Synthesis of Conformationally Locked 2＇-Deoxy-2＇-nucleobase-5＇- Isonucleosides: 2＇-Deoxy-2＇-nucleobase-5＇ deoxy-1＇, 4＇ :3＇, 6＇-dianhydro-D-mannitol

Novel bicyclic isonucleosides, 2＇ -deoxy- 2＇ -nucleobase- 5＇ -deoxy- 1＇ , 4＇ : 3＇ , 6＇ -dianhydro D-mannitol 10a-10c, were synthesized from D-glucose. The computer-assisted molecular simu lation indicated that the sugar conformations of compounds 10a-10c were restricted to N-con formation.     

Synthesis of Conformationally Locked Isonucleosides: 2'-Deoxy-2'-nucleobase-5'- deoxy-1', 4' : 3' , 6'-dianhydro-D-mannitol

IntroductionA novel class of nucleoside analogues, termed conformationa1ly locked nucleosides, hasattracted much attention owing to their conformationally restricted structures and their potentbiological activities. Griseolutic acids(I ), a family of naturally occurring bicyclic nucleosides,were isolated from StrePtomyces grisroaurantiacus and showed the inhibitory activities againstc--AMP phosphodiesterase and were able to induce the differentiation of murine neuroblas-tomaLl3. A large num…     

Synthesis of novel L-2',3'-dideoxy-2'-trifluoromethyl-4'- thiocytidines from alpha-trifluoromethyl-alpha,beta-unsaturated ester

A short and efficient synthesis of L-2',3'-dideoxy-2'-trifluoromethyl-4'-thiocytidines is described. (2R,4S/2S,4S)-5-(tert-Butyldimethylsiloxy)-2-trifluoromethylpentan-4-olide (3a and 3b) are prepared from alpha-trifluoromethyl-alpha,beta-unsaturated ester (1) in three steps and converted to compounds 6a and 6b. The corresponding 1-O-acetyl derivatives 8a and 8b were obtained via the usual Pummerer rearrangement from 6a and 6b in two steps, which were in turn used to synthesize L-4'-thiocytidines 10a and 10b.     

3'-氟-2'-O,3'-C-乙烯基键联并环尿苷的合成与表征

设计合成了氟化并环核苷衍生物3'-氟-2'-O,3'-C-乙烯基键联的并环尿苷(1), 并通过¹H NMR, ¹³C NMR和HRMS分析表征了其结构. 同时, 对具有乙炔基及氟原子取代的重要中间体7的结构进行了分析确证, 并提出其可能的形成机理.     

Stereoselective synthesis of carbocyclic L-4'-fluoro-2',3'-dideoxyadenosine

[formula: see text] L-(1'S,3'S)-9-[3-Fluoro-3-(hydroxymethyl)cyclopentan-1-yl]adenine 15 has been synthesized from ester 2, which can be conveniently prepared from 2,3-isopropylidene-D-glyceraldehyde 1 in six steps. The key ring closure has been accomplished through an intramolecular nucleophilic substitution reaction.     

Enantiomeric syntheses of conformationally restricted D- and L-2', 3'-dideoxy-2',3'-endo-methylene nucleosides from carbohydrate chiral templates

D- and L-2',3'-dideoxy-2',3'-endo-methylene nucleosides were synthesized as potential antiviral agents. The key intermediates 5-O-tert-butyldiphenylsilyl-D- and L-2,3-dideoxy-2, 3-endo-methylenepentofuranoses (20 and 33, respectively) were obtained by selective protection of the D- and L-2,3-dideoxy-2, 3-endo-methylenepentose derivatives 19 and 32 which were prepared from 1,2:5,6-di-O-isopropylidene-D-mannitol and L-gulonic gamma-lactone, respectively, and converted to 5-O-tert-butyldiphenylsilyl-D- and L-2,3-dideoxy-2, 3-endo-methylenepentofuranosyl acetates (21 and 34, respectively) or the chlorides 22 and 35. The acetates and chlorides were condensed with pyrimidine and purine bases by Vorbrüggen conditions or S(N)2-type condensation. Vorbrüggen conditions using the acetates gave mostly alpha-isomers. In contrast, S(N)2-type condensation using the chlorides greatly improved the beta/alpha ratio. From the synthesis, several D- and L-2',3'-dideoxy-2',3'-endo-methylene nucleoside analogues have been obtained, and their structures have been elucidated by NMR spectroscopy and X-ray crystallography. The synthesized D- and L-adenine derivatives were tested as substrates of adenosine deaminase, which indicated that the D-adenosine derivative 4a was a good substrate of a mammalian adenosine deaminase from calf intestinal mucosa (EC 3.5.4.4) while its L-enantiomer 10a was a poor substrate. Either the D-adenine derivative 4a or its L-enantiomer 10a did not serve as an inhibitor of the enzyme.     

