Asymmetric synthesis via acetal templates. 15. The preparation of enantiomerically pure mevinolin analogs

An efficient asymmetric synthesis of the hydroxylactone moiety of mevinolin 1 is described. The key step is the TiCl₄-catalyzed coupling reaction of acetals 3a and 3b derived from (R)-1,3-butanediol with 1,3-bis(trimethylsilyloxy)-1-methoxybuta-1,3-diene 4 to give the δ-alkoxy-β-keto ester 5.     

Stereocontrolled synthesis of enantiomerically pure unsaturated analogues of 2,6-DAP. Part 5

An efficient new stereocontrolled synthesis of (2R,6R)-(+)- and (2S,6S)-(−)-2,6-diamino-4-methylene-1,7-heptanedioic acid 8a and 9a, respectively, has been accomplished starting from the glycine-derived chiral synthon 1. The enantiomerically pure α-alkyl derivatives 8b–d and 9b–d have also been synthesized. The absolute configuration of the new stereocenters was assigned on the basis of ¹H NMR spectra.     

Analogs of purine nucleosides. 4. 7-Alkylated 9-(2-hydeoxymethyl)guanine

7,9-Disubstituted guaninium hydrohalides were synthesized by the reaction of 9- and 7-(2-hydroxymethyl)guanines with alkyl halides. The effect of the structure of the alkylating agent on the direction and yield of the alkylation reaction was established. The possibility of the conversion of the salts obtained to the free bases in a weakly alkaline medium was investigated. The synthesized compounds were characterized by the UV and ¹H and ¹³C NMR spectra. The ability of the synthesized compounds to inhibit replication of the herpes virus (VPG-1) was demonstrated.See [1] for Communication 3.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 5, pp. 641–646, May, 1989.     

Analogs of purine nucleosides. 3. Alkoxyalkylation of hypoxanthine by the silyl method

The reaction of bis(trimethylsilyl)hypoxanthine with methyl trichloromethyl ether has been investigated. 1-Methoxymethyl-, 7-methoxymethyl-, and 9-methoxymethyl-hypoxanthine, as well as 1,7-, 1,9-, and 3,7-bismethoxymethylhypoxanthine, have been isolated from the reaction mixture. The structures of the isomers have been established on the basis of an analysis of their UV, IR, ¹H NMR, ¹³C NMR, and ¹⁵N NMR spectra. The influence of the conditions under which the reaction is carried out on the yield of the alkylation products and the isomeric composition of the reaction mixture has been studied.For report 2, see [1].Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 4, pp. 518–524, April, 1986.     

Sugar allyltins in the synthesis of carbobicycles. Preparation of highly oxygenated enantiomerically pure decalins

Readily available unsaturated bicyclic ketones—obtained conveniently from sugar allyltins—are converted into highly oxygenated unsaturated decalins. The corresponding cis- and trans-diols resulting from oxidation of the double bond were obtained with 100% selectivity. Stereospecific introduction of nitrogen into the decalin system via azidation was also realized.     

Benzothiazines in organic synthesis. The preparation of enantiomerically pure 4-substituted quinolones

3,4-Dihydroquinolin-2(1H)-ones have potential biological and pharmacological significance. Enantiomerically pure benzothiazines, readily available via an intramolecular addition of a sulfoximine-stabilized carbanion to an alpha,beta-unsaturated ester, could be used as templates for making a series of enantiomerically pure 3,4-dihydroquinolin-2(1H)-ones under mild conditions.     

Carbocyclic analogs of nucleosides. Part 2.. Synthesis of 2′,3′-dideoxy-5′-homonucleoside analogs

A set of derivatives of cyclopentaneacetic acid cis-substituted at position 3 by nucleoside bases (both purines and pyrimidines) were prepared and characterized (see 11, 14 , and 23a, b; Schemes 2–4). These molecules are carbocyclic analogs of 2′,3′-dideoxy-5′-homonucleosides. In this synthesis, the skeleton was constructed from norbornanone and a novel method based on Mitsunobu chemistry used for the introduction of nucleoside-base substituents. The scope of this method was further explored via the preparation of a cyclobutyl analog of dideoxyguanosine (see 17 , Scheme 3).     

Carbocyclic Analogs of Nucleosides. Part 3. Synthesis of a new sulfone analog of cyclic adenosine 3′,5′-monophosphate

The novel uncharged analog 2 of adenosine 3′,5′ -monophosphate (1) was prepared in its racemic form. To increase membrane permeability, the phosphate diester monoanion group of 1 was replaced by a dimethylene sulfone unit ( = methanosulfonylmethano group), and the 2′-OH group was removed. To decrease lability against acid-catalyzed depurination, the ring O-atom was replaced by a CH₂ group. All three modifications are also expected to increase the stability of analog 2 towards enzymatic degradation. The carbocyclic skeleton of 2 was constructed from trinorbornenecarbaldehyde 3 (see Scheme 1–3), and the adenine precursor 6-chloropurine was introduced in the carbocyclic unit via an S_N2 reaction based on Mitsunobu chemistry (Schemes 4 and 5).     

