- Total Synthesis of Tetrahydrolipstatin, Its Derivatives, and Evaluation of Their Ability to Potentiate Multiple Antibiotic Classes against Mycobacterium Species
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Tetrahydrolipstatin (THL, 1a) has been shown to inhibit both mammalian and bacterial α/β hydrolases. In the case of bacterial systems, THL is a known inhibitor of several Mycobacterium tuberculosis hydrolases involved in mycomembrane biosynthesis. Herein we report a highly efficient eight-step asymmetric synthesis of THL using a route that allows modification of the THL α-chain substituent to afford compounds 1a through 1e. The key transformation in the synthesis was use of a (TPP)CrCl/Co2(CO)8-catalyzed regioselective and stereospecific carbonylation on an advanced epoxide intermediate to yield a trans-β-lactone. These compounds are modest inhibitors of Ag85A and Ag85C, two α/β hydrolases of M. tuberculosis involved in the biosynthesis of the mycomembrane. Among these compounds, 10d showed the highest inhibitory effect on Ag85A (34 ± 22 μM) and Ag85C (66 ± 8 μM), and its X-ray structure was solved in complex with Ag85C to 2.5 ? resolution. In contrast, compound 1e exhibited the best-in-class MICs of 50 μM (25 μg/mL) and 16 μM (8.4 μg/mL) against M. smegmatis and M. tuberculosis H37Ra, respectively, using a microtiter assay plate. Combination of 1e with 13 well-established antibiotics synergistically enhanced the potency of few of these antibiotics in M. smegmatis and M. tuberculosis H37Ra. Compound 1e applied at concentrations 4-fold lower than its MIC enhanced the MIC of the synergistic antibiotic by 2-256-fold. In addition to observing synergy with first-line drugs, rifamycin and isoniazid, the MIC of vancomycin against M. tuberculosis H37Ra was 65 μg/mL; however, the MIC was lowered to 0.25 μg/mL in the presence of 2.1 μg/mL 1e demonstrating the potential of targeting mycobacterial hydrolases involved in mycomembrane and peptidoglycan biosynthesis.
- Khan, Saniya S.,Sudasinghe, Thanuja D.,Landgraf, Alexander D.,Ronning, Donald R.,Sucheck, Steven J.
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- Total synthesis of tetrahydrolipstatin and stereoisomers via a highly regio- and diastereoselective carbonylation of epoxyhomoallylic alcohols
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A concise enantioselective synthesis of tetrahydrolipstatin (THL) and seven stereoisomers has been achieved. The synthesis of THL was accomplished in 10 steps and 31% overall yield from an achiral ynone. Key to the success of the approach is the use of a bimetallic [Lewis acid]+[Co(CO)4]- catalyst for a late-stage regioselective carbonylation of an enantiomerically pure cis-epoxide to a trans-β-lactone. The success of this route to THL and its stereoisomers also demonstrated the practicality of the carbonylation catalyst for complex molecule synthesis as well as its functional group compatibility.
- Mulzer, Michael,Tiegs, Brandon J.,Wang, Yanping,Coates, Geoffrey W.,O'Doherty, George A.
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supporting information
p. 10814 - 10820
(2014/08/18)
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- Asymmetric synthesis of anti-aldol segments via a nonaldol route: Synthetic applications to statines and (-)-tetrahydrolipstatin
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(Chemical Equation Presented) An asymmetric synthesis of anti-aldol segments via a nonaldol route is described. The strategy involves a highly diastereoselective synthesis of functionalized tetrahydrofuran derivatives from optically active 4-phenylbutyrolactone. Treatment of the tetrahydrofuran derivatives with a Lewis acid and acetic anhydride provided the corresponding ring-opened styrene derivatives. Oxidative cleavage of the styrene derivatives provided access to the anti-aldol segments. The utility of this methodology was demonstrated by the synthesis of statine derivatives and pancreatic lipase inhibitor, (-)-tetrahydrolipstatin.
- Ghosh, Arun K.,Shurrush, Khriesto,Kulkarni, Sarang
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experimental part
p. 4508 - 4518
(2009/09/30)
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- Tetrahydrolipstatin analogues as modulators of endocannabinoid 2-arachidonoylglycerol metabolism
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A series of 21 analogues of tetrahydrolipstatin (THL, 1) were synthesized and tested as inhibitors of the formation or hydrolysis of the endocannabinoid 2-arachidonoylglycerol (2-AG). Three of the novel compounds, i.e., 11, 13, and 15, inhibited 2-AG formation via the diacylglycerol lipase α (DAGLα) with IC50 values lower than 50 nM (IC50 of THL = 1 μM) and were between 23- and 375-fold selective vs 2-AG hydrolysis by monoacylglycerol lipase (MAGL) as well as vs cannabinoid CB1 and CB2 receptors and anandamide hydrolysis by fatty acid amide hydrolase (FAAH). Three other THL analogues, i.e., 14, 16, and 18, were slightly more potent than THL against DAGLα and appreciably selective vs MAGL, CB receptors, and FAAH (15-26-fold). One compound, i.e., 8, was a potent inhibitor of MAGL-like activity (IC50 = 0.41 μM), and relatively (~7-fold) selective vs the other targets tested.
