Domino‐Heck Reactions of Carba‐ and Oxabicyclic,Unsaturated Dicarboximides: Synthesis of Aryl‐Substituted,Bridged Perhydroisoindole Derivatives

The C? C coupling of the two bicyclic, unsaturated dicarboximides 5 and 6 with aryl and heteroaryl halides gave, under reductive Heck conditions, the C‐aryl‐N‐phenyl‐substituted oxabicyclic imides 7a – c and 8a – c (Scheme 3). Domino‐Heck C? C coupling reactions of 5, 6 , and 1b with aryl or heteroaryl iodides and phenyl‐ or (trimethylsilyl)acetylene also proved feasible giving 8, 9 , and 10a – c , respectively (Scheme 4). Reduction of 1b with LiAlH₄ (→ 11 ) followed by Heck arylation and reduction of 5 with NaBH₄ (→ 13 ) followed by Heck arylation open a new access to the bridged perhydroisoindole derivatives 12a , b and 14a , b with prospective pharmaceutical activity (Schemes 5 and 6).     

Enantioselective Synthesis of a Polyfunctionalized Tetracycle Related to Pentacyclic Triterpenes by Using an Anionic Cycloaddition Reaction

Herein we report a convergent enantioselective synthesis of a polyfunctionalized ABCD tetracycle by using an anionic cycloaddition reaction between a chiral bicyclic CD Nazarov intermediate (see 6 ), derived from the (?)‐Weiland–Mischer ketone, and an achiral cyclohexenone (see 5 ) adequately functionalized to furnish the ring A of pentacyclic triterpenes (Scheme 5). The chiral bicyclic CD Nazarov intermediate forms ring B upon cycloaddition with the achiral cyclohexenone to yield an ABCD tetracycle with a cis‐anti‐trans‐anti‐trans configuration (see 4 ). Further transformations on this adduct allowed reduction of the angular aldehyde function at C(10) to a Me group (→ 17 ) and introduction of an unsaturation at C(5)? C(6) by using the ketone function at C(7) (→ 3 ; Scheme 6).     

Preparation of β2‐Amino Acid Derivatives (β2hThr, β2hTrp, β2hMet, β2hPro, β2hLys,Pyrrolidine‐3‐carboxylic Acid) by Using DIOZ as Chiral Auxiliary

The title compounds were prepared from valine‐derived N‐acylated oxazolidin‐2‐ones, 1 – 3, 7, 9 , by highly diastereoselective (≥ 90%) Mannich reaction (→ 4 – 6 ; Scheme 1) or aldol addition (→ 8 and 10 ; Scheme 2) of the corresponding Ti‐ or B‐enolates as the key step. The superiority of the ‘5,5‐diphenyl‐4‐isopropyl‐1,3‐oxazolidin‐2‐one’ (DIOZ) was demonstrated, once more, in these reactions and in subsequent transformations leading to various t‐Bu‐, Boc‐, Fmoc‐, and Cbz‐protected β²‐homoamino acid derivatives 11 – 23 (Schemes 3–6). The use of ω‐bromo‐acyl‐oxazolidinones 1 – 3 as starting materials turned out to open access to a variety of enantiomerically pure trifunctional and cyclic carboxylic‐acid derivatives.     

Synthesis of Novel 8,14‐Secoursane Derivatives: Key Intermediates for the Preparation of Chiral Decalin Synthons from Ursolic Acid

The novel 8,14‐secoursatriene derivative 6 was synthesized starting from ursolic acid ( 1 ) via methyl esterification of the 17‐carboxylic acid group and benzoylation of the 3‐hydroxy group (→ 2 ; Scheme 1), ozone oxidation of the C(12)?C(13) bond (→ 3 ), dehydrogenation with Br₂/HBr (→ 4 ), enol acetylation of the resulting carbonyl group (→ 5 ; Scheme 2), and ring‐C opening with the aid of UV light (→ 6 ). Ring‐C‐opened dienone derivative 7 of ursolic acid was also obtained via selective hydrolysis of 6 (Scheme 2). Both compounds 6 and 7 are key intermediates for the preparation of chiral decalin synthons from ursolic acid.     

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.     

