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1-(3′-Fluoro-2′,3′,6′-trideoxy-β-D-allofuranosyl)thymine [7] and 1-(3′-fluoro-2′,3′,6′-trideoxy-α-L-talofuranosyl) thymine [8] were synthesized starting from the corresponding 2,3′-anhydro nucleoside derivatives. The fluorine was introduced stereoselectively by opening of the anhydro bridge in the presence of HF/AIF3. The 5′-C-methyl derivatives, [7] and [8], of 3′-fluoro-3′-deoxythymidine (FLT) were evaluated for their inhibitory effect against human immunodeficiency virus type 1 (HIV-1) and type 2 (HIV-2). The compounds [7] and [8] had antiviral activity which was three orders of magnitude lower than the reference compound 3′-fluoro-3′-deoxythymidine. None of the compounds showed appreciable activity against other RNA or DNA viruses at subtoxic concentrations.

Methyl 5- acetamido-7,8,9-tri -O- acetyl-4-azido-2,3-didehydro-2,3,4,5-tetradeoxy- d -glycero- d -talo- nonulopyranosonate with N-bromosuccinimide in methanol gave methyl (methyl 5- acetamido-7,8,9-tri -O- acetyl-4-azido-3-bromo-3,4,5-trideoxy-α- d -glycero- d -talo- nonulopyranosid)onate and methyl (methyl 5- acetamido-7,8,9-tri -O- acetyl-4-azido-3-bromo-3,4,5-trideoxy-β- d -glycero- d -talo- nonulopyranosid)onate , which on reductive acetylation with H 2 PdC in acetic anhydride-ethyl acetate yielded the corresponding 4-acetamido analogues. Debromination with Bu 3 SnH AIBN in toluene, followed by hydrolysis, gave methyl 4-acetamido-N-acetyl-4-deoxy-α-and β-4-epi-neuraminic acids.

We have continued our work to develop novel analogues of sialic acid [1–4] that may specifically modulate the interaction between endogenous sialic acid and influenza virus haemagglutinin [3,5,6]. Functional groups of sialic acid that have been implicated for this virus-host recongnition are the glycerol side chain, N -acetyl group and the axially oriented carboxylic acid function In this report we describe the synthesis of two analogues, namely, 4-epi-2-deoxy-2-H eq - N -acetylneuraminic acid (4-epi-2-d-2-H eq -Neu5Ac) and 2,4-dideoxy-2-H eq - N -acetylneuraminic acid (2,4-d 2 -2-H eq -Neu5Ac).

A Convenient Route to D-Apio-β-D-furanosyl- and 2′-Deoxyapio-β-D-furanosyl Nucleosides 2,3-O-Isopropylidene-D-apio-β-D-furanose (1), available in 40% overall yield by modified literature procedures, is acylated regioselectively to the new 3′-O-benzoyl-derivative 2. This is converted to the anomeric triacetates 4 (β-4; α-4 = 1.8:1) by cleavage of the isopropylidene protecting group from 2 followed by peracetylation. Reaction of compounds 4 with silylated nucleobases and subsequent deprotection gives the D-apio-β-D-furanosyl nucleosides 8–10 in good yields. Regioselective hydrazinolysis of the protected nucleosides 5 and 6 affords the 2′-hydroxy-derivatives 11 and 12, respectively, which are converted to the 2′-deoxyapio-β-D-furanosyl nucleosides 17 and 18, respectively, via deoxygenation of the corresponding thionocarbonates 13 and 14 with tris(trimethylsilyl)silane and subsequent deprotection. The 2′-deoxyapio-β-D-furanosyl cytosine 20 is prepared from the 2′-deoxyapio-β-D-furanosyl uracil derivative 16.

A Convenient Route to 3′-Deoxy-α-L- and 3′-Deoxy-β-D-apionucleosides The cyclic thionocarbonate 3, easily available in three steps from 3′-O-benzoyl-2,3-O-isopropylidene-D-apio-β-D-furanose (1), is deoxygenated with n-Bu3SnH to yield the 3′-deoxy epimers 4 [methyl 3-C-(benzoyloxymethyl)-3-deoxy-α-L-threo-tetrofuranoside] and 6 [methyl 3-C-(benzoyloxymethyl)-3-deoxy-β-D-erythro-tetrofuranoside]. These are separated by chromatography and further converted to the 3′-deoxy-α-L-apionucleosides 11–13, and the 3′-deoxy-β-D-apionucleosides 17–19, respectively.

Efficient stereospecific N-formylation of ribosylamine has been achieved, affording the α-anomer directly (by reaction with formic-acetic anhydride) and the β-anomer via the corresponding formamidine derivative (by reaction with dimethylformamide dimethyl acetal). Dehydration of the α-anomer gave the corresponding isocyanide without compromising the anomeric purity. The amidine route was extended to give the N-formyl derivatives of α-xylosylamine and α-arabinosylamine.

1-(3′-Azido-2′,3′,5′-trideoxy-β-D-allofuranosyl)thymine 12 (homo-AZT) was synthesized starting from 1,2;5,6-di-O-isopropylidene- 3-O-mesyl-α-D-allofuranose 1 in an eleven step sequence (overall yield: 4%).

