A Concise, Phosphate-Mediated Approach to the Total Synthesis of (−)-Tetrahydrolipstatin

Abstract

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...

Novel Electrophilic Scaffold for Imaging of Essential Penicillin-Binding Proteins in Streptococcus pneumoniae

“…28 The most well-known β -lactone, tetrahydrolipstatin (THL; Orlistat), is a long-term antiobesity drug that functions by irreversibly inhibiting a lipase. 29 Natural products containing this moiety were first reported ~ 50 years ago; 30,31 however, only a small number are known to possess antibiotic activity, including obafluorin, 32 SQ 26,517, 30,33 hymeglusin, 31 and THL (Figure 2a). 34 Recent work has illuminated several classes of enzymes involved in β -lactone biosynthesis, 35–37 but the bacterial targets of β -lactone activity remain largely undetermined.…”

The Asymmetric Synthesis of Tetrahydrolipstatin

“…In 2010, the Hanson laboratory preparedT HL (1)u sing aG rubbs' ring-closing metathesis to desymmetrize aC 2s ymmetric phosphate 169 (Scheme 27). [61] The Hanson route started with the Noyori asymmetric hydrogenation of a1 ,5-dichloro-2,4-diketonet op reparet he bis-chlorohydrin 166.Ab isalkylation/eliminationr eaction of 166 with as ulfur-ylide reagent gave the C2 symmetric diene diol (S,S)-167.A fter formation of the cyclic phosphate 169 (167 + 168), aG rubbs II-catalyzed ring-closing metathesis reactionw as used to cyclize 169 to bicyclic phosphate 171.Asubsequent cross metathesis and diimider eduction was used to install the undecyl group in 173.A nexo-face addition of an alkylcuprate reagent in an S N 2' fashion was used to install the C2 hexyl group in 174.T he phosphate group was reductively removed with LiAlH 4 and the diol was selectively protected as TIPS ether 175.A na lkene oxidative cleavage reactionc onverted 175 into b-hydroxy acid 176.F inally the b-lactonew as formed, the TIPS group was removed,a nd the N-formyl-l-leucineg roup was added to yield THL (1).…”

Phosphate tether-mediated ring-closing metathesis for the generation of medium to large, P-stereogenic bicyclo[n.3.1]phosphates

“…Over the past decade, our group has utilized phosphate triesters as temporary tethers to desymmetrize a number of 1,3- anti -diol-containing dienes via ring-closing metathesis (RCM). 9 Focused on the chemistry of the bicyclo[4.3.1]phosphate, 10 this method served as the cornerstone in the synthesis en route to several natural products, including dolabelide C, 11 salicylihalimide A (formal synthesis), 12 (−)-tetrahydrolipstatin, 13 (+)-strictifolione, 14 and lyngbouilloside. 15 In 2013, we reported 16 a detailed study of the effects of ring size and stereochemical complexity in the phosphate tether-mediated desymmetrization of C 2 -symmetric 1,3- anti diol dienes 17 via RCM reaction to form P -stereogenic 18 , 19 bicyclo[4.3.1]-, bicyclo[5.3.1]-, 20 and bicyclo[7.3.1]phosphates 21 (Figure 1).…”