Dipeptide Derivatives with a Phosphonate Instead of Carboxylate Terminus by C-Alkylation of Protected (Decarboxy-dipeptidyl)phosphonates

Z-Protected diphenyl (decarboxy-dipeptidyl)phosphonates 5a - c with a (decarboxysarcosinyl)phosphonate moiety are prepared from Z-L-alanine ( 1a ). Z-L-valine ( 1b ), and Z-L-phenylalanine ( 1c ) by the following series of steps: coupling with methyl sarcosinate (→ 2a – c ), saponification (→ 3a – c ), Hofer-Moest oxidative decarboxyiation by electrolysis in MeOH (→ 4a – c ), and Arbuzov reaction with P(OPh)₃/TiCl₄ (Scheme 3). Double deprotonation and alkylation lead to non-stereoselective incorporation of side chains next to the phosphonate group (products of type 6 – 8 , nine examples, see Scheme 4). In the cases of 6a – c and 8c , the diastereoisomers could be separated and the configuration of the newly formed stereogenic center deduced. We assign the L,D-configuration to the diastereoisomers for which the ³¹ P-NMR signal appears at higher field.     

The 1,3-Dipolar Cycloadditions of Nitrile Oxides and Nitrile Imines to Alkyl Dicyanoacetates

The readily available alkyl dicyanoacetates 1 reacted with the 1,3-dipolar reagents arenecarbonitrile oxides 2 ′ and arenecarbonitrile imines 5 ′ to afford 1,2,4-oxadiazol and 1,2,4-triazol derivatives. The arenecarbonitrile oxides 2 ′ with electron-donating groups on the arene ring gave products 3a – d resulting from addition on both CN groups of 1 , and those with electron-withdrawing groups provided mono-adducts 4a – e (Scheme 1). Arylnitrile imines 5 ′ reacted with 1 to offer both bis- and mono-addition products (Scheme 2); the bis-adducts 8a , b possess an ester structure, whereas the mono-adducts 6a – d present a ketene-hemiacetal structure.     

Proton magnetic resonance studies of compounds with bridgehead nitrogen atoms—XX: The NMR spectra and stereochemistry of some hexahydropyrido[2, 1-c] [1, 4] oxazin-3(4H)-ones and related compounds

A series of substituted hexahydropyrido [2,1-c] [1,4] oxazin-3(4H)-ones has been synthesised, and the configurations of these bicyclic lactones assigned utilising chemical and spectral data. All the compounds adopt trans-fused conformations and the conformation of the lactone ring is discussed with reference to the magnitude of the geminal coupling constant of the N? CH₂? C(O)? O protons, and the vicinal couplings between the angular proton and the methylene protons adjacent to the ring oxygen atom. The lactone ring conformation is shown to differ slightly from the half chair conformation described for some monocyclic δ -lactones. The synthesis and NMR spectra of some related compounds possessing the bridgehead N? CH₂? C(O)? O system are discussed and these compounds are also shown to adopt a trans-fused ring conformation.     

Nucleotides,Part LXIII,New 2-(4-Nitrophenyl)ethyl(Npe)- and 2-(4-Nitrophenyl)ethoxycarbonyl(Npeoc)-Protected 2′-Deoxyribonucleosides and Their 3′-Phosphoramidites – Versatile Building Blocks for Oligonucleotide Synthesis

A series of new base-protected and 5′-O-(4-monomethoxytrityl)- or 5′-O-(4,4′-dimethoxytrityl)-substituted 3′-(2-cyanoethyl diisopropylphosphoramidites) and 3′-[2-(4-nitrophenyl)ethyl diisopropylphosphoramidites] 52 – 66 and 67 – 82 , respectively, are prepared as potential building blocks for oligonucleotide synthesis (see Scheme). Thus, 3′,5′-di-O-acyl- and N ²,3′-O,5′-O-triacyl-2′-deoxyguanosines can easily be converted into the corresponding O⁶-alkyl derivatives 6 , 8 , 10 , 12 , 14 , and 16 by a Mitsunobu reaction using the appropriate alcohol. Mild hydrolysis removes the acyl groups from the sugar moiety (→ 9 , 11 , 13 , 15 , and 19 (via 18 ), resp.) which can then be tritylated (→ 38 – 42 ) and phosphitylated (→ 57 – 61 ) in the usual manner. N ²-[2-(4-nitrophenyl)ethoxycarbonyl]-substituted and N ²-[2-(4-nitrophenyl)ethoxycarbonyl]-O⁶-[2-(4-nitrophenyl)ethyl]-substituted 2′-deoxyguanosines 5 and 7 , respectively, are synthesized as new starting materials for tritylation (→ 28 , 35 , and 37 ) and phosphitylation (→ 54 , 56 , 70 , and 78 ). Various O⁴-alkylthymidines (see 20 – 24 ) are also converted to their 5′-O-dimethoxytrityl derivatives (see 43 – 47) and the corresponding phosphoramidites (see 62 – 66 and 79 – 82 ).     