2,2′-Anhydro-1-(5,6-di-O-benzoyl-β-D-altrofuranosyl)thymine 6 and uracil derivative 7 are prepared by transformation of the corresponding 5′,6′-di-O-benzoyl-3′-O-mesyl-β-D-glucofuranosyl nucleosides 4 and 5 into the 2,2′-anhydro derivatives 6 and 7 using DBU.

A series of neuraminic acid derivatives modified in the side chain or at C-3, C-4 or C-5 were tested as substrates of inhibitors of N-acetylneuraminate lyase (EC 4.1.3.3) from Clostridium perfringens. The results, together with Km and Ki values reported previously, indicate that the region most important for the binding of sialic acids is an equatorial zone reaching from C-8 via the ring oxygen atom to C-4 of the sugar molecule, whereas the substituents at C-9 and C-5 may be varied to a higher extent without significantly disturbing enzyme action. It is shown that stereo-electronic factors are responsible for the immediate heterolytic fragmentation of the cyclic sialic acid into pyruvic acid and 2-acetamidomannose or a related C-6 sugar.

The α-methylketoside of N-acetylneuraminic acid methylester (4) is transformed via the deacetylated compound5 into the 9,8-O-isopropylidenderivative6 which could be oxidized regioselectively by RuO4 to the corresponding 4-oxo-sialic acid analogue7. Reduction with the boraneammonia complex produces a 1:1 mixture of6 and the desired α-methylketoside of 9,8-O-isopropyliden-4-epi-N-acetyl-neuraminic acid methylester (8). Removing of the isopropylidene group gives the α-methylketoside of 4-epi-N-acetylneuraminic acid methylester (9), which was further transformed to the ammonium salt of 4-epi-N-acetylneuraminic acid α-methylketoside (10). On the other hand compound5 was turned into the 4,8,9-tri-O-t-butyldimethylsilylderivative11 a from which the corresponding 7-oxo-compound12 by oxidation with RuO4 derives. The reduction of12 with BH3 - NH3 yielded a 1:1 mixture of the starting material11 a and the desired 7-epi-derivative13 a which gives either via the purified peracetylated α-methylketosid of 7-epi-N-acetylneuraminic acid methylester (14) or a direct saponification the sodium salt of 7-epi-N-acetylneuraminic acid-α-methylketoside (15).

2-Deoxy-2-Heq-N-acetylneuraminic acid (1a) has been shown to be a versatile mimic for sialosyl 2-α-glycosides to study the hemagglutinin-sialic acid interaction. Starting with a 4-oxo derivative of 2-deoxy-2-Heq-sialic acid, we obtained the 4-C-methylax and 4-C-methyleq derivatives 4 and 5 as a separable mixture. The derivative 4 was formed as a single product by using tributoxymethylzirconium. The 4-C-methylene derivative 10 was formed by treatment of the ketone with Cp2ZrCl2/Zn/CH2I2. Catalytic hydrogenation of the exo-methylene compound 10 yielded the two 4-deoxy-4-C-methyl diastereomers 13 and 14. All above-mentioned derivatives could be transformed into the unprotected 4-branched 2-deoxy-2-Heq-sialic acids 7, 9, 12, 16, and 18. 2-Deoxy-2Heq-4-oxosialic acid (21) was synthesized by a different pathway.

The 5'-azidonucleosides 3 and 4 were obtained by treating thymidine and 2'-deoxyuridine with TPP/DEAD/HN3. The 3'-O-silylated 5'-azido-5'-deoxythymidine 5 and the corresponding 2'-deoxyuridine derivative 6 were transformed to the formamides (7 and 8, respectively) and dehydrated to the protected 5'-isocyano derivatives 9 and 10; deblocking gave 5'-isocyano-5'-deoxythymidine (11) and 5'-isocyano-2',5'-dideoxyuridine (12). 2,3'-Anhydro-5'-formamido derivatives of thymidine and 2'-deoxyuridine (19 and 20, respectively) were prepared by three different ways. In the most direct synthesis 3 and 4 were transformed to the 2,3'-anhydro-5'- azidonucleosides 17 and 18 by using TPP/DEAD; following the reaction with TPP/HCO2COCH3 gave 19 and 20. Nucleophilic opening reaction with LiN3 yielded the 3'-azido-5'-formylamino derivatives 21 and 22. Dehydration to 3'-azido-5'-isocyano-3',5'-dideoxythymidine (23) and 3'-azido-5'-isocyano-2',3',5'-trideoxyuridine (24) was achieved with tosyl chloride/pyridine. In contrast with 3'-azido-3'-deoxythymidine, compounds 11, 12, 23, and 24 were devoid of any marked inhibitory effect against DNA and RNA viruses including human immunodeficiency virus type I (HIV).

Reaction of Dialkyl Phosphites with α-Enones, II. – 2:1 Adducts from Dimethyl Phosphite and α-Enones: Synthesis of (1-Hydroxy-1,3-alkanediyl)diphosphonates and 5-Dimethoxyphosphoryl-2-methoxy-1,2-oxaphospholane P-Oxides On NaOCH3-catalyzed reaction with two equivalents of dimethyl phosphite (2), various α-enones 1 are transformed into the diphosphonates 5 (e.g. 5a, 5b, 5e, 5f), which, depending on the structure of the enone, can further react with ring closure to give the 1,2-oxaphospholanes 6 (e.g. 6c, 6g, 6h), or with phosphonate-phosphate rearrangement of the α-hydroxyphosphonate moiety to yield compounds 7 (e.g. 7d). The formation of the 2:1 adducts is believed to occur via addition of 2 to the carbonyl group of the (3-oxoalkyl)phosphonates 4, formed from thermodynamically controlled 1,4 addition of 2 to 1. Compounds 4 could also be treated with 2 to yield 2:1 adducts (e.g. 4c 5c, 4d 5d, 4d 7d).

