Functionalized chiral vinyl aminosulfoxonium salts: asymmetric synthesis and application to the synthesis of enantiopure unsaturated prolines, beta,gamma-dehydro amino acids, and cyclopentanoid keto aminosulfoxonium ylides

Methylation of the enantiopure functionalized vinyl sulfoximines 5a-e and 14a-d followed by a F- ion or DBU-mediated isomerization of the vinyl aminosulfoxonium salts 7a-e and 15a-d, respectively, gave the allyl aminosulfoxonium salts 10a-e and 17a-d, respectively. A concomitant intramolecular substitution of the aminosulfoxonium group of 10a-e and 17a-d by the amino group afforded the unsaturated prolines 8a-e and 18a-d, respectively. The starting vinyl sulfoximines are accessible through a highly selective and stereo-complementary aminoalkylation of the corresponding sulfonimidoyl-substituted mono- and bis(allyl)titanium complexes with the imino ester 4. The vinyl aminosulfoxonium salts 34, 7a-d, and E-15c experienced upon treatment with the Cl- ion a migratory substitution with formation of the delta-chloro-beta,gamma-dehydro amino acids 36, E/Z-37a-d, and 38, respectively. A migratory substitution of the hydroxy-substituted vinyl aminosulfoxonium salts 46a and 46b furnished the delta-chloro allyl alcohols E/Z-48a and E-48b, respectively. A facile one-pot conversion of the vinyl sulfoximines 31b, 5c and 45a to the allyl chlorides 36, E/Z-37c and E/Z-48a, respectively, was achieved upon treatment with a chloroformiate. A tandem cyclization of the vinyl aminosulfoxonium salts 7b, Al-7b and 57 with LiN(H)tBu yielded the cyclopentanoid keto aminosulfoxonium ylides 54, Al-54, 59, 60 and 61, respectively. The structure of the tricyclic keto aminosulfoxonium ylide Al-54 has been determined by X-ray crystal structure analysis. Ab initio calculations and a NBO analysis of the tricyclic keto aminosulfoxonium ylide XXIII show a polar structure stabilized by electrostatic interactions between the ylidic C atom and both the carbonyl C atom and the S atom.     

Synthesis and characterization of mono- and bis-methano[60]fullerenyl amino acid derivatives and their reductive ring-opening retro-bingel reactions

The addition of N-(diphenylmethylene)glycinate esters (Ph2C=NCH2CO2R) 3-6 to [60]fullerene under Bingel conditions gives, respectively, the methano[60]fullerenyl iminoesters 7-10. Upon treatment of 7-9 with sodium cyanoborohydride, in the presence of a protic or a Lewis acid, a novel reductive ring-opening reaction occurred to give the corresponding 1,2-dihydro[60]fullerenyl glycine derivatives 11-13. Using tethered bis-N-(diphenylmethylene)glycinate esters 33 and 34derived from m- and p-benzenedimethanol scaffolds, the corresponding bis-methano[60]fullerenyl iminoesters 35-38 were synthesized under double Bingel reaction conditions. The m-benzenedimethanol derivative 33 gave the trans-4 (35) and cis-3 (36) regioisomeric bisadducts in a ratio of 80:20. The analogous para-tethered derivative 34 afforded the trans-3 (37) and trans-4 (38) regioisomers in a 80:20 ratio. The regiochemistry of the major bisadducts 35 and 37 (via the trans-esterified 39) were unequivocally determined using 2D INADEQUATE and C-C TOCSY NMR experiments. The regiochemistry of these bis-additions were unexpected on the basis of literature precedents. These results unequivocally show that the regiochemistry of tethered bis-additions is not solely dependent on the nature of the tether. A mixture of the trans-4 and cis-3 nonsymmetrical bisadducts 45 and 46 was obtained from the double-Bingel cyclopropanation of a bis-N-(diphenylmethylene)glycinate tether based on a 1,3-naphthyldimethanol scaffold. The regiochemistry of these compounds (45 and 46) was identified by correlation with the diethyl esters 40 and 47, prepared by trans-esterification of 35/45 and 36/46, respectively. The INADEQUATE and molecular modeling experiments allowed topological mapping of the fullerene surfaces of the bis-methano[60]fullerenes 38 and 42. Reductive ring-opening reactions on the tethered bis-methano[60]fullerenes 35-37, 45, and 46 gave none of the expected bis-fullerenylglycinates rather the reductive ring-opening-retro-Bingel products, the 1,2-dihydro[60]fullerenylglycinates 48, 49, 52, and 53. These compounds resulted from the reductive ring-opening of one methanoimino ester moiety and a retro-Bingel reaction of the other. Under analogous reductive ring-opening-retro-Bingel conditions, the nontethered bis-methano[60]fullerene 40 afforded the 1,2-dihydro[60]fullerenylglycinate 12. Thus, it was concluded that the tether was not the driving force for the reductive elimination of one of the methano groups.     

