Uvaricin

Allylic alcohols can serve as 7t-allyl cation precursors to act as electrophiles in Sn reactions with a tethered O-nucleophile giving rise to the formation of spiroannulated tetrahydrofurans <2000TL3411>. Michael acceptors are also suitable electrophiles for the cyclization to tetrahydrofuran rings <2003T1613>. The Tsuji-Trost allylation has found widespread application in the synthesis of carbo- and heterocyclic compounds. Allylic substitution has been employed in the stereoselective synthesis of 2-vinyl-5-substituted tetrahydrofurans <2001H(54)419>. A formal total synthesis of uvaricin makes twofold use of the Tsuji-Trost reaction in a double cyclization to bis-tetrahydrofurans (Equation 73) <20010L1953>. 

Scheme 10-26. Formal total synthesis of uvaricin by Burke and Jiang.

A wide variety of natural products has been isolated from the Annonaceae. However, the report in 1982 of the isolation of the acetogenin uvaricin (1) from Uvaria accuminate was the first example of what is now a large and growing series of acetogenins found in these sources. More than one-hundred examples have been reported in the intervening decade.3- That these compounds often exhibit remarkably potent cytotoxic and other biological activity has fueled interest in this class. 

Beginning with our report in 1986 describing the relative configuration of the bis-THF portion of uvaricin. research has yielded many complementary methods for... 

Model compounds of bis-THF structure prepared for NMR correlation studies observation that H NMR shifts of acetate methyl groups correlate with relative configuration of C(15)/C(16) and C(23)/C(24) in uvaricin (later proven to be correct). 

H NMR correlation studies suggest that bis-THF portion of uvaricin possesses threo/trans/threo/trans/erythro relative configuration among C(15)-C(24). Establishes general method for determining relative configuration. 

Synthesis of 15,16,19,20,23,24-/>exep/-uvaricin (a diastereomer of the natural product) confirms relative configuration and establishes absolute configuration (via Mosher esters) of the first acetogenin, uvaricin. 

Figure 7. Acetate CJds Chemical Shifts of Uvaricin Acetate (12) Define the...

Figure 8. Graphical Comparison of Proton Chemical Shift Data for Model bis-Acetates 11a-l and the Peracetate Derivatives of Uvaricin (12), Rolliniastatin I (14), and Asimicin (15).

Further proof has come through the recent total synthesis of several Annonaceous acetogenins. The first of these to be constructed was (+)-(15,16,19,20,23,24)-hexepf-uvaricin (19), an unnatural diastereomer of uvaricin (1) reported from our laboratories in 1991.27 Knowing the relative, but not the absolute, configuration among C(15)-C(24) of... 

Related to a resolution, a desymmetrization reaction was used in an approach to Uvaricin. Use of AD-mix [1 gave only moderate diastereoselection with 21, but the use of (DHQD)2AQN gave 22 after two cycles the first reaction was run to 50% completion and the recycled diene 21 was then subjected to the reaction conditions for a second time (Scheme 3.17) [320]. 

Burke and Jiang reported that the palladium-catalyzed diastereoselective double allylation of the diol bis(allylic acetate) 613 using (R,R) DPPBA 607 afforded the bis-tetrahydrofuran core 614 in 97% yield (Scheme 187).265 The resulting diene 614 was further transformed into a known intermediate 615 for the synthesis of uvaricin. They demonstrated that palladium (0)-catalyzed desymmetrization of the C2 diol 616 with Trost s ligand 607 afforded the tetrahy-drofuran 617 diastereoselectively (Scheme 188).266 The product 617 was manipulated to the F ring of halichondrin B (618). 

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