The peracetylated methyl ester 1 of N-acetylneuraminic acid was transformed into the oxazoline derivative 2, which was hydrogenated with Pd/C/H2 to give the 4-deoxy-Neu5Ac2en derivative 3. Acid cleavage of the oxazoline 2 by trifluoroacetic acid (THF) gave the 4-epi-Neu5Ac2en derivative 4a, which was saponified to the known 4-epi-Neu5Ac2en 4b. Treatment of 4a with triphenylphosphane/diethylazodicarboxylate (DEAD)/HN3 in toluene gave the 4-azido-4-deoxy-Neu5Ac2en derivative 5a as well as the 4-epi-azido-4-deoxy-Neu5Ac2en derivative 6a. Both epimers could be saponified yielding the free dehydrosialic acid derivatives 5b and 6b. Furthermore, 4-formamido-4-deoxy-Neu5Ac2en 7b was prepared via the derivative 7a, which was formed from 5a by reaction with triphenylphosphane/formyl acetate. In addition, the free dehydrosialic acid derivatives 5b and 6b were transformed into the stable PN ylides 8 and 10, but only 8 could be hydrolyzed to the triethylammonium salt of 4-amino-4-deoxy-Neu5Ac2en 9a, which was converted into the zwitter ionic compound 9b. Finally 4-acetamido-4-deoxy-Neu5Ac2en 11e was prepared from 4-acetamido-4-deoxy-N-acetylneuraminic acid 10 via the derivatives 11a and 11b by well-known methods. The compounds 4b, 5b, 6b, 7b, 9b, and 11c were investigated as inhibitors of Vibrio cholerae sialidase, and their Ki values were determined.

Reaction of Dialkyl Phosphites with α-Enones, I. – Synthesis and Allylic Rearrangement of Dimethyl (1-Hydroxy-2-alkenyl)- and (1-Hydroxy-2-cycloalkenyl)phosphonates Various β,γ-unsaturated α-hydroxyphosphonates 3 are prepared in good yields by NaOCH3-catalyzed regioselective 1,2-addition of dimethyl phosphite to acyclic and cyclic α-enones at −35°C. On acid-catalyzed acetylation, the allylic α-hydroxyphosphonates 3 (R1, R2 + H) rearrange under thermodynamic control; yielding the new 3-acetyloxy-1-(cyclo)alkenyl derivatives 8, from which the transposed allylic alcohols 11 are readily obtained. Using shorter reaction times, acetylation of compounds 3 affords mixtures of 1- and 3-acetylated products, 10 and 8, respectively.

The synthesis of 5-acetamido-2,6-anhydro-3,5-dideoxy-D- erythro-L-manno-nonic acid (3b, 7,8-epi2-2-d-2-HeqNeu5Ac) and sodium 5-acetamido-2,6-anhydro-3,5-dideoxy-L-threo-L-manno-nonate (6b, 8-epi-2-d-2-Heq-Neu5Ac) could be realized by transformation of 5-acetamido-3,5-dideoxy-L-glycero-L-altro-2-nonulopyranosonic acid (2a, 7,8-bis-epi-Neu5Ac) and 5-acetamido-3,5-dideoxy-3-L-glycero-D-galacto-2-nonulosonic acid (5a, 8-epi-Neu5Ac) into the corresponding peracetylated 2-chloro derivatives and subsequent catalytic hydrogenation. As this procedure could not be applied to the synthesis of the 7-epi, 7-deoxy and 8-deoxy derivatives a new strategy, which started with the methyl 5-acetamido-2,6-anhydro-3,5-dideoxy-D-erythro-L-manno-nonoate (1e), was designed. For this purpose, a gram-scale preparation of 1e was developed. Transformation of protecting groups and radical reduction of selectively introduced tolylthiocarbonate groups led to the corresponding 5-acetamido-2,6-anhydro-3,5,7-trideoxy-D-glycero-L-manno-nonoic acid (12b, 2,7-d2-2Heq-Neu5Ac) and sodium 5-acetamido-2,6-anhydro-3,5,8-trideoxy-D-glycero-L-manno-nonate (11b, 2,8-d2-2Heq-Neu5Ac). An oxidation — reduction sequence yielded 5-acetamido-2,6-anhydro-3,5-dideoxy-D-threo-L-manno-nonoic acid (9c, 2d-2Heq-7-epi-Neu5Ac). Also the sialic acid analog 6b could be prepared according to this newly designed strategy.

