Oligosaccharide Analogues of Polysaccharides,Part 23 , Synthesis of a Dimeric Acetyleno Cyclodextrin from a Mannopyranose‐Derived Dialkyne

The 1,4‐cis‐diethynylated α‐D ‐mannopyranose analogue 11 has been prepared from 1,6 : 2,3‐dianhydro‐β‐D ‐allopyranose ( 6 ) by alkynylating epoxide and acetal opening (Scheme 2). Eglinton coupling of 11 gave the cyclodimer 18 (Scheme 3). Crystal‐structure analysis of the corresponding bis(methanesulfonate) 19 revealed substantially bent butadiyne moieties; one mannopyranosyl ring adopts the ⁴C₁ and the other one a slightly distorted ^OS₂ conformation (Fig. 1). Hydrogenation of 18 , followed by deprotection, gave the stable butane‐1,4‐diyl‐bridged cyclodimer 21 (Scheme 3). Crystal‐structure analysis shows the ⁴C₁ conformation of the mannopyranosyl units (Fig. 2). The two butane fragments are characterised by a combination of gauche and antiperiplanar arrangements.     

Stereoselective Synthesis of [5‐[4,4,4,4′,4′,4′‐Hexafluoro‐N‐(2‐hydroxyethoxy)‐D‐valine]]‐ and [5‐[4,4,4,4′,4′,4′‐Hexafluoro‐N‐(2‐hydroxyethoxy)‐L‐valine]cyclosporin A

Addition of various amines to the 3,3‐bis(trifluoromethyl)acrylamides 10a and 10b gave the tripeptides 11a – 11f , mostly as mixtures of epimers (Scheme 3). The crystalline tripeptide 11f ₂ was found to be the N‐terminal (2‐hydroxyethoxy)‐substituted (R,S,S)‐ester HOCH₂CH₂O‐D ‐Val(F₆)‐MeLeu‐Ala‐O^tBu by X‐ray crystallography. The C‐terminal‐protected tripeptide 11f ₂ was condensed with the N‐terminus octapeptide 2b to the depsipeptide 12a which was thermally rearranged to the undecapeptide 13a (Scheme 4). The condensation of the epimeric tripeptide 11f ₁ with the octapeptide 2b gave the undecapeptide 13b directly. The undecapeptides 13a and 13b were fully deprotected and cyclized to the [5‐[4,4,4,4′,4′,4′‐hexafluoro‐N‐(2‐hydroxyethoxy)‐D ‐valine]]‐ and [5‐[4,4,4,4′,4′,4′‐hexafluoro‐N‐(2‐hydroxyethoxy)‐L ‐valine]]cyclosporins 14a and 14b , respectively (Scheme 5). Rate differences observed for the thermal rearrangements of 12a to 13a and of 12b to 13b are discussed.     

Glycosylidene Carbenes. Part 32

Acylation and sulfonylation of the N,N′‐unsubstituted glucosylidenespirodiaziridines 1A / 1B 95 : 5 with Ac₂O, BzCl, FmocCl, TsCl, (naphthalen‐2‐yl)sulfonyl, and (2,4,6‐triisopropylphenyl)sulfonyl chloride, and concomitant rearrangement gave the acylated and sulfonylated gluconolactone hydrazones 2B – 2G in 40–83% yield (Scheme 2). Similarly, the galacto and manno analogues 3A / 3B 95 : 5 and 5A / 5B 55 : 45 and the mannofuransoylidene‐diaziridine 30 were acetylated and tosylated to give 4A, 4B, 6, 31A , and 31B (55–73% yield; Schemes 2 and 5). ¹⁵N‐Labelling of 11A / 11B and 14A / 14B showed that the pseudoequatorial NH of the gluco diaziridines 1 and the pseudoaxial NH of the galacto diaziridines 3 were preferentially acetylated and tosylated (Scheme 3). Sulfonylation of the N‐methylated diaziridines 19A / 19B 72 : 28, 22A / 22B 85 : 15, 25A / 25B 85 : 15, 28A / 28B 80 : 20, and 33A / 33B / 33C / 33D 76 : 4 : 12 : 8 yielded the N‐methyl‐N‐tosylglyconolactone hydrazones 20, 23, 26, 29 , and 34 (44–66%; Schemes 4 and 5). The methylated N‐atom of the diaziridines proved more reactive, irrespective of the configuration at C(2) and C(4). The products were readily hydrolysed to glyconolactones.     

