Asymmetric synthesis of (−)-tetrahydrolipstatin

Raghavan, Sadagopan; Rathore, Kailash

doi:10.1016/j.tet.2009.09.062

Cited by 18 publications

(7 citation statements)

References 52 publications

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“…The Fráter-Seebach alkylation provides a convenient entry to α-alkylated β-hydroxy esters and is a crucial step in the preparation of a variety of biologically important compounds, which include natural products [1][2][3] and derivatives thereof, [4][5][6][7] enzyme inhibitors [8,9] and other key chiral building blocks. [10,11] In Fráter's early studies, ethyl (S)-3hydroxybutyrate was alkylated with methyl, allyl, butyl and benzyl bromide to give the corresponding (2S,3S)-alkylated products in good yield and excellent diastereoselectivity, [12,13] and the methodology was also used for the alkylation of ethyl (R)-3-hydroxyvalerate using propyl iodide as the electrophile.…”

Section: Introductionmentioning

confidence: 99%

The Synthesis of Long‐Chain α‐Alkyl‐β‐Hydroxy Esters Using Allylic Halides in a Fráter–Seebach Alkylation

et al. 2011

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The Fráter-Seebach alkylation is a highly efficient means to diastereoselectively introduce α-substituents to chiral β-hydroxy esters, however, the yields of reactions in which longer chain alkyl halides are used can be disappointing. To provide a more robust protocol for the alkylation of β-hydroxy esters, we prepared a variety of long-chain allylic iodides with the view that the greater reactivity of the allylic system would

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Section: Introductionmentioning

confidence: 99%

The Synthesis of Long‐Chain α‐Alkyl‐β‐Hydroxy Esters Using Allylic Halides in a Fráter–Seebach Alkylation

et al. 2011

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“…One year after Kumaraswamy's synthesis, Raghavan and coworkers published their approacht oT HL (1), which used (R)-(+ +)-methyl phenyl sulfoxide 152 as the chiral auxiliary (Scheme 25). [56,57] Sulfoxide 152 can be prepared via vanadyl acetylacetonate (VO(acac) 2 )-catalyzed asymmetrico xidation of 150 with chiral ligand 151.S ulfoxide 152 was coupled with unsaturated ester 149 to give 153 via aC laisen condensation and chelation-controlled reduction sequence. AW acker-type oxidation was used to convert allylic alcohol into ketone 154.…”

Section: Raghavan'ss Ynthesis 2009mentioning

confidence: 99%

The Asymmetric Synthesis of Tetrahydrolipstatin

2015

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The various syntheses of the over-the-counter anti-obesity drug tetrahydrolipstatin (also known as Orlistat) are reviewed. The 31 various syntheses cover the development of enantioselective natural products synthesis since the first synthesis of tetrahydrolipstatin (THL) by Schneider in 1987. After Schneider'sl andmark synthetic effort there have been numeroust otal and formal syntheses of THL, which have involvedadiverse range of approaches. These various syntheses can be classified by the methodst hat were used to install the stereochemistry,f or instance, chiral auxiliary,a symmetrica ldol, asymmetric allylation/crotylation, asymmetricr eductions,a symmetricr esolutions, asymmetric oxidations, and chiron approach. These routes also feature the elegant use of ac hiral phosphate template, at andem [2+ +2]-Mukaiyama aldol-lactonization, an anti-aldol segment via an on-aldol route, aP rins cyclization,a nd an epoxide carbonylation.

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“…Since the first synthesis of THL by Schneider, 6a there have been numerous total 6 − 12 and formal syntheses of THL, 13 which have involved a diverse range of approaches. In terms of how they derive absolute stereochemistry, these approaches can be classified into the following categories: (1) chiral auxiliary, 6 (2) asymmetric aldol, 7 (3) asymmetric allylation/crotylation, 8 (4) asymmetric reductions, 9 (5) asymmetric resolutions, 10 (6) asymmetric oxidations, 11 and (7) chiron approach. 12 These routes include the elegant use of a chiral phosphate template, 9c a tandem Mukaiyama aldol lactonization, 7e , 7i an anti-aldol segment via a non-aldol route, 7h and a Prins cyclization for stereocontrol.…”

Section: Introductionmentioning

confidence: 99%

Total Synthesis of Tetrahydrolipstatin and Stereoisomers via a Highly Regio- and Diastereoselective Carbonylation of Epoxyhomoallylic Alcohols

et al. 2014

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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.

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Asymmetric synthesis of (−)-tetrahydrolipstatin

Cited by 18 publications

References 52 publications

The Synthesis of Long‐Chain α‐Alkyl‐β‐Hydroxy Esters Using Allylic Halides in a Fráter–Seebach Alkylation

The Synthesis of Long‐Chain α‐Alkyl‐β‐Hydroxy Esters Using Allylic Halides in a Fráter–Seebach Alkylation

The Asymmetric Synthesis of Tetrahydrolipstatin

Total Synthesis of Tetrahydrolipstatin and Stereoisomers via a Highly Regio- and Diastereoselective Carbonylation of Epoxyhomoallylic Alcohols

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