The reaction of peracetylated N-acetylneuraminic acid methyl ester 1 with nitrosyl acetate affords a mixture of anti/syn-N-nitroso derivatives 2a and 2a′, which can be transformed with sodium trifluoroethanolate into the 5-diazo compound 3. The reaction of 3 with tetrabutylammonium acetate/acetic acid yields methyl 2,4,5,7,8,9-hexa-O-acetyl-3-deoxy-D-clycero-β-D-galacto-2-nonulopyranosidonate (KDN) (4a). On the other hand, 5-azido-5-deoxy-KDN (5a) is formed by treating 3 with hydrazoic acid in toluene. Heating of 2a/2a′ in toluene furnishes a mixture of the peracetylated deaminated furanoid sialic acid derivative 10 with probably changed configuration at C-5 and C-6 and the deaminated 5,6- and 4,5-didehydrosialic acid derivatives 6 and 7. Catalytic hydrogenation of 6 and 7 yields the 5-deoxy-KDN derivative 9a and - after hydrogen-olysis of the 4-acetoxy group - a minor amount of compound 8. The compounds 4a, 5a, and 9a have been converted into the free deaminated sialic acids 4e, 5e, and 9e via the 4-me-thylumbelliferyl 2α-glycosides 4c, d, 5c, d, and 9c, d.

The methyl ester of N-acetylneuraminic acid β-methyl ketoside (Neu5Ac1Me-2β-Me) (1) is used as common starting material for the synthesis of the title compounds. Combined derivatization reactions with reagents thiophosgene, p-cresol, benzoyl chloride, and acetic anhydride/pyridine lead to the thiocarbonate derivatives 2, 6–8, and 12. Further transformation with iodomethane yields the 9-iodo compounds 3, 9, and 13, which are reduced by tributyltin hydride to the deoxy derivatives 4, 10, and 14. Hydrolysis of 14, 10, and 4 affords the desired 9-deoxy, 7,9-dideoxy-, and 4,7,9-trideoxy-N-acetylneuraminic acids 15 (9-d-Neu5Ac), 11 (7,9-d2-Neu5Ac), and 5 (4,7,9-d3-Neu5Ac), respectively. — The sialic acid analogues 11 and 5 were activated by CMP-sialate synthase [E,C.2.7.7.43] to an extent of 30–40 and 50–60%, respectively, relative to N-acetylneuraminic acid.

The 4-, 7-, and 8-oxo-sialic acid β-methyl ketosides 7, 10a, and 11a were obtained by transformation of easily available derivatives of N-acetylneuraminic acid (1a). The carbonyl migration from C-7 to C-8 can be carried out under well-defined conditions with formation of the ketone 11b. Starting from 7- and 8-ketones 17 and 20 the corresponding dimethyl acetals are prepared. The 4-ketone 7 behaves as a moderate competitive inhibitor of CMP-sialate synthase [EC 2.7.7.43], whereas the 8-ketone 11a, the 8,8-dimethyl acetal 19, and the 7,7-dimethyl acetal 23 prove not to be inhibitors of this enzyme. The 7-ketone 10a was not tested because of instability under test conditions at pH 8.5.

A 4-C-methylene sialic acid derivative 3 was obtained by the reaction of the corresponding 4-oxocompound 2 with CH 2 I/Zn/CP 2 ZrCl 2 . The product was transformed into a mixture of the 4-deoxy-4-(R)-methyl- and 4-(S)-methyl derivatives 4 and 5 . Sialic acids 6 and 7 were obtained after the removal of protective groups.

Readily available β-glycofuranosyl isocyanides1,2,4,5,6,18,19,20 are transformed into the corresponding protected tetrahydrofurans21,22,23,24,25,26 by means of tributyltin hydride andAIBN. The synthesis of18 and19 by dehydration of the formamide15 is described. Starting with 6-deoxy-1,2-O-isopropyliden-α-D-allofuranose (7) crystalline 1,2-O-diacetyl-3,5-dibenzoyl-β-D-allofuranose (9) is obtained.9 is first transformed into the anomeric azides11,12 and13,14 and subsequently into the formamide15.

1-(3′-Azido-2′,3′,5′-trideoxy-β-D-allofuranosyl)thymine 12 (homo-AZT) was synthesized starting from 1,2;5,6-di-O-isopropylidene- 3-O-mesyl-α-D-allofuranose 1 in an eleven step sequence (overall yield: 4%).

Starting from 3-O-mesyl-1,2-O-isopropylidene-alpha-D-allofuranose (9) the anomeric mixtures of the requisite carbohydrates 1,2-di-O-acetyl-6-O-benzoyl-5-deoxy-3-O-mesyl-D-allofuranoses++ + 17A alpha/beta, 1,2-di-O-acetyl-5,6-di-O-benzoyl-3-O-mesyl-D-allofuranoses 17B alpha/beta, and 1,2-di-O-acetyl-5,6-di-O-benzoyl-3-O-mesyl-L-talofuranoses 17C alpha/beta were synthesized. 1,2-Di-O-acetyl-5-O-benzoyl-6-deoxy-3-O-mesyl-D-allofuranoses++ + 17D alpha/beta and the corresponding L-talofuranoses 17E alpha/beta were obtained from 6-deoxy-3,5-di-O-benzoyl-1,2-O-isopropylidene-alpha-D- allofuranose (12) and the corresponding beta-L-talofuranose 13. Coupling of these sugar derivatives with thymine gave the beta-nucleoside derivatives 18A-E. Treatment of compounds 18A-E with DBU produced the corresponding 2,3'-anhydro nucleosides 19A-E with a free 2'-OH group. After deoxygenation of 2'-O-[[(4-methylphenyl)oxy]thiocarbonyl] compounds 20A-E with tributyltin hydride the 2,3'-anhydro bridge of the 2'-deoxynucleosides 21A-E was opened with LiN3 to produce the protected 3'-azido-2,3'-dideoxynucleoside derivatives 22A-G. Saponification with NaOCH3 gave 1-(3'-azido-2',3',5'-trideoxy-beta-D-allofuranosyl)thymine (2; homo-AZT), the 5'-C-(hydroxymethyl) derivatives of AZT 1-(3'-azido-2',3'- dideoxy-beta-D-allofuranosyl)thymine (3) and 1-(3'-azido-2',3'-dideoxy-alpha-L-talofuranosyl)thymine (4), and the 5'-C-methyl derivatives of AZT 1-(3'-azido-2',3',6'-trideoxy-beta-D-allofuranosyl)thymine (5) and 1-(3'-azido-2',3',6'-trideoxy-alpha-L-talofuranosyl)thymine (6). Compounds 2-6 were evaluated for their inhibitory effect on human immunodeficiency virus type 1 (HIV-1) and type 2 (HIV-2) replication in MT-4 cells and found inactive at subtoxic concentrations. Compounds 2-4 and 6 are not effective against herpes simplex virus type 1 (HSV-1) and type 2 (HIV-2), vaccinia virus (VV), and vesicular stomatitis virus (VSV) at 400 micrograms/mL. 5 is slightly active against HSV-1, HSV-2 and VV at 150, 300, and 300 micrograms/mL, respectively.

