The chiral and stereoselective synthesis of (+)-lactacystin 1, the first non-protein neurotrophic factor, is described; the y-lactam portion possessing a quaternary carbon in 1 was constructed stereoselectively from D-glucose using the allylic trichloroacetimidate rearrangement (Overman rearrangement) as the key reaction.Lactacystin 1 is a novel amino acid derivative isolated from the culture broth of Streptomycesl and reported to inhibit cell proliferation and induce neurite outgrowth in the mouse neuroblastoma cell line Neuro 2A.1 Such interesting neurotrophic activity as well as its unique structure2 attracted synthetic interest and three elegant total syntheses of 1, all employing amino acids as the starting material, have been reported to date.3 Recently, reports on the synthesis4 and the structure-activity relationship study5 of analogues of 1 have appeared. The structural feature of 1 is the presence of a highly functionalized y-lactam with four contiguous chiral centres including a quaternary carbon. For construction of the quaternary carbon, previous successful syntheses adopted Seebach's protocol6 using oxazolidine3" and oxazoline3b derivatives, and the aldol reaction of the bicyclic siloxypyrrole.3~ Here we report an alternative approach to 1, which involves the stereoselective generation of the quaternary carbon by the rearrangement of the allylic trichloroacetimidate (Overman rearrangement),7.8 starting from D-glucose.The known 3-deoxy-l,2-0-isopropylidene-3-C-methyl-a-~-allofuranose 2,9 prepared from diacetone-D-glucose in four steps, was chosen as the starting material. Reaction of 2 with dibutyltin oxide10 followed by treatment with benzyl bromide afforded 3 in 66% yield. Jones oxidation of 3 gave 4, which was subjected to a Wittig reaction to give alkene 5 as an inseparable mixture of (E)-and (a-isomers (1 : 1) in 78% yield from 3. Reduction of the ester function in 5 with DIBAL-H gave 6, the substrate for the Overman rearrangement7 [(E) : (Z) = 1 : 11, in 90% yield. Allylic alcohol 6 was converted into trichloroacetimidate 7, which, without isolation, was heated in toluene at 150 "C (in a sealed tube) for 89 h to provide the inseparable mixture of rearranged product 8 and its C(5) epimer in a ratio of 4.8 : 1 (determined by 270 MHz 1H NMR) in 60% yield from 6. Acid hydrolysis of the mixture followed by chromatographic separation afforded 9 in 72% isolated yield as an anomeric mixture (6 : 1). Periodate oxidation of 9 provided hemiaminal derivative 10. Jones oxidation of 10 gave the corresponding lactam, whose protecting (N-trichloroacetyl and 0-formyl) groups were cleanly removed by treatment with N a B b to furnish the y-lactam 11 in 75% yield from 9. The observed NOE in 11 clearly supported the assigned structure, revealing that the newly formed stereocentre at C(3) should be R (Scheme 1).Silylation of the hydroxy group in 11 followed by removal of the 0-benzyl group gave 12 in 74% yield (Scheme 2). Moffatt oxidation of 12 afforded 13, which, without isolation, was treated with isopropylmagnes...
Mass vaccination is the most important strategy to terminate the coronavirus disease 2019 (COVID-19) pandemic. Reports suggest the potential risk of the development of new-onset or relapse of minimal change disease (MCD) following COVID-19 vaccination; however, details on vaccine-associated MCD remain unclear. A 43-year-old man with MCD, who had been in remission for 29 years, developed nephrotic syndrome 4 days after receiving the third dose of the Pfizer-BioNTech vaccine. His kidney biopsy revealed relapsing MCD. Intravenous methylprednisolone pulse therapy followed by oral prednisolone therapy was administered, and his proteinuria resolved within 3 weeks. This report highlights the importance of careful monitoring of proteinuria after COVID-19 vaccination in patients with MCD, even if the disease is stable and no adverse events occurred during previous vaccinations. Our case report and literature review of COVID-19 vaccine-associated MCD indicated that MCD relapse tends to occur later after vaccination and slightly more often following the second and subsequent vaccine doses than new-onset MCD.
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