Morris J. Robins

2' And 3'-ketonucleosides and their arabino and xylo reduction products: Convenient access via selective protection and oxidation of ribonucleosides☆

Abstract A number of 2,5- or 3,5-diprotected ribonucleosides and 5-protected 2- or 3-deoxy-β-D-erythro-pentofuranosyl nucleosides have been oxidized to the corresponding 3 or 2-ketonucleoside derivatives using chromium trioxide/pyridine/acetic anhydride or dimethyl sulfoxide/ acetic anhydride. Reduction of the carbonyl functions with sodium borohydride gave the inverted arabino, xylo, or deoxy-threo isomers as predominant products by attack at the less hindered α-face of the sugar ring. Parallel reductions using sodium borodeuteride corroborated the epimeric ratios by demonstrating that complete oxidation of the original hydroxyl groups had occurred. The deuterium labeling also aided in making NMR spectral assignments.

Nucleic acid related compounds. 31. Smooth and efficient palladium-copper catalyzed coupling of terminal alkynes with 5-iodouracil nucleosides

Abstract Coupling of terminal alkynes with protected 5-iodouracil nucleosides in the presence of dichlorobis(triphenylphosphine)palladium and copper(I) iodide in triethylamine gives the corresponding 5-(alkyn-1-yl)uracil nucleosides in 72–92% yields.

A mild conversion of vicinal diols to alkenes. Efficient transformation of ribonucleosides into 2′-ene and 2t',3′-dideoxynucleosides

Abstract α-Acetoxyisobutyryl bromide in “moist” acetonitrile converted adenosine to trans -3′(2′)-bromo-2′(3′)-acetates with

Nucleic acid related compounds. II. A rapid and quantitative preparation of 2′-O- and 3′-O-methyl nucleosides

Abstract By the use of catalytic amounts of stannous chloride dihydrate, ribonucleosides are essentially quantitatively monomethylated at the 2′- and 3′-hydroxyl functions by diazomethane. These monomethyl nucleosides are readily separated on Dowex 1-X2 (OH−). Adenosine is preferentially methylated at the 3′-OH whereas cytidine undergoes predominantly 2′-OH methylation. Natural product 2′-O-methyl nucleosides are readily prepared and biochemical rationale for the preparation of analogs and results of biochemical and physical studies are discussed.

Nucleic acid related compounds. 43. A convenient procedure for the synthesis of 2′ and 3′-ketonucleosides

Abstract Chromium trioxide/pyridine/acetic anhydride effects smooth oxidation of selectively protected nucleosides to give high yields of 2′ or 3′-ketonucleosides, whose reduction provides the inverted nucleoside epimers.

Regiospecific and stereoselective conversion of ribonucleosides to 3′-deoxynucleosides. A high yield three-stage synthesis of cordycepin from adenosine.

Abstract Treatment of 2′,3′-anhydroadenosine (obtained2 in 92% yield from adenosine) with lithium triethylborohydride (or deuteride) gave cordycepin (or its 3′( R )-deuterio derivative) in ≈90% overall yields with no 2′-deoxy isomer detected.

Renal transport of 2′-deoxytubercidin in mice☆

Previous results [J. F. Kuttesch, Jr. and J. A. Nelson, Cancer Chemother, Pharmac. 8, 221 (1982)] from this laboratory indicate that mechanisms exist for renal secretion of 2-deoxyadenosine and possibly for reabsorption of adenosine in humans and in mice. Since significant metabolism of these purine nucleosides occurs even in the presence of adenosine deaminase inhibitors, the renal handling of a compound which is not significantly metabolized by the deaminase or by kinases was studied. Unlike 2-deoxyadenosine itself, the 2-deoxyadenosine analog, [4-amino-7-(2-deoxy-beta-D-erythro-pentofuranosyl)-pyrrolo-(2,3-d)pyrimidine; 2-deoxytubercidin], is not significantly metabolized by mammalian tissues. In mice, the renal plasma clearance of 2-deoxytubercidin exceeded that of inulin by about 3-fold. Also, mouse kidney slices concentratively accumulated 2-deoxytubercidin by a saturable and metabolically dependent process. The uptake by mouse kidney slices was inhibited by classical substrates for the organic cation secretory system (tetraethylammonium, choline and N1-methylnicotinamide) but was not markedly inhibited by classical substrates for the organic anion secretory system (p-aminohippurate, phenol red and probenecid). Since 2-deoxytubercidin inhibited the active, concentrative uptake of [14C]tetraethylammonium, but failed to inhibit the uptake of p-[14C]aminohippurate by mouse kidney slices, it is concluded that 2-deoxytubercidin may be secreted by the organic cation system. Additional studies are required, however, to unequivocally establish the relationships between 2-deoxytubercidin, 2-deoxyadenosine and tetraethylammonium renal secretory mechanisms.

High-yield synthesis of 3′-amino-3′-deoxynucleosides. Conversion of adenosine to 3′-amino-3′-deoxyadenosine

A 5′-O-silylated-2′,3′-anhydroadenosine derivative underwent epoxide opening smoothly with dimethylboron bromide. The N-benzyl carbamate derived from the trans bromohydrin was ring-closed with sodium hydride. Deprotection (fluoride, hydroxide, and hydrogenolysis) gave 3′-amino-3′-deoxyadenosine (6) in 66% yield from adenosine (9 steps).

Synthesis of Substituted-Benzyl and Sugar-Modified Analogues of 6-N-(4-Nitrobenzyl)adenosine and Their Interactions with “ES” Nucleoside Transport Systems

Abstract Four classes of 6-X-benzylated purine nucleosides, (i) 6-N-(substituted-benzyl)adenosines, (ii) 6-N-(4-nitrobenzyl)adenine nucleosides with modified sugars, (iii) 6-N(S)-(4-azidobenzyl) derivatives of adenosine, 6-thioinosine, and 6-thioguanosine, and (iv) 6-N-{4-N-[acyl(sulfonyl)amino]benzyl}adenosines, were synthesized and their binding interactions with “es-NT” ( e quilibrative, inhibitor-sensitive nucleoside transport) systems were studied. Several tight-binding analogues were found.

Nucleic acid related compounds. 20. Sugar, base doubly modified nucleosides at the 5′-terminal “cap” of mRNAs and in nuclear RNA

Abstract N 6, O 2′-Dimethyladenosine (III) has recently been reported to occur adjacent to the modified guanosine at the 5′-terminal “cap” of a number of mRNAs and in nuclear RNA. The possible presence of N 6, N 6, O 2′-trimethyladenosine (V) in adenovirus mRNA “caps” has been suggested on the basis of labeled methyl distribution between sugar and base fractions. Methylation of 2′- O -methyladenosine (I) gave N 1, O 2′-dimethyladenosine hydroiodide (II) which was rearranged to give III. Sugar methylation of 6-chloropurine riboside (IV) followed by replacement of chloro with dimethylamine gave V plus its O 3′-isomer (VI). Thin layer chromatography systems which cleanly resolve II, III, and V have been devised. Adenosine aminohydrolase (E.C. 3.5.4.4) deaminates III slowly, but has no effect on V. Identifying spectral data are tabulated.