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Classic psychiatry patients are rare; real-world patients tend to have overlapping features of multiple disorders. Striving for diagnostic certainty, and treatments aimed at tentative diagnoses, often fail these patients. In such cases, tolerating diagnostic ambiguity and "treating the symptoms" can sometimes be transformative. An important symptom, often undertreated in a diagnosis-based approach, is rumination. We present a case study of a woman who, after 20 years of treatment failure, achieved significant symptom relief when her primary complaint-"labored thinking"-was targeted specifically. However, because no seriously ill person has only 1 symptom, 6 clinicians from different subdisciplines will discuss the patient's other issues, ones that an overfocus on rumination might leave out.

The design and synthesis of a new series of high efficacy β2-agonists devoid of the key benzylic alcohol present in previously described highly efficacious β2-agonists is reported. A hypothesis for the unprecedented level of efficacy is proposed based on considerations of β2-adrenoceptor crystal structure, other biophysical data and modeling studies.

A series of dibasic des-hydroxy β2 receptor agonists has been prepared and evaluated for potential as inhaled ultra-long acting bronchodilators. Determination of activities at the human β-adrenoreceptors demonstrated a series of highly potent and selective β2 receptor agonists that were progressed to further study in a guinea pig histamine-induced bronchoconstriction model. Following further assessment by; onset studies in guinea pig tracheal rings and human bronchial rings contracted with methacholine (guinea pigs) or carbachol (humans), duration of action studies in guinea pigs after intratracheal (i. t.) administration and further selectivity and safety profiling AZD3199 was shown to have an excellent over all profile and was progressed into clinical evaluation as a new ultra-long acting inhaled β2 receptor agonist with rapid onset of action.

The inclusion of a C-2 trialkylsilyl substituent into allylic amine precursors allows the base-induced aza-[2,3]-Wittig sigmatropic rearrangement to proceed in excellent yield and diastereoselectivity. The rearrangement precursors require a carbonyl-based nitrogen protecting group that must be stable to the excess of strong base required for the reaction. The N-Boc and N-benzoyl group are very good at stabilizing the product anion and initiating deprotonation. The migrating groups (G) need to stabilize the intial anion by resonance and require G-CH3 pKa > 22 in order for the initial anion to be reactive enough for rearrangement. Products 7, 20b−d,f,g, and 23 are formed with high (10−20:1) anti diastereoselectivity. Product 23 containing the morpholine amide group is useful for preparing other carbonyl derivatives.

The design and synthesis of a new series of high efficacy β(2)-agonists devoid of the key benzylic alcohol present in previously described highly efficacious β(2)-agonists is reported. A hypothesis for the unprecedented level of efficacy is proposed based on considerations of β(2)-adrenoceptor crystal structure, other biophysical data and modeling studies.

The first racemic synthesis of the non-proteinogenic amino acid (2S,3R,4R)-4-hydroxy-3-methylproline (1) has been achieved via iodolactonisation of an unnatural amino acid derivative 4. The relative stereochemistry was derived from an efficient silicon assisted aza-[2,3]-Wittig sigmatropic rearrangement of 2.

The mild and high yielding protodesilylation of C-2 trialkylsilyl terminal alkenes can be effected via a hydroboration–Peterson elimination protocol or, in the case of the phenyldimethylsilyl analogues, a one pot procedure using t-BuOK–18-C-6–TBAF can be used.

[reaction: see text] Benzylboranes are noticeably uncommon partners within Suzuki-Miyaura coupling reactions. B-Benzyl-9-BBN was successfully coupled to a range of aryl/heteroaryl bromides, chlorides, and triflates to give pharmacologically important methylene-linked biaryl structures. Activated, deactivated, and sterically hindered substrates were successfully coupled in high yield using Pd(PPh(3))(4) or Pd(OAc)(2) with SPhos as the catalyst system.

The first racemic synthesis of the non-proteinogenic amino acid (2S,3R,4R)-4-hydroxy-3-methylproline (1) has been achieved via iodolactonisation of an unnatural amino acid derivative 4. The relative stereochemistry was derived from an efficient silicon assisted aza-[2,3]-Wittig sigmatropic rearrangement of 2.

The inclusion of a C-2 trialkylsilyl substituent into allylic amine precursors allows the base-induced aza-[2,3]-Wittig sigmatropic rearrangement to proceed in excellent yield and diastereoselectivity. The rearrangement precursors require a carbonyl-based nitrogen protecting group that must be stable to the excess of strong base required for the reaction. The N-Boc and N-benzoyl group are very good at stabilizing the product anion and initiating deprotonation. The migrating groups (G) need to stabilize the intial anion by resonance and require G-CH3 pKa > 22 in order for the initial anion to be reactive enough for rearrangement. Products 7, 20b−d,f,g, and 23 are formed with high (10−20:1) anti diastereoselectivity. Product 23 containing the morpholine amide group is useful for preparing other carbonyl derivatives.

The mild and high yielding protodesilylation of C-2 trialkylsilyl terminal alkenes can be effected via a hydroboration–Peterson elimination protocol or, in the case of the phenyldimethylsilyl analogues, a one pot procedure using t-BuOK–18-C-6–TBAF can be used.