A practical and scalable synthesis of several base modified 3'-O-methyl ribonucleosides.

An easy and efficient large-scale synthesis of 1, 2,-di-O-acetyl-5-O-benzoyl-3-O-methyl-d-ribofuranose (8) was accomplished from commercial 1,2:5,6-di-O-isopropylidene-α-d-allofuranose in 7-steps and 30 % overall yield. The utility of protected 8 was demonstrated via synthesis of 9-(3'-O-methyl-ß-d-ribofuranosyl)-6-chloropurine (21) and six other nucleoside analogues in good yields. A library of five novel base modified nucleosides were generated starting from purine nucleoside 21 via functional group manipulations. The 3'-O-modified nucleosides are known to act as chain terminator exerting antiviral activity. The synthesis strategy described herein offers direct access to 3'-O-alkylated nucleosides with wide range of applications, including cap analogues for mRNA vaccine production. This protocol provides a route to exclusive synthesis of 3'-O-alkylated nucleosides, devoid of isomeric 2'-O-alkylated products essential for both therapeutic and biological research.

An Improved Scalable Synthesis of the Potent Antiviral (S)-HPMPA.

We present an improved synthesis of (S)-HPMPA (1) from an easily accessible and commercially available compound, (S)-3-(benzyloxy)propane-1,2-diol (10). Tritylation of primary alcohol 10 was highly selective, and pure product was isolated in good yield. Alkylation of (R)-1-(benzyloxy)-3-(trityloxy)propan-2-ol (11) with diethyl p-toluenesulfonyloxymethyl phosphonate (6) using sodium hydride in tetrahydrofuran followed by detritylation afforded the desired chiral synthon 12. Tosylation of the primary alcohol and subsequent reaction with sodium adeninate afforded protected S-HPMPA (14). Global deprotection using concentrated hydrochloric acid in a sealed tube afforded S-HPMA (1), and the deprotected 1 was crystallized from water and acetone to obtain a 99% pure product. © 2022 Wiley Periodicals LLC. Basic Protocol 1: Preparation of (R)-1-(benzyloxy)-3-(trityloxy)propan-2-ol (11) Basic Protocol 2: Preparation of diethyl (S)-(((1-(benzyloxy)-3-hydroxypropan-2-yl)oxy)methyl)phosphonate (12) Basic Protocol 3: Preparation of (R)-3-(benzyloxy)-2-((diethoxyphosphoryl)methoxy)propyl-4-methylbenzenesulfonate (13) Basic Protocol 4: Preparation of diethyl (S)-(((1-(6-amino-9H-purin-9-yl)-3-(benzyloxy)propan-2-yl)oxy)methyl)phosphonate (14) Support Protocol 1: Preparation of sodium adeninate Basic Protocol 5: Preparation of (S)-(((1-(6-amino-9H-purin-9-yl)-3-hydroxypropan-2-yl)oxy)methyl)phosphonic acid (1).

An efficient synthesis tetrazole and oxadiazole analogues of novel 2'-deoxy-C-nucleosides and their antitumor activity.

Various tetrazole and oxadiazole C-nucleoside analogues were synthesized starting from pure α- or ß-glycosyl-cyanide. The synthesis of glycosyl-cyanide as key precursor was optimized on gram-scale to furnish crystalline starting material for the assembly of C-nucleosides. Oxadizole C-nucleosides were synthesized via two independent routes. First,  the glycosyl-cyanide was converted into an amidoxime which upon ring closure offered an alternative pathway for the assembly of 1,2,4-oxadizoles in an efficient manner. Second, both anomers of glycosyl-cyanide were transformed into tetrazole nucleosides followed by acylative rearrangement to furnish 1,3,4-oxadiazoles in high yields. These protocols offer an easy access to otherwise difficult to synthesize C-nucleosides in good yield and protecting group compatibility. These C-nucleosides were evaluated for their antitumor activity. This work paves a path for facile assembly of library of new chemical entities useful for drug discovery.

Copper(II)nitrate catalyzed regioselective protection of primary alcohols with 4,4'-dimethoxytrityl and 2,7-dimethyl-9-phenyl xanthen-9-yl groups in nucleosides and carbohydrates.

