- One-step modification to identify dual-inhibitors targeting both pancreatic triglyceride lipase and Niemann-Pick C1-like 1
-
Pancreatic triglyceride lipase (PTL) and Niemann-Pick C1-like 1 (NPC1L1) have been identified as attractive therapeutic targets for obesity and hypercholesteremia, respectively. Obesity and hypercholesteremia usually co-exist, however no dual-inhibitors against PTL and NPC1L1 were reported for the treatment of obesity patients with hypercholesteremia so far. In this work, molecular hybridization-based one-step modification screening identified a potent dual-inhibitor against PTL and NPC1L1. Compound P1-11 has IC50 values of 2.1 μM against PTL through covalent binding, as well as significantly reduces cholesterol absorption in a non-competitive inhibitory manner. Molecule docking and molecular dynamics studies revealed the reason of its activity to both PTL and NPC1L1. Moreover, the gene and protein expression levels of PTL and NPC1L1 were also determined respectively after the treatment of P1-11. Development of dual-inhibitors against PTL and NPC1L1 could provide novel treatment options for obesity patients with hypercholesteremia. The results of current research would great support the development of dual-inhibitors against PTL and NPC1L1.
- Zhang, Renshuai,Song, Zhengming,Wang, Xueting,Xue, Jiao,Xing, Dongming
-
-
- Total Synthesis of Tetrahydrolipstatin, Its Derivatives, and Evaluation of Their Ability to Potentiate Multiple Antibiotic Classes against Mycobacterium Species
-
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.,Landgraf, Alexander D.,Ronning, Donald R.,Sucheck, Steven J.,Sudasinghe, Thanuja D.
-
-
- Refining method for key intermediate of orlistat
-
The invention discloses a refining method for a key intermediate of orlistat as well as key intermediate impurities and a preparation method thereof. The refining method comprises the step that a compound I is recrystallized in an organic solvent or a mixed organic solvent to remove impurities 1-5 which are difficult to remove in a process. The method has good selectivity on the impurities 1-5, and is simple and convenient to operate, low in cost and suitable for industrial production. The invention also provides an impurity 3 and a preparation method thereof, and application of the impurity 3 as an impurity reference substance of an orlistat key intermediate (3S,4S)-3-hexyl-4-[(R)-2-(hydroxytridecyl)]oxetan-2-one (the compound I).
- -
-
Paragraph 0020; 0039-0041
(2021/04/10)
-
- Orlistat derivatives
-
The invention relates to orlistat derivatives. In particular, the invention relates to the general formula (I) compound of formula, wherein R such as specification and defined in the claims. The general formula (I) indicated by the compounds can be used as anti-tumor and inhibit lipase activity of the drug.
- -
-
-
- COMPOUNDS FOR THE REDUCING LIPOTOXIC DAMAGE
-
Provided herein are novel lipase inhibitors and methods for using the same to treat inflammation, multisystem organ failure, necrotic pancreatic acinar cell death, acute pancreatitis, sepsis (e.g., culture negative sepsis), burns, and acne. For example, provided herein are two novel lipase inhibitors useful in the methods described herein: (I) (II) or a pharmaceutically acceptable salt thereof.
- -
-
-
- Asymmetric syntheses of the lactone core of tetrahydrolipstatin and tetrahydroesterastin and of the oriental hornet Vespa Orientalis pheromone
-
Abstract A synthetic approach to the lactone core of the anti-obesity drugs tetrahydrolipstatin and tetrahydroesterastin has been developed starting from readily accessible methyl (5S)-5-{[tert-butyl(dimethyl)silyl]-oxy}-3-oxohexadecanoate. (6S)-6-Undecyltetrahydro-2H-pyran-2-one, the oriental hornet Vespa Orientalis pheromone, has also been synthesized. A formal synthesis of (3S,4R,6S)-dihydroxy-6-undecyltetrahydro-2H-pyran-2-one (metabolite of a fungus separated from mangrove seeds) has been proposed.
- Mineeva
-
p. 842 - 848
(2015/08/06)
-
- Total synthesis of tetrahydrolipstatin and stereoisomers via a highly regio- and diastereoselective carbonylation of epoxyhomoallylic alcohols
-
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.
