Hydroxy-Directed Diastereoselective Installation of a Methyl Group on Indalone Models and Spiroketal Potential Precursors for the Bafilomycin A₁C15−C25 Subunit

Abstract

Current efforts devoted to the synthesis of Bafilomycin A(1) led us to investigate a synthetic route through a spiroketal intermediate for the construction of the C15-C25 subunit. Preliminary studies for the diastereoselective installation of the methyl-16 cis with respect to the vicinal OH-15 group through radical opening of either siloxafuran intermediate 7 or cyclopropyl compounds 9 and 13 have been carried out using model compounds derived from commercial Indalone 6. In each case the expected "cis" diastereoisomer was obtained in good to excellent yield. Application of these results to Bafilomycin A(1) synthon led to the opposite "trans" stereoselectivity when alpha-carboxy- or alpha-keto-substituted spiroketals 4 or 19 were used. However, the expected potential intermediate has been obtained from the alpha-hydroxymethyl cyclopropanated synthon 21. A Barton-Motherwell xanthate radical deoxygenation-cylopropane opening methodology, followed by a hydroboration-oxidation of the exovinylic intermediate, delivered the expected product 22cis in high yield and excellent stereoselectivity.

Diastereodivergent Synthesis of 4‐Hydroxy‐2,3‐methanopipecolic Acid Derivatives as Conformationally Constrained Homoserine Analogues

“…The OH‐directed cyclopropanation of γ‐hydroxy‐α,β‐unsaturated esters has been reported in a handful of cases, i.e. by samarium/mercury amalgam in conjunction with diiodomethane14–15 and by the Furukawa modification of the Simmons–Smith reaction 16. In both cases, the hydroxy group exerted complete stereocontrol, so we explored the use of both Sm– and Zn‐carbenoids for the cyclopropanation of enantiopure 2 , and the results are reported in Table 1.…”

Synthesis of Conformationally North-Locked Pyrimidine Nucleosides Built on an Oxabicyclo[3.1.0]hexane Scaffold

“…13 It is likely that the fused vinyl ether system raises the energy of the LUMO of the dipolarophile and prevents formation of the cycloaddition product. 14 Switching to Simmons-Smith based methods (CH 2 I 2 /diethylzinc; 15 /diethylzinc/O 2 ; 16 CH 2 ICl/diethylzinc; 17 CH 2 I 2 /triethylaluminum; 18 CH 2 I 2 /Zn(Cu); 19 and CH 2 I 2 , Zn, CuCl, acetyl chloride 20 ), which are used for cyclopropanating activated olefins, was also unsuccessful and in all cases unchanged starting material 8 was reisolated. In an attempt to influence the electronic properties of the C=C double bond, we converted the nitrile in 8 to the corresponding methyl ester ( 11 ) by reaction with sodium methoxide and subsequent hydrolysis of the imidate (see Scheme 4).…”

Diastereocontrolled Synthesis of Highly Functionalized Spiroketals: Application to the Synthesis of a Precursor of the C-12-C-25 Fragment of Bafilomycin A1

“…Our previously published results on the cyclopropanation-radical opening methodology are summarized in Scheme 8. 10 Complexation Interestingly from a chemo-diversity point of view, the C-15-epimeric alcohol epi-39 was synthesized as a major isomer through Stork's TPS methodology. 35 The preparation of an 15-epi C-12-C-25 synthon opens the possibility of performing the macrolactonization reaction of a bafilomycin A 1 secoester precursor under Mitsunobu conditions.…”

“…For the required methylation at C-16, cis to the OH group, we recently reported a methodology involving a cyclopropanation reaction directed by the vicinal OH-17 group, followed by a radical opening to deliver the C-16 methyl group in a completely stereoselective manner. 10 A prerequisite to applying this methodology is the preparation of alcohol 27. Here again, a reasonable attack of a hydride from the b-side of the spiroketal was originally anticipated.…”

“…Such a 'chiral economy' strategy, which could be claimed to combine both cost-effectiveness and simple classical reaction conditions, was already tackled in a precedent preliminary study for installing the required C-16 methyl group of bafilomycin A 1 on the unsaturated spiroketal 4 through a cyclopropane formation-radical opening reaction. 10 Such an approach requires that one or a few pivotal stereogenic centers be Harvard University, where she participated in the total synthesis of bryostatin. In 1993, she joined the CNRS as Chargée de Recherche at the Ecole Polytechnique (Palaiseau), where she also has held a teaching position since 1998.…”