Total Synthesis of Pseudodehydrothyrsiferol

Abstract

An enantioselective total synthesis of pseudodehydrothyrsiferol has been accomplished. The synthetic sequence highlights formation of the highly strained tetrahydropyran C-ring by a Mitsunobu-type S(N)2 reaction with an oxygen nucleophile.

Total Synthesis of the Protein Phosphatase 2A Inhibitor Lactodehydrothyrsiferol

“…[25] The cyclic carbonate was converted into diol 27 through methanolysis, selective tosylation of the primary alcohol of the resulting triol by the Lilly protocol [32] (at which point a single diastereomer could be isolated), and reduction with NaBH 4 in warm HMPA. [33] The final ring closure was conducted by exposing 27 to the Tsunoda dehydration reagent (Me 3 P=C(H)CN), [34] a step that is analogous to the endgame of the synthesis of pseudodehydrothyrsiferol reported by Hioki et al [6] This led to the formation of 28 in 40 % yield. Silyl ether cleavage by Bu 4 NF resulted in the isolation of 1.…”

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Red algae are a prolific source of squalene-derived polyethers [1] that show moderate to high levels of cytotoxicity [2] and very selective protein phosphatase 2A (PP2A) inhibition. [3] These unique structures (see Figure 1 for examples) have inspired total syntheses of the family members venusatriol, [4] thyrsiferol and its esters, [4b, 5] pseudodehydrothyrsiferol, [6] and dioxepanedehydrothyrsiferol, [7] in addition to subunit and analogue syntheses. [8] Our interest in this molecule class arose from our work [9] on the construction of cyclic ethers through epoxide-opening cascade reactions.

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Total Synthesis of the Protein Phosphatase 2A Inhibitor Lactodehydrothyrsiferol

“…Red algae are a prolific source of squalene‐derived polyethers1 that show moderate to high levels of cytotoxicity2 and very selective protein phosphatase 2A (PP2A) inhibition 3. These unique structures (see Figure 1 for examples) have inspired total syntheses of the family members venusatriol,4 thyrsiferol and its esters,4b, 5 pseudodehydrothyrsiferol,6 and dioxepanedehydrothyrsiferol,7 in addition to subunit and analogue syntheses 8. Our interest in this molecule class arose from our work9 on the construction of cyclic ethers through epoxide‐opening cascade reactions 10.…”

“…The cyclic carbonate was converted into diol 27 through methanolysis, selective tosylation of the primary alcohol of the resulting triol by the Lilly protocol32 (at which point a single diastereomer could be isolated), and reduction with NaBH 4 in warm HMPA 33. The final ring closure was conducted by exposing 27 to the Tsunoda dehydration reagent (Me 3 PC(H)CN),34 a step that is analogous to the endgame of the synthesis of pseudodehydrothyrsiferol reported by Hioki et al6 This led to the formation of 28 in 40 % yield. Silyl ether cleavage by Bu 4 NF resulted in the isolation of 1 .…”

Thyrsiferol inhibits mitochondrial respiration and HIF-1 activation

“…Dehydrothyrsiferol has been shown to be moderately cytotoxic to human breast tumor cell lines (Pec et al, 1999) and MDR + (P-glycoprotein)-expressing epidermoid carcinoma KB cell lines (Pec et al, 1998). The structural uniqueness and potential anticancer activity of 1 and its analogues have inspired numerous projects aimed at their total synthesis (González and Forsyth, 1999; McDonald and Wei, 2002; Nishiguchi and Little, 2005; Nishiguchi et al, 2006, Hioki et al, 2009, etc.). However, the mechanism(s) of action for 1 to suppress tumor cells has remained unknown.…”