Total synthesis of (+)-phorboxazole A exploiting the Petasis-Ferrier rearrangement.

A highly convergent, stereocontrolled total synthesis of the potent antiproliferative agent (+)-phorboxazole A (1) has been achieved. Highlights of the synthesis include: modified Petasis-Ferrier rearrangements for assembly of both the C(11-15) and C(22-26) cis-tetrahydropyran rings; extension of the Julia olefination to the synthesis of enol ethers; the design, synthesis, and application of a novel bifunctional oxazole linchpin; and Stille coupling of a C(28) trimethyl stannane with a C(29) oxazole triflate. The longest linear sequence leading to (+)-phorboxazole A (1) was 27 steps, with an overall yield of 3%.     

Expedient approach to chiral cyclobutanones: asymmetric synthesis of cyclobut-G

An efficient one-pot asymmetric synthesis of cyclobutanones from chiral enol ethers is described. The approach is illustrated with alkyl- and functionalized alkyl-substituted enol ethers (nine examples). A new enantioselective synthesis of cyclobut-G (Lobucavir) could thus be achieved.     

Singlet oxygen oxidation of enol ethers; the synthesis of optically active 1,2-dioxetanes-II

Several chiral enol ethers, among which two derived from (+)-fenchone have been converted to (chiral) 1,2-dioxetanes by photosensitized oxygenation.     

Asymmetric synthesis of cyclobutanones: synthesis of cyclobut-G

A simple, efficient, and stereoselective approach has been developed for obtaining chiral cis- and trans-disubstituted cyclobutanones from readily available alkyl- and functionalized alkyl-substituted enol ethers. The usefulness of these cyclobutanones is illustrated by an enantioselective synthesis of cyclobut-G (Lobucavir).     

The enantioselective Birch-Cope sequence for the synthesis of carbocyclic quaternary stereocenters. Application to the synthesis of (+)-mesembrine

A synthetic technique for generating carbocyclic quaternary stereocenters with exceptionally high levels of enantioselectivity is described. A sequence of three reactions, enantioselective Birch reduction-allylation, enol ether hydrolysis, and Cope rearrangement, is used to stereoselectively generate chiral quaternary centers on a 2-cyclohexen-1-one ring. The products of the sequence are 4,4-disubstituted-2-carboxamide-2-cyclohexen-1-one structures which are versatile intermediates in complex natural product synthesis. An application of the sequence to the synthesis of (+)-mesembrine illustrates the utility of these intermediates.     

Stereoselective amination of chiral benzylic ethers using chlorosulfonyl isocyanate: total synthesis of (+)-sertraline

The stereoselective amination of various chiral benzylic ethers using chlorosulfonyl isocyanate is developed, and the application of this method to the total synthesis of a potent antidepressant, (+)-sertraline, from readily available 1-naphthol is also described.     

A short enantioselective synthesis of (+)-eleutherin, (+)-allo-eleutherin and a formal synthesis of (+)-nocardione B

A short enantioselective synthesis of (+)-eleutherin, (+)-allo-eleutherin and the formal synthesis of (+)-nocardione B is described. The synthesis is completed in six steps in overall yields of 8% for eleutherin and 14% for allo-eleutherin. The synthetic strategy features an efficient combination of the Dötz annulation reaction with a chiral alkyne and an oxa-Pictet Spengler reaction as the keys steps in the stereodivergent synthesis of (+)-eleutherin and (+)-allo-eleutherin. The synthesis of (S)-(+)-2-(2′-hydroxypropyl)-5-methoxy-1,4-naphthoquinone entails the formal synthesis of (+)-nocardione B.     

Asymmetric [2 + 2] cycloaddition: total synthesis of (-)-swainsonine and (+)-6-epicastanospermine

[reaction: see text] An asymmetric total synthesis of (-)-swainsonine and (+)-6-epicastanospermine is described from a common intermediate, which is obtained through diastereoselective [2 + 2] cycloaddition of dichloroketene to a chiral enol ether.     

