Benzodiazepine Analogues. Part 8.1 Trimethylsilyl Azide Mediated Schmidt Rearrangement of Thioflavanone and Thiochromanone Precursors

The synthesis and Schmidt rearrangment of a series of thioflavanone analogues to benzothiazepinone derivatives is described.     

Oligosaccharide Analogues of Polysaccharides. Part 4. Synthesis of a monosaccharide-derived octamer

NaSMe in toluene leads to regioselective de-C-silylation of the bis[(trimethylsilyl)ethynyl]saccharide 2 , but to decomposition of butadiynes such as 1 or 12 . We have, therefore, combined the known reagent-controlled, regioselective desilylation of 2 and of 12 (AgNO₂/KCN) with a substrate-controlled regioselective de-C-silylation, based on C-silyl groups of different size. This combination was studied with the fully protected 3 which was mono-desilylated to 4 or to 5 (Scheme 1). Triethylsilylation of 5 (→ 6 ) was followed by removal of the Me₃Si group (→ 7 ), introduction of a (t-Bu)Me₂Si group (→ 8 ) and removal of the Et₃Si group yielded 9 ; these high-yielding transformations proceed with a high degree of selectivity. Iodination of 4 gave 10 . The latter was coupled with 5 to the homodimer 11 and the heterodimer 12 , which was desilylated to 13 . The second building block for the tetramer was obtained by coupling 14 (from 7 ) with 5 , leading to 15 and 16 . Removal of the Me₃Si group (→ 17 ) and iodination led to 18 which was coupled with 13 to the homotetramer 20 and the heterotetramer 19 (Scheme 2). Deprotection of 19 gave 21 , which was, on the one hand, iodinated to 22 , and, on the other hand, protected by the (t-Bu)Me₂Si group (→ 23 ). Removal of the Et₃Si group (→ 24 ) and coupling afforded the homooctamer 26 and the heterooctamer 25 . Yields of iodination, silylation, and desilylation were consistently high, while heterocoupling proceeded in only 50–55%. Cleavage of the (i-Pr)₃SiC and MeOCH₂O groups of 11 (→ 27 ), 15 (→ 28 ), 20 (→ 29 ) and 26 (→ 30 ) proceeded in high yields (Scheme 3). Complete deprotection in two steps of the heterocoupling products 16 (→ 31 → 32 ), 19 (→ 33 → 34 ), and 25 (→ 35 → 36 ) gave the unprotected dimer 32 , tetramer 34 , and octamer 36 in high yields (Scheme 4). Only the dimer 32 is soluble in H₂O; the ¹H-NMR spectra of 32 , 34 , and 36 in (D₆)DMSO (relatively low concentration) show no signs of association.     

The Synthesis of Hetero-Halogenated Derivatives of Phloroglucide Analogues[1]

A short synthesis of the title compounds is reported. Most of the compounds prepared were found to be active against a number of pathogenic microorganisms in vitro.     

Chemistry of Diamantane Part II. Synthesis of 3,5-Disubstituted Derivatives

Although chemical¹ and microbiological² methods for functionalisation of one or more of the bridgehead positions of diamantane are available, there have been no reports of substitution reactions at the methylene positions apart from that of the preparation of diamantanone (1)¹ by sulphuric acid oxidation of the hydrocarbon. There are three structural arrangements possible for a non-bridgehead disubstituted diamantane, but the synthetic route described here leads exclusively to 3,5-disubstituted derivatives.

When treated with sodium azide in cold methanesulphonic acid diamantanone (1) underwent a Schmidt fragmentation-recyclisation reaction of the type described by Sasaki et al.,³ yielding a compound which was not isolated but which was presumed to be the keto-mesylate (2) since treatment of the reaction mixture with sodium hydroxide caused a second fragmentation and the final product was the unsaturated acid (3) in 41% yield. The structure of the acid is based on the spectral data and on subsequent chemical transformations. The normal Schmidt rearrangement product, which is probably a mixture of the two possibilities (4) and (5), was also isolated in 50% yield. The unsaturated acid was readily recyclised under acidic conditions. Use of 96% sulphuric acid resulted in the formation of the lactone (6), but use of hot 50% sulphuric acid furnished 5ax-hydroxydiamantan-5-one (7) as the preponderant product (82%). That the hydroxyl-group occupied the axial config-     