Synthesis of 3'-fluoro-2',3'-dideoxy-2',3'-didehydro-4'-ethynyl-D- and -L-furanosyl nucleosides

An efficient procedure has been developed for the synthesis of 3'-fluoro-2',3'-dideoxy-2',3'-didehydro-4'-ethynyl D- and L-furanosyl nucleosides (1 and 2) starting from 2,3-O-isopropylidene-d-glyceraldehyde. The key intermediate 1-O-benzoyl-3E-fluoro-3,4-unsaturated-5,6-di(tert-butyldimethylsilyloxy)-2-hexanone 8 was obtained in nine steps with the overall yield of 22%. The alpha,beta-unsaturated ketone 8 was then treated with ethynylmagnesium bromide in a typical Grignard reaction procedure to afford the two intermediates 9 and 10, which after deprotection, oxidation, and acetylation gave the corresponding 4-ethynyl-substituted D- and L-sugar moieties 15 and 16, respectively. A series of D- and L-pyrimidine and purine nucleosides were prepared by the coupling of the sugar moieties with various silylprotected bases. The anomeric mixtures were obtained after condensation. After separation, the beta-isomers were further deprotected to yield the target nucleosides. All the newly synthesized 4'-substituted nucleosides were tested for their activities against HIV, among which the D-adenine derivative showed moderate anti-HIV activity (EC(50) = 25.1 microM) without significant cytotoxicity.     

Synthesis of 2',3'-dideoxy-6',6'-difluorocarbocyclic nucleosides

2',3'-Dideoxy-6',6'-difluorouracils, a novel series of gem-difluoromethylenated carbocyclic nucleosides, were synthesized from (Z)-but-2-ene-1,4-diol in 14 steps. A notable step was the construction of the carbocyclic ring via ring-closing metathesis and the incorporation of gem-difluoromethylene group by way of silicon-induced Reformatskii-Claisen reaction of chlorodifluoroacetic ester 3.     

2′,3′-位异丙叉化核苷类化合物的合成

合成5′_位修饰的核苷化合物须先对2′_OH和3′_OH进行保护。经对三种不同的保护体系,即丙酮二氯亚砜原甲酸三甲酯、高氯酸原甲酸三甲酯丙酮、三氯氧磷丙酮筛选,选用前一体系合成了异丙叉保护的腺苷和肌苷。最佳的工艺条件为:常温反应6h,氯化亚砜用量为底物的3倍,丙酮和原甲酸三甲酯的用量分别为每克底物10mL和0.2～0.3mL,收率90.2%(腺苷)和89.1%(肌苷)。通过红外光谱和核磁共振氢谱对产物结构进行了确认。     

Synthesis of 3',3'-difluoro-2'- hydroxymethyl-4',5'-unsaturated carbocyclic nucleosides

3',3'-Difluoro-2'-hydroxymethyl-4',5'-unsaturated carbocyclic nucleosides 1-3 have been stereoselectively synthesized from ester 10, which can be conveniently prepared from 2,3-isopropylidene-d-glyceraldehyde 7 in five steps. The whole synthesis highlighted the stereoselective Reformatskii-Claisen rearrangement, ring-closing metathesis (RCM), and palladium-catalyzed allylic alkylation, in which the regioselectivity was reversed from that of nonfluorinated substrates.     

A short and efficient synthesis of L-5,5,5,5',5',5'-hexafluoroleucine from N-Cbz-L-serine

[reaction: see text] 5,5,5,5',5',5'-Hexafluoroleucine (6), a fluorous analogue of leucine, is of considerable interest as a building block in the design of fluorous proteins and peptides. We report a short and efficient synthesis of 6, which is obtained from N-Cbz-L-serine (1) in 50% overall yield, 99% enantiomeric excess, and in multigram quantities. Key steps are addition of a serine-derived organozincate to hexafluoroacetone to construct the hexafluoroleucine side chain, followed by radical-mediated deoxygenation of the resulting tertiary alcohol.     

Synthesis of L-beta-3'-deoxy-3',3'-difluoro-4'-thionucleosides

[Structure: see text] An efficient route to L-beta-3'-deoxy-3',3'-difluoro-4'-thionucleosides, thio-containing analogues of highly bioactive gemcitabine, is described. Our synthesis highlighted the installation of the thioacetyl group in high efficiency and construction of 3-deoxy-3,3-difluorothiofuranose skeleton in a novel method.     