Synthesis and Characterization of New Heptalenes with Extended π‐Systems Attached to Them

Methyl heptalenecarboxylates of type A and B with π(1) and π(2) substituents in 1,4‐relation (Scheme 1) were synthetized starting with dimethyl 1‐methylheptalene‐4,5‐dicarboxylates 5b and 6b derived from 7‐isopropyl‐1,4‐dimethylazulene (=guaiazulene) and 1,4,6,8‐tetramethylazulene by thermal reaction with dimethyl acetylenedicarboxylate. The further general way of proceeding for the introduction of the π(1) and π(2) substituents is displayed in Scheme 3, and the thus obtained methyl heptalene‐5‐carboxylates of type A and B are listed in Table 1. The C?C bonds of the 2‐arylethenyl and 4‐arylbuta‐1,3‐dien‐1‐yl groups of π(1) and π(2) were in all cases (E)‐configured and showed s‐trans conformation at the C? C bonds (X‐ray and ¹H‐NOE evidence) in the B ‐type as well as in the A ‐type heptalenes (cf. Figs. 5–12). All B ‐type heptalenes showed a strongly enhanced heptalene band I in the wavelength region 440–490 nm in hexane/CH₂Cl₂ 9 : 1 (cf. Table 4 and Figs. 13–20). The A ‐type heptalenes showed in this region only weak absorption, recognizable as shoulders or simply tailing of the dominating heptalene bands II/III (Table 5). Absorption band I of the B ‐type heptalenes appeared almost at the same wavelength as the longest wavelength absorption band of comparable open‐chain α,ω‐diarylpolyenes (cf. Fig. 21). The cyclic double bond shift (DBS) of the A ‐ and B ‐type heptalenes could be photochemically steered in one or the other direction by selective irradiation (cf. Fig. 22).     

Highly Diastereo‐ and Enantioselective Aziridination of α,β‐Unsaturated Amides with Diaziridine and Mechanistic Consideration on Its Stereochemistry

During studies of aziridination of α,β‐unsaturated amides with diaziridine, we found that we could prepare both the cis‐ and trans‐aziridinecarboxamides by choosing an appropriately substituted diaziridine. While 3‐monosubstituted diaziridine 2 was suitable for the trans‐selective aziridination, employment of 3,3‐dialkyldiaziridine 1 resulted in the formation of cis‐aziridine carboxamides, irrespective of the geometry of the substrate (Scheme 1 and Tables 1 and 2). To elucidate the unique nonstereospecificity and to expand these aziridinations to asymmetric ones, several optically active diaziridines were newly prepared. Aziridination with an optically active 3‐monosubstituted diaziridine, 3‐cyclohexyl‐1‐[(1R)‐1‐phenylethyl]diaziridine 16 , proceeded smoothly with high trans‐selectivity as well as excellent enantioselectivity (up to 98% ee; see Table 3). On the other hand, highly enantioselective cis‐aziridination was achieved (>99% ee) with optically active 3,3‐dimethyl‐1‐[(1R)‐1‐phenylethyl]diaziridine 15 , though the yield was low (4%). This aziridination was considered to proceed stepwise by way of the enolate intermediate (Scheme 2). Careful inspection of the stereochemistry and its solvent‐dependence suggested that the diastereoselection of the reaction was kinetically controlled: the 1,4‐addition of N‐lithiated diaziridine was a crucial step for determination of the stereochemical course of the aziridination (Figs. 2–4).     

Heterospirocyclic N‐(2H‐Azirin‐3‐yl)‐L‐prolinates: New Dipeptide Synthons

The synthesis of methyl N‐(1‐aza‐6‐oxaspiro[2.5]oct‐1‐en‐2‐yl)‐L ‐prolinate ( 1e ) has been performed by consecutive treatment of methyl N‐[(tetrahydro‐2H‐pyran‐4‐yl)thiocarbonyl]‐L ‐prolinate ( 5 ) with COCl₂, 1,4‐diazabicyclo[2.2.2]octane (DABCO), and NaN₃ (Scheme 1). As the first example of a novel class of dipeptide synthons, 1e has been shown to undergo the expected reactions with carboxylic acids and thioacids (Scheme 2). The successful preparation of the nonapeptide 16 , which is an analogue of the C‐terminal nonapeptide of the antibiotic Trichovirin I 1B, proved that 1e can be used in peptide synthesis as a dipeptide building block (Scheme 3). The structure of 7 has been established by X‐ray crystal‐structure analysis (Figs. 1 and 2).     

