Forwards and backwards – synthesis of Laurencia natural products using a biomimetic and retrobiomimetic strategy incorporating structural reassignment of laurefurenynes C–F

Laurefurenynes C–F are four natural products isolated from Laurencia species whose structures were originally determined on the basis of extensive nuclear magnetic resonance experiments. On the basis of a proposed biogenesis, involving a tricyclic oxonium ion as a key intermediate, we have reassigned the structures of these four natural products and synthesized the four reassigned structures using a biomimetic approach demonstrating that they are the actual structures of the natural products. In addition, we have developed a synthesis of the enantiomers of the natural products laurencin and deacetyllaurencin from the enantiomer of (E)-laurefucin using an unusual retrobiomimetic strategy. All of these syntheses have been enabled by the use of tricyclic oxonium ions as pivotal synthetic intermediates.

The synthesis and structural reassignment of laurefurenynes C–F has been achieved, with the new structures fitting with a proposed biosynthesis. Also reported is the synthesis of ent-laurencin and ent-deacetyllaurencin via a retrobiomimetic approach.     

Synthesis and absolute configuration of three natural ent-halimanolides with biological activity

The first three natural ent-halimanolides known until now have been synthesized from ent-halimic acid. Their structure have been confirmed as well as their absolute configurations established. Bestmann methodology has been used for the synthesis of butenolides and for the γ-hydroxybutenolides synthesis the Boukouvalas method has been employed. Biological testing has been carried out on these compounds.     

Synthesis of (+)-agelasine C. A structural revision

An efficient synthesis of (+)-agelasine C has been achieved from ent-halimic acid. The structure and absolute configuration of the natural product (−)-agelasine C was established and a structure for epi-agelasine C, is proposed.     

Enantiodivergent synthesis of muricatacin related lactones from d-xylose based on the latent symmetry concept: preparation of two novel cytotoxic (+)- and (−)-muricatacin 7-oxa analogs

Enantiodivergent formal synthesis of (+)- and (−)-muricatacins from d-xylose has been accomplished through utilization of the latent plane of symmetry present in the starting monosaccharide. This approach was extended to the preparation of two novel (+)- and (−)-muricatacin 7-oxa analogs (2 and ent-2, respectively), which showed in vitro antitumor activity toward some human malignant cells. The analog ent-2 showed a powerful antiproliferative activity against the K562 cell line, being 36-fold more potent than the standard cytotoxic agent, doxorubicin. Compound 2, however, showed a powerful cytotoxic activity against HL-60 cells, being more than 17-fold more potent with respect to the reference compound.     

Novel cytotoxic kaurane-type diterpenoids from the New Zealand Liverwort Jungermannia species

Novel cytotoxic rearranged kaurene- and ent-kaurene-type diterpenoids against HL-60 cells have been isolated from the unidentified New Zealand liverwort Jungermannia species together with previously known ent-kaurane-type diterpenoids. Their structures were determined by extensive NMR techniques, chemical degradation and X-ray crystallographic analysis.     

Biogenetically related caged ent-kaurane diterpenoids from Isodon eriocalyx var. laxiflora

Two novel caged ent-kauranoids, neolaxiflorins D (1) and E (2), along with three other new ent-kauranoids, neolaxiflorins F–H (3–5), and a known one, eriocalyxin B (6), were obtained from Isodon eriocalyx var. laxiflora. Neolaxiflorin D (1) is the first 15,16-seco-16,17-dinor-ent-kaurane diterpenoid, and neolaxiflorin E (2) is the first 15,16-seco-17-homo-ent-kauranoid. The absolute configurations of ent-kauranoids 1 and 2 were determined by single-crystal X-ray diffraction analyses. Structural analysis of intermediate compounds 3–5 indicated that eriocalyxin B (6) is a biogenetic precursor of caged ent-kauranoids 1 and 2 as illustrated. The cytotoxic activity of the new compounds was evaluated by an MTT assay.     

