Jens Frackenpohl

On the biodegradation of β-peptides

A consortium of microorganisms was established that was able to grow with the β‐tripeptide H‐β‐HVal‐β‐HAla‐β‐HLeu‐OH, with the β‐dipeptide H‐β‐HAla‐β‐HLeu‐OH, and with the β‐amino acids H‐β‐HAla‐OH, H‐β‐HVal‐OH, and H‐β‐HLeu‐OH as the sole carbon and energy sources. This growth was achieved after several incubation‐transfer cycles with the β‐tripeptide as the substrate. During degradation of the β‐tripeptide H‐β‐HVal‐β‐HAla‐β‐HLeu‐OH, the temporary formation of a metabolite was observed. The metabolite was identified as the β‐dipeptide H‐β‐HAla‐β‐HLeu‐OH by nuclear magnetic resonance spectroscopy and mass spectrometry. This result indicates that in the course of the degradation of the β‐tripeptide, the N‐terminal β‐HVal residue was cleaved off by a not yet known mechanism. During the subsequent degradation of the β‐dipeptide, formation of additional metabolites could not be detected. The growth–yield coefficients Yx/s for growth on the β‐di‐ and β‐tripeptide both had a value of 0.45. When a 1:1 mixture of the β‐tripeptide and the corresponding α‐tripeptide H‐Val‐Ala‐Leu‐OH was added to the enrichment culture, the α‐peptide was completely utilized in six days and thereafter growth of the culture stopped. This result indicates that even in β‐peptide enrichment cultures, α‐peptides are the preferred substrates. Our experiments clearly show for the first time that β‐peptides and β‐amino acids are amenable to biodegradation and that a microbial consortium was able to utilize these compounds as sole carbon and energy sources. Furthermore, the preparation of β‐amino acids, of derivatives thereof, and of β‐di‐ and β‐tripeptides is described.

Synthesis of oxazatwistanes and their homo- and bishomo-analogues from quinidine — Medium ring systems derived from cinchona alkaloids

Abstract Suitable functionalization of the vinyl group of quinidine ( 1a ) allows cyclization involving the C9 hydroxyl group, giving novel 6-, 7- and 8-membered rings containing a distorted 1-azabicyclo-[2.2.2]octane framework. TIPS-triflate mediated cyclization of hydroxyaldehydes 13a and 15b to silylated tricyclic hemiacetals 14 and 16 is superior to an intramolecular S N 2-approach, especially for the formation of 7- and 8-membered rings.

The Miraculous CD Spectra (and Secondary Structures?) ofβ-Peptides as They Grow Longer, Preliminary Communication

The recently improved conditions for solid-phase synthesis of β3-peptides by the Fmoc strategy were used to synthesize a β-tetracosapeptide (4, Scheme) composed of eight different β-amino acid residues; 11 of the 24 residues carry functionalized proteinogenic side chains (namely those of Glu, Lys, Ser, and Tyr). The highly H2O-soluble β-tetracosapeptide was identified by 1H-NMR spectroscopy (in MeOH), analytical HPL chromatography, and ESI-mass spectrometry (Fig. 1). The expected 314-helical secondary structure of the new β-peptide was designed to have one hydrophobic and two hydrophilic faces, and to be compared with other β-peptides (1 – 3), two of which are also of amphipathic character in this secondary structure (Fig. 2). In the absence of NMR-structural proof, the CD spectra of the four β-peptides were compared (Figs. 3 and 4). The β-tetracosapeptide exhibits an unprecedented CD pattern (in MeOH and in H2O solution) that may arise from a new type of secondary structure or from an unordered conformation.

