Highly efficient approach to orthogonally protected (2S,4R)- and (2S,4S)-4-hydroxyornithine.

[reaction: see text] A concise stereoselective approach to both orthogonally protected (2S,4R)- and (2S,4S)-4-hydroxyornithine, key constituents of the biphenomycin- and clavalanine-type antibiotics, respectively, has been developed. The approach is based on bis(oxazoline) copper(II)-complex-catalyzed diastereoselective Henry reactions of nitromethane with the homoserine-derived aldehyde 6. The synthesis of this versatile chiral building block has been markedly improved.

Synthesis and antimicrobial activity of tetrodecamycin partial structures.

An efficient synthetic approach to the core structure 5 of the novel polyketide antibiotic tetrodecamycin (1) was developed. This approach features the acid-catalyzed cyclization of a tert-butyldimethylsilyl protected methyl alpha-(gamma-hydroxyacyl) tetronate, leading to the novel tricyclic ring skeleton exhibited by 5, and an efficient strategy for the parallel introduction of the cis-diol and exo-methylene function. In addition to 5, diastereomer 26, analogue 6 and several derivatives (16, 27-29) were prepared and evaluated for their antibacterial activities against Staphylococcus aureus (including MRSA) and Enterococcus faecalis and for their cytotoxic activities against human leukemia cell lines (HL-60, Jurkat T-cells).

Stereoselective synthesis and receptor binding of conformationally restricted and flexible 2,4-disubstituted 1,3-dioxanes derived from benzomorphans.

The key steps in the stereoselective synthesis of the tricyclic aminomethyl derivatives 19 and 20 and the aminoethyl substituted 1,3-dioxanes 24 and 25 are nucleophilic addition of aryllithium intermediates to the nitroalkene 13, intramolecular transacetalization of the addition products 15 and 16 (only for the tricyclic derivatives 19 and 20) and subsequent reduction of the nitro group. The affinities of the secondary and tertiary amines 19c,d, 20c,d, 24c,d, and 25c,d for the ion channel binding site of the NMDA receptor, for mu-, kappa-, and sigma-receptors have been investigated. In the group of tricyclic compounds only 19d shows remarkable sigma-receptor affinity (Ki = 21.

Noncompetitive NMDA antagonists: a novel synthesis of 1-phenyltetrahydro-3-benzazepines.

The key step in the synthesis of the pharmacologically interesting 1-phenyltetrahydro-3-benzazepine skeleton is the Michael addition of (2-lithiophenyl)acetaldehyde acetals, which are generated in situ upon treatment of the bromo acetals 5a,b with n-butyllithium, to beta-nitrostyrene (6). The reductive ring closure of the nitro acetals 7a,b succeeded with zinc dust and hydrochloric acid to give the 3-benzazepines 11a,b in good yields. The unsubstituted 3-benzazepine 11a showed a considerable affinity for the phencyclidine binding site of the NMDA receptor (Ki = 6.

Tricyclic CNS active agents by intramolecular Oxa-Pictet-Spengler reaction.

Mitsunobu inversion of the (S)-configurated lactate (S)-7, which is prepared in four steps starting from (S)-tyrosine, leads to the (R)-configurated lactate (R)-7. The key step in the transformation of the enantiomeric lactates (S)-7 and (R)-7 into the benzomorphan analogous tricycles (R,S)-16a,b, (S,R)-16a,b, (S,S)-22, and (R,R)-22 is an intramolecular Oxa-Pictet-Spengler reaction: The amides (S)-13, (R)-13, (S)-19 and (R)-19, in which the carbonyl moiety-masked as an acetal-is linked to the 2-phenylethanol moiety, are cyclized to give the tricyclic amides (R,S)-15, (S,R)-15, (S,S)-21, and (R,R)-21, respectively. In a concentration of 100 microM both enantiomers of 16a, 16b, and 22 are not able to compete with 3H-(+)-MK 801 for the phencyclidine binding sites of NMDA receptors.

[Synthesis and CNS-activity of spirocyclic pethidine and prodine analogs].

The bromoacetals 5a and 5b react with n-butyllithium and the piperidone 7 to yield the hydroxyacetals 8b and 8c, respectively. Cyclization of 8b and 8c followed by acid hydrolysis affords the spirocyclic hemiacetals 10b and 10c which are oxidized by PCC to give the spirocyclic prodine analogues 4b and 4c. The corresponding spirocyclic pethidine derivative 2 is prepared by alkylation of the 2-benzopyran-3-one 16 with N-Lost (17).

[Benzomorphan analogs with doxpicomine partial structure: synthesis andpsychopharmacologic investigations of 5-aminomethyl- and 5-(alpha-aminobenzyl)- substituted 2,6-epoxy-3-benzoxocines].

Addition of the beta-alanine derivative 6 to the homophthalaldehyde monoacetal 5 and subsequent LiAlH4-reduction led to the dihydroxy acetal 8, which was cyclized with acid to give the 5-aminomethyl-2,6-epoxy-3-benzoxocines 2a and 2b. The reaction of 5 with the anion of the beta-lactam 9 yielded two separable diastereomers: 10a with u,l-configuration and 10b with 1,1-configuration. Via the 2-benzopyran 11a (11b), the aminoalcohol 12a (12b), and the secondary amine 13a (13b), the beta-lactam adduct 10a (10b) was transformed to give the 5-(alpha-dimethylaminobenzyl)-2,6-epoxy-3-benzoxocine 3d (3b).

[2,6-Epoxy-3-benzazocines: centrally acting N/O-acetals produced by cyclization of amino- and amidoacetals].

Under acidic conditions the secondary amines 10a and 10b, the primary amine 15, the amide 17a, and the urethane 17b were cyclized to yield the 2,6-epoxy-3-benzazocines 11a, 11b, 16, 18a and 18b, respectively. Ring closure of the inverse amide 5a, however, failed to give the tricyclic N/O-acetal 6. With LiAlH4 the epoxy bridge of the urethane 18b was opened to afford the bicyclic 3-benzazocine 20.

[Synthesis and central effects of 4-hydroxy-(alkyl)- and 4-amino-(alkyl)-substituted 2,6-epoxy-3-benzoxocines].

The tricyclic hemiacetal 1 is transformed with amines to the N/O-acetals 3 and 10, with nitromethane to the 4-nitromethyl derivative 13, and with the Wittig reagents 15a and 15b to the 2-benzopyrans 16 and 19. Reduction and methylation of 13 yield the tertiary amine 4; through three steps the secondary amine 18 and the tertiary amine 5 are prepared from 16 and 19, respectively. The 1,3-dioxane ring of all these 2,6-epoxy-3-benzoxocine derivatives exists in the chair conformation with an equatorial C-4 substituent.