Enantioselective total synthesis of the potent antitumor agent (-)-mucocin using a temporary silicon-tethered ring-closing metathesis cross-coupling reaction

The enantioselective total synthesis of the annonaceous acetogenin (-)-mucocin (1) was accomplished using a triply convergent 12-step sequence (longest linear sequence) in 13.6% overall yield. This represents the first application of the temporary silicon-tethered (TST) ring-closing metathesis (RCM) cross-coupling reaction and the enantioselective alkyne/aldehyde addition to the synthesis of a complex annonaceous acetogenin. Moreover, all three fragments required for the coupling reactions are conveniently prepared in 5-6 steps from two readily available enantiomerically enriched epoxides. Finally, this synthesis stimulated the development of a new approach for the construction of 3-hydroxy-2,6-disubstituted tetrahydropyrans, using the bismuth tribromide-mediated reductive etherification reaction, which represents a motif that is prevalent in a wide range of pharmacologically significant natural products.     

First synthesis of a branched beta-C-tetrasaccharide using a triple ring closing metathesis cyclization

The first synthesis of a branched beta-C-tetrasaccharide has been carried out through the use of an esterification-ring closing metathesis (RCM) strategy. The precursor triacid 2a was readily prepared via standard chemical methods from a known starting material, and dehydrative coupling with an excess of olefin alcohol 1a gave triester 3a in excellent yield. Methylenation of the triester 3a and subsequent triple RCM reaction was followed by an in situ hydroboration-oxidation to furnish the branched beta-C-tetrasaccharide 6a in good overall yield.     

Total synthesis of (+/-)-mycoepoxydiene,a novel fungal metabolite having an oxygen-bridged cyclooctadiene skeleton

[reaction: see text] The first total synthesis of (+/-)-mycoepoxydiene has been accomplished. A ring-closing olefin metathesis (RCM) approach was employed for the construction of the oxygen-bridged eight-membered bicyclic skeleton. The RCM product was converted to the target natural product featuring the oxidative rearrangement of a furfuryl alcohol introduced as the side chain and the stereoselective 1,2-reduction of a delta-keto-beta,gamma-unsaturated alpha-lactol intermediate.     

A chemoenzymatic total synthesis of the phytotoxic undecenolide (-)-cladospolide A

An eleven-step synthesis of the title compound (1) from biocatalytically-derived and enantiomerically pure 'building blocks' alcohol (R)-(-)-9 and ester 13 is described. Attempts to construct the twelve-membered lactone ring of cladospolide A in a direct manner by using a ring-closing metathesis (RCM) reaction failed. However, a ten-membered lactone 19, could be constructed by such means and this was then subject to a two-carbon homologation sequence involving, inter alia, Wadsworth-Horner-Emmons and Yamaguchi lactonisation reactions in the closing stages of the synthesis. The impact of substituent stereochemistries and protecting groups on the RCM reaction leading to various ten-membered lactones is also described.     

Ring-closing metathesis (RCM) based synthesis of the macrolactone core of amphidinolactone A

A convergent synthesis of the macrolactone core of amphidinolactone A has been achieved, in a 10 step linear sequence with 32% overall yield, through a ring-closing metathesis reaction as the macrolactonization step. The RCM precursor was obtained by the union of acid and alcohol fragments derived from (R)-epichlorohydrin and (R)-2,3-O-isopropylidene glyceraldehyde, respectively.     

Synthesis of the C12-C19 fragment of (+)-peloruside A through a diastereomer-discriminating RCM reaction

[reaction: see text]. A short and efficient asymmetric synthesis of the C12-C19 fragment of the cytotoxic macrolide (+)-peloruside A has been achieved via a highly diastereomer-discriminating RCM of alpha-branched but-3-enoate ester of a methallylic alcohol derived from hydrolytically resolved (S)-(-)-propylene oxide.     

Stereochemical control of skeletal diversity

[reaction: see text]. Substrates having appendages that pre-encode skeletal information (sigma-elements) can be converted into products having distinct skeletons using a common set of reaction conditions. The sequential use of the Ugi 4CC-IMDA reaction, followed by allylation, hydrolysis, and acylation of a chiral amino alcohol appendage (sigma-element), leads to substrates for a ROM/RCM or RCM reaction. The stereochemistry of the sigma-element and not its constitution controls the outcome of the pathway selected. This work illustrates the potential of linking stereochemical control to the challenging problem of skeletal diversity.     