Exaltone® (=Cyclopentadecanone) from Isomuscone® (=Cyclohexadecanone), a One‐C‐Atom Ring‐Contraction Methodology via a Stereospecific Favorskii Rearrangement: Regioselective Application to (−)‐(R)‐Muscone

Treatment of cyclohexadecanone ( 1g ; with I₂ (2.2 mol‐euqiv.) and KOH in MeOH) furnished the unsaturated (Z)‐ester 2g in 83% yield, via a stereospecific Favorskii rearrangement (Scheme 1). Further treatment with 3‐chloroperbenzoic acid (m‐CPBA) afforded the unreported epoxy ester 3g (88% yield), which was cleaved in 33% yield to Exaltone^® (=cyclopentadecanone; 1f ) with NaOH in MeOH/H₂O and then HCl at 65°. This methodology was similarly extended to higher (C₁₇) and lower (C₁₅ to C₁₁) cyclic ketone analogues, as well as regioselectively to (?)‐(R)‐muscone ( 5c ) and homomuscone ( 5f ) (Scheme 2). Olfactive properties of the corresponding macrocyclic 1‐oxaspiro[2,n]alkanes and ‐alkenes 4 and 8 , resulting from a Corey? Chaykovsky oxiranylation, are also presented.     

Oligosaccharide Analogues of Polysaccharides Part 25

The ethynylated gluco‐azide 11 was prepared from the dianhydrogalactose 7 by ethynylation, transformation into the dianhydromannose 10 , and opening of the oxirane ring by azide (Scheme 1). The retentive alkynylating ring opening of 11 and of the corresponding amine 12 failed. (2‐Acetamidoglucopyranosyl)acetylenes were, therefore, prepared from the corresponding mannopyranosylacetylenes. Retentive alkynylating ring opening of the partially protected β‐D ‐mannopyranose 15 , possessing a C(3) OH group, gave a 85 : 15 mixture of 16 and the (E)‐enyne 17 . The alkyne 16 was deprotected to the tetrol 18 that was selectively protected and transformed into the C(2) O triflate 20 . Treatment with NaN₃ in DMF afforded a 85 : 15 mixture of the β‐D ‐gluco configured azide 21 and the elimination product 22 . Similarly, the α‐D ‐mannopyranosylacetylene 23 was transformed into the azide 26 . Retentive alkynylating ring opening of the ethynylated anhydromannose 28 gave the expected β‐D ‐mannopyranosyl 1,4‐dialkyne 29 as the main product besides the diol 28 , the triol 31 , and the (E)‐enyne 30 (Scheme 2). This enyne was also obtained from 31 by a stereoselective carboalumination promoted by the cis (axial) HO C(2) group. Deprotection of the dialkynylated mannoside 31 led to 32 , whereas selective silylation, triflation, and azidation gave a 3 : 7 mixture of the 1‐ethynylglucal 35 and the β‐D ‐gluco azide 36 , which was transformed into the diethynylated β‐D ‐GlcNAc analogue 38 . Similarly, the diethynylated α‐D ‐mannopyranoside 39 was transformed into the disilylated α‐D ‐GlcNAc analogue 41 , and further into the diol 42 and the monosilyl ether 43 (Scheme 5). Eglinton coupling of 41 gave the symmetric buta‐1,3‐diyne 44 , which did not undergo any further Eglinton coupling, even under forcing conditions. However, Eglinton coupling of the monosilyl ether 43 and subsequent desilylation gave the C₁‐symmetric cyclotrimer 45 in moderate yields.     

Glycosylidene Carbenes. Part 4. Synthesis of Spirocyclopropanes from Acetamidoglycosylidene-Derived Diazirines

The synthesis of the first glycosylidene-derived 2-acetamido-2-deoxydiazirine 4 from N-acetylglucosamine 6 is described. Thus, 6 was transformed into the 3-O-mesylglucopyranoside 9 by glycosidation with allyl alcohol, benzylidenation, and mesylation (Scheme 2). Solvolysis of 9 gave the allopyranoside 10 which, upon benzylation and glycoside cleavage, yielded the hemiacetals 12 . Using our established method (via the lactone oxime 14 and the diaziridines 16 ), 12 gave the diazirine 4 . Thermolysis of this diazirine in the presence of i-PrOH gave the dihydro-1,3-oxazole 5 (Scheme 1); in the presence of acrylonitrile, the four diastereoisomeric spirocyclopropanes 17–20 and the acetamidoallal 21 were obtained and separated by prep. HPLC (Scheme 3). Assignment of the configuration of 17–20 is based on NOE measurements and on the effect of diamagnetic anisotropy of the CN group. The ratio of the four cyclopropanes, which is in keeping with earlier results, is rationalized.     

