Library

Notes: In connection with the proposed structure of a trans-membrane cellular ion channel consisting of a complex between poly[(R)-3-hydroxy butanoate] (P(3-HB)) and calcium polyphosphate, CaPPi (ca. 150 units each), which is supposed to contain s-cis-bonds or even more highly strained ester conformations, we have prepared and studied the properties of the cyclic dimer of 3-HB, the diolide 1. All possible forms of 1, the rac-, the meso-, and the enantiomerically pure (R,R)- and (S,S)-compounds were prepared, purified, and characterized. The synthesis (Scheme 1) started from dimethyl succinate with the key step being the Baeyer-Villiger oxidation of the rac- and meso-2,5-dimethylcyclohexane-1,4-diones 5. The rac-diolide 1 was resolved by preparative chromatography on a Chiralcel OD column (Fig.1). The crystal structures of rac- 1 (Fig.3) and of meso- 1 (Fig.5) were determined by X-ray diffraction: the diolides 1 contain s-cis-ester bonds and an ester group with a conformation half way to the transition state of rotation (Fig.2). Strain energies for the diolides 1 of up to 17.8 kcal/mol are suggested. Accordingly, these compounds show reactivities similar to those of carboxylic-acid anhydrides or even acid chlorides. They cannot be chromatographed on silica gel, and they react with primary, secondary, and tertiary alcohols, and with amines to form derivatives of open chain 3-HB ‘dimers’, hydroxy acids 6, esters 7, and amides 8 (Scheme 2). The rate of acid-catalyzed ring opening of the diolides 1 with alcohols has been measured (Fig.6 and 7). From the results described, we conclude that it is unlikely for strained and reactive ester conformations to occur as part of ion channels through phospholipid bilayers of cells.

Notes: An efficient combination of electrospray mass spectrometry (ES-MS), spectrophotometric and 1H-NMR titrations in solution is used to characterize the assembly of the segmental ligand 2-{6-[1-(3,5-dimethoxybenzyl)-1H-benzimidazol-2-yl]pyridin-2-yl}-1, 1′-dimethyl-5,5′-methylene-2′-(5-methylpyridin-2-yl)bis[1H- benzimidazole] (L2) with ZnII and 4f metal ions, LnIII. Ligand L2 reacts with Zn(ClO4)2 in MeCN to give successively [Zn(L2)2]2+, where the metal ion is coordinated by the tridentate binding units of the ligands, and the double-helical head-to-head complex [Zn2(L2)2]4+. When L2 reacts with Ln(ClO4)3 (Ln = La, Eu, Lu), LaIII only leads to a well-defined cylindrical C1-symmetrical homodinuclear head-to-tail complex [La2(L2)3]6+ in solution, while chemical-exchange processes prevent the 1H-NMR characterization of [Eu2(L2)3]6+, and LuIII gives complicated mixtures of complexes. However, stoichiometric amounts of LnIII (Ln = La, Ce, Pr, Nd, Sm, Eu, Tb, Y, Lu), ZnII, and L2 in a 1:1:3 ratio lead to the selective formation of the C3-symmetrical heterodinuclear complexes [LnZn(L2)3]5+ under thermodynamic control. Detailed NOE studies show that the ligands are wrapped about the C3 axis defined by the metal ions, and the separation of dipolar and contact contributions to the 1H-NMR paramagnetic shifts of the axial complexes [LnZn(L2)3]5+ (Ln = Ce, Pr, Nd, Sm, Eu) in MeCN establishes that ZnII occupies the pseudo-octahedral capping coordination site defined by the three bidentate binding units, while LnIII lies in the resulting ‘facial’ pseudo-tricapped trigonal prismatic site produced by the three remaining tridentate units. Photophysical measurements show that [LnZn(L2)3]5+ (Ln = Eu, Tb) are only weakly luminescent because of quenching processes associated with the C3-cylindrical structure of the complexes. The use of 3d metal ions to control and design isomerically pure ‘facial’ tricapped trigonal prismatic lanthanide building blocks is discussed together with the calculation of a new nephelauxetic parameter associated with heterocyclic N-atoms coordinated to LnIII.

Notes: Reaction of the tartrate-derived diol (R,R)-α,α,α′,α′-tetraphenyl-2,2-dimethyl-1,3-dioxolane-4,5-dimethanol (TADDOL) with chlorodiphenylphosphane gives a new bis(diphenylphosphanyl) ligand (TADDOP). The complex 4 formed with PdCl2 has been crystallized and its structure determined by X-ray diffraction (Fig.1). The complex is used for Pd-catalyzed enantioselective 1,3-diphenylallylations of various nucleophiles which give products with enantiomer ratios of up to 88:12 (Scheme 2). Crystallization procedures lead to the enantiomerically pure (〉 99:1) product 11 derived from dimethyl malonate. The structure of the TADDOP complex 4 is compared with those of other transition-metal complexes containing chelating bis(diphenylphosphanyl) ligands (Fig.2). A crystallographic data base search reveals that the structures of transition-metal complexes containing two Ph2P groups (superpositions in Fig.3) fall into one of two categories: one with approximate C2 symmetry and the other with C1 symmetry (20 and 19 examples, resp.). A mechanistic model is proposed which correlates the conformational chirality (δ or λ) of the four Ph groups' arrangement in such complexes with the topicity of nucleophile approach on Pd-bound trans,trans-1,3-diphenylallyl groups (Scheme 3 and Table).

Notes: The regioselectivity of multiple cyclopropanations of C70 with 2-bromopropanedioates in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) as base (Bingel reaction) was investigated in a systematic study. Bisadduct formation occurred preferentially at the 6—6 bonds formed by the most pyramidalized sp2-C-atoms at the two opposite poles of the fullerene and, in the reaction with achiral bis[(ethoxycarbonyl)methyl]2-bromopropanedioate (13a), yielded three constitutionally isomeric bis(methano)fullerenes (Scheme 2). Two of them, C2-symmetrical (±)-1 and (±)-2, are chiral; a fact which had not been considered in previous investigations. Formation of the third, C2v-symmetrical isomer 3 was observed for the first time. Configurational descriptions for fullerene derivatives which possess a chiral chromophore as a result of specific functionalization patterns are proposed. Cyclopropanations of C70 with optically active bis[(S)-1-phenylbutyl] 2-bromopropanedioate (13b) yielded five optically active, C2-symmetrical bis-adducts 7-11 which could be separated by preparative HPLC and fully characterized (Scheme 3, Fig.4). Compounds 7/8 and 9/10 represent two constitutionally isomeric pairs of diastereoisomers, and their circular dichroism (CD) spectra show pronounced Cotton effects mainly due to strong chiroptical contributions from the chirally functionalized fullerene chromophores (Fig.7). Since the addition patterns on the fullerene surface in each pair of diastereoisomers have an enantiomeric relationship, their CD spectra closely resemble those expected for two enantiomers. In the third constitutional isomer 11, the addition pattern on the fullerene surface is C2v-symmetrical, and optical activity only results from the chiral addends. Its CD spectrum shows weak Cotton effects mainly from induced circular dichroism originating from the perturbation of the achiral fullerene chromophore by the attached chiral addends. Addition of diethyl 2-bromopropanedioate (2 equiv.) to the C2-symmetrical racemic bis-adduct (±)-2 yielded a mixture of tris-adducts and one major, C2-symmetrical tetrakis-adduct (±)-4 which was isolated in pure form (Scheme 4). Starting from the achiral C2v-symmetrical bis-adduct 3, one single Cs-symmetrical tris-(5) and one C2v-symmetrical tetrakis-adduct (6) were obtained as major products which were isolated and fully characterized (Scheme 5). The regioselectivity for introduction of a second addend in the same hemisphere of C70 is high and resembles the preferred pattern of bis-addition seen in the functionalization of C60.

Notes: It is shown that strains of the marine ciliate Euplotes raikovi are subtly variable in their production of secondary metabolites. Strains GA8 and 39W from Mediterranean and SB8 from Californian coasts produce the sesquiterpenoid epiraikovenal (3), while strains GA8 and SB8 also produce secoepiraikovenal (4), which play an instrumental niche-exploitation role and have also taxonomic significance. Comparison of 3 and 4 with raikovenal (2) and its putative biogenetic precursor 1, which have similar roles in the conspecific strain Morl from Casablanca coast in the Atlantic Ocean, inspired us the first case of intramolecular tele-dienone-olefin [2+2] photocycloaddition, exemplified here by the transformation of 1 into ent-3. This served also to unequivocally clarify the stereochemical relationship between 3 and 2.

Notes: The 5′-amino-5′-deoxy-2′,3′-O-isopropylideneadenosine (4) was obtained in pure form from 2′,3′-O-isopropylideneadenosine (1), without isolation of intermediates 2 and 3. The 2-(4-nitrophenyl)ethoxycarbonyl group was used for protection of the NH2 functions of 4 (→7). The selective introduction of the palmitoyl (= hexadecanoyl) group into the 5′-N-position of 4 was achieved by its treatment with palmitoyl chloride in MeCN in the presence of Et3N (→5). The 3′-O-silyl derivatives 11 and 14 were isolated by column chromatography after treatment of the 2′,3′-O-deprotected compounds 8 and 9, respectively, with (tert-butyl)dimethylsilyl chloride and 1H-imidazole in pyridine. The corresponding phosphoramidites 16 and 17 were synthesized from nucleosides 11 and 14, respectively, and (cyanoethoxy)bis(diisopropylamino)phosphane in CH2Cl2. The trimeric (2′-5′)-linked adenylates 25 and 26 having the 5′-amino-5′-deoxyadenosine and 5′-deoxy-5′-(palmitoylamino)adenosine residue, respectively, at the 5′-end were prepared by the phosphoramidite method. Similarly, the corresponding 5′-amino derivatives 27 and 28 carrying the 9-[(2-hydroxyethoxy)methyl]adenine residue at the 2′-terminus, were obtained. The newly synthesized compounds were characterized by physical means. The synthesized trimers 25-28 were 3-, 15-, 25-, and 34-fold, respectively, more stable towards phosphodiesterase from Crotalus durissus than the trimer (2′-5′)ApApA.

Notes: The 1′,2′-unsaturated 2′,3′-secoadenosine and 2′,3′-secouridine analogues were synthesized by the regioselective elimination of the corresponding 2′,3′-ditosylates, 2 and 18, respectively, under basic conditions. The observed regioselectivity may be explained by the higher acidity and, hence, preferential elimination of the anomeric H-C(1′) in comparison to H—C(4′). The retained (tol-4-yl)sulfonyloxy group at C(3′) of 3 allowed the preparation of the 3′-azido, 3′-chloro, and 3′-hydroxy derivatives 5-7 by nucleophilic substitution. ZnBr2 in dry CH2Cl2 was found to be successful in the removal (85%) of the trityl group without any cleavage of the acid-sensitive, ketene-derived N,O-ketal function. In the uridine series, base-promoted regioselective elimination (→19), nucleophilic displacement of the tosyl group by azide (→20), and debenzylation of the protected N(3)-imide function gave 1′,2′-unsaturated 5′-O-trityl-3′-azido-secouridine derivative 21. The same compound was also obtained by the elimination performed on 2,2′-anhydro-3′-azido-3′-azido-3′-deoxy-5′-O-2′,3′-secouridine (22) that reacted with KO(t-Bu) under opening of the oxazole ring and double-bond formation at C(1′).

Notes: An eight-step synthetic sequence led from the known D-xylo-pentodialdose 8 to imidazo-L-xylo-piperidinose 15, the key steps being the build-up of imidazole compound 12 by a van Leusen methodology and the intramolecular SN2 ring closure of the O-triflated benzylidene derivative 13. xylo-Piperidinose 15 appears in a half-chair conformation like the oxocarbonium ions which are the postulated intermediates in the glycoprocessing of the pyranose polysaccharides. This bicyclic azasugar should be a glycosidase inhibitor.

Notes: In 10 steps, 3′,4′-diethynyl-2′,3′,5′-trideoxy-5′-noruridine (14) was synthesized in 5% overall yield from commercial uridine, using conventional methods of nucleoside chemistry. As two functional groups capable to react with each other are present in the same molecule, the synthetic compound is able to form polymers, similar to the polynucleotides, by an acetylene coupling reaction.

Notes: The synthesis of spiropyrans 11 and 12 and spirooxazines 13-17 containing a thiophene moiety is described. Two different synthetic approaches were used. The spectrokinetic properties of these new compounds are reported.