New asymmetric approach to natural pyrrolizidines: synthesis of (+)-amphorogynine A, (+)-amphorogynine D, and (+)-retronecine

Three natural pyrrolizidines, (+)-amphorogynines A and D and (+)-retronecine, have been prepared from a common lactam intermediate. This central compound, in turn, was synthesized in diastereomerically enriched form through a highly selective [2 + 2]-cycloaddition of dichloroketene with a chiral enol ether, followed by Beckmann ring expansion and reduction. Subsequent stereocenters were then cleanly introduced through internal induction.     

Total synthesis of (+)-boronolide, (+)-deacetylboronolide,and (+)-dideacetylboronolide

Total synthesis of (+)-boronolide, (+)-deacetylboronolide, and (+)-dideacetylboronolide has been achieved from a single intermediate 26, which was synthesized in 11 steps from a d-mannitol-derived intermediate 8 in an overall yield of 10%. The key steps in the synthesis are inversion of a chiral center by taking an advantage of the inherent mechanism involved in the ring closing to an epoxide via intramolecular S(N)2 reaction and lactonization of a diol using Fetizons reagent. The strategy is amenable to preparation of analogues of (+)-boronolide in sufficient amount for further screening of biological activity.     

Asymmetric total synthesis of (+)-curcutetraol and (+)-sydonol

The asymmetric total syntheses of (+)-curcutetraol and (+)-sydonol, phenolic bisabolane-type sesquiterpenoids having chiral tertiary alcohol moiety in the o-position of a phenol, were achieved in high enantiomeric excesses (99% ee). The chiral tertiary benzylic alcohol moiety of these compounds was constructed by an asymmetric synthesis using an easily available chiral aminal, (−)-(2R,5S)-2-methoxycarbonyl-3-phenyl-1,3-diazabicyclo[3.3.0]octane. The absolute configurations of both (+)-curcutetraol and (+)-sydonol have been assumed to be S-configuration based on the stereochemical course of the well established asymmetric synthesis used in the syntheses.     

Total synthesis of (+)-alpha-onocerin in four steps via four-component coupling and tetracyclization steps

A remarkably short (four steps, 31% overall yield) enantioselective synthesis of the structurally unique C2-symmetric tetracyclic triterpene (+)-alpha-onocerin (1) has been developed. The brevity of this mechanism depends on the assembly of four fragments (two molecules of a chiral epoxy ketone and two molecules of vinyllithium) to generate the chiral bis-epoxide 4 in one step, and on the efficient formation of all four carbocyclic rings in one step by cation-olefin tetracyclization. New and general methodology for the conversion of vinyl tert-butyldimethylsilyl ethers to vinyl triflates with retention of E or Z olefinic geometry also was utilized in the synthesis of 1. A short enantioselective synthesis of a non-C2-symmetric diastereomer of 1 is also described which uses the new methodology.     

Facile synthesis of naphthoquinone spiroketals by diastereoselective oxidative [3 + 2] cycloaddition

A highly selective oxidative [3 + 2] cycloaddition of chiral enol ethers and hydroxynaphthoquinone is described. This convergent strategy is amenable to an enantioselective synthesis of beta-rubromycin and related naphthoquinone spiroketals. Several compounds were found to inhibit DNA-polymerase and telomerase in a manner resembling alpha-rubromycin and beta-rubromycin.     

Stereoselective synthesis of (+)-secosyrin 1

A Chiron approach for the synthesis of (+)-secosyrin 1 from d-mannitol has been described. The key steps are a stereoselective Wittig reaction and an intramolecular Michael addition on the disubstituted butenolide, leading to a highly stereoselective formation of the tertiary chiral centre of (+)-secosyrin 1.     

Synthesis of (+)-madindoline A and (+)-madindoline B

The allene ether version of the Nazarov cyclization was used to construct the cyclopentane dione portion of madindolines A and B. The racemic cyclopentane dione from the Nazarov cyclization was converted to an enol ether that was combined with the chiral, nonracemic hydroxyfuroindoline in a Mannich reaction. Deprotection and oxidation led to (+)-madindoline A and (+)-madindoline B. [reaction: see text].     