- Ortar, Giorgio,Bisogno, Tiziana,Ligresti, Alessia,Morera, Enrico,Nalli, Marianna,Di Marzo, Vincenzo
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experimental part
p. 6970 - 6979
(2009/11/30)
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- Asymmetric synthesis of tetrahydrolipstatin and valilactone
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The highly diastereoselective aldol reaction between acyl complexes of the iron chiral auxiliary [(η5-C5H5)Fe(CO)(PPh3)] and β-hydroxy aldehydes (obtained via a Noyori asymmetric hydrogenation), followed by a tandem oxidative decomplexation-cyclisation process gives access to β-substituted and α,β-disubstituted β-lactones in high ee. This methodology has been employed in the asymmetric syntheses of tetrahydrolipstatin and valilactone.
- Case-Green, Stephen C.,Davies, Stephen G.,Roberts, Paul M.,Russell, Angela J.,Thomson, James E.
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experimental part
p. 2620 - 2631
(2009/04/06)
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- PROCESS FOR PREPARATION OF OXETAN-2-ONES
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The present invention relates to a process for the preparation of diastereomerically and enantiomerically pure oxetan-2-ones. The present invention also relates to a process for the preparation of ester derivatives of oxetan-2-ones. The present invention further relates to compounds prepared by such processes.
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Page/Page column 14-15
(2010/02/10)
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- The total synthesis of (-)-tetrahydrolipstatin
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Careful control during the bromolactonisation of β,γ-unsaturated acid 3 was required to afford regioselectively the trans-β-lactone 4 as the major diastereomer. Radical debromination of 4 followed by a three-step sequence of reactions afforded the lipase inhibitor (-)-tetrahydrolipstatin.
- Bodkin, Jennifer A.,Humphries, Edward J.,McLeod, Malcolm D.
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p. 2869 - 2872
(2007/10/03)
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- The total synthesis of (-)-tetrahydrolipstatin
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Careful control during the bromolactonization of β,γ-unsaturated acid (4) was required to regioselectivity afford the trans-β-lactone (3) as the major diastereomer. Radical debromination of (3) followed by a three-step sequence of reactions afforded the lipase inhibitor (-)-tetrahydrolipstatin (1).
- Bodkin, Jennifer A.,Humphries, Edward J.,McLeod, Malcolm D.
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p. 795 - 803
(2007/10/03)
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- A stereoselective synthesis of (-)-tetrahydrolipstatin
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A stereoselective synthesis of (-)-tetrahydrolipstatin has been accomplished utilizing olefin metathesis of an acrylate ester as the key step.
- Ghosh, Arun K.,Liu, Chunfeng
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p. 1743 - 1744
(2007/10/03)
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- Stereocontrol in organic synthesis using silicon-containing compounds. A synthesis of (-)-tetrahydrolipstatin using the alkylation of a β-silyl ester and the hydroboration of an allylsilane
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Conjugate addition of bis(Z-tridec-1-enyl)cuprate Z-10 to (5S)-1-[(Z)-3′-dimethyl(phenyl)silylprop-2-enoyl]-5-(trityloxymethyl) pyrrolidin-2-one Z-6 gave the 3A-imide Z-12. Subsequent enolate n-hexylation of the benzyl ester Z-13a derived from this imide gave the 2R,3S-ester Z-14a. Reduction of the ester group and protection of the alcohol as its TBDMS group gave the allylsilane (Z)(7 R,8S)-7-(tert-butyldimethylsilyloxymethyl)-8-dimethyl(phenyl)silylhenicos-9-ene Z-15. Hydroboration-oxidation gave the 7R,8S,10S-alcohol 16. Protection of the C-10 hydroxy as its benzyl ether, removal of the silyl protecting group and oxidation gave (2R,3S,5S)-5-benzyloxy-3-dimethyl(phenyl)silyl-2-hexylhexadecanoic acid 19. Silyl-to-hydroxy conversion, β-lactone formation, and hydrogenolysis gave the known alcohol (3S,4S)-3-hexyl-4-[(S)-2′-hydroxytridecyl]oxetan-2-one 22, from which tetrahydrolipstatin 1 was prepared by a conventional esterification. Each of the stereochemistry determining steps, 4 → Z-6, 7 → E-8, E-8 → Z-9, Z-6 + Z-10 → Z-12, Z-13a → Z-14a and Z-15 → 16, took place with a remarkably high level of open-chain stereocontrol.
- Fleming, Ian,Lawrence, Nicholas J.
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p. 2679 - 2686
(2007/10/03)
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- Synthesis of Tetrahydrolipstatin
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An asymmetric synthesis of tetrahydrolipstati (4) is described.Application of our previously described in situ cyclopentadiene alkylation-asymmetric hydroboration protocol provided the key chiral alcohol 9.In the course of this work, the presence of a free hydroxyl group was found to exert a strong directing effect on the regioselectivity of a Baeyer-Villiger reaction (16 --> 17).Subsequent transformations of lactone 17 produced tetrahydrolipstatin.
- Chadha, N. K.,Batcho, A. D.,Tang, P. C.,Courtney, L. F.,Cook, C. M.,et al.
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p. 4714 - 4718
(2007/10/02)
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