2,3-Didehydro-2-deoxy- N -trifluroacetylneuraminic acid (5-trifluoroacetyl-Neu2en) ( 3 ) has been synthesised from Neu5Ac2en ( 1 ) by hydrazinolysis, to give Neu2en ( 2 ), followed by N -trifluoroacetylation. 2,3-Didehydro-2,3-dideoxy- d - glycero - d - galacto -2-nonulopyranosonic acid (Kdn2en, 8 ) and 5-azido-2,3-didehydro-2,3,5-trideoxy- d - glycero - d - galacto -2-nonulopyranosonic acid (5-azido-5-deoxy-Kdn2en, 9 ) have been prepared from the acetylated methyl esters of Kdn ( 4 ) and 5-azido-5-deoxy-Kdn ( 5 ) via Zemplen saponification. The behaviour of the above 2,3-didehydro-2-deoxysialic acids towards Vibrio cholerae sialidase has been investigated

The synthesis of 2,3′- anhydro-[l- (6′-0 - benzoyl- 2′,5′- dideoxy-β-D-glucofuranosyl)thymine] 10, a versatile starting material for homo-2′, 3′- dideoxynucleosides is described. 10 is transformed to homo-AZT.

On the Synthesis of 5-(X-Methyl)ribofuranosyl-1,2,3-triazole Nucleosides The synthesis of the reactive 5-(bromomethyl)-1-(2′,3′,5′,-tri-O-benzoyl-β-D-ribofuranosyl)-1,2,3-triazole (3) via 1,3-dipolar cycloaddition of the β-oxoalkylidenephosphorane 2 to the ribofuranosyl azide 1 under elimination of triphenylphosphane oxide is described. The nucleosides 4a - d are obtained by substitution of the bromide in 3 by N3−, SCN−, AcO− and AcS−. With P(OCH3)3 3 leads in an Arbuzow reaction to the 5-(dimethoxyphosphorylmethyl)-1,2,3-triazole nucleoside 4e. The β-oxoalkylidenephosphoranes 5a and b react with 1 to form the corresponding 5-substituted 1,2,3-triazoles 4f and g, respectively. Removal of the benzoyl groups in 4a, c, e, and g, with CH3 OH/NH3 leads to the 1-β-D-ribofuranosyl-1,2,3-triazoles 6a, c, e, and g. -The biological activity of the nucleosides of the typ 6 has been tested.

Vitamin D2 and D3 are transformed with triphenylphosphane-diethylazodicarboxylate-HN3 into the epimeric azidoderivatives 1 and 3 with inversion of the configuration at C-3. Reduction with LiAlH4 yields 3-desoxy-3-epiamino-vitamin D2 and D3 2 and 4, which are characterized as their acetamides 2a and 4a. Furthermore epivitamin D3-p-nitrobenzoate 5 is produced by reaction of vitamin D3 with triphenyl- phosphanediethylazodicarboxylate-p-nitrobenzoic acid, which yields epivitamin D3 5a after saponification. Utilizing the same method as above leads with epivitamin D3 to 5a 3-desoxy-3-azidovitamin D3 6, which is reduced to 3-desoxy-3-amino-vitamin D3 7 by LiAlH4 and characterized as its acetamide 7a.

Readily available Neu5Ac derivatives1 and7 are oxidized by RuO4 to the ketones2 and8 which are reduced diastereoselectively by the borane-ammonia complex to yield the4- and 8-epimers4a and10. Subsequent deprotection leads to the title compounds5 and12. This few step procedure is also applicable on gram scale.

