Total synthesis and reassignment of stereochemistry of obyanamide

The total synthesis of a marine cytotoxic cyclic depsipeptide obyanamide is reported. The synthesis has led to a reassignment of the C-3 configuration in β-amino acid residue. And this revision is also supported by biological test.     

The first total synthesis and reassignment of the relative stereochemistry of 16-hydroxy-16,22-dihydroapparicine

We report the first total synthesis and reassignment of the relative stereochemistry of naturally occurring 16-hydroxy-16,22-dihydroapparicine. Our novel route proceeds by a cascade reaction to efficiently construct a 1-azabicyclo[4.2.2]decane core, along with two stereocenters (C-15 and C-16). The C-16 quaternary carbon was constructed through stereospecific 1,2-addition using an indole nucleophile to an aldehyde or a methylketone. The stereospecific synthesis of two diastereomers of the target product has revealed the true relative stereochemistry of the natural compound.     

The absolute stereochemistry of grenadamide

3-(2S-Heptylcycloprop-1S-yl)propanoic acid 2-phenylethanamide was synthesised from cis-cyclopropan-1,2-dimethanol via enzymatic desymmetrisation of the dibutyrate; it gave identical NMR spectroscopic data to those reported for grenadamide but had an equal and opposite absolute rotation, indicating that the latter is the 2R,1R-enantiomer.     

First total synthesis of (-)-achilleol B: reassignment of its relative stereochemistry

The first total synthesis of (-)-achilleol B was achieved using a convergent approach with a longest linear sequence of 14 steps. Three key steps were employed, including an enantioselective Robinson annelation for the construction of the bicyclic moiety. The monocyclic synthon was prepared through a Ti(III)-mediated cylization of a chiral monoepoxide obtained via asymmetric dihydroxylation of geranylacetone. The asymmetric preparation of these subunits also permitted us to achieve the enantioselective synthesis of elegansidiol, achilleol A, and farnesiferol B.     

Diverted total synthesis of falcitidin acyl tetrapeptides as new antimalarial leads

We report not only the convergent total synthesis of falcitidin, a natural inhibitor of falcipain-2 from myxobacterium Chitinophaga, but also its diversification into a new antimalarial class of N-acyl tetrapeptides (Acyl-His-Ile-Val-Pro-NH₂). Despite the lack of whole-cell activity of falcitidin itself, our study led to the identification of a trifluoromethyl (CF₃) analogue displaying sub-micromolar IC₅₀ activity against Plasmodium falciparum 3D7 in a standard blood-cell assay, but only when N-tritylated on its histidine (imidazole) residue.     

Stereoselective total syntheses and reassignment of stereochemistry of the freshwater cyanobacterial hepatotoxins cylindrospermopsin and 7-epicylindrospermopsin

A stereoselective total synthesis of the structure 1 proposed for the freshwater cyanobacterial heptatotoxin cylindrospermopsin has been accomplished in approximately 30 operations starting from commercially available 4-methoxypyridine. Utilizing methodology developed by Comins, the tetrasubstituted piperidine A-ring unit of the hepatotoxin was efficiently constructed. The two remaining stereocenters in the natural product were then set by a stereospecific intramolecular N-sulfinylurea Diels-Alder cyclization/Grignard ring opening/allylic sulfoxide [2,3]-sigmatropic rearrangement sequence previously developed in these laboratories, leading to key intermediate 29. The stereochemical assignment of alcohol 29, which contains all six of the stereogenic centers of the natural product, was confirmed by an X-ray crystal structure determination of a derivative. Installation of the D-ring uracil moiety was effected by using our new methodology developed for this purpose, and construction of the C-ring guanidine completed the total synthesis of racemic structure 1. However, the (1)H NMR data for this compound do not match that of cylindrospermopsin, but instead agree with the data reported for 7-epicylindrospermopsin, a minor toxic metabolite that co-occurs with cylindrospermopsin. Therefore, we propose a revision of the stereochemical assignments of these natural products such that cylindrospermopsin is now represented as structure 2 and 7-epicylindrospermopsin is 1. This reassignment was further confirmed by Mitsunobu inversion of the C-7 alcohol 51 to epimer 52, and conversion of this compound to tetracyclic diol 57, which has previously been transformed to cylindrospermopsin (2).     