Total synthesis of epothilone B, epothilone D, and cis- and trans-9,10-dehydroepothilone D

The phosphonium salt 35, representing one of the two principal subunits of the epothilones, was prepared from propargyl alcohol via heptenone 22. A Wittig reaction of the phosphorane from 35 with aldehyde 33, obtained from aldol condensation of ketone 27 with aldehyde 28, afforded 37. Seco acid 42 derived from 37 underwent lactonization to give cis-9,10-dehydroepothilone D (43) which was selectively reduced with diimide to yield epothilone D (4) and, after epoxidation, epothilone B (2). An alternative route to epothilone D employed alkyne 39, obtained from 33, in a Castro-Stephens reaction with allylic bromide 34 to furnish enyne 40. The latter was semi-hydrogenated to provide 37. Alkyne 46, prepared from alcohol 45, was converted to trans-vinylstannane 47 which, in a Stille coupling with allylic chloride 50, gave 51. Seco acid 52 derived from 51 underwent lactonization to give trans-9,10-dehydroepothilone D (54). Bioassay data comparing the antiproliferative activity and tubulin polymerization of 43 and 54 with epothilone B (2), epothilone D (4), and paclitaxel (7) showed that the synthetic analogues were less potent than their natural counterparts, although both retain full antiproliferative activity against a paclitaxel-resistant cell line. No significant difference in potency was noted between cis analogue 43 and its trans isomer 54.     

The rearrangement of some cyclopentanone-aryloximes: synthesis of (±)-aplysin, (±)-filiformin and of their debromo analogues.

Upon acid catalyzed rearrangement after Sheradsky, the aryloximes A gave the tricyclic aminals C, which suffered hydrolysis to lactols E. The unique alcohol 29 was then prepared through a highly stereoselective equilibration-reductive alkylation of the epimeric mixture of lactols 22a,b. Two routes, one of which was stereospecific, allowed cyclization of 29 to (±)-aplysin 34. The yield was 2.5 % from oximes 2a,b. The isomeric epi-aplysin 35 and filiformin 36 were also obtained from 29. The debromo analogues 37,38 and 39 and their trideutero derivatives 41,42 and 43 were synthesized along similar line and allowed unequivocal structure elucidation by NMR spectroscopy.     

Spiropentane mimics of nucleosides: analogues of 2'-deoxyadenosine and 2'-deoxyguanosine. Synthesis of all stereoisomers, isomeric assignment, and biological activity

Synthesis of spirocyclic analogues of 2'-deoxyadenosine and 2'-deoxyguanosine (12a-15a and 12b-15b) is described. Rhodium-catalyzed reaction of ethyl diazoacetate with methylenecyclopropane 19, obtained from 2-bromo-2-bromomethylcyclopropane 17 via debromination (16), reduction (18), and acetylation (19), gave a mixture of all four isomeric spiropentanes 20a-20d. Hydrolysis afforded hydroxy carboxylic acids 21a-21d. Acetylation of separated proximal + medial-syn isomers 21a + 21b and medial anti + distal isomers 21c + 21d furnished acetates 22a + 22b and 22c + 22d. Curtius rearrangement effected by diphenylphosphoryl azide in tert-butyl alcohol performed separately with mixtures 22a + 22b and 22c + 22d led to BOC-amino spiropentanes 23a + 23b and 23c + 23d. After deacetylation all isomers 24a-24d were separated and deprotected to give aminospiropentane hydrochlorides 25a-25d. Free bases were of limited stability. The heterocyclic moieties were introduced into individual isomers 25a-25d via 6-chloropurine derivatives 26a-26d or 30a-30d. Ammonolysis of 26a-26d furnished the adenine isomeric series 12a-15a, whereas guanine derivatives 12b-15b were obtained by hydrolysis of 30a-30d with formic acid. The isomeric assignments followed from IR spectra of BOC-aminospiropentanes 24a-24d and NMR spectra of 12a-15a including NOE and (H,H) COSY. The proximal and medial-syn isomers 12a and 12b were modest inhibitors of human cytomegalovirus (HCMV) and Epstein-Barr virus (EBV) in culture, whereas the medial-anti isomer 12c was a substrate for adenosine deaminase. The distal isomer 15b was an anti-EBV agent. The medial-syn phosphoralaninate 34 was an effective inhibitor of HCMV replication in vitro. It was also active against herpes simplex virus type 1 (HSV-1), varicella zoster virus (VZV), human immunodeficiency virus (HIV-1), hepatitis B virus (HBV), and EBV with a varying degree of cytotoxicity.     

Analogues of Sialic Acids as Potential Sialidase Inhibitors. Synthesis of C6 and C7 Analogues of N-Acetyl-6-amino-2,6-dideoxyneuraminic Acid