Oligosaccharide Analogues of Polysaccharides. Part 9. Synthesis and Thermolysis of Acetylenosaccharide-Derived 1,2-Dialkynylbenzenes

Thermolysis of the 1,2-bis(glucosylalkynyl)benzenes 6 and 16 was studied to evaluate the effects of intramolecular H-bonding on the activation energy of the Bergman-Masamune-Sondheimer cycloaromatization, and to evaluate the use of the cycloaromatization for the synthesis of di-glycosylated naphthalenes. The dialkynes were prepared by cross-coupling of the O-benzylated or O-silylated glucosylalkynes 1 and 4 (Scheme 1). Thiolysis of the known 1 , or acetolysis of 1 , followed by deacetylation ( →2→3 ) and silylation gave 4 . Cross-coupling of 1 or 4 with iodo- or 1,2-diiodobezene depended upon the nature of the added amine and on the protecting group, and led to the mono- and dialkynylbenzenes 5 and 6 , or 12, 13 , and 15 , respectively. The benzyl ethers 5 and 6 gave poor yields upon acetolysis catalyzed by BF₃ · OEt₂, while Ac₂O/CoCl₂ · 6 H₂O transformed 6 in good yields into the regioselectively debenzylated 10 . Desilylation of 7 and 13 gave the alcohols 8 and 14 , respectively. Thermolysis of 6 in PhCl gave 22 and 23 , independently of the presence or absence of 1,4-cyclohexadiene; 23 was formed from 22 (Scheme 2). Acetolysis of 22 gave the hexaacetate 24 that was completely debenzylated by thiolysis, yielding the diol 26 and trans-stilbene, evidencing the nature and position of the bridge between the glucosyl moieties (Scheme 3). Thiolysis of 22 yielded the unprotected 2,3-diglucosylnaphthalene 28 , a new type of C-glycosides. Depending upon conditions, hydrogenation of 22 led to 29 (after acetylation), 30 , or 32 . NMR and particularly NOE data evidence the threo-configuration of the bridge. The structure of 23 was confirmed by hydrolysis to the diol 34 and diphenylacetaldehyde, and by correlation of 23 with 22 via the common product 31 . Formation of 22 is rationalized by a Bergman cyclization to a diradical, followed by regioselective abstraction of a H-atom from the BnO? C(2) group, and diastereoselective combination of the doubly benzylic diradical (Scheme 4). While thermolysis of 3 in EtOH sets in around 140°, 16 did not react at 160° and decomposed at 180–220°. No evidence for intramolecular H-bonds of 16 , as compared to 14 , were found.     

Regioselective A-Ring Chlorination of Benzodiazepine Analogues Using tert-Butyl Hypochlorite

Treatment of 2-phenyl-2,3-dihydro-1,4-benzodiazepin-5(4H)-one and a series of 1,4-benzoxazepinone analogues with tert-butyl hypochlorite affords products shown, by NMR and MS spectroscopy, to be chlorinated exclusively in the A-ring at positions 7 and/or 9.     

