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A practical and scalable synthesis of phosphonooxymethyl prodrugs of HIV-1 attachment inhibitors is described. Starting from azaindoles 1 and 2, this two-step sequence features an efficient alkylation using chloromethyl phosphate 5 and an exceptionally mild deprotection for tert-butyl phosphates. After a salt formation, the API is formed in 82% and 70% overall yield for 3a and 4a, respectively. This chemistry was used to prepare multikilogram quantities of API.

A mechanistic approach to identify the driving force for crystallization and to determine the solubility of solids crystallized from solutions containing multiple conformers is presented. It is assumed that only one conformer, which is referred to as the right conformer (RC), integrates into the crystal surface if the energy barrier of transition between conformers is higher than 10 kcal/mol. Conformers that do not integrate into the crystal surface are lumped into a single conformation which is referred to as the wrong conformer (WC). This approach, which is referred to as the approach of the RC, was applied to two organic substances that presented unusual solubility and crystallization behaviors: constant or retrograde solubility and sharply decreasing crystallization duration with temperature. For both substances, 1 H NMR data indicated the presence of multiple conformations in solution and rotomers’ peak coalescence was reached at relatively high temperature indicating high energy barriers of transition between conformers. In addition, ab initio calculations revealed that the RC is the high energy conformer indicating that the WC levels in solution are higher. On the basis of these observations, the approach of the RC was considered to be applicable for the substances studied. This approach considers that the RC is the only species in true equilibrium with the solid at saturation. The intrinsic solubility and the total solubility are introduced for non-ionizable organic molecules and are defined respectively as the concentration of the RC and the concentration of all conformers at saturation. The intrinsic supersaturation (ISS), defined as the concentration of the RC minus the intrinsic solubility, is considered to be the driving force for the crystallization and expressions relating the total solubility and the ISS to crystallization parameters are derived. Computed total solubility was in agreement with either the constant or retrograde solubility observed experimentally for the substances studied. Slow crystallization was attributed to the low levels of the calculated ISS and to crystal growth inhibition caused by high levels of the WC. In addition, this approach provided a simple means for the experimental estimation of the energy difference between the two main conformers. Finally, on the basis of the predicted increase of ISS with temperature, an alternate crystallization procedure based on a single heating ramp was utilized to provide crystals with improved powder properties.

The scope of the lanthanide mediated, sequential hydroamination/C–C cyclization reaction was determined for the formation of tricyclic and tetracyclic aromatic nitrogen heterocycles. An array of ring sizes was explored to determine the diastereoselectivity. The electronic characteristics of the aromatic ring was also varied to determine how it affected the cascade reaction. It was found that the benzo[a]quinolizine and the pyrido[2,1,a]isoindolizine ring systems formed with the highest diastereoselectivity (>20:1), regardless of the electronic characteristics of the aromatic ring. Additionally, a tetracyclic indole nitrogen heterocycle was formed with a 2.3:1 diastereomeric ratio. A novel procedure for substrate preparation is also presented.

A diastereoselective, lanthanocene-catalyzed, intramolecular hydroamination reaction was applied to the preparation of 2,6-disubstituted piperidines. Various metal/ligand arrays in the catalysts were examined using a model substrate to allow optimization of the diastereoselectivity. It was determined that the relationship between metal size and ligand bulk plays an integral role in the transformation. The complex Cp2NdCH(TMS)2 converted 2-substituted 8-nonen-4-amines to 2,6-disubsituted piperidines with greater than 100:1 selectivity for the formation of the cis isomer. A short synthesis of pinidinol, an alkaloid isolated from various pine and spruce species, was then carried out to exploit this stereoselective reaction.

Allysine ethylene acetal [(S)-2-amino-5-(1,3-dioxolan-2-yl)-pentanoic acid (2)] was prepared from the corresponding keto acid by reductive amination using phenylalanine dehydrogenase (PDH) from Thermoactinomyces intermedius ATCC 33205. Glutamate, alanine, and leucine dehydrogenases, and PDH from Sporosarcina species (listed in order of increasing effectiveness) also gave the desired amino acid but were less effective. The reaction requires ammonia and NADH. NAD produced during the reaction was recyled to NADH by the oxidation of formate to CO(2) using formate dehydrogenase (FDH). PDH was produced by growth of T. intermedius ATCC 33205 or by growth of recombinant Escherichia coli or Pichia pastoris expressing the Thermoactinomyces enzyme. Using heat-dried T. intermedius as a source of PDH and heat-dried Candida boidinii SC13822 as a source of FDH,98%, but production of T. intermedius could not be scaled up. Using heat-dried recombinant E. coli as a source of PDH and heat-dried Candida boidinii 98%. In a third generation process, heat-dried methanol-grown P. pastoris expressing endogenous FDH and recombinant Thermoactinomyces98% ee.

A diastereoselective, lanthanocene-catalyzed, intramolecular hydroamination reaction was applied to the preparation of 2,6-disubstituted piperidines. Various metal/ligand arrays in the catalysts were examined using a model substrate to allow optimization of the diastereoselectivity. It was determined that the relationship between metal size and ligand bulk plays an integral role in the transformation. The complex Cp2NdCH(TMS)2 converted 2-substituted 8-nonen-4-amines to 2,6-disubsituted piperidines with greater than 100:1 selectivity for the formation of the cis isomer. A short synthesis of pinidinol, an alkaloid isolated from various pine and spruce species, was then carried out to exploit this stereoselective reaction.

The scope of the lanthanide-mediated, intramolecular amination/cyclization reaction was determined for the formation of substituted quinolizidines, indolizidines, and pyrrolizidines. A methyl group was installed at diverse positions in the substrates to determine the sense and magnitude of diastereoselection. High diastereoselectivity (>20:1) was achieved for the formation of some quinolizidines and indolizidines. The sense of relative asymmetric induction was contrary to previously studied systems, and although some questions remain, a rationalization for these results is put forward.