Synthesis of new hydrolyzable polyurethanes from L‐gulonic acid‐derived diols and diisocyanates

New polyurethanes with lactone groups in the pendants and main chains were synthesized by the polyaddition of two kinds of L ‐gulonolactone‐derived diols (2,3‐O‐isopropylidene‐L ‐gulono‐1,4‐lactone and 5,6‐O‐isopropylidene‐L ‐gulono‐1,4‐lactone) with hexamethylene diisocyanate and methyl (S)‐2,6‐diisocyanatohexanoate and by the subsequent deprotection of isopropylidene groups. They were hydrolyzed more quickly than the polyurethane derived from methyl β‐D ‐glucofuranosidurono‐6,3‐lactone in a phosphate buffer solution, the pH value of which was 8.0, at 27 °C. © 2002 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 40: 4158–4166, 2002     

Stereoselective Synthesis of 8‐Oxabicyclo[3.2.1]octane‐2,3,4,6,7‐pentols and Total Asymmetric Synthesis of 2,6‐Anhydrohepturonic Acid Derivatives and of β‐C‐manno‐Pyranosides Suitable for the Construction of (1→3)‐C,C‐Linked Trisaccharides

Enantiomerically pure (+)‐(1S,4S,5S,6S)‐6‐endo‐(benzyloxy)‐5‐exo‐{[(tert‐butyl)dimethylsilyl]oxy}‐7‐oxabicyclo[2.2.1]heptan‐2‐one ((+)‐ 5 ) and its enantiomer (−)‐ 5 , obtained readily from the Diels‐Alder addition of furan to 1‐cyanovinyl acetate, can be converted with high stereoselectivity into 8‐oxabicyclo[3.2.1]octane‐2,3,4,6,7‐pentol derivatives (see 23 – 28 in Scheme 2). A precursor of them, (1R,2S,4R,5S,6S,7R,8R)‐7‐endo‐(benzyloxy)‐8‐exo‐hydroxy‐3,9‐dioxatricyclo[4.2.1.0^2,4]non‐5‐endo‐yl benzoate ((−)‐ 19 ), is transformed into (1R,2R,5S, 6S,7R,8S)‐6‐exo,8‐endo‐bis(acetyloxy)‐2‐endo‐(benzyloxy)‐4‐oxo‐3,9‐dioxabicyclo[3.3.1]non‐7‐endo‐yl benzoate ((−)‐ 43 ) (see Scheme 5). The latter is the precursor of several protected 2,6‐anhydrohepturonic acid derivatives such as the diethyl dithioacetal (−)‐ 57 of methyl 3,5‐di‐O‐acetyl‐2,6‐anhydro‐4‐O‐benzoyl‐D ‐glycero‐D ‐galacto‐hepturonate (see Schemes 7 and 8). Hydrolysis of (−)‐ 57 provides methyl 3,5‐di‐O‐acetyl‐2,6‐anhydro‐4‐O‐benzoyl‐D ‐glycero‐D ‐galacto‐hepturonate 48 that undergoes highly diastereoselective Nozaki‐Oshima condensation with the aluminium enolate resulting from the conjugate addition of Me₂AlSPh to (1S,5S,6S,7S)‐7‐endo‐(benzyloxy)‐6‐exo‐{[(tert‐butyl)dimethylsilyl]oxy}‐8‐oxabicyclo[3.2.1]oct‐3‐en‐2‐one ((−)‐ 13 ) derived from (+)‐ 5 (Scheme 12). This generates a β‐C‐mannopyranoside, i.e., methyl (7S)‐3,5‐di‐O‐acetyl‐2,6‐anhydro‐4‐O‐benzoyl‐7‐C‐[(1R,2S,3R,4S,5R,6S,7R)‐6‐endo‐(benzyloxy)‐7‐exo‐{[(tert‐butyl)dimethylsilyl]oxy}‐4‐endo‐hydroxy‐2‐exo‐(phenylthio)‐8‐oxabicyclo[3.2.1]oct‐3‐endo‐yl]‐L ‐glycero‐D ‐manno‐heptonate ((−)‐ 70 ; see Scheme 12), that is converted into the diethyl dithioacetal (−)‐ 75 of methyl 3‐O‐acetyl‐2,6‐anhydro‐4,5‐dideoxy‐4‐C‐{[methyl (7S)‐3,5,7‐tri‐O‐acetyl‐2,6‐anhydro‐4‐O‐benzoyl‐L ‐glycero‐D ‐manno‐heptonate]‐7‐C‐yl}‐5‐C‐(phenylsulfonyl)‐L ‐glycero‐D ‐galacto‐hepturonate ( 76 ; see Scheme 13). Repeating the Nozaki‐Oshima condensation to enone (−)‐ 13 and the aldehyde resulting from hydrolysis of (−)‐ 75 , a (1→3)‐C,C‐linked trisaccharide precursor (−)‐ 77 is obtained.     