The piperidines 12 – 18 , piperidmose analogues of Neu5Ac ( 1 ) with a shortened side chain, were synthesized from N-acetyl-D -glucosamine via the azidoalkene 32 and tested as inhibitors of Vibrio cholerae sialidase. Deoxygenation at C(4) of the uronate 22 , obtained from the known D -GlcNAc derivative 20 , was effected by β-elimination (→ 23 ), exchange of the AcO at C(3) with a (t-Bu)Me₂SiO group and hydrogenation (→ 26 ; Scheme 1). Chain extension of 26 by reaction with Me₃SiCH₂MgCl gave the D -ido-dihydroxysilane 28 , which was transformed into the unsaturated L -xylo-mesylate 29 and further into the L -lyxo-alcohol 30 , the mesylate 31 , and the L -xylo-azide 32 . The derivatives 29 – 31 prefer a sickle zig-zag and 32 mainly an extended zig-zag conformation (Fig. 2). The piperidinecarboxylate 15 was obtained from 32 by ozonolysis (→ 33 ), intramolecular reductive animation (→ 34 ), and deprotection, while reductive animation of 34 with glycolaldehyde (→ 35 ) and deprotection gave 16 (Scheme 2). An intramolecular azide-olefin cycloaddition of 32 yielded exclusively the fused dihydrotriazole 36 , while the lactone 39 did not cyclize (Scheme 3). Treatment of 36 with AcOH (→ 37 ) followed by hydrolysis (→ 38 ) and deprotection led to the amino acid 18 . To prepare the (hydroxymethyl)piperidinecarboxylates 12 and 17 , 32 was first dihydroxylated (Scheme 4). The L -gluco-diol 40 was obtained as the major product, in agreement with Kishi's rule. Silylation of 40 (→ 42 ), oxidation with periodinane (→ 44 ), and reductive animation gave the L -gluco-piperidine 45 . It was, on the one hand, deprotected to the amino acid 12 and, on the other hand, N-phenylated (→ 46 ) and deprotected to 17 . While 45 and 12 adopt a ²C₅ conformation, the analogous N-Ph derivatives 46 and 17 adopt a ₅C² and a B_3,6 conformation, respectively, on account of the allylic 1,3-strain. The conformational effects of this 1,3-strain are also evident in the carbamate 47 , obtained from 45 (Scheme 5), and in the C(2)-epimerized bicyclic ether 48 , which was formed upon treatment of 47 with (diethylamino)sulfur trifluoride (DAST). Fluorination of 40 with DAST (→ 49 ) followed by treatment with AcOH led to the D -ido-fluorohydrin 50 . Oxidation of 50 (→ 51 ) followed by a Staudinger reaction and reduction with NaBH₃CN afforded the (fluoromethyl)piperidine 52 , while reductive amination of 51 with H₂/Pd led to the methylpiperidine 55 , which was similarly obtained from the keto tosylate 54 and from the dihydrotriazole 36 . Deprotection of 52 and 55 gave the amino acids 13 and 14 , respectively. The aniline 17 does not inhibit V. cholerae sialidase; the piperidines 12 – 16 and 18 are weak inhibitors, evidencing the importance of an intact 1,2,3-trihydroxypropyl side chain.     

Synthesis of Some New [1,8]Naphthyridine,Pyrido[2,3‐d]‐Pyrimidine,and Other Annulated Pyridine Derivatives

2‐Aminopyridine‐3‐carbonitrile derivative 1 reacted with each of malononitrile, ethyl cyanacetate, benzylidenemalononitrile, diethyl malonate, and ethyl acetoacetate to give the corresponding [1,8]naphthyridine derivatives 3 , 5 , 8 , 11 , and 14 , respectively. Further annulations of 3 , 5 , and 8 gave the corresponding pyrido[2,3‐b][1,8]naphthyridine‐3‐carbonitrile derivative 17 , pyrido[2,3‐h][1,6]naphthyridine‐3‐carbonitrile derivatives 18 and 19 , respectively. The reaction of 1 with formic acid, formamide, acetic anhydride, urea or thiourea, and 4‐isothiocyanatobenzenesulfonamide gave the pyridopyrimidine derivatives 20a , b , 21 , 22a , b , and 26 , respectively. Treatment of compound 1 with sulfuric acid afforded the amide derivative 27 . Compound 27 reacted with 4‐chlorobenzaldehyde and 1H‐indene‐1,3(2H)‐dione to give the pyridopyrimidine derivative 28 and spiro derivative 30 , respectively. In addition, compound 1 reacted with halo compounds afforded the pyrrolopyridine derivatives 32 and 34 . Finally, treatment of 1 with hydrazine hydrate gave the pyrazolopyridine derivative 35 . The structures of the newly synthesized compounds were established by elemental and spectral data.     

Deoxy-nitrosugars. 17th communication. Synthesis of ketose-derived nucleosides from 1-deoxy-1-nitroribose

A new approach to ketose-derived nucteosides is described. It is based upon a chain elongation of 1-deoxy-1-nitroaldoses, followed by activation of the nitro group as a leaving group, and introduction of a pyrimidine or purine base. Thus, the nitroaldose 7 was prepared from 3 by pivaloylation (→ 4 ), synthesis of the anomeric nitrones 5/6 , and ozonolysis of 6 (Scheme 1). Partial hydrolysis of 4 yielded 8/9 , which were characterized as the acetates 10/11 and transformed into the nitrones 12/13 . Ozonolysis of 12/13 gave 14/15 , which were acetylated to 16/17 . Henry reaction of 7 lead to 19 and 20 , which were acetylated to 21 and 22 (Scheme 2). Michael addition of 7 to acrylonitrile and to methyl propynoate yielded the anomers 23/24 and 25/26 , respectively. Similar reactions of 16/17 were prevented by a facile β-elimination. Therefore, the nitrodiol 15 was transformed into the orthoesters 27 and then, by Henry reaction, partial hydrolysis, and acetylation, into 28 and 29 (Scheme 2). The structure of 19 was established by X-ray analysis. It was the major product of the kinetically controlled Henry reaction of 7 . Similarly, the β-D-configurated nitroaldoses 23 and 25 were the major products of the Michael addition. This indicates a preferred ‘endo’-attack on the nitronate anion derived from 7 . AMI calculations for this anion indicate a strong pyramidalization at C(1), in agreement with an ‘endo’-attack. Nucleosidation of 21 by 31 afforded 32 and 33 . Yields depended strongly upon the nature and the amount of the promoter and reached 77% for 33 , which was transformed into 34 , 35 , and the known ‘psicouridine’ ( 36 ; Scheme 3). To probe the mechanism, the trityl-protected 30 was nucleosidated yielding 37 , or 37 and 38 , depending upon the amount of FeCl₃. Nucleosidation of the nitroacetate 28 was more difficult, required SnCl₂ as a promoter, and yielded 39 and 40 . The β-D-anomer 40 was transformed into 36 . Nucleosidation of 23 (SnCl₄) yielded the anomers 41 and 42 , which were transformed into 43 and 44 , and hence into 45 and 46 (Scheme 4). Similarly, nucleosidation of 25 yielded 47 and 48 , which were deprotected to 49 and 50 , respectively. The nucleoside 49 was saponified to 51 . Nucleosidation of 21 by 52 (SnCl₂) afforded the adenine nucleosides 53 and 54 (Scheme 5). The adenine nucleoside 53 was deprotected (→ 55 → 56 ) to ‘psicofuranine’ (1), which was also obtained from 58 , formed along with 57 by nucleosidation of 28 . The structure and particularly the conformation of the nitroaldoses, nitroketoses, and nucleosides are examined.     