Reversed Stereochemical Course of the Michael Addition of Cyclohexanone to β-Nitrostyrenes by Using 1-(Trimethylsiloxy)cyclohexene/Dichloro(diisopropoxy)titanium. Preliminary Communication

Induced by a stoichiometric excess of dichloro(diisopropoxy)titanium, 1-(trimethylsiloxy)cyclohexene and p-substituted β-nitrostyrenes (Y = H,CH₃,CH₃O,CN) combine in CH₂Cl₂ solution at ?90° preferentially with relative topicity ul – opposite to the corresponding reaction of enolates or enamines. The primary products are the bicyclic nitronates 3–5 which can be separated, and which are cleaved by KF in MeOH to give the aryl(nitroethyl)-substituted cyclohexanones 1 and 2 (Tables 1 and 2, two typical procedures are given). The major products (2:1 to 4:1) are the hitherto not readily available diastereoisomers 2 of l-configuration. Instead of being solvolyzed, the bicyclic nitronate 5 can be used for nitroaldol additions (→ 6 ) and for [3 + 2]-dipolar cycloadditions (→ 7 ), diastereoselectively furnishing products with 4 asymmetric C-atoms (not counting acetal centers). The Michael addition described here is yet another example of an ul-combination of trigonal centers induced by Lewis acids, overriding the influence of the configuration of the donor component.     

Reactions of Chiral 2-(tert-Butyl)-2H,4H-1,3-dioxin-4-ones Bearing Functional Groups in the 6-Position and Diastereoselective Catalytic Hydrogenation to cis-2,6-Disubstituted 1,3-Dioxan-4-ones

(R)-5-Bromo-6-(bromomethyl)-2-(tert-butyl)-2H,4H-1,3-dioxin-4-one ( 2 ) derived from (R)-3-hydroxybutanoic acid is used for substitutions and chain elongations at the side-chain C-atom in the 6-position of the heterocycle (→ 3–6 , 10–13 ). Subsequent simultaneous reductive debromination and double-bond hydrogenation (Pd/C,H₂)occurs with essentially complete diastereoselectivity (>98% ds), with H transfer from the face opposite to the t-Bu group (→ 15–20 , Table 1). Hydrolytic cleavages of the dioxanones then lead to enantiomerically pure β-hydroxy-acid derivatives (overall self-reproduction of the stereogenic center of 3-hydroxybutanoic acid or alkylation in the 4-position of this acid with preservation of configuration).     

Hydroxyalkylierungen von Cystein über das Enolat von (2R,5R)-2(tert-Butyl)-1-aza-3-oxa-7-thiabicyclo[3.3.0]octan-4-on und unter Selbstreproduktion des Ciralitätszentrums

Hydroxyalkylations of Cysteine through the Enolate of (2R,5R)-2(tert-Butyl)-1-aza-3-oxa-7-thiabicyclo[3.3.0]octan-4-one with Self-Reproduction of the Center of Chirality The heterobicyclic compound 1 specified in the title is readily prepared as a single stereoisomer from (R)-cysteine, formaldehyde, and pivalaldhyde. While it is not possible to generate the enolate 10 from 1 qunatitatively – due to β-elimination of thiolate (→6) – an in-situ addition to aromatic aldehydes such as benzaldehydes (→13–16) , pyrrol-, furan-, and thiophen-2-carbaldehydes (→17–19) , pyridine-3-carbaldehyde (→21) , as well as to other non-enolizable aldehydes like cinnamaldehyde (→22) , can be achieved in yields of ca. 50%. The adducts ( 8 and 9 ) of lithium diisopropylamide or t-butoxide to these aldehydes are acting, probably as bases for deprotonation and as in-situ sources of the electrophilic aldehyde species (cf. 11, 12 ). - Of the four possible diastereoisomeric products, one is usually formed with >90% selectivity (Table). It is assumed that the preferred stereochemical course of the reaction corresponds to that observed previously with the analogous proline-derived enolate (See 23,24 ). A chemical correlation with l-α-methyl-β-phenylserine (25) proves the relative configuration of the benzaldehyde adduct 13 . All hydroxyalkylated products (13–19, 21, 22) are obtained as crystalline, diastereoisomerically pure compounds and are fully characterized. – The benzaldehyde derivative 13 was used to exemplify the various possible transformations of these products to monocyclic or acyclic amino-acid derivatives such as the oxazolidionenes 26 and 29 (cleavage of the ring containing the S -atom), the thiazolidines 28 , 31 , and 32 (cleavage of the cyclic N,O-acetal) and the α-branched cysteine 27 and the phenylserines 25 and 30 (cleavage of both rings to give open-chain aminoacids).     

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]).     

