Alkaloids cyclopeptide

The natural product westiellamide (158) and other unnatural cyclopeptide alkaloids were synthesised by cyclooligomerisation reactions <00T9143>. The benzene-based tripodal tris(oxazolines) 159 were developed as new selective receptors toward alkylammonium ions <00CEJ3399>. 

The pyrrolidine ring is part of numerous natural products, and we have restricted the field to those alkaloids that contain an isolated pyrrolidine ring. We have thus excluded the so-called Sceletium (mesembrine) and Dendrobium (den-drobine) alkaloids, which have also been reviewed (3-5). The pyrrolidine ring is frequently encountered in proline residues of cyclopeptide alkaloids these have been reviewed already (7) and will not be discussed here. 

Cyclic tautomers of tryptamines and tryptophans, chemistry and reactions, 34, I (1988) Cyclopeptide alkaloids, 15, 165 (1975)... 

Zhu and co-workers used S Ar reactions to create the biaryl ether bond in their synthesis of cyclopeptide alkaloids [55-57] (Scheme 5). The electrophile in this case is an aryl fluoride, often additionally activated by an electron-withdrawing group such as a nitro group. The necessity of such an activation auxiliary obviously has a negative impact on general applicability of this method. 

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. 

A multicomponent reaction/cyclization strategy was employed to synthesize simplified cyclopeptide alkaloid analogues 82. The enamide double bond found in many natural derivatives is missing, but biologically active cyclopeptide alkaloids with a hydrated enamide double bond (like sanjoi-nine G1 [55, 56]) are known. The synthesis is considerably simplified by omitting this unsaturation, obviously not required for biological activity. 

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. 

Cyclopeptide alkaloids 91-96 were synthesized in analogy to 90 (Table 1). Isonitrile derivatives of 85 could be used in the same way. 

Cristau P, Vors JP, Zhu JP (2006) Rapid synthesis of cyclopeptide alkaloid-like para-cyclophanes by combined use of Ugi-4CR and intramolecular SNAr reaction. Qsar Comb Sci 25 519-526... 

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]. 

Scheme 15 Mimics of natural cyclopeptide alkaloids by Ugi CR + Sn2 cyclization...

Morel, A. F., Maldaner, G., Ilha, V., Missau, F., Silva, U. F. and Dalcol, 1.1. 2005. Cyclopeptide alkaloids from Scutia buxifolia reiss and their antimicrobial activity. Phytochemistry, 66 2571-2576. 

Cyclopeptide Alkaloids Containing a Styrylamine Ring Unit R. Tschesche, Heterocycles, 1976, 4, 107-116. 

The four new cyclopeptide alkaloids (19a)—(19d) isolated from the shrub Ceanothus integerrimus contain a para-bridged fourteen-membered-ring nucleus (19), for which the name phencyclopeptine has been proposed.16 The crude alkaloidal extract from Ceanothus sanguineus17 showed the presence of five major components on composite field-desorption mass spectrometry. H.p.l.c., however, yielded six alkaloids, two of which were isomeric and one of which was a new alkaloid (20). The bark of Scutia buxifolia contains five scutianine alkaloids (B, C, D, E, and H) H is new, and is (21).18 Two new cyclopeptides, sativanines A and B, have been identified as (22) and (23) by m.s.-n.m.r. study.19... 

The first and second papers in a series on medicinal plants of Pakistan report the presence of thirteen-membered cyclopeptide alkaloids in the leaves of Cocculus villosus20 and in their stems.21 A study on the cyclization of ansapep-tides , e.g. (24), has shown that the fourteen-membered ring was not obtained from (24 R = H) but that fifteen-, sixteen-, and seventeen-membered rings were produced from (24 R = COCH2NH2).22... 

The term peptide alkaloid was first proposed by Goutarel and co-workers. However, since these alkaloids, with one known exception, are cyclic ones the term cyclopeptide alkaloids seems to be more appropriate the lone exception (lasiodine-A) could in fact arise by secondary opening of the cyclic system. In this review only those alkaloids are treated which incorporate a hydroxystyrylamino group... 

In 1963 a group of Swiss authors (12) isolated zizyphine from Zizyphus oenoplia and recognized isoleucine and proline as components. Two years later Zbiral etal. (13) proposed a complete structure which was later revised (14). Pais et al. (15) in an earlier preliminary report suggested the structure of pandamine which had been isolated from Panda oleosa. This was confirmed in 1966, and the structure of the similarly constituted pandamine was reported (17). Shortly thereafter Tschesche and co-workers (18) reported the structure of an alkaloid of this type scutianine-A from Scutia buxifolia. Since then the number of cyclopeptide alkaloids of known structure has risen to more than sixty, a figure which Klein and Rapoport had envisioned in 1968 (20). The workers at Gif-sur-Yvette and at Bonn have been in the forefront of these researches but others have made important contributions (19-26). 

Cyclopeptide alkaloids are particularly common in plants of the Rhamnaceae family (fourteen species thus far), but they have also... 

The pure alkaloids generally crystallize easily the amphibines and the mauritines have only been obtained in the amorphous state. The melting points, with a few exceptions as noted in Tables I-VI, are mostly over 200°. The reduced bases generally melt 20-80° higher. Most of the alkaloids are levorotatory (— 200 to — 400° in chloroform or alcohols) but aralionine-A ( + 82°, methanol) and lasiodine-A ( + 38°, chloroform) are dextrorotatory. The dihydro derivatives show an increase in the positive direction. The dependence of the optical activity on the solvent and on the degree of methylation of the amino group in the 15-member cyclopeptide alkaloids is worthy of note (Table V). 

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