Synthesis of the 6-C-Methyl and 6-C-(Hydroxymethyl) Analogues of N-Acetylneuraminic Acid and of N-Acetyl-2,3-didehydro-2-deoxyneuraminic Acid

The synthesis of 6-C-methyl-Neu2en5Ac ( 4 ), 6-C-(hydroxymethyl)-Neu2en5Ac ( 5 ), and 6-C-methyl-Neu5Ac ( 6 ) is described. The 4-methylumbellyferyl glycosides 8 and 9 were also prepared but proved unstable. Protection of the previously reported nitro ether 10 (→ 11 ) followed by a Kornblum reaction gave the branched-chain derivative 13 which was transformed into aldehyde 14 and hence via 16 into the-protected 6-C-hydroxymethylated 20 and into the 6-C-methyl-substituted 18 (Scheme 1). Debenzylidenation of 20 and 18 afforded the diols 21 and 19 , respectively. Selective oxydation of 19 followed by esterification (→ 22 ), acetylation (→ 23 ), and elimination led to the protected 6-C-methyl-Neu2en5Ac derivative 24 (Scheme 2). Bromomethoxylation yielded mainly 25 and some 26 , which were reductively debrominated to 27 and 28 , respectively. Attempted deprotection of 27 did not lead to the corresponding acid, but to the 2,7- and 2,8-anhydro compounds 29 and 30 which were characterised as their peracetylated esters 31 and 32 (Scheme 3). The structure of 32 was established by X-ray analysis. Oxydation of 19 and 21 , followed by deprotection, esterification, and acetylation gave 37 and 38 , respectively (Scheme 4). The branched-chain Neu2en5Ac derivatives 4 and 5 were obtained by β-elimination (→ 39 and 40 ) and deprotection. Omission of the esterification after oxydation of 33 and 34 gave the lactones 35 and 36 which were transformed into 37 and 38 , respectively. Bromoacetoxylation of 39 gave 41-43 which were reductively debrominated to 44 (from 41 and 42 ) and 45 (Scheme 5). Bromoacetoxylation of 40 yielded 46 which was debrominated to 47. Glycosidation of the glycosyl chlorides obtained from 44 and 47 led to the α -D-glycosides 48 and 49 and to the elimination products 39 and 40 , respectively (Scheme 6). Transesterification of 48 , followed by saponification gave the unstable glycoside 8 and hence 6-C-methyl-Neu5Ac ( 6 ). The unstable glycoside 9 was obtained by similar treatment of 49 but yielded 50 under acidic conditions. The branched-chain 4 and 5 were weak inhibitors of Vibrio cholera sialidase, and 8 and 9 were very poor substrates.     

Thermolysis and Photosensitized Oxygenation of Tetrasubstituted Cyclopropenes

Bicyclic cyclopropenes 14a, 14b, and 26 were prepared by various synthetic routes. Polymer rose Bengal (p-RB) photosensitized oxygenation of bicyclooctenes 14a,b in CDCl(3) proceeded sluggishly (variable O(2) uptake of ca. 0.35-0.75 equiv in 8 h) and was accompanied by sensitizer bleaching. Preparative gas chromatography of the complex product mixtures from 14a and 14b yielded both dienes (Z- and E-29, 30, and 31) and enones (E- and Z-12, 32, 34). By contrast, p-RB photosensitized oxidation of bicyclononene 26 in CDCl(3) proceeded somewhat more rapidly (O(2) uptake of ca. 1 equiv in 2.5 h) yielding enones (20, 42-45) exclusively upon GC separation. The diene products, observed in the case of 14, result from the thermolysis of the remaining unreacted cyclopropenes, while the enones are the oxygenation products. The oxygenation was slowed by radical inhibitors, but not by (1)O(2) quenchers; nor were any oxidation products observed when these cyclopropenes were reacted with triphenylphosphine ozonide, a chemical (1)O(2) source. The data indicates that a photosensitizer-initiated free radical autoxidative process is involved. Likely intermediates in this oxygenation are epoxide 27 or 37 and hydroperoxide 28 or 38, for the bicyclooctene (14) and bicyclononene (26) systems, respectively. The absence of (1)O(2) product in these cyclopropene systems, in contradistinction to their higher homologues, may be attributable to either the relatively long C(alpha)-H(allylic) distance in alkylcyclopropenes, which places the abstractable allylic hydrogen "out of reach", or their relatively high IP. Either, or both, of these factors may have slowed the rate of the singlet oxygenation of the cyclopropenes to a point where free radical processes compete favorably. In the course of this study, we also explored the singlet oxygenation (DABCO inhibited) of enones 12a,b and 20. These generated, respectively, a mixture of peroxides identified as alpha-keto hydroperoxides 51/54 and hemiperketals 52/55 (the cyclic form of beta-keto hydroperoxides 53/56). Phosphine reduction of these peroxides yields the corresponding alcohols 33/43 and 32/42.     

