bis-THF Core Research Articles

Concise Preparation of the Bis-THF Core of Annonaceous Acetogenins

A concise preparation of the all-(R) threo/trans/threo/ trans/threo bis-THF core present in natural acetogenins is presented. Starting from a terminal alkene, homometathesis and two consecutive stereoselective cyclizations afforded the bis-THF core through a short and efficient sequence. In addition, the isomeric erythro/trans/ threo/trans/erythro bis-THF core was also synthesized in high yield. The starting alkene was previously prepared from a homochiral cis-diol derived from biotransformation of bromobenzene.

Synthesis of bis-tetrahydrofuran core of salzmanolin using intramolecular oxymercuration reaction

The bis-THF core of salzmanolin was commenced from d-glucose as starting material. Stereoselective bis-THF ring has been established following intramolecular oxymercuration as the key reaction.

Asymmetric synthesis of bis-tetrahydrofuran cores in annonaceous acetogenins

The bis-THF cores of annonaceous acetogenins were synthesized using (3R,4R)-1,5-hexadiene-3,4-diol (1) as the sole source of carbon atoms. The methylene acetal function was applied as a new linker/tether to facilitate the ring-closing metathesis.

Oxidative Cyclization Reactions of Trienes and Dienynes: Total Synthesis of Membrarollin

Trienes and dienynes containing one electron-deficient double bond were shown to undergo regio- and stereoselective oxidative cyclization in the presence of permanganate ion to afford 2,5-bis-hydroxyalkyltetrahydrofurans (THF diols). The THF diols produced retained either alkene or alkyne functionalities, which provided convenient handles for the metal oxo-mediated introduction of an adjacent THF ring with overall control of relative and absolute stereochemistry. Adjacent bis-THFs possessing threo-cis-threo-trans-erythro, threo-cis-threo-trans-threo, threo-cis-threo-cis-erythro, threo-cis-erythro-cis-threo, or threo-cis-erythro-trans-threo relationships were synthesized by appropriate selection of alkene geometry and methodology for the closure of the second ring. The threo-cis-threo-cis-erythro stereochemical arrangement is embodied within the bis-THF core units of a number of Annonaceous acetogenins including membrarollin, while trilobacin has a threo-cis-erythro-trans-threo configured core. As an application of the selective oxidative cyclization approach, a total synthesis of membrarollin was completed in 17 linear steps from dodecyne. The C21,C22 double epimer of membrarollin was also synthesized in 15 linear steps and without recourse to the use of hydroxyl group protection.

Synthesis of the non-adjacent bis-THF core of cis-sylvaticin using a double oxidative cyclisation

A short synthesis of the non-adjacent bis-THF core of the Annonaceous acetogenin cis-sylvaticin (1) is described. C(2) Symmetrical (Z,E,E,Z)- and (E,E,E,E)-tetraenes and were synthesised in six and three steps respectively from (1E,5E,9E)-cyclododeca-1,5,9-triene. Subsequent permanganate promoted asymmetric bi-directional oxidative cyclisation of tetraene was used to create the non-adjacent bis-THF core of 1, installing seven of the nine stereogenic centres present in the natural product in a single step. Desymmetrization of the oxidative cyclisation product by mono-tosylation gave access to a C11-C32 fragment of cis-sylvaticin.

First Total Synthesis and Structural Reassignment of (−)-Aplysiallene

The first total synthesis of (-)-aplysiallene has been completed in 16 steps and features a key sequential Mukaiyama aerobic oxidative cyclization to prepare the fused bis-THF core. The original stereochemical assignment has been revised as shown.

Systematic Synthesis of Diastereomeric THF Ring Cores and Total Synthesis of Anti-Tumor Annonaceous Acetogenins

We have developed a systematic synthesis of the poly-THF ring cores of anti-tumor Annonaceous acetogenins by utilizing asymmetric alkynylation and subsequent stereodivergent THF ring formation as key steps. The asymmetric alkynylation of α-oxyaldehyde and α-tetrahydrofuranic aldehyde with an (S)-3-butyne-1,2-diol derivative proceeded in good yield with very high diastereo­selectivity. These adducts were converted into mono- and bis-THF cores by two different methods involving one-pot THF ring formation. The total syntheses of murisolin, 16,19-cis-murisolin, and longimicin D, which show cytotoxic activity against the human ­tumor cell, were accomplished by applying this methodology.