-
supporting information
p. 10814 - 10820
(2014/08/18)
-
- MNBA-mediated β-lactone formation: Mechanistic studies and application for the asymmetric total synthesis of tetrahydrolipstatin
-
Various β-lactones were prepared from β-hydroxycarboxylic acids by intramolecular dehydration condensation using MNBA, an effective coupling reagent, along with a nucleophilic catalyst. The transition state that provides the desired 4-membered ring model system is disclosed by density functional theory (DFT) calculations, and the structural features of the transition form are discussed. This method was successfully applied to the asymmetric total synthesis of tetrahydrolipstatin (THL), an antiobestic drug used in clinical treatment to inhibit the activity of pancreatic lipase.
- Shiina, Isamu,Umezaki, Yuma,Kuroda, Nobutaka,Iizumi, Takashi,Nagai, Shunsuke,Katoh, Takashi
-
p. 4885 - 4901
(2012/07/30)
-
- Inhibitors of an essential mycobacterial cell wall lipase (Rv3802c) as tuberculosis drug leads
-
The first targeted inhibitors of an essential M. tuberculosis cell wall lipase, Rv3802c, are described. Lead compounds exhibited nanomolar inhibition of the enzyme, and encouraging antibacterial activity against M. tuberculosis in vitro, supporting Rv3802c as a novel TB drug target.
- West, Nicholas P.,Cergol, Katie M.,Xue, Millie,Randall, Elizabeth J.,Britton, Warwick J.,Payne, Richard J.
-
p. 5166 - 5168
(2011/06/10)
-
- THE PREPARATION METHOD OF (3S,4S)-3-HEXYL-4-((R)-2-HYDROXYTRIDECYL)-OXETAN-2-ONE AND THE PRODUCT OF THAT METHOD
-
The present invention relates to a method for the preparation of (3S,4S)-3-hexyl-4-((R)-2-hydroxytridecyl)-oxetan-2-one and a product of the method. The method includes the following steps: a) reducing a substance represented by formula (II) to obtain a substance represented by formula (III), and then oxidizing the substance represented by formula (III) to form a substance represented by formula (IV); b) acylating n-octanoic acid to obtain n-octanoyl chloride using thionyl dichloride, then condensing the obtained n-octanoyl chloride with 2-mercapto-pyridine under basic condition to form a substance represented by formula (V), and then converting the substance represented by formula (V) to a substance represented by formula (VI); c) reacting the substance obtained in the step a) with the substance obtained in the step b) under catalytic condition of Lewis acid to generate a substance represented by formula (VII), and then reacting with a Lewis acid. The meanings of the signs in these formulas are the same as those in the description.
- -
-
Page/Page column 11-12
(2011/02/25)
-
- A concise, phosphate-mediated approach to the total synthesis of (-)-tetrahydrolipstatin
-
(Figure Represented) 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 eight total steps from a readily prepared (S,S)-triene. The strategy incorporates selective cross-metathesis, regioselective hydrogenation, regio- and diastereoselective cuprate addition, and Mitsunobu inversion for installation of the C5 formamide ester subunit.
- Venukadasula, Phanindra K. M.,Chegondi, Rambabu,Maitra, Soma,Hanson, Paul R.
-
supporting information; experimental part
p. 1556 - 1559
(2010/06/16)
-
- METHOD FOR PREPARING (3S,4S)-4-((R)-2-(BENZYLOXY)TRIDECYL)-3-HEXYL-2-OXETANONE AND NOVEL INTERMEDIATE USED THEREFOR
-
The present invention relates to a high-yield method for preparing highly pure (3S,4S)-4-((R)-2-(benzyloxy)tridecyl)-3-hexyl-2-oxetanone using a metal salt of (2S,3S,5R)-2-hexyl-3,5-dihydroxyhexadecanoic acid as an intermediate.