Synthesis of N-Acetylallosamine-Derived Disaccharides

The protected disaccharide 44 , a precursor for the synthesis of allosamidin, was prepared from the glycosyl acceptor 8 and the donors 26–28 , best yields being obtained with the trichloroacetimidate 28 (Scheme 6). Glycosidation of 8 or of 32 by the triacetylated, less reactive donors 38–40 gave the disaccharides 46 and 45 , respectively, in lower yields (Scheme 7). Regioselective glycosidation of the diol 35 by the donors 38–40 gave 42 , the axial, intramolecularly H-bonded OH? C(3) group reacting exclusively (Scheme 5). The glycosyl acceptor 8 was prepared from 9 by reductive opening of the dioxolane ring (Scheme 3). The donors 26–28 were prepared from the same precursor 9 via the hemiacetal 25 . To obtain 9 , the known 10 was de-N-acetylated (→ 18 ), treated with phthalic anhydride (→ 19 ), and benzylated, leading to 9 and 23 (Schemes 2 and 3). Saponification of 23 , followed by acetylation also gave 9 . Depending upon the conditions, acetylation of 19 yielded a mixture of 20 and 21 or exclusively 20 . Deacetylation of 20 led to the hydroxyphthalamide 22 . De-N-acetylation of the 3-O-benzylated β-D -glycosides 11 and 15 , which were both obtained from 10 , was very sluggish and accompanied by partial reduction of the O-allyl to an O-propyl group (Scheme 2). The β-D -glycoside 30 behaved very similarly to 11 and 15 . Reductive ring opening of 31 , derived from 29 , yielded the 3-O-acetylated acceptor 32 , while the analogous reaction of the β-D -anomer 20 was accompanied by a rapid 3-O→4-O acyl migration (→ 34 ; Scheme 4). Reductive ring opening of 21 gave the diol 35 . The triacetylated donors 38–40 were obtained from 20 by debenzylidenation, acetylation (→ 36 ), and deallylation (→ 37 ), followed by either acetylation (→ 38 ), treatment with Me₃SiSEt (→ 39 ), or Cl₃CCN (→ 40 ).     

Brominations of Cyclic Acetals from α-Amino Acids and α- or β-Hydroxy Acids with N-Bromosucinimide

The preparation of novel electrophilic building blocks for the synthesis of enantiomerically pure compounds (EPC) is described. Thus, the 2-(tert-butyl)dioxolanones, -oxazolidinones, -imidazolidinones, and -dioxanones obtained by acetalization of pivalaldehyde with 2-hydroxy-, 3-hydroxy-, or 2-amino-carboxylic acids are treated with N-bromosuccinimide under typical radical-chain reaction conditions (azoisobuytyronitril/CCl₄/reflux). Products of bromination in the α-position of the carbonyl group of the five-membered-ring acetals are isolated or identified ( 2, 5 , and 8 ; Scheme 1). The dioxanones are converted to 2H, 4H-dioxinones under these conditions ( 12 , 14 , 15 , 21 , and 22 ; Schemes 2 and 3). The products can be converted to chiral derivatives of pyruvic acid (methylidene derivatives 3 and 6 ) or of 3-oxo-butanoic and -pentanoic acid ( 16 and 23 ). The mechanism of the brominations is interpreted. The conversion of serine to enactiomcrically pure dioxanones 26–28 (Scheme 4) is also discussed.     

Photochemical Reactions of N‐(2‐Halogenoalkanoyl) Derivatives of Anilines

The photochemical reactions of 2‐substituted N‐(2‐halogenoalkanoyl) derivatives 1 of anilines and 5 of cyclic amines are described. Under irradiation, 2‐bromo‐2‐methylpropananilides 1a – e undergo exclusively dehydrobromination to give N‐aryl‐2‐methylprop‐2‐enamides (=methacrylanilides) 3a – e (Scheme 1 and Table 1). On irradiation of N‐alkyl‐ and N‐phenyl‐substituted 2‐bromo‐2‐methylpropananilides 1f – m , cyclization products, i.e. 1,3‐dihydro‐2H‐indol‐2‐ones (=oxindoles) 2f – m and 3,4‐dihydroquinolin‐2(1H)‐ones (=dihydrocarbostyrils) 4f – m , are obtained, besides 3f – m . On the other hand, irradiation of N‐methyl‐substituted 2‐chloro‐2‐phenylacetanilides 1o – q and 2‐chloroacetanilide 1r gives oxindoles 2o – r as the sole product, but in low yields (Scheme 3 and Table 2). The photocyclization of the corresponding N‐phenyl derivatives 1s – v to oxindoles 2s – v proceeds smoothly. A plausible mechanism for the formation of the photoproducts is proposed (Scheme 4). Irradiation of N‐(2‐halogenoalkanoyl) derivatives of cyclic amines 5a – c yields the cyclization products, i.e. five‐membered lactams 6a , b , and/or dehydrohalogenation products 7a , c and their cyclization products 8a , c , depending on the ring size of the amines (Scheme 5 and Table 3).     

