An efficient synthesis of (−)-tetrahydrolipstatin (THL) is reported. This method takes advantage of a phosphate tether-mediated, one-pot, sequential RCM/CM/hydrogenation protocol to deliver THL in 8 total steps from a readily prepared (S,S)-triene. The strategy incorporates selective cross metathesis, regio-selective hydrogenation, regio-and diastereoselective cuprate addition and Mitsunobu inversion for installation of the C5 formamide ester subunit.(−)-Tetrahydrolipstatin (THL, 1) is an anti-obesity drug marketed under generic name Orlistat ® and is a stable saturated form of the naturally occuring lipstatin (2) (Figure 1). Lipstatin is a protein-reactive natural product and an irreversible pancreatic lipase inhibitor which was first isolated in 1987 from Streptomyces toxytricini. 1 The biological activity inherent to this family of molecules is based on the reactivity of the β-lactone moiety which is readily acylated by the pancreatic lipase enzyme. This process ultimately inhibits the enzyme reactivity aimed at hydrolyzing triglycerides to produce free fatty acids which are then readily absorbed into the dietary system. 1b,2 Recently, the discovery of selective inhibition of thioesterase activity of fatty acid synthase (FAS) in cancer cells has elevated the potential of Orlistat ® as an anticancer drug. 3,4 The inhibition of FAS stops both endothelial cell proliferation and angiogenesis and ultimately delays tumor progression in a variety of cancer cells. This promising activity highlights the broad and interesting biological profile of Orlistat ® and has prompted renewed synthetic efforts and corresponding biology of THL, lipstatin and analogs thereof.4 ,5 Herein we report a concise total synthesis of (−)-tetrahydrolipstatin via a strategy utilizing a phosphate-tether-mediated, one-pot, sequential RCM/CM/hydrogenation pathway of triene (S,S)-7. 6 Overall, the reported phanson@ku.edu. Supporting Information Available Experimental details and spectroscopic data of new compounds. This material is available free of charge via the Internet at http://pubs.acs.org. NIH Public Access Author ManuscriptOrg Lett. Author manuscript; available in PMC 2011 April 2. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript synthetic route comprises 9 total steps from the readily prepared diene diol-(S,S)-8 and highlights the utility of phosphate tethered processes and one-pot, multi-step operations.The first total synthesis of THL was achieved in 1987 by Schneider and coworkers utilizing Wittig olefination and an aldol condensation as key steps in a non-stereoselective process.7 Numerous total syntheses,8 formal syntheses 9 and synthetic analogues have followed this initial report, with the majority of synthetic pathways comprised of 14-25 steps. The shortest routes to THL reported to-date range from 10-12 steps using an array of synthetic strategies, including, (i) a 12-step anti-aldol approach,8i (ii) a 12-step diastereoselective allylation and crotylation sequence utilizing allyl/crotyltri...
Recent advances in phosphate tether-mediated natural product synthesis are reviewed. Synthetic approaches toward dolabelide C, (-)-salicylihalimide A, (-)-tetrahydrolipstatin, and (+)-strictifolione are included. In addition, current efforts in method development are briefly reviewed, including a detailed study on the effect of stereochemical complexity on the phosphate-mediated, diastereoselective ring-closing metathesis reaction and recent advances in multi-reaction, one-pot sequential processes mediated by the phosphate tether. Overall, this review seeks to highlight the utility of phosphate triesters to serve as multifunctional tethers with protecting group and latent leaving group characteristics and the ability to orchestrate multiple, orthogonal reaction pathways to allow for the facile synthesis of complex, bioactive small molecules and their analogs.
An array of examples of diastereoselective, phosphate tether-mediated ring-closing metathesis reactions, which highlight the importance of product ring size and substrate stereochemical compatibility, as well as complexity, is reported. Studies focus primarily on the formation of bicyclo[n.3.1]phosphates, involving the coupling of C2-symmetric dienediol subunits with a variety of simple, as well as complex alcohol cross-partners.
A phosphate tether-mediated ring-closing metathesis study towards the synthesis of P-stereogenic bicyclo[6.3.1]-, bicyclo[7.3.1]-, and bicyclo[8.3.1]phosphates is reported. This study demonstrates expanded utility of phosphate tether-mediated desymmetrization of C2-symmetric, 1,3-anti-diol dienes in generating complex medium to large, P-stereogenic bicyclo[n.3.1]phosphates..
The synthesis of the C9–C25 subunit of the marine natural product spirastrellolide B is reported. The key synthetic features included the union of the two key fragments 5 and 6 via a Suzuki–Miyaura coupling reaction and a late-stage, one-pot sequential deprotection/cascade Achmatowicz rearrangement–spiroketalization to install the key spirocyclic intermediate present in the C9–C25 fragment of spirastrellolide B. The synthesis of the C9–C16 fragment 6 was accomplished via a phosphate tether mediated ring-closing metathesis (RCM), a subsequent hydroboration–oxidation protocol, followed by other stereoselective transformations in a facile manner. The spirocyclic intermediate was further functionalized utilizing a Lindlar/NaBH4 reduction protocol to furnish the C9–C25 subunit 3.
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