Facile Stereoselective Approach to Diverse Spiroheterocyclic Tetrahydropyrans: Concise Synthesis of (+)‐Broussonetine G and H

A highly diastereoselective copper‐catalyzed multicomponent cyclization of exocyclic enol ethers/enamines with methylene malonate and aldehydes has been developed to furnish spiroheterocyclic tetrahydropyrans in high yields with greater than 95:5 d.r. This method is practical, in that 36 examples, including a range of aldehydes and exo‐vinyl heterocycles, are presented. By applying the newly developed method, the total synthesis of (+)‐broussonetine G and formal synthesis of (+)‐broussonetine H were achieved in a concise way.     

A highly enantioselective total synthesis of (+)-goniodiol

A high-yielding enantioselective total synthesis of the bioactive styryllactone (+)-goniodiol has been realised, starting from readily available (S)-glycidol. A key step is an oxygen-to-carbon rearrangement of a silyl enol ether linked via an anomeric centre, facilitating the rapid and diastereoselective construction of this functionalised system.     

Enantioselective total synthesis of (+)-tricycloclavulone

The first total synthesis of (+)-tricycloclavulone having a unique tricyclo[5,3,0,01,4]decane skeleton and six chiral centers was achieved in a highly stereoselective manner. It includes a catalytic enantioselective [2+2]-cycloaddition reaction using novel chiral copper catalyst, extremely effecting an intramolecular ester transfer reaction, and asymmetric reduction of the carbonyl group on the alpha-chain using Noyori's chiral ruthenium catalyst.     

Stereocontrolled total synthesis of (+)-concanamycin F: the strategic use of boron-mediated aldol reactions of chiral ketones

A highly stereocontrolled total synthesis of the 18-membered macrolide (+)-concanamycin F, a potent inhibitor of vacuolar ATPases, is described that proceeds in 5.8% yield over 26 steps. The three key fragments, C1-C13 vinyl iodide, C14-C22 vinyl stannane and C23-C28 aldehyde, were efficiently constructed using asymmetric boron-mediated aldol reactions of appropriate chiral ketone building blocks. The nature of the silyl protection of the C7/C9 hydroxyls proved to be critical for achieving macrocyclisation, with TES ethers being superior to a cyclic silylene derivative. Following a Liebeskind-Stille cross-coupling reaction between the C1-C13 vinyl iodide and C14-C22 vinyl stannane fragments to assemble the (12E,14E)-diene, a modified Yamaguchi macrolactonisation delivered the requisite 18-membered macrocyclic core. This advanced intermediate was also obtained by an alternative sequence using an esterification step to connect the C1-C13 and C14-C22 fragments followed by a Pd-catalysed intramolecular Stille reaction to install the (12E,14E)-diene. Conversion of the resulting macrocyclic intermediate into a methyl ketone then enabled a highly diastereoselective Mukaiyama aldol coupling of the derived silyl enol ether with the C13-C28 aldehyde fragment to install the fully elaborated side chain, whereby subsequent global deprotection of the resulting β-hydroxyketone under suitable conditions (TASF followed by p-TsOH) afforded (+)-concanamycin F.     

New perspective for natural products synthesis: concise synthesis of (+)-sch 642305 by chiral auxiliary multiuse methodology

The synthesis of (+)-Sch 642305 is an example of chiral auxiliary multiuse methodology, which shows a new perspective for the synthesis of compounds with multiple asymmetric centers. Thus, (+)-Sch 642305 was concisely synthesized from the known compound. Every reaction is stereoselective, and the chiral nonracemic hydrobenzoin worked as chiral auxiliary for desymmetrization of diene, as a template for attaining regio- and stereoselective reactions, as an oxygen source at the C4-position, and as a protecting group of hydroxyl functions. Namely, the chiral auxiliary played a role in every step throughout the synthesis. Furthermore, the synthesis contains a new protocol for obtaining alpha'-alkylated enone compounds.