Broadly Applicable Stereoselective Syntheses of Serrulatane, Amphilectane Diterpenes, and Their Diastereoisomeric Congeners Using Asymmetric Hydrovinylation for Absolute Stereochemical Control.

A stereogenic center, placed at an exocyclic location next to a chiral carbon in a ring to which it is attached, is a ubiquitous structural motif seen in many bioactive natural products, including di- and triterpenes and steroids. Installation of these centers has been a long-standing problem in organic chemistry. Few classes of compounds illustrate this problem better than serrulatanes and amphilectanes, which carry multiple methyl-bearing exocyclic chiral centers. Nickel-catalyzed asymmetric hydrovinylation (AHV) of vinylarenes and 1,3-dienes such as 1-vinylcycloalkenes provides an exceptionally facile way of introducing these chiral centers. This Article documents our efforts to demonstrate the generality of AHV to access not only the natural products but also their various diastereoisomeric derivatives. Key to success here is the availability of highly tunable phosphoramidite Ni(II) complexes useful for overcoming the inherent selectivity of the chiral intermediates. The yields for hydrovinylation (HV) reactions are excellent, and selectivities are in the range of 92-99% for the desired isomers. Discovery of novel, configurationally fluxional, yet sterically less demanding 2,2'-biphenol-derived phosphoramidite Ni complexes (fully characterized by X-ray) turned out to be critical for success in several HV reactions. We also report a less spectacular yet equally important role of solvents in a metal-ammonia reduction for the installation of a key benzylic chiral center. Starting with simple oxygenated styrene derivatives, we iteratively install the various exocyclic chiral centers present in typical serrulatane [e.g., a (+)- p-benzoquinone natural product, elisabethadione, nor-elisabethadione, helioporin D, a known advanced intermediate for the synthesis of colombiasin and elisapterosin] and amphilectane [e.g., A-F, G-J, and K,L pseudopterosins] derivatives. A concise table showing various synthetic approaches to these molecules is included in the Supporting Information. Our attempts to synthesize a hitherto elusive target, elisabethin A, led to a stereoselective, biomimetic route to pseudopterosin A-F aglycones.

Effect of high-frequency chest wall oscillation on the central and peripheral distribution of aerosolized diethylene triamine penta-acetic acid as compared to standard chest physiotherapy in cystic fibrosis.

BACKGROUND AND OBJECTIVES: High-frequency chest wall oscillation (HFCWO) has been shown to be as effective as standard chest physiotherapy (SCPT) for removal of pulmonary secretions as well as increasing FEV(1) in cystic fibrosis (CF) patients. Patients using HFCWO often administer aerosolized medications simultaneously, reducing time required for daily care. While peripheral pulmonary distribution of tracer in normal subjects has been shown to be unaffected by HFCWO, this has not been studied in CF patients. We evaluated distribution of aerosolized (99m)Tc diethylene triamine penta-acetic acid (DTPA) administered simultaneously with HFCWO and compared this with DTPA aerosolized after SCPT. STUDY DESIGN: Ten CF patients, ages 22 to 38 years, with moderate-to-severe obstructive disease were studied in a crossover design after documentation of stable lung function. (133)Xe was administered to delineate total lung volume. DTPA was aerosolized (Pari LC Plus nebulizer and Pulmo-Aide compressor; Pari Respiratory Equipment Inc.; Richmond, VA) to delineate airway deposition. The central to peripheral deposition ratio (C/P ratio) of each lung was analyzed in each study group. Central regions were represented by the inner one third of the (133)Xe scan as demonstrated in previous research models. RESULTS: The mean C/P ratio (+/- SD) for both lungs was 1.45 +/- 0.31 with HFCWO and 1.46 +/- 0.28 following SCPT (p = not significant [NS]). Right lung mean C/P ratio was 1.74 +/- 0.43 with HFCWO and 1.85 +/- 0.63 after SCPT (p = NS). Left lung mean C/P ratio was 1.25 +/- 0.29 with HFCWO and 1.21 +/- 0.35 after SCPT (p = NS). There was no correlation between C/P ratio and FEV(1) or FVC. CONCLUSIONS: Use of HFCWO in combination with aerosolized DTPA did not result in increased central deposition as compared with aerosolized DTPA administered after SCPT. Further study is required to determine if combining HFCWO with aerosolized medications can be modified to improve peripheral deposition.