Synthesis of the Cytotrienin A Core via Metal Catalyzed C−C Coupling

Abstract

A synthetic approach to the C17-benzene ansamycins via metal catalyzed C-C coupling is described. Key bond formations include direct iridium catalyzed carbonyl crotylation from the alcohol oxidation level followed by chelation-controlled Sakurai-Seyferth dienylation to form the stereotriad, which is attached to the arene via Suzuki cross-coupling. The diene-containing carboxylic acid is prepared using rhodium catalyzed acetylene-aldehyde reductive C-C coupling mediated by gaseous hydrogen. Finally, RCM delivers the cytotrienin core.Beginning with the discovery of the antibacterial rifamycin B, ansamycin antibiotics continue to evoke interest as antibiotic and antineoplastic agents. 1 An important ansamycin subclass is represented by the ansatrienins, which are classified as triene-containing C17-benzene ansamycins. Members of this subclass, which are produced from various Steptomyces and Bacillus species, include the mycotrienins and mycotrienols, 2 the trienomycins 3 and the cytotrienins (Figure 1).4 Whereas the mycotrienins exhibit potent anti-fungal activity,2d,e the trienomycins and cytotrienins display antineoplastic properties. 3a ,5 For example, cytotrienin A induces apoptosis in human acute promyelocytic leukemia HL-60 cells (ED50 = 7.7 nM). 5c Following their stereochemical assignment,6 total syntheses of trienomycins A and F and thiazinotrienomycin E were reported by Smith, 7a-c total syntheses of mycotrienol I and mycotrienin I were reported by Panek7d,e and a total synthesis of cytotrienin A was reported by Hayashi. 7f Finally, Kirschning and Panek reported syntheses of the ansatrienol and cytotrienin cores, respectively. 8 Here, we report initial efforts toward the development of a synthetic approach to triene-containing C17-benzene ansamycins featuring C-C bond forming hydrogenations and transfer hydrogenations developed in our laboratory. 9 Retrosynthetically, it was envisioned that diverse C17-benzene ansamycins may be accessed through modular assembly of fragments A-D. Specifically, Suzuki cross-coupling of vinyl bromide A and the organoboron building block B would deliver an arene-containing C11-C17 substructure. Chelation-controlled pentadienylation of the latent C11-aldehyde employing reagent C followed by reduction of the nitroarene and amidation of the resulting mkrische@mail.utexas.edu. Supporting Information Available. Characterization data for all new compounds ( 1 H NMR, 13 C NMR, IR, HRMS, [α]). This material is available free of charge via the internet at http://pubs.acs.org. High levels of anti-diastereo-and enantioselectivity are obtained using the isolated orthocyclometallated iridium C,O-benzoate precatalyst modified by (S)-SEGPHOS. As efforts toward corresponding syn-diastereoselective processes are underway, 11d the present firstgeneration synthesis requires conversion of the anti-adduct to the syn-diastereomer via Mitsunobu inversion employing p-nitrobenzoic acid 12 to deliver the crystalline pnitrobenzoate 3. Saponification of 3 followed by Williamson ether synthesis p...

Macrocyclic Drugs and Synthetic Methodologies toward Macrocycles

“…Cytotrienins A–D ( 63 – 66 , Scheme 18), new ansamycin compounds, possess an unique E,E,E -triene motif and four chiral centers, constituting a 21-membered macrocyclic lactam. Based on their challenging structure and promising biological activity, cytotrienins were synthesized using different strategies by the Panek [158], Krische [159], and Hiyashi [160] groups, but the RCM reaction constituted a pivotal step of constructing this macrocyclic lactam from the E,E,E -triene motif. Panek commenced the RCM macrocyclization from the bis-1,3-diene 68 fragment (Scheme 18) [161].…”

“…On the other hand, Krische and coworkers employed hydrogen-mediated Suzuki-coupling reaction of bromoalkene and pinacol borane to facilitate the formation of the C16-C17 bond (Scheme 19) [159]. Following several transformations, the key precursor bis(diene) 69 was obtained.…”

Metallacycle-mediated cross-coupling in natural product synthesis

“…Nevertheless, this reaction proved to be part of an effective strategy to generate trienomycin A and F, as well as the core of cytotrienin A (not depicted). 118 …”

Synthesis of an Advanced Fragment of (+)-Trienomycinol

“…BuLi (1.6 M in hexanes, Aldrich) was used as solution and its concentration was determined following the Wittig-Harborth Double Titration method [(total base) -(residual base after reaction with 1,2-dibromoethane)]. 23 NMR spectra were recorded on Bruker Avance 300 ( 1 H NMR, 300 MHz; 13 C NMR, 75.5 MHz) and Bruker Avance 400 ( 1 H NMR, 400 MHz; 13 C NMR, 100.6 MHz). Chemical shifts were referred on partial deuterated chloroform (δ H = 7.26 and accordingly δ C = 77.06) and given in ppm on the δ scale.…”

“…9 Total synthesis of different members of ansatrienins have been also described by Panek,5b,10 Hayashi, 11 Kirschning, 12 and Krische. 13 A series of SAR studies were performed to screen the most active parts of the triene ansamycins. These results indicate that the stereotriad C11-C13, the methyl group at C14, and the stereogenic methoxy group at C3 are essential.…”