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.     

Synthesis of (±)‐Glaucine and (±)‐Neospirodienone via an One‐Pot Bischler?Napieralski Reaction and Oxidative Coupling by a Hypervalent Iodine Reagent

Condensation of 3,4‐dimethoxybenzeneethanamine ( 3d ) and various benzeneacetic acids, i.e., 4a – e , via a practical and efficient one‐pot Bischler–Napieralski reaction, followed by NaBH₄ reduction, produced a series of 1‐benzyl‐1,2,3,4‐tetrahydroisoquinolines, i.e., 5a – e , in satisfactory yields (Scheme 3). Oxidative coupling of the N‐acyl and N‐methyl derivatives 6a – e of the latter with hypervalent iodine ([IPh(CF₃COO)₂]) yielded products with two different skeletons (Scheme 4). The major products from N‐acyl derivatives 6a – c were (±)‐N‐acylneospirodienones 2a – c , while the minor was the 3,4‐dihydroisoquinoline 7 . (±)‐Glaucine ( 1 ), however, was the major product starting from N‐methyl derivative 6e . Possible reaction mechanisms for the formation of these two types of skeleton are proposed (Scheme 5).     

From 1-(Silyloxy)Butadiene to 4-Amino-4-Deoxy-DL-Erythrose and to 1-Amino-1-Deoxy-DL-Erythritol Derivatives via Hetero-Diels-Alder Reactions with Acylnitroso Dienophiles

Acylnitroso dienophiles 4 reacted instantly with 1-(silyloxy)butadiene 5α and led in good yield to the regioisomeric cycloadducts 6 (major) and 7 (minor; Scheme 2, Table 1). cis-Hydroxylation of these primary cycloadducts with OsO₄ (catalyst) occurred stereospecifically and in high yield (→ 8 and 9 , resp.; Scheme 2). It was followed by reductive ring cleavage to give either 1-amino-1-deoxy-DL -erythritol or 4-amino-4-deoxy-DL -erythrose derivatives 10 and 14 , respectively, depending on the nature of the reducing agent (Schemes 3 and 4).     

In 2- und 3-Stellung verzweigte,enantiomerenreine 4,4,4-Trifluor-3-hydroxy-buttersäure-Derivate aus 6-Trifluormethyl-1,3-dioxan-und -dioxin-4-onen

Preparation of Enantiomerically Pure 4,4,4-Trifluoro-3-hydroxy-butanoic Acid Derivatives, Branched in the 2- or 3-Position, from 6-Trifluoromethyl-1,3-dioxan- and -dioxin-4-ones Enantiomerically pure 3-hydroxy-3-trifluoromethyl-propionic acid and esters, substituted in the 2- or 3-position, are prepared (13 examples) from (R)- or (S)-4,4,4-trifluoro-3-hydroxy-butanoic acid. Key intermediates are the 2-t-butyl-6-trifluoromethyl-1,3-dioxan- and -dioxin-4-ones. The Li enolate of the cis-dioxanone is generated with t-BuLi and reacts with electrophiles (alkyl halides, aldehydes, imines, nitroolefins, Br₂, I₂) with predominant formation of trans,trans-2,5,6-trisubstituted dioxanones (9 examples). Elimination of HBr from the 5-Br-substituted dioxanone gives the (R)- or (S)-dioxinone, a chiral derivative of 4,4,4-trifluoro-3-oxo-butanoic acid (trifluoro-acetoacetate). Michael additions of cuprates or of CuCl-doped Grignard reagents to the dioxinone produce 6,6-disubstituted dioxanones (10 examples) bearing a CF₃ group in the 6-position. In most cases this addition is highly diastereoselective, with the new substituent winding up in the trans position. There are, however, surprising exceptions, such as the product formed with benzylmagnesium chloride which is an abnormal adduct with a p-quinoid structure ( 26 ) and with the newly introduced group in the cis position with respect to the t-Bu group. The structures of four trisubstituted dioxanones bearing CF₃ groups are determined by X-ray crystal structure analysis (Figure 1, Table 1), one of them including the absolute configuration (by anomalous diffraction). Besides the well-known sofa, a twist-boat conformation of dioxanones appears to be favorable. The solution conformations of the different types of CF₃-substituted dioxanones are derived from Nuclear Overhauser NMR measurements and compared with the crystal structures (Figure 3).