- -
-
Page/Page column 12-13
(2010/06/11)
-
- Activity-based proteome profiling of potential cellular targets of orlistat - An FDA-approved drug with anti-tumor activities
-
Orlistat, or tetrahydrolipstatin (THL), is an FDA-approved antiobesity drug with potential antitumor activities. Cellular off-targets and potential side effects of Orlistat in cancer therapies, however, have not been extensively explored thus far. In this study, we report the total of synthesis of THL-like protein-reactive probes, in which extremely conservative modifications (i.e., an alkyne handle) were introduced in the parental THL structure to maintain the native biological properties of Orlistat, while providing the necessary functionality for target identification via the bio-orthogonal click chemistry. With these natural productlike, cell-permeable probes, we were able to demonstrate, for the first time, this chemical proteomic approach is suitable for the identification of previously unknown cellular targets of Orlistat. In addition to the expected fatty acid synthase (FAS), we identified a total of eight new targets, some of which were further validated by experiments including Western blotting, recombinant protein expression, and site-directed mutagenesis. Our findings have important implications in the consideration of Orlistat as a potential anticancer drug at its early stages of development for cancer therapy. Our strategy should be broadly useful for off-target identification against quite a number of existing drugs and/or candidates, which are also covalent modifiers of their biological targets.
- Yang, Peng-Yu,Liu, Kai,Ngai, Mun Hong,Lear, Martin J.,Wenk, Markus R.,Yao, Shao Q.
-
supporting information; experimental part
p. 656 - 666
(2010/03/25)
-
- Asymmetric synthesis of anti-aldol segments via a nonaldol route: Synthetic applications to statines and (-)-tetrahydrolipstatin
-
(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
-
experimental part
p. 4508 - 4518
(2009/09/30)
-
- BETA-LACTONE COMPOUNDS
-
The present invention provides compounds having the general structure A, or a pharmaceutically acceptable derivatives thereof: wherein R is an alkyl group, and R1 comprises at least one moiety selected from a group consisting of an alkyl, an alkenyl, an aryl, a heterocycle, hydroxyl, ester, amido, aldehyde, and a halogen.
- -
-
Page/Page column 42-43
(2009/05/28)
-
- Asymmetric synthesis of (-)-tetrahydrolipstatin from a β-hydroxy- δ-oxo sulfoxide
-
An asymmetric synthesis of (-)-tetrahydrolipstatin is described. A palladium-catalyzed regioselective oxidation of an alkene to a ketone, highly diastereoselective reduction of a β-hydroxy ketone, selective oxidation of a diol, and modular synthesis are the key features of the synthesis. Georg Thieme Verlag Stuttgart.
- Raghavan, Sadagopan,Rathore, Kailash
-
scheme or table
p. 1285 - 1288
(2009/12/01)
-
- Asymmetric synthesis of (-)-tetrahydrolipstatin
-
Attempts toward the asymmetric synthesis of (-)-tetrahydrolipstatin are described. A palladium catalyzed Wacker-type reaction to convert an alkene to a ketone, highly diastereoselective reduction of a β-hydroxy ketone, selective oxidation of a diol, and modular synthesis are the key features of the successful approach.
- Raghavan, Sadagopan,Rathore, Kailash
-
experimental part
p. 10083 - 10092
(2010/02/27)
-
- Tetrahydrolipstatin analogues as modulators of endocannabinoid 2-arachidonoylglycerol metabolism
-
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
-
experimental part
p. 6970 - 6979
(2009/11/30)
-
- Synthesis of novel &β-lactone inhibitors of fatty acid synthase
-
Fatty acid synthase (FAS) is necessary for growth and survival of tumor cells and is a promising drug target for oncology. Here, we report on the syntheses and activity of novel inhibitors of the thioesterase domain of FAS. Using the structure of orlistat as a starting point, which contains a β-lactone as the central pharmacophore, 28 novel congeners were synthesized and examined. Structural features such as the length of the α- and β-alkyl chains, their chemical composition, and amino ester substitutions were altered and the resulting compounds explored for inhibitory activity toward the thioesterase domain of FAS. Nineteen congeners show improved potency for FAS in biochemical assays relative to orlistat. Three of that subset, including the natural product valilactone, also display an increased potency in inducing tumor cell death and improved solubility compared to orlistat. These findings support the idea that an orlistat congener can be optimized for use in a preclinical drug design and for clinical drug development.
