Whole-cell biooxidation of bromobenzene with Pseudomonas putida 39D or the recombinant Escherichia coli JM109 (pDTG601) yields (1S,2S)-3-bromocyclohexa-3,5-diene-1,2-diol (9a), which is protected as the acetonide and converted to vinylaziridines 7, 15a, 63, and 64. Our route to (+)-pancratistatin features the coupling of a higher order cyanocuprate (derived by ortho-metalation from N,N-dimethyl-2-[(tert-butyldimethylsilyl)oxy]-3,4-(methylenedioxy)benzamide) with aziridine 7 to generate 28, which contains the carbon framework of the title alkaloid. Functional group manipulations resulted in the preparation of epoxydiol 50, which was transformed in a unique fashion and under mild conditions (H2O/PhCO2Na) to (+)-pancratistatin, thus completing a concise synthesis of (+)-pancratistatin in 14 steps from bromobenzene (2% overall yield). To improve this first generation attempt, a new route was devised utilizing carbomethoxyaziridine 64 and its coupling to the cuprate of 3,4-(methylenedioxy)bromobenzene. The adduct was converted to (+)-7-deoxypancratistatin in a total of 11 steps from bromobenzene (3% overall yield), and the basis for further improvement toward a practical synthesis of pancratistatin-type alkaloids was formulated.

Protective variables for Coronavirus Disease 2019 (COVID-19) are unknown. “Trained immunity” of the populace as a result of Bacille Calmette–Guérin (BCG) vaccination policy implementation and coverage had been suggested to be one of the factors responsible for the differential impact of COVID-19 on different countries. Several trials are underway to evaluate the potential protective role of BCG vaccination in COVID-19. However, the lack of clarity on the use of appropriate controls concerning the measures of “trained immunity” or the heterologous cell-mediated immunity conferred by BCG vaccination has been a cause of concern leading to more confusion as exemplified by a recently concluded trial in Israel that failed to find any protective correlation with regard to BCG vaccination. Whereas, when we analyze the COVID-19 epidemiological data of European countries without any regard for BCG vaccination policy but with similar age distribution, comparable confounding variables, and the stage of the pandemic, the prevalence of tuberculin immunoreactivity—a measure of cell-mediated immunity persistence as a result of Mycobacterium spp. (including BCG vaccine) exposure of the populations—is found consistently negatively correlated with COVID-19 infections and mortality. We seek to draw attention toward the inclusion of controls for underlying “trained immunity” and heterologous cell-mediated immunity prevalence that may be preexisting or resulting from the intervention (e.g., BCG vaccine) in such trials to arrive at more dependable conclusions concerning potential benefit from them.

Protective variables for COVID-19 are unknown. ′Trained immunity′ of the populace as a result of BCG policy implementation and coverage had been suggested to be one of the factors responsible for the differential impact of COVID-19 on different countries. Several trials are underway to evaluate the potential protective role of BCG vaccination in COVID-19. However, the lack of clarity on the use of appropriate controls concerning ′trained immunity′ has been a cause of concern leading to more confusion as exemplified by a recently concluded trial in Israel that failed to find any correlation. Whereas, when we analyze the COVID-19 data of European countries without any mandatory BCG vaccination policy but with similar age distribution, comparable confounding variables, and the stage of the pandemic, the prevalence of Mycobacterium spp.(including BCG vaccine) exposure of the populations is consistently negatively correlated with COVID-19 infections per million population at all the time points evaluated [r(20): -0.5511 to -0.6338; p-value: 0.0118 to 0.0027]. The results indicate that the on-going and future studies evaluating the effect of BCG vaccination on COVID-19 outcomes should consider the inclusion of ′controls′ for underlying ′trained immunity′ prevalence or that resulting from the intervention (BCG vaccine) in such trials to arrive at more dependable conclusions.