Concise Asymmetric Synthesis of Fully Substituted Isoxazoline‐N‐Oxide through Lewis Base Catalyzed Nitroalkene Activation

Abstract

Structurally unique heterocycles are of great importance in chemical and biological related research.[1] The isoxazoline-N-oxide and its derivatives are an interesting class of compounds in this family [2] and have been applied as biologically active compounds [3] and drug candidates [4] in many research areas. Moreover, with the unique functionality-enriched structures, isoxazoline-N-oxides have also been recognized as versatile synthetic building blocks that could be readily converted into useful intermediates for complex molecules [5] and natural product syntheses.[6]The conventional strategies for the preparation of isoxazoline frameworks include the intramolecular 5-exo-tet cyclization of nitro compounds [7] and intermolecular [3 + 2] cycloaddition.[8] However, both approaches suffered from limited substrate scope and low overall efficiency.[9] In addition, efficient asymmetric synthesis of isoxazoline-N-oxides is rare. [10,11] Thus, the practical synthesis of isoxazoline-Noxides remains big challenge and new efficient methodologies are highly desirable.Recently, our group reported the amine-catalyzed b-alkyl nitroalkene activation as a new approach in promoting complex-molecule cascade synthesis. Based on this strategy, several cascade processes have been successfully developed. [12,13] All of these new methods were carried out in a one-pot fashion, providing complex products with high efficiency and good stereoselectivity. Among these new methods, one particularly interesting reaction was the synthesis of isoxazoline-N-oxide through nitroalkene and vinyl ester condensation (Scheme 1). [14] This cascade approach revealed an efficient strategy in producing active diene intermediate A in-situ, which allowed the preparation of isoxazoline-N-oxide without the challenging nitronate intermediate synthesis. However, this method possessed three limitations: 1) the C-4 position was limited to aliphatic groups, 2) two identical vinyl groups on C-3 and C-5 positions, and 3) poor enantioselectivity (<15 % ee was observed in all cases with different chiral amines).Owing to the unique mechanism and strong desire for effective synthesis of enantiomerically enriched isoxazolines, we investigated the asymmetric synthesis of these fully substituted isoxazoline-N-oxides. Herein, we report a simple aldehyde condensation with amine-activated nitroalkene for the formation of diene intermediates and chemoselective condensation with chiral sulfide ylides, forming fully substituted isoxazoline-N-oxides in one-pot with excellent yields and stereoselectivity. Moreover, from the functional-groupenriched products, simple transformations gave the (À)-clausenamide analogue in four steps with good yield and excellent stereochemistry control.First, we postulated that the diene intermediate A, besides the nitroalkene/vinyl ester condensation, could also be achieved through the Lewis based mediated Henry reaction between a nitroalkene and an aldehyde. Thus, the isoxazo-

Novel Concise Synthesis of (−)‐Clausenamide

“…The stereochemistry of (＋)-10 was assigned on the basis of the following NMR studies. Vicinal coupling constant J 4,5 (10.0 Hz) and J 5,6 (10.4 Hz) suggested all the three protons at 4-, 5-, and 6-positions are in axial orientations in this chair-like six-membered cyclic molecule. The coupling constants of two 3-Hs with 4-H (J 3a,4 ＝9.6 Hz and J 3e,4 ＝6.4 Hz), as well as the strong NOE observed between 4-H and 6-H, also confirmed the axial 4-H.…”

“…Currently, pilot scale preparation of (−)-1 is carried out in our laboratory through optical resolution of 7. In addition to our progress, other groups [6][7][8][9][10] also accomplished elegant asymmetric syntheses of (−)-or (＋)-1. As a continuation of our endeavor to develop more efficient synthesis of clausenamide-type compounds, [11] we report herein a recently finished concise synthesis of (−)-1.…”

Oxidative cyclizations of oximes using hypervalent iodine reagents

“…[29][30][31] The oxidation of ketoximes initially generates oxonitrenium ions as active intermediate species, intramolecular cyclization of which forms the corresponding heterocycles (see Section 3).…”

N‐Bromosuccinimide‐Mediated Thiocyanation of Cyclohexene‐Fused Isoxazoline N‐Oxides

“…Isoxazoline N-oxide derivatives play ak ey role in constructing new classes of organic compounds. Awide variety of strategies have been reported in the literaturef or the syntheses of various N-oxide derivatives, [1] In our recent publications, we successfully utilized cyclohexene-fused isoxazoline N-oxides to synthesize highly functionalizedl ong-chain diketohalocyano skeletons, [2a-b] cyclohexanone ring-fused isoxazoled erivatives, [2c] and 2-halomethylene-3-oxoketoxime derivatives. [2d] In order to explore more synthetic utilities of cyclohexene-fused isoxazoline N-oxides and to widen their applications, we focused our attention for the synthesis of organosulfur compoundsv ia thiocyanation.…”

“…Substrates with o-substitution on the phenyl ring were tested first. The reactions of o-substituted derivatives such as 2-fluoro, 2-chloro, 2-bromo, and 2-iodo produced the expected products in good yields ( Table 3, entries [1][2][3][4]. Subsequently,wetreated different m-substituted isoxazoline N-oxides under the optimized reaction conditions.…”