Notes: A conformational analysis of the (3′S,5′R)-2′-deoxy-3′,5′-ethano-α-D-ribonucleosides (a-D-bicyclodeoxynucleosides) based on the X-ray analysis of N4-benzoyl-α-D-(bicyclodeoxycytidine) 6 and on 1H-NMR analysis of the α-D-bicyclodeoxynucleoside derivatives 1-7 reveals a rigid sugar structure with the furanose units in the l′-exo/2′-endo conformation and the secondary OH groups on the carbocyclic ring in the pseudoequatorial orientation. Oligonucleotides consisting of α-D-bicyclothymidine and α-D-bicyclodeoxyadenosine were successfully synthesized from the corresponding nucleosides by phosphoramidite methodology on a DNA synthesizer. An evaluation of their pairing properties with complementary natural RNA and DNA by means of UV/melting curves and CD spectroscopy show the following characteristics: i) α-bcd(A10) and α-bcd(T10) (α = short form of α-D)efficiently form complexes with complementary natural DNA and RNA. The stability of these hybrids is comparable or slightly lower as those with natural β-d(A10) or β-d(T10)( β = short form ofβ-D). ii) The strand orientation in α-bicyclo-DNA/β-DNA duplexes is parallel as was deduced from UV/melting curves of decamers with nonsymmetric base sequences. iii) CD Spectroscopy shows significant structural differences between α-bicyclo-DNA/β-DNA duplexes compared to α-DNA/β-DNA duplexes. Furthermore, α-bicyclo-DNA is ca. 100-fold more resistant to the enzyme snake-venom phosphodiesterase with respect to β-DNA and about equally resistant as α-DNA.

Notes: The course of the thermocatalytic rearrangement of cycloprop-2-ene-1-carboxylates in the presence of dirhodium(II) tetrakis(perfluorobutyrate) ([Rh2(pfb)4]) was investigated by varying the substituents of the cyclopropene ring. Product composition is markedly influenced by the number, nature, and position of the substituents, which determine the regio- and stereoselectivity of the cyclopropene-ring cleavage. A mechanism is proposed in which attack of the electrophilic RhII species is concerted with disrotatory ring opening of the incipient cyclopropyl cation and affords a metal-complexed vinylcarbene. The chemoselectivity of the latter is consistent with that of other carbenes generated in the presence of [Rh2(pfb)4].

Notes: Under the co-operative influence of two prosthetic groups, and independent of the TiCl4 concentration, complete and constant diastereofacial π-selection was achieved during the [4 + 2] cycloaddition of cyclopentadiene to N,N′-fumaroyl-di[(2R)-bornane-10,2-sultam] ((-)-1c); reactive conformations are discussed.

Notes: The β-dienoate (+)-(5S)-13a (86% ee; meaning of α and β as in α- and β-irone, resp.) was obtained from (-)-(5S)-9a via acid-catalyzed dehydration of the diastereoisomer mixture of allylic tertiary alcohols (+)-(1S,5S)-15/(+)-(1R,5S)-15 (Scheme 3). Prolonged treatment gave clean isomerization via a [1,5]-H shift to the α-isomer (-)-(R)-16a with only slight racemization (76% ee; Scheme 4). In contrast, the SnCl4-catalyzed stereospecific cyclization of (+)-(Z)-6 to (-)-trans-8a (Scheme 2), followed by a diastereoselective epoxidation to (+)-11 gave, via acid-catalyzed dehydration of the intermediate allylic secondary alcohol (-)-12, the same ester (+)-13a (Scheme 3), but with poor optical purity (13% ee), due to an initial rapid [1,2]-H shift. The absolute configuration of (-)-16a-c was confirmed by chemical correlation with (-)-trans-19 (Scheme 4). 13C-NMR Assignments and absolute configurations of the intermediate esters, acids, aldehydes, and alcohols are presented.

Notes: The Diels-Alder adduct of 2,4-dimethylfuran to 1-cyanovinyl (1′R)-camphanate ((+)-(1R,2S,4R)-2-exo-cyano-1,5-dimethyl-7-oxabicyclo[2.2.1]hept-5-en-2-endo-yl (1′R)-camphanate ((+)-1)) was converted into (+)-2,7-dideoxy-2,4-di-C-methyl-L-glycero- ((+)-6) and -D-glycero-L-altro-heptono-1,4-lactone ((+)-7), into (-)-(3R,4R,5R,6S)-3,4:5,7-bis(isopropylidenedioxy)-4,6-dimethylheptan-2-one ((-)-22), and into (+)-(2R,3R,4R,5S,6S)-3,4:5,6-bis(isopropylidenedioxy)-2,4-dimethylheptanal ((+)-34). Condensation of ((+)-34 with the lithium enolate of (-)-(1R,4R,5S,6R)-6-exo-[(tert-butyl)dimethylsilyloxy]-1,5-endo-dimethyl-7-oxabicyclo[2.2.1] heptan-2-one ((-)-38; derived from (+)-1) gave a 3:2 mixture of aldols (+)-39 and (+)-40 (mismatched pairs of a α-methyl-substituted aldehyde and (E)-enolate) whereas the reaction of (±)-34 with (±)-38 gave a 10:1 mixture of aldols (±)-41 and (±)-39. A single aldol, (-)-44, was obtained to condensing (+)-34 with the lithium enolate of (+)-(1S,4S,5S,6S)-5-exo-(benzyloxy)-1,5-endo-dimethyl-7-oxabicyclo[2.2.1]heptan-2-one ((+)-43; derived from (-)-(1S,2R,4S)-2-exo-cyano-1,5-dimethyl-7-oxabicyclo[2.2.1]hept-5-en-2-endo-yl (1′S)-camphanate ((-)-3)). All these cross-aldolisations are highly exo-face selective for the bicyclic ketones. The best stereochemical matching is obtained when the lithium enolates and α-methyl-substituted aldehydes can realize a ‘chelated transition state’ that obeys the Cram and Felkin-Anh models (steric effects). Polypropionate fragments containing eleven contiguous stereogenic centres and tertiary-alcohol moieties are thus prepared with high stereoselectivity in a convergent fashion. The chiral auxiliaries ((1R)- and (1S)-camphanic acid) are recovered at the beginning of the syntheses.

Notes: The Diels-Alder adduct (±)-3 of 2,4-dimethylfuran and 1-cyanovinyl acetate was converted stereoselectively into benzyl 6-(4-chlorophenylsulfonyl)-1,3-exo,5-trimethyl-7-oxabicyclo[2.2.1]hept-5-en-2-exo-yl (26) and -2-endo-yl ether (36). Addition of LiAlH4 to the latter led to the 3-O-benzyl derivatives 28 and 37 of (1RS,2SR,3SR,6SR)- and (1RS,2SR,3RS,6SR)-5-(4-chlorophenylsulfonyl)-2,4,6-trimethylcyclohex-4-ene-1,3-diol, respectively. Methylenation of 6-exo-(4-chlorophenylthio)-1-methyl-5-methylidene-7-oxabicyclo[2.2.1]heptan-2-one (16), obtained by reaction of (±)-3 with 4-Cl-C6H4SCl and saponification gave, 6-exo-(4-chlorophenylthio)-1-methyl-3,5-dimethylidene-7-oxabicyclo [2.2.1]heptan-2-one (43), the reduction of which with K-Selectride afforded 6-exo-(4-chlorophenylthio)-1,3-endo-dimethyl-5-methylidene-7-oxabicyclo[2.2.1]heptan-2-endo-ol (44). The 3-O-benzyl derivative 48 of (1RS,2RS,3RS,6SR)-5-(4-chlorophenylsulfonyl)- 2,4,6-trimethylcyclohex-4-ene-1,3-diol was derived from 44 via based-induced oxa-ring opening of benzyl 6-endo-(4-chlorophenylsulfonyl)-1,3-endo-5-endo-trimethyl-7-oxabicyclo[2.2.1]hept-2-endo-yl ether (49). Benzylation of 28, followed by reductive desulfonylation and oxidative cleavage of the cyclohexene moiety afforded (2RS,3SR,4RS,5RS)-3,5-bis(benzyloxy)-2,4-dimethyl-6-oxoheptanal (32).

Notes: A series of tetra-N-alkylated 1,4,8,11-tetraazacyclotetradecanes have been synthesized and their complexation potential towards Ni2+ and Cu2+ studied. In the case of sterically demanding alkyl substituents, such as i-Pr, PhCH2, or 2-MeC6H4CH2, no metal complexes are formed, whereas for substituents such as Me, Et, and Pr, the metal ion is incorporated into the macrocycle. The spectroscopic properties of the Ni2+ and Cu2+ complexes in aqueous solution indicate that, depending on the sterical hindrance of the N-substituents, the complexes are either square planar or pentacoordinated. All these Ni2+ and Cu2+ complexes react with N3- to give ternary species, the stability of which have been determined by spectrophotometric titrations. The tendency to bind N3- decreases with increasing steric hindrance of the alkyl substituents. The X-ray studies of the Ni2+ complex with the macrocycle 11, substituted by two Me and two Pr groups, and that of the Cu2+ complex with the tetraethyl derivative 8 show that in the solid state, the metal ions exhibit square planar coordination with a small distortion towards tetrahedral geometry.

Notes: The title compounds 6 and 7 have been prepared from the known 2,3-di-O-benzyl-4,6-O-benzylidene-D-galactose (18) and N2-acetyl-tri-O-benzyl-D-glucosamine oxime (29) in eight and six steps, respectively. The azidonitrile leading to the benzylated galacto-tetrazole 16 was prepared from 14 and cyclized under the conditions of its formation (Scheme 1). The alcohol 13 was obtained by oxidation of 10 followed by reduction. Better yields and diastereoselectivities were realized, when the benzylidene-protected D-galacto-alcohol 20 was subjected to oxido-reduction, yielding the L-altro-alcohol 22 via the ketone 21 (Scheme 2). Treatment of the corresponding tosylate 24 with NaN3 yielded the tetrazole 25, which was deprotected to 6. The tetrabenzyl ether 16 (from 14, or from 25 via 27) was reduced to 28 and deprotected to give the known deoxygalactostain 8 (Scheme 2). Oxidation of the hydroxynitrile 30, derived from 29, followed by reduction of 32 yielded mostly the L-ido-hydroxynitrile (Scheme 3), which was tosylated and treated with NaN3 to give the tetrazole 35a and its manno-isomer 36a, while Al(N3)3 yielded (E)- and (Z)-38 (Scheme 4). The intermediate azide 39 was isolated besides 40 when NH4N3/DMF was used; thermolysis of 39 gave mostly 35a, which was deprotected to 7, besides some elimination product 41. Both 6 and 7 are stable in the pH range 1-10; at pH 12, 6 is unaffected but, 7 shows some epimerization to the manno-configurated isomer 43. The tetrazole 6 is a competitive inhibitor of the β-galactosidases from E. coli (K1 = 1 μM, pH 6.8) and bovine liver (K1 = 0.8 μM, pH 7.0); the N-acetyl-β-D-glucosaminidase from bovine kidney is competitively inhibited by 7 (K1 ≊ 0.2 μM, pH 4.1).

Notes: (R)-and (S)-γ-cyclogeranic acid ((R)-and (S)-9, resp.) were obtained by resolution of the racemate, and their absolute configurations determined by chemical correlation. The γ-acids (R)-and (S)-9 were converted into (R)-and (S)-methyl γ-cyclogeranate ((R)-and (S)-6, resp.), and (R)-and (S)-γ-damascone ((R)-and (S)-5, resp.). A more direct entry to (R)-and (S)-9 consisted in the enantioselective protonation of a thiol ester enolate with (-)- or (γ)-N-isopropylephedrine((-)- or (γ)-20) and subsequent hydrolysis of the (R)-and (S)-S-phenyl γ-thiocyclogeranate ((R)- and (S)-24, resp.; 97% ee). The esters (R)- and (S)-24 were also used as precursors of (R)- and (S)-γ-damascone ((R)- and (S)-5, resp.). Alternatively, (S)-5 (75% ee) was obtained by enantioselective protonation of ketone enolate 29 with (-)-N-isopropylephedrine ((-)-20). Organoleptic evaluation demonstrated that the (S)-enantiomers of methyl γ-cyclogeranate and γ-damascone are markedly superior to their (R)-enantiomers.

Notes: The microscopic ionization behavior of piroxicam was investigated using two different approaches, i.e., direct UV spectroscopy and an indirect analogue approach (deductive method). The best microscopic pKa values (pKa12 = 4.60, pKa21 = 5.40, pKa22 = 2.72, and pKa11 = 1.92) were obtained by the deductive method using as pKa22 the pKa of the enolic O-methylated piroxicam 2. The results show remarkable electrostatic effects in the protonation/deprotonation equilibria, a marked increase in the acidity of the enolic function (2.68 pKa units) being caused by the pyridinium group. The electronic structure of piroxicam was studied based on 1H-NMR chemical shifts at various ionization states, indicating an extended electron conjugation through the molecule. The partition measurements in octan-1-ol/H2O of zwitterionic compound 3 (the pyridyl N-methyl derivative of piroxicam (1)) suggest that the two opposite charges in zwitterionic piroxicam are indeed in a close intramolecular proximity.