- Richardson, Robyn D.,Knowles, Lynn M.,Cieplak, Piotr,Smith, Jeffrey W.,Ma, Gil,Oyola, Yatsandra,Zancanella, Manuel,Romo, Daniel
-
experimental part
p. 5285 - 5296
(2010/04/02)
-
- Asymmetric synthesis of tetrahydrolipstatin and valilactone
-
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.
-
experimental part
p. 2620 - 2631
(2009/04/06)
-
- Enantioselective total synthesis of (-)-tetrahydrolipstatin using Oppolzer's sultam directed aldol reaction
-
A highly practical and concise stereoselective total synthesis of (-)-tetrahydrolipstatin is achieved using Oppolzer's sultam directed aldol reaction as the key step.
- Kumaraswamy,Markondaiah
-
p. 327 - 330
(2008/09/17)
-
- Enantioselective synthesis of a key intermediate in a new process for orlistat using asymmetric hydrogenation and a grignard reagent promoted lactone cyclization
-
A new enantioselective synthesis of Orlistat suitable for large-scale preparation is described. Therein, the first isolated key intermediate (R)-3-hexyl-5,6-dihydro-4-hydroxy-6-undecyl-2H-pyran-2-one (12) is prepared via (a) the asymmetric hydrogenation of methyl 3-oxotetradecanoate to (S)-3-hydroxytetrade-canoate (9); (b) the acylation of 9 with 2-bromooctanoyl halide (bromide/chloride) to (R)-3-[(2-bromo-1-oxooctyl)oxy]-tetradecanoic acid methyl ester (11) and finally (c) the tert-butyl magnesium chloride promoted cyclization of 11 to the single enantiomer 12. The single enantiomer intermediate 12, previously published as a mixture of enantiomers 2, has been carried on through several steps to Orlistat (1) without any process changes.
- Schwindt, Mark A.,Fleming, Michael P.,Han, Yeun-Kwei,Hodges, Lewis M.,Johnston, David A.,Micheli, Roger P.,Roberts, Chris R.,Snyder, Roger,Topping, Robert J.,Puentener, Kurt,Scalone, Michelangelo
-
p. 524 - 533
(2012/12/31)
-
- A chiron approach to (-)-tetrahydrolipstatin
-
An efficient chiron approach to the total synthesis of (-)- tetrahydrolipstatin is described. The main features of the synthetic strategy, which starts from tri-O-acetyl-D-glucal, are copper-mediated C-C bond formation, Frater alkylation, and Barton-McCombie deoxygenation. Georg Thieme Verlag Stuttgart.
- Yadav,Vishweshwar Rao,Prasad
-
p. 3888 - 3894
(2008/02/09)
-
- Stereoselective syntheses of (-)-tetrahydrolipstatin via Prins cyclisations
-
Stereoselective syntheses of (-)-tetrahydrolipstatin have been achieved via two divergent approaches through Prins cyclisations as the key steps. PCC mediated oxidative cleavage, Frater alkylation, Keck allylation, Sharpless asymmetric epoxidation and allylic cleavage were the other key steps employed.
- Yadav,Reddy, M. Sridhar,Prasad
-
p. 4995 - 4998
(2007/10/03)
-
- Total synthesis and comparative analysis of orlistat, valilactone, and a transposed orlistat derivative: Inhibitors of fatty acid synthase
-
Concise syntheses of orlistat (Xenical), a two-carbon transposed orlistat derivative, and valilactone are described that employ the tandem Mukaiyama aldol-lactonization (TMAL) process as a key step. This process allows facile modification of the α-side chain. Versatile strategies for modifying the δ-side chain are described, involving cuprate addition and olefin metathesis. Comparative antagonistic activity of these derivatives toward a recombinant form of the thioesterase domain of fatty acid synthase is reported along with comparative activity-based profiling.
- Ma, Gil,Zancanella, Manuel,Oyola, Yatsandra,Richardson, Robyn D.,Smith, Jeffrey W.,Romo, Daniel
-
p. 4497 - 4500
(2007/10/03)
-
- Stereoselective synthesis of (-)-tetrahydrolipstatin via a radical cyclization based strategy
-
An efficient and flexible approach for the total synthesis of (-)-tetrahydrolipstatin is described. The main features of the synthetic strategy are a stereocontrolled radical cyclization and the successful utilization of commercially available S-malic acid.