Oligosaccharide Analogues of Polysaccharides. Part 26

The anthraquinone derivatives T‐x‐x ( x = 2, 4, and 8), possessing two cellobiosyl, cellotetraosyl, and cellooctaosyl chains, respectively, C‐glycosidically bonded at C(1) and C(8) were synthesised as potential mimics of cellulose I. The anthraquinone template enforces a parallel orientation of the cellodextrin chains at a distance corresponding to the one between the crystallographically independent chains of cellulose I, and the ethynyl and buta‐1,3‐diynyl linker units ensure an appropriate phase shift between them. The H‐bonding of the T‐x‐x mimics was analysed and compared to the one of the mono‐chained analogues T‐x and of the known cellulose II mimics N‐x‐x and N‐x where one or two cellodextrin chains are O‐glycosidically bonded to naphthalene‐1,8‐diethanol, or to naphthalene‐1‐ethanol. The OH signals of T‐x and T‐x‐x in solution in (D₆)DMSO were assigned on the basis of DQFCOSY, HSQC, and TOCSY (only of T‐4, T‐4‐4 , and T‐8‐8 ) spectra and on a comparison with the spectra of N‐x and N‐x‐x. Hydrogen bonding was analysed on the basis of the chemical shift of OH groups and its temperature dependence, coupling constants, SIMPLE ¹H‐NMR experiments, and ROESY spectra. T‐4‐4 and T‐8‐8 in (D₆)DMSO appear to adopt a V‐shape arrangement of the cellosyl chains, avoiding inter‐chain H‐bond interactions. The well‐resolved solid‐state CP/MAS ¹³C‐NMR spectra of the mono‐chained T‐x ( x = 1, 2, 4, and 8) show that only T‐8 is a close mimic of cellulose II. While the solid‐state CP/MAS ¹³C‐NMR spectrum of the C₁‐symmetric diglucoside T‐1‐1 is well‐resolved, the spectra of T‐2‐2 and T‐4‐4 show broad signals, and that of T‐8‐8 is rather well resolved. The spectrum of T‐8‐8 resembles that of cellulose I_β. A comparison of the X‐ray powder‐diffraction spectra of T‐8‐8 and T‐8 with those of celluloses confirms that T‐8‐8 is a H‐bond mimic of cellulose I and T‐8 one of cellulose II. Surprisingly, there is little difference between the CP/MAS ¹³C‐NMR spectra of the acetyl protected mono‐chained C‐glycosylated anthraquinone derivatives A‐x and the double‐chained A‐x‐x ( x = 2, 4, and 8). The spectra of A‐4 and A‐4‐4 resemble strongly the one of cellulose triacetate I ( CTA I ). The (less well‐resolved) spectra of the cellooctaosides A‐8 and A‐8‐8 , however, resemble the one of CTA II . The similarity between the solid‐state CP/MAS ¹³C‐NMR spectra of A‐4 and A‐4‐4 to the one of CTA I , and of A‐8 and A‐8‐8 to the one of CTA II is opposite to the observations in the acetylated cellodextrin series. The mono‐chained A‐x cellulose triacetate mimics 21 ( A‐2 ), 32 ( A‐4 ), and 55 ( A‐8 ) were synthesised by Sonogashira coupling of the cellooligosyl‐ethynes 15, 28 , and 50 , followed by selective deacetylation. Complete deacetylation provided the corresponding T‐x mimics. The double‐chained A‐x‐x mimics 24 ( A‐2‐2 ), 35 ( A‐4‐4 ), and 58 ( A‐8‐8 ) were prepared from A‐x by triflation and Sonogashira coupling with the cellosyl‐buta‐1,3‐diynes 19, 31 , and 53 . Their deacetylation provided the corresponding T‐x‐x mimics 25, 36 , and 59 . The cellooligosyl‐ethynes and cellooligosyl‐buta‐1,3‐diynes required for the Sonogashira coupling were prepared by stepwise glycosylation of the partially O‐benzylated β‐cellobiosyl‐ethyne and β‐cellobiosyl‐buta‐1,3‐diyne 13 and 17 , respectively, with the cellobiosyl donor 2 and the cellohexaosyl donor 47 .     

Synthesis of Ether-Linked Di- and Trisaccharide Derivatives Part I- Synthesis Of Disaccharides from 5,6-Anhydro-D-Glucose Derivatives

Abstract

We have synthesized a series of A-O-B disaccharides of the type A(6→n)B obtained by linking the D-glucose derivative (A) with each of the D-fructose, D-galactose, D-glucose, xylitol and glycerol derivatives (B). The key step in each case is the nucleophilic attack of a monosaccharide alkoxide on the C-6 site of 3-O-alkyl-5,6-anhydro-1,2-O-isopropylidene-α-D-glucofuranose; each reaction was performed in toluene-DMSO and using KOH as the base.     

Synthesis of Some New Quinazoline Derivatives Analogues to MKC-442 and TNK 561

A series of different acyclo quinazoline nucleosides 6 , 7 , 8 , 10 , 12 , 13 , and 14 have been synthesized. The site of glycosylation was confirmed by 1 H-NMR and 13 C-NMR spectroscopy.     

