Synthesis of Obyanamide, a Marine Cytotoxic Cyclic Depsipeptide

Obyanamide 1 is a cyclic depsipeptide that was recently isolated from the marine cyanobacterium Lyngbya confervoides by Moore and co-workers1. This compound displayed a potent inhibitory effect on both KB and LoVo cells in vitro. Several structural analog…     

Stereochemical Assignment of the Protein–Protein Interaction Inhibitor JBIR‐22 by Total Synthesis

Recent reports have highlighted the biological activity associated with a subfamily of the tetramic acid class of natural products. Despite the fact that members of this subfamily act as protein–protein interaction inhibitors that are of relevance to proteasome assembly, no synthetic work has been reported. This may be due to the fact that this subfamily contains an unnatural 4,4‐disubstitued glutamic acid, the synthesis of which provides a key challenge. A highly stereoselective route to a masked form of this unnatural amino acid now enabled the synthesis of two of the possible diastereomers of JBIR‐22 and allowed the assignment of its relative and absolute stereochemistry.     

Total Synthesis and Structure Correction of the Cyclic Lipodepsipeptide Orfamide A

A total synthesis of the cyclic lipodepsipeptide natural product orfamide A was achieved. By developing a synthesis format using an aminoacid ester building block and SPPS protocol adaptation, a focused library of target compounds was obtained, in high yield and purity. Spectral and LC-HRMS data of all library members with the isolated natural product identified the ⁵Leu residue to be d - and the 3’-OH group to be R-configured. The structural correction of orfamide A by chemical synthesis and analysis was confirmed by biological activity comparison in Chlamydomonas reinhardtii, which indicated compound configuration to be important for bioactivity. Acute toxicity was also found against Trypanosoma brucei, the parasite causing African sleeping sickness.     

Expedient Synthesis of (+)‐Lycopalhine A

Two amino acids play a key role in the first total synthesis of lycopalhine A. l ‐glutamic acid serves as a convenient chiral starting material for the 13‐step synthesis, and l ‐proline promotes an unusual 5‐endo‐trig Mannich cyclization that generates the central pyrrolidine ring of the Lycopodium alkaloid. The bicyclo[3.3.0]octanol moiety of the molecule is formed through an intramolecular aldol addition that may occur spontaneously in nature.     

A General Strategy for the Catalytic,Highly Enantio‐ and Diastereoselective Synthesis of Indolizidine‐Based Alkaloids

Sixteen indolizidine‐based alkaloids (IBAs) that were isolated as poison constituents of the skin of frogs were synthesized in a highly flexible and stereoselective manner. As a key step, a three‐component, organocatalytic, highly enantio‐ and diastereoselective vinylogous Mukaiyama–Mannich reaction was employed furnishing optically highly enriched butyrolactams as central intermediates on a multigram scale. The attached six‐membered ring was constructed through cyclization of the pendant enoate moiety onto the pyrrolidine ring. The absolute configuration of the bridgehead chiral center and the adjacent 8‐position was established in the initial vinylogous Mannich reaction, whereas the 3‐ and 5‐substituents were introduced through organometallic addition at a late stage of the synthesis with full stereochemical control from the substrate. With this strategy, simple as well as even more complex alkaloids were accessible in good overall yields as single stereoisomers. These syntheses also served to establish the absolute and relative configuration of those IBAs that had never been synthesized before.     

Total synthesis of (+)-blasticidin s

The first total synthesis of the peptidyl nucleoside antibiotic, blasticidin S (1), has been achieved by the coupling reaction of cytosinine (3) and blastidic acid (2). A key step in the synthesis of cytosinine (3) is the sigmatropic rearrangement of allyl cyanate 24; this reaction provided efficient and stereoselective access to 2,3-dideoxy-4-amino-D-hex-2-enopyranose (26 a). Further elaboration of 26 a gave methyl hex-2-enopyranouronate 29, and cytosine N-glycosylation of 31 using the Vorbrüggen conditions for the silyl Hilbert-Johnson reaction furnished the differentially protected cytosinine (32) in 11 steps from 2-acetoxy-D-glucal (14) (4.0 % overall yield). Synthesis of the Boc-protected blastidic acid 47 in nine steps starting from chiral carboxylic acid 35 (23 % overall yield) utilized Weinreb's protocol for the preparation of benzyl amide 38 and Fukuyama's protocol for the synthesis of the secondary amine 40. Assembly of the protected cytosinine (32) and blastidic acid (47) by the BOP method in the presence of HOBt, and finally elaboration to 1 by deprotection of the fully protected 54 established the total synthesis of blasticidin S (1).     

Total Synthesis and Configurational Assignment of Chondramide A

The first total synthesis of the cyclodepsipeptide chondramide A ( 2 b ) is described. This depsipeptide is composed of four subunits, namely L ‐alanine, N‐Me‐D ‐tryptophan, 3‐amino‐2‐methoxy‐propionic acid (β‐tyrosine derivative), and a 7‐hydroxy‐alkenoic acid. While the configuration of the stereogenic centers in the 7‐hydroxy‐alkenoic acid were known, the configuration of the tyrosine derivative required clarification and turned out to be (2S,3R) or (2L ,3L ), respectively. The synthesis of the 3‐amino‐2‐methoxy‐3‐arylpropanoic ester 20 b relied on an asymmetric dihydroxylation yielding diol ent‐ 15 a followed by a regioselective Mitsunobu substitution leading to 3‐azido‐2‐hydroxypropanoate 18 b . We could also show that the ester bond in the seco compound 26 b can be fashioned by a Mitsunobu esterification by using hydroxy ester (7S)‐ 7 and the tripeptide acid 25 b . This synthesis should allow for the preparation of various analogues.     

Aminotenuazonic Acid: Isolation,Structure Elucidation,Total Synthesis and Herbicidal Activity of a New Tetramic Acid from Fruiting Bodies of Laccaria Species

(5S,6S)-Aminotenuazonic acid, a new 3-acyltetramic acid, related to the well-known mycotoxin tenuazonic acid has been isolated from fruiting bodies of Laccaria bicolor. Its structure was mostly established by analysis of its 2D NMR and HR-(+)-ESI-MS spectra. A total synthesis starting from N-Boc-l -isoleucine gave (5S,6S)-aminotenuazonic acid in 8 % yield over nine steps (67 % de). The key steps of the total synthesis are a light-initiated Hofmann–Löffler–Freytag radical chain reaction and a Dieckmann cyclisation. The relative and absolute configurations of the natural product were determined by comparison of its NMR and CD spectra with those of the corresponding enantiopure synthetic compounds. Metabolic profiling of crude extracts of different mushrooms showed that aminotenuazonic acid is present in all four of the investigated Laccaria species. Aminotenuazonic acid shows phytotoxic activities against the root and shoot growth of Lepidium sativum, Pinus sylvestris and Arabidopsis thaliana comparable to those of tenuazonic acid.     

Synthesis of jasplakinolide analogues containing a novel omega-amino acid

The synthesis of the omega-amino acid 4 is described utilizing a two-dimensional synthesis strategy combined with an enzymatic differentiation of homotopic ester groups. The amino acid 4 features two non-bonded interactions that result in conformational constraints on a cyclic construct. This amino acid was incorporated into the four macrolactams 17, 22, 31, and 37. The ring in 17 and 22 is 18-membered, whereas 31 and 37 have a 19-membered ring. The pairs with the same ring size differ in a N-methyl group. For the larger macrolactams (31 and 37) conformational analysis showed that the macrocyclic rings are somewhat more rigid than in the natural lead, the depsipeptide jasplakinolide. Nevertheless, their conformations are comparable to the natural product. There are no intramolecular hydrogen bonds, neither is the cis-rotamer populated in the N-methyl compound 37. Due to the increased flexibility of the smaller macrolactams 17 and 22 and signal overlap, a distinct solution structure could not be obtained for these compounds. The amino acid 4 should be useful for restricting the conformation of other small peptides.     

Total Synthesis of the Hamigerans

The first total synthesis of hamigerans D, G, L, and N–Q has been accomplished. A convergent approach was used to build the basic tricarbocyclic ring system bearing a 5‐6‐6 structure. A sequence of oxidative cleavage, homologation, and ring regeneration provided access to the 5‐7‐6 skeleton of hamigeran G. Based on the biogenetic hypothesis, elegant and highly efficient biomimetic transformations of hamigeran G into hamigerans D, N–Q, and L were achieved.     

A First Total Synthesis of Ganglioside HLG‐2

A neuritegenic ganglioside from sea cucumber , HLG‐2 (see figure), has been synthesized for the first time. The unique tandem of sialic acids, Neu5Gc‐α(2,4)‐NeuAc, was established by the combination of a reactive N‐Troc sialyl donor and a 1,5‐lactamized sialyl acceptor. The ceramide counterpart was assembled in a stereoselective manner. Direct connection of the trisaccharide and the ceramide successfully afforded a precursor of HLG‐2, which was converted to ganglioside HLG‐2 in pure form.

     

Phormidolides B and C,Cytotoxic Agents from the Sea: Enantioselective Synthesis of the Macrocyclic Core

New cytotoxic polyketide macrolides named phormidolides B and C were isolated from a marine sponge of the Petrosiidae family collected off the coast of Pemba (Tanzania). The isolation, structure elucidation, and enantioselective synthesis of three diastereomers of the macrocyclic core is described herein. The described synthetic methodology started from 2‐deoxy‐D ‐ribose or 2‐deoxy‐L ‐ribose and afforded the desired macrocycles with high enantiomeric purity. The key step of the synthesis is the formation of the Z‐trisubstituted double bond using a Julia–Kocienski olefination. The versatility of the synthetic methodology may provide access to other enantiopure macrocycles by making changes in the starting materials or chiral inductors.