Tricyclanos: conformationally constrained nucleoside analogues with a new heterotricycle obtained from a d-ribofuranose unit

Abstract

A novel type of nucleoside analogue in which the sugar part is replaced by a new tricycle, 3,7,10-trioxa-11-azatricyclo[5.3.1.0]undecane has been prepared by substrate-controlled asymmetric synthesis. 1,5-Dialdehydes obtained from properly protected or unprotected uridine, ribothymidine, cytidine, inosine, adenosine and guanosine by metaperiodate oxidation reacted readily with tris(hydroxymethyl)aminomethane to provide the corresponding tricyclic derivatives with three new stereogenic centers. Through a double cyclisation cascade process the tricyclic compounds were obtained in good to high yields, with very high diastereoselectivity. Formation of one stereoisomer, out of the eight possible, was observed in all cases. The absolute configuration of the new stereotriad-containing tricyclic systems was aided by conventional NMR experiments followed by chemical shift calculations using an X-ray crystal structure as reference that was in good agreement with H-H distances obtained from a new ROESY NMR method. The synthesis was compatible with silyl, trityl and dimethoxytrityl protecting groups. A new reagent mixture containing ZnCl, EtSiH and hexafluoroisopropanol was developed for detritylation of the acid-sensitive tricyclano nucleosides.

Induction of New Lactam Derivatives From the Endophytic Fungus Aplosporella javeedii Through an OSMAC Approach

“…The absolute configuration of the γ-lactam ring of compound 2 is assumed to be identical to that of 1 based on biogenetic considerations whereas that of the OH group in the side chain at C-7 could not be elucidated. In order to solve this problem, DFT-NMR calculations were performed on the epimeric model compounds (3 R ,4 S ,5 S ,7 R )- 2mod and (3 R ,4 S ,5 S ,7 S )- 2mod ( Lodewyk et al, 2012 ; Kicsák et al, 2018 ; Mándi and Kurtán, 2019 ). B3LYP/6-31 + G(d,p) re-optimization of the initial 169 and 205 conformers resulted in 8 and 15 low-energy conformers over 1% Boltzmann population, respectively ( Supplementary Figures S93 , S94 ).…”

Recent Advances in the Chemical Synthesis and Evaluation of Anticancer Nucleoside Analogues

“…Azanucleosides were originally defined as nucleoside analogues where the furanosyl oxygen is replaced by nitrogen, however this group of analogues has been extended to include nucleosides where the resultant pyrrolidine core has been replaced by other nitrogen containing rings, including heterocycles, heterotricycles and acyclic nitrogen-containing nucleosides [16,17]. This class of compound have proven successful in the treatment of cancer [18] and have also been established as having antiviral and antibacterial properties [19].…”

Stereocontrolled Synthesis of Functionalized Azaheterocycles from Carbocycles through Oxidative Ring Opening/Reductive Ring Closing Protocols

“…Reductive aminations were accomplished directly with different amines including benzylamine at pH 5 (acidified with AcOH) in the presence of NaBH 3 CN as reducing agent. After purification, both diastereomeric morpholines were isolated in 22 % yield (Scheme ) . Herczegh and co‐workers applied the oxidative C−C cleavage/cyclization protocol to provide various so‐called “tricyclanos” regarded as conformationally constrained nucleoside analogues with a new heterotricycle …”

“…A number of methods was published for the synthesis of Nheterocycles by the application of ring closing of linear dialdehydes under reductive amination. [11,12,[49][50][51][52][53][54][55][56][57] Bols and co-workers developed a new method for the synthesis of substituted hydroxypiperidines. The synthetic process started from epoxide 35 affording hemiacetal 36 in a two-step transformation.…”