Highly Enantioselective Aryl Additions of [AlAr₃(thf)] to Ketones Catalyzed by a Titanium(IV) Catalyst of (S)‐Binol

Abstract

The asymmetric catalytic C À C bond formation by addition of an organozinc reagent to aldehydes for the synthesis of enantiomerically pure secondary alcohols as building blocks for bioactive compounds has been extensively studied, and numerous catalytic systems have been developed to yield excellent enantioselectivities.[1] Since tertiary alcohols appear in bioactive compounds, [2] the construction of chiral quaternary carbon centers is synthetically important owing to the inertness of ketones toward additions of carbon nucleophiles and less differentiation of the two groups attached to the carbonyl carbon atom. Despite efforts in recent years, only limited examples of catalytic asymmetric additions to ketones have been reported to give excellent stereoselectivities. Organozinc compounds have been used for asymmetric additions of alkyl compounds to ketones [3] or a-ketoesters [4] and for additions of vinyl, [5] alkynyl, [2c, 6] or aryl compounds [7] to ketones. For allyl addition reactions, the considerably toxic allyl tin compounds have been the commonly used reagents, [8] and in fewer cases, allyl silicon [2e, 9] or allyl boron compounds [10] have been used. In addition to these reagents, organoaluminum compounds are excellent nucleophiles for organic reactions [11] owing their high reactivities, a greater Lewis acidity of the aluminum center, and low toxicities. However, the use of organoaluminum compounds in asymmetric catalysis is rare. In the past few years, asymmetric catalytic alkylation, [12] allylation, [13] and alkynylation [14] reactions employing organoaluminum reagents have been established to achieve good to excellent enantioselectivities. Recently, we demonstrated that the novel [AlAr 3 (thf)] reagents are powerful aryl nucleophiles for additions to aldehydes catalyzed by the titanium catalyst of (R)-H 8 -binol (binol = 2,2'-dihydroxy-1,1'-binaphthyl) with the reactions complete in only 10 min. [15] In studies of asymmetric aryl additions to ketones, [7] only a few papers have been reported in just two catalytic systems. The first system is a zinc catalyst of (+)-daib (3-exo-(dimethylamino)isoborneol) with which direct additions of the ZnPh 2 reagent afford phenylation products.[7a] The second system is a series of titanium catalysts of disulfonamides [16] with which additions of ZnPh 2 or aryl zinc reagents furnish phenylation or arylation products. [7b-f] However, generation of aryl zinc reagents from excess ZnEt 2 and aryl boron compounds requires reaction conditions at elevated temperatures for 12-16 h. Furthermore, the arylation reactions have not reached a satisfactory level in yields and stereoselectivities.[7f] To extend applications of [AlAr 3 (thf)] reagents in catalysis, we report herein the first example of asymmetric aryl additions of organoaluminum reagents to ketones. The (S)-binol molecule was selected as the ligand since binol is a remarkable ligand applied to many varieties of asymmetric reactions [17] and since dititanium complexes of binol ligands with known structures [...

Enantioselective Additions of Aryltitanium Tris(isopropoxide) to Ketones: Structure of [(i‐PrO)2Ti{μ‐(S)‐BINOLate}(μ‐O‐i‐Pr)TiPh(O‐i‐Pr)2], Study of Mechanistic and Stereochemical Insights

“…(2)], and results summarized in Table 2. Similar to the AlAr x Et 3− x (THF)7a,e ( x =3 or 1) addition reactions, the titanium catalyst of ( S )‐BINOL worked well for ArTi(O‐ i‐ Pr) 3 addition reactions of aromatic ketones, affording products 3 in excellent enantioselectivities of ≥90% ee (entries 1–10) except for 2′‐methylacetophenone ( 2a ). The addition of PhTi(O‐ i‐ Pr) 3 to the steric hindered substrate of 2a was rather slow, and the reaction over 48 h furnished 3a in only a 50% yield with an enantioselectivity of 85% ee (entry 1).…”

“…In order to determine the stereochemistry of addition products, the phenyl addition to 2′‐iodoacetophenone ( 2h ) was conducted over 168 h to furnish 3h in a 45% yield but with an excellent enantioselectivity of 94% ee (entry 8). The absolute structure of 3h was confirmed as the R‐ configuration7a,18 that is derived from a Re ‐face addition of the phenyl nucleophile to the carbonyl carbon of 2h . However, the same titanium catalyst of ( S )‐BINOL induces an opposite Si ‐face addition of the nucleophiles to the aldehydes 2…”

Gratwanderung zwischen Reaktivität und Selektivität

“…Lewis‐basische Additive wie Phosphoramidate führten zur zusätzlichen Aktivierung des Zinkorganyls und damit zu erhöhter Ausbeute und Enantioselektivität. Anstelle von Zink‐ können auch Al‐Organyle zu enantioselektiven Arylierungen verwendet werden, wie Gau et al kürzlich zeigten 10). Aus preiswertem BINOL bildet sich mit überschüssigem Ti(OiPr)4 eine Spezies, welche die verschiedenen Aryl‐ und Alkenylmethylketone mit Triarylaluminiumreagenzien hochselektiv umsetzt (Abbildung 2d, S. 39).…”

A New Aspect of Magnesium Bromide‐Promoted Enantioselective Aryl Additions of Triaryl(tetrahydrofuran)aluminum to Ketones Catalyzed by a Titanium(IV) Catalyst of trans‐1,2‐Bis(hydroxycamphorsulfonylamino)cyclohexane

“…[24] We also reported on a titanium catalytic system of (S)-BINOL that catalyzes AlAr 3 A C H T U N G T R E N N U N G (THF) additions to a wide variety of ketones, and afforded tertiary alcohols in excellent stereocontrol. [25] Recently, a zinc catalyst of chiral phosphoramides has been established to induce excellent stereocontrol in ZnPh 2 /ZnEt 2 additions to ketones. [26] To continue our efforts in asymmetric catalysis [27] and to compare AlAr 3 A C H T U N G T R E N N U N G (THF) and arylzinc reagents in asymmetric aryl additions to ketones, we herein report asymmetric AlAr 3 A C H T U N G T R E N N U N G (THF) additions to ketones catalyzed by titanium catalysts of chiral ligand 2, which have been used in titanium-catalyzed arylzinc additions to ketones.…”