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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.
(2021/09/27)

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.
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(2019/01/30)

Stereochemical Structure Activity Relationship Studies (S-SAR) of Tetrahydrolipstatin
Tetrahydrolipstatin (THL), its enantiomer, and an additional six diastereomers were evaluated as inhibitors of the hydrolysis of p-nitrophenyl butyrate by porcine pancreatic lipase. IC50s were found for all eight stereoisomers ranging from a low of 4.0 nM for THL to a high of 930 nM for the diastereomer with the inverted stereocenters at the 2,3,2′-positions. While the enantiomer of THL was also significantly less active (77 nM) the remaining five stereoisomers retained significant inhibitory activities (IC50s = 8.0 to 20 nM). All eight compounds were also evaluated against three human cancer cell lines (human breast cancers MCF-7 and MDA-MB-231, human large-cell lung carcinoma H460). No appreciable cytotoxicity was observed for THL and its seven diastereomers, as their IC50s in a MTT cytotoxicity assay were all greater than 3 orders of magnitude of camptothecin.
Liu, Xiaofan,Wang, Yanping,Duclos, Richard I.,O'Doherty, George A.
supporting information
p. 274 - 278
(2018/03/21)

Weight-reducing medicine orlistat synthesis method
The invention discloses a weight-reducing medicine orlistat synthesis method. The synthesis method includes that in existence of (R,R)-(-)-N,N'-bis(3,5-ditert-butyl-salicylidene)-1,2-cyclohexyl diamine cobalt, lipstatin and sodium borohydride are subjected to reduction reaction under catalysis of cuprous chloride to obtain orlistat. The orlistat synthesis method is quick in reaction, and reaction yield is increased effectively. By adoption of (R,R)-(-)-N,N'-bis(3,5-ditert-butyl-salicylidene)-1,2-cyclohexyl diamine cobalt as a stabilizer of a reducing agent, low side reaction quantity, easiness in product purification and suitableness for industrial expanded production are realized.
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Paragraph 0018; 0019; 0020; 0021; 0022; 0023; 0024-0036

(2017/08/28)

Method for preparing weight-reducing medicine orlistat
The invention discloses a method for preparing a weight-reducing medicine orlistat. The method comprises the following steps of using lipstatin as a starting raw material, and under the catalysis of pentacarbonyl iron, making the lipstatin generate reduction reaction with a hydrazine hydrate to obtain the orlistat. The method for preparing the orlistat, which is provided by the invention, is mild in reaction condition and simple to operate; the reaction yield is effectively improved; the hydrazine hydrate is adopted as a reducing agent and a hydrogen source; reaction by-products are few; the after treatment is simple.
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Paragraph 0009; 0020; 0021; 0022; 0223; 0024; 0025-0037

(2017/08/28)

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.
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)

Use of orlistat for the anti-parasitic treatment of a parasitic disease
The present invention relates to the field of medicine, parasitology and microbiology and more particularly to the use of Orlistat as a therapeutic agent for preventing, treating or eliminating a protozoal and parasitic disease in an animal including a human.
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(2011/12/14)

PROCESS FOR THE PREPARATION OF ORLISTAT
The present invention provides a process for preparing orlistat from amino orlistat using Pivaloyl Formic Anhydride (PFA) as an alkanoylating agent.
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(2010/08/03)

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.
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(2010/06/11)

Process for production of lipstatin and microorganisms therefore
This invention relates to improved processes for the production of lipstatin and /or orlistat and means therefore. In particular, the invention relates to microorganisms characterized by abolished or reduced activity of the BKD complex, e.g. mutated branched-chain 2-oxo acid dehydrogenase (BKD) having reduced or abolished activity, nucleotide sequences suitable for achieving reduced or abolished BKD activity, and microorganisms having reduced or abolished BKD activity. The invention in particular relates to lipstatin-producing microorganisms of the genus Streptomyces. Furthermore, this invention relates to the use of these nucleotide sequences, microorganisms or BKD having reduced or abolished activity in the production of lipstatin and/or orlistat.
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(2010/01/29)

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)

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.
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Page/Page column 15; 17; 29

(2009/05/28)

Synthesis of bioactive natural products by asymmetric syn-and anti-aldol reactions
The use of several variants of the asymmetric aldol reaction as key steps in the syntheses of bioactive target molecules is described. Georg Thieme Verlag Stuttgart.
Ghosh, Arun K.,Dawson, Zachary L.
body text
p. 2992 - 3002
(2010/04/02)

PROCESS FOR THE PREPARATION OF ORLISTAT
The present invention provides a process for preparing orlistat (I) by alkanoylating an amino orlistat using formic acid anhydride as an alkanoylating agent to obtain orlistat substantially free of the byproduct, (S)-N-acetylleucine (1S)-1-[[(2S, 3S)-3-hexyl-4-oxo-2-oxetanyl]methyl] dodecyl ester (deformyl-N-acetyl orlistat).
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(2009/07/17)