Chemistry of Substituted Quinolinones. Part II Synthesis of Novel 4-Pyrazolylquinolinone Derivatives

4-Hydrazino-1-methyl-2(1H)quinolinone (2) was treated with chlorophthalazine, nitrous acid, isothiocyanates and isatines, and also utilized as' a precursor for some new 4-pyrazolylquinolinones. Reaction of 2 with certain 3-acylquinolinones afforded quinolinylpyrazoloquinolinones and/or quinolinylpyrazolylquinolinones.     

Heterocyclic Synthesis Using Nitrilimines:Part 16. Synthesis of Some New Pyrazole and Spiropyrazoline Derivatives

1,3‐Dipolar cycloaddition of the nitrilimines with the 2‐propylidene‐3‐coumaranone afforded the corresponding pyrazole derivatives. Similar reactions of nitrilimines with 3‐ethylidene‐1‐indanone furnished spiropyrazoline derivatives. The spectral data of the synthesized compounds are in full agreement with its molecular structure.     

Oligosaccharide Analogues of Polysaccharides. Part 7. Synthesis of a monosaccharide-derived monomer for amylose and cyclodextrin analogues

The synthesis of monomers of type C (Scheme 1) is described. In a first approach, chloro-acetyl-addition to the dioxolane 2 (Scheme 2), followed by treatment of the resulting chlorides 3 (α-D /β-D 1:3) with excess AgOTf and Bu₃SnC?CSiMe₃ gave the axial C-alkynyl-glycoside 4 (31%) and the C-arylglycoside 5 (29%). The structure of the dialkyne 6 , obtained by deacetylation of 4 , was established by X-ray analysis. The yield of the C-alkynyl-glycoside was slightly improved by protecting the C(4)-ethynyl group as the triethysilyl derivative, but not by substituting the benzyl by allyl or 2,6-difluorobenzyl groups. Silylation of the diol 1 with (chloro)diethyl[2-(trimethylsilyl)ethynyl]silane ( 19 ) resulted in 90% of the monosilyl ether 20 . HO? C(3) of 20 should favor coordination of a Lewis acid to O? C(6), and intramolecular, inverting acetal opening should lead to the product of axial alkynylation. Indeed, treatment of 20 with in situ generated BuAlCl₂, followed by treatment of the crude product with 0.1M HCl in MeOH, gave the dialkynylated triol 22 in yields of 85 to 90%. Under similar conditions, the disilyl ether 21 reacted more slowly to 22 (75%). The slower reaction correlates with the assumed intramolecular interaction of the precoordinated Lewis acid with O? C(6) in 20 .     

新型苯并二氮卓类化合物的合成

分别以2-氯-3-硝基吡啶和4,6-二氯-5-硝基嘧啶为起始原料,经取代、还原、Bischler-Napieralski关环和氧化反应合成了新型含酮羰基的吡啶并苯并二氮卓类化合物(6a~6c)和嘧啶并苯并二氮卓类化合物(6d),其结构经1H NMR,13C NMR和ESI-MS表征。并重点考察了氧化反应条件,实验结果表明,合成6a~6c时,用乙腈作溶剂,硅藻土作载体,氧化效果较好;合成6d时,以THF为溶剂、活性炭为载体,效果较好。     

Functionalization of Piperidine Derivatives for the Site-Selective and Stereoselective Synthesis of Positional Analogues of Methylphenidate

Rhodium-catalyzed C−H insertions and cyclopropanations of donor/acceptor carbenes have been used for the synthesis of positional analogues of methylphenidate. The site selectivity is controlled by the catalyst and the amine protecting group. C−H functionalization of N-Boc-piperidine using Rh₂(R-TCPTAD)₄, or N-brosyl-piperidine using Rh₂(R-TPPTTL)₄ generated 2-substitited analogues. In contrast, when N-α-oxoarylacetyl-piperidines were used in combination with Rh₂(S-2-Cl-5-BrTPCP)₄, the C−H functionalization produced 4-susbstiuted analogues. Finally, the 3-substituted analogues were prepared indirectly by cyclopropanation of N-Boc-tetrahydropyridine followed by reductive regio- and stereoselective ring-opening of the cyclopropanes.