Insecticidal heterolignans—Tubuline polymerization inhibitors with activity against chewing pests

Starting from natural product podophyllotoxin 1 substituted heterolignans were identified with promising insecticidal in vivo activity. The impact of substitution in each segment of the core structure was investigated in a detailed SAR study, and variation of substituents in both aromatic moieties afforded derivatives 5 and 43 with broad insecticidal activity against lepidopteran and coleopteran species. In vitro measurements supported by modeling studies indicate that heterolignans 3-134 act as tubuline polymerization inhibitors interacting with the colchicine-binding site. Insect specific structure-activity effects were observed showing that the insecticidal SAR described herein differs from reported cytotoxicity studies.

Cross-coupling reactions in Cinchona alkaloid chemistry: aryl-substituted and dimeric quinine, quinidine, as well as quincorine and quincoridine derivatives

Cross-coupling reactions of modified Cinchona alkaloids provide access to a wide variety of novel arylated and dimeric derivatives of quinine and quinidine containing a single and double 1,2-amino alcohol functionality. Sonogashira and Heck reactions allow functionalization of ethynyl and 11-iodovinyl precursors. The role of bystander functionality is investigated.

Synthesis of 10,11-DidehydroCinchona Alkaloids and Key Derivatives

A series of 10,11-didehydro Cinchona alkaloids containing an ethynyl group at C(3) were prepared efficiently in two steps from the naturally occurring Cinchona alkaloids (Scheme 1). 10,11-Didehydroquinine (4c) and 10,11-didehydroquinidine (4a) belong to a significantly new class of semi-natural Cinchona alkaloids. They are more polar and basic than the natural compounds and serve as versatile building blocks for further functionalization; they were transformed into the corresponding 11-halo and 11-pseudohalo derivatives and (Z)-vinyl halides (Schemes 2 and 3). The conformation of the alkaloids was elucidated by NOE and X-ray crystal diffraction analysis of 4a (Fig.), and the cytostatic activity of selected didehydroquinidine derivatives was evaluated (Table 5).

Recent Advances in the Solid-Phase Synthesis of Long-Chain β-Peptides

β-Peptides built of homologated amino acids with proteinogenic side chains fold to secondary structures with as few as six residues [1]. We were interested to find out up to which chain length these β-peptidic structures are stable in solution as α-peptidic helices, which rarely exceed chain lengths of 25 residues in proteins. Several problems had to be solved on the way to larger β-peptides. All β3-peptides with non-functionalized or protected functionalized side-chains and with terminal protection become insoluble in organic solvents and in H2O with increasing chain lengths. Therefore, sequential synthesis or fragment coupling in solution is prevented.

Cleavage of sulfonamides with phenyldimethylsilyllithium

The toluene-p-sulfonamides of secondary amines and indoles are cleaved by treatment with phenyldimethylsilyllithium to give the secondary amines. Aziridine toluene-p-sulfonamides, however, are opened by attack of the silyllithium reagent on carbon to give β-silylethyl sulfonamides. The aziridine toluene-p-sulfonamide 22 derived from norbornene is different in giving the 2-[dimethyl(phenyl)silyl]-4-methylbenzenesulfonamide 23 of exo-norbornylamine. The aziridine toluene-p-sulfonamides 26, 28 and 30, derived from methyl cinnamate, methyl acrylate and cinnamyl acetate, are also anomalous, giving 3-[N-(p-tolylsulfonyl)amino]-3-phenylpropionic acid 27, {3-[N-(p-tolylsulfonyl)amino]propionyl}dimethyl(phenyl)silane 29 and trans-cinnamyl alcohol 31, respectively, each derived by opening of the aziridine ring followed by loss of the silyl group.

Synthesis of tricyclic N,O-acetals from α-functionalized rubanone. A masked 1,2,3-tricarbonyl system from quinidine

A series of protected 2-bromorubanones derived from quinidine has been prepared diastereoselectively and converted into tricyclic N,O-acetals containing a masked 1,2,3-tricarbonyl functionality. Good yields have been achieved using formyl-, acetyl- and propionyl-protecting groups. The novel one-pot conversion of protected 2-bromorubanones into tricyclic Cinchona cage compounds is suggested to include a reduction–oxidation sequence and an intramolecular acyl transfer.