Systematic synthesis of antitumor annonaceous acetogenins

Systematic synthesis of mono- and bis-THF ring cores, synthetic intermediates of antitumor annonaceous acetogenins, has been achieved by asymmetric alkynylation and subsequent stereodivergent THF ring formation as key steps. The asymmetric alkynylation of alpha-oxyaldehyde and alpha-tetrahydrofuranic aldehyde with (S)-3-butyne-1,2-diol derivatives gave good yield with very high diastereoselectivity. These adducts were converted into mono- and bis-THF cores via two kinds of one-pot THF ring formation, respectively. In addition, the total synthesis of murisolin, which shows cytotoxic activity against human tumor cell lines with potency from 10(5) to 10(6) times that of adriamycin, was also achieved.

Systematic synthesis of Bis-THF ring cores in annonaceous acetogenins.

Systematic synthesis of bis-THF ring cores, synthetic intermediates of adjacent bis-THF annonaceous acetogenins, has been achieved by asymmetric alkynylation and subsequent stereodivergent THF ring formation. The asymmetric alkynylation of alpha-tetrahydrofuranic aldehyde with (S)-3-butyne-1,2-diol derivatives gave good yields of erythro- and threo-adducts with very high diastereoselectivity. These adducts were converted into four types of bis-THF cores via two kinds of one-pot THF ring formation. [reaction: see text]

Quinone-annonaceous acetogenins: synthesis and complex I inhibition studies of a new class of natural product hybrids.

The natural product hybrids quinone-mucocin and quinone- squamocin D were synthesized. In these hybrids, the butenolide unit of the annonaceous acetogenins mucocin and squamocin D is exchanged for the quinone moiety of the natural complex I substrate ubiquinone. For both syntheses, a modular, highly convergent approach was applied. Quinone-mucocin was constructed out of a tetrahydropyran (THP) component 1, a tetrahydrofuran (THF) unit 2, and a quinone precursor 3. A stereoselective, organometallic coupling reaction was chosen for the addition of the THP unit to the rest of the molecule. In the final step, the oxidation to the free quinone was achieved by using cerium(IV) ammonium nitrate (CAN) as the oxidizing agent. Quinone-squamocin D was assembled in a similar manner, from the chiral side chain bromide 16, the central bis-THF core 17, and the quinone precursor 18. Inhibition of complex I (isolated from bovine heart mitochondria) by the quinone acetogenins and several smaller building blocks was examined; quinone mucocin and quinone-squamocin D act as strong inhibitors of complex I. These results and the data from the smaller substructures indicate that other substructures of the acetogenins besides the butenolide group, such as the polyether component and the lipophilic left-hand side chain, are necessary for the strong binding of the acetogenins to complex I.

A Modular Synthesis of the Bis-Tetrahydrofuran Core of Rolliniastatin from Pyranoside Precursors

The iodoetherification of C6 allyllated 2,3-dideoxypyranosides has been shown to give cis-2,5-disubstituted tetrahydrofurans in high stereoselectivity. This result is applied to a modular synthesis of the bis-THF core of the acetogenin, rolliniastatin.

Total Syntheses of Squamocin A and Squamocin D, Bi-tetrahydrofuran Acetogenins from Annonaceae

The total syntheses of the Annonaceous acetogenins squamocin A and squamocin D have been achieved. The synthesis follows a modular strategy, wherein a left-side chain, the central bis-THF core and the right-side chain are assembled together. Key reactions are additions of organomagnesium compounds to bi-THF aldehydes. At the end of the synthesis the butenolide moiety was introduced. This modular synthetic approach should be useful for the synthesis of other related natural products as well as pharmacologically interesting analogs.

Total Syntheses of Squamocin A and Squamocin D, Bi-tetrahydrofuran Acetogenins from Annonaceae

The total syntheses of the Annonaceous acetogenins squamocin A and squamocin D have been achieved. The synthesis follows a modular strategy, wherein a left-side chain, the central bis-THF core and the right-side chain are assembled together. Key reactions are additions of organomagnesium compounds to bi-THF aldehydes. At the end of the synthesis the butenolide moiety was introduced. This modular synthetic approach should be useful for the synthesis of other related natural products as well as pharmacologically interesting analogs.