157733-19-2Relevant academic research and scientific papers
Total synthesis of myxovirescin A1
Fuerstner, Alois,Bonnekessel, Melanie,Blank, Jarred T.,Radkowski, Karin,Seidel, Guenter,Lacombe, Fabrice,Gabor, Barbara,Mynott, Richard
, p. 8762 - 8783 (2007)
A convergent total synthesis of the antibiotic macrolide myxovirescin A1 (1) is described that is largely based on reagent- and catalyst-controlled transformations. This includes a highly regioselective Negishi reaction of dibromo-alkene 48 with an alkynyl-zinc reagent, and a palladium catalyzed alkyl-Suzuki coupling of the resulting enyne derivative 12 with the 9-BBN-adduct derived from alkene 61. The latter was obtained via an asymmetric hydrogenation of the chlorinated β-ketoester 49 and an anti-selective oxyallylation of the functionalized aldehyde 53 as the key steps. The preparation of the bis-borylated allyl-donor 57 used in the oxyallylation step, however, required careful optimization and led to important insights into the nature of the classical hydroborating agent "di(isopinocampheyl)borane (IpC2BH)". It was unambiguously shown by X-ray crystallography that in the solid state this compound is dimeric, but it is prone to undergo an essentially quantitative mono-deborylation when dissolved in CH 2Cl2 or benzene; its composition in ethereal solvents is even more complex as evident from 11B NMR data. Product 71 derived from 12 and 61 was elaborated into the enyne-yne derivative 75, which served as the substrate for an exquisitely selective ring closing alkyne metathesis reaction (RCAM) catalyzed by the molybdenum tris-amido complex 20 activated in situ with CH2Cl2. The resulting cyclic enyne 76 was subjected to a ruthenium catalyzed trans-hydrosilylation/proto-desilylation tandem. Although [Cp*Ru(MeCN)3]PF6 had previously been recommended as catalyst of choice for trans-hydrosilylation reactions of internal alkynes, this complex failed to afford the desired product, whereas its sterically less hindered congener [CpRu(MeCN)3]PF6 permitted the reaction to be performed in appreciable yield, but at the expense of a lower stereoselectivity. AgF-mediated proto-desilylation of the isomeric silanes 79 and 80 followed by cleavage of the remaining acetal protecting groups afforded myxovirescin A1 and its hitherto unknown 14Z-isomer 81, respectively.
Total Synthesis of Myxovirescins, 1. Strategy and Construction of the "Southeastern" Part
Seebach, Dieter,Maestro, Miguel A.,Sefkow, Michael,Adam, Geo,Hintermann, Samuel,Neidlein, Axel
, p. 701 - 718 (2007/10/02)
In this and the following two papers the synthesis of myxovirescins A1, A2 and M2, 28-membered macrocyclic lactam-lactones with antibiotic activity, is described.A retrosynthetic analysis of the myxovirescin family of ca. 30 target molecules leads to a strategy which could be applied to approximately half of them by slight variations of the building blocks used (Schemes 1-3 and following paper).The southeastern part of the molecule, containing the atoms O(1)-C(14) of myxovirescins A and M is described in this first paper (Scheme 3).The assembly is achieved by using the following appropriately protected units: (S)-2-hydroxy-pentanoic acid, (dithian-2-ylmethyl)-amine (Scheme 4), the triflate of (S,R)-2,2-dimethyl-5-vinyl-dioxolan-4-ylmethanol, (E)-3-bromo-2-buten-1-ol, and (E)-2-bromo-2-buten-1,4-diol (Scheme 5), the starting materials for these being malic acid, aminoacetaldehyde, ribose, crotyl alcohol and butyne-1,4-diol.The building blocks are put together by using the following key steps: Kolbe electrolysis, amide formation, lithiodithiane alkylation, and Suzuki coupling (Schemes 6 and 8).The only newly created chirality center is generated stereoselectively by a Li-selectride reduction/Mitsunobu inversion (Table 1, Scheme 7).The termini of the O(1)-C(14) fragment (2 in Scheme 8) carry a (protected) hydroxy acid and an aldehyde group for the Julia coupling and lactonization, respectively, in the final steps of the synthesis.All intermediates are fully characterized.The X-ray crystal structures of two compounds prepared for incorporation as N(4)-C(11) and as C(12)-C(14) of the target molecules are also described (Figures 1 and 2). - Key Words: Myxovirescins / Myxococcus virescens Mx v48 / Suzuki coupling / Macrolides / Lactones / Lactams / 1,3-Dioxolanes / 1,3-Dithianes / Antibiotics
