Design of Phosphorus Ligands with Deep Chiral Pockets: Practical Synthesis of Chiral β‐Arylamines by Asymmetric Hydrogenation

Abstract

Despite the signficant advances in asymmetric hydrogenation, the development of novel and efficient chiral phosphorus ligands to solve new synthetic challenges continues to an important goal. [1] C 2 -Symmetric chiral bisphosphorus ligands such BINAP, [2] DuPhos, [3] and TangPhos [4] are among the most versatile and important ligands for asymmetric hydrogenation, yet they are not universal. To expand their synthetic utilities, one common strategy is to develop structurally similar ligands, such as Tol-BINAP, Xyl-BINAP, Et-DuPhos, or iPr-DuPhos by increasing the size of the substituents on the phosphorus centers (Figure 1 a). Such modifications lead to the design of ligands with deeper chiral pockets mainly owing to the increased bulk of the R groups, which protrude slightly forward to the substrate coordination. In this study we adopt a new strategy to design a ligand with a deep chiral pocket by installing R groups that protrude directly forward to the substrate coordination site. There are two advantages of this strategy: 1) The R groups that protrude directly forward to the substrate coordination site can lead to a dramatic conformational variation of the chiral pocket; 2) the R groups are in close proximity to the metal center and the substrate, thereby providing a well-defined and deep chiral pocket. We herein report the development of WingPhos (L5) by using this strategy.Chiral b-arylamines exist in numerous biologically interesting natural products and therapeutic agents. For examples, such moieties commonly exist in a series of naphthylisoquinoline alkaloids such as michellamine B and korupensamine A (Scheme 1). [5] They also serve as pivotal structural units for many active pharmaceutical ingredients such as 3,4-methylenedioxyamphetamine (MDA), [6a] tamsulosin, [6b] selegiline, [6c] arformoterol, [6d] rotigotine, [6e] and silodosin. [6f] Development of efficient asymmetric synthetic methods of chiral b-arylamines has thus become a subject of significant interest. [7] However, the asymmetric hydrogenation of b-aryl enamides to prepare chiral b-arylamines remains underdeveloped. Zhang, Lei, and co-workers reported high enantioselectivities on the asymmetric hydrogenation of (Z)-b-aryl enamides by using a Rh-TangPhos catalyst. [8] Nevertheless, low ee values were observed with thermodynamically more stable sub-Figure 1. Design of novel chiral bisphosphorus ligand L5 (WingPhos) with a deep chiral pocket (9-An = 9-anthracenyl). Scheme 1. Selected natural products and therapeutic agents containing chiral b-arylamines.

Enantioselective Rhodium‐Catalyzed Addition of Arylboroxines to N‐Unprotected Ketimines: Efficient Synthesis of Cipargamin

“…[7] One salient feature of these ligands is the substitution at the 4,4'-positions,a djacent to the phosphorus atoms, providing tunability of their chiral pockets in shape,d epth, and electronic properties ( Figure 2). Fore xample,W ing-Phos, [8] bearing two 9-anthryl groups at the 4,4'-positions, possesses deep chiral pockets and is efficient for rhodiumcatalyzed enantioselective addition of arylboroxine to ketones.H erein we report the applications of WingPhos as well as arelated ligand, PFBO-BIBOP,inthe enantioselective rhodium-catalyzed addition of arylboroxines to N-unprotected ketimines,l eading to the direct formation of chiral atrifluoromethyl-a,a-diaryl amines and 3-amino-3-aryloxindoles in excellent enantioselectivities and yields. Chiral a-(trifluoromethyl)amines [9] have become increasingly important building blocks in medicinal chemistry and exist in structures of several therapeutic agents such as odanacatib [9b] and DPC-083.…”

Highly Enantioselective Rhodium‐Catalyzed Addition of Arylboroxines to Simple Aryl Ketones: Efficient Synthesis of Escitalopram

“…[10] Thed esign of chiral phosphorus ligands capable of long-range stereocontrol remain asignificant challenge with limited success.Because of the less reactive nature and low coordinative ability of simple ketones,i nc omparison with aldehydes or imines,t he intermolecular addition of arylboron reagents to simple ketones relies upon the metal catalyst to bring the two reaction partners into close proximity,a sw ell as provide good stereocontrol at ag reater distance from the metal center ( Figure 2). In this sense,( R,R,R,R)-WingPhos, [11] having two anthryl groups in its structure,c ould not only offer the required stereocontrol, but also help bring two reaction partners into close proximity and lead to high reactivity.H erein we describe the applications of the Rh/(R,R,R,R)-WingPhos catalyst in enantioselective addition of arylboroxines to simple aryl ketones. In this sense,( R,R,R,R)-WingPhos, [11] having two anthryl groups in its structure,c ould not only offer the required stereocontrol, but also help bring two reaction partners into close proximity and lead to high reactivity.H erein we describe the applications of the Rh/(R,R,R,R)-WingPhos catalyst in enantioselective addition of arylboroxines to simple aryl ketones.…”

“…In this sense,( R,R,R,R)-WingPhos, [11] having two anthryl groups in its structure,c ould not only offer the required stereocontrol, but also help bring two reaction partners into close proximity and lead to high reactivity.H erein we describe the applications of the Rh/(R,R,R,R)-WingPhos catalyst in enantioselective addition of arylboroxines to simple aryl ketones. As olvent study (entries [8][9][10][11][12] proved that MTBE is among the best for this transformation. We were pleased that the desired tertiary alcohol 3aa was obtained in 25 %y ield and 97 % ee.S creening of various inorganic bases (entries 1-8) showed CsF provided ab est yield (85 %) and an almost perfect ee value (> 99 % ee).…”

“…Am etal catalyst equipped with ad iphosphine ligand having as hallow chiral pocket (Figure 2a)w ill be inefficient for such ar eaction in terms of both enantioselectivity and reactivity,whereas acatalyst equipped with aligand having adeep chiral pocket ( Figure 2b)might offer improved reactivity as well as good long-range stereocontrol. In this sense,( R,R,R,R)-WingPhos, [11] having two anthryl groups in its structure,c ould not only offer the required stereocontrol, but also help bring two reaction partners into close proximity and lead to high reactivity.H erein we describe the applications of the Rh/(R,R,R,R)-WingPhos catalyst in enantioselective addition of arylboroxines to simple aryl ketones. We chose 4-methoxyphenylboroxine 2a as the aryl boron reagent for the rhodium-catalyzed nueclophilic addition to acetophenone.T he reaction was performed in tert-butyl methyl ether (MTBE) under nitrogen for 18 hours with acetophenone (0.10 mmol), 4-methoxyphenylboroxine (0.20 mmol), and K 2 CO 3 as the base in the presence of [{Rh(C 2 H 4 ) 2 Cl} 2 ]( 1.5 mol %) and (R,R,R,R)-WingPhos (3.6 mol %; Table 1, entry 1).…”

“…We were pleased that the desired tertiary alcohol 3aa was obtained in 25 %y ield and 97 % ee.S creening of various inorganic bases (entries 1-8) showed CsF provided ab est yield (85 %) and an almost perfect ee value (> 99 % ee). As olvent study (entries [8][9][10][11][12] proved that MTBE is among the best for this transformation. As lightly better yield was achieved when the reaction was performed at 100 8 8C(entry 13).…”