Über Umlagerungen bei der Cyclialkylierung von Arylpentanolen zu 2,3‐Dihydro‐1H‐inden‐Derivaten, 2. Mitteilung

On Rearrangements by Cyclialkylations of Arylpentanols to 2,3‐Dihydro‐1 H ‐indene Derivatives. Part 2. An Unexpected Rearrangement by the Acid‐Catalyzed Cyclialkylation of 2,4‐Dimethyl‐2‐phenylpentan‐3‐ol under Formation of trans ‐2,3‐Dihydro‐1,1,2,3‐tetramethyl‐1 H ‐indene The acid catalyzed‐cyclialkylation of 4‐(2‐chloro‐phenyl)‐2,4‐dimethylpentan‐2‐ol ( 1 ) gave two products: 4‐chloro‐2,3‐dihydro‐1,1,3,3‐tetramethyl‐1H‐indene ( 2 ) and also trans‐4‐chloro‐2,3‐dihydro‐1,1,2,3‐tetramethyl‐1H‐indene ( 3 ). A mechanism was proposed in Part 1 (cf. Scheme 1) for this unexpected rearrangement. This mechanism would mainly be supported by the result of the cyclialkylation of 2,4‐dimethyl‐2‐phenylpentan‐3‐ol ( 4 ), which, with respect to the similarity of ion II in Scheme 1 and ion V in Scheme 2, should give only product 5 . This was indeed the experimental result of this cyclialkylation. But the result of the cyclialkylation of 1,1,1,2′,2′,2′‐hexadeuterated isomer [²H₆]‐ 4 of 4 (cf. Scheme 3) requires a different mechanism as for the cyclialkylation of 1 . Such a mechanism is proposed in Schemes 5 and 6. It gives a satisfactory explanation of the experimental results and is supported by the result of the cyclialkylation of 2,4‐dimethyl‐3‐phenylpentan‐3‐ol ( 9 ; Scheme 7). The alternative migration of a Ph or of an i‐Pr group (cf. Scheme 6) is under further investigation.     

Biodegradable polymers based on renewable resources. VII. Novel random and alternating copolycarbonates from 1,4:3,6‐dianhydrohexitols and aliphatic diols

Novel copolycarbonates containing 1,4:3,6‐dianhydro‐D ‐glucitol or 1,4:3,6‐dianhydro‐D ‐mannitol units, with various methylene chain lengths, were synthesized by bulk and solution polycondensations, of several combinations of carbonate‐modified sugar derivatives and aliphatic diols. Bulk polycondensations of 1,4:3,6‐dianhydro‐2,5‐bis‐O‐(phenoxycarbonyl)‐D ‐glucitol or 1,4:3,6‐dianhydro‐2,5‐bis‐O‐(phenoxycarbonyl)‐D ‐mannitol with four α,ω‐alkanediols having methylene chain lengths of 4, 6, 8, and 10, respectively, at 180 °C afforded the corresponding copolycarbonates with number‐average molecular weight (M_n) values up to 19.₂ × 10³. ¹³C NMR analysis disclosed that these polymers had scrambled structures in which the sugar carbonate and aliphatic carbonate moieties were nearly randomly distributed along a polymer chain. However, solution polycondensations between 1,4:3,6‐dianhydro‐2,5‐bis‐O‐(p‐nitrophenoxycarbonyl)‐D ‐glucitol or 1,4:3,6‐dianhydro‐2,5‐bis‐O‐(p‐nitrophenoxycarbonyl)‐D ‐mannitol, and the α,ω‐alkanediols in sulfolane or dimethyl sulfoxide at 60 °C gave well‐defined copolycarbonates having regular structures consisting of alternating sugar carbonate and aliphatic carbonate moieties with M_n values up to 33.₈ × 10³. Differential scanning calorimetry demonstrated that all the copolycarbonates were amorphous with glass‐transition temperatures ranging from 1 to 65 °C, which decreased with increasing lengths of the methylene chain of the aliphatic diols. Additionally, all the copolycarbonates were stable up to 310–330 °C as estimated by thermogravimetric analysis. © 2003 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 41: 2312–2321, 2003     

