Conversion of Phorbol into Des-D-Ring Tricycle and Crotonianoid B via Peroxidation Reaction.

Phorbol (1) has a tetracyclic ABCD-ring and is readily isolable from a natural source. We previously synthesized 1 and 16 structurally related natural products using common ABC-ring intermediate 2. Here we report a new synthetic route to 2 using 1 as a starting material. Key features of the synthesis are chemoselective removal of the D-ring via cyclopropane opening, peroxidation, and retro-aldol reactions. The high utility of the peroxidation was further demonstrated in the first synthesis of crotonianoid B (9).

Total Syntheses of Phorbol and 11 Tigliane Diterpenoids and Their Evaluation as HIV Latency-Reversing Agents.

Tigliane diterpenoids possess exceptionally complex structures comprising common 5/7/6/3-membered ABCD-rings and disparate oxygen functionalities. While tiglianes display a wide range of biological activities, compounds with HIV latency-reversing activity can eliminate viral reservoirs, thereby serving as promising leads for new anti-HIV agents. Herein, we report collective total syntheses of phorbol (13) and 11 tiglianes 14-24 with various acylation patterns and oxidation states, and their evaluation as HIV latency-reversing agents. The syntheses were strategically divided into five stages to increase the structural complexity. First, our previously established sequence enabled the expeditious preparation of ABC-tricycle 9 in 15 steps. Second, hydroxylation of 9 and ring-contractive D-ring formation furnished phorbol (13). Third, site-selective attachment of two acyl groups to 13 produced four phorbol diesters 14-17. Fourth, the oxygen functionalities were regio- and stereoselectively installed to yield five tiglianes 18-22. Fifth, further oxidation to the most densely oxygenated acerifolin A (23) and tigilanol tiglate (24) was realized through organizing a 3D shape of the B-ring. Assessment of the HIV latency-reversing activities of the 12 tiglianes revealed seven tiglianes (14-17 and 22-24) with 20- to 300-fold improved efficacy compared with prostratin (12), a representative latency-reversing agent. Therefore, the robust synthetic routes to a variety of tiglianes with promising activities devised in this study provide opportunities for advancing HIV eradication strategies.

Unified Total Syntheses of Rhamnofolane, Tigliane, and Daphnane Diterpenoids.

Rhamnofolane, tigliane, and daphnane diterpenoids are structurally complex natural products with multiple oxygen functionalities, making them synthetically challenging. While these diterpenoids share a 5/7/6-trans-fused ring system (ABC-ring), the three-carbon substitutions at the C13- and C14-positions on the C-ring and appending oxygen functional groups differ among them, accounting for the disparate biological activities of these natural products. Here, we developed a new, unified strategy for expeditious total syntheses of five representative members of these three families, crotophorbolone (1), langduin A (2), prostratin (3), resiniferatoxin (4), and tinyatoxin (5). Retrosynthetically, 1-5 were simplified into their common ABC-ring 6 by detaching the three-carbon units and the oxygen-appended groups. Intermediate 6 with six stereocenters was assembled from four achiral fragments in 12 steps by integrating three powerful transformations, as follows: (i) asymmetric Diels-Alder reaction to induce formation of the C-ring; (ii) π-allyl Stille coupling reaction to set the trisubstituted E-olefin of the B-ring; and (iii) Eu(fod)3-promoted 7-endo cyclization of the B-ring via the generation of a bridgehead radical. Then 6 was diversified into 1-5 by selective installation of the different functional groups. Attachment of the C14-ß-isopropenyl and isopropyl groups led to 1 and 2, respectively, while oxidative acetoxylation and C13,14-ß-dimethylcyclopropane formation gave rise to 3. Finally, formation of an α-oriented caged orthoester by C13-stereochemical inversion and esterification with two different homovanillic acids delivered 4 and 5 with a C13-ß-isopropenyl group. This unified synthetic route to 1-5 required only 16-20 total steps, demonstrating the exceptional efficiency of the present strategy.

Coalescence Dynamics of Acoustically Levitated Droplets.

