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

Abstract

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.

The chemistry of the carbon-transition metal double and triple bond: Annual survey covering the year 2014

“…149) for synthesis of Hagens gland lactones [493]; (8) 1-octene with an amino acid derived acrylate ester [494], and with a homoallylic alcohol derivative [495]; (9) 1-decene with a vinyl-γ-lactone derivative for preparation of disparlures [496]; (10) 1-tridecene with a homoallylic alcohol derivative for preparation of a nonadecylphenol natural product [497], and with an allyl ether connected to a bis(carbohydrate) system (also employs 1-pentadecene or an allylglycerol derivative) [498]; (11) A c c e p t e d M a n u s c r i p t 28 antimalarial premarineosins [508]; (20) benzyl 13-tetradecenoate (158) and an alkene protected polyol derivative (e.g. 157) for total synthesis of penarolide sulfate A2 [509]; (21) a 1,5-diene ester derivative and an allylic alcohol derivative [510]; (22) styrene derivatives with a vinyltetrahydropyran for preparation of rhoiptelol B [511], with allylic diol for preparation of ginger diols [512], and with an alkene-phosphine oxide (e.g.…”

The Asymmetric Synthesis of Tetrahydrolipstatin

“…In 2014, Coates and O'Doherty published an enantioselective synthesis of THL (1)a sw ell as all the possible trans-b-lactone diastereomers (Scheme 31). [68] The key to the successo ft he route is the use of al ate-stage co-catalyzed carbonylation [69] to form the desired b-lactone. Their synthesis required ten steps and occurred in a3 1% overall yield.…”

Recent Advances in the Organocatalytic Enantioselective Synthesis of Functionalized β‐Lactones

“…Moreover, β‐lactone‐containing natural product obafluorin ( III ) is an antibacterial agent, whilst a rocaglate‐derived β‐lactone ( IV ) has shown activity towards serine hydrolase . In addition, omuralide ( V ) is a β‐lactone‐containing natural product that possesses remarkable proteasome‐inhibition properties, whilst the antiobesity drug tetrahydrolipstatin ( VI ) contains a disubstituted β‐lactone group, which inhibits the absorption of dietary fat …”

“…[6] In addition, omuralide (V)i sab-lactone-containing naturalp roduct that possesses remarkable proteasome-inhibition properties, [7] whilst the antiobesity drug tetrahydrolipstatin (VI)c ontains ad isubstituted b-lactone group, which inhibits the absorption of dietary fat. [8] Besides the biological properties of b-lactones, the intrinsic strain in its four-membered ring also makes these molecules attractive substrates for synthetic transformations. For instance, an ucleophile can add to the C=Og roup of a b-lactone through an addition-elimination pathway,w hilst addition to the CÀOs ingle bond proceeds in an S N 2m anner.G iven the significance of b-lactones in natural-product chemistry,a nd their utility in furthers ynthetic manipulations, the development of catalytic methods for the selective synthesis of these compounds under mild conditions has received considerable attention in the last two decades.…”