Development of a highly beta-selective ribosylation reaction without using neighboring group participation: total synthesis of (+)-caprazol, a core structure of caprazamycins

Full details of the total synthesis of (+)-caprazol are described. The key elements of our approach include the early stage introduction of the aminoribose in a highly beta-selective manner, using the steric hindrance in the transition state and the construction of the diazepanone by a modified intramolecular reductive amination. The 5'-C-glycyluridine derivative 9, which was prepared stereoselectively via Sharpless asymmetric aminohydroxylation, was ribosylated with 2,3-O-alkylidene ribofuranosyl donors. It was revealed that increasing the size of the alkyl substituents of the acetal unit resulted in improving the stereoselectivity of the anomeric position, and the desired ribosides 21b (1' '-beta) and 22b (1' '-alpha) were obtained in 80% yield (21b/22b = 24.0/1) when the ribosyl fluoride 16 possessing a more sterically hindered 3-pentylidene group was used. The origin of the stereoselectivity of the ribosylation was also discussed. Construction of the diazepanone system was optimized with the model aldehyde 37, and the desired diazepanone 38 was obtained in 88% yield via two-step reaction sequence including catalytic hydrogenation followed by hydride reduction. Application of this method to the aldehyde 44 successfully afforded the diazepanone derivatives 45 and 46, functional group manipulation of which completed the total synthesis of (+)-caprazol.     

Photochemische Reaktionen. 83. Mitteilung. Verbindungen der 3,4-Dihydrojonon-Reihe als Modelle zur Photochemie γ, δ- bzw. δ, ϵ-ungesättigter Ketone und Aldehyde

Compounds of the 3,4-dihydro-ionone series as models for the photochemistry of γ, δ- and δ,?- unsaturated ketones and aldehydes . The photochemistry of γ, δ- and δ,?-unsaturated carbonyl compounds of the dihydro-ionone series has been studied, with special attention to the investigation of oxetane formation versus hydrogen abstraction. UV.-irradiation of the dihydro-β-ionone compounds with structure A ( 1 , 7 , 14 , 18 , 24 , 29 ) led to isomeric ethers with structures B ( 2 , 8 , 15 , 19 , 25 , 30 ), C ( 3 , 9 , 16 , 20 , 26 , 31 ) and D ( 4 , 21 , 27 ), isomeric bicyclic alcohols with structure E ( 5 , 10 , 17 , 22 , 28 ), and photoreduction products with structure F ( 6 , 11 , 12 , 13 ). Photolysis of dihydro-γ-ionone ( 32 ) gave a complex mixture containing fragmentation product 35 , hydrocarbon 36 , β-ambrinol ( 34 ), oxetane 33 , as well as dihydro-β-ionone ( 1 ) and three of its photoproducts ( 2 , 3 , 5 ). The dihydro-α-ionone compounds 37 and 40 gave mixtures of fragmentation products and the oxetanes 38 and 41 . Irradiation of the side-chain homologues 42 and 45 yielded 43 , which photo-cyclizes to 44 . In contrast, 3 , 4 -dihydro-3′,4′-dehydro-β-ionone ( 46 ) gave merely the isomeric open-chain triene-ketone 47 . The structures assigned to the ethers 2 , 3 , 33 , 38 and to the alcohols 5 , 10 , 13 could be confirmed by chemical reactions and mutual interconversions. The structure of the ether 21 had to be established by X-ray analysis, details of which are described. A novel intramolecular hydrogen transfer is involved in formation of ethers B . The photocyclization A → D probably proceeds by addition of the carbonyl-C atom to the double bond ( A → h ), followed by methyl (1 → 2)-shift ( h → i ). Process A → h may also be involved in formation of compounds of type C and E .     

Glycosylsulfenyl- und (Glycosylthio)sulfenyl-halogenide (Halogeno- bzw. Halogenothio-(1-thioglycoside)): Herstellung und Umsetzung mit Alkenen

