Highly Stereoselective One‐Pot Synthesis of Bicyclic Isoxazolidines with Five Stereogenic Centers by an Organocatalytic Process

Abstract

Dedicated to Professor Pierre Vogel on the occasion of his 65th birthday Intramolecular nitrone/alkene cycloadditions have received a great deal of attention as a useful methodology for the formation of the intriguing frameworks found in natural products and biologically interesting compounds.[1] The key feature of this approach is the suitable elaboration of the primary cycloadducts, which has proven to be a practical strategy for making different heterocyclic systems.[2] Owing to the labile nature of the NÀO bond under mild reducing conditions, the isoxazolidines provide easy access to a variety of 1,3-difunctional amino alcohols.[3] Particularly, if the intramolecular cycloaddition of nitrone is linked to olefin moiety by a tether of appropriate length, the regio-and diastereoselectivities can be dramatically improved. Most importantly, the introduction of a stereogenic center at the a position of the nitrone can result in asymmetric induction, leading to the generation of new stereocenters having defined configurations.[4] However, multistep synthetic routes were required to synthesize molecules bearing stereocenters at the a position of the nitrone and the olefin moiety from optical sources, such as amino acids and sugars. Although several organocatalytic asymmetric nitrone [3+2] cycloadditions have been documented, [5] the enantioselective intramolecular version remains a challenge. Herein, we disclose an organocatalytic one-pot asymmetric synthesis of bicyclic isoxazolidines through a domino process involving a Michael addition/ in situ condensation/intramolecular nitrone [3+2] cycloaddition sequence.In 2003, our group first described the a-aminoxylation of aldehydes with excellent enantioselectivity. [6a,b] Recently, we also reported highly stereoselective syntheses of tetrahydro-1,2-oxazines by tandem a-aminoxylation and aza-Michael addition.[6] Surprisingly, when we changed the electron-withdrawing group in an aldehyde from a nitro or a malonate group to an ester group, an unexpected bicyclic isoxazolidine product was obtained in 11 % yield with high regioselectivity, endo/exo selectivity, and diastereoselectivity (Scheme 1), by an intramolecular nitrone [3+2] cycloaddition. This finding led us to investigate whether enantiopure bicyclicisoxazolidine products could be obtained if we introduced a stereogenic center at the a position of the aldehyde by asymmetric organocatalysis, which would then undergo subsequent in situ condensation and intramolecular nitrone [3+2] cycloaddition.Recently, asymmetric organocatalytic domino reactions have provided efficient ways to construct complex molecules, and have become a powerful tool in organic chemistry. [7] Among the organocatalytic reactions explored, extensive efforts have been devoted to the Michael addition of aldehydes to nitroolefins. [8] We rationalized that by introducing a stereocenter at the a position of the aldehyde through an asymmetric Michael addition and then subsequent in situ condensation and intramolecular cycloaddition, a novel approach to ...

Ring Opening Metathesis Polymerization of a New Monomer Derived from a Nitroso Diels–Alder Reaction

“…[35,52,[54][55][56][57] One of the most widely used methods involves treatment of the isoxazolidine with Mo(CO) 6 and NaBH 4 . [29] Alternatively, Ji and Miller [58] and others [59][60][61][62] have previously shown that catalytic hydrogenation can be an effective route toward N-O reductive cleavage. Unfortunately for us, these methods led to intractable product mixtures or no observable reaction, respectively (Supporting Information).…”

Organocatalyzed Cycloadditions

“…A one-pot synthesis of bicyclic isoxazolidines with five stereogenic centers by catalyst 12 was reported by Zhong and his co-workers, Scheme 3.85 [107]. This domino sequence involved Michael reaction of 7-oxohept-2-enoate 267 to nitroolefins 60 [108] and subsequent intramolecular nitrone [3 + 2] cycloaddition to give enantiopure bicyclic isoxazolidines 268.…”

Part I: Nitroalkenes in the synthesis of heterocyclic compounds

“…247 Reaction of 7-oxohept-2-enoate derivatives 395 with nitro-olens 15 were investigated by Zhong et al to give highly stereoselective bicyclic isoxazolidines 396 bearing ve stereogenic centers (Scheme 135). 248 The reaction proceeded via domino Michael addition/nitrone formation/intramolecular [3 + 2] nitrone-olen cycloaddition catalysed by 10 mol% of chiral a,adiphenyl prolinol trimethylsilyl ether Cat-8 and AcOH (20 mol%) as an additive. The products were obtained in good-toexcellent yields with excellent diastereo-and enantioselectivities of up to 94% de and >99% ee, respectively.…”