The contactless coalescence of a droplet is of paramount importance for physical and industrial applications. This paper describes a coalescence method to be used mid-air via acoustic levitation using an ultrasonic phased array system. Acoustic levitation using ultrasonic phased arrays provides promising lab-on-a-drop applications, such as transportation, coalescence, mixing, separation, evaporation, and extraction in a continuous operation. The mechanism of droplet coalescence in mid-air may be better understood by experimentally and numerically exploring the droplet dynamics immediately before the coalescence. In this study, water droplets were experimentally levitated, transported, and coalesced by controlled acoustic fields. We observed that the edges of droplets deformed and attracted each other immediately before the coalescence. Through image processing, the radii of curvature of the droplets were quantified and the pressure difference between the inside and outside a droplet was simulated to obtain the pressure and velocity information on the droplet's surface. The results revealed that the sound pressure acting on the droplet clearly decreased before the impact of the droplets. This pressure on the droplets was quantitatively analyzed from the experimental data. Our experimental and numerical results provide deeper physical insights into contactless droplet manipulation for futuristic lab-on-a-drop applications.

Acoustic Manipulation of Droplets under Reduced Gravity.

Contactless manipulation of matter is essential for studying physical phenomena. Acoustic manipulation of liquid samples using ultrasonic phased arrays provides a novel and attractive solution for mid-air manipulation, such as levitation, transportation, coalescence, mixing, separation, evaporation, and extraction, with a simple and single sequence. Despite the importance of gravity in droplet dynamics, its effect on a levitated droplet with an ultrasonic phased array remains unclear. To disseminate acoustic manipulation, better understanding of the fundamental physics of a droplet manipulated by ultrasonic phased arrays is required. Here, we show contactless levitation, transportation, and coalescence of multiple droplets under both ground and reduced gravity. Under ground gravity, the possible levitation size of the sample is limited to below the half wavelength of sound. Under reduced gravity, however, droplets that are larger than the limit can be successfully levitated, transported, and coalesced. Furthermore, the threshold of sound pressure for droplet levitation and manipulation could be minimised with the suppression of nonlinear acoustic phenomena under reduced gravity. These insights promote the development of contactless manipulation techniques of droplets for future space experiment and inhabitancy.

Contactless Fluid Manipulation in Air: Droplet Coalescence and Active Mixing by Acoustic Levitation.

Acoustic manipulation by an ultrasonic phased array provides an entirely new approach to processes such as coalescence, mixing, separation, and evaporation occurring in the generation of new materials, physical property measurement, the biomedical industry, etc. However, to date, ultrasonic phased arrays have not been fully investigated for applications in fluid manipulation. This paper provides contactless coalescence and mixing techniques for droplets in air by controlling the acoustic potential by using an ultrasonic phased array. We focused on mode oscillation to propose an efficient mixing technique for liquid without contact. A comparison of mixing performance between cases with mode oscillation and without mode oscillation showed that the flow induced by mode oscillation promotes droplet mixing. Our paper demonstrates the feasibility of contactless coalescence and mixing as a first step in fluid manipulation with a phased array.

Severe hyponatremia in a patient with schizophrenia associated with prolonged consciousness disturbance.

Hyponatremia presents with various central nervous system symptoms during its course and treatment. We treated a patient who presented with a prolonged consciousness disorder and was suspected of having complications of neuroleptic malignant syndrome and osmotic demyelination syndrome (ODS) during the treatment for his hyponatremia, which was caused by syndrome of inappropriate secretion of antidiuretic hormone (SIADH). The patient was a 30-year-old Japanese man who had been under treatment for schizophrenia. He presented with profound hyponatremia (96 mEq/L) and a consciousness disorder. Because he was taking a number of antipsychotic drugs and since psychogenic polydipsia was present along with laboratory findings, the patient was diagnosed with SIADH. However, the consciousness disorder reappeared after his serum sodium concentrations were normalized, and it persisted over a long period. Although ODS was suspected from the clinical course and imaging findings, there were several inconsistencies, such as the lack of quadriplegia. The patient also showed muscular rigidity and fever, and we, therefore, diagnosed complications of malignant hyperthermia syndrome caused by the discontinuation of all antipsychotic drugs at the time of onset. There have been no reports of complications of these two conditions, and we report this case for its clinically valuable information.