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)

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 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)

Process for preparing crystalline forms of orlistat
The present invention relates to a process for preparing crystalline forms of orlistat, in particular orlistat crystalline Form I and orlistat crystalline Form II.
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(2008/06/13)

PROCESS FOR THE PREPARATION OF ORLISTAT
The present invention provides a process for preparing orlistat (I) by alkanoylating an amino orlistat using formic acid anhydride as an alkanoylating agent to obtain orlistat substantially free of the byproduct, (S)-N-acetylleucine (1S)-1-[[(2S, 3S)-3-hexyl-4-oxo-2-oxetanyl] methyl] dodecyl ester (deformyl-N-acetyl orlistat).
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(2010/11/26)

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 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)

PROCESS FOR THE PREPARATION OF AN ORLISTAT DERIVATIVE USEFUL AS REFERENCE STANDARD IN THE DETERMINATION OF THE PURITY OF ORLISTAT AND PROCESS FOR THE PREPARATION OF ORLISTAT
The invention relates to a leucine derivative, N-2[(S)-2-N-formylamino-4-methyl pentanoic acid (S)-1-[[3(S)-hydroxy-5-oxo-4-hexyl methyl]dodecyl ester] amino-4-methyl pentanoic acid (S)-1-[(2S, 3S)-3-hexyl-4-oxo-2-oxetanyl]methyl dodecyl ester of Formula (I), and process for isolating it. More particularly, it relates to the preparation of pure orlistat, which is (S)-2-Formylamino-4-methyl pentanoic acid (S)-1-[(2S, 3S)-3-hexyl-4-oxo-2-oxetanyl]methyl]dodecyl ester. The invention also relates to the use of the Compound of Formula (I) as reference standard or reference marker for checking the purity of orlistat.
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(2008/06/13)

USE OF SUBSTITUTED 2 PHENYLBENZIMIDAZOLES AS MEDICAMENTS
The present invention relates to the use of a substituted 2-phenylbenzimidazole of formula I wherein R1, R2, R3, R 4, R5 and m have the meanings given in the claims, for the preparation of a medicament for the treatment or prevention of diseases involving glucagon receptors, as well as new compounds of formula I wherein R1 is a group of formula
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(2008/06/13)

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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(2010/02/10)

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)

Orlistat compositions
A pharmaceutical combination or composition containing a lipase inhibitor, preferably orlistat, and a bile acid sequestrant is useful for treating obesity.
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(2008/06/13)

Pharmaceutical composition containing psyllium fiber and a lipase inhibitor
The present invention provides orally administrable pharmaceutical compositions containing an inhibitor of gastrointestinal lipase, and at least one compound selected from the group consisting of psyllium husk, its seeds and leaves thereof. Methods are provided for preventing and treating anal leakage of oil in a patient to whom a composition containing an inhibitor of gastrointestinal lipase is orally administered.
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(2008/06/13)

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 rapid synthesis of (-)-tetrahydroiipstatin
(-)-Tetrahydrolipstatin (1) has been synthesised starting from diketene using photoalkylation and β-lactone enolate alkylation as key steps. Thieme Stuttgart.
Parsons, Philip J.,Cowell, Justin K.
p. 107 - 109
(2007/10/03)

Pharmaceutical composition containing chitosan
The present invention provides orally administrable pharmaceutical compositions containing an inhibitor of gastrointestinal lipase, and at least one compound selected from the group consisting of chitosan, its derivatives and salts thereof. Methods are provided for preventing and treating anal leakage of oil in a patient to whom a composition containing an inhibitor of gastrointestinal lipase is orally administered.
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(2008/06/13)

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)

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)

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)

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
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
p. 7768 - 7781
(2007/10/02)

OXETANONES AND PROCESS FOR THEIR PRODUCTION
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(2008/06/13)

Synthesis of Tetrahydrolipstatin
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.
p. 4714 - 4718
(2007/10/02)

A synthesis of (-)-tetrahydrolipstatin in which the relative stereochemistry is controlled by a phenyldimethylsilyl group
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.
p. 3645 - 3648
(2007/10/02)

A synthesis of (-)-tetrahydrolipstatin
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Pons,Kocienski
p. 1833 - 1836
(2007/10/02)

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
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
p. 1218 - 1221
(2007/10/02)

Syntheses of tetrahydrolipstatin and absolute configuration of tetrahydrolipstatin and lipstatin
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Barbier,Schneider
p. 196 - 202
(2007/10/02)

Stereoselective syntheses of tetrahydrolipstatin and of an analogue, potent pancreatic-lipase inhibitors containing a β-lactone moiety
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Barbier,Schneider,Widmer
p. 1412 - 1418
(2007/10/02)