Sowohl das β-D-Ribofuranosylazid 1 als auch das α-Anomere 3 liefern bei der Staudinger-Reaktion das gleiche P-N-Ylid 2. Mit Alkylisocyanaten RNCO [R - CH3, (CH3)2CH, C2H5OCOCH2 und (S)-C2H5OCOCH(CH3)] entstehen die Carbodiimidderivate als Diastereomerengemische 5, welche mit HN3 in die 1-(β-Ribofuranosyl)-5-(alkylamino)tetrazole 6 umgewandelt werden. Teilweise oder ganzliche Entfernung der Schutzgruppen fuhrt zu den Produkten 7a, c, d und 7d′–d′". Vom β-D-Mannofuranosylazidderivat 8 aus gelangt man uber das P-N-Ylid 9 zum Carbodiimidderivat 10 und schlieslich zum Aminotetrazolderivat 11. Die Umsetzung von 2 mit Phenylisocyanat liefert die 5-[(β- und 5-[(α-D-Ribofuranosyl)amino]-1-phenyltetrazole 18 bzw. 19 uber die Carbodiimidzwischenstufen 12 und 13. Ferner entstehen die 1-Isocyanatozuckerderivate 14 und 15, welche fur die Entstehung der Folgeprodukte 16, 17 und 20–22 verantwortlich sind. Aus 2 und Malonsaure-monoethylester-azid entsteht das Nucleosidderivat 23. Die Darstellung der Ribosyltetrazole 26 und 27 aus 2 last sich nur mit Acetylcyanid uber das syn/anti-Gemisch 24a/24a′ durch Umsetzung mit HN3 verwirklichen. Als Zwischenstufe wird das (α-Ribosylimino)nitril 25 postuliert. Glycosyl Azides as Starting Materials for the Synthesis of Nucleoside Analogues, 2. — Synthesis of Tetrazole Nucleosides The β-D-ribofuranosyl azide derivative 1 as well as the corresponding α-anomeric compound 3 yield via Staudinger reaction the same P-N-ylide 2. Treatment with alkyl isocyanates RNCO [R = CH3, (CH3)2CH, C2H5OCOCH2, (S)-C2H5OCOCH(CH3)] affords the diastereomeric carbodiimide derivatives 5 which can be transformed by HN3 regioselectively into the 1-(β-ribofuranosyl)-5-(alkylamino)tetrazole derivatives 6. Partial or total removal of the protecting groups affords the products 7a, c, d, and 7d′–d′". The β-D-mannofuranosyl azide derivative 8 is converted via the P-N-ylide 9 into the carbodiimide 10 and the aminotetrazole derivative 11. The reaction of 2 with phenyl isocyanate yields the 5-[(β- and 5-[(α-D-ribofuranosyl)amino]-1-phenyltetrazoles 18 and 19 passing the carbodiimide intermediates 12 and 13. Additionally the 1-isocyanato sugar derivatives 14 and 15 arise which provide for the formation of the products 16, 17, and 20–22. The ethyl [(β-D-ribofuranosyl)-5-tetrazolyl]acetate 23 is formed by reaction of 2 with the azide of monoethyl malonate. The preparation of the ribosyltetrazole derivatives 26 and 27 can be achieved only by preceding synthesis of the syn/anti mixture 24a/24a originating from 2 and acetyl cyanide followed by treatment with HN3. The α-ribosyliminonitrile 25 is assumed to be an intermediate.