Notes: The synthesis of the trisaccharide β-D-Galp-(1→3)-β-D-GalpNAc-(1→3)-α-D-Galp-1-OPr (2) and of the tetrasaccharide α-L-Fucp-(1→2)-β-D-GalpNAc-(1→3)-β-D-Galp-1-OPr (3), starting from the disaccharidic dihydrooxazole donor 5, is described. Glycosylation of 5 with 6 in the presence of Me3SiOTf gave the trisaccharide 7 which was deprotected with standard methods to give, via 8, compound 2 (Scheme 1). Alternatively, protection of 8 as the 4′,6′-O-benzylidene derivative 9 followed by glycosylation with 10 and by standard deprotection afforded the tetrasaccharide 3 (Scheme 2). Biological testing showed that trisaccharide 2 is unable to inhibit the binding of the monoclonal antibody MBr1 to the target tumor cells MCF7, while tetrasaccharide 3 inhibits the binding in ca. 7-fold extent with respect to the previously tested trisaccharide α-L-Fucp-(1→2)-β-D-Galp-(1→3)-β-D-GalpNAc-1-OPr. These results indicate that the galactose corresponding to the unit D of compound 1 plays an important role in defining the MBr1-recognized epitope and confirm the essential role of fucose for MAb recognition.

Notes: Two pairs of enantiomerically pure cis-fused cyclopenteno-1,2,4-trioxanes (7, ent-7 and 8, ent-8) are prepared (Schemes 1-3). Their identities are established by dye-sensitized photo-oxygenation of ent-7 and 8, ent-8 to the allylichydroperxides, reduction to the corresponding alcohols, and conversion to the (1S)-camphanates (Scheme 4), the structures of which are determined by X-ray analysis. The dynamic properties of ent-7 are investigated by NMR spectroscopy and PM3 calculations. Evidence for an easily accessible twist-boat conformation is obtained. The in vitro and in vivo antimalarial activities of 7, ent-7,8, and ent-8 as well as those of the racemic mixtures are evaluated against Plasmodium falciparum, P. berghei, and P. yoelii. No correlation is observed between configuration and activity. Racemates and pure enantiomers have commensurate activities. The mode of action on the intraerythrocytic parasite is rationalized in terms of close docking by the twist-boat conformer of the trioxane on the surface of a molecule of heme, single-electron transfer to the O—O σ* orbital, and scission to the acetal radical which then irreversibly isomerizes to a C-centered radical, the ultimate lethal agent (Scheme 5).

Notes: An efficient synthesis of enantiomerically pure (R)- and (S)-2-(aminomethyl)alanine ((R)- and (S)-Ama) 1a and (R)- and (S)-2-(aminomethyl)leucine ((R)- and (S)-Aml) 1b is described (Schemes 1 and 2). Resolution of the racemic amino acids was achieved using L-phenylalanine cyclohexylamide (2) as chiral auxiliary. The free amino acids 1a, b were converted to the Nα-Boc,Nγ-Z-protected derivatives 11a, b (Scheme 3) ready for incorporation into peptides. Based on the three crystal structures of the diastereoisomeric peptides 8a, 8b, and 9b, the absolute configurations in both series were determined. β-Turn type-I geometries were observed for structures 8b and 9b, whereas 8a crystallized in an extended backbone conformation.

Notes: The absolute configuration of a series of naturally occurring and semi-synthetic halogenated furanones is proposed on the basis of chemical interconversions and X-ray and CD analyses. The CD analyses clearly reveal that the presence of the allylic O-atom has a strong influence in determining the sign and intensity of the low energy π→π* transition.

Notes: Benz[a]azulene (1) is synthesized in five steps (cf. Scheme 2) starting from commercially available 2-iodobenzyl alcohol (4) and tropylium tetrafluoroborate in an overall yield of 44%. The key step (cf. also Scheme 1) is the intramolecular Heck reaction of the 8-phenylsulfonyl-substituted heptafulvene 7, which leads in nearly quantitative yield directly to 10-(phenylsulfonyl)benz[a]azulene (8). The desulfonylation of 8 can be accomplished by Julia's method with Na2S2O4/NaHCO3 in DMF/H2O at 85-90°, thus leading to pure 1 in 78% yield. The phenylation of 8 with PhLi or PhCul at -78° in THF occurs regioselectively at C(9). Dehydrogenation of the formed dihydroazulenes with o-chloroanil in toluene at room temperature gives 9-phenyl-10-(phenylsulfonyl)-benz[a]azulene (9) in 70% yield (cf. Scheme 3), which, again, can be desulfonylated with Na2S2O4/NaHCO3 in DMF/H2O in good yields. The addition of PhLi to 1 in THF occurs at temperatures ≥ -25°. Ionic dehydrogenation (1. Ph3C+BF4-/MeCN; 2. Et3N) of the dihydro forms leads to 3, as the main product, and its positional isomers.

Notes: Dialkynes of the type 3 (Scheme 1) are regioselectively deprotected by treating them either with base in a protic solvent (→4), or- after exposing the OH group- by catalytic amounts of base in an aprotic solvent (→5 and 8). The Me3Si-protected 12 (Scheme 2) is inert to catalytic BuLi/THF which transformed 11 into 9, while K2CO3/MeOH transformed both 10 into 9, and 12 into 13, evidencing the requirement for a more hindered (hydroxypropyl)silyl substituent. C-Silylation of the carbanions derived from 17-19 (Scheme 3) with 15 led to 20-22, but only 22 was obtained in reasonable yields. The key intermediate 27 was, therefore, prepared by a retro-Brook rearrangement of 23, made by silylating the hydroxysulfide 16 with 15. The OH group of 27 was protected to yield the {[dimethyl(oxy)propyl]dimethylsilyl}acetylenes (DOPSA's) 21, 28, and 29. The orthogonally protected acetylenes 20-22, 28, and 29 were de-trimethylsilylated to the new monoprotected acetylene synthons 30-34. The scope of the orthogonal protection was checked by regioselective deprotection of the dialkynes 39-42 (Scheme 4), prepared by alkylation of 35 (→39), or by Pd0/CuI-catalyzed cross-coupling with 36-38 (→40-42). The cross-coupling depended upon the solvent and proceeded best in N,N,N′,N′ -teramethylethylenediamine (TMEDA). Main by-product was the dimer 43. On the one hand, K2CO3/MeOH removed the Me3Si group and transformed 39-42 into the monoprotected 44-47; catalytic BuLi/THF, on the other hand, transformed the alcohols 48-51, obtained by hydrolysis of 39-42, into the monoprotected dialkynes 52-55, all steps proceeding in high yields. Addition of the protected DOPSA groups to the lactones 56 (→57-59) and 62 (→63) (Schemes 5 and 6) gave the corresponding hemiketals. Reductive dehydroxylation of 57 and 58 failed; but similar treatment of 59 yielded the alcohol 61. Similarly, 63 was transformed into 64 which was protected as the tetrahydropyranyl (Thp) ether 65. In an optimized procedure, 62 was treated sequentially with lithiated 31, BuLi, and Me3SiCl (→66), followed by desilyloxylation to yield 60% of 67, which was protected as the Thp ether 68. Under basic, protic conditions, 68 yielded the monoprotected bisacetylene 69; under basic, aprotic conditions, 67 led to the monoprotected bisacetylene 70. These procedures are compatible with the butadiynediyl function. The butadiyne 73 was prepared by cross-coupling the alkyne 69 and the iodoalkyne 71 (obtained from 70, together with the triiodide 72) and either transformed to the monosilylated 76 or, via 77, to the monosilylated 78. Formation of the homodimers 74 and 75 was greatly reduced by optimizing the conditions of cross-coupling of alkynes.

Notes: 1,3,4,6,8-Pentamethylazulene (9), when heated at 100° in supercritical CO2 at 150 bar in the presence of 4 equiv. of dimethyl acetylenedicarboxylate (ADM), led to the formation of 16% of a 1:1 mixture of dimethyl 3,5,6,8,10-pentamethylheptalene-1,2-dicarboxylate 12a) and its double-bond-shifted isomer 12b as well as 4% of the corresponding azulene-1,2-dicarboxylate 13 (Scheme 4). The formation of the [1 + 2] adduct 11 (cf. Scheme 2) was not observed. Similarly, benz[a]azulene (25) yielded in supercritical CO2 (150°/170 bar) in the presence of 4 equiv. of ADM dimethyl benzo[d]heptalene-6,7-dicarboxylate (29; 30%) and dimethyl benzo[a]cyclopent[cd]azulene-1,2-dicarboxylate (28; 22%; Scheme 5). The reaction of 5,9-diphenylbenz[a]azulene (26) and ADM in supercritical CO2 (100°/150 bar) gave the corresponding benzo[d]heptalene-6,7-dicarboxylate 31 (22%) and dimethyl 5,9-diphenyl-4b,10-etheno-10H-benz[a]azulene-11,12-dicarboxylate(30; 25%; Scheme 5).

Notes: Tetraethynylethene (3,4-diethynylhex-3-ene-1,5-diyne) molecular scaffolding provided access to novel macrocyclic nanometer-sized C-rich molecules with unusual structural and electronic properties. Starting from cis-bis-deprotected cis-bis(trialkylsilyl)protected tetraethynylethenes, the per(silylethynyl)ated octadehydro[12]annulenes 1 and 2 and the corresponding dodecadehydro[18]annulenes 4 and 5 were prepared by oxidative Hay coupling. X-Ray crystal-structure analyses of (i-Pr)3Si-protected 2 and Me3Si-protected 4 showed that both annulene perimeters are perfectly planar. Electronic absorption spectral comparisons provided strong evidence that the macro rings in the deep-purple-colored 1 and 2 are antiaromatic (4n π-electrons), whereas those in yellow 4 and 5 are aromatic ((4n + 2) π-electrons). Although unstable in solution, the antiaromatic compound 2 gave high-melting crystals in which the individual octadehydro[12]annulene chromophores are isolated and stabilized in a matrix-type environment formed by the bulky (i-Pr)3Si groups. Electrochemical studies demonstrated that the antiaromatic octadehydro[12]annulene 2 undergoes two stepwise one-electron reductions more readily that the aromatic chromophore 5. This redox behavior is best explained by the formation of an aromatic (4n + 2) π-electron dianion from 2, whereas 5 loses its aromaticity upon reduction. The Me3Si derivative 4 was deprotected with borax in MeOH/THF to give the highly unstable hexaethynyl-dodecadehydro[18]annulene 6, a C30H6 isomer and macrocyclic precursor to a two-dimensional all-C-network. Deprotection of 2 did not give isolable amounts of tetraethynyl-octadehydro[12]annulene 3 due to the extreme instability of the latter. Starting from dimeric and trimeric acyclic tetraethynylethene oligomers, a series of expanded radialenes were obtained. They possess large C-cores with silylethynyl-protected peripheral valences and can be viewed as persilylated C40 (7), C50 (8), and C60 (9) isomers. These expanded C-sheets are high-melting, highly stable, soluble materials which were readily characterized by laser-desorption time-of-flight (LD-TOF) mass spectrometry. Due to inefficient macrocyclic cross-conjugation and/or non-planarity, the extent of π-electron delocalization in 7-9 is limited to the longest linearly conjugated π-electron fragment. In agreement with these properties, all three expanded radialenes exhibited similar redox behavior; they are difficult to oxidize but undergo several reversible one-electron reductions in similar potential ranges. Presumably, the reduced π-electron delocalization is also at the origin of the particularly high stability of 7-9.

Notes: trans-4,4,10-Trimethyl-9-decalone ( = trans-5,5,8a-trimethyl-octahydronaphthalen-1(2H)-one; 1), when treated with trifluoroperacetic acid, gave the unexpected hydroxyspirolactone 7-hydroxy-7,11,11-trimethyl-1-oxaspiro[5.5]undecan-2-one (6), in which the two new O-atoms were introduced in a 1,2-trans relationship. The structure of this compound was conclusively proven by X-ray crystallography. The process involves the intermediacy of 7-membered lactone 2, the expected Baeyer-Villiger product, which could also be successfully prepared under controlled conditions at 0° in a buffered medium containing Na2HPO4.

Notes: The intermediacy of metallocarbenes in decomposition reactions of iodonium ylides with [Rh2(OAc)4] was established by comparison with reactions of the corresponding diazo compounds. The sensitivity of the RhII-catalyzed intermolecular cyclopropane formation from substituted styrenes and bis(methoxycarbonyl)(phenyliodono)methanide (1a) or dimethyl diazomalonate (1b) is identical. The Hammett plot (with σ+) has a slope of -0.47. Iodonium ylides and diazo compounds afford the same products in [Rh2(OAc)4]-catalyzed cyclopropane formations, cycloadditions, and intramolecular CH insertions, and exhibit the identical selectivity in intramolecular competitions for cyclopropane formation and insertion. The intramolecular CH insertion of the ylide 20c, when carried out in the presence of a chiral catalyst ([Rh2{(-)-(S)-ptpa}4]), results in formation of 21a having an ee of 67%, identical to the ee obtained with the diazo compound 20b.

