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.     

A short enantioselective synthesis of (−)-chloramphenicol and (+)-thiamphenicol using tethered aminohydroxylation

An efficient enantioselective synthesis of (−)-chloramphenicol (1) and (+)-thiamphenicol (2) is described. These antibiotics have been synthesized from commercially available 4-nitrobenzaldehyde and 4-(methylthio)benzaldehyde, respectively, using tethered aminohydroxylation and Sharpless asymmetric epoxidation as the chirality inducing steps.     

Stereoselective synthesis of (−)-cytoxazone and (+)-epi-cytoxazone

Optically pure (−)-cytoxazone was synthesized, starting from methyl p-methoxycinnamate, in six steps and in 31% overall yield. The required anti-aminoalcohol configuration was established by combining Sharpless asymmetric aminohydroxylation with the configurational inversion of the intermediate amidoalcohol via an oxazoline. The synthesis of (+)-epi-cytoxazone is also described.     

Enantioselective divergent approaches to both (−)-platensimycin and (−)-platencin

Enantioselective divergent approaches to (−)-platencin and (−)-platensimycin have been developed. A rationally designed chiral synthetic intermediate, possessing a useful α,β-unsaturated sulfone functionality, which served as a masked ketone as well as a good Michael acceptor, was successfully prepared via the highly enantioselective catalytic asymmetric intramolecular cyclopropanation (CAIMCP) developed in our laboratory.     

First total synthesis of (±)-epocarbazolin A and epocarbazolin B, and asymmetric synthesis of (−)-epocarbazolin A via Shi epoxidation

Epoxidation of the trisilyl-protected carbazomadurins A and B with dimethyldioxirane followed by desilylation provides a simple route to racemic epocarbazolin A and a non-diastereoselective access to epocarbazolin B. The Shi epoxidation has been applied to an asymmetric synthesis of the non-natural (−)-epocarbazolin A.     

Asymmetric synthesis of naturally occurring (−)-seimatopolides A and B

Asymmetric total synthesis of polyhydroxylated naturally occurring nonenolide seimatopolide A (3S,6S,7S,9R) and seimatopolide B (3S,6R,9R) is described in this article. An E-selective cross metathesis (CM) reaction between two suitable fragments followed by macrolactonization reaction is the main highlight of our synthesis for the two natural products. The fragment containing 6S,7S,9R stereocenters for seimatopolide A has been synthesized from l-tartaric acid as a chiral pool starting material, by employing (R)-CBS-mediated stereoselective keto reduction reaction. Another fragment, which is common for both the molecules, containing the 3S stereocenter was prepared by ME-DKR (metal enzyme combined dynamic kinetic resolution) method. The fragment having 6R,9R stereocenters for seimatopolide B has been prepared from n-decanal by adopting (R)-CBS-mediated keto reduction and Brown asymmetric allylation reaction.     

Modular and stereoselective formal synthesis of MeBmt, an unusual amino acid constituent of cyclosporin A

A convergent, flexible and stereoselective formal synthesis of MeBmt, the nonproteinogenic amino acid constituent of cyclosporin A is disclosed. The sulfinyl moiety has been exploited as the internal nucleophile to stereo- and regioselectively functionalize an allylic carbamate.     

Flexible approach for the asymmetric synthesis of (−)-hyacinthacine A1 and its 7a-epimer

The diastereoselective nucleophilic addition of organic boronic ester to 3-hydroxy-2-substituted N-acyliminium ions 9 led to the formation of 2,5-cis-pyrrolidine 10, from which a convenient synthesis of (−)-7a-epi-1 was developed. In addition, an efficient asymmetric synthesis of (−)-hyacinthacine A1 1 was achieved through the reduction/ring-opening process.     

Enantiodivergent synthesis of (−)-methylenolactocin and (+)-methylenolactocin from d-mannitol

An enantiodivergent synthesis of both enantiomers of methylenolactocin is described through stereocontrolled addition of n-pentyl magnesium bromide to two d-mannitol-derived diastereomerically related aldehydes having an α-chiral center with a β hetero atom.     

An enantioselective total synthesis of (S)-(−)-licochalcone E: determination of the absolute configuration

The absolute configuration of (−)-licochalcone E (1) was determined to be (S) via the first enantioselective total synthesis of the compound. The chirality in (S)-(−)-licochalcone E (1) was installed by asymmetric methylation of the Evans' oxazolidinone derivatives.     

Enantiodifferentiating tetrahydrofuranylation of but-3-enyl carboxylates using optically active hypervalent iodine(III) reagents via a 1,3-dioxan-2-yl cation intermediate

Optically active methyl 2-[2-(diacetoxyiodo)phenoxy]propanoate and its derivative were prepared and used for oxygenation of but-3-enyl carboxylates leading to tetrahydrofuran-3-yl carboxylates as an enantiomerically enriched form.     