Glycosylsulfenyl snf (Glycosylthio) sulfenyl Halides (Halogeno and Halogenothio 1-Thioglycosides, Resp.): Preparation and Reaction with Alkenes The disulfides 11–17 and 20 were prepared from 7, 9 , and 18 via the dithiocarbonates 8, 10 , and 19 , respectively (Scheme 2). The structure of 11 and of 13 was established by X-ray analysis. Chlorolysis (SO₂Cl₂) of 11 gave mostly the sulfenyl chloride 24 , characterized as the sulfenamide 26 , a small amount of 21 , characterized as the (glycosylthio)sulfenamide 23 , and the glycosyl chloride 27 (Scheme 3). Bromolysis of 11 followed by treatment of the crude with PhNH₂ yielded only 28 . Chlorolysis of the diglycosyl disulfide 13 , however, gave mostly the (glycosylthio)sulfenyl chloride 21 and 27 , besides 24 . Bromolysis of 13 (→ 22 and traces of 25 ) followed by treatment with PhNH₂ gave an even higher proportion of 23 . Similarly, 20 led to 29 and hence to 30 . In solution (CH₂Cl₂), the sulfenyl chloride 24 decomposes faster than the (thio)sulfenyl chloride 21 , and both interconvert. Addition of crude 24 to styrene (?78°) yielded the chloro-sulfide 31 and some 37 , both in low yields. The product of the addition of 24 to l-methylcyclohexene was transformed into the triol 32 . Silyl ethers of allylic alcohols reacted with 24 only at room temperature, yielding, after desilylation, isomer mixtures 33 and 34 , and pure 35 . Much higher yields were achieved for the addition of (thio)sulfenyl halides yielding halogeno-disulfides. Good diastereoselctivites were only obtained with 21 , its cyclohexylidene-protected analogue, and 22 , and this only in the addition to styrene (→ 36, 37, 38 ), to (E)-disubstituted alkenes (→ 46, 48, 49a/b, 50a/b, 53 ), and to trisubstituted alkenes (→ 47, 51, 52, 54, 55 ). Other monosubstituted alkenes (→ 41–45 ) and (Z)-hex-2-ene (→ 49c/d,50c/d ) reacted with low diastereoselectivities. Where structurally possible, a stereospecific trans-addition was observed; regioselectivity was observed in the addition to mono- and trisubstituted alkenes and to derivatives of allyl alcohols. The absolute configuration of the 2-chloro-disulfides was either established by X-ray analysis ( 47a ) or determined by transforming (LiAlH₄) the chloro-disulfides into known thiiranes (Scheme 5). Thus, 37, 48 , and the mixture of 49a/b and 50a/b gave the thiiranes 56, 61 , and 64 , respectively, in good-to-acceptable yields (Scheme 5). Harsher conditions transformed 56 into the thiols 57 and 58 . Similarly, 61 gave 62 . The enantiomeric excesses of these thiols were determined by GC analysis of their esters obtained with (?)-camphanoyl chloride. Addition of 21 to {[(E)-hex-2-enyl]oxy}trimethylsilane, followed by LiAlH₄ reduction and desilylation, gave the known 66 (63%, e.e. 74%). The diastereoselectivity of the addition of 21 to trans-disubstituted and trisubstituted alkenes is rationalized by assuming a preferred conformation of the (thio)sulfenyl chloride and destabilizing steric interactions with one of the alkene substituents, while the diastereoselectivity of the addition to styrene is explained by postulating a stabilizing interaction between the phenyl ring and the C(1)–S substituent (Fig.4).     

Synthesis of Enantiomerically Pure Ferrocenes from Glycofuranosyl-cyclopentadienes,synthetic equivalents of (alkoxyalkyl)fulvenes

Cyclopentadienyl C-glycosides (= glycosyl-cyclopentadienes) have been prepared as latent fulvenes. Their reaction with nucleophiles leads to cyclopentadienes substituted with (protected) alditol moieties and, hence, to enantiomerically pure metallocenes. Treatment of 1 with cyclopentadienyl anion gave the epimeric glycosyl-cyclopentadienes 6 / 7 (Scheme 1). Each epimer consisted of a ca. 1:1 mixture of the 1, 3-and 1, 4-cyclopentadienes a and b , respectively, which were separated by prep. HPLC. Slow regioisomerisation occurred at room temperature. Diels-Alder addition of N-phenylmaleimide to 6a / b ca. 3:7 at room temperature yielded three ‘endo’-adducts, i.e., a disubstituted alkene ( 8 or 9 , 25%) and the trisubstituted alkenes 10 (45%) and 11 (13%). The structure of 10 was established by X-ray analysis. Reduction of 6 / 7 (after isolation or in situ) with LiAlH₄ gave the cyclopentadienylmannitols 12a / b (80%) which were converted to the silyl ethers 13a / b (Scheme 2). Lithiation of 13a / b and reaction with FeCl₂ or TiCl₄ led to the symmetric ferrocene 14 (76%) and the titanocene 15 (34%), respectively. The mixed ferrocene 16 (63%) was prepared from 13a / b and pentamethylcyclopentadiene. Treatment of 6 / 7 with PhLi at ?78° gave a 5:3 mixture of the 1-C-phenylated alcohols 17a / b and 18a / b (71%) which were silylated to 19a / b and 20a / b , respectively. Lithiation of 19 / 20 and reaction with FeCl₂ afforded the symmetric ferrocenes 21 and 22 and the mixed ferrocene 23 (54:15:31, 79%) which were partially separated by MPLC. The configuration at C(1) of 17–22 was assigned on the basis of a conformational analysis. The reaction of the ribofuranose 24 with cyclopentadienylsodium led to the epimeric C-glycosides 27a / b and 28a (57%, ca. 1:1, Scheme 3). The in-situ reduction of 27 / 28 with LiAlH₄ followed by isopropylidenation gave 25a / b (65%) which were transformed into the ferrocene 26 (79%) using the standard method. Phenylation of 27 / 28 , desilylation, and isopropylidenation gave a 20:1 mixture of 33a / b and 34a / b (86%) which was separated by prep. HPLC. The same mixture was obtained upon phenylation of the fulvene 32 which was obtained in 36% yield from the reaction of the aldehydo-ribose 30 with cyclopentadienylsodium at ?100°. Lithiation of 33 / 34 and reaction with FeCl₂ gave the symmetric ferrocene 35 (88%). Similarly, the aldehydo-arabinose 36 was transformed via the fulvene 37 (32%) into a 18:1 mixture of 38a / b and 39a / b (78%) and, hence, into the ferrocene 40 (83%). Conformational analysis allowed to assign the configuration of 33–35 , whereas an X-ray analysis of 40 established the (1S)-configuration of 38a / b and 40 . The opposite configuration at C(1) of 38a / b and 33a / b was established by chemical degradation (Scheme 4). Hydrogenation (→ 41 and 44 , resp.), deprotection (→ 42 and 45 , resp.), NaIO₄ oxidation, and NaBH₄ reduction yielded (+)-(S)- 43 and (?)-(R)- 43 , respectively.     