- Yadav,Vishweshwar Rao,Sridhar Reddy,Prasad
-
p. 4393 - 4395
(2007/10/03)
-
- A mild and efficient desilylation of O-tert-butyldimethylsilyl ethers mediated by chlorotrimethylsilane and potassium fluoride dihydrate in acetonitrile
-
Desilylation of O-tert-butyldimethylsilyl ethers was achieved by a reagent system consisting of chlorotrimethylsilane and potassium fluoride dihydrate in acetonitrile. This alternative desilylation procedure is chemoselective, generally effective and operationally simple, and should find practical applications in organic synthesis. Georg Thieme Verlag Stuttgart.
- Peng, Yu,Li, Wei-Dong Z.
-
p. 1165 - 1168
(2007/10/03)
-
- PROCESS FOR PREPARATION OF OXETAN-2-ONES
-
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
(2010/02/10)
-
- Diastereoselective allylations and crotylations under phase-transfer conditions using trifluoroborate salts: An application to the total synthesis of (-)-tetrahydrolipstatin
-
A mild protocol for diastereoselective allylations and crotylations of α- and β-silyloxy substituted aldehydes utilizing potassium allyl/crotyltrifluoroborates is described. The reactions proceed to completion within 30 min at room temperature in biphasic or aqueous media in the presence of a phase transfer catalyst. The resulting homoallylic alcohols are obtained in high yields and moderate to excellent diastereoselectivities. The method was applied to the asymmetric total synthesis of the antiobesity agent tetrahydrolipstatin (orlistat).
- Thadani, Avinash N.,Batey, Robert A.
-
p. 8051 - 8055
(2007/10/03)
-
- The total synthesis of (-)-tetrahydrolipstatin
-
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.
-
p. 795 - 803
(2007/10/03)
-
- The total synthesis of (-)-tetrahydrolipstatin
-
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.
-
p. 2869 - 2872
(2007/10/03)
-
- PROCESS FOR MAKING (2S, 3S, 5S) OXETANONE DERIVATIVES
-
This invention relates to novel processes for making (2S, 3S, 5S) oxetanone derivative lipase inhibitor compounds and intermediates therefor, which processes for producing such derivatives that are useful as lipase inhibitors are capable of being scaled to commercial quantities. Further the invention relates to processes for producing salts and for producing pharmaceutical compositions compounds comprising at least one such oxetanone derivative or salt, as well as methods for using such compounds and compositions for inhibiting lipases.
- -
-
-
- Asymmetric synthesis of (-)-tetrahydrolipstatin: an anti-aldol-based strategy.
-
A stereoselective synthesis of (-)-tetrahydrolipstatin is described. The synthesis involves an asymmetric ester derived titanium enolate anti-aldol reaction, a nitro-aldol reaction to append the C-2' C(11) side chain, and a diastereoselective reduction of a beta-hydroxy ketone to an anti-1,3-diol functionality followed by its elaboration to (-)-tetrahydrolipstatin.
- Ghosh,Fidanze
-
p. 2405 - 2407
(2007/10/03)
-
- A stereoselective synthesis of (-)-tetrahydrolipstatin
-
A stereoselective synthesis of (-)-tetrahydrolipstatin has been accomplished utilizing olefin metathesis of an acrylate ester as the key step.
- Ghosh, Arun K.,Liu, Chunfeng
-
p. 1743 - 1744
(2007/10/03)
-
- Oxazoline N-oxide-mediated [2+3] cycloadditions. Application to a synthesis of (-)-tetrahydrolipstatin
-
Formula presented A [2+3] cycloaddition of camphor-derived oxazoline N-oxide to α,β-unsaturated ester afforded adduct 8. Tetrahydrolipstatin 1 was prepared from this compound in a nine-step sequence of reactions.
- Dirat,Kouklovsky,Langlois, Yves
-
p. 753 - 755
(2008/02/12)
-
- Anti-aldol reactions of lactate-derived ketones. Application to the synthesis of (-)-tetrahydrolipstatin
-
(-)-Tetrahydrolipstatin (1) was prepared with a high level of stereocontrol (>98% ds) by employing a boron-mediated, anti-selective, aldol coupling between the (R)-lactate-derived ketone 7 and the aldehyde 8.
