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Ketones and Aldehydes as O-Nucleophiles in Iridium-Catalyzed Intramolecular Asymmetric Allylic Substitution Reaction Ye Wang, Wen-Yun Zhang, and Shu-Li You J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 28 Jan 2019 Downloaded from http://pubs.acs.org on January 28, 2019
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Journal of the American Chemical Society
Ketones and Aldehydes as O-Nucleophiles in IridiumCatalyzed Intramolecular Asymmetric Allylic Substitution Reaction Ye Wang,† Wen-Yun Zhang,† and Shu-Li You*†‡ †
State Key Laboratory of Organometallic Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 345 Lingling Lu, Shanghai 200032, China ‡
Collaborative Innovation Center of Chemical Science and Engineering, Tianjin 30072, China
ABSTRACT: Ketones and aldehydes are employed as enol O-nucleophiles in an iridium-catalyzed asymmetric allylic substitution reaction. The reaction proceeds well in the presence of a well-defined chiral iridium complex under mild conditions. A series of chiral 2H-1,4-oxazine skeletons can be obtained in up to 94% yield with 99% ee. The utility of this novel method has been demonstrated by its implementation in the first enantioselective synthesis of (+)-chelonin A.
Iridium-catalyzed asymmetric allylic substitution is an important synthetic reaction that exhibits great potentials in the synthesis of diverse functional molecules, natural prod1 ucts, and pharmaceutical agents. The versatility of this reaction has been illustrated by the robust tolerance of a wide range of heteroatom and carbon nucleophiles. Particularly, ketones and aldehydes are useful C-nucleophiles, which has been exemplified in a great deal of excellent works of α2 3 4 allylation reactions developed by Hartwig, Carreira, Zhang 5 and others (Scheme 1a). Interestingly, Carreira and coworkers reported an iridium-catalyzed diastereo- and enantioselective spiroketalization in which ketone proceeded allylic 6 substitution reaction via a hemiacetal intermediate. To the best of our knowledge, the direct utilization of ketones and aldehydes as O-nucleophiles in iridium-catalyzed asymmetric allylic substitution reactions remained unknown.
Scheme 1. Ketones and aldehydes as nucleophilic precursors in iridium-catalyzed allylic substitution.
(S,S)-enantiomer of reboxetine is a potential treatment of fibromyalgia and neuropathic pain, and more potent NRI 9 than the reboxetine racemate. Additionally, chiral morpholine derivatives also play an important role in organic synthe10 sis, not only as versatile synthetic units, but also as chiral 11 auxiliaries. However, catalytic asymmetric construction of chiral morpholines, particularly the construction of morpholines that contain multiple chiral centers is still underdevel12 oped. Herein, we describe an intramolecular iridiumcatalyzed asymmetric allylic substitution reaction using a ketone or aldehyde moiety as an O-nucleophile (Scheme 13 1b). The products are readily transformed into chiral morpholines by simple reduction of the endocyclic double 14 bond. Based on this method, the first enantioselective synthesis of (+)-chelonin A has been realized. Our study began by evaluating the reaction of substrate 1a (Table 1). It was found that the treatment of 1a with Ircatalyst derived from [Ir(cod)Cl]2 (2 mol %) and Feringa ligand L1 (4 mol %), and Cs2CO3 (1 equiv) in THF at 50 C gave 15,16 product 2a in 34% NMR yield with 92% ee (entry 1). Careful investigations of a variety of ligands (entries 2-7) showed that Alexakis ligand L2 was the most efficient for this reaction, which afforded 2a in a moderate NMR yield (45%) with excellent ee (98%). Notably, instead of the in situ preparan 17 tion of the Ir-catalyst via PrNH2 activation, the utilization of L2-derived cyclometallated Ir-complex K1 improved the 18 NMR yield of 2a to 70% (entry 8). Further screening of solvents and bases (see the Supporting Information for details) revealed that better results were obtained with K2CO3 (76% NMR yield and 98% ee of 2a, entry 9) or DBU (84% NMR yield and 94% ee of 2a, entry 10) as the base. Notably, when the loading of DBU was lowered to 0.5 equiv, the yield of 2a was further increased (89% NMR yield, 88% isolated yield on 0.2 mmol scale) with the high enantiopurity remained (94% ee).
Table 1. Optimization of the reaction conditions.a
Chiral morpholine derivatives are widely distributed in 7 many natural products and biologically active molecules. For example, (-)-chelonin A and (+)-chelonin C possess an8 timicrobial and anti-inflammatory activities. (±)-Reboxetine is an orally active noradrenaline reuptake inhibitor (NRI) used for the treatment of depression. Importantly, the (+)-
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2-benzofuryl and 2-pyridyl ketone derived allylic carbonates 1q and 1r also proved to be suitable substrates for this reaction (2q and 2r, 85-87% yields, 92-98% ee; entries 17-18). Ketone 1s bearing an α-substituent was tolerated but gave a lower yield of 2s (24% yield, 99% ee, entry 19). Pleasingly, ketone 1t bearing a malonate diester linker proved to be a good substrate for this reaction (2t, 82% yield, 99% ee, entry 20). In addition, substrates 1u and 1v were accommondated. The desired dihydrofuran and -pyran derivatives were obtained efficiently (2u and 2v, 86-94% yield, 95-96% ee, entries 21-22). The Thorpe–Ingold effect was not necessary for the cyclization reaction. Gram-scale synthesis of 2a (1.23 g) gave identical results in terms of yield (80%) and enantiopurity (95% ee) with a much lower catalyst loading (0.5 mol %), which showed the robustness and practicality of this method.
Table 2. Substrate Scope.a b
entry
ligand
base
yield (%)
ee c (%)
1
L1
Cs2CO3
34
92
2
L2
Cs2CO3
45
98
3
L3
Cs2CO3
trace
-
4
L4
Cs2CO3
trace
-
5
L5
Cs2CO3
trace
-
6
L6
Cs2CO3
trace
-
7
L7
Cs2CO3
