Macrocycles cyclopeptides

Total synthesis of complex (macrocyclic) natural products using fast and flexible strategies and diversity-oriented synthesis of natural product-like macrocycles are important research topics in our laboratory. The following sections describe the total synthesis of epothilone D and epothilone D5 analogues, DOS of cyclopeptide alkaloid analogues, of biaryl ether macrocycles, and of steroid/peptide hybrid macrocycles, respectively. 

The obvious disconnection in cyclopeptide alkaloids and indeed the strategy employed in most total syntheses of this type of compound is the formation of the aryl ether bond. Many groups chose to form the macrocyclic aryl ether by S Ar reaction. We decided to follow the inverse strategy, i.e., displacement of an allylic leaving group by a phenolate. In case of the natural cyclopeptide alkaloids, this would involve activation of yS-hydroxy-a-amino acids, which is likely to be accompanied by extensive elimination. Elimination is not possible when a-methylene- -hydroxy acids are used. Additionally, the double bond activates the leaving group and provides a handle for a possible later side chain attachment. 

Ugi reaction of acid 88 with isonitrile 85, isobutyraldehyde and isopropylamine furnished dipeptide 89 in 67% yield. Similar Ugi reactions with other components afforded linear cyclization precursors in yields up to 98%. The final macrocyclization was not straightforward (no similar reactions were described in literature), but after optimization of the reaction conditions (varying base, solvent, concentration and reaction time) cyclopeptide alkaloid analogue 90 was obtained in 96% yield after treatment with K2CO3 and catalytic 18-crown-6 in acetone. 

Keywords Cyclopeptides Depsipeptides Peptoids Macrocycles Diketopiper-azines Benzodiazepines Ugi-reaction Polycyclic compounds Orthogonal reactivity Sequential reactions Iteration Bifunctional building blocks Medium sized rings Beta-turn motif... 

The Joullie, Zhu, and Wessjohann groups reported the synthesis of different M-alkyl ansa-cyclopeptides and the corresponding ansa-cyclopeptoids. These are inspired by natural cyclopeptide alkaloids. The first approaches to combine the Ugi reaction with a macrocyclization toward cyclopeptide alkaloids was done by Joullie and coworkers [73-75]. 

A rapid synthesis of cyclodepsipeptides containing sugar moieties was reported by Zhu and coworkers (Scheme 20) [88]. A three-component reaction of a sugar amino acid derivative 20a, an aldehyde b, and a dipeptide isocyanide c, followed by saponification and trifluoroacetic acid-promoted macrocyclization was employed to afford the cyclic amino sugar cyclopeptides d. This approach allows to systematically modify the amino acids and the carbohydrate residue, as well as the size of the macrocycle. Again, the only reagents used to mediate the formation of the... 

However, this strategy failed when applied to the synthesis of the cyclopeptide lissoclinamide 7. Here, the serine-derived oxazoline moiety could not be selectively thiolyzed in the presence of the threonine-derived oxazoline in the cyclopeptide 334. " The authors attributed this lack of chemoselectivity to the increased stability and thus reduced reactivity, of the serine-derived oxazoline in the macrocyclic scaffold. AU three oxazoline moieties reacted under the prolonged reaction conditions to give the trithio cyclopeptide 335 (Scheme 8.102). The structure of 335 was confirmed by conversion to the tristhiazoline cyclopeptide 336. 

Reaction of the ligand 4-H4 with (acac)2Mo02 should lead to the macrocyclic complex in which the biologically active WAG-sequence of the cyclopeptidic Sege-talins A/B is stabilized in a loop-type fashion. 

Cyclopeptides as Macrocyclic Host Molecules for Charged Guests... 

Calixarenes provided the main inspiration for the artifidal receptors studied in my group. We wanted to develop a new class of macrocyclic host with binding properties and structural variability similar to calixarenes but a closer relationship to natural systems. The obvious choice was, of course, to base such receptors on cyclopeptides, macrocydic compounds that are composed of the same subunits as the natural systems. 

The MALDI-TOF monitored SP preparation of lysobactin, a natural cyclopeptide antibiotic, on PS resin bearing the Rink amine linker 1.6 has been reported (141). The SPS scheme is shown in Fig. 1.21. The classical peptide coupling steps, the allyl deprotection (see Section 1.3.5), and the macrocyclization step were all monitored by MALDI-TOF, and the purity of the products was also determined using this technique. The presence of small impurities in compounds 1.56-1.61 was easily detected, and the reaction conditions for the key deprotection of 1.59 and cyclization of 1.60 were rapidly optimized. A total yield of 15% was obtained after HPLC purification of released 1.62 (lysobactin). 

Indeed, this MCR worked extremely well by simply stirring the three components in trifluoroethanol (TFE) at room temperature. Interestingly, no high-dilution conditions were required for the above transformation. Authors prepared 12-, 15-and 18-membered macrocycles and even nine-membered medium-sized cycles in excellent yields with diastereoselectivities. Two examples were depicted in Scheme 11. Thus, stirring a TFE solution of aziridine aldehyde 29, dipeptide 30 and ferf-butyl isocyanide at room temperature for 4 h afforded a nine-membered cycle 31 in 83% yield. Similarly, a 18-membered cyclopeptide 33 was obtained in 77% yield by the reaction of 29, pentapeptide 32 and ferf-butyl isocyanide. In both examples, the cyclic compounds 31 and 33 were formed with high diastereoselectivities (dr > 20/1). This is intriguing, as Ugi reaction provided generally low to moderate stereoselection when chiral substrates was used as inputs ([66-72] for enantioselective isocyanide-based MCRs, see [73-80]). 

This process enabled the synthesis of cyclopeptide [183] and macrolide [184] model compounds with ring sizes up to 37. The acyclic starting materials were conveniently cyclized, with yields between 25 and 50 %. One major problem connected with this thioether method is the incorporation of the electron-donating group into the macrocyclic ring systems. A practical way of overcoming this dis-... 

That the electron-transfer step occurs predominantly in an intramolecular fashion is probably because of complexation effects in the ground state of the substrates. The synthesis of cyclopeptide model compounds was intensively investigated by use of this photo-decarboxylation route. The yields of these macrocyclizations did not depend on spacer length but on the position of the amide group relative to... 

A novel steroidal cyclopeptide (Figure 38) has been synthesized by Albert and Feigel from a steroidal amino acid [55]. Since a variety of amino acids can be incorporated into the macrocycle, this strategy offers attractive possibilities for the construction of functionalized macrocycles for catalyst design. 

In 1974, Deber and Blout [59,60] reported for the first time that they could discriminate between ions of D- and L-amino acids with the help of macrocyclic peptides. In 13C-NMR spectra cyclopeptides c(L-Pro-L-Gly)3 or c(L-Pro-L-Gly)4 showed different chemical shifts for the carbon atoms of D- and L-amino acids salts. 

Guidelines for the synthesis of cyclopeptides have it that pendant groups should be connected to the cyclic scaffold after ring closure. Moreover, peptide bond formation is generally preferred to ester bond formation as a means to accomplish macrocyclization of depsipeptide frameworks, and it is also well established that primary amino groups react more efficiently than secondary ones in peptide bond forming reactions i.e., secondary amides are more readily formed than tertiary ones. Retrosynthetic dissection of the only pair of secondary amide bonds in luzopeptin A-C precursor 11 leads to pentadepsipeptide 12 (Scheme 3). 

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