An RCM‐Based Total Synthesis of the Antibiotic Disciformycin B

The total synthesis of the potent new antibiotic disciformycin B ( 2 ) is described, which shows significant activity against methicillin‐ and vancomycin‐resistant Staphylococcus aureus (MRSA/VRSA) strains. The synthetic route is based on macrocyclization of a tetraene substrate to the 12‐membered macrolactone core by ring‐closing olefin metathesis (RCM). Although macrocyclization was accompanied by concomitant cyclopentene formation by an alternative RCM pathway, conditions were established to give the macrocycle as the major product. Key steps in the construction of the RCM substrate include a highly efficient Evans syn‐aldol reaction, the asymmetric Brown allylation of angelic aldehyde, and the stereoselective Zn(BH₄)₂‐mediated 1,2‐reduction of an enone. The synthesis was completed by late‐stage dehydrative glycosylation to introduce the d ‐arabinofuranosyl moiety and final chemoselective allylic alcohol oxidation.     

Asymmetric synthesis of (+)-pyrido[3,4-b]homotropane

(+)-pyrido[3,4- b]homotropane (PHT) was efficiently constructed in 12 steps from N, N-diisopropylisonicotinamide. The synthesis features (i) RCM reaction in installing the homotropane skeleton, (ii) Snieckus ortho-lithiation of N, N-diisopropylisonicotinamide followed by acylation, (iii) Myer reduction of bulky tertiary amide to alcohol with LiBH 3NH 2, and (iv) utilization of L-glutamic acid to introduce and establish the requisite stereogenic centers.     

Studies towards the total synthesis of Phostriecin

A synthetic approach toward the phostriecin, an antitumor natural product is described. The key features of the present synthesis are Wittig reaction, synthesis of homoallylic alcohol using Brown’s protocol (alkoxyallylboration) and RCM for the creation of unsaturated lactone moiety of phostriecin.     

An efficient synthesis of oseltamivir phosphate (Tamiflu) via a metal-mediated domino reaction and ring-closing metathesis

An efficient synthesis of the influenza neuraminidase inhibitor prodrug oseltamivir phosphate (Tamiflu) from cheap, commercially available d-ribose is described. The main features of this approach comprise a metal (Zn, In)-mediated domino reaction and ring-closing olefin metathesis (RCM) of the resultant functionalized dienes to produce the Tamiflu skeleton. The synthesis described in this Letter represents a new and efficient transformation of a shikimic acid derivative into a 1,2-diamino compound which involved oxidation of an alcohol followed by reductive amination, regioselective ring opening of an amino pentylidene ketal and stereospecific nucleophilic replacement of a triflate with an azide.     

Formal total synthesis of (+)-salicylihalamides A and B: a combined chiral pool and RCM strategy

The formal total synthesis of the (+)-salicylihalamides A and B is detailed, utilizing a chiral pool approach to generate the three stereogenic centers and a ring-closing metathesis (RCM) for the formation of the macrocyclic ring structure. Starting from a known glucose-derived alcohol, the formal total synthesis was achieved in an efficient 13-step protocol in 26% overall yield. It was found that substitution at the remote phenolic group significantly influenced the ratio of the E- and Z-double bond products in the RCM step. The introduction of phenol protecting groups provided E-isomers preferentially and also enhanced the rates of the RCM reactions.     

New strategy for the total synthesis of macrosphelides a and B based on ring-closing metathesis

[reaction: see text] A new total synthesis of macrosphelides A and B using ring-closing metathesis (RCM) as a macrocyclization step is described. The substrate of the RCM could be synthesized from readily available chiral materials, methyl (S)-(+)-3-hydroxybutyrate and methyl (S)-(-)-lactate, with a high efficiency. The RCM proceeded in the presence of Grubbs' Ru-complex, providing a new effective synthetic route to these natural products.     

Stereoselective total synthesis of microcarpalide

A stereoselective total synthesis of microcarpalide using ring-closing metathesis (RCM) as a key step is reported. l-Ascorbic acid was used as a chiral pool material for the construction of the olefinic alcohol and an asymmetric aldol reaction provided the chiral precursor for the synthesis of olefinic acid.     

