Fragment linkage method

Figure 2. Schematic representation of fragment linkage methods. In A a tricyclic ring linker connects three previously placed key fragments avoiding bumping the receptor. In B a bump occurs (signalled by the arrow).

The Julia Alkenation and Related Reactions. In 1973, Julia and Paris reported a new connective and regioselective alkene synthesis (eq 10) based on the reductive elimination of fi-acyloxy sulfones. The Juha alkenation is now one of the principal methods for fragment linkage in complex natural product synthesis. Mono-, di-, tri-, and tetrasuhstituted alkenes can he prepared in moderate to good yield, depending on the substrate. The three-step sequence, illustrated in eq 11, entails (a) condensation of a metalated sulfone with an aldehyde or ketone, (h) O-functionalization of the adduct as the acetate, henzoate, or mesylate (to prevent retroaldohzation), and (c) reductive elimination using 6% Na(Hg) in THF-MeOH (3 1) at —20 °C. In favorable cases, step (b) can be omitted and the reductive elimination performed on a... 

In addition to the synthesis of azacalix[4] aromatics that are composed of either identical or varied aromatic rings and substituents on nitrogen linkages, the fragment coupling method is also powerful in the construction of azacalixaromatics of... 

When this method, in a slightly modified form, was applied to Salmonella free lipid A, mainly two compounds were liberated which were detected by gas-liquid chromatography and characterized by mass spectrometry. The spectrum of the first compound was identical with that of authentic 3-hydroxytetradecanoic acid, 3-0-acylated by dodecanoic acid (3-0-dodecanoyl-tetradecanoic acid methyl ester, 3-0(12 0)-14 0) (27). The mass spectrum of the second peak showed, inter alia, characteristic fragments at 496 (M ), 465 (M-31), 239, 240 and 241, thus corresponding to 3-0-hexadecanoyl-tetradecanoic acid methyl ester (3—0(16 0)—14 0). Therefore, the two components present in Salmonella lipid A in amide linkage and released by the above described procedure... 

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