Of saframycin

The Pictet-Spengler reaction has been carried out on various solid support materials " and with microwave irradiation activation.Diverse structural analogues of (-)-Saframycin A have been prepared by carrying out the Pictet-Spengler isoquinoline synthesis on substrates attached to a polystyrene support. Amine 20 was condensed with aldehyde 21 followed by cyclization to give predominantly the cis isomer tetrahydroisoquinoline 22 which was further elaborated to (-)-Saframycin A analogues. 

A strategy similar to that described above has been used for the total synthesis of saframycin A by Fukuyama and co-workers (90JA3712, 90TL5989). The aldol condensation has been extensively used in the synthesis of bicyclomycin (85JA3253 83TL5627), neoechinulin A(80TL2817), etc. The X-ray structure and photoelectron spectra of cyclo(dehydro-Ala)2 have been determined (85T2015). 

E (431) and F (432), were isolated from the Palau sponge Rertiera sp. (353). The structures of renieramycins A-D previously found in a sponge of the same genus (354) were reassigned to 433-436, in which the stereochemistry is identical with that of saframycins, metabolites of Streptomyces sp. whose structures were based on X-ray analysis (355). 

Figure 15.11 Enantioselective solid-phase synthesis of saframycin analogs by the Myers group [36, 39, 40],...

Myers and Lanman [405] have reported the preparation of stractural analogs of Saframycin on a soHd support (Scheme 120). 

Saframycin belongs to a family of complex polycyclic alkaloids endowed with spectacular antiproliferative activity. The successful demonstration that analogues of the natural product are clinically effective for the treatment of solid tumors has stimulated intense efforts towards the total synthesis and medicinal chemistry of these alkaloids. Myers and Lanman adapted their solution phase synthesis of saframycin to a ten-step solid phase synthesis, leading to the preparation of 16 analogues [40]. The key steps are two Pictet-Spengler reactions, which are used... 

Figure 10 Nonribosomal peptide biosynthesis in myxobacteria (a). Biosynthesis of saframycin Mx1 (30) in Myxococcus xanthus DM504/15. The tetramoduiar assembiy iine foiiows textbook biochemistry, except for the unusuai reductive chain reiease by the terminai Red domain. The iinear peptide chain (27) then undergoes severai cyciization steps (the underiying mechanisms are not fuiiy understood) and is further decorated with functionai groups (highiighted in gray) by enzyme activities, which have not been identified to date. Based on the absence of E domains in the assembiy iine and the absoiute configuration of the end product 30, an L-configuration was assigned to the incorporated amino acids.

Cyclization. A remarkable formation of the skeleton of saframycin A has been reported. 

The Pictet-Spengler reaction has also been developed on solid-support materials. This advancement provided the opportunity for the synthesis of an array of structurally diverse analogues of saframycin A, an important anti-tumor antibiotic. 

Myers, A.G. and Plowright, A.T., Synthesis and evaluation of bishydroquinone derivatives of (-)-saframycin A identification of a versatile molecular template imparting potent antiproliferative activity, J. Am. Chem. Soc., 123, 5114, 2001. 

FIGURE 11.66 Saframycin A structure and 3,9-diazabicyclo[3.3.1]non-6-ene core. (From Myers, A.G. and Lanman, B.A., A solid-supported, enantioselective synthesis suitable for the rapid preparation of large numbers of diverse stractural analogs of (-)-saframycin A, 7. Am. Chem. Soc., 124, 12969, 2002 Orain, D., Koch, G., and Giger, R., From solution phase studies to solid-phase synthesis a new indole based scaffold for combinatorial chemistry, Chimia, 57, 255, 2003.)... 

Scheme 11 Total Synthesis of Saframycin A analogs on solid phase by Myers et al.

Saito, N., Ohira, Y, Wada, N., and Kubo, A. (1990) Synthesis of saframycins. V. Selenium oxide oxidation of hexahydro-l,5-imino-3-benzazocin-7,10-dione a useful method for constructing saframycins C and D from saframycin B. Tetrahedron, 46, 7711-7728,... 

Martinez, E.J. and Corey, E.J. (1999) Enantioselective synthesis of saframycin A and evaluation of antitumor activity relative to ecteinascidin/saframycin hybrids. Org. Lett, 1, 75-77. 

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