Total Synthesis of (−)‐Zampanolide and Structure–Activity Relationship Studies on (−)‐Dactylolide Derivatives

A new total synthesis of the marine macrolide (?)‐zampanolide ( 1 ) and the structurally and stereochemically related non‐natural levorotatory enantiomer of (+)‐dactylolide ( 2 ), that is, ent‐ 2 , has been developed. The synthesis features a high‐yielding, selective intramolecular Horner–Wadsworth–Emmons (HWE) reaction to close the 20‐membered macrolactone ring of 1 and ent‐ 2 . The β‐keto phosphonate/aldehyde precursor for the ring‐closure reaction was obtained by esterification of a ω‐diethylphosphono carboxylic acid fragment and a secondary alcohol fragment incorporating the THP ring that is embedded in the macrocyclic core structure of 1 and ent‐ 2 . THP ring formation was accomplished through a segment coupling Prins‐type cyclization. Employing the same overall strategy, 13‐desmethylene‐ent‐ 2 as well as the monocyclic desTHP derivatives of 1 and ent‐ 2 were prepared. Synthetic 1 inhibited human cancer cell growth in vitro with nM IC₅₀ values, while ent‐ 2 , which lacks the diene‐containing hemiaminal‐linked side chain of 1 , is 25‐ to 260‐fold less active. 13‐Desmethylene‐ent‐ 2 as well as the reduced versions of ent‐ 2 and 13‐desmethylene‐ent‐ 2 all showed similar cellular activity as ent‐ 2 itself. The same activity level was attained by the monocyclic desTHP derivative of 1 . Oxidation of the aldehyde functionality of ent‐ 2 gave a carboxylic acid that was converted into the corresponding N‐hexyl amide. The latter showed only μM antiproliferative activity, thus being several hundred‐fold less potent than 1 .     

Synthesis of 12-epi-ent-polyalthenol an antitumour indole sesquiterpene alkaloid

The synthesis of 12-epi-ent-polyalthenol, 10, and its epimer at C-19, 11, from ent-halimic acid as starting material has been carried out. The structure of the natural product polyalthenol 1 is confirmed in this way. The synthesized indole sesquiterpenes 10 and 11 and their acetylderivatives 32 and 33 inhibited cellular proliferation of a number of human leukaemic and solid tumour cell lines.     

Enantiopure hydroxylactones from d-xylose. A novel approach to the enantiodivergent synthesis of (+)- and (−)-muricatacin suitable for the preparation of 7-oxa analogues

A new route towards enantiopure hydroxylactones 3 and ent-3, the final chiral precursors in an enantiodivergent synthesis of (+)- and (−)-muricatacin, has been developed starting from d-xylose.     

Synthesis and absolute configuration of (−)-chettaphanin I and (−)-chettaphanin II

An efficient synthesis of chettaphanin I and II has been achieved from ent-halimic acid. The absolute configuration of the natural products was established by nOe experiment and by X-ray analysis of chettaphanin II.     

Toward the synthesis of 1′E-isomer of ent-hyptenolide

A short total synthesis of a diacetoxylated E,E-diene lactone ent-hyptenolide, was achieved involving from Phosphonate and cis-butene 1,4-diol. Brown Asymmetric allylation, Acrylation, Acetylation, Ring-closing metathesis as the key steps has been described. Moreover, the biological activity of ent-hyptenolide was evaluated on HeLa, A549, IMR32, and MDA-MB231 cancer cell lines. The ent-hyptenolide selectively and potently inhibited the growth of IMR32 cell line.     

Synthesis of quinone/hydroquinone sesquiterpenes

ent-Halimic acid has been used in the synthesis of the quinone/hydroquinone sesquiterpenes (−)-aureol, (−)-smenoqualone, (−)-neomamanuthaquinone and in the formal synthesis of (−)-cyclosmenospongine.     

Synthesis of tetrahedral diarylheptanoid ent-diospongin A and epimer-diospongin B by employing Julia–Kocienski olefination

Total synthesis of ent-diospongin A and epimer-diospongin B has been accomplished in good yield with high optical purity. The key steps of diospongin synthesis involve Julia–Kocienski olefination, Weinreb amide formation, Grignard reaction, reduction, acetonide deprotection, Lewis acid catalyzed cyclization, and Wacker oxidation.     

ent-Kaurene diterpenoids from Isodon phyllostachys

Four new ent-kaurene diterpenoids, phyllostachysins M–P (1–4) have been isolated from the aerial parts of Isodon phyllostachys. Compound 1 features a novel dihydro-2H-pyran ring motif, which was formed by an unusual cleavage in ring-A. 2 and 3 bear a rare 20-nor-ent-kaurene structure, but 4 has a rare 7,20-cyclo-ent-kaurene skeleton. Their structures were elucidated on the basis of extensive spectroscopic analyses. Compounds 1, 3, and 4 were evaluated for their cytotoxic activity against five human tumor cell lines.     

