Lewis Base Catalyzed Enantioselective Allylation of α,β‐Unsaturated Aldehydes

Abstract

The invention and development of highly enantioselective catalytic reactions with a low catalyst loading is one of the current challenges in organic chemistry. One such area is the activation of reactants by Lewis base/acid pairing.[1] Especially attractive in this regard is the enantioselective allylation of carbonyl compounds (Sakurai-Hosomi reaction) with allylmetals to give chiral homoallylic alcohols that can be used as building blocks in the synthesis of complex molecules. [2] In the last decade, considerable attention has been paid to a possible variant of this reaction based on the activation of allyltrichlorosilane or its derivatives by chiral Lewis bases, such as pyridine N-oxides. A variety of bi-or monodentate [2][3][4][5][6] catalysts have been synthesized and applied in the catalytic allylation of aromatic aldehydes, which is used as a benchmark reaction to assess the catalytic activity and the scope of asymmetric induction. Although in some cases high enantioselectivity was observed, this trend was not general and the asymmetric induction was often highly dependent on the presence of electron-accepting or -donating groups. Another problem is the synthesis of the catalyst being often complicated.We showed that the above-mentioned problems could be overcome by the use of unsymmetrical diastereoisomeric bis(tetrahydroisoquinoline) N,N'-dioxides 1 and appropriate choice of solvent.[7] Lewis bases 1 were prepared in three steps by a one-pot microwave-induced cross-cyclotrimerization [8] of hexadecatetrayne with benzonitrile and (R)-tetrahydrofurannitrile followed by oxidation with MCPBA.The presence of the additional center of chirality within the molecular framework allowed easy separation of both diastereoisomers by using simple column chromatography on silica gel. The correct configuration was unequivocally confirmed by a single-crystal X-ray analysis (Figure 1). Second, the allylation of various benzaldehydes catalyzed by 1 (1 mol %, À78 8C, 1 h) in THF proceeded with high enantioselectivity (up to 96 %) and high yields regardless of electronic properties of the substituents on the aromatic ring. [7a] Although the N-oxide-catalyzed allylation of benzaldehydes has been extensively studied, the reaction with a,bunsaturated aldehydes has been rather neglected. There have been reported allylations of three aldehydes: cinnamaldehyde, [3, 4b,c, 5b-d, 9-11] a-methylcinnamaldehyde, [5c, 9] and 2-decenal [3] with maximum enantioselectivities of 83, 76, and 81 % ee, respectively. The lack of data in this area provided the necessary impetus to study enantioselective allylation by using 1.Initially, the allylation of cinnamaldehyde 2 a with allyltrichlorosilane in the presence of (R,R)-1 (1 mol %, 1 h) was carried out in various solvents and gave 3 a with the following results: 92 % yield, 97 % ee in THF; 40 % yield, 88 % ee in dichloromethane; 43 % yield, 88 % ee in toluene; 84 % yield, 96 % ee in methoxycyclopentane; and 52 % yield, 96 % ee in 2-methylTHF [12] . Interestingly, the reaction in MeCN did n...

On the Mechanism of Asymmetric Epoxidation of Enones Catalyzed by α,α‐L‐Diarylprolinols: A Theoretical Insight

“…In that case, as recently pointed out by Clark et al., only functionals which take into account dispersion forces provide reliable results, of quality comparable to those of post Hartree–Fock correlated methods 21. Moreover B97D was already employed to unravel the reaction mechanism and the origin of enantioselectivity of oxygen superbases and to study the enantioselective allylation of α,β‐unsaturated aldehydes 22,23. The SVP basis set in conjunction with the density fitting approximation was employed in geometry optimizations and frequency computations.…”

Enantioselective Allylation of (2E,4E)‐2,4‐Dimethylhexadienal: Synthesis of (5R,6S)‐(+)‐Pteroenone

“…The use of ( S )‐TRIP‐PA (Figure 2),15 a chiral Brønsted acid,16 to catalyze addition of the allylboronic acid pinacol ester gave rise to 3 in high yields (78–99 %) and with good optical purity (83–87 % ee ) even at low catalyst loadings (Entries 4–7). The allylation with allyltrichlorosilane in the presence of diastereoisomeric ( R,R a )‐ and ( R,S a )‐ N , N ′‐dioxide catalysts (Figure 2) proceeded somewhat disappointingly with regard to asymmetric induction, especially as excellent results have been achieved in the case of allylation of α,β‐unsaturated aldehydes 17. However, these conditions provided 3 with only mediocre optical purity in the range of 55–69 % ee (Entries 8–10).…”

“…It is worth mentioning that in all cases (except Entries 3 and 4) of the TRIP‐PA and N , N ′‐dioxide catalyzed reactions the ( S )‐catalysts gave the (4 S )‐products and vice versa, which is in agreement with the previously observed facial selectivity 15. 17…”

Heteroaromatic N-Oxides in Asymmetric Catalysis: A Review

“…Additionally, the resulting homoallylic alcohols are considered the cornerstones of organic synthesis. Mostly, they are used in the synthesis of numerous natural products as building blocks but also in the synthesis of drug candidates and other functional molecules [11][12][13][14][15][16][17]. Apart from allylation there were also reported examples of using N-oxides in the catalytic ring-opening of meso-epoxides [18][19][20][21], propargylation [22], allenylation [23], aldol reaction [24,25] and reduction of ketoimines [26,27].…”

“…Inversion of product configuration was observed when dichloromethane was applied. N-oxide catalysts were successfully applied to the synthesis of a few natural products [12][13][14][15][16][17]. For example, duloxetine, which is used in the treatment of major depression, was synthesized involving the allylation of 2-thiophenecarboxaldehyde with (aR,S)-34a as catalyst (see Scheme 7) [12].…”