Enantioselective total synthesis of (−)-microcarpalide

The enantioselective total synthesis of the actin-targeting metabolite (−)-microcarpalide is described. Key steps include ring-closing metathesis (RCM) for the final construction of the 10-membered lactone framework and stereoselective homologation of boronic esters for the insertion of all stereocentres with the desired absolute configuration. In particular, the acidic fragment was prepared in seven steps from a suitable chiral bromomethane boronate by means of two sequential stereoselective homologations to install the two stereocentres with the correct final R stereochemistry, employing (−)-pinanediol as the chiral director. Subsequent elaboration to the required C₇ backbone entailed nucleophilic displacement with a vinyl Grignard reagent, oxidative cleavage of the boronic scaffold and protection-deprotection manipulations. Interestingly, when the tribenzyloxy diene ester resulting from DCC-mediated coupling of the two key synthons was subjected to RCM in the presence of Grubbs' catalyst, the reaction proceeded stereoselectively to yield the desired trans oxecin-2-one, albeit with poor conversion.     

Chiral vicinal diols as platforms for separable diastereomers in Johnson-Claisen rearrangement: a new short route to (−)-nor-canadensolide, (−)-canadensolide and (−)-sporothriolide

The chiral vicinal diols prepared by asymmetric dihydroxylation in high enantioselectivities provide an excellent platform for separable diastereomers in the Johnson-Claisen rearrangement. The separated syn-diastereomers were converted into the advanced γ-(lactone-lactol) intermediates (in six steps, 26-27% overall yields) for the synthesis of (−)-nor-canadensolide, (−)-canadensolide and (−)-sporothriolide.     

Total synthesis of (−)-muricatacin

A total synthesis of (−)-muricatacin has been achieved using a commercially available starting material and our furan approach to oxacyclic systems, the proven scope of which is thus broadened.     

The use of (−)-8-phenylisoneomenthol and (−)-8-phenylmenthol in the enantioselective synthesis of 3-functionalized 2-azabicyclo[2.2.1]heptane derivatives via aza-Diels-Alder reaction

The asymmetric aza-Diels-Alder reaction of the (1R)-8-phenylmenthyl or (1R)-8-phenylisoneomenthyl glyoxylate-derived N-benzylimine with cyclopentadiene resulted in the enantioselective synthesis of the corresponding pure [(1S,3-exo)-2-benzyl-2-azabicyclo[2.2.1]hept-5-ene]-3-carboxylates (80 or 69% yield, respectively). Reduction of these cycloadducts with LiAlH₄ afforded pure (−)-[(1S,3-exo)-2-benzyl-2-azabicyclo[2.2.1]hept-5-en-3-yl]methanol. Furthermore, a reaction sequence based on Barbier-Wieland degradation of both (1S,3-exo)-adducts afforded pure (+)-(1R)-2-benzoyl-2-azabicyclo[2.2.1]heptan-3-one. In the course of the two transformation sequences referred, the chiral auxiliaries were recovered in a virtually quantitative way.     

Total synthesis of (−)-petrosiol E

(−)-Petrosiol E, a metabolite of sponge Petrosia strongylata, has been synthesized in 32% overall yield from cheap natural d-xylose in 10 steps. Our strategy provides an efficient way for the total synthesis of other petrosiol members, featuring the three contiguous stereogenic centers are easily constructed from d-xylose chiral template.     

Chiral diamines for asymmetric synthesis: an efficient RCM construction of the ligand core of (−)- and (+)-sparteine

An efficient RCM-based approach was applied to the total asymmetric synthesis of a tricyclic diamine and, formally, of its enantiomer, widely known as efficient and versatile chiral ligands of the sparteine-like type.     

Stereocontrolled total synthesis of (−)-aspidophytine

The enantioselective stereocontrolled total synthesis of aspidophytine is described. The key indole intermediate was prepared by radical cyclization of 2-alkenylphenylisocyanide, followed by Sonogashira-coupling with a highly functionalized terminal acetylene. The 11-membered cyclic amine, a precursor for the formation of the aspidosperma skeleton, was synthesized using nitrobenzenesulfonamide chemistry. After construction of the pentacyclic skeleton, the lactone ring was formed to complete the total synthesis.     

Asymmetric syntheses of (−)-isoretronecanol and (−)-trachelantamidine

Short and concise total asymmetric syntheses of (−)-isoretronecanol and (−)-trachelantamidine are reported. Oxidative cleavage of tert-butyl (S,S,S,Z)-7-[N-benzyl-N-(α-methylbenzyl)amino]cyclohept-3-ene-1-carboxylate, followed by hydrogenolysis promoted in situ cyclisation/reduction, which provided rapid access to the bicyclic core within (−)-isoretronecanol. Analogous treatment of the C(1)-epimer gave (−)-trachelantamidine. Overall, the syntheses of (−)-isoretronecanol and (−)-trachelantamidine were completed in eight and seven steps and 20 and 9.5% yield, respectively, from commercially available starting materials.     

Asymmetric synthesis of (−)-(S,S)-homaline

The asymmetric synthesis of (−)-(S,S)-homaline was achieved in 8 steps from commercially available starting materials using the diastereoselective conjugate addition of the novel lithium amide reagent lithium (R)-N-(3-chloropropyl)-N-(α-methyl-p-methoxybenzyl)amide to methyl cinnamate to install the correct stereochemistry. Subsequent functional group manipulation of the resultant β-amino ester and Sb(OEt)₃-mediated macrolactamisation was followed by homodimerisation to give (−)-(S,S)-homaline in 18% overall yield, representing the first asymmetric, and by far the most efficient synthesis of this natural product reported to date.