Enantiomerically pure chiral building blocks for syntheses of carbocyclic nucleoside analogues: A formal synthesis of aristeromycin

Abstract

Key Words: Antiviral agents / Aristeromycin / Cyclaradine / (+)-( 1 R,4R)-5-Norbornen-2-one / 2-Norbornanones, 5,6-dihydroxy- (?) was prepared in 78.5% yield by oxidative degradation of (+)-(1R)-endobicyclo[2.2.l]hept-5-ene-2-carboxylic acid (4) by using an improved procedure for the oxidation of the dianion of 4 with dioxygen. Dihydroxylation of 7 with osmium tetroxide furnished the cis exo addition product 8c and, via reversible retro aldol reaction, the trans isomer 8 t which was characterized by X-ray crystal structure analysis. 8c was transformed in four reaction steps into the lactone 2 which is a known starting material for a synthesis of the antiviral antibiotic aristeromycin (1). 8 t is a potential starting material for syntheses of carbocyclic analogues of arabinofuranosyl nucleotides, e. g., the antiviral agent cyclaradine (3). able for a synthesis of the antiviral agent cyclaradine (3)L41 was also obtained. (+)-(lR,4R)-Bicyclo[2.2.1]hept-5-en-2-one (-) -Aristeromycin(+)-( 1R)-endo-5-Norbornene-2-carboxylic acid (4), prepared via asymmetric Diels-Alder yields (+)-(lR)-5-norbornen-2-one (7) via a simple three-step sequence (Scheme 1) involving as a key step the oxidation of the dianion of 4 with dioxygen at low temperature in the presence of triethyl phosphite to give a mixture of diastereomeric a-hydroxy carboxylic acids 5. Several procedures have been published for effecting this Initially we experienced difficulties and, therefore, we explored several published procedures and variants of our own (cf Table 1). Excellent, reproducable results were obtained under the conditions given under entry 5 in Table 1. The subsequent steps to (+)-7 via 6 were carried out as described by Paquette[6b]. Because of the extreme volatility of (+)-7 we used a simple low temperature high vacuum condensation technique to remove the solvent and for purification. The value of the optical rotation of the bicyclic ketone (+)-7 was in excellent agreement with values reported in the literature (cf. Experimental).Our synthetic plan called for cis-dihydroxylation of the double bond of 7 and subsequent oxidative cleavage of the C2-C3 bond. To our surprise, reaction of 7 with osmium tetroxidelN-methylmorpholine N-oxide['] gave mainly the trans-diol 8t (ratio 8 t : 8 c ca. 4: 1). The constitution of the reaction products was deduced from the 'H and I3C NMR spectra. However, spectroscopy did not allow unambiguous assignment of the relative configurations. The cis-ex0 configuration of 8 c has been confirmed by the synthesis of

Synthesis of 2-Substituted (±)-(2R,3R,5R)-Tetrahydrofuran-3,5-dicarboxylic Acid Derivatives

“…We initially sought to follow the exact reaction sequence of Auberson and Vogel . Accordingly, ketone 9 was converted to the enol silyl ether 10 according to literature procedure . Treatment of 10 with Br 2 in CH 2 Cl 2 gave the desired α-bromo ketone 11 .…”

“…( ± )-2-[Dimethyl( tert -butyl)siloxy]-5,6- exo,exo -(isopropylidenedioxy)bicyclo[2.2.1]heptan-2-e ne (10). Compound 10 was prepared according to the literature procedure …”

2-Chlorobicyclo[2.2.1]hept-5-ene-2-carboxamide and 2-chlorobicyclo[2.2.1]heptane-2-carboxamide as precursors of bicyclo[2.2.1]hept-5-en-2-one and bicyclo[2.2.1]heptan-2-one: resolution, absolute configuration and hydrogen-bonding properties

“…In a previous work, compound (+)-2 had been prepared from endo-(+)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid via a four-step procedure. 18,31 The maximal rotations for endo-and exo-bicyclo[2.2.1]hept-5-ene-2-carboxylic acids and their saturated congeners have been determined, and the configuration has been correlated among these four compounds and their methyl esters. 32 The configuration of (À)-exo-bicyclo[2.2.1]heptane-2-carboxylic acid was correlated with (À)-exo-2-acetyl bicyclo[2.2.1]heptane.…”

“…For example, the motif occurs in complex natural products such as dolabellane, 1 echinosporin 2 and the sesquiterpene pheromone from a stink bug, 3 as well as in synthetic materials, such as norbornyl-containing peptides where the norbornane group templates the folding of the peptide in a well-defined manner. 4 Bicyclo[2.2.1]heptan-2-one (norcamphor) 1, bicyclo[2.2.1]-hept-5-en-2-one (5,6-dehydronorcamphor) 2 and their substituted analogues have been used as starting points or key intermediates for the synthesis of many chiral compounds with highly substituted cyclopentyl moieties, such as prostaglandins, 5-9 some terpenes, 10-12 some iridoids, 13,14 methyl epi-jasmonate, 15 11-fluorojasmonate, 16 carbocyclic sugars, 17,18 and cyclopentane-containing polymers. 19 We intend to use the framework of bicyclo[2.2.1]hept-5-en-2-one 2 as a starting point for the synthesis of conformationally constrained pheromone analogues.…”

Stereospecific Synthesis of Carbanucleotides Designed for Antisense Methodology.

“…Finally, diol 19 was transformed into optically pure (e.e. > 97%) ()-norbornenone 1 by oxidation with sodium periodate following the procedure described by Helmchen and co-workers [19].…”