Notes: The stereoselectivity of radical reactions using cyclic iodohydrins and 2-alkoxy iodides was investigated on a simple model system obtained from indene (see 1a-d). The low level of stereoselectivity inherent to this type of systems could neither be overcome by using large protective group on the O-atom of 1c nor by complexation with Lewis acids. However, starting from the free alcohol 1c, it was possible to obtain very high selectivities (trans/cis 〉 100:1) by forming an aluminium alkoxide derivative upon treatment with methylaluminium bis[2,6-di(tert-butyl)-4-methylphenoxide] (MAD) before running the radical reaction. Despite the high steric demand of these complexes, the reactions gave satisfactory yields even for the formation of C—C bonds.

Notes: The stereoselectivity in reactions of 2-oxy-substituted radicals of type B was investigated. As expected, minimization of allylic 1,3-strain was the major controlling factor. Under standard conditions, only a modest level of stereoselectivity was observed. E.g., deuteration of the benzylated radical (R1 = benzyl) gave diastereoisomer ratios ≤ 2:1. Use of a bulky protective group on the O-atom (R1 = (t-Bu)Ph2Si) enhanced slightly the selectivity (ratio 4.1:1). However, a dramatic increase of the stereoselectivity (ratio 13:1) was obtained, when the reaction was performed with the free alcohol after treatment with bulky methylaluminium bis(phenoxide) derivatives (methyl-aluminium bis[2,6-di(tert-butyl)-4-methylphenoxide] (MAD) and methylaluminium bis(2,6-diphenylphenoxide) (MAPH)).

Notes: The complexation of N-benzyloxycarbonyl (Cbz) derivatives of the excitatory amino acids L-aspartic acid (Asp; 1), L-glutamic acid (Glu; 3), and, for the first time, L-kainic acid ((2S,3S,3S)-2-carboxy-4-(1-methylethenyl)pyrrolidine-3-acetic acid; Kai; 5) was studied in CDCl3 with a diversity of chiral receptors consisting of a 1,1′-binaphthyl spacer with (carboxamido)pyridine (CONH(py)) functionality attached to the 6,6′-positions in the major groove. Receptors of type A possess two N-(pyridin-2-yl)carboxamide H-bonding sites (e.g. 7), whereas type B-receptors have two N-(pyridine-6,2-diyl)acetamide residues attached (e.g. 8 and 9). Complexes of excitatory amino-acid derivatives and other, achiral α,β-dicarboxylic acids with these receptors are primarily stabilized by two sets of C=O···H—N and O—H ··· N H-bonds. Optically active type-A receptors such as (R)- and (S)-7 showed a preference for the larger Glu derivative, whereas type-B receptors such as (R)- and (S)-8 and (R)- and (S)-9 formed more stable complexes with the smaller Cbz-Asp. To improve the poor enantioselectivity shown by 7-9, additional functionality was introduced at the 7,7′-positions of the 1,1′-binaphthyl spacer, and the nature of the H-bonding sites in the 6,6′-positions was varied. Screening the diversity of new racemic receptors for binding affinity, which had been shown in many examples by Cram to correlate with enantioselectivity, demonstrated that (+)-10 and (+)-11 formed the most stable complexes with dicarboxylic acids, and these receptors were synthesized in enantiomerically pure form. Both are type-B binders and contain additional PhCH2O (10) and MeO (11) groups in the 7,7′-positions. By 1H-NMR binding titrations, the complexation of (R)- and (S)- 10 and (R)- and (S)-11 with the excitatory amino-acid derivatives was studied in CDCl3, and association constants Ka between 103 and 2 · 105 l mol-1 were measured for the 1:1 host-guest complexes formed. Whereas both 10 and 11 formed stable complexes, enantioselective binding was limited to the PhCH2O-substituted receptor 10, with the (R)-enantiomer complexing Cbz-Asp by 0.7 kcal mol-1 more tightly than the (S)-enantiomer. The structures of the diastereoisomeric complexes were analyzed in detail by experimental methods (complexation-induced changes in 1H-NMR chemical shifts, 1H{1H} nuclear Overhauser effect (NOE) difference spectroscopy) and computer modeling. These studies established that an unusual variety of interesting aromatic interactions and secondary electrostatic interactions are responsible for both the high binding affinity (—ΔG° up to 7.2 kcal mol-1) and the enantioselection observed with (R)- and (S)-10. In an approach to enhance the enantioselectivity by reducing the conformational flexibility of the 1,1′-binaphthyl spacer, an additional crown-ether binding site was attached to the 2,2′-positions in the minor groove of the type-B receptors (R)- and (S)-48. Both the binding affinity and the enantioselectivity (Δ(ΔG°) up to 0.7 kcal mol-1) in the complexation of the excitatory amino-acid derivatives by (R)- and (S)-48 were not altered upon complexation of Hg(CN)2 at the crown-ether binding site, demonstrating lack of cooperativity between the minor- and major-groove recognition sites.

Notes: 2′,3′-O-Isopropylidene-5-methyl(15N2)[O2,O4-17O2]uridine (= 2′,3′-O-isopropylidene (15N2)[O2,O4-17O2]-ribosylthymine; 1) was analyzed by 15N-and 17O-NMR spectroscopy. The 15N and 17O chemical shifts revealed, in the absence and presence of unlabelled 2′,3′-O-isopropylideneadenosine (2), the formation of thymine-thymine and thymine-adenine base pairs in CHCl3. As expected, cyclic complexes stabilized by two H-bonds occurred at low temperatures, but at elevated temperatures, the data suggest that open complexes involving only one H-bond prevailed. The 17O-NMR data showed the cyclic thymine-adenine pair in a reverse base pair geometry. The open base pair involved contacts to the urea-derived carbonyl O-atom of thymine. The thermodynamics of complex formation of the cyclic and open forms in both homo and hetero pairs were calculated from the temperature and concentration dependence of the 15N-NMR data using a new method. It involves a fitting procedure onto the experimental isotherms using a theoretically derived function with the standard Gibbs free energy as a parameter to be optimized. ΔH° and ΔS° were derived from a linear regression of ΔG°(T) vs. T. The fitting procedure circumvents the baseline problem and could be automated and used to calculate correct thermodynamics from UV-monitored melting curves of oligonucleotides. Since titrations are not involved, this dilution method should also be a useful alternative for stability studies of supramolecular complexes in H2O and in organic solvents.

Notes: As compounds from a calcareous sponge, Leucetta sp., of the Coral Sea, we isolated a series of novel naamidine-type alkaloids, 6-10, which are oxidized at a single benzylic position. We also report on the first marine, mixed-ligand metal complex 5 and on the first natural metal complexes 3 and 4 derived from classical naamidines, i.e., 1 and 2. The latter are also present in free form in the sponge.

Notes: The first systematic electrochemical study by cyclic voltammetry (CV) and rotating-disk electrode (RDE) of the changes in redox properties of covalent fullerene derivatives (2-11) as a function of increasing number of addends is reported. Dialkynylmethanofullerenes 2-4 undergo multiple, fullerene-centered reduction steps at slightly more negative potentials than C60 (1; see Table and Fig. 1). The two C-spheres in the dumbbell-shaped dimeric fullerene derivative 4 show independent, identical redox characteristics. This highlights the insulating character of the sp3-C-atoms in methanofullerenes which prevent through-bond communication of substituent effects from the methano bridge to the fullerene sphere. In the series of mono- through hexakis-adducts 5-11, formed by tether-directed remote functionalization, reductions become increasingly difficult and more irreversible with increasing number of addends (see Table and Fig. 2). Whereas, in 0.1M Bu4NPF6/CH2Cl2, the first reduction of mono-adduct 5 occurs reversibly at -1.06 V vs. the ferrocene/ferricinium couple (Fc/Fc+), hexakis-adduct 11 is reduced irreversibly only at - 1.87 V. Hence, with incremental functionalization of the fullerene, the LUMO of the remaining conjugated framework is raised in energy. Reduction potentials are also dependent on the relative spatial disposition of the addends on the surface of the fullerene sphere. Observed UV/VIS spectral changes and changes in the chemical reactivity along the series 5-11 are in accord with the results of electrochemical measurements. Further, with increasing number of addends, the oxidation of derivatives 5-11 becomes more reversible. Whereas oxidations are increasingly facilitated upon going from mono-adduct 5 (+1.22 V) to tris-adduct 7 (+0.90 V), they occur at nearly the same potential (+0.95 to +0.99 V) in the higher adducts 8-11. This indicates that the oxidations occur in these compounds at a common sub-structural element, for which a ‘cubic’ cyclophane is proposed (see Fig. 3). This sub-structure is fully developed in hexakis-adduct 11.

Notes: It is shown that the 2-(hydroxymethyl)-1-methylazulenes 6 are being oxidized by activated MnO2 in CH2Cl2 at room temperature to the corresponding azulene-1,2-dicarbaldehydes 7 (Scheme 2). Extension of the MnO2 oxidation reaction to 1-methyl- and/or 3-methyl-substituted azulenes led to the formation of the corresponding azulene-1-carbaldehydes in excellent yields (Scheme 3). The reaction of unsymmetrically substituted 1,3-dimethyl-azulenes (cf. 15 in Scheme 4) with MnO2 shows only little chemoselectivity. However, the observed ratio of the formed constitutionally isometric azulene-1-carbaldehydes is in agreement with the size of the orbital coefficients in the HOMO of the azulenes. The reaction of guaiazulene (18) with MnO2 in dioxane/H2O at room temperature gave mainly the expected carbaldehyde 19. However, it was accompanied by the azulene-diones 20 and 21 (Scheme 5). The precursor of the demethylated compound 20 is the carbaldehyde 19. Similarly, the MnO2 reaction of 7-isopropyl-4-methyalazulene (22) as well as of 4,6,8-trimethylazulene (24) led to the formation of a mixture of the corresponding azulene-1,5-diones and azulene-1,7-diones 20/23 and 25/26, respectively, in decent yields (Schemes 6 and 7). No MnO2 reaction was observed with 5,7-dimethylazulene.

Notes: The dehydrogenation reaction of the heptalene-4,5-dimethanols 4a and 4d, which do not undergo the double-bond-shift (DBS) process at ambient temperature, with basic MnO2 in CH2Cl2 at room temperature, leads to the formation of the corresponding heptaleno[1,2-c]furans 6a and 6d, respectively, as well as to the corresponding heptaleno[1,2-c]furan-3-ones 7a and 7d, respectively (cf. Scheme 2 and 8). The formation of both product types necessarily involves a DBS process (cf. Scheme 7). The dehydrogenation reaction of the DBS isomer of 4a, i.e., 5a, with MnO2 in CH2Cl2 at room temperature results, in addition to 6a and 7a, in the formation of the heptaleno[1,2-c]-furan-1-one 8a and, in small amounts, of the heptalene-4,5-dicarbaldehyde 9a (cf. Scheme 3). The benzo[a]heptalene-6,7-dimethanol 4c with a fixed position of the C=C bonds of the heptalene skeleton, on dehydrogenation with MnO2 in CH2Cl2, gives only the corresponding furanone 11b (Scheme 4). By [2H2]-labelling of the methanol function at C(7), it could be shown that the furanone formation takes place at the stage of the corresponding lactol [3-2H2]-15b (cf. Scheme 6). Heptalene-1,2-dimethanols 4c and 4e, which are, at room temperature, in thermal equilibrium with their corresponding DBS forms 5c and 5e, respectively, are dehydrogenated by MnO2 in CH2Cl2 to give the corresponding heptaleno[1,2-c]furans 6c and 6e as well as the heptaleno[1,2-c]furan-3-ones 7c and 7e and, again, in small amounts, the heptaleno[1,2-c]furan-1-ones 8c and 8e, respectively (cf. Scheme 8). Therefore, it seems that the heptalene-1,2-dimethanols are responsible for the formation of the furan-1-ones (cf. Scheme 7). The methylenation of the furan-3-ones 7a and 7e with Tebbe's reagent leads to the formation of the 3-methyl-substituted heptaleno[1,2-c]furans 23a and 23e, respectively (cf. Scheme 9). The heptaleno[1,2-c]furans 6a, 6d, and 23a can be resolved into their antipodes on a Chiralcel OD column. The (P)-configuration is assigned to the heptaleno[1,2-c]furans showing a negative Cotton effect at ca. 320 nm in the CD spectrum in hexane (cf. Figs. 3-5 as well as Table 7). The (P)-configuration of (-)-6a is correlated with the established (P)-configuration of the dimethanol (-)-5a via dehydrogenation with MnO2. The degree of twisting of the heptalene skeleton of 6 and 23 is determined by the Me-substitution pattern (cf. Table 9). The larger the heptalene gauche torsion angles are, the more hypsochromically shifted is the heptalene absorption band above 300 nm (cf. Table 7 and 8, as well as Figs. 6-9).

