Highly Enantioselective and Diastereoselective Cycloaddition of Cyclopropanes with Nitrones and Its Application in the Kinetic Resolution of 2‐Substituted Cyclopropane‐1,1‐dicarboxylates

Abstract

Trisoxazolines [1] have been applied widely in asymmetric catalysis [2] and molecular recognition. [3] In our efforts to develop superior catalysts that are cheap, readily accessible, air stable, and water tolerant, we designed and synthesized the pseudo-C 3 -symmetric trisoxazoline 1 b (Scheme 1) by the sidearm approach, and found that 1 b/Cu II promoted smoothly the highly enantioselective Friedel-Crafts reaction of indoles with arylidene malonates [4] and the Kinugasa reaction.[5] We also described tox/Co II -catalyzed [3+2] cycloaddition reactions between nitrones and alkylidene malonates in which the endo/exo selectivity could be controlled well by the reaction temperature. Thus, both cis and trans isoxazolidines could be prepared enantioselectively.[6] Herein, we report that the system tox/Ni II catalyzes the [3+3] cycloaddition of racemic 2-substituted cyclopropane-1,1-dicarboxylates with nitrones to provide ready access to optically active tetrahydro-1,2-oxazine derivatives with high diastereoselectivity and enantioselectivity. Furthermore, this reaction can be employed for the kinetic resolution [7] of 2-substituted cyclopropane-1,1-dicarboxylates to furnish these compounds in optically active form with excellent ee values.Tetrahydro-1,2-oxazine derivatives occur frequently in biologically active compounds [8] and are valuable synthetic intermediates.[9] Among the methods developed for the preparation of such compounds, [10] the [3+3] cycloaddition of donor-acceptor cyclopropanes with nitrones, pioneered by Kerr and co-workers, [11] is a particularly elegant approach. They found that nitrones 3 react smoothly with cyclopropanes 2 in the presence of Yb(OTf) 3 ·x H 2 O to give the cis isomers 4 diastereospecifically (see Table 1). Recently, Sibi et al. developed a highly efficient asymmetric version of this reaction. [12] They reported that nitrones react with cyclopropane-1,1-dicarboxylates to afford tetrahydro-1,2-oxazine derivatives with high enantioselectivity in the presence of dbfox/Ni II (10 mol %; dbfox = 4,6-dibenzofurandiyl-2,2-bisoxazoline). When 2-substituted cyclopropane-1,1-dicarboxylates were used as substrates, and the quantity of the catalyst was increased to 30 mol %, the reactions proceeded smoothly to give the products with high ee values but with low diastereoselectivities (the cis/trans ratio ranged from 1.0:1.4 to 1.0:0.8).Gratifyingly, we found that diethyl 2-phenylcyclopropane-1,1-dicarboxylate (2 a) reacted smoothly with nitrone 3 a to furnish the cycloaddition adduct in 99 % yield with excellent diastereoselectivity (d.r. > 99:1) in the presence of a catalytic amount of 1 b/Ni(ClO 4 ) 2 ·6 H 2 O. Further studies showed that ligands derived from iPr-box (box = bisoxazoline) influenced strongly both the enantioselectivity and diastereoselectivity of the reaction. The bisoxazoline 1 a without a pendant group gave the desired product with good diastereoselectivity (d.r. 97:3) but only 20 % ee (Table 1, entry 1). However, when a pyrid-2-yl or oxazolinyl group was introduced as a pend...

Z‐bpy, a New C2‐Symmetric Bipyridine Ligand and Its Application in Enantioselective Copper(I)‐Catalyzed Cyclopropanation of Olefins

“…[8] Also, the high strain and unique bonding of cyclopropanes make them competent intermediates in synthesis of other molecules via ring opening or expansion. [9] Therefore, the development of highly efficient chiral catalysts, such as Cu-, Rh-, Ru-, and Co-based complexes, resulted in important advances in cyclopropane chemistry, providing access to the smallest ring compounds with a wide variety of functional groups, including ethers, amines, phosphonates, and carbonyl groups.…”

Synthesis and Reactivity of Donor-Acceptor Substituted Aminocyclopropanes and Aminocyclobutanes

“…In addition, DA cyclopropanes have been used as 1,3 dipoles also in other type of annulations. (See footnote 1) For examples, nitrones have been widely employed to afford tetrahydro-1,2-oxazines derivatives [164][165][166][167]. (See footnote 1) For examples, nitrones have been widely employed to afford tetrahydro-1,2-oxazines derivatives [164][165][166][167].…”

Cyclopentadienones via a Tandem C‐Cyclopropylnitrone Cyclization‐Cycloreversion Sequence

“…13 Similar transformations of 1,1-cyclopropane diesters in the presence of Ni(ClO 4 ) 2 and chiral bisoxazoline ligands have been reported. 14 Also (3+2)-cycloadditions of nitrocyclopropane carboxylates with nitrones, catalyzed by urea derivatives, were shown to give 1,2-oxazinane derivatives. 15 …”