Sharpless Asymmetric Epoxidation: Applications in the Synthesis of Bioactive Natural Products

: This review discusses an important synthetic tool proposed by K. B. Sharpless in 1980, known as the Sharpless asymmetric epoxidation of allylic alcohols, and examines its use in the total synthesis of representative exponents of biologically active natural products. Focus is given to the synthesis of simple to highly complex secondary metabolites, including lactones, amino acids, diterpenes, and macrolides. The Sharpless approach involves the use of a catalyst, titanium tetraisopropoxide [Ti(OiPr)4], dialkyl tartrate as chiral ligand, and tert-butyl hydroperoxide (TBHP) as oxidizing agent. The method allows converting allylic alcohols to epoxides, which are chiral building blocks and versatile intermediates in the synthesis of natural products. The biological and synthetic importance of epoxides lies in the susceptibility of the threemembered heterocyclic ring to stereo- and regioselective opening by nucleophilic or acidic reagents, providing oxygen adducts.

First Total Synthesis of Jomthonic Acid A

A stereoselective total synthesis of jomthonic acid A is described. The key features of the synthetic strategy are a Sharpless asymmetric epoxidation, a Gilmann reagent-induced methylation, a Mitsunobu reaction, a Yamaguchi esterification, and an O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU)-mediated amide coupling. Jomthonic acid A is an architecturally rare amino acid containing a β-methylphenylalanine residue and a 4-methyl-(2E,4E)-hexa-2,4-dienoate moiety. It shows antidiabetic and antiatherogenic activities when tested against mouse ST-13 preadiopocytes.

A New Formal Synthetic Route to Entecavir

We describe a new and straightforward approach to the formal synthesis of the hepatitis B virus inhibitor entecavir, an important hepatitis B drug, in ten steps overall. Key features of the route are a Morita–Baylis–Hillman reaction, a Sharpless asymmetric epoxidation, a reductive epoxide opening of an α,β-epoxy ketone, and a Riley selenium dioxide oxidation.

Enantioselective Synthesis of 4-Amino-3-hydroxybenzopyran Flavanol Derivatives from Chalcones

A concise method that is easily amenable for analogue synthesis has been developed to enantioselectively access 4-amino-3-hydroxybenzopyrans from chalcones. Epoxy alcohols were formed from chalcones through a Corey–Bakshi–Shibata reduction of the enone and subsequent Sharpless asymmetric epoxidation of the allylic alcohol. The epoxy alcohols were protected, regioselectively opened with various amines using catalytic europium(III) triflate, and the resulting free alcohols were orthogonally protected. Concomitant deprotection and intramolecular nucleophilic aromatic substitution provided the benzopyran core, which is poised to undergo additional reactions to provide a diverse chemical library with ideal properties for biological evaluation.

The Lee Synthesis of (−)-Crinipellin A

The crinipellins are the only tetraquinane natural products. The enone crinipellins, including crinipellin A 3, have anticancer activity. Hee-Yoon Lee of the Korea Advanced Institute of Science and Technology (KAIST) envisioned (J. Am. Chem. Soc. 2014, 136, 10274) the assembly of 2 and thus 3 by the intramolecular dipolar cycloaddition of the diazoalkane derived from the tosylhydrazone 1. The initial cyclopentene was prepared from commercial 4 following the Williams procedure. Conjugate addition of the Grignard reagent 5 in the presence of TMS-Cl led to the silyl enol ether 6. Regeneration of the enolate followed by allylation gave 7. The preparation of the racemic ketone was completed by ozonolysis followed by selec­tive reduction and protection. Addition of hydride in an absolute sense led to separa­ble 1:1 mixture of diastereomers. Reoxidation of one of the diastereomers delivered enantiomerically enriched 8. A few steps later, after coupling with 10, the sidechain stereocenter was set by Sharpless asymmetric epoxidation. Oxidation of 11 gave the aldehyde, that was converted to the alkyne 12 by the Ohira protocol. Addition of the Grignard reagent 13 gave the allene 14 as an inconse­quential 1:1 mixture of diastereomers. Deprotection then led to the tosylhydrazone 1. The transformation of 1 to 2 proceeded by initial formation of the diazo alkane 15. Intramolecular dipolar cycloaddition gave 16, that lost N2 to give the trimethylene–methane diradical 17. The insertion into the distal alkene proceeded with remarkable stereocontrol, to give 2 as a single diastereomer—in 87% yield from 1. Direct α-hydroxylation of the ketone derived from 2 gave the wrong diastereo­mer, and hydride addition to 18 reduced the wrong ketone. As an alternative, the enantiomerically-pure sulfoximine anion was added to the more reactive ketone, and the product was reduced and protected to give 19. Allylic oxidation converted the alkene to the enone, and heating to reflux in toluene reversed the sulfoximine addi­tion, leading to 20. Epoxidation of 20 followed by α-methylenation delivered the enone 21, that proved to be particularly sensitive. Eventually, success was found with TASF. With a similarly sensitive substrate, Douglass F. Taber of the University of Delaware observed (J. Am. Chem. Soc. 1998, 120, 13285) that TBAF in THF buffered with solid NH4Cl worked well.

A Short Asymmetric Synthesis of Sauropunols A–D

A short and efficient asymmetric synthesis of natural sauropunols A, B, and C/D has been accomplished in 6 steps from divinylcarbinol with overall yield of 19%, 7% and 32%, respectively. The key synthetic steps include effective Sharpless asymmetric epoxidation of penta-1,4-dien-3-ol and a highly diastereoselective Pd-catalysed oxycarbonylation of pentene-1,2,3-triol. The structures of sauropunols A and B have been confirmed.

First Stereoselective Synthesis of (6R,7R,8S)-8-Chlorogoniodiol

A stereoselective synthesis of (6R,7R,8S)-8-chlorogoniodiol has been achieved in a linear sequence of 12 steps and 19.8% overall yield from cinnamyl alcohol. The key steps include Sharpless asymmetric epoxidation, regioselective ring opening of epoxide, indium-mediated Barbier allylation, and Still–Gennari olefination.

Synthesis of the C1–C9, C11–C19 Pyran Core and C19–C24 Fragments­ of Macrolactin 3

We describe herein an efficient synthesis of the C1–C9, C11–C19 pyran moiety and C18–C24 core fragments of macrolactin 3. The prominent features of this work include construction of the Z-double bond of the 1,3-(Z,E)-diene system utilizing Horner–Wadsworth–Emmons­ reaction under Still–Gennari conditions. A Sharpless asymmetric epoxidation and subsequent epoxide opening under BF3·OEt2 conditions were applied to generate the stereogenic centers at C15 and C16, oxa-Michael addition and Jacobsen resolution facilitate the synthesis of the fragments.