Microbial and Enzymatic Synthesis of Optically Pure D- and L-3-Trimethylsilyl-alanine by Deracemization of D,L-5-Trimethylsilyl-methyl-hydantion

 The sterospecificities of hydantoinases and N-carbamoyl amino acid amidohydrolases (N-carbamoylases) from different microbial sources were investigated for the stereoselective syntheses of the unnatural silicon-containing amino acids D- and L-3-trimethylsilyl-alanine (3) from the respective racemic hydantoin D,L-1. In a preparative biotransformation, whole resting cells of Agrobacterium sp. IP I 671, immobilized in a Ca-alginate matrix, were used for the synthesis of amino acid D-3 in 88% yield and 95% enantiomeric excess. Since the purified D-N-carbamoylase from Agrobacterium sp. IP I 671 was shown to be 100%D-selective, the enantiomeric purity of 95% of D-3 arising from the transformation with the immobilized cells must be explained by the participation of a further, L-selective N-carbamoylase or, which is more likely, by racemization of the final hydrolysis product by the action of an amino acid racemase. Isolated hydantoinases from Bacillus thermoglucosidasius, Thermus sp., Arthrobacter aurescens DSM 3745, and Arthrobacter crystallopoietes DSM 20117 turned out to be stereospecific for the conversion of the D-form of hydantoin D,L-1. The enantiomerically pure L-form of 3 was also prepared. It was synthesized from racemic N-carbamoyl amino acid D,L-2 by enantiomer-specific hydrolysis of the L-form in presence of L-N-carbamoylase from Arthrobacter aurescens DSM 3747.     

Microbial and Enzymatic Synthesis of Optically Pure D- and L-3-Trimethylsilyl-alanine by Deracemization of D,L-5-Trimethylsilyl-methyl-hydantion

Summary.  The sterospecificities of hydantoinases and N-carbamoyl amino acid amidohydrolases (N-carbamoylases) from different microbial sources were investigated for the stereoselective syntheses of the unnatural silicon-containing amino acids D- and L-3-trimethylsilyl-alanine (3) from the respective racemic hydantoin D,L-1. In a preparative biotransformation, whole resting cells of Agrobacterium sp. IP I 671, immobilized in a Ca-alginate matrix, were used for the synthesis of amino acid D-3 in 88% yield and 95% enantiomeric excess. Since the purified D-N-carbamoylase from Agrobacterium sp. IP I 671 was shown to be 100%D-selective, the enantiomeric purity of 95% of D-3 arising from the transformation with the immobilized cells must be explained by the participation of a further, L-selective N-carbamoylase or, which is more likely, by racemization of the final hydrolysis product by the action of an amino acid racemase. Isolated hydantoinases from Bacillus thermoglucosidasius, Thermus sp., Arthrobacter aurescens DSM 3745, and Arthrobacter crystallopoietes DSM 20117 turned out to be stereospecific for the conversion of the D-form of hydantoin D,L-1. The enantiomerically pure L-form of 3 was also prepared. It was synthesized from racemic N-carbamoyl amino acid D,L-2 by enantiomer-specific hydrolysis of the L-form in presence of L-N-carbamoylase from Arthrobacter aurescens DSM 3747. Received December 20, 1999. Accepted January 7, 2000     

Synthesis of new 2',3'-dideoxy-6',6'-difluoro-3'-thionucleoside from gem-difluorohomoallyl alcohol

[reaction: see text] 2',3'-Dideoxy-6',6'-difluoro-3'-thionucleoside 1b, an analogue of 3Tc that has high biological activities against HIV and HBV, has been synthesized from gem-difluorohomoallyl alcohol 3 in an efficient way. The key intermediate 4-amino-3,3-difluorotetrahydrothiophen-2-ylmethyl benzoate 15 was prepared from 2,2-difluoro-1-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]but-3-en-1-ol 3 in 11 steps. The construction of pyrimidine ring with the amino group of compound 15 gave the target compound 1.     

Synthesis of thiopyrano[4″,3″:4′,5′]pyrido[3′,2′:4,5]furo[3,2-d]pyrimidines

<正>Reactions of the 6-hydroxy-thiopyrano[3,4-c]pyridine-5-carbonitrile derivative 1 withα-halo-carbonyl compounds gave the ortho-substituted intermediates 2a-c which were converted into furo[2,3-b]thiopyrano[4,3-d]pyridines 3a-c by fusion of a furan moiety under basic conditions.Further cyclization of 3a-c led to a fusion of a pyrimidine ring,yielding the tetracyclic products 6,7 and 8.In addition,condensation of 6 with various aromatic aldehydes afforded the corresponding imines 9a,b.Mannich reaction of 7 gave products 10a,b.     

3",3"-二甲基吡喃[3',4']2,4,2'-三羟基查尔酮的首次全合成

以2,4---羟基苯乙酮和2,4-二羟基苯甲醛为起始原料,经过C-异戊烯基化、保护酚羟基、羟醛缩合、去保护基反应首次成功地完成了天然产物3",3"-二甲基吡喃[3’,4’]2,4,2’-三羟基查尔酮的全合成,总产率18.4％,其结构经1H NMR,IR和MS表征.中间体8未见文献报道.