Solid-Phase Total Synthesis of Yaku'amide B Enabled by Traceless Staudinger Ligation

We report a solid-phase strategy for total synthesis of the peptidic natural product yaku'amide B ( 1 ), which exhibits antiproliferative activity against various cancer cells. Its linear tridecapeptide sequence bears four β,β-dialkylated α,β-dehydroamino acid residues and is capped with an N-terminal acyl group (NTA) and a C-terminal amine (CTA). To realize the Fmoc-based solid-phase synthesis of this complex structure, we developed new methods for enamide formation, enamide deprotection, and C-terminal modification. First, traceless Staudinger ligation enabled enamide formation between sterically encumbered alkenyl azides and newly designed phosphinophenol esters. Second, application of Eu(OTf)₃ led to chemoselective removal of the enamide Boc groups without detaching the resin linker. Finally, resin-cleavage and C-terminus modification were simultaneously achieved with an ester–amide exchange reaction using CTA and AlMe₃ to deliver 1 in 9.1 % overall yield (24 steps from the resin).     

Lobatamide C: total synthesis,stereochemical assignment,preparation of simplified analogues,and V-ATPase inhibition studies

The total synthesis and stereochemical assignment of the potent antitumor macrolide lobatamide C, as well as synthesis of simplified lobatamide analogues, is reported. Cu(I)-mediated enamide formation methodology has been developed to prepare the highly unsaturated enamide side chain of the natural product and analogues. A key fragment coupling employs base-mediated esterification of a beta-hydroxy acid and a salicylate cyanomethyl ester. Three additional stereoisomers of lobatamide C have been prepared using related synthetic routes. The stereochemistry at C8, C11, and C15 of lobatamide C was assigned by comparison of stereoisomers and X-ray analysis of a crystalline derivative. Synthetic lobatamide C, stereoisomers, and simplified analogues have been evaluated for inhibition of bovine chromaffin granule membrane V-ATPase. The salicylate phenol, enamide NH, and ortho-substitution of the salicylate ester have been shown to be important for V-ATPase inhibitory activity.     

Solid‐Phase Total Synthesis of Yaku'amide B Enabled by Traceless Staudinger Ligation

We report a solid‐phase strategy for total synthesis of the peptidic natural product yaku'amide B ( 1 ), which exhibits antiproliferative activity against various cancer cells. Its linear tridecapeptide sequence bears four β,β‐dialkylated α,β‐dehydroamino acid residues and is capped with an N‐terminal acyl group (NTA) and a C‐terminal amine (CTA). To realize the Fmoc‐based solid‐phase synthesis of this complex structure, we developed new methods for enamide formation, enamide deprotection, and C‐terminal modification. First, traceless Staudinger ligation enabled enamide formation between sterically encumbered alkenyl azides and newly designed phosphinophenol esters. Second, application of Eu(OTf)₃ led to chemoselective removal of the enamide Boc groups without detaching the resin linker. Finally, resin‐cleavage and C‐terminus modification were simultaneously achieved with an ester–amide exchange reaction using CTA and AlMe₃ to deliver 1 in 9.1 % overall yield (24 steps from the resin).     

Total synthesis of the cyclopeptide alkaloid paliurine E. insights into macrocyclization by ene--enamide RCM

The total synthesis of (-)-paliurine E is described in 14 steps and 11% overall yield. The first successful application of ene--enamide ring-closing metathesis for macrocyclization serves as the foundation for this synthesis and allowed for a straightforward installation of the challenging cyclic enamide together with the macrocycle. In the course of these synthetic studies, we also found that very subtle and minor structural modification of the enamide resulted in dramatic and unexpected changes of their reactivity since a primary amide or an aromatic aldehyde can be obtained after reaction with Grubbs' second-generation catalyst. Further insights on the macrocyclization by ene--enamide RCM are also discussed.     

Total synthesis and stereochemical assignment of the salicylate antitumor macrolide lobatamide C(1)

The total synthesis and stereochemical assignment of the potent antitumor macrolide lobatamide C is reported. The synthesis involves Cu(I)-mediated enamide formation and Na(2)CO(3)-mediated esterification of a beta-hydroxy acid and a salicylate cyanomethyl ester. Macrolactonization was accomplished using a Mitsunobu protocol. The stereochemical assignment of lobatamide C was achieved by Mosher ester analysis and comparison with prepared stereoisomers.     

Synthesis and cell cycle inhibition of the peptide enamide natural products terpeptin and the aspergillamides

Total syntheses of the peptide enamide natural products terpeptin and aspergillamides A and B are reported. An oxidative decarboxylation-elimination protocol is employed to construct the indolic enamide moiety. Unambiguous stereochemical assignment of (−)-terpeptin is accomplished by synthesis of all possible stereochemical analogues. Select compounds have been evaluated in cell cycle inhibitor assays which show that the natural amino acid configuration of terpeptin has the most potent inhibitory activity.     

Studies on the syntheses of heterocyclic and natural products. Part 979. Attempted asymmetric synthesis of yohimbol by photocyclization of the enamide

An asymmetric synthesis of yohimbane alkaloid has been attempted by the photolysis of the corresponding enamide ( 3 ) as a key reaction.     

Solution- and solid-phase synthesis of natural product-like tetrahydroquinoline-based polycyclics having a medium size ring

A solid-phase synthesis of tetrahydroquinoline-derived polycyclic 4, having a medium size ring with an enamide functionality, was achieved from tetrahydroquinoline derivative 3 in five steps with overall 40-45% yield. An enantiopure, tetrahydroquinoline-derived beta-amino ester, 1, was converted into compound 2 that has a free phenolic hydroxyl group as an anchoring site for solid-phase synthesis. The solid-phase worked well for this sequence, in which the synthesis of the unsaturated eight-membered enamide lactam was obtained by a ring-closing metathesis approach. Compound 4 is a novel, natural product-like polycyclic derivative that could further be utilized in library generation for developing small molecule chemical probes.     

Practical solid-phase parallel synthesis of Delta(5)-2-oxopiperazines via N-acyliminium ion cyclization

A practical solid-phase strategy for the synthesis of Delta(5)-2-oxopiperazines via N-acyliminium ion cyclization has been developed. A key step in the library synthesis is tandem acidolytic cleavage with subsequent in situ iminium formation, followed by stable enamide transformation. This approach is exemplified by the preparation of a 192-member pilot library using bromoacetal resins without further purification.     

A new type of corrin synthesis

Work towards a synthesis of vitamin B₁₂ has inspired a new type of corrin synthesis. The key step is a light-induced 1,16-hydrogen transfer leading to an antarafacial (π→σ)-cycloisomerization of a seco-corrinoid metal complex. The construction of the seco-corrinoid ligand system is achieved by coupling monocyclic ring precursors in their enamide or enamine form through the methods of sulfide-contraction via oxidative coupling and of iminoester-enamine condensation.     

A new entry to the synthesis of substituted azetidines: [2+2] cycloaddition reaction of four-membered endocyclic enamides to ketenes

The first example of a [2+2] cycloaddition reaction of a four-membered endocyclic enamide (2-azetine) to dichloroketene is described and constitutes a new entry to the synthesis of substituted azetidines. Preliminary studies concerning the Baeyer-Villiger oxidation of the [2+2] cycloadduct revealed an unusual regioselectivity. The synthesis of a new azetidine-3-carboxylic acid derivative from the [2+2] cycloadduct is also presented.     

Diastereoselective synthesis of (2S,5R)-5-hydroxypipecolic acid and 6-substituted derivatives

[reaction: see text] Herein, we report a diastereoselective synthesis of the natural product (2S,5R)-5-hydroxypipecolic acid and 6-substituted derivatives thereof. The key step in the synthetic sequence is a novel highly diastereoselective epoxidation reaction of an enantiomerically pure cyclic enamide intermediate.     

Synthesis of ent-alantrypinone.

This paper presents a synthesis of ent-alantrypinone (ent-6), the enantiomer of a natural product produced by the fungus Penicillium thymicola. The synthesis revolves around the Li[Me(3)AlSPh]-promoted isomerization of iminobenzoxazine 33 to quinazolinone 34, an N-acyliminium ion cyclization that converts enamide 9 to bridged indole 35, and rearrangement of 35 to oxindole ent-6. Ancillary chemistry that involves thermal fragmentation of an iminobenzoxazine to a nitrile ylide and Me(2)AlSPh-mediated cyclization of oxime ether-ester 22 to pyrrolidinone 23 is also described.     

Total synthesis of an oxepine natural product, (±)-janoxepin

The total synthesis of (±)-janoxepin, a novel antiplasmodial d-leucine derived oxepine-pyrimidinone-ketopiperazine isolated from the fungus Aspergillus janus, is described. The cornerstones of the synthetic route are pyrimidinone preparation, ring-closing metathesis, aldol introduction of the enamide, and dihydro-oxepine elaboration. This synthetic route proved very efficient for the formation of a number of janoxepin analogues, including dihydro-janoxepin and tetrahydro-janoxepin.     

An improved synthesis of cis-4-phenyl-2-propionamidotetralin (4-P-PDOT): a selective MT(2) melatonin receptor antagonist

A novel, efficient and diastereoselective procedure was developed for the gram-scale synthesis of cis-4-phenyl-2-propionamidotetralin (4-P-PDOT), a selective MT(2) melatonin receptor antagonist. The synthetic strategy involved the conversion of 4-phenyl-2-tetralone to enamide followed by diastereoselective reduction affording cis-4-P-PDOT in good yield. The mechanism of the reduction step was explored by employing deuterated reagents.     

Expedient asymmetric synthesis of all four isomers of N,N'-protected 2,3-diaminobutanoic acid

2,3-Diaminobutanoic acid (DAB) is found in several peptide antibiotics, toxins, and biologically active molecules. This paper describes the practical and highly enantioselective synthesis of all four N,N'-protected DAB stereoisomers using an asymmetric Rh(I)-phosphine-catalyzed hydrogenation of isomeric enamides as the key step. Thermal and photochemical isomerization of the enamide hydrogenation substrates coupled with catalyst-geometric isomer pairing allows targeted synthesis of single DAB isomers in maximum yield.     

Efficient synthesis of a trisubstituted 1,6-naphthyridone from acetonedicarboxylate and regioselective Suzuki arylation

[reaction: see text] An efficient five-step synthesis of 1,6-naphthyridone 3b, a p38 mitogen-activated protein (MAP) kinase inhibitor intermediate, in 32% overall yield starting from acetonedicarboxylate (ADC) is described. The synthesis began with a selective monoamidation of ADC dimethyl ester enolate 9. A novel concomitant enamine formation and an imide cyclization afforded the nitrogen differentially protected enamide imide 12. Treatment of 12 with KO(t)Bu and 3-ethoxyacrylate produced lactam 15 quantitatively, which was converted to tetrachloronaphthyridone 19 via a one-pot p-methoxybenzyl (PMB) deprotection and bischlorination. A highly regioselective Pd(OAc)2/IMes-catalyzed Suzuki coupling completed the synthesis.     

Synthesis of 7,6‐Fused Bicyclic Lactams for Use as Beta‐Turn Mimics

An improved synthesis of the 7,6‐fused bicyclic lactam is presented starting from readily available chiral starting materials. (S)‐allylglycine is protected as the phthalimide derivative and coupled with (S)‐2‐amino‐6‐hydroxyhexanoic acid methyl ester. Oxidation of the hydroxyl group to the aldehyde followed by enamide synthesis and acyl iminium ion cyclization provide the bicyclic system as a single diastereomer in good overall yield.     

Synthetic studies on chartelline C: stereoselective construction of the core skeleton

What a core-ker! The title synthesis was achieved using a route featuring an intramolecular Mitsunobu reaction of a nosyl amide, stereoselective construction of the β-lactam, and formation of an enamide moiety by selenoxide elimination. The stereochemistry of the alkylation for the formation of the β-lactam was controlled by a secondary hydroxy group on the ten-membered ring. SEM=2-(trimethylsilyl)ethoxymethyl; TBS=tert-butyldimethylsilyl.     

Stereospecific total synthesis of somocystinamide A

The first total synthesis of somocystinamide A, a disulfide dimer with extremely labile enamide functional groups, was accomplished in a concise and stereospecific manner. Somocystinamide A is reported to possess exceptionally potent antiangiogenic and tumoricidal activities. The current work should enable further pharmacological investigation of this important natural product.