Notes: The 1H-pyrrole derivative obtained from diethyl L-glutamate hydrochloride and tetrahydro-2,5-dimethoxyfuran was cyclized with BBr3 to ethyl (5S)-5,6,7,8-tetrahydro-8-oxoindolizine-5-carboxylate (18). Catalytic hydrogenation of 18 over Pd/C in AcOH gave ethyl (5S,8aR)-octahydroindolizine-5-carboxylate (21), whereas hydrogenation over Rh/Al2O3 in EtOH/AcOH 99:1 afforded mainly ethyl (5S,8S,8aS)-octahydro-8-hydroxyindolizine-5-carboxylate (22). By functional-group interconversions, 21 was transformed into piclavine A (1) and indolizidine 209D (2). Similarly, (5R,8R,8aS)-octahydro-5-pentylindolizine-8-methanol (37), the final relay for indolizidine 209B (3), was obtained from 22.

Notes: A series of novel open-chain and cyclic conformationally constrained (R)- and (S)-α,α-disubstituted tyrosine analogues 1a-e were synthesized in good yields and high optical purities (Schemes 1 and 2). The absolute configurations of these tyrosine analogues were unambiguously determined based on the X-ray structures of the precursor diastereoisomeric peptides of type 4 and 5. Four of these structures are described (Figs. 1-4), showing β-turn type-I geometries for dipeptides 4a, 5b, and 4c and an extended conformation for peptide 5c (Table 3). The conversion of the free amino acids 1a-c into suitably protected building blocks 11a-d and 15d,e for peptide synthesis is discussed (Schemes 3 and 4).

Notes: Base pairing in p-RNA (β-D-ribopyranosyl-(4′ → 2′)-oligonucleotides) is not only stronger than in DNA and RNA, but also more selective in the sense that it is strictly confined to the Watson-Crick mode. Homopurine sequences (tested up to decamers) exist as single strands under conditions where they undergo reverse-Hoogsteen self-pairing in homo-DNA or Hoogsteen self-pairing in DNA. This exceptional pairing selectivity is rationalized as hinging on two structural features of p-RNA: the large inclination between backbone axis and base-pair axes in p-RNA duplexes, and the higher rigidity of the p-RNA backbone compared with RNA, DNA, and homo-DNA. The most important consequence of the pairing selectivity refers to the potential of p-RNA to replicate. Replicative copying of sequence information by nonenzymatic template-controlled ligation is not hampered by self-pairing of guanine-rich templates, as it is known to be the case in the RNA series. We have demonstrated two replicative cycles in which G-rich p-RNA-octamer templates induce sequence-selective ligation of tetramer-2′-phosphate derivatives to complementary C-rich octamer sequences, and in which the latter, with comparable efficiency, induce corresponding ligation reactions back to the original G-rich octamers. Ligation is most satisfactorily achieved after pre-activation of the 2′-phosphate groups as 2′,3′-cyclophosphate derivatives; in this version, the process does not proceed as oligocondensation, but as a genuine oligomerization. This is of considerable promise for the search for potentially natural conditions under which homochiral p-RNA strands might self-assemble and self-replicate.

Notes: The 2-(4-nitrophenyl)ethylsulfonyl (npes) group is developed as a new sugar OH-blocking group in the ribonucleoside series. Its cleavage can be performed in a β-eliminating process under aprotic conditions using 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) as the most effective base. Since sulfonates do not show acyl migration, partial protection of 1,2-cis-diol moieties is possible leading to new types of oligonucleotide building blocks. A series of Markiewicz-protected ribonucleosides 1-10 is converted into their 2′-O-[2-(4-nitrophenyl)ethylsulfonyl] derivatives 29-38 in which the 5′-O—Si bond can be cleaved by acid hydrolysis forming 39-45. Subsequent monomethoxytritylation leads to 46-50, and desilylation affords the 5′-O-(monomethoxytrityl)-2′-O-[2-(4-nitrophenyl)ethylsulfonyl]ribonucleosides 51-55. Acid treatment to remove trityl groups do also not harm the npes group (→56-58). Unambiguous syntheses of fully blocked 2′-O-[2-(4-nitrophenyl)ethylsulfonyl]ribonucleosides 96-102 are achieved from the corresponding 3′-O-(tert-butyl)dimethylsilyl derivatives. Furthermore, various base-protected 5′-O-(monomethoxytrityl)- and 5′-O-(dimethoxytrityl)ribonucleosides, i.e. 59-77, are treated directly with 2-(4-nitrophenyl)ethylsulfonyl chloride forming in all cases a mixture of the 2′,3′-di-O- and the two possible 2′- and 3′-O-monosulfonates 107-148 which can be separated into the pure components by chromatographic methods. The npes group is more labile towards DBU cleavage than the corresponding base-protecting 2-(4-nitrophenyl)ethyl (npe) and 2-(4-nitrophenyl)ethoxycarbonyl (npeoc) groups allowing selective deblocking which is of great synthetic potential.

Notes: The experimental conditions developed for the detection of rather stable radical cations in solution by electrospray-ionization mass spectrometry (ESI-MS) of a FeII complex of 2-amino-5,6,7,8-tetrahydro-5-methylpteridin-4 (3H)-one (1c) are used to observe the formation of the more unstable radical cations formed from 2-amino-5,6,7,8-tetrahydropteridin-4(3H)-one (1a) and tris(pentane-2,4-dionato)iron(III) ([FeIII(acac)3]; 4) and to monitor their oxidation to the corresponding p-quinonoid dihydropterin complexes. These results contribute to the understanding of the important role played by 6β-5,6,7,8-tetrahydro-L-biopterin (1b; a homologue of 1a) together with iron as constituent of some cofactors. The complexes obtained from 1a and iron may be considered, e.g. as a model of the cofactor of the phenylalanine hydroxylase. Moreover, we describe an improved synthesis of 1c.

Notes: Copper(II) complexes of the ligands N2-[(R)-2-hydroxypropyl]- and N2-[(S)-2-hydroxypropyl]-(S)-phenylalaninamide performed chiral separation of N-dansyl-protected and unmodified amino acids in HPLC (reversed phase). With the aim of investigating which species are potentially involved in the discrimination mechanism, the two ligands were synthesized and their complexation equilibria with Cu2+ studied by potentiometry and spectrophotometry in aqueous solution up to pH 11.7. The formation constants of the species observed, [CuL]2+, [CuL2]2+, [CuLH-1]+, [CuL2H-1]+, [CuL2H-2], and [CuL2H-3]-, were quite similar for both compounds and were compared to those of (S)-phenylalaninamide. Most probably, in [CuL2H-3]- the ligands behave as terdentate, with the deprotonated OH group occupying an apical position.

Notes: Phosphonopyruvates: Syntheses, NMR Investigations, and ReactionsThe new 3-(diethoxyphosphoryl)-2-oxopropanoates 5-24 and -propanamides 25-38 with various substituents at C(3) were prepared in moderate-to-good yields (Schemes 2 and 3, Tables 1 and 2). It was shown that they adopt a preferred conformation in which the diethoxyphosphoryl group and the substituent at C(4) are antiperiplanar to each other (see B). The keto-enol tautomerization of phosphonopyruvates with Ph—C(3) (see 20) and MeS—C(3) (see 24 and 33) was examined. In CHCl3, two tautomeric species exist, whereas in dimetylsulfoxide (DMSO), three tautomeric forms are observed. Oxime ethers, an oxime, and a phenylhydrazone of unsubstituted phosphonopyruvates were prepared (see 40-44), and quinoxalin-2(1H)-ones could be obtained from the reaction of pyruvates with 4,5-dimethylbenzene-1,2-diamine (see 45-47).

Notes: The substituent reactivity and tautomerism of isoguanine nucleosides is studied. Benzoylation or tosylation of isoguanine nucleosides (pyridine, room temperature) yields the 2-benzoyl derivatives 7c, 11, and 12 or the 2-tosyl compounds 13 and 14. The isobutyrylation of the 6-amino group which did not occur under these conditions was induced in the presence of Me3SiCl. In the absence of Me3SiCl, the reactivity of isoguanine substituents decreases in the order from 2-oxo → 5′-OH → 3′-OH → 6-NH2. From isoguanine nucleosides, the N1-(2b), N3-(17), N6-(15a,b), and 2-O-alkylated (3b) derivatives were prepared. Their pKa values were determined and the UV and 13C-NMR spectra compared with regard to the alkylation position. Also the tautomeric forms of isoguanine nucleosides were determined UV-spectrophotometrically in aqueous and nonaqueous solution. Isoguanosine (1a), its 2′-deoxy analogue 1b as well as the N6-methyl- and 8-substituted derivatives form lactam tautomers in aqueous solution, whereas the lactim form is present in dioxane.

Notes: An Unexpected Ring Enlargement of 3-(Dimethylamino)-2,2-dimethyl-2H-azirine to 4,5-Dihydropyridin-2(3H)-one DerivativesThe reaction of 3-(dimethylamino)-2,2-dimethyl-2H-azirine (1a) and 4,4-disubstituted 2-(trifluoromethyl)-1,3-oxazol-5(4H)-ones 7 in MeCN at 70° afforded 5-(dimethylamino)-3,6-dihydropyrazin-2(1H)-ones 10 (Scheme 4), whereas no reaction could be observed between 1a and 2-allyl-4-phenyl-2-(trifluoromethyl)-1,3-oxazol-5(2H)-one (8a) or 4,4-dibenzyl-2-phenyl-1,3-oxazol-5(4H)-one (9). The formation of 10 is rationalized by a mechanism via nucleophilic attack of 1a onto 7. The failure of a reaction with 9 shows that only activated 1,3-oxazol-5(4H)-ones bearing electron-withdrawing substituents do react as electrophiles with 1a. The amino-azirine 1a and 2,4-disubstituted 1,3-oxazol-5(4H)-ones 2b-e in refluxing MeCN undergo a novel ring enlargement to 4,5-dihydropyridin-2(3H)-ones 11 (Scheme 5). Several side products were observed in these reactions. Two different reaction mechanisms for the formation of 11 are proposed: either 1a undergoes a nucleophilic addition onto the open-chain ketene tautomer of 2 (Scheme 6), or 2 reacts as CH-acidic compound (Scheme 7).

Notes: The solution structure and the aggregation behavior of (E)-2-lithio-1-(2-lithiophenyl)-1-phenylpent-1-ene (1) and (Z)-2-lithio-1-(2-lithiophenyl)ethene (2) were investigated by one- and two-dimensional 1H-, 13C-, and 6Li-NMR spectroscopy. In Et2O, both systems form dimers which show homonuclear scalar 6Li,6Li spin-spin coupling. In the case of 2, extensive 6Li,1H coupling is observed. In tetrahdrofuran and in the presence of 2 mol of N,N,N′,N′-tetramethylethylylenediamine (tmeda), the dimeric structure of 1 coexists with a monomer. The activation parameters for intra-aggregate exchange in the dimers of 1 and 2 (1 (Et2O): ΔH≠ = 62.6 ± 13.9 kJ/mol, ΔS≠ = 5.8 ± 14.0 J/mol K, ΔG≠(263) = 61.1 kJ/mol; 2 (dimethoxyethane): ΔH≠ = 36.9 ± 6.5 kJ/mol, ΔS≠ = -61 ± 25 J/mol K, ΔG≠(263) = 54.0 kJ/mol) and the thermodynamic parameters for the dimer-monomer equilibrium for 1 (ΔH°; = 26.7 ± 5.5 kJ/mol, ΔS° = 63 ± 27 J/mol K), where the monomer is favored at low temperature, were determined by dynamic NMR studies.

Notes: Diphenyl phosphorazidate (DPPA) was used as the azide source in a one-pot synthesis of 2,2-disubstituted 3-amino-2H-azirines 1 (Scheme 1). The reaction with lithium enolates of amides of type 2, bearing two substituents at C(2), proceeded smoothly in THF at 0°; keteniminium azides C and azidoenamines D are likely intermediates. Under analogous reaction conditions, DPPA and amides of type 3 with only one substituent at C(2) gave 2-diazoamides 5 in fair-to-good yield (Scheme 2). The corresponding 2-diazo derivatives 6-8 were formed in low yield by treatment of the lithium enolates of N,N-dimethyl-2-phenylacetamide, methyl 2-phenylacetate, and benzyl phenyl ketone, respectively, with DPPA. Thermolysis of 2-diazo-N-methyl-N-phenylcarboxamides 5a and 5b yielded 3-substituted 1,3-dihydro-N-methyl-2H-indol-2-ones 9a and 9b, respectively (Scheme 3). The diazo compounds 5-8 reacted with 1,3-thiazole-5 (4H)-thiones 10 and thiobenzophenone (13) to give 6-oxa-1,9-dithia-3-azaspiro[4.4]nona-2,7-dienes 11 (Scheme 4) and thiirane-2-carboxylic acid derivatives 14 (Scheme 5), respectively. In analogy to previously described reactions, a mechanism via 1,3-dipolar cycloaddition, leading to 2,5-dihydro-1,3,4-thiadiazoles, and elimination of N2 to give the ‘thiocarbonyl ylides’ of type H or K is proposed. These dipolar intermediates with a conjugated C=O group then undergo either a 1,5-dipolar electrocyclization to give spirohetrocycles 11 or a 1,3-dipolar electrocyclization to thiiranes 14.

