Formal Total Synthesis of Oximidine II via a Suzuki-Type Cross-Coupling Macrocyclization Employing Potassium Organotrifluoroborates

Abstract

A formal total synthesis of oximidine II has been achieved, employing a Suzuki-type coupling approach to construct the highly strained, polyunsaturated 12-membered macrolactone. To achieve this goal, benefit was derived from the stability of potassium alkenyltrifluoroborates to establish conditions for the macrocyclization. The stereocontrolled formation of the cis-1,2-diol subunit was accomplished using a diastereoselective, reagent controlled addition to a chiral aldehyde utilizing the Carreira protocol. Advantage was taken of the Snieckus hydroborating reagent to gain access to the key trifluoroborate needed for the macrocyclization.

Kinetically Controlled Ring‐Closing Metathesis: Synthesis of a Potential Scaffold for 12‐Membered Salicylic Macrolides

“…After the mixture had been continuously stirred for 6 h at room temperature, it was diluted with water and extracted with Et 2 O. The organic layer was washed with brine and dried over MgSO 4 , and the solvent was evaporated to leave a residue, which was purified by chromatography on silica gel to afford the corresponding aldehyde (2.18 g, 92 %) as a pale-yellow oil.…”

“…After the mixture had been stirred for 30 min at room temperature, the aldehyde (2.18 g, 6.92 mmol) in THF was added and the resulting mixture was stirred for 10 h. The reaction mixture was diluted with saturated NH 4 Cl and the aqueous mixture was extracted with Et 2 O. The organic layer was dried over MgSO 4 and then evaporated.…”

“…To date, considerable efforts have been devoted toward the syntheses of these salicylic lactones and related model compounds, and many of these studies rely on a ringclosing metathesis (RCM) strategy for constructing the 12-membered lactone core. [1,4] While RCM is a powerful methodology in the field of organic synthesis and has been utilized for numerous synthetic studies, including the synthesis of cyclic natural compounds, [5] it is important to note that the prediction of the stereochemical outcome (the E/Z selectivity of the olefin product) is not always simple in cases of large-ring formation. Although mixtures of both geometrical isomers are formed with various ratios, generally according to the thermodynamic stabilities, this drawback has been overcome by controlling the reaction conditions, by tuning the protecting groups affecting the conformation of the substrates, and ultimately by chromatographic separation of the isomers.…”

Preparation of 1,3-dienyl organotrifluoroborates and their Diels–Alder/cross-coupling reactions

“…Phenyl substituted halo dienes (43)(44)(45) were directly generated from the corresponding allenic alcohol (41) using the established protocol of Ma et al 49 We found that the temperature of the rearrangement reaction has significant impact on the product yield for the formation of the iodo-substituted diene (43). In the presence of 1.5 mol% Pd catalyst the reaction could be performed at 40°C for both the bromo-and chloro-substituted dienes (44,45). 50 Attempts to run the rearrangement reaction at temperatures even 10 o C higher than this for the iodo-substituted diene (43) resulted in product yields of <10% yield.…”

“…Newly formed halo-dienes (43)(44)(45) were first subjected to the protocol (used for formation of the unsubstituted 2-BF 3 diene (27)) to attempt to prepare the corresponding BF 3 -substituted dienes. The first step was to generate the corresponding Grignard reagent followed by addition of trimethoxy borate and quenching by KHF 2 /H 2 O.…”