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.     

Total synthesis of the proposed structure for spirofungin B: a reassignment of the stereochemistry

[structure: see text] The total synthesis of the proposed structure for spirofungin B (2) is described. The data for the synthetic material did not compare with that for the natural product leading to the conclusion that the structure 2 assigned for spirofungin B is incorrect. Analysis of the NMR data reported for spirofungins A and B as well as related spiroketals allowed for the reassignment of the stereochemistry of spirofungin B to be that corresponding to 15-epi-spirofungin A (27).     

First total synthesis and assignment of the stereochemistry of crispatenine

The first racemic and enantioselective synthesis of crispatenine 1 has been achieved, which involved a few steps, enabling the assignment of the absolute and relative configurations.     

First total synthesis and reassignment of absolute configuration of diosniponol A and B

Enantioselective first total synthesis of diosniponol A and B has been achieved starting from commercially available vanillin. Wittig reaction, Keck allylation, and Prins cyclization reactions are the key steps involved in the target synthesis.     

Studies on the stereochemistry of 1,2,6-trimethyl-4-piperidone

In the effort to create new derivatives of analgesically active spiropiperidines intermediate 1,2,6-trimethyl-4-piperidone was synthesized. The substitution of the skeleton gives rise to configurational as well as conformational isomerism. Despite the symmetry of 1,2,6-trimethyl-4-piperidone two different sets of signals were present in the ¹H and ¹³C NMR spectra. They were supposed to arise from a cis/trans mixture of 1,2,6-trimethyl-4-piperidone. In contrast to this explanation only two signals of the methyl groups and hydrogens at carbon atoms 2 and 6 were observed in the ¹H and ¹³C NMR spectra, normally expecting one for the cis- and two for the trans-isomer. To solve this discrepancy, the kind of isomeric mixture of 1,2,6-trimethyl-4-piperidone leading to the ¹H and ¹³C NMR spectra was examined. Energy differences between chair conformations of both the cis- and the trans-isomer of 1,2,6-trimethyl-4-piperidone and the potential energy surface of the equilibration process of the trans-isomer of 1,2,6-trimethyl-4-piperidone between its chair conformers were determined by quantum chemical calculations. The barrier height of the equilibration process was measured by high and low temperature NMR measurements to confirm the theoretical outcome. The results of all investigations agree nicely and proved a cis-/trans-mixture of 1,2,6-trimethyl-4-piperidone being present at room temperature.     

Michael reaction,VI. Effect of carbonyl compounds on the stereochemistry and mechanism of the reaction

Zusammenfassung Die Stereochemie einer zweistufigen Gleichgewichts-Michael-Reaktion zwischen Dialkylamiden der Phenylessigsäure und Methylestern oder Dialkylamiden der Zimtsäure wird von den neutralen Carbonylverbindungen stark beeinflußt. Dieser Effekt kann mit der Zerstörung einer intramolekularen Chelatstruktur des Addukts und der darauffolgenden Bildung einer offenen Metallform mit einem dem neutralen Addukt ähnlichenerythro-threo-Verhältnis erklärt werden. Die Zunahme der elektrischen Leitfähigkeit des Reaktionsgemisches stützt diese Vorstellung.Es wird ein über das Chelat verlaufender Mechanismus im nichtpolaren Medium postuliert. Dieser Mechanismus ist in guter Übereinstimmung sowohl mit der geringen Stereoselektivität (bei kinetischer Kontrolle) als auch mit dem Einfluß der Lösungsmittel auf die Stereochemie.