- Paterson,Doughty
-
p. 393 - 394
(2007/10/03)
-
- Method for synthesizing oxetan-2-ones and intermediates for their preparation
-
A method is described for the synthesis of oxetan-2-ones comprising protection of the hydroxy group of an hydroxy ester with an acid-labile acetal protecting group, reduction of this O-protected hydroxy ester to an O-protected hydroxy aldehyde, condensation of this aldehyde with a metal enolate of an activated carboxylic acid derivative and spontaneous deprotection of the hydroxy group during the acidic workup procedure. Using the new O-protected hydroxy aldehydes as intermediates the oxetan-2-ones can be obtained after separation in diastereomerically and enantiomerically pure form, in a remarkably reduced number of steps, and in a significantly improved overall yield.
- -
-
-
- 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
-
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.
-
p. 2679 - 2686
(2007/10/03)
-
- An asymmetric synthesis of (-)-tetrahydrolipstatin
-
A key step in a short asymmetric synthesis of the potent pancreatic lipase inhibitor (-)-tetrahydrolipstatin (2) is a Lewis acid-catalysed [2 + 2] cycloaddition of n-hexyl(trimethylsilyl)ketene (5) to (R)-3-(tertbutyldimethylsilyloxy)tetradecanal (4a).
- Pommier,Pons
-
p. 1294 - 1300
(2007/10/02)
-
- Total synthesis of (-)-tetrahydrolipstatin
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The total synthesis of (-)-tetrahydrolipstatin utilizing two approaches is described. In the first, L-malic acid was used as a chiral template to obtain enantiomerically pure (R)-3-(benzyloxy)-tetradecanal (11) which was chain- extended using 1-(trimethylsilyl)-2-nonene and a Lewis acid. This advanced intermediate was further elaborated to the target compound in good overall yield. The second approach utilized lauraldehyde as a starting material and capitalizes on an asymmetric allylboronation (91% ee). The product could be obtained enantiomerically pure by conversion to the (R)-acetoxymandelate ester and hydrolysis. Oxidative cleavage of the terminal double bond led to 11 which was further extended using 1,3- and 1,2-asymmetric induction based on existing neighboring chirality. The synthesis of tetrahydrolipstatin using the second approach comprises seven steps from 11 and proceeds in 38% overall yield.
- Hanessian,Tehim,Chen
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p. 7768 - 7781
(2007/10/02)
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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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- A synthesis of (-)-tetrahydrolipstatin in which the relative stereochemistry is controlled by a phenyldimethylsilyl group
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The alkylation ofa β-silylenolate and the hydroboration of an allylsilane successively control the relative stereochemistry of the three stereogenic centres on the carbon backbone in a synthesis of the esterase inhibitor tetrahydrolipstatin (21).
- Fleming, Ian,Lawrence, Nicholas J.
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p. 3645 - 3648
(2007/10/02)
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- Synthesis of Tetrahydrolipstatin and Tetrahydroesterastin, Compounds with a β-Lactone Moiety. Stereoselective Hydrogenation of a β-Keto δ-Lactone and Convertion of the δ-Lactone into a β-Lactone
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Stereoselective syntheses of tetrahydrolipstatin (1) and tetrahydroesterastin (2) are described.The key intermediate β-ketoδ-lactone 7 is hydrogenated stereoselectively to yield hydroxy δ-lactone 9, which is transformed into hydroxy β-lactone 10.Esterification of 10 with (S)-N-formylleucine under Mitsunobu's conditions yields tetrahydrolipstatin (1).Esterification of 10 with (S)-N-acetylasparagine under the same conditions yields 17 (mixture of two diastereomers), which gives by saponification hydroxy β-lactone 18.Reaction of the latter with the mixed anhydride of (S)-N-Z-asparagine, hydrogenation, and acetylation give tetrahydroesterastin (2).
- Barbier, Pierre,Schneider, Fernand
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p. 1218 - 1221
(2007/10/02)
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