Aromatic Spiroketal Bisphosphine Ligands: Palladium‐Catalyzed Asymmetric Allylic Amination of Racemic Morita–Baylis–Hillman Adducts

Abstract

The design of chiral ligands plays a central role in the development of chiral catalysts for asymmetric reactions, in which the right combination of a sterically well-defined scaffold with a chelating moiety can lead to excellent enantioselective control in the catalysis. [1] From this point of view, spirobackbones (Scheme 1) have been recognized as one of the privileged structures for the construction of chiral ligands [2] ever since the pioneering work by Chan et al. (SpirOP), Sasai and co-workers, and Zhou and co-workers (SDP). [3] In contrast, van Leeuwen and co-workers reported the development of the bisphosphine ligands SPANphos which have an interesting spiro-2,2'-bis(chroman) backbone and their transition-metal complexes have been studied in catalysis. [4] Despite the success of their rhodium(I) complexes in the catalysis of methanol carbonylation, [4c] the application of spiro-2,2-bis(chroman)-based chiral ligands in asymmetric catalysis still remains relatively unexplored. [4e,g, 5] Very recently, we developed a catalytic asymmetric synthesis of aromatic spiroketals by the tandem hydrogenation and spiroketalization of a,a'-bis(2-hydroxyarylidene)ketones [6a] using Ir/SpinPHOX as the catalyst, [6] and it provides a facile and practical synthesis of a new type of enantiopure analogoue to SPANphos, namely SKP (1). In our ongoing endeavor towards seeking new spirochiral ligands for asymmetric catalysis, we communicate herein our preliminary results on the synthesis of one type of chiral bisphospine ligand having an aromatic spiroketal motif (1; SKP) and their application in palladium-catalyzed enantioselective allylic amination of racemic Morita-Baylis-Hillman (MBH) adducts [7] with aromatic amines. The developed methodology has provided a facile and efficient synthesis of optically active b-lactam derivatives, [8] including the chiral drug Ezetimibe which is used to treat high cholesterol. [9] As shown in Scheme 2, synthesis of the enantiopure spiro-2,2'-bis(chroman)-based bishosphine ligands (R,R,R)-1 is quite simple and straightforward from readily available a,a'-bis(2-hydroxy-3-bromophenylidene)ketone (2) by using our previously published procedure. [6a] The key intermediate, the 3-bromo-substituted aromatic spiroketal (R,R,R)-3 was treated with nBuLi and the resulting lithium salt was reacted with Ar 2 PCl in THF to afford the corresponding enantiopure spiroketal-based bisphosphine ligands (R,R,R)-1 a-f in moderate to good yields (40-80 %) on gram scale.Optically active a-alkylidene-b-arylamino carbonyl compounds represent one type of valuable building blocks with wide applications in the synthesis of medicinally relevant molecules and natural products, [10] but these building blocks are not readily accessible using direct asymmetric aza-MBH reactions because of the electron-rich nature of the corresponding N-aromatic imines. [7,11] In contrast, the enantioselective, metal-catalyzed allylic amination is a useful method for the preparation of enantiomerically enriched allylic amines. [12] Despite...

Modulation of Multifunctional N,O,P Ligands for Enantioselective Copper‐Catalyzed Conjugate Addition of Diethylzinc and Trapping of the Zinc Enolate

“…Synthesis of chiral Ph-BINMOL-based aldehyde 2 c [10b] and corresponding phosphine ligand L6: a) [1,2]-Wittig rearrangement, [12] iBuLi, THF, À78 8C; b) TMSCl (TMS = trimethylsilyl), NaI; c) NaH, MOMCl; d) nBuLi, DMF, Et 2 O; e) HCl, THF; and f) CH 2 Cl 2 /EtOH, at room temperature. Synthesis of chiral Ph-BINMOL-based aldehyde 2 c [10b] and corresponding phosphine ligand L6: a) [1,2]-Wittig rearrangement, [12] iBuLi, THF, À78 8C; b) TMSCl (TMS = trimethylsilyl), NaI; c) NaH, MOMCl; d) nBuLi, DMF, Et 2 O; e) HCl, THF; and f) CH 2 Cl 2 /EtOH, at room temperature.…”

Asymmetric N‐Allylic Alkylation of Hydrazones with Morita–Baylis–Hillman Carbonates

“…Most recently, Ding [11] and Liu [12] reported the palladium-catalyzed N-allylic alkylation of MBH adducts with simple aromatic amines through a p-allylpalladium complex. Considering the strong electron-withdrawing effect of the tosyl group, we wondered whether tosylhydrazone could be utilized as a suitable nucleophile to react with MBH carbonates for the construction of optically active N-alkylated tosylhydrazones.…”

“…Having identified the best catalyst, the effect of the solvents was also tested. Among the various solvents screened, to our surprise, we found that almost all of them had a negligible effect on the enantioselectivity except for toluene (entries [11][12][13][14][15][16]. However, the regioselectivity showed a strong solvent dependence.…”

Palladium‐Catalyzed Asymmetric Construction of Vicinal Tertiary and All‐Carbon Quaternary Stereocenters by Allylation of β‐Ketocarbonyls with Morita–Baylis–Hillman Adducts

“…[11] We envisioned that SKP/Pd-catalyzed AAA of MBH adducts with nucleophiles of b-ketocarbonyl compounds [12] might provide an excellent approach for the construction of vicinal chiral tertiary and quaternary centers.Accordingly,the reaction of the MBH adduct 1a and b-ketoester 2a was taken for aproof-of-concept prototype to survey the reaction conditions (Table 1). [11] We envisioned that SKP/Pd-catalyzed AAA of MBH adducts with nucleophiles of b-ketocarbonyl compounds [12] might provide an excellent approach for the construction of vicinal chiral tertiary and quaternary centers.Accordingly,the reaction of the MBH adduct 1a and b-ketoester 2a was taken for aproof-of-concept prototype to survey the reaction conditions (Table 1).…”

“…[b] 3aa/4aa [c] d.r. [a] Unless otherwise noted, the reactions were performed under conditionsB.The data within parentheses are the yields of isolated 3.In each case, the b/l and d.r.values were determined by 1 Considering the bifunctional role of SKPs in the allylic substitution of MBH acetates, [11] as well as the sense of asymmetric induction in the titled reaction, as chematic representation of the stereocontrol model is proposed in Figure 1. Except for 3ap,all the products (3aaao)w ere obtained in excellent enantioselectivities (93-> 99 % ee).…”