Iodalkane konnen mit Iod(III)-trifluoracetat in Ether bei uberraschend milden Reaktionsbedingungen unter Oxidation an einer benachbarten C–H-Bindung in 2-Iodalkyltrifluoracetate umgewandelt werden. Bei der Umsetzung in CH2Cl2 gelangt man unter Austausch des Halogens der 2-Iodalkyltrifluoracetate weiter zu entsprechenden Glykolesterabkommlingen. Nur als Nebenreaktionen werden bisweilen auch einfache Substitutionen registriert, wie das aus 1-Octyliodid erhaltene Octyltrifluoracetat (1a), der Ethyloctylether (2a) und das aus 2-Iodoctan isolierte 1-Methylheptyltrifluoracetat (7a) beweisen. — Als dominante Reaktionsprodukte der Umsetzung yon 2-Iodbutan mit I(OCOCF3)3 in Ether erhalt man das (45:55)-Gemisch der threo- und erythro-2-Iod-1-methylpropyltrifluoracetate (3a bzw. b). In CH2Cl2 bildet sich dagegen ein (45:55)-Gemisch aus rac-2,3-Butandiolbis(trifluoracetat) (4a) und meso-2,3-Butandiolbis(trifluoracetat) (4b). Aus optisch aktivem 2-Iodbutan in Ether entstehen unter Racemisierung 3a und 3b. 2-Iodoctan ergibt unter gleichen Bedingungen die beiden Stereoisomerengemische threo- und erythro-1-(1-Iodethyl)hexyltrifluoracetat (5a bzw. 5b) sowie threo- und erythro-2-Iod-1-methylhepeptyltrifluoracetat (6a bzw. 6b). Iodcyclohexan liefert in Ether stereospezifisch trans-2-Iodcyclohexyltrifluoracetat (8a) und in CH2Cl2 hauptsachlich cis-1,2-Cyclohexandiolbis(trifluoracetat) (9a) neben wenig trans-Form 9b. Aus Iodcyclopentan wird in Ether trans-2-lodcyclopentyltrifluoracetat (10a) gebildet. 3α-Iodcholestan wird ausschlieslich in 3α-Iod-2β-cholestanyltrifluoracetat (11a) umgewandelt; in geringerer Ausbeute entsteht 11a auch aus 3β-Iodcholestan. Vergleichende Versuche mit Cyclohexen lieferten nur 50% 8a, zusatzlich aber 30% trans-2-Ethoxycyclohexyltrifluoracetat (8b). 2-Cholesten setzt sich im Vergleich zu 3α-Iodcholestan etwa 10 mal langsamer zu 11a um. 2-Cyclohexenyltrifluoracetat ergibt ein Gemisch der beiden stereoisomeren 2-Iod-1,3-cyclohexandiolbis(trifluoracetate) 12a und 12b, die aus 8a und I(OCOCF3)3 in Ether nicht entstehen. Reactions of Polyvalent Iodine Compounds, VII. — Reactions of Aliphatic Iodine Compounds with Iodine(III) Trifluoroacetate Iodoalkanes react with iodine(III) trifluoracetate in ether under remarkably mild conditions via oxidation in the neighboring C–H bond to give 2-iodalkyl trifluoracetates. In dichloromethane the reaction proceeds by replacement of the halogen to form the bis(trifluoroacetate) derivates of the corresponding glycols. Simple substitution processes can be observed only as side reactions, e. g. transformations of 1-iodooctane into octyl trifluoroacetate (1a) and ethyl octyl ether (2a) or of 2-iodooctane into 1-methylheptyl trifluoroacetate (7a). — The sole products of the reaction of I(OCOCF3)3 with 2-iodobutane in ether are obtained as a (45:55)-mixture of the threo- and erythro form of the two 2-iodo-1-methylpropyl trifluoroacetates (3a and 3b, respectively). The same racemic mixture of 3a and 3b is obtained with optically active 2-iodobutane and I(OCOCF3)3 in ether. The corresponding (45:55)-mixture of rac-2,3-butanediole bis(trifluoroacetate) (4a) and meso-2,3-butanediol bis(trifluoroacetate) (4b) is formed by oxidation of 2-iodobutane in CH2Cl2. By the same procedure 2-iodooctane yields two mixtures of stereoisomeric compounds: threo- and erythro-1-(1-iodoethyl)hexyl trifluoroacetate (6a and 6b, respectively). Iodocyclohexane is transformed stereospecifically in ether to trans-2-iodocyclohexyl trifluoroacetate (8a) and in CH2Cl2 to cis-1,2-cyclohexanediol bis(trifluoroacetate) (9a) including a trace of trans-form 9b. Iodocyclopentane in ether affords trans-2-iodocyclopentyl trifluoroacetate (10a). 3α-Iodocholestane can be changed exclusively to 3α-iodo-2β-cholestanyl trifluoroacetate (11a), which is formed in smaller amounts from 3β-iodocholestane. Cyclohexene is oxidized with I(OCOCF3)3 in ether to trans-2-ethoxy-cyclohexyl trifluoroacetate (8b; 30%) besides 50% 8a. In comparison to 3α-iodocholestane, 2-cholestene reacts ten times slower yielding 11a. The two stereoisomeric 2-iodo-1,3-cyclo-hexanediol bis(trifluoroacetates) 12a and 12b are obtained by oxidation of 2-cyclohexenyl trifluoroacetate.

Oxidation of the α- and β-4-phenyl-1,2,4-triazolin-3,5-dione adducts of vitamin D3 (2 and1) withMCPBA yields two diastereomeric mixtures of the (5,10)-(7,8)-dioxiranes3 a,3 b,3 c and4 a,4 b respectively. The corresponding benzoates5 a,5 b,6 a and6 b were prepared and the X-ray crystal structure of5 b was determined. This analysis proved5 b to be the (5R, 1 OS)-(7R, 8R)-dioxirane of the β-resp. (6S)-4-phenyl-1,2,4-triazolin-3,5-dione adduct1 of vitamin D3.

Ausgehend von trans-1,2-Chlor- und Bromhydrinen 1a, b oder trans-1,2-Azidoalkoholen 1c wird mit Triphenylphosphan/Azodicarbonsaure-diethylester/HN3 bzw. Alkylhalogeniden RX (X =I, Br) durch invertierende Substitution der Hydroxygruppe die Darstellung der 5- bis 7-gliedrigen cyclischen cis-1,2-Azidhalogenide 2a-c erreicht. Diese lassen sich mit Kalium-tert-butanolat in die bisher unbekannten cyclischen 5- bis 7-gliedrigen Vinylazide 3a-c uberfuhren. 3b liefert mit m-Chlorperbenzoesaure uber ein 1-Azido-1,2-epoxycyclohexan in einem Fragmentierungsprozes 5-Formylpentannitril (4). Auf gleichem Reaktionswege lassen sich die beiden cis-konfigurierten Steroide 3β-Azido-2β-chlorcholestan (5) und 2α-Azido-3α-chlorcholestan (6) aus den trans-Chlorhydrinen darstellen und in 3-Azido- (7) und 2-Azido-2-cholesten (8) uberfuhren. Synthesis of Cyclic Vinyl Azides Cyclic trans-1,2-chloro- and bromohydrins 1a, b or trans-1,2-azido alcohols 1c are converted by triphenylphosphane/diethyl azodicarboxylate/HN3, or alkyl halides RX (X =I, Br), respectively, by an inverting substitution process of the hydroxy group to give the 5-, 6-, and 7-membered cyclic cis-1,2 azide halides 2a-c. These have been transformed by potassium tert-butoxide into the hitherto unknown cyclic vinyl azides 3a-c. 3b reacts with m-chloroperbenzoic acid via a 1-azido-1,2-epoxycyclohexane by a fragmentation reaction to give the 5-formylpentanenitrile (4). By the same reaction path are obtained the cis-steroids 3β-azido-2β-chloro-cholestane (5) and 2α-azido-3α-chloro-cholestane (6) which give the vinyl azides 3-azido- (7) and 2-azido-2-cholestene (8).