Notes: Syntheses of a series of enantiomerically pure, substituted analogues 7b-t of SDZ EAB 515 (7a) were described (Schemes 1 and 2). Affinites for the NMDA receptor were measured ([3H]CGP-39653 binding assay) and competitive NMDA antagonistic potencies determined in a functional test (rat neocortical slice preparation). Structure-activity relationships show that attachment of an OH group at position 4 of the chain-inserted benzene ring of the biphenyl moiety and/or expansion of the angle between the planes of the two benzene rings by ortho-substituents increase in vitro activities into the low nanomolar range.

Notes: A novel approach to modeling the angular geometry about the metal centre in transition-metal complexes, using a variation of classical molecular-mechanics calculations, is presented. The approach is based on the combination of 1,3-nonbonded interactions around the metal centre and a harmonic sine function with a ligandfield-dependent force constant for the L-M-L′ terms. Force-field parameters for four-, five-, and six-coordinated first-row transition-metal coordination centres and a variety of ligands containing N-, S-, and O-donor sets are given. The new ‘electronically doped’ force field is shown to generally lead to computed structures with higher accuracy than those obtained when the coordination geometries are modeled with 1,3-nonbonded interactions alone.

Notes: The dendritic cyclophanes (dendrophanes )1-3 containing a [6.1.6.1]paracyclophane as the initiator core embedded in dendritic poly(ether-amide) shells of first (1), second (2), and third (3) generation were prepared and characterized. The X-ray crystal-structure analyses of esters 7 and 4, derivatives of cyclophane core 9 and first-generation dendrophane 1, respectively, displayed open cavity binding sites suitable for the inclusion complexation of aromatic substrates. With their carboxylate surface groups, dendrophanes 1-3 were readily soluble in aqueous phosphate buffer (pH 8.0), and the complexation of naphthalene derivatives was investigated by 1H-NMR and fluorescence titrations. The binding studies demonstrated that the cyclophane cavity remains open and accessible to appropriate substrates even at higher dendritic generations. The 1:1 complexes formed in aqueous buffer were of similar stability to those formed by the unbranched core 9 (Ka between 1000 and 10000 1 mol-1, 300 K). Investigations with the fluorescent probe 6-(p-toluidino)naphthalene-2-sulfonate (12) showed that the micropolarity at the dendrophane core decreases with increasing generation number.

Notes: The unimolecular fragmentation reactions of the radical cations of diethyl, diisopropyl, dipropyl, isopropyl propyl, and di(tert-butyl) peroxide have been investigated by mass spectrometric and isotopic labeling techniques. Two competing pathways for unimolecular decomposition in the μs time regime (metastable ions) are observed: i) A combination of an α-C—C bond cleavage and a H migration gives rise to proton-bound dimers of two ketone or aldehyde molecules. ii) Ion/dipole complexes of alkyl cations and alkylperoxy radicals are generated by C-O bond cleavage. These complexes either exhibit direct losses of alkylperoxy radicals, or they rearrange via a coupled proton and H-atom transfer, this sequence of unprecedented isomerizations is completed by losses of alkyl radicals. Collisional activation experiments confirm that the ionic products of the latter process correspond to RR′C=OOH+; these ions can be regarded as protonated carbonyl oxides. In addition, we observe the elimination of alkenes leading to hydroperoxide radical cations and the expulsion of HO2⋅ radicals. The latter process implies a C—C bond formation step between the two alkyl fragments leading to higher alkyl cations.

Notes: Several cyclic and acyclic enones and their ethylene ketals/acetals were reacted with dimethyl diazomalonate under bis(acetylacetonato)copper(II) catalysis. Cyclohex-2-en-1-one (1) yielded only C-H insertion products 2 and 3, whereas but-3-en-2-one gave a cyclopropane albeit in very low yield. The ethylene ketals 6 of cyclopent-2-en-1-one and cyclohex-2-en-1-one gave the corresponding cyclopropanes 7, which were in turn cleaved to the ketones 8. The acetals 9 and 10 of crotonaldehyde ((E)-but-2-enal) and cinnamaldehyde ((E)-3-phenylprop-2-enal), respectively, yielded C-O insertion and [2,3]-sigmatropic rearrangement products 11b, c and 12b, c, as well as cyclopropanes 11a and 11b, all of which are polyfunctional and synthetically useful compounds.

Notes: Light-induced cyclizations of suitably functionalized polyalkene terpenoids, such as geranyl, all-trans-farnesyl, and all-trans-geranylgeranyl derivatives, via formation of radical cations are proven to be a powerful method for the single-step synthesis of mono- and mostly all-trans-fused polycyclic compounds from readily available precursors. Whereas some of these highly stereo- and chemoselective transformations required the use of micel ar media, they can now be conveniently performed in homogeneous solutions upon suitable choice of the electron acceptors and of the functionality pattern of the polyalkene substrates. Moreover, the mode of cyclization, i.e., 6- vs. 5-membered ring formation and termination of the cyclization cascades, are steered efficiently by the substituents of the polyalkenes (polyalkenyl acetate vs. α,β-unsaturated ethyl polyalkenoate and polyalkene-1,1-dicarbonitrile). At the same time, the protic solvents used add highly stereoselectively to the ω-alkene sites of the polyalkens in anti-Markovnikov sense which strongly suggests that radical cations are intercepted. Interestingly, the transformations achieved here upon photoelectron transfer parallel the biosynthetic paths of non-oxidative terpene cyclizations which are thought to occur purely by protonation of the isoprenoid polyalkenes.

Notes: It is proposed to study the influence of interresidue H-bonds on the structure and properties of polysaccharides by comparing them to a series of systematically modified oligosaccharide analogues where some or all of the glycosidic O-atoms are replaced by buta-1,3-diyne-1,4-diyl groups. This group is long enough to interrupt the interresidue H-bonds, is chemically versatile, and allows a binomial synthesis. Several approaches to the simplest monomeric unit required to make analogues of cellulose are described. In the first approach, allyl α-D-galactopyranoside (1) was transformed via 2 and the tribenzyl ether 3 into the triflate 4 (Scheme 2). Substitution by cyanide (→ 5-7) followed by reduction with DIBAH led in high yield to the aldehyde 9, which was transformed into the dibromoalkene 10 and the alkyne 11 following the Corey-Fuchs procedure (Scheme 3). The alkyne was deprotected via 12 or directly to the hemiacetal 13. Oxidation to the lactone 14, followed by addition of lithium (trimethylsilyl)acetylide Me3SiC≡CLi/CeCl3 (→ 15) and reductive dehydroxylation afforded the disilylated dialkyne 16. The large excess of Pd catalyst required for the transformation 11 → 13 was avoided by deallylating the dibromoalkene 10 (→ 17 → 18), followed by oxidation to the lactone 19, addition of Me3SiC≡CLi to the anomeric hemiketals 20 (α-D/β-D 7:2), dehydroxylation to 21, and elimination to the monosilylated dialkyne 22 (Scheme 3). In an alternative approach, treatment of the epoxide 24 (from 23) with Me3SiC≡CLi/Et2AlCl according to a known procedure gave not only the alkyne 27 but also 25, resulting from participation of the MeOCH2O group (Scheme 4). Using Me3Al instead of Et2AlCl increased the yield and selectivity. Deprotection of 27 (→ 28), dibenzylation (→ 29), and acetolysis led to the diacetate 30 which was partially deacetylated (→ 31) and oxidized to the lactone 32. Addition of Me3SiC≡CLi/TiCl4 afforded the anomeric hemiketals 33 (α-D/β-D 3:2) which were deoxygenated to the dialkyne 34. This synthesis of target monomers was shortened by treating the hydroxy acetal 36 (from 27) with (Me3SiC≡C)3Al (Scheme 5): formation of the alkyne 37 (70%) by fully retentive alkynylating acetal cleavage is rationalised by postulating a participation of HOC(3). The sequence was further improved by substituting the MeOCH2O by the (i-Pr)3SiO group (Scheme 6); the epoxide 38 (from 23); yielded 85% of the alkyne 39 which was transformed, on the one hand, via 40 into the dibenzyl ether 29, and, on the other hand, after C-desilylation (→ 41) into the dialkyne 42. Finally, combined alkynylating opening of the oxirane and the 1,3-dioxolane rings of 38 with excess Et2Al C≡CSiMe3 led directly to the monomer 43 which is thus available in two steps and 77% yield from 23 (Scheme 6).

Notes: A series of transformations of cytochalasin D (1; zygosporin A) was carried out. After treatment of the diol 7 with mesyl chloride and pyridine, and subsequent chromatography on silica gel, the 17-acetyl derivatives 12 and 13, the first members of the hitherto unknown [10]cytochalasans, were obtained. The alcohol 8 was converted to the chlorosulfinate 18 under the same conditions. Replacement of pyridine by triethylamine in the mesylation reaction led to the cyclohepta[4,5]benz[1,2-d]isoindole derivative 20, also representing a novel ring system.

Notes: Synthetic (+)-makomakine (6) was transformed in six steps into (+)-17R,18R)-17,18-dihydrohobartine-17,18-diol ((+)-5) with an overall yield of 38% (Scheme 2). This compound was shown to be identical with natural hobartinol, a monoterpene indole alkaloid from Aristotelia australasica, originally believed to be the (17S)-epimer 1. At the same time, the synthesis of (+)-5 delineates the hitherto unknown absolute configuration of this metabolite.

Notes: Allylpalladium complexes with chiral bis(dihydrooxazole) ligands were studied as catalysts for the enantioselective allylic substitution reaction of rac-1,3-diphenylprop-2-enyl acetate (rac-5) with the anion of dimethyl malonate (Scheme 1). Using enantiomerically pure (S,E)-1-(4-tolyl)-3-phenylprop-2-enyl acatete ((S)-25) as substrate, the reaction was shown to proceed by a clean ‘syn’ displacement of acetate by dimethyl malonate (Scheme 6). The [Pd11(η3-allyl)] complex 18 and the analogous [Pd(η3-1,3-diphenylallyl)] complex 20, both containing the same bis(dihydrooxazole) ligand, were characterized by X-ray structure analysis and by NMR spectroscopy in solution. The structural data reveal that steric interactions of the allyl system with the chiral ligand result in selective electronic activation of one of the allylic termini. The higher reactivity of one allylic terminus toward nucleophilic attack is reflected in a significantly longer Pd—C bond and a shift of the corresponding 13C-NMR resonance to higher frequency.

Notes: Accurate low-temperature X-ray crystal structures of the isomeric Diels-Alder monoadducts of C70 1a, bridged at the [6,6] bond between C(1) and C(9), and 1b, bridged at the [6,6] bond between C(7) and C(8), have been determined. The latter structure is the first one solved for a 7,8-C70 monoadduct. The C1-symmetrical 1a and Cs-symmetrical 1b co-crystallize with CS2 molecules in the space groups P21/c and Pnma, respectively, and the distances between bridgehead atoms are 1.603(3) and 1.584(3) Å. The degree of pyramidalization of atoms involved in [6,6] bonds near the ‘unsubstituted’ pole and near the equator of the fullerene was estimated; it is shown for the unsubstituted pole region that atoms corresponding to C(1) and C(9) are slightly more pyramidal than those corresponding to C(7) and C(8), in agreement with ab initio calculations obtained for the C70 spheroid. Some aspects of the crystal packings are discussed.

Notes: The crystal structure of [3,O-didehydro-MeBmt1, Val2]cyclosporin (PSC-833; 1) was investigated by X-ray analysis. Data were collected from two different crystal modifications. Modification I crystallizes in P3121, a = b = 21.419 (2) Å, c = 32.101 (3) Å with one molecule in the asymmetric unit, modification II in P3221, a = b = 21.313 (2) Å, c = 62.053(3) Å with two molecules per asymmetric unit. This non-immunosuppressive analogue of cyclosporin A adopts a similar backbone conformation to that found in the crystal structure of cyclosporin A and other analogues. Three different data sets of modification I were collected using an Enraf-Nonius-CAD4 diffractometer with CuKα radiation at 20°, a Stoe-Siemens four-circle diffractometer with MoKα radiation at - 120°, and an EMBL image-plate scanner with synchrotron radiation at 12°. The quality of the data sets was evaluated by internal consistency, independent structure solution, and refinement. The structural parameters reported here for modification I are based on the synchrotron data.

Notes: The preparation of the diastereoisomers of 1-amino-2-bromocyclopropanecarboxylic acid is described using the methyl (1RS, 5SR)-2-oxo-3-oxabicyclo[3.1.0]hexane-1-carboxylate 5 as starting material. The key step is the oxidation of 9 with subsequent radical introduction of bromine according to the Barton procedure. The 2-bromo-cyclopropanecarboxylates cis-11 and trans-11 were obtained as diastereoisomer mixture in a ratio of 3:1. They were converted into cis- and trans-esters 12 and the acids 13.