Studies with polyfunctionally substituted heteroaromatics: A facile route for the synthesis of polyfunctionally substituted N-aminopyridines, 1,2,4-triazolo[1,5-a]pyridines and isoquinolines

The reactions of formaldehyde and acetaldehyde with active methylene compounds, followed by reaction with cyanoacetic acid hydrazide 2, afforded N-aminopyridine-2-one derivatives 5a-f. In contrast, the reactions of cyanoacetic acid hydrazide 2 with aliphatic aldehydes and cyanothioacetamide afforded pyridinethione derivatives 11a-b. Also, the reactions of active methylene compounds with formaldehyde and cyanoacetamide afforded pyridin(1H)-2-one derivatives 12a-c. The reactions of 5b with aldehydes and ketones afforded compounds 13a, b, 14, and 15, respectively. The reactions of 5b with arylidinemalononitriles 16a,b afforded isoquinoline derivatives 19a,b. Compound 19b by hydrolysis gave the final product 20. Compound 20 could also be formed by hydrolysis of 5b to give 21, followed by the reaction with 16b. © 1997 John Wiley & Sons, Inc.     

Synthesis of quinone derivatives of quinocarcin

O-Demethyl-DX-52-1 (3a) was prepared from quinocarcin (1) in two steps (cyanation and O-demethylation). Upon treatment with Fremy's salt, 3a and its esters 3b, 3c afforded the desired quinone 4-6 in good yields. Various substituted quinones 12-37, 47-50 were prepared from 4-6 by Thiele acetylation followed by hydrolysis of acetates and halogenation, by direct addition of amine, alcohol and mercaptan, and by epoxidation and subsequent opening of the epoxide ring with aniline. The quinonemonoketals 39b and 40 were obtained from the corresponding methoxyphenols 7b and 38b. Addition of hydroxylamine gave the quinoneoxime 44 regiospecifically. The antitumor activity of the bis-methylthioquinone (37) among the various derivatives was the most promising.     

Internally Protected Amino Sugar Equivalents from Enantiopure 1,2‐Oxazines: Synthesis of Variably Configured Carbohydrates with C‐Branched Amino Sugar Units

A stereodivergent synthesis of differently configured C2‐branched 4‐amino sugar derivatives was accomplished. The Lewis acid mediated rearrangement of phenylthio‐substituted 1,2‐oxazines delivered glycosyl donor equivalents that can directly be employed in glycosidation reactions. Treatment with methanol provided internally protected amino sugar equivalents that have been transformed into the stereoisomeric methyl glycosides 28 , ent‐ 28 , 29 , ent‐ 29 and 34 in two simple reductive steps. Reaction with natural carbohydrates or bicyclic amino sugar precursors allowed the synthesis of homo‐oligomeric di‐ and trisaccharides 44 , 46 and 47 or a hybrid trisaccharide 51 with natural carbohydrates. Access to a bivalent amino sugar derivative 54 was accomplished by reaction of rearrangement product 10 with 1,5‐pentanediol. Alternatively, when a protected L ‐serine derivative was employed as glycosyl acceptor, the glycosylated amino acid 60 was efficiently prepared in few steps. In this report we describe the synthesis of unusual amino sugar building blocks from enantiopure 1,2‐oxazines that can be attached to natural carbohydrates or natural product aglycons to produce new natural product analogues with potential applications in medicinal chemistry.     

Oligosaccharide Analogues of Polysaccharides,Part 21 , Towards New Cellulose I Mimics: Synthesis of Dialkynyl C‐glucosides of peri‐Substituted Anthraquinone