Total syntheses of chaetocin and ent-chaetocin

The first total synthesis of chaetocin (1), a potent histone methyltransferase inhibitor, is described in detail. Key reactions were radical bromination for α-oxidation of the diketopiperazine ring, and reductive radical coupling for construction of the dimeric core structure. Stereoselective construction of the disulfide bridges was achieved via substitution reaction with H₂S. The total synthesis of 1 was accomplished in nine steps starting from known d-amino acid derivatives. Total synthesis of non-natural ent-chaetocin (ent-1) was also achieved via the established synthetic route, starting from l-amino acid derivatives.     

N-Benzyloxymalimide for an easy access to 5-alkyl-3-pyrrolin-2-ones: asymmetric synthesis of the mixed imide substructure of the potent immunosuppressant microcolin B

O-Benzyl-N-benzyloxymalimide 12 has been synthesized as a useful variant of the chiral building blocks 9. The advantage of the malimide 12 over 9 was demonstrated by mild and high-yielding reductive N-deprotection of N-benzyloxylactams 18a–i to give a series of (4R,5S)-5-alkyl-4-hydroxy-pyrrolidin-2-ones, which are key intermediates for the asymmetric synthesis of pyrrolidines, pyrrolizidines, and indolizidines, as well as β-hydroxy γ-amino acids. Lactam ent-11a has been applied to the synthesis of the mixed imide 25, a key intermediate for the total synthesis of microcolin B, which also demonstrated that lactam ent-11a or 11a can serve as a latent form of the 5-methyl-3-pyrrolin-2-one substructure of majusculamide D 4, deoxymajusculamide D, and the jamaicamides A–C.     

New synthesis of diterpenoid (16<Emphasis Type="Italic">S</Emphasis>)-dihydrosteviol

A new procedure has been developed for the synthesis of diterpenoid (16S)-dihydrosteviol [(16S)-13-hydroxy-ent-kauran-19-oic acid] by acid hydrolysis (0.7% hydrochloric acid) of SWETA food sweetener and subsequent reduction of the resulting mixture of caurenoids with hydrazine hydrate over Raney nickel. The molecular geometry of (16S)-dihydrosteviol, as well as of Δ¹⁵-steviol (13-hydroxy-ent-kaur-15-en-19-oic acid), was determined for the first time by X-ray analysis.     

Total synthesis of (−)-jaspine B and its 4-epi-analogue from d-xylose

The total synthesis of the HCl salts of (−)-jaspine B ent-1 and its 4-epi-congener ent-4 was accomplished starting from the common template 13 derived from d-xylose. The cornerstone of our synthesis was [3,3]-heterosigmatropic rearrangements, which effectively provided scaffolds with a chiral amino group. A subsequent Wittig olefination installed a C₁₄ alkyl side chain and acid-mediated ring-closing reaction established the tetrahydrofuran core.     

A stereoselective total synthesis of the HCl salts of mycestericins F,G and ent-F

The total synthesis of the HCl salts of two natural sphingolipid-related amino acid derivatives, mycestericins F 4 and G 5 together with unnatural ent-4·HCl, starting from the four crucial scaffolds 6, 8, 9, 11 and utilizing the Wittig reaction to build the C₂₀ backbone, has been achieved. The selection of selective functional group interconversions accompanied with suitable protection–deprotection protocols in the coupling products 20 and 34 gave the desired structures.     

Stereoselective synthesis and anticancer activity of broussonetine analogues

The stereoselective synthesis of two broussonetine analogues 14·HCl and ent-14·HCl with differing stereochemistry of the polyhydroxylated pyrrolidine core and a simple C₁₃ alkyl fragment has been achieved. For their construction, the known oxazolidinones 15 and 16 were chosen as appropriate advanced scaffolds. The common hydrophobic side chain was incorporated at an early stage of the synthesis through Grubbs’ cross metathesis chemistry. The required pyrrolidine skeleton was then formed by the cyclization of open chain intermediates 17 and 18. Four synthesized compounds were screened in vitro for antiproliferative/cytotoxic activity against six cancer cell lines by MTT assay. Compounds 14·HCl (HeLa and A-549) and ent-14·HCl (Caco-2 and Jurkat) showed comparable or higher potency than conventional anticancer agent cisplatin on at least two evaluated cancer cells, respectively.