The synthesis of the title compound from 1,2:5,6-Di-O-isopropyliden-α-D-glucofuranose (1) via 1,2:5,6-Di-O-isopropyliden-α-D-gulofuranose (4) is reported. The key-step is the introduction of the azido function into4 which is achieved by using Triphenylphosphane/Diethylazodicarboxylate/HN3.

(Imidazolylmethyl)-, (thiazolylmethyl)-, and (5-oxo-5,6-dihydroimidazo [1,2-c] pyrimidinylmethyl) triphenylphosphonium bromides (2, 3, 4) react with diethyl phosphiteanion or with the carbanion of ethyl diethoxyphosphorylacetate to give the corresponding heteroarylmethyl- or heteroarylphosphonates 5, 6, 8, 10, 12, 13. The free phosphonic acids 7, 8, 11, 14 can be prepared by cleavage with bromotrimethylsilane

(2,3-Epoxy-4-oxoalkyl)phosphonsaureester 6 konnen mit Thioharnstoff-Derivaten oder Thioamiden in sehr guten Ausbeuten zu den neuen [2-Hydroxy-2-(5-thiazolyl)ethyl]phosphonaten 12–16 oder zu den (Thiazolylvinyl)phosphonsaureestern 17–21 umgesetzt werden. Beide Verbindungstypen erlauben die Spaltung zu bisher unbekannten Phosphor-freien Thiazolen: Die β-Hydroxy-phosphonate 15 und 16 mit R4 = Ph bzw. 3-Pyridyl reagieren mit CsF erwartungsgemas unter Abspaltung von Diethylphosphat zu den 5-Alkenylthiazolen 22 bzw. 23, wahrend die Verbindungen 13 und 14 mit R4 = NHPh bzw. NHMe unter analogen Reaktionsbedingungen zu (1-Formylalkyl)phosphonsaureestern und den an C-5 unsubstituierten Thiazolen 24 bzw. 25 gespalten werden. — Die (Thiazolylvinyl)phosphonate 17′ (R4 = NHAc) und 20 (R4 = Ph) werden mit N-Methylmorpholin-N-oxid/OsO4 zu den threo-Diolen 26 bzw. 27 umgesetzt, die thermisch oder bei saurer Katalyse leicht und regioselektiv zu den sehr reaktiven Enolen der Acylphosphonate 28 bzw. 29 dehydratisiert werden konnen. Diese reagieren mit Wasser, Alkoholen und Aminen glatt zu den bisher unbekannten Thiazolylessigsaure-Derivaten 34–38. Dialkyl (2,3-Epoxy-4-oxoalkyl)phosphonates as Synthones for Thiazoles On reaction with thioureas and thioamides, the dialkyl (2,3-epoxy-4-oxoalkyl)phosphonates 6 can be transformed either into the new [2-hydroxy-2-(5-thiazolyl)ethyl]phosphonates 12–16, or to the (thiazolylvinyl)phosphonates 17–21. Cleavage of both systems into formerly unknown phosphorus-free thiazoles is readily achieved: fluoride-induced olefin synthesis occurs as expected with compounds 15 (R4 = Ph) and 16 (R4 = 3-pyridyl), yielding the 5-alkenylthiazoles 22 and 23, respectively. Under analogous reaction conditions the (β-hydroxyalkyl)phosphonates 13 (R4 = NHPh) and 14 (R4 = NHMe) are cleaved in an alternative way to give (1-formylalkyl)phosphonates and the C-5-unsubstituted thiazoles 24 and 25, respectively. — On reaction with N-methylmorpholine N-oxide/OsO4 the (thiazolylvinyl)phosphonates 17′ (R4 = NHAc) and 20 (R4 = Ph) are converted into the threo-diols 26 and 27, which by thermolysis or under acid catalysis are dehydrated regioselectively to give the very reactive acylphosphonates 28 and 29, respectively. These, on reaction with water, alcohols or amines, readily afford the new thiazolylacetic acid derivatives 34–38.

N-Bromsuccinimid reagiert mit dem Vitamin-D3-Triensystem stereoselektiv zum Bromhydrin 2a. Substitution des 19-Bromids durch verschiedene Nucleophile und anschliesende saurekatalysierte Eliminierung der tertiaren 8-Hydroxygruppe ergibt einen einfachen Zugang zu 19-substituierten Tachysterol- und Isotachysterolderivaten. Die Nutzlichkeit dieser Methode wird anhand der Darstellung von 19-Acetamidotachysterol (3c) und 19-Acetamidoisotachysterol (4c) gezeigt. On the Selective Oxidation of the Vitamin-D3 Triene System – The Reaction of Vitamin D3 with N-Bromosuccinimide – A Simple Entry to C-19-substituted Tachysterol and Isotachysterol Derivatives N-Bromosuccinimide adds across the vitamin D3 triene system to give the bromohydrine 2a in a stereoselective manner. Nucleophilic displacement of the 19-bromide with various nucleophiles and subsequent acidic elimination of the tertiary 8-hydroxy group offers a convenient entry to 19-functionalized tachysterol and isotachysterol derivatives. The utility of this method is demonstrated by synthesizing 19-acetamidotachysterol (3c) and 19-acet-amidoisotachysterol (4c).