Synthesis of trans-fused polycyclic ethers with angular methyl groups using sulfonyl-stabilized oxiranyl anions

An efficient method has been developed for the synthesis of trans-fused tetrahydropyrans with angular methyl groups adjacent to the ring oxygen. The procedure involves the coupling reaction of a sulfonyl-stabilized oxiranyl anion with an appropriate triflate followed by 6-endo cyclization, and is effective for the construction of 6/6- and 6/7/6-cyclic ether ring systems with sterically congested 1,3-diaxial methyl groups.     

A convergent coupling strategy for the formation of polycyclic ethers: stereoselective synthesis of the BCDE fragment of brevetoxin A

A stereoselective synthesis of the BCDE fragment of brevetoxin A has been completed. anti-Glycolate aldol, glycolate alkylation, and ring-closing metathesis reactions were employed as key bond-forming events. A convergent assembly strategy was employed that relied on a Horner-Wadsworth-Emmons union of two complex fragments. Subsequent cyclization and dehydration led to efficient generation of an intermediate endocyclic enol ether, which was advanced to a tetracyclic fragment. [reaction: see text]     

A convergent total synthesis of epolactaene: an application of the bridgehead oxiranyl anion strategy

The generation and reaction of a lactone-derived oxiranyl anion is described. The aldol-type reaction of the epoxylactone and aldehydes was accomplished by a two-step procedure via the trimethylsilyl epoxylactone. The application of this methodology to the total synthesis of (+)-epolactaene and its analogs is described.     

A convergent strategy for the synthesis of beta-carba-galacto-disaccharides

[reaction in text] A convergent strategy for the synthesis of beta-carba-galacto-disaccharides is illustrated by the preparation of 1 and 4, from a central "glycone" component 22, and the corresponding "aglycone" segments, monosaccharide alcohols, 23a or 23b. The key step is the formation of the carbasugar ring via an oxocarbenium ion-enol ether cyclization.     

Studies toward the total synthesis of gambieric acids, potent antifungal polycyclic ethers: convergent synthesis of the CDEFG-ring system

[reaction: see text] A convergent synthetic route to the CDEFG-ring system of gambieric acids, potent antifungal polycyclic ether marine natural products, has been developed. The present synthesis features convergent union of the CD- and G-rings through esterification, formation of the E-ring as a lactone form, stereoselective allylation to set the C26 stereocenter, and ring-closing metathesis reaction to construct the nine-membered F-ring.     

Efficient strategy for convergent synthesis of trans-fused polycyclic ethers based on an intramolecular SmI2-promoted cyclization of iodo ester

An efficient convergent strategy for the construction of a trans-fused 6-6-6-6-membered tetracyclic ether ring system was developed. The key steps involve coupling of two cyclic ethers by esterification, SmI₂-promoted intramolecular reductive cyclization of iodo ester to hemiacetal, dehydration to dihydropyran, hydroboration, oxidation, intramolecular acetalization, and Lewis-acid catalyzed silane reduction.     

Total synthesis of (-)-brevenal: a streamlined strategy for practical synthesis of polycyclic ethers

We describe a streamlined strategy for the practical synthesis of trans-fused polycyclic ethers and its application to a concise total synthesis of (-)-brevenal, a new pentacyclic polyether natural product with intriguing biological activities. The B-, D-, and E-rings were constructed by TEMPO/PhI(OAc)(2)-mediated oxidative lactonization of the corresponding 1,6-diols, with minimal need for manipulation of oxygen functionalities. The B- and E-ring lactones were appropriately functionalized by Suzuki-Miyaura coupling of lactone-derived enol phosphates and subsequent stereoselective hydroboration. The A-ring was formed by our mixed thioacetalization methodology. The AB- and DE-ring fragments were assembled through Suzuki-Miyaura coupling, and the C-ring was forged in the same manner as that for the A-ring. More than two grams of the pentacyclic polyether core of (-)-brevenal have been synthesized by the synthetic route developed in this study.     