Notes: The bicyclic keto lactone 26 was synthesized for the purpose of developing a viable route to marine diterpenes of the crenulatan type. Following the efficient conversion of (S)-citronellol (5) to the allylated alcohol 9a (Scheme 2), the αβ-unsaturated lactone 12 was efficiently accessed in preparation for stereocontrolled conjugate addition. The hydroxymethyl equivalent most suited to this task was (i-PrO)Me2SiCH2MgCl, which gave 13 predominantly in the presence of CuI and Me3SiCl. Once the OH group was deprotected (→ 14), it proved an easy matter to implement acid-catalyzed isomerization to lactone 15, oxidation of which gave the pivotal aldehyde 16. Condensation of 16 with PhSeCH2Li led via 21 to 22 (Scheme 3). Once the OH group was protected (→ 22b), it proved possible to effect aldolization with crotonaldehyde (→ 23). Exposure of 23 to acid gave the sub-target compound 25. Its subsequent oxidation and thermal activation resulted in sequential selenoxide elimination with Claisen rearrangement (→ 26). The structural features of 26 require that a chair-like transition state be adopted during the [3.3]sigmatropic event. With the clarification of these issues, a highly serviceable and more advanced assault on the crenulatans should prove capable of being mounted.

Notes: The molecular clefts (R)- and (S)-3, incorporating 9,9′-spirobi[9H-fluorene] as a spacer and two N-(5,7-dimethyl-1,8-naphthyridin-2-yl)carboxamide (CONH(naphthy)) units as H-bonding sites were prepared via the bis(succinimid-N-yl esters) of (R)-and (S)-9,9′-spirobi[9H-fluorene]-2,2′-dicarboxylic acid (5). Derivative 6, with one CONH(naphthy) unit and one succinimid-N-yl ester residue allowed easy access to spirobifluorene clefts with two different H-bonding sites, as exemplified by the synthesis of 4. Binding studies with (R)- and (S)-3 and optically active dicarboxylic acids in CDCl3 exhibited differences in free energy of the formed diastereoisomeric complexes (Δ(ΔGº)) between 0.5 and 1.6 kcal mol-1 (T 300 K). Similar enantioselectivities were observed with the spirobifluorene clefts (R)- and (S)-1, bearing two N-(6-methylpyridin-2-yl)carboxamide (CONH(py)) H-bonding sites. The thermodynamic quantities ΔHº and ΔSº for the recognition processes with (R)- and (S)-1 were determined by variable-temperature 1H-NMR titrations and compared to those with (R)- and (S)-2, which have two CONH(py) moieties attached to the 6,6′-positions of a conformationally more flexible 1,1′-binaphthyl cleft. All association processes showed high enthalpic driving forces which are partially compensated by unfavorable changes in entropy. Pyranosides bind to the optically active clefts 1 and 3 in CDCl3 with -ΔGº = 3.0-4.3 kcal mol-1. Diastereoisomeric selectivities up to 1.2 kcal mol-1 and enantioselectivities up to 0.4 kcal mol-1 were observed. Cleft 4 and N-(5,7-dimethyl-1,8-naphthyridin-2-yl)acetamide (25) complexed pyranosides 22-24 as effectively as 3 indicating that only one CONH(naphthy) site in 3 associates strongly with the sugar derivatives. Based on the X-ray crystal structure of 3, a computer model for the complex between (S)-3 and pyranoside 22 was constructed. Molecular-dynamics (MD) simulations showed that differential geometrical constraints are at the origin of the high enantioselectivity in the complexation of dicarboxylic acid (S)-7 by (R)- and (S)-1 and (R)- and (S)-3.

Notes: Nocardicin A analogues 30, 34, and 38 as well as the highly strained quinone methide 43 were synthesized. β -Lactam 34 was found biologically active against several Gram-negative microorganisms in vitro; pyridinium N-oxide derivative 38 possessed activity against Gram-positive S. aureus bacterium. Masked p-quinone methide β -lactam 43 exhibited significant antimicrobial activity in vitro. A mechanism involving an oxidation in vivo is proposed for the unprecedented biological properties of nocardicins.

Notes: Synthesis of Tetradecano-14-lactone by Ring EnlargementThe aldehyde 3, prepared by ozonolysis of 2-allyl-2-nitrocyclododecanone, gave the ring-enlargement product 5(85%) by treatment with (i-Bu)2AlH. Its transformation to the tetradecano-14-lactone (8) via the aldol ester 6 and other routes (best is reduction with Bu3SnH, AlBN, toluene) was difficult. Remarkable is the smooth denitrification of 3 (loss of HNO2) to the conjugated dione 4 by chromatography on silica gel or base treatment.

Notes: (+)-Multifidence ((+)-1) has been synthesized starting from (R)-(cyclopent-2-enyl)methanol ((+)-2) via its chloroformate 4, Co-mediated radical cyclization reaction to the lactone (+)-6, and introduction of the olefinic side chains.

Notes: A procedure was developed for the biosynthetic preparation of 15N-labelled guanosine and inosine through the action of a mutant Bacillus subtilis strain. Crude [N2,1,3,7,9-15N]guanosine and [1,3,7,9-15N]inosine were isolated from the culture filtrate by precipitation and anion-exchange chromatography (Scheme 1). No cell lysis and no enzymatic degradation was necessary. The per-isobutyrylated derivatives 1 and 2 were isolated from a complex mixture, purified by virtue of their different lipophilicity, and separated in three steps involving normal-and reversed-phase silica-gel chromatography. One litre of complex nutrient medium yielded 8.44 mmol of guanosine derivative and 2.84 mmol of inosine derivative with high average 15N enrichment (83.5 and 91.9 atom-%, resp.). [N6,1,3,7,9-15N]Adenosine (4) was obtained from 2′,3′,5′-tri-O-isobutyryl[1,3,7,9-15N]inosine (1) through the ammonolysis of its 1,2,4-triazolyl derivative with aqueous 15NH3 (Scheme 2).

Notes: Two cis-fused cyclopenteno-1,2,4-trioxanes, 1a and 1b, were subjected to Zn in AcOH or FeCl2 · 4H2O in MeCN. In the first case, the main course was deoxygenation to give cyclopentanone (18) and the 1,4-diphenyl- or 1,4-bis(4-fluorophenyl)cyclopent-3-ene-1,2-diol 10 (Scheme 5). In the second case, isomerization chiefly occurred resulting in the formation of a dimer 9 of the respective 3,5-diaryl-5-hydroxycyclopent-2-enyl 5-hydroxypentanoates 8 (Scheme 3).

Notes: The Rh11-catalyzed carbenoid addition of diazoacetates to olefins was investigated with [Rh2{(4S)-phox}4] (1;phox = tetrakis[(4S)-tetrahydro-4-phenyloxazol-2-one]), [Rh2{(2S)-mepy}4] (2; mepy = tetrakis[methyl (2S)-tetrahydro-5-oxopyrrole-2-carboxylate]), and [Rh2(OAc)4] (3). While catalysis with 2 and 3 afford preferentially trans-cyclopropanecarboxylates, the cis-isomers are the major products with 1. In general, the enantioselectivities achieved with 1 and 2 are comparable. Additions catalyzed by 1 are strongly sensitive to steric effects. Highly substituted olefins afford cyclopropanes in only poor yield. The preferential cis-selectivity observed in reactions catalyzed by 1 is attributed to dominant interactions between the ligand of the catalyst and the substituents of both olefin and diazoacetate, which overrule the steric interactions between olefin and diazoacetate in the transition state for carbene transfer.

Notes: A New Access to 2′-O-Alkylated Ribonucleosides and Properties of 2′-O-Alkylated OligoribonucleotidesA general access to 2′-O-alkylated ribonucleosides using the key intermediate 5 is presented. The incorporation of 2′-O-‘ethyleneglycol’- and 2′-O-‘glycerol’-substituted (i.e., 2′-O-(2-hydroxyethyl)- and 2′-O-(2,3-dihydroxypropyl)-substituted) ribonucleosides into oligonucleotides affords a new generation of oligonucleotides with high affinity for RNA, high specificity, and increased nuclease resistance.

Notes: The objectives of this study were to gain insights into the structure-lipophilicity relationships of peptides and to propose an improved model for estimating their lipophilicity. First, existing databases were extended to obtain the distribution coefficients of a total of 208 free or protected peptides (di- to pentapeptides). The polarity parameters (Λ) of 23 free amino acids and 19 protected amino acids (AcNH—CHR—CONH2) and of their side chains were calculated from experimental distribution coefficients and computed molecular volumes. An analysis of the polarity parameters revealed that the hydrophobicity of the amino-acid side chains is largely reduced due to the polar field of the backbone. The polarity parameters of the peptides were then obtained in a similar manner and shown to be highly correlated with the sum of the polarity parameters of their side chains, i.e., the lipophilicity of peptides can be calculated from their molecular volume and the sum of their side-chain polarities using the regression established for each individual series of peptides (Fig. 1). This last restriction is essential since the polarity and lipophilic increment of a NH—C*H—CO unit were shown to decrease with increasing length of backbone.

Notes: The spiro[cyclohexane-1,2′-[2H]indene] derivatives 15a,b with molecular dimensions and nucleophilic functional groups similar to known steroid 5α-reductase inhibitors (e.g. 2) were synthesized. The spiro[cyclohexane-1,2′-[2H]indene]-1′(3′H),4-dione (5) was synthesized from 5-methoxyindan-l-one ( = 2,3-dihydro-5-methoxy-1H-inden-1-one). A Grignard reaction and a dehydration step led to the cyclohexene (±)-7 which, upon a stereoselective hydrogenation catalyzed by Raney-Ni under mild conditions, gave 8a as a pure epimer. Further hydrogenation and hydrogenolysis of 8a over Pd/C at room temperature reduced the keto group to give pure 9a. Finally, the 5′-substituted derivatives 12a, 14a, and 15a were generated by deprotection and Heck-type reaction.

Notes: Cationic Pd-complexes modified by dicyclohexyl{(R)-1-[(S)-2-(diphenylphosphino)ferrocenyl]ethyl}phosphine (1a) give very active catalytic systems for the regioregular isotactic specific copolymerization of propene with CO. Other alk-1-enes also give stereoregular and regioregular copolymers, even if with lower productivity. The copolymers are isolated as poly(4-alkyl-tetrahydrofuran-2,2,5,5-tetrayl-2-oxy-2-methylenes) B in the solid state and give the isomeric poly(2-alkyl-1-oxopropane-1,3-diyls) A by dissolution in (CF3)2CHOH. Solid polymer A (R = Et) is formed back at least partially when the dissolved material is reprecipitated from MeOH. The use of the related (ferrocenyl)diphosphine ligands 1b-e and 2 as the catalyst modifier shows that the presence of both elements of chirality and of large substituents on the P-atoms of the ligand is necessary to achieve good stereocontrol, and that the large difference in basicity between the two P-atoms is probably the reason for the good catalytic activity.

Notes: Boron Trifluoride Catalyzed Reaction of 3-Amino-2H-azirines and Amides: Formation of 4,4-Disubstituted 4H-ImidazolesReaction of trifluoroacetamide and 3-amino-2H-azirines 1 in refluxing MeCN affords 4-amino-2-(trifluoromethyl)-4H-imidazoles 5 in fair yields (Scheme 3). Less acidic amides do not react with 1 under similar conditions. Therefore, a procedure involving BF3-catalysis has been elaborated: the aminoazirine 1 in CH2Cl2 at -78° is treated with BF3 · Et2O and then with a solution of the sodium salt of an amide in THF, prepared by addition of sodium hexamethyldisilazane at -78°. The 4H-imidazoles of type 5 are formed in ca. 50% yield (Scheme 4). Reaction mechanisms for this ring enlargement of 1 are proposed in Schemes 5 and 6.

Notes: The 4-hydroxyheptadecan-7-one (1) and 14-hydroxyoctadecan-8-one (2), two new hydroxyketones isolated from leaves of Chiococca alba, were synthesized, for the first time, by hydroxy-functionalized nitroalkanes 4 and 9, respectively, via two chemoselective key steps: i) nitroaldol condensation with basic alumina, and ii) direct Nef conversion of nitroalkenes to carbonyl derivatives with sodium hypophosphite, in order to preserve the OH group.

Notes: Electron Transfer and Ion Pair Formation Single Crystal Structure of Bis(sodium 1,1′-biphenyl-2-thiolate-diglyme): An Intermediate in the Reductive Ring Opening of DibenzothiopheneOn Na-metal reduction of dibenzothiophene, the five-membered sulfur ring opens to form a colorless 1,1′-biphenyl-2-thiolate sodium salt, which, according to its single-crystal structure determination, is a dimer containing a four-membered, twice diglyme-solvated ring (diglyme···Na⊕⊖SR)2. Additional measurements provide the following information: cyclic voltammetry in aprotic MeCN solution shows one quasi-reversible electron transfer at E1/2Red = -2.58 V. The dibenzothiophene radical anion can be generated in aprotic THF solution at a K mirror and characterized by an 81-line ESR spectrum and its simulation. This blue species is also the first UV/VIS detectable one before the solution changes via green (due to blue + yellow color mixing) to yellow, yielding across an isosbestic point a second and diamagnetic compound. All of the above results suggest a consecutive two-electron reduction followed by an intersystem protonation, M + (e⊖) → M.⊖ (blue) + (e⊖) → (M⊖⊖, yellow?) + (H⊕) → MH⊖ (colorless), to yield the crystallized and structurally characterized reaction intermediate. The diglyme-solvated sodium-salt dimer provides a basis for a quantum-chemical discussion of some facets of the most likely microscopic reduction pathway.

