Apoptolidin

A remarkable example of the compatibility of the sulfoxide method with polyene functionality is taken from a key step in the synthesis of apoptolidin (Scheme 4.59) [361],... 

D-Oleandrose and L-olivomycose (3-C-methyl-L-olivose) together with 6-de-oxy-4- O-methyl-L-glucosc are constituents of the oligosaccharide in apoptolidin, isolated from Nocardiopsis sp., which was the subject of intense synthetic and biological investigation because of its potential for the treatment of cancer.151 155... 

A novel synthetic approach was developed by R.E. Taylor et al. for the preparation of the triene portion of the biologically active polyketide apoptolidin. The allylic chloride substrate was prepared from an allylic alcohol via a thionyl chloride mediated rearrangement. Next, the allylic chloride was subjected to the Ganem oxidation by treating it with five equivalents of trimethylamine A/-oxide (TMANO) in DMSO at room temperature to obtain the desired a,p-unsaturated aldehyde. Interestingly, the original Kornblum oxidation conditions were not well suited for this system because of the required high reaction temperature. 

The total synthesis of apoptolidin was accomplished in the laboratory of K.C. Nicolaou. The key C12-C28 vinyl iodide fragment was prepared using the Schwartz hydrozirconation of an internal alkyne followed by trapping of the alkenylzirconium intermediate with iodine (I2). The vinyl iodide was formed as a 6 1 mixture of regioisomers. Under the reaction conditions, the methyl orthoester was converted to the methyl glycoside moiety at C21, which was presumably facilitated by the complexation of Zr with the pyranoside oxygen atom. 

Other important natural products, such as crocacin D (46), 9,80 bafilomycin Ai (47), i 2 poly-cephalin C (48), 3 dictyostatin (49), 4 (+)-tubelactomidn A (50), fostriecin (51a) and 8-epi-fostriecin (51b),86 87 archazolid B (52), and apoptolidin (53) have been synthesized by using the alkenyl-alkenyl coupling are shown in Figure 5.4.1. 

Fig. 2.3 Structures of discodermolide and apoptolidin - two extremely challenging pharmacologically interesting target molecules. 

Lewis acid-catalyzed allylation is widely used for incorporation of aUyl moieties in the total synthesis of biologically active and pharmaceutically important compounds. Magnesium bromide-catalyzed allylation has been used in the total synthesis of pamamycin-607 (Scheme 12.6) [22] and the convergent synthesis of the C1-C21 macrocyclic segment of apoptolidin (Scheme 12.6) [23]. 

It is worthy of note that palladium-mediated cross-coupling between a vinyl halide and a vinylstannane has been used in synthesis of a macrolide. For access to apoptolidin a C11-C12 bond was formed by use of the Cl-Cll and C12-C28 vinyl components to give the desired C1-C28 segment (Scheme 12.91) [193]. Intramolecular coupling under the influence of palladium catalyst resulted in the formation of the desired macrolactone, which was converted to (-)-lasonolide (Scheme 12.92) [194]. 

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