Side chains, fully elaborated

Treatment of this enone with 4-fluorobenzaldehyde under the conditions of Stetter, utilizing A -cthylthiazolium catalyst 20 under anhydrous conditions produced the highly substituted 1,4-diketone 21 in 80% yield. Treatment of diketone 21 with the diethyl acetal of 3-amino-propanal under the carefully controlled conditions described above (1 equivalent of pivalic acid) afforded penta-substitued pyrrole 22 in 43% yield and, very significantly, demonstrated that a totally convergent synthesis was possible. With this result in hand, it became possible to envision a route in which a fully elaborated side-chain could be combined with the appropriate 1,4-diketone (i.e. 21), to assemble the entire molecule in one operation. 

A third route developed by this group started with the commercially available alcohol 32," a compound which has also been the subject of considerable process development due to its use as a common intermediate in the synthesis of several HMGR inhibitors.Conversion of 32 to the 4-halo or 4-nitrobenzenesulfonate 33 followed by displacement with sodium cyanide provided 34 in 90% yield, which is the z-butyl-ester analog of 29. It was noted that this procedure was most scaleable employing the 4-chlorobenzenesulfonate 33a due to the instability of the 4-bromo and 4-nitro-analogs to aqueous hydrolysis. Ra-Ni reduction as before provided the fully elaborated side-chain 35 as the f-butyl ester (Scheme 8). 

A variation of this route was applied to the preparation of a-methylenecyclo-pentane 179, an intermediate that was employed for the synthesis of prostaglandin PGF2o, (180) (Scheme 6.82). The acetonide-protected oxime-diol 175 [derived from propanal (174)] was treated with sodium hypochlorite without the addition of base. This led to the tricyclic adduct 176 with high stereoselectivity. One of the side chains was subsequently elaborated and the fully protected cyclopentano-isoxazo-line (177), when exposed to Raney Ni/boron trichloride, gave the 2-hydroxymethyl-cyclopentanone (178). This compound was dehydrated using mesyl chloride/ pyridine to furnish enone (179) (324). In another related synthesis of PGF2q, the p-side-chain (3-hydroxyoctenyl) was introduced prior to the cycloaddition (325). 

The first total synthesis of altohyrtin C (spongistatin 2 4b) was accomplished via diastereoselective aldol coupling of the C1-C15 AB and C16-C28 CD segments, Wittig coupling of the ABCD and the C29-C43 EF segments, addition of the C44-C51 side chain to the fully elaborated ABCDEF system, and the regiose-lective macrolactonization (Fig. 8). 

Subsequently, compound 91 was elaborated to primary alcohol 92 with the H-ring functionality in a similar manner to the Sasaki synthesis (Scheme 11). For the introduction of the triene side chain, a simple and practical method for the stereoselective synthesis of (Z)-vinyl iodide, which is expected to be more reactive than the bromide counterpart, was developed [105]. Thus, PCC oxidation of alcohol 92 followed by treatment of the resultant aldehyde with tetraiodomethane and triphenylphosphine gave diiodoalkene 93. Reduction of 93 with the zinc-copper couple in the presence of acetic acid provided (Z)-vinyl iodide 94 in high yield. Since deprotection of the fully protected... 

The assumption would be that the terpene moiety is fully elaborated to the level of baccatin III and the C-13 side chain is attached last [16]. 

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