Total synthesis of the cytotoxic macrocycle (+)-hitachimycin

Abstract

The first total synthesis of the antitumor antibiotic (+)-hitachimycin (a.k.a. stubomycin) (1) has been achieved in 22 steps and 1.1% overall yield. The cornerstone of the synthetic strategy was a highly stereoselective three-component coupling of (-)-5-methoxycyclopentenone (4) with a zincate derived from vinyl iodide 3a and aldehyde (-)-51.

Gold(I)‐Catalysed Hydroarylation of Lactam‐Derived Enynes as an Entry to Tetrahydrobenzo[g]quinolines

“…On the other hand, when the tosyl group was replaced by a hydrogen, the free energy barrier dropped to 4.2 kcal mol –1 . On the basis of these results, we decided to remove the N ‐tosyl group of 9a by means of the radical anion sodium naphthalenide, obtaining the secondary amine 10a . The 1 H NMR spectrum of 10a (Figure , II ) clearly shows that the protons of the CH 2 groups are not split anymore, as rapid interconversion between the two enantiomers is now allowed.…”

“…Synthesis of 8‐Methoxy‐10‐methyl‐1,2,3,4‐tetrahydrobenzo[ g ]quinoline (10a): The N ‐tosyl deprotection was performed according to a literature procedure. [26a] A solution of 9a (1.0 Equation 0.2 mmol) in anhydrous DME (0.1 m ) was cooled down to –78 °C. A 1.0 m solution of Na and naphthalene (6.0 equiv.)…”

Total Synthesis of the Antitumor Acetogenin Mosin B (I): Desymmetrization Approach to the Stereodivergent Synthesis of threo/trans/erythro‐Type Acetogenins.

“…We therefore abandoned the coupling reaction of the aldehyde with the acetylide and planned an alternative route with the Nozaki ± Hiyama ± Kishi reaction. [21] Synthesis of the g-lactone segment 47 started from the known aldehyde 42 [22] prepared from d-glutamic acid, which was converted into a diol 43 by Takai×s olefination [23] followed by deacetalization. Selective triflation of the primary alcohol in 43 with Tf 2 O at À 50 8C and subsequent silylation of the secondary alcohol with TBSOTf at 0 8C were carried out in a one-pot reaction.…”

“…The mixture was extracted with EtOAc, and the extract was washed with water and brine prior to drying and solvent evaporation. The residue was purified by chromatography (hexane) to give 20 (13.5 (8R,9R,12R,13S)-8,13-Bis(tert-butyldimethylsilyloxy)-9,12-epoxytetaracosanal (22): NaIO 4 (187 mg, 0.876 mmol) was added to a stirred solution of 21 (274 mg, 0.416 mmol) in CH 2 Cl 2 /acetone/water (10:6:1, 9 mL) at 0 8C. After stirring at RT for 12 h, Et 2 O was added to the mixture.…”

Multicomponent Reactions in the Total Synthesis of Natural Products

“…In the early 1990s, Smith and co-workers reported on the total synthesis of the antitumor antibiotic macrolactam (þ)-hitachimycin 35 (Figure 12.1) using a Noyori three-component coupling to assemble the polysubstituted cyclopentane unit [24]. The jasmonates are another class of disubstituted cyclopentanoid natural products very reminiscent of the prostaglandins.…”