New strategy for convergent steroid synthesis

We published recently our results on a new and convergent synthesis of natural steroids. The strategy was based on a cycloaddition reaction of Nazarov reagents 2 and 5 with cyclohexenones 1 and 4. In this paper we report results that deal with the synthesis of two new bicyclic Nazarov reagents (13 and 19) and their cycloaddition with two cyclohexenones (1 and 4). These new results constitute an important improvement concerning the versatility of the strategy since tetracycles having the stereochemistry found in natural steroids are now available.     

Studies toward the total synthesis of gambieric acids, potent antifungal polycyclic ethers: convergent synthesis of a fully elaborated GHIJ-ring fragment

A stereocontrolled synthesis of a fully elaborated GHIJ-ring fragment of gambieric acids, which are potent antifungal polycyclic ether natural products, has been accomplished. The synthesis features convergent assembly of the tetracyclic polyether skeleton through aldol coupling/cyclodehydration/reductive etherification processes and stereoselective construction of the J-ring side chain by a CeCl₃-promoted Julia-Kocienski olefination.     

A pentenyl dianion-based strategy for convergent synthesis of ene-1,5-diols

A convergent two-step process is described for the synthesis of ene-1,5-diols that provides for union of two carbonyl electrophiles via a formal pentenyl dianion equivalent.     

A highly convergent and flexible strategy for the synthesis of a-ring aromatic steroids

Using Hendrickson's criteria for systematic synthesis design, a strategy featuring a linear six carbon synthon (7) for bis-annulation has been devised for economic, flexible and highly convergent syntheses of A-ring aromatic steroids.     

Formal total synthesis of hemibrevetoxin B by a convergent strategy

Concise construction of the trans-fused 7/7/6/6 tetracyclic ether part of hemibrevetoxin B (1) was achieved by a convergent strategy based on coupling reaction of an acyl anion equivalent, reductive cyclization of an α,ε-dihydroxyketone, and introduction of a methyl group at the central ring junction by the Nicolaou method. The resultant tetracyclic ether was transformed into the known intermediate, which was already converted to 1 by the Yamamoto group, thereby completing the formal total synthesis of 1.     

Stereoselective synthesis of naturally occurring alpha-methylenebis-gamma-butyrolactones: an application of novel oxiranyl "remote" anions.

Stereospecific deprotonation of the epoxy proton at the beta-position of the alpha,beta-epoxy esters 5 and 6 yielded oxiranyl "remote" anions 7 and 8, which could then be used for alkylation. The anions 7 and 8 underwent a consecutive aldol lactonization to give, respectively, epoxy lactones 11 and 13 with high stereoselectivity. Generation of the remote anions as well as their stereoselective reactions served as a new synthetic route to the naturally occurring alpha-methylenebis-gamma-butyrolactones, 1.     

Trifluoromethyl-stabilized optically active oxiranyl and aziridinyl anions for stereospecific syntheses of trifluoromethylated compounds

Optically active 2,3-epoxy-1,1,1-trifluoropropane was converted into the corresponding oxiranyl anion and reacted with electrophiles such as aldehydes, ketones and halides to give the corresponding adducts in moderate to good yields. The whole reaction occurred with retention of configuration at the stereogenic carbon center. In a similar manner, trifluoromethyl stabilizing aziridinyl anions were generated from the optically active N-tosyl and N-anisyl-2-trifluoromethylaziridines. They also reacted well with various electrophiles. The products of these reactions are versatile synthetic intermediates useful for the synthesis of a variety of trifluoromethylated compounds with quaternary chiral carbon centers.     

Comprehensive synthesis of ER related high-mannose-type sugar chains by convergent strategy

Systematic synthesis of high-mannose-type sugar chains of asparagine-linked glycoproteins is described. To construct the target sugar chains, we employed the convergent route, using three oligosaccharide components, the common hexasaccharide, branched tri-, tetra- and pentasaccharides, and mono-, di-, and triglucosyl fragments. Construction of the β-mannoside linkage was performed using p-methoxybenzyl-assisted intramolecular aglycon delivery. The hexasaccharide fragment was coupled with the branched mannooligosaccharide donors such as M5, M4B, M4C, and M3 to give undecasaccharide (M9), decasaccharide (M8B and M8C), and nonasaccharide (M7), respectively. Incorporation of mono-, di-, and triglucosyl fragments toward them gave tetradecasaccharide (G3M9), tridecasaccharide (G2M9), dodecasaccharide (G1M9), undecasaccharide (G1M8B and G1M8C), and decasaccharide (G1M7), respectively.     

