Cryptophycin

Aldol reaction of ester 253 with benzyloxyacetaldehyde gave exclusively syn aldol adduct 254 in 93% yield this was transformed into alkene 255. Subsequent transformation yielded tetrahydrofuran derivative 256. This cyclic bromoether serves as masked functionality for the labile exocyclic 

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Stereospecific deoxygenations in the cryptophycin family of natural products from Nostocaceae were reported by Moore [47]. The products were important in the elucidation of the natural product s structure and for the preparation of novel cryptophycin derivatives. 

C domains can display functions that deviate from typical amide bond formation. Several C domains are postulated to act as ester synthases, catalyzing ester formation instead of amide formation. NRPS modules containing C domains that display this activity are present in the biosynthetic pathways for the kutznerides, cryptophycins, " cereulide, valinomycin, hectochlorin, and beauvericin. Each of these C domains likely utilizes a PCP-bound a-hydroxyl acceptor in the condensation reaction. Another NRPS C domain that catalyzes ester bond formation is involved in the biosynthesis of the polyketide-derived mycotoxins known as the fiimonisins. Du and coworkers have shown that a recombinant PCP-C didomain of an NRPS involved in the biosynthetic pathway of the fnmonisins can catalyze ester bond formation between hydroxyfumonisins and the A-acetylcysteamine thioester of tricarballylic acid, even though PCP-bound tricarballylic acid is not... 

Many NRPs such as cyclosporin, complestatin, actinomycin, and chondramide contain N-methyl amides. M-Methyl transferase (N-MT) domains utilize S-adenosylmethionine (SAM) as a cofactor to catalyze the transfer of the methyl group from SAM to the a-amine of an aminoacyl-S-PCP substrate. The presence of M-methylamides in NRPs is believed to protect the peptide from proteolysis. Interestingly, N-MT domains are incorporated into the A domains of C-A-MT-PCP modules, between two of the core motifs (A8 and A9). MT domains contain three sequence motifs important for catalysis. ° 0-Methyl transferase domains are also found in NRPSs and likewise use the SAM cofactor. For instance, cryptophycin and anabaenopeptilide synthetases contain 0-MT domains for the methylation of tyrosine side chains. These 0-MT domains lack one of the three core motifs described for N-MT domains. ... 

A simple yet powerful application of the Grubbs reaction is specific homologation of a terminal vinyl group. When there is more than one alkene in the molecule, suitably disposed, one would worry about competing cyclizalion. In studies directed toward the cryptophycins, Mark Lautcns of the University of Toronto has reported (Organic Lett. 2004,6, 1883) that the second generation Grubbs catalyst 2 smoothly converts 1 to 3. The alternative cyclization product 4 is produced only in trace amounts. 

Twenty-five cryptophycins, e.g. cryptophycin 1 (162), have been isolated from a Nostoc sp. strain. They exhibit various degrees of cytotoxicity against three tumor cell lines, namely KB (human nasopharyngeal), LoVo (human colorectal adenocarcenoma), and SKOV3 (human ovarian carcinoma). Removal of the chlorine atom leads to a 10-fold reduction in cytotoxicity [124]. The antitumor activity of a number of cryptophycins from Nostoc sp. has been evaluated [125]. 

A related example (Scheme 15) of the utility of (3-lactams as acylating agents for macrolactonization has been reported by Georg in an approach to the antimicotic agent cryptophycin 37 from precursor 36 [79, 80]. 

Scheme 15 P-Lactams as intramolecular O-acylating reagents (II). A route to Cryptophycin...

Li T, Shih C (2002) Structure Activity Relationships of Cryptophycins, A Novel Class of Antitumor Antimitotic Agents. Front Biotechnol Pharmaceut 3 1972... 

Tius, MA (2003) Cryptophycin Synthesis. In Gribble GW (ed) Handbook of Environmental Chemistry. Springer, Berlin, p 265... 

Barrow RA, Hemscheidt T, Liang J, Paik S, Moore RE, Tius MA (1995) Total Synthesis of Cryptophycins. Revision of the Structures of Cryptophycins A and C. J Am Chem Soc 117 2479... 

Golakoti T, Ogino J, Heltzel CE, Husebo TL, Jensen CM, Larsen LK, Patterson GML, Moore RE, Mooberry SL, Corbett TH, Valeriote FA (1995) Structure Determination, Conformational Analysis, Chemical Stability Studies, and Antitumor Evaluation of the Cryptophycins. Isolation of 18 New Analogs from Nostoc sp. Strain GSV 224. J Am Chem Soc 117 12030... 

Chaganty S, Golakoti T, Heltzel C, Moore RE, Yoshida WY (2004) Isolation and Structure Determination of Cryptophycins 38, 326, and 327 from the Terrestrial Cyanobacterium Nostoc sp. GSV 224. J Nat Prod 67 1403... 

Eisser S, Stoncius A, Nahrwold M, Sewald N (2006) The Synthesis of Cryptophycins. Synthesis 3747... 

McCubbin JA, Maddess ML, Lautens M (2006) Total Synthesis of Cryptophycin Analogues via a Scaffold Approach. Org Lett 8 2993... 

Wagner MM, Paul DC, Shih C, Jordan MA, Wilson L, Williams DC (1999) In Vitro Pharmacology of Cryptophycin 52 (LY355703) in Human Tumor Cell Lines. Cancer Chemother Pharmacol 43 115... 

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