Conjugate Addition of Lithiated (S)‐4‐Isopropyl‐3‐ [(methylthio)methyl]‐5,5‐diphenyloxazolidin‐2‐one to Cinnamoyl Derivatives: Preparation of Enantiomerically Pure 1,4‐Diols

The Li derivative of (S)‐4‐isopropyl‐3‐[(methylthio)methyl]‐5,5‐diphenyloxazolidin‐2‐one (Li‐ 2 ; synthetically equivalent to a chiral formyl anion) adds to enones and enoates in a 1,4‐fashion. Best results are obtained with 1,3‐diarylpropenones (chalcones; Scheme 2), trityl enones, and 2,6‐di(tert‐butyl)‐4‐methoxyphenyl cinnamates (Scheme 3), with yields up to 80% and diastereoselectivities up to and above 99 : 1 of the products ( 5a – f and 8a , b , e ) containing three stereogenic centers! X‐Ray crystal‐structure analysis reveals that the C,C‐bond formation occurs preferentially with relative topicity ul (Re/Si; Fig. 2). The MeS group of the 1,4‐adducts can be replaced by RO groups in Hg²⁺‐assisted substitutions, with subsequent removal and facile recovery of the chiral auxiliary (Schemes 4–6). 4‐Hydroxycarbonyl derivatives (‘homoaldols') and mono‐, di‐, and trisubstituted 1,4‐diols are, thus, accessible in enantiomerically pure forms (cf. 15, 16 , and 18 – 20 ).     

Solution 1H and 13C NMR of new chiral 1,4‐oxazepinium heterocycles and their intermediates from the reaction of 2,4‐pentanedione with α‐L‐amino acids and (R)‐(—)‐2‐phenylglycinol

The reaction of 2,4‐pentanedione ( 1 ) with (R)‐(—)‐2‐phenylglycine methyl ester ( 2 ), (R)‐(—)‐2‐phenylglycinol ( 3 ) and the proteinogenic amino acids (2S,3R)‐(—)‐2‐amino‐3‐hydroxybutyric acid (L ‐threonine) ( 4 ) and (R)‐(—)‐2‐amino‐3‐mercaptopropionic acid (L ‐cysteine) ( 5 ) methyl esters was investigated. The corresponding enamines 6 , 7 and 8 were isolated and characterized spectroscopically whereas 9 , which is unstable, was transformed in situ into 13 . Treatment of 7 , 8 and 9 with boron trifluoride etherate afforded the new [1,4]oxazepines 10 , 11 and [1,4]thiazepine ( 12 ) as their BF₃O^? salts. The structures of the enamines and their corresponding seven‐membered heterocycles were assessed by 1D and 2D NMR spectroscopy. Variable‐temperature experiments revealed different molecular mobility behavior among these heterocycles. Copyright © 2003 John Wiley & Sons, Ltd.     

Total Synthesis of the Spermidine Alkaloid 13‐Hydroxyisocyclocelabenzine

A convergent total synthesis of 13‐hydroxyisocyclocelabenzine was developed. (3S)‐Methyl 3‐amino‐3‐phenylpropanoate ( 4 ) was used as the chiral building block. The 3,4‐dihydro‐4‐hydroxyisoquinolin‐1(2H)‐one derivative ( 5 ), the key fragment for the total synthesis, was prepared by a novel base‐catalyzed lactone‐lactam ring enlargement (Scheme 3). The resulting target C(13) epimers 3a / 3b from macrocyclization (Scheme 4) were separated by repeated flash chromatography. The absolute configuration of the synthetic alkaloid was determined by an X‐ray crystal‐structure analysis, which enabled us to determine the absolute configuration (9S,13R) for natural 3a with positive [α]_D.     