Total syntheses of conformationally locked difluorinated pentopyranose analogues and a pentopyranosyl phosphate mimetic

Trifluoroethanol has been elaborated, via a telescoped sequence involving a metalated difluoroenol, a difluoroallylic alcohol, [2,3]-Wittig rearrangement, and ultimately an RCM reaction and requiring minimal intermediate purification, to a number of cyclooctenone intermediates. Epoxidation of these intermediates followed by transannular ring opening or dihydroxylation, then transannular hemiacetalization delivers novel bicyclic analogues of pentopyranoses, which were elaborated (in one case) to an analogue of a glycosyl phosphate.     

Synthesis of (+)-didemniserinolipid B: application of a 2-allyl-4-fluorophenyl auxiliary for relay ring-closing metathesis

The synthesis of didemniserinolipid B utilizing a ketalization/ring-closing metathesis (K/RCM) strategy is described. In the course of this work, a novel 2-allyl-4-fluorophenyl auxiliary for relay ring-closing metathesis (RRCM) was developed, which increased the yield of the RCM. The resulting 6,8-dioxabicyclo[3.2.1]octene core was selectively functionalized by complimentary dihydroxylation and epoxidation routes to install the C10 axial alcohol. This bicyclic ketal core was further functionalized by etherification and an alkene cross metathesis with an unsaturated alpha-phenylselenyl ester en route to completing the total synthesis.     

Ring-closing metathesis as a basis for the construction of aromatic compounds

The use of metathesis, especially in the context of ring-closing metathesis (RCM) to form five- and six-membered rings, is widespread in organic chemistry today. However, there are surprisingly few examples of the reaction being used to form aromatic compounds. The central place of aromatic compounds in both medicinal chemistry and natural products synthesis, coupled with the efficiency and functional group tolerance of RCM catalysts, means that there is now an interesting opportunity to use RCM for the synthesis of arenes. Although the formation of an aromatic compound was viewed in many early examples as an undesirable degradation product, several rationally designed methods towards the preparation of aromatic compounds by RCM have recently been developed.     

新型大环磺酰胺肽模拟物的设计及其关键前体的合成

动植物、微生物和病毒等都含有微量的环肽 ,其中大多具有明显的生理活性 ,因此 ,受到科学家们的高度重视 [1] .设计与合成具有生理活性的新型环肽是目前有机合成的前沿课题 [2～ 4 ] .烯烃复分解闭环反应 ( RCM)已成为构成碳环和杂环的重要手段 [5～ 7] .由于 Schrock和 Grubbs催化剂的高活性和官能基适用性 ,烯交换闭环反应已被应用于肽的合成 [8～ 10 ] .在研究通过烯交换闭环反应设计与合成新型肽化合物的基础上 [11] ,我们设计了通过烯交换闭环反应从含有两个末端烯双键化合物合成新型大环磺酰胺肽模拟物的新途径 ,如 Scheme 1 ,其中…     

Total synthesis of (-)-microcarpalide, a novel microfilament disrupting metabolite

The stereoselective total synthesis of (-)-microcarpalide, a recently discovered 10-membered lactone of fungal origin displaying a remarkable disrupting action on actin microfilaments, was accomplished by using ring-closing metathesis (RCM) as the key step for the formation of the medium-sized ring. The diene ester required for the macrocyclization reaction was assembled via DCC-mediated esterification of two suitable partners, each bearing a terminal alkene group. The alcohol fragment was synthesized from n-bromohexane through a seven-step sequence entailing two consecutive stereoselective homologations of chiral boronic esters as strategic transformations for the sequential insertion of the two stereocentres with the final S absolute configuration, using (+)-pinanediol as the chiral director; final elaboration to the desired C(11) framework envisaged treatment with an allyl Grignard reagent and oxidative cleavage of the boronic scaffold. In contrast, the acidic fragment was prepared in ten steps from d-tartaric acid, whose C(4) backbone was elongated to the required C(7) skeleton by means of two distinct Swern-Wittig oxidation-homologation sequences.     

Enantioselective synthesis of the 4-hydroxy buteneolide terminus of mucocin and related annonaceous acetogenins

The 4-hydroxy buteneolide terminus 3, applicable to mucocin 1 and related annonaceous acetogenins, was prepared in an expeditious manner from the selenocarbonate 2 via an intramolecular acyl radical cyclization followed by an enantioselective Lewis-acid catalyzed Keck-allylation reaction.