Regioselective protection of primary hydroxyl group in nucleoside and carbohydrate analogs was accomplished using dimethoxytrityl alcohol (DMTr-OH) or dimethylpixyl alcohol (DMPx-OH) in presence of copper(II)nitrate as a Lewis acid catalyst. Excellent selectivity was observed for the protection of primary hydroxyl group over secondary while glycosidic bond remain unaffected. Utility of this methodology was further exemplified via DMTr- and DMPx-protection of alipahtic acyclic and cyclic diols.

Palladium mediated intramolecular multiple C-X/C-H cross coupling and C-H activation: synthesis of carbazole alkaloids calothrixin B and murrayaquinone A.

Straightforward palladium mediated syntheses of calothrixin B and murrayaquinone A are described. Regioselective palladium mediated intramolecular multiple C-X/C-H cross coupling reaction on N-(4-((2-bromophenyl)amino)-2,5-dimethoxybenzyl)-N-(2-iodophenyl)acetamide followed by CAN oxidation afforded calothrixin B in excellent yield in two steps. A linear synthesis has also been developed for calothrixin B. Utilizing C-H functionalization as well as palladium mediated intramolecular C-X/C-H cross coupling reaction, murrayaquinone A synthesis was achieved. Overall, these synthetic methodologies provide an expedient entry to these biologically active alkaloids in a short reaction sequence.

Total synthesis of pactamycin and pactamycate: a detailed account.

This article describes synthetic studies that culminated in the first total synthesis of pactamycin and pactamycate and, in parallel, the two known congeners, de-6-MSA-pactamycin and de-6-MSA-pactamycate, lacking the 6-methylsalicylyl moiety. Starting with L-threonine as a chiron, a series of stereocontrolled condensations led to a key cyclopentenone harboring a spirocyclic oxazoline. A series of systematic functionalizations led initially to the incorrect cyclopentanone epoxide, which was "inverted" under solvolytic conditions. Installation of the remaining groups and manipulation of the oxazoline eventually led to pactamycin, pactamycate, and their desalicylyl analogues.

Convenient route to both enantiomers of a highly functionalized trans-disubstituted cyclopentene. Synthesis of the carbocyclic core of the nucleoside BCA.

[structures: see text] Synthesis of both enantiomers of a highly functionalized cyclopentenol derivative, versatile building block for a vast array of biologically active compounds, is described. The key steps involve stereocontrolled synthesis of a diene with two syn-disposed substituents from a (R)-(+)-glyceraldehyde derivative, ring-closing metathesis of this diene, and functional group manipulation of the resulting trans-disubstituted cyclopentene. One of the enantiomers of the cyclopentenol thus obtained has been converted to an amino cyclopentene, the carbocyclic core of the nucleoside (-)-BCA, a potent inhibitor of HIV reverse transcriptase.

Intramolecular [2 + 2] photocycloaddition of alkenes incorporated in a carbohydrate template. Synthesis of enantiopure bicyclo[3.2.0]heptanes and -[6.3.0]undecanes.

Intramolecular [2 + 2] photocycloaddition of alkenes with a furano sugar placed between them have been investigated under both copper(I)-catalyzed and sensitized conditions. The copper(I)-catalyzed photocycloaddition of the dienes 4a, 4b, and 4c led to unexpected formation of the thermodynamically less stable cis-syn-cis 4-5-5 tricyclic adducts 5a, 5b, and 5c, respectively. The sensitized photocycloaddition of the diene 14 also gave the cis-syn-cis adduct 15 showing that the copper(I) catalyst does not have any influence on the stereochemical course through coordination with the anomeric ring oxygen of the furano sugar. The identical stereochemical course observed under both catalyzed and sensitized photoaddition reactions have been attributed to be of steric origin. Bis(dienes) 25a and 25b, which gave an intractable mixture on copper(I)-catalyzed irradiation, underwent smooth photocycloaddition in the presence of benzophenone, and the resulting 1,2-divinyl cyclobutanes underwent spontaneous [3.3]-rearrangement at room temperature to produce bicyclo[6.3.0]undecanes 30a and 30b, respectively. This investigation provides an approach for the construction of enantiopure bicyclo[3.2.0]heptanes and -[6.3.0]undecanes.

Splenunculus masquerading as colonic malignancy.

A 60-year-old woman presented with a hard lump of 5 x 3 cm in the left hypochondrium of 4 months duration. Clinical evaluation and investigations pointed towards a probably malignant colonic growth near the splenic flexure. She underwent an exploratory laparotomy with resection of the lump with the associated colon. Histopathology proved it to be a splenunculus. The rarity of such a case is highlighted and the diagnostic challenge it poses is discussed.