Fused 1,2‐Dithioles. Part VII

The 1,2‐dithiolosultam derivative 14 was obtained from the (α‐bromoalkylidene)propenesultam derivative 9 (Scheme 1). Regioselective cleavage of the two ester groups (→ 1b or 2b ) allowed the preparation of derivatives with different substituents at C(3) in the dithiole ring (see 27 and 28 ) as well as at C(6) in the isothiazole ring (see 17 – 21 ; Scheme 2). Curtius rearrangement of the 6‐carbonyl azide 21 in Ac₂O afforded the 6‐acetamide 22 , and saponification and decarboxylation of the latter yielded ‘sulfothiolutin’ ( 30 ). Hydride reductions of two of the bicyclic sultams resulted in ring opening of the sultam ring and loss of the sulfonyl group. Thus the reduction of the dithiolosultam derivative 14 yielded the alkylidenethiotetronic acid derivative 33 (tetronic acid=furan‐2,4(3H,4H)‐dione), and the lactam‐sultam derivative 10 gave the alkylidenetetramic acid derivative 35 (tetramic acid=1,5‐dihydro‐4‐hydroxy‐2H‐pyrrol‐2‐one) (Scheme 3). Some of the new compounds ( 14, 22, 26 , and 30 ) exhibited antimycobacterial activity. The oxidative addition of 1 equiv. of [Pt(η²‐C₂H₄)L₂] ( 36a , L=PPh₃; 36b , L=1/2 dppf; 36c , L=1/2 (R,R)‐diop) into the S? S bond of 14 led to the cis‐(dithiolato)platinum(II) complexes 37a – c . (dppf=1,1′‐bis(diphenylphosphino)ferrocene; (R,R)‐diop={[(4R,5R)‐2,2‐demithyl‐1,3‐dioxolane‐4,5‐diyl]bis(methylene)}bis[diphenylphosphine]).     

Mechanisms for the Formation of Diamides and Polyamides by Aminolysis of d‐Glucaric Acid Esters

¹H and ¹³C NMR were employed to chart the conversion of the five‐membered lactone esters methyl d‐glucarate 1,4‐lactone (1) and ethyl d‐glucarate 6,3‐lactone (5) to N,N′‐dipropyl‐d‐glucaramide with n‐propylamine in DMSO‐d₆. These experiments were carried out to model the amide forming steps in polycondensation reactions between esterified d‐glucaric acid and diamines to give poly(d‐glucaramides). It was clear from the resulting NMR spectra that the lactones 1 and 5 were each converted in three consecutive steps to the product diamides; aminolysis of the lactone ester to the corresponding acyclic N‐propyl‐d‐glucaramide monoester, followed by lactonization to a five‐membered lactone amide, and concluding with aminolyis of the lactone amide to N,N′‐dipropyl‐d‐glucaramide (4). Comparison of the reaction pathways from 1 and 5 by ¹H NMR analysis suggests that ring opening of the 1,4‐lactone ester (1) and 1,4‐lactone amide (7) is faster than ring opening of the corresponding 6,3‐lactone ester (5) and 6,3‐lactone amide (3). Aminolysis of dimethyl l‐tartrate, which cannot form a five‐membered lactone, with n‐propylamine in DMSO‐d₆ was much slower than aminolysis of esterified glucaric acid, indicating that the lactone forming/lactone aminolysis steps are the dominant aminolysis rate enhancing steps from glucarate.     

C2-Symmetrical Pyrrolidine Derivatives Chiral Auxiliaries in Radical Chemistry

Fumaramides 3b and 3c bearing the C₂-symmetrical pyrrolidine moieties (2R,5R)-2,5-bis(methoxymethyl)pyrrolidine ( 2b ) or 1,3:4,6-di-O-benzylidene-2,5-dideoxy-2,5-imino-L -idit ( 2c ), respectively, as a chiral auxiliary lead to high diastereoselectivities in radical reactions (‘tin method’;Scheme 1). Removal of the chiral auxiliaries affords the corresponding alkylated fumaric acids Scheme 2. Single-crystal X-ray structures of 3b and 3c support arguments that lead to the model of 1,4-stereoinduction.