Notes: Absolute rate constants and their temperature dependence were determined by time-resolved electron spin resonance for the addition of the radicals PhĊH2 and PhĊMe2 to a variety of alkenes in toluene solution. To vinyl monomers CH2=CXY, PhĊH2 adds at the unsubstituted C-atom with rate constants ranging from 14 M-1S-1 (ethoxyethene) to 6.7 · 103 M-1S-1 (4-vinylpyridine) at 296 K, and the frequency factors are in the narrow range of log (A/M-1S-1) = 8.6 ± 0.3, whereas the activation energy varies with the substituents from ca. 51 kJ/mol to ca. 26 kJ/mol. The rate constants and the activation energies increase both with increasing exothermicity of the reaction and with increasing electron affinity of the alkenes and are mainly controlled by the reaction enthalpy, but are markedly influenced also by nucleophilic polar effects for electron-deficient substrates. For 1,2-disubstituted and trisubstituted alkenes, the rate constants are affected by additional steric substituent effects. To acrylate and styrenes, PhĊMe2 adds with rate constants similar to those of PhĊH2, and the reactivity is controlled by the same factors. A comparison with relative-rate data shows that reaction enthalpy and polar effects also dominate the copolymerization behavior of the styrene propagation radical.

Notes: Lactones from Epoxycyclodecanone Derivatives by Ring Enlargement Involving Fragmentation ReactionsA stereospecific ring-enlargement reaction of alkyl esters of 2,3-epoxy-1-(3-hydroxypropyl)-10-oxocyclo-decanecarboxylic-acid derivatives is described, involving Grob fragmentation of in situ formed hemiacetals. The assignment of the relative configuration of the starting materials was accomplished on the basis of 1H-NMR data. The rearrangement of the epoxides 9 and 10 (with cis-orientation of the ester group and the epoxide ring, Scheme 1) gives the lactone 15 as the single and as the major product, respectively, with (Z)-configuration of the newly formed C=C bond. A concerted reaction mechanism is assumed. The formation of a small amount of 12 from 10 is probably due to a competitive two-step carbanion pathway. The reaction of the diastereoisomers 7 and 8 leads to the lactones 11 and 12, respectively, as the only ring-enlargement products (Scheme 1), with (E)-configuration of the newly formed C=C bond. On the basis of our results, we cannot distinguish in this case between a concerted and a two-step carbanion mechanism. This type of reaction takes place only in the presence of an ester group; no ring enlargement was detected in case of compound 20 (Scheme 3), which is the de(alkoxycarbonyl) derivative of 9. The eliminative opening of the epoxide ring in the epoxylactone 17 affords 11 as the single product (Scheme 2). A carbanion mechanism was assumed for this reaction.

Notes: A number of new glycosyl donors, O-(1-phenyl-1H-tetrazol-5-yl) glycosides, are prepared from the corresponding hemiacetals, commercially available 5-chloro-1-phenyl-1H-tetrazole (2), and tetrabutylammonium fluoride (Bu4NF) in either THF or DMF. The mild reaction conditions are compatible with a variety of protecting groups. The glycosyl donors are treated with hydrogen fluoride-pyridine complex (HF·py) to rapidly provide glycosyl fluorides in good-to-excellent yields, apparently by a (single or double) SN2 mechanism as studied by both 1H- and 19F-NMR spectroscopy. Under acidic conditions, glycosyl fluorides equilibrate partially or completely, equilibration requiring a large excess of HF · py.

Notes: Enantioselective Synthesis of Allyl-, Propargyl-, and 4-En-2-ynyl-amines via 1,2-Addition of Organocerium Reagents to Chiral Aldehyde Imines(E)- and (Z)-Allyl-, propargyl-, and 4-en-2-ynyl-amines 5 and 14, useful bifunctional building blocks and of pharmaceutical interest, are synthesized in high enantiomeric purity (e.e. ≥ 97%). Key step is the diastereoselective 1,2-addition (d.e. 86 to ≥ 98%) of organocerium reagents to chiral α,β-unsaturated aldehyde imines 3 or 8 to produce adduct amines 4 and 9 (Schemes 1 and 4, resp.). The propargylamine 9 is a substrate for Pd-catalyzed coupling with alkenyl halides to produce the enynylamine 11a and the thienyl-substituted alkynylamine 11b. The chiral auxiliary (S,S)-2 is removed from 4 and 11 in 3 steps affording the title compounds 5 and 14. Diastereoisomer enrichment of the hydrochloride of 6 by crystallization is possible.

Notes: An improved synthesis of 3,5-bis(trifluoromethyl)pyrazole (1) is described. This compound was used for the high-yield syntheses of the tris(pyrazoly1)borates Nd[HB(3,5-(CF3),-pz)3] (2a) and the corresponding potassium salt, 2b, starting from 1 and NaBH4 and KBH4, respectively. A convenient route to the corresponding thallium(I) salt, 2c, using thallium(I) acetate and either 2a or 2b in CHCI3, is also described. The sodium (3a), potassium (3b), and thallium (3c) salts of bis(pyrazolyl)borate [H2B(3,5-(CF3)2-pz)2]- were also prepared. The above pyrazolylborates were characterized by 1H-, 13C-, 19F-, and 11B-NMR spectroscopy. The X-ray crystal structure of the thallium derivative 2c was determined. The compound crystallizes in the monoclinic space group P21/m with a = 8.248(9) Å, b = 15.034(12) Å c = 9.243(8) Å, β = 100.10(7)°, Z = 2. The Tl-atom adopts a pyramidal geometry with respect to the three N-atoms. However, two TI-N distances (2.725(7) Å) are longer than the third (2.675(10) Å).

Notes: ‘Bare’ FeO+ reacts in the gas phase with norbornane with collision efficiency, and the most prominent cationic products correspond to [FeC5H6]+ (32%), [FeC7H8]+ (19%), [FeC3H6O]+ (19%) and [FeC6H6]+ (14%), which are structurally characterized by ligand exchange as well as collision-induced dissociation experiments. Circumstantial evidence is provided which indicates that the complexes [FeC5H6]+, [FeC7H8]+, and [FeC6H6]+ originate from an Fe(norbornene)+ intermediate which itself is formed by elimination of H2O from the [FeO(norbornane)]+ encounter complex. Although the reactions are preceded and/or accompanied by partial H/D exchange, the isotope distribution in the productions clearly points to a preferential endo-attack of bare FeO+, with an endo/exo-ratio of ca. 10.3 and kinetic isotope effects kH/kD for the endo-abstraction of 2.4 and of 7.7 for approaching an exo-C—H bond. The preferred endo-approach of bicyclo[2.2.1]heptane by ‘bare’ FeO+ is in distinct contrast to the P-450-mediated or the iron(III)porphyrin-catalyzed hydroxylation of this substrate which favor reactions at the exo-face.

Notes: The structures 9 and 8 are proposed for the single isolated irradiation product of 5-oxo-5,10-secocholest-1(10)-en-3α-yl acetate (6) [2] and for the minor product of irradiation of 5-oxo-5,10-secocholest-1(10)-en-3β-yl acetate (1) [3], respectively. These compounds are formed in an alternative reaction with respect to the originally observed intramolecular Paterro-Büchi photoprocess (transformation of 1 to oxetane 2). The formerly postulated ‘active’ conformations for 1 and 6 still allow explanation of their generation.

Notes: Formation of 1,2,4-Trithiolanes in Three-Component Reactions of Phenyl Azide, Aromatic Thiones, and 2,2,4,4-Tetramethylcyclobutanethiones: A Sulfur-Transfer Reaction to ‘Thiocarbonyl-thiolates’ ((Alkylidenesulfonio)-thiolates) as Reactive IntermediatesThe reaction of PhN3 and aromatic thioketones 18 (two-component reaction) at 80° yields only the corresponding imines 22, S, and N2. Under similar conditions, in the presence of sterically crowded 2,2,4,4-tetramethyl-cyclobutanethiones 19 (three-component reaction), 1,2,4-trithiolanes of type 20 are formed in good yields in addition to imines 22 (Scheme 4). In case of 19a and 19c (X = CO, CS), the symmetrical trithiolanes 21a and 21b, respectively, are also isolated. With 4,4-dimethyl-2-phenyl-1,3-thiazole-5(4H)-thione (24) instead of aromatic thioketone 18, imine 25, trithiolane 21a, and 1,4,2-dithiazolidine 26 are formed (Scheme 5). A reaction mechanism for the formation of 1,2,4-trithiolanes 20 and 21, including an S-transfer to generate ‘thiocarbonyl-thiolates’ 2b and/or 2c and 1,3-dipolar cycloaddition with a thioketone, is proposed in Scheme 7.

Notes: Three 1,4-dimethylidenecyclohexanes, bridged in the 2,6- and 3,5-positions by two ethano (4), one ethano and one propano (5), and two propano bridges (6) have been synthesized. The interaction of the two exocyclic methylidene groups has been investigated by He(I) photoelectron (PE) spectroscopy. It revealed a slightly larger energy difference (0.8 eV) for 4 and 5 as compared to the parent 1,4-dimethylidenecyclohexane (7) (0.7 eV). The interpretation of the PE spectra was based on the comparison with PE data of related systems and with the results of semiempirical calculations on 4-6.

Notes: The [Rh2(OAc)4]-catalyzed addition of methyl diazoacetate to N-benzylideneaniline (1a) afforded the imine cis-2 in 35% yield. Under catalysis by chiral RhII catalysts, however, only racemic 1a was produced, and the yield was low. In the presence of dimethyl maleate, aziridine formation was suppressed, and an intermediate ylide 6 was trapped as cycloadduct 7. No aziridines were obtained, however, from 1b, 1c, and 3. The iminium salt 8 reacted with (trimethylsilyl)diazomethane in the absence of [Rh2(OAc)4] via dipolar cycloaddition followed by extrusion of N2 to 10.

Notes: The cross-coupling of the homopropargylic ether 1 and the halopropargylic ethers 2a and 2b was optimized, and aspects of the coupling mechanism were studied. Coupling promoted by Pd° and Cu1 in the presence of an amine yielded a mixture of the heterodimer 3 and the homodimers 4 and 5 (Scheme 1). Optimizations were first directed at suppressing homo-coupling. Homo-coupling is partially due to a H/I exchange (1 + 2a ⇌ 6 + 7) promoted by CuI and an amine. The exchange, but not the formation of homodimers, was largely suppressed in DMSO. The influence of phosphine ligands was also evaluated. Weaker σ-donors (with the exception of PPh3) lead to a faster coupling and to a higher ratio of hetero- to homodimers, with P(fur)3 leading to the cleanest reaction. Homodimers are also formed (together with I2 · (i-Pr)2NH) by reductive dimerization of the iodoalkyne 2a in the presence of [Pd2(dba)3], CuI, and (i-Pr)2NH. Bulky and acceptor-substituted amines reduced the extent of the dimerization of 2a, but the bulkiest amines did not promote coupling. Better results were obtained by using the bromoalkyne 2b. Neither dimerization of 2b, nor H/Br exchange between 1 and 2b were observed. Coupling of 1 and 2b was slower than the one of 1 and 2a, but gave higher yields of the heterodimer 3. The yield of 3 and the ratio of hetero-to homodimers was greatly improved by addition of LiI; no phosphine ligand is then required. While the oxidative addition of the iodoalkyne 2a to [Pd(PPh3)4] (2a → 8a) was rapid, the one of the bromoalkyne 2b was much slower and proceeded via the η2-complex 9 as evidenced by 1H-NMR spectroscopy. The rearrangement of 9 to the bromopalladium σ-complex 8b follows first-order kinetics (k = 0.014 min-1). CuBr greatly increased the rate of this rearrangement. LiI caused rapid substitution of Br by I in the Pd σ-complex (8b → 8a), but not in 9, nor in 2b. The σ-complex 8a did not react with the alkyne 1 in the presence of (i-Pr)2NH, unless CuI was added. The alkynes 10 or 1 did not react with CuI and either TMEDA or (i-Pr)2NH to yield detectable amounts of the Cu-acetylides 11 or 12. These observations are rationalized by the mechanism shown in Scheme 3, postulating the intermediacy of the binuclear alkyne-Pd-Cu complexes C and J, and some or all of E-H, and highlighting the role of CuI in this coupling.