Enantioselective Diels–Alder Reactions with Anomalous endo/exo Selectivities Using Conformationally Flexible Chiral Supramolecular Catalysts

Abstract

On the basis of Woodward-Hoffmann frontier molecular orbital interactions and steric interactions between dienes and dienophiles during the formation of [2+4] pericyclic transition states, endo/exo selectivity in the Diels-Alder reaction strongly depends on the substrates.[1] Therefore, it is quite difficult to control both enantioselectivity [2] and anomalous endo/exo selectivity by conventional chiral catalysts, which can discriminate only the enantiofaces of the dienophiles. For example, in the reaction between cyclopentadiene (1) and acrolein (2 a), an endo preference is observed with regard to second-order orbital interactions without significant steric interactions [Eq. (1)]. In sharp contrast, in the reaction between 1 and an a-substituted acrolein (R ¼ 6 H), such as methacrolein (2 b), an exo preference is observed with regard to steric interactions between the methylene moiety of 1 and the substituent R at the a position of the dienophile [Eq. (2)]. Therefore, enantiomerically enriched endo-3 a and exo-3 b have been synthesized by using many conventional chiral catalysts.[2] Moreover, thermodynamically more stable and enantiomerically enriched exo-3 a can be generated by the epimerization of endo-3 a [Eq. (1)]. Alternatively, catalystinduced anomalous exo-selective Diels-Alder reactions that contravene the endo rule have been performed by Yamamoto and co-workers [3] in a non-asymmetric manner, and later by Maruoka and co-workers, [4] Sibi et al., [5] and Hayashi et al. [6] in an asymmetric manner. In contrast, enantiomerically enriched endo-3 b with a quaternary carbon center can not be generated by the epimerization of exo-3 b or by other known synthetic methods [Eq. (2)]. To the best of our knowledge, no examples of catalyst-induced anomalous endo-selective enantioselective Diels-Alder reactions with a-substituted acroleins have been reported to date. To address this major yet unexplored subject, catalysts must discriminate chiral transition-state structures by precisely recognizing the re or si face of dienophiles, and the endo or exo approach of dienes, thus, the rational design of conformationally flexible chiral supramolecular catalysts, such as