The bis‐C‐glucoside 2 has been synthesised as the first representative of a series of templated glucosides and cellooligosaccharides that mimick part of the unit cell of cellulose I. As expected, there are, at best, weakly persistent H‐bonds between the two glucosyl residues in (D₆)DMSO and (D₇)DMF solution. The acetylated oct‐1‐ynitol 7 and deca‐1,3‐diynitol 12 were prepared from the gluconolactone 5 (Scheme 1). Coupling of 12 to PhI and 2‐iodothiophene yielded 13 and 14 , respectively, while dimerisation of the benzylated and acetylated deca‐1,3‐diynitols 10 and 12 afforded the bis‐C‐glucosyloctatetrayne 15 and the less stable 16 , respectively. The 2‐glucosylthiophene 17 was obtained by treating the C‐silylated deca‐1,3‐diynitol 9 with Na₂S. Cross‐coupling of (trimethylsilyl)acetylene (TMSA) with 1,8‐bis(triflyloxy)‐9,10‐anthraquinone ( 20 ) at elevated temperature gave the dialkynylated 21 ; its structure was established by X‐ray analysis (Scheme 2). Sequential coupling of 6 or 7 and TMSA to 20 gave the symmetric dialkyne 21 , the mixed dialkynes 23 (from 6 ) and 25 (from 7 ), and the symmetric diglucoside 36 (from 7 ) in modest yields; a stepwise coupling to the acetylated monotriflate 28 proved advantageous. It led to the oct‐1‐ynitol 29 and the deca‐1,3‐diynitol 33 that were transformed into the triflates 30 and 34 , respectively. Coupling of the triflate 34 to the oct‐1‐ynitol 7 gave the unsymmetric bis‐C‐glucoside 35 ; this was obtained in higher yields by coupling the triflate 30 to the deca‐1,3‐diynitol 12 . Coupling of the bistriflate 20 with either 7 or 12 afforded the symmetric bis‐C‐glucosides 36 and 37 , respectively. Deacetylation (KCN in MeOH) of 35 – 37 provided the unsymmetric bis‐C‐glucoside 2 and the symmetric analogues 3 and 4 .     

A new synthetic approach to (+)-lactacystin based on radical cyclisation of enantiopure alpha-ethynyl substituted serine derivatives to 4-methylenepyrrolidinones

Treatment of the acetylenic bromoamide 42c, derived from the enantiopure alpha-amino alcohol 40, with Bu(3)SnH-AlBN results in an efficient 5-exo dig radical cyclisation to the 4-methylenepyrrolidinone 43/44 (2:1). Cleavage of the alkene bond in 43/44, using O(3)-Me(2)S, next gave the corresponding 4-ketopyrrolidinone 45/46. Alpha-phenylsulfanylation of 45/46, using S-methyl-p-toluenethiosulfonate-Et(3)N, proceeded in a stereoselective manner and led to the methylsulfanyl derivative 48 (ca. 9:1 selectivity). Manipulation of the functionality in 48, using two separate sequences, then led to the substituted pyrrolidinones 49b, 50 and 53 which are advanced intermediates in a previous synthesis of (+)-lactacystin 1. In related studies, the acetylenic bromoamide 28a containing all the carbon atoms in lactacystin was synthesised, but this substrate failed to undergo an anticipated radical cyclisation to the 4-methylenepyrrolidinone 30, analogous to 43/44. Instead, only the product of reduction of 28a, i.e. 28b, was produced, possibly resulting from adventitious intramolecular hydrogen-abstraction processes from the carbon centred radical intermediate 29, i.e. 32 to 33 and/or 31 to 34.     

Oligosaccharide Analogues of Polysaccharides,Part 22 , Synthesis of Cyclodextrin Analogues Containing a Buta‐1,3‐diyne‐1,4‐diyl or a Butane‐1,4‐diyl Unit

The peracetylated hexaamylose (maltohexaose) 18 was obtained by an improved acetolysis of cyclomaltohexaose (α‐cyclodextrin, α‐CD, 16 ), and transformed into the benzyl‐ and 4‐chlorobenzyl‐protected thioglycosides 22 and 23 , respectively (Scheme 2). Sequential chain elongation of 22 and 23 by glycosidation of the C‐ethynylated glucosides 9 and 11 gave the α‐anomeric heptaglycosides 24 and 26 , respectively, and their anomers 25 and 27 (Scheme 3). These were transformed into the glycosyl acceptors 28 , 30 , and 31 . Glycosidation of 28 and 30 by 13 and 15 , respectively, led to the benzyl‐protected octasaccharides 32 (αα₅α) and 33 (βα₅α), and to the chlorobenzylated analogues 34 (αα₅α) and 35 (βα₅α), while glycosidation of 31 led to the 4‐chlorobenzyl‐protected analogues 36 (αα₅β) and 37 (βα₅β) (Scheme 4). Hay coupling of O‐Bn‐ and O‐Ac‐protected linear octaoses 32 (αα₅α) and 33 (βα₅α) led to the cyclooctaamylose (γ‐cyclodextrin) analogues 38 and 43 , respectively (Scheme 5). Similarly, the 4‐chlorobenzyl‐protected analogues 34 and 35 gave 39 and 44 , and the anomeric linear precursors 36 and 37 provided the cyclootaamylose analogues 48 and 50 , respectively (Scheme 6). The influence of the constitution and configuration of the linear precursors on the rate and yield of the cyclisation was relatively weak. Deprotection and hydrogenation of 38 and 43 yielded the γ‐CD analogues 42 (αα₅α) and 47 (βα₅α), where one glycosidic O‐atom is replaced by a butanediyl group, while FeCl₃‐promoted dechlorobenzylation of 39 and 44 did not affect the butadiyne moiety and afforded the acetyleno γ‐CD's 40 (αα₅α) and 45 (βα₅α), respectively. Similarly, deprotection of 48 and 50 afforded the acetyleno γ‐CD analogues 49 (αα₅β) and 51 (βα₅β), respectively, which contain one butanediyl moiety instead of a glycosidic O‐atom. MM3* Force‐field calculations evidence the strong influence of the configuration and constitution of the new γ‐CD analogues on the shape of the cavity.