A two-step route to MK-4482 (EIDD-2801, 1) was developed consisting of an esterification and hydroxamination of cytidine. The selective acylation and direct amination eliminate the need for protecting and activating...
Molnupiravir (MK-4482,
EIDD-2801) is a promising orally bioavailable
drug candidate for the treatment of COVID-19. Herein, we describe
a supply-centered and chromatography-free synthesis of molnupiravir
from cytidine, consisting of two steps: a selective enzymatic acylation
followed by transamination to yield the final drug product. Both steps
have been successfully performed on a decagram scale: the first step
at 200 g and the second step at 80 g. Overall, molnupiravir has been
obtained in a 41% overall isolated yield compared to a maximum 17%
isolated yield in the patented route. This route provides many advantages
to the initial route described in the patent literature and would
decrease the cost of this pharmaceutical should it prove safe and
efficacious in ongoing clinical trials.
A semester-long research project for second-semester organic chemistry lab sections was developed. Student projects were based on preliminary data from faculty research that suggested the natural product neurolenin B to be a treatment for lymphatic filariasis. Students isolated neurolenins from the Central American plant Neurolaena lobata and proposed syntheses of previously unknown analogues using reactions learned in firstand second-semester organic chemistry. Using literature-based procedures, students ran reactions on neurolenins and analyzed their results by TLC and NMR spectroscopy. The semester culminated with a public poster session and final report using the Organic Letters template. Students in a total of 5 lab sections over 3 different semesters of the class completed this pilot course, and 15 sections in the same time span conducted traditional lab experiments. Qualitative and quantitative assessment data were collected to demonstrate the efficacy of the course. Students did not self-select into the pilot sections, were demographically similar to those in the traditional lab sections, and performed at the same level in the lecture portion of the course. Survey results from all students (traditional and pilot) were compared, and the students in the pilot sections showed higher levels of self-reported topic understanding, general motivation, and interest in organic chemistry.
Skipped polyenes featuring high (E)-selectivity and varying methyl substitution patterns are synthesized using a nickel-catalyzed cross-coupling reaction between allyl trifluoroacetates and vinyl bromides. The utility of this cross-electrophile coupling is showcased in part, by the synthesis of the RST fragment of the marine ladder polyether, maitotoxin. Construction of this fragment is particularly challenging due to the alternating methyl substitution pattern.
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