Endo-oxacyclizations of polyepoxides: biomimetic synthesis of fused polycyclic ethers

Boron trifluoride-etherate promotes the endo-selective oxacyclization of polyepoxides derived from various acyclic terpenoid polyalkenes, including geraniol, farnesol, and geranylgeraniol, providing an efficient and stereoselective synthesis of substituted oxepanes and fused polyoxepanes. The mechanism of the oxacyclization reaction probably involves intramolecular nucleophilic addition of epoxide oxygen to open another epoxide that is activated as an electrophile by the Lewis acid. These oxacyclizations proceed stereospecifically with inversion of configuration upon opening of each epoxide to provide trans-fused polycyclic products. The oxacyclization cascade is terminated by a tethered nucleophile, which may be the carbonyl oxygen of a ketone, ester, or carbonate, or a trisubstituted alkene. The best oxacyclization yields are generally observed with tert-butyl carbonate as the terminating nucleophile, although in some cases the oxacyclization products include formation of tert-butyl ethers as a minor product. The oxacyclization transformations described herein may mimic ring-forming steps in the biosynthesis of trans-syn-trans-fused polycyclic ether marine natural products.     

Convergent synthesis of polycyclic ethers via the intramolecular allylation of alpha-acetoxy ethers and subsequent ring-closing metathesis

The Lewis acid mediated reaction of alpha-acetoxy ethers 15-22 gave the corresponding cyclized products 23, 25, 27, 29, 31, 32, 34, and 36 in good yields with high stereoselectivities. Those cyclized products were subjected to ring-closing metathesis to afford the polycyclic ethers 38-42, 44, and 45 in good yields. The usefulness of the present methodology was demonstrated by the convergent synthesis of the CDEF ring system of brevetoxin B (1) and the CDEFG ring system of gambierol (2).     

A convergent approach to polycyclic aromatic hydrocarbons

A new concise route to Polycyclic Aromatic Hydrocarbons (PAHs) through radical addition and cyclisation of xanthates is described.     

Generation and reactions of novel oxiranyl ‘Remote’ anions

Deprotonation of an oxiranyl β-proton takes place in a stereoselective manner providing the corresponding oxiranyl ‘remote’ anion. The anion is stabilized by chelation between the lithium and the carbonyl moiety of an ester, lactone, imide, or keto-group in the form of a five-membered cyclic intermediate. Certain ester-stabilized oxiranyl anions are stable and can be left in THF solution at −78°C for several hours. The generated anions undergo a stereoselective alkylation reaction to provide products, which could be useful intermediates in the synthesis of bioactive naturally occurring α-methylene bis-γ-butyrolactones.     

Efficient synthesis of S-linked glycopeptides in aqueous solution by a convergent strategy

In naturally occurring glycopeptides and glycoproteins the glycan residues generally possess N- and O-linkages to the peptide backbone. Here we report the synthesis of the corresponding S-linked glycopeptides by a convergent strategy to provide compounds which should be quite stable to glycosidases. To this end, peptides that contain beta-bromoalanine and gamma-bromohomoalanine were generated either directly by bromination of serine and homoserine residues, respectively, or by standard ligation of the corresponding amino acids. 1-Thiosugars of O-acetyl protected GalNAc, GlcNAc, and lactose were prepared by known procedures. Reaction of the thiosugars with these peptides in an ethyl acetate/water two-phase system, which contained TBAHS and NaHCO(3), or in a one-phase system that consists of DMF/water and which contains NaHCO(3), led to the desired S-linked glycopeptides cleanly and in almost quantitative yield. This reaction also worked well for O-unprotected 1-thiosugars.