Analogs of pyrimidine nucleosides. 13. 1-Substituted 4-thiouracils

4-Thiouracil derivatives with various oxygen-containing groupings as substituents attached to the N₁ atom were obtained by thionation of 1-substituted uracils with phosphorus pentasulfide. It is demonstrated that the yield of the 4-thiouracil derivative depends on the strength of the C-N pseudoglycoside bond in the starting 1-substituted uracil.See [1] for communication 12.Translated from Khimlya Geterotsiklicheskikh Soedinenii, No. 8, pp. 1109–1113, August, 1980.     

Asymmetric synthesis of enantiomerically pure 7-isopropenyl-4a-methyl-3-methyleneoctahydrochromen-2-ones

Four stereoisomers of 7-isopropenyl-4a-methyl-3-methyleneoctahydrochromenon-2-one have been obtained for the first time. The key step of the synthesis involves asymmetric Michael addition of chiral enamines derived from dihydrocarvone to acrylate 1. Absolute configurations were established by X-ray analysis.     

Mass spectrometry of nucleoside derivatives. Seleno analogs of purine and pyrimidine bases and nucleosides

Mass spectra of certain selenobases and selenonucleosides, and some of their trimethylsilyl and O,N-permethyl derivatives have been studied from the standpoint of structural characterization, and in order to ascertain the influence of selenium on normal fragmentation patterns. Molecular ion abundances of the selenouracils are intermediate between those of the corresponding oxygen and sulfur analogs. Fragmentation processes are similar to those of the corresponding normal bases and nucleosides but with additional ions resulting from expulsion of Se or SeH in most cases. Trimethylsilylation occurs at approximately the same rate as for normal bases and nucleosides but the products show decreasing stability with prolonged heating. A least squares procedure is demonstrated which generates monoisotopic mass patterns and assists in interpretation of the mass spectra.     

A practical approach to enantiomerically pure cis-epoxides. synthesis of (+)-disparlure

An efficient synthesis of (+)-disparlure has been achieved in >99.8% ee via the Sharpless asymmetric dihydroxylation followed by Mitsunobu inversion of one hydroxyl group and conversion of the resultant erythro diol to the cis epoxide.     

Chemoenzymatic synthesis of glycosylated enantiomerically pure 4-pentene 1,2- and 1,3-diol derivatives

1-Dimethylthexylsiloxy-2-chloroacetoxy-4-pentene 2 and 1-dimethylthexylsiloxy-3-chloroacetoxy-4-pentene 3 were saponified with Pseudomonas lipase to give (R)-1-dimethylthexylsiloxy-4-pentene-2-ol (ee=99%) and (S)-2 (ee=99%) and (S)-1-dimethylthexylsiloxy-4-pentene-3-ol (ee=99%) and (R)-3 (ee=98%), respectively. All enantiomers were chemically transformed into the corresponding enatiomerically pure 2-benzoyloxy-4-pentene-1-ols 8 and 3-benzoyloxy-4-pentene-1-ols 14, respectively. Mannosylation of (R)-8 and (S)-14 with 2,3,4,6-tetra-O-benzoyl-a-d-mannopyranosyl trichloroacetimidate afforded the corresponding mannopyranosides.     

Pyrazolopyrimidine nucleosides. Part VIII The synthesis of certain 4-substituted pyrazolo[3,4-d]pyrimidine nucleosides

1-(β-D-Ribofuranosyl)pyrazolo[3,4-b]pyrimidine-4-thione ( 6 ), obtained by a three-step synthesis from allopurinol riboside (3), was treated with certain alkyl and aryl halides to provide the corresponding 4-alkylthio derivatives. The nucleoside 4-methylthio-1-(β-D-ribofuranosyl)pyra-zolo[3,4-d]pyritnidine ( 7 ) has served as the precursor for the preparation of the 4-methylamino ( 11 ), 4-dimethylamino ( 12 ), 4-hydrazino ( 13 ), and the 4-hydroxylamino ( 14 ) analogs.     

Nucleosides. Part LV. Efficient synthesis of arabinoguanosine building blocks

From guanosine ( 1 ) as starting molecule, protected arabinoguanosine derivatives such as phosphoramidite precursors and arabinoguanosine ( 18 ) itself were prepared in high yields. Inversion of the configuration at C(2′) was achieved by introduction of the (trifluoromethyl)sulfonyl residue and subsequent displacement by nucleophiles like acetate, bromide, and azide. The guanine moiety was protected at the amide function by the 2-(4-nitrophenyl)ethyl (npe) group on O⁶ and at the NH₂ function by the 2-(4-nitrophenyl)ethoxycarbonyl (npeoc) group.