Regioselective Functionalization of 7-Azaindole by Controlled Annular Isomerism: The Directed Metalation-Group Dance.

The regioselective functionalization of 7-azaindole by controlled annular isomerism employing a directed metalation-group migration is reported. The N7 carbamoyl azaindoles undergo regioselective metalation and quenching with an electrophile to furnish C6-substituted derivatives which, in the presence of a catalytic amount of ClCONR2 promotes a carbamoyl group shift or dance from N7 to N1. A second directed metalation/electrophile quench sequence leads to 2,6-substituted azaindoles. Optimization of the metalation conditions for C2 and C6, separately and iteratively, is presented. Using the directed metalation group dance strategy, a late-stage deuteration of an antipsychotic drug is described. Overall, the controlled migration of the carbamoyl directing group allows multiple functionalization events of the bioactive azaindole scaffold.

Directed Remote Lateral Metalation: Highly Substituted 2-Naphthols and BINOLs by In Situ Generation of a Directing Group.

A general synthesis of highly substituted 2-naphthols based on a new carbanionic reaction sequence is demonstrated. The reaction exploits the dual nature of lithium bases consisting of consecutive ring opening of readily available coumarins with either LiNEt2 or LiNiPr2 into Z-cinnamamides, thus generating a directing group in situ and allowing, by conformational freedom, a lateral directed remote metalation for ring closure to give the aryl 2-naphthols in good to excellent yields. These transformations can be combined to provide a more efficient one-pot process. Mechanistic insight into the remote lateral metalation step, demonstrating the requirement of Z-cinnamamide, is described. Application of this methodology to the synthesis of highly substituted 3,3'-diaryl BINOL ligands is also reported.

Directed Ortho and Remote Metalation of Naphthalene 1,8-Diamide: Complementing SEAr Reactivity for the Synthesis of Substituted Naphthalenes.

Mono- and dianion species of 1,8-naphthalene diamide 2 were generated under sec-BuLi/TMEDA conditions and trapped with a variety of electrophiles to give 2- and 2,7- substituted products 3 and 4. Using Suzuki-Miyaura cross-coupling, mono- and di-iodinated products were converted into the corresponding 2-aryl (5) and 2,7-diaryl (6) products, respectively. The amide-amide rotation barrier of 2 was established by VT NMR, and the structure of fluorenone structure 9, obtained by remote metalation, was secured.

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.

Measuring patient satisfaction in the pharmacy specialty immunization clinic: a pharmacist-run Immunization Clinic at the Veterans Affairs San Diego Healthcare System.

OBJECTIVE: The aim was to measure patient satisfaction with the Pharmacy Specialty Immunization Clinic (PSIC), a pharmacist-run vaccination clinic. METHODS: Patient satisfaction was measured using a non-validated instrument containing 10 items with a five-point Likert scale (strongly agree, agree, not sure, disagree and strongly disagree). Patients who were seen at the PSIC and who received at least one vaccination were eligible to take part in the patient satisfaction survey. Priority index, a method used to identify areas where limited resources can be used to maximize patient satisfaction, was calculated for the different items of the instrument to determine areas for quality improvement. This study was conducted at the Veterans Affairs San Diego Healthcare System (VASDHS). KEY FINDINGS: A total of 188 (55.1%) out of 341 patients who received at least one vaccine in the PSIC completed the survey. Prior to any encounter with the PSIC, patients perceived that the VASDHS was doing a good job providing vaccinations (92.5% answered agree or strongly agree). This perception continued when asked about overall satisfaction after receiving vaccination through the PSIC (86.9% answered agree or strongly agree). When asked about the time the pharmacist spent with the patient, nearly all answered that the pharmacist spent as much time as necessary (97.8% answered agree or strongly agree). Patient satisfaction with pharmacist counselling was equally well received and reflected good communication between patient and pharmacist (97.8% answered agree or strongly agree). In regard to pharmacist competency, 98.9% (n = 184) of patients agreed that pharmacists in the PSIC administered vaccinations appropriately. Priority index identified access to the vaccine as an area where performance-improvement efforts should be committed to improve patient satisfaction. CONCLUSIONS: Patients perceived good overall satisfaction with the pharmacist-run immunization clinic in terms of professionalism and access to vaccination. Priority index identified access to vaccination as a focus for future quality improvement.

The Tetraethylphosphorodiamidate (OP(O)(NEt2)2) Directed Metalation Group (DMG). Directed ortho and Lateral Metalation and the Phospha Anionic Fries Rearrangement.

We report on the tetraethylphosphorodiamidate (-OP(O)(NEt2)2) group as an effective directed metalation group (DMG). Lithiation-electrophile quench of 1 provides a general synthesis of ortho-substituted aryl and naphthyl phosphorodiamidates 4-8. We also describe the phospha anionic ortho-Fries (AoF) rearrangement of the phosphorodiamidates 1a,1b → 2 or 3 and its vinylogous counterpart to the ortho-tolyl phosphorodiamidates 5b → 13. Intermolecular competition experiments demonstrate the approximately equal DMG strength of the -OP(O)(NEt2)2 and the most powerful OCONEt2 groups.

Tetraethylphosphorodiamidate-Directed Metalation Group: Directed Ortho and Remote Metalation, Cross Coupling, and Remote Phospha Anionic Fries Rearrangement Reactions.

The linked directed ortho and remote metalation (DoM and DreM) and cross-coupling reactions of aryl phosphorodiamidates (Ar-OP(O)(NEt2)2) is reported. The o-iodo and o-boronato aryl tetraethylphosphorodiamidates 3, prepared by DoM, undergo orthogonal Ni- and Pd-catalyzed Suzuki-Miyaura cross coupling to furnish biaryls 4 and 5 in good to excellent yields. Silicon group protection of biaryl 4 via DoM followed by previously unobserved DreM phospha anionic Fries rearrangement affords biaryls 11 which, under acidic conditions, furnish oxaphosphorine oxides 12.

Asymmetric lithiation-substitution of amines involving rearrangement of borates.

Asymmetric lithiation of substituted benzylamines, N-Boc-pyrrolidine, or N-Boc-indoline using Beak's methodology was followed by electrophilic quench with trialkylboranes. The resulting borate intermediates rearrange with concomitant C-N bond breakage to give, after oxidation, chiral secondary alcohols with high enantioselectivity.

Dynamic resolution of N-Boc-2-lithiopiperidine.

Dynamic thermodynamic resolution of N-Boc-2-lithiopiperidine is possible using a chiral ligand; the two enantiomers of this organolithium can be resolved with selectivities of up to 85 : 15 from a selection of 26 chiral diamino-alkoxide ligands screened.

Dynamic kinetic and kinetic resolution of N-Boc-2-lithiopiperidine.

Asymmetric substitution of 2-lithiopiperidines can be achieved by dynamic resolution; the organolithium is formed as a racemic mixture by proton abstraction (or tin-lithium exchange) and is resolved in the presence of a chiral ligand.

Dynamic kinetic resolution of N-Boc-2-lithiopyrrolidine.

Asymmetric substitution of the organolithium derived either from N-Boc-2-tributylstannylpyrrolidine by tin-lithium exchange or from N-Boc-pyrrolidine by deprotonation occurs in the presence of a commercially available chiral diamine ligand with high levels of enantioselectivity by a dynamic kinetic resolution pathway.

Cost-utility analysis of bevacizumab versus ranibizumab in neovascular age-related macular degeneration using a Markov model.

OBJECTIVE: To evaluate the cost-effectiveness of intravitreal bevacizumab to ranibizumab in patients with neovascular age-related macular degeneration (AMD). METHODS: A cost-utility analysis using a Markov model was performed to evaluate incremental cost-effectiveness ratio [ICER, $US per quality-adjusted life year (QALY) gained] between bevacizumab and ranibizumab from a US payer perspective. Transition probabilities for ranibizumab and bevacizumab were extrapolated from published studies and local institutional data. Utility values, likewise, were obtained from another published study. Mortality rates were determined from the Centers for Disease Control 2003 Life Tables. Resource utilization and total direct costs were estimated using the Centers for Medicare and Medicaid Services and the Veterans Affairs Decision Support System. A hypothetical cohort of 1000 patients was simulated through the model for 20 years. Sensitivity analyses were performed using univariate and probabilistic sensitivity analysis (PSA) on all costs, transition probabilities and utility values. An acceptability curve was generated to illustrate the cost-effectiveness probability of bevacizumab to ranibizumab with increasing willingness-to-pay (WTP). RESULTS: The cost-effectiveness ratios (CER) for bevacizumab and ranibizumab were $1405 per QALY and $12,177 per QALY, respectively. The ICER for bevacizumab was dominant compared to ranibizumab. The base-case CER was sensitive to drug costs of the study medications with a breakeven point of $44 for ranibizumab and $2666 for bevacizumab. PSA revealed a 95% probability of bevacizumab being more cost-effective than ranibizumab at a WTP of $50,000 per QALY gained. CONCLUSION: Based on a WTP defined at $50,000 per QALY gained, bevacizumab was cost-effective versus ranibizumab 95% of the time because of lower acquisition costs and increased efficacy.

Dynamic thermodynamic and dynamic kinetic resolution of 2-lithiopyrrolidines.

Dynamic resolution has been studied as a method for the asymmetric synthesis of 2-substituted pyrrolidines. Highly enantioselective electrophilic substitutions of racemic 2-lithiopyrrolidines in the presence of a chiral ligand have been achieved. The organolithium compounds were prepared by tin-lithium exchange from the corresponding tributylstannanes and n-butyllithium or by deprotonation of N-(tert-butyloxycarbonyl)pyrrolidine with sec-butyllithium. A range of N-substituents and chiral ligands were investigated for the dynamic resolution. Electrophilic quench of the resolved diastereomeric 2-lithiopyrrolidine-chiral ligand complexes provided the enantiomerically enriched 2-substituted pyrrolidines. With N-alkyl derivatives, the resolution occurs conveniently at (or just below) room temperature and either enantiomer of the product can be formed by appropriate choice of the chiral ligand. The asymmetric induction occurs as a result of a thermodynamic preference for one of the diastereomeric complexes. The minor complex was found to have a faster rate of reaction with the electrophile. The use of N-allylic derivatives provides a means to prepare the N-unsubstituted pyrrolidine products. Best results were obtained with the N-2,3-dimethylbut-2-enyl derivative, and this N-substituent could be cleaved using 1-chloroethyl chloroformate. With N-Boc-2-lithiopyrrolidine, the enantioselectivity arises by a kinetic resolution and high levels of asymmetric induction in the presence of excess n-butyllithium can be obtained. Dynamic kinetic resolution of the N-Boc derivative is limited in the scope of electrophile that can be used.