---

Michael reaction, VI. Effect of carbonyl compounds on the stereochemistry and mechanism of the reaction

The equilibrium stereochemical result of the two-stepMichael reaction between phenylacetic acid dialkylamides and methyl cinnamate or cinnamic acid dialkylamides is affected by the neutral carbonyl compounds taking part in the synthesis. This effect is explained by breakdown of the intramolecular chelate structure of the reaction adduct and appearance of an open metal form with isomeric partitioning close to that of the neutral adduct. This is further supported by the increased electroconductivity of the reaction mixtures. A chelate mechanism for the reaction in nonpolar medium is postulated which is in good agreement with the low stereoselectivity under kinetic conditions as well as with the effect of the polarity of the solvent on the kinetic stereochemical result.

     

Epimerization and kinetic protonation as factors determining the stereochemistry of the Michael reaction

Summary Model compounds in which the only possibility for isomerization is epimerization were synthesized. They undergo isomerization under the conditions widely used in the Michael addition. Conclusions are drawn as to the possibilities for epimerization or kinetic protonation in the actual Michael adducts.

---

Epimerisierung und kinetische Protonierung als Faktoren der Stereochemie der Michael-Reaktion

Zusammenfassung Modellverbindungen, bei denen nur eine C-2 Epimerisierung möglich ist, wurden synthetisiert und einer Isomerisierung bei verschiedenen Reaktionsbedingungen unterworfen. Die Epimerisierung und kinetische Protonierung der Michaeladdukte wird diskutiert.

     

Assignment of absolute stereochemistry and total synthesis of (-)-spongidepsin

[structure: see text] An enantioselective total synthesis of (-)-spongidepsin (2) and elucidation of the absolute stereochemistry of its four stereocenters are described. Spongidepsin (2), a 13-membered depsipeptide isolated from the Vanuatu marine sponge Spongia sp., has shown potent antitumor properties against a variety of NCI tumor cell lines. Our synthesis is convergent, and the absolute stereochemistry of four of the five chiral centers was assigned through synthesis.     

First asymmetric total synthesis of (+)-steganacin determination of absolute stereochemistry

(+)-Steganacin was synthesized in a new and highly specific asymmetric pathway based on the novel application of chiral γ-lactone as a chiral synthon. By this synthesis the absolute stereochemistry of natural (?)-steganacin could be determined in unequivocal way.     

Reassigning the stereochemistry of bioactive cepharanthine using calculated versus experimental chiroptical spectroscopies

The absolute configuration of cepharanthine (1), a strongly bioactive bisbenzylisoquinoline alkaloid exhibiting 12 specific bioactivities without any reported negative side-effects, has been reassigned from (1R,1′S) to (1R,1′R) using quantum theory. The absolute configurations (ACs) of 13 other analogues of 1 were also systematically reassigned. Six quaternary salts were prepared from 1 and one exhibited strong anti-bacterial activity against Bacillus subtilis with MIC 0.31?μM, while Ciprofloxacin, the positive control medicine was 3.88?μM. This work established the critical importance of correlating chiroptical experimental spectra with their quantum mechanically predicted spectra for accurate stereogenic center assignments.     

The naturally occurring ketene acetal benesudon: total synthesis and assignment of relative and absolute stereochemistry

The densely functionalized ketene acetal benesudon, which is a bioactive fungal metabolite, was synthesized from D-glucose by a route involving radical cyclization to form the five-membered ring, and oxidative decarboxylation to generate the key central double bond. The originally suggested stereochemistry for the quaternary center C(5) must be revised, as both C(5) epimers were prepared and a comparison with an authentic sample was made. The absolute configuration of benesudon is 4S,5R,6S.     

Unexpected epimerization and stereochemistry revision of IMDA adducts from sorbate-related 1,3,8-nonatrienes

Intramolecular Diels-Alder (IMDA) reaction of two sorbate-related 1,3,8-nonatrienes has been investigated in MeCN at 180 °C for 1.5 h under controlled microwave heating. On checking the crude product mixture before purification, partial epimerization of the major adduct was found during the reaction. After column chromatographic purification over silica gel, only two cis adducts were obtained and their structures have been thoroughly established by X-ray crystallographic analysis. It is concluded that the putative major trans adduct predicted by the IMDA reaction mechanism undergoes facile epimerization at high temperature or in the presence of silica gel. Structural revision on the adducts has been made.