzoxazocines and 1,5-benzodiazocines.

Short and efficient enantioselective syntheses of (–)-paroxetine and (+)-laccarin are described based on the highly stereospecific cleavage of C(3)-substituted 1,3-cyclic sulfamidates.

Five and six ring α-phosphono lactams 14–20 are available by reaction of 1,2- and 1,3-cyclic sulfamidates respectively with enolates derived from ethyl dialkylphosphonoacetates 3 and 4. Subsequent Wadsworth–Emmons olefination provides the enantiomerically pure exo-alkylidene variants e.g.25, which is efficiently converted to vinyl triflate 29 (>98% ee). Suzuki coupling of 29 to a range of aryl and vinyl boronic acids leads to a structurally diverse range of pyrrolidinones exemplified by 30 and 34. The degree of epimerisation at the base-sensitive C(5) stereocentre during the Suzuki coupling of 29 is shown to be dependent on both the nature of the aryl boronic acid and the reaction conditions used.

A full account of studies which led to the efficient asymmetric synthesis of (−)-aphanorphine 1 is reported. Two routes to the key cyclic sulfamidate intermediate 5 are described, the first was based on a chiral auxiliary approach and the second utilised asymmetric hydrogenation methodology. A range of C(3)-substituted lactams (4, 22 and 25) were synthesised and evaluated as precursors for Pd(0) catalysed entries (based on (i) α-arylation of a lactam enolate and (ii) reductive Heck reaction) to the 3-benzazepine core of 1. These approaches were less effective than an aryl radical cyclisation which allowed the completion of a synthesis of 1 in 12 steps from anisaldehyde.

A structurally representative series of 1,2- and 1,3-cyclic sulfamidates react with enolates derived from methyl α-phenylthioacetate 9b to give 5- and 6-substituted α-phenylthio lactams 20–24. These products provide, via the corresponding sulfoxides, an entry to α,β-unsaturated lactams e.g.12, 27, 29 and their α-phenylthio analogues e.g.26 and 30. With the enantiomerically pure 1,2-cyclic sulfamidates 10, 15 and 17, these reactions all proceed with no detectable loss of stereochemical integrity.

The synthesis of (±)-epiquinamide 1 and (±)-C(1)-epiepiquinamide 2 based on the use of a Curtius rearrangement to introduce the C(1) amino residue is reported. In a competition binding assay for [3H]epibatidine binding to rat brain membranes neither (±)-1 nor (±)-2 showed any significant level of nicotinic activity.The synthesis of (±)-epiquinamide and (±)-C(1)-epiepiquinamide is reported. In a competition binding assay for [3H]epibatidine binding to rat brain membranes neither ligand showed any significant level of nicotinic activity.

A short and efficient enantioselective synthesis of (−)-aphanorphine is described based on the use of a cyclic sulfamidate to provide a suitably functionalised lactam that allows for construction of the tricyclic 3-benzazepine scaffold.

The synthesis of racemic cytisine 1 has been completed using (i)N-selective alkylation of 6-bromopyridone with bromide 6 and (ii) Pd(0) mediated intramolecular α-arylation of lactam 8 as key steps to achieve rapid assembly of the tricyclic core skeleton of the lupin alkaloids.

Four racemic phenyl-substituted analogues 3–6 of the potent nicotinic agonist UB-165 1 have been synthesised and evaluated against the α4β2, α3β4, and α7 neuronal nicotinic receptors. The 2′-phenyl derivative 3 shows no activity at these major receptor subtypes, while the 4′-phenyl analogue 4 shows an enhanced level of α7 selectivity as compared to UB-165 and deschloro UB-165 2. These results are discussed within the context of recent pharmacophore models.Four phenyl substituted analogues of UB-165 have been synthesised and evaluated as nicotinic ligands. The 2′-phenyl derivative shows no activity at these major receptor subtypes, while the 4′-phenyl analogue shows an enhanced level of α7 selectivity.

Reaction of the β-lactam-based oxazolidinone 5 with N-sulfonylimines provides the exo and endo azapenams 8 in 22–54% yield. The reactivity of 2H-azirines as 1,3-dipolarophiles towards β-lactam-based azomethine ylides derived from oxazolidinones 5 and 15 has also been evaluated. Azirines 11 and 12a provide cycloadducts 13a,b and 16 respectively, which incorporate the novel 2,6-diazatricyclo[4.2.0.02,4]octan-7-one ring system. These adducts were resistant towards C–N cleavage as the basis of an entry to 1-azacephams (1,5-diazabicyclo[4.2.0]octan-8-ones) 4. The use of the 3-(4-methoxyphenyl)-2H-azirine 19 provides a labile initial cycloadduct, which undergoes in situ ring-cleavage and further reaction to give the 2 ∶ 1 adduct 1-azacepham 22. The initial product is stable when 3-(4-nitrophenyl)-2H-azirine 23 is employed, and cycloadducts 24a and 24b are converted under mild reducing conditions to the 1-azacepham derivatives 25 and 26.

UB-165 (5), a hybrid corresponding to natural anatoxin-a and epibatidine, has been synthesised and shows significant potency at the high affinity nicotine binding site in rat brain. Ent-(5) shows a much lower level of activity which parallels the sense of enantiospecificity associated with anatoxin-a.UB-165, a hybrid of anatoxin-a and epibatidine, is a potent nicotinic ligand and shows a significant degree of enantiospecificity.

Asymmetric reduction of enones 1a-g using either a stoichiometric or catalytic amount of oxazaborolidine 3 proceeds to give the synthetically useful allylic cycloalkanols 2a-g in 83–96% e.e.Reduction of enones 1 using oxazaborolidine 3 proceeds to give the synthetically useful allylic cycloalkanols 2 in 83–96 %e.e.

A full account of studies which led to the efficient asymmetric synthesis of (−)-aphanorphine 1 is reported. Two routes to the key cyclic sulfamidate intermediate 5 are described, the first was based on a chiral auxiliary approach and the second utilised asymmetric hydrogenation methodology. A range of C(3)-substituted lactams (4, 22 and 25) were synthesised and evaluated as precursors for Pd(0) catalysed entries (based on (i) α-arylation of a lactam enolate and (ii) reductive Heck reaction) to the 3-benzazepine core of 1. These approaches were less effective than an aryl radical cyclisation which allowed the completion of a synthesis of 1 in 12 steps from anisaldehyde.

Five and six ring α-phosphono lactams 14–20 are available by reaction of 1,2- and 1,3-cyclic sulfamidates respectively with enolates derived from ethyl dialkylphosphonoacetates 3 and 4. Subsequent Wadsworth–Emmons olefination provides the enantiomerically pure exo-alkylidene variants e.g.25, which is efficiently converted to vinyl triflate 29 (>98% ee). Suzuki coupling of 29 to a range of aryl and vinyl boronic acids leads to a structurally diverse range of pyrrolidinones exemplified by 30 and 34. The degree of epimerisation at the base-sensitive C(5) stereocentre during the Suzuki coupling of 29 is shown to be dependent on both the nature of the aryl boronic acid and the reaction conditions used.

Short and efficient enantioselective syntheses of (–)-paroxetine and (+)-laccarin are described based on the highly stereospecific cleavage of C(3)-substituted 1,3-cyclic sulfamidates.

When combined with an appropriate nucleophilic component, 1,2- and 1,3-cyclic sulfamidates function as versatile precursors to a range of substituted and enantiopure heterocyclic classes. Functionalised enolates provide a direct entry to C-3 functionalised lactams, as exemplified by total syntheses of (−)-aphanorphine, (+)-laccarin and (−)-paroxetine. Heteroatom nucleophiles, such as thiol esters, amino esters and bromo phenols, provide concise access to a range of enantiomerically pure thiomorpholine, piperazine and benzofused heterocyclic scaffolds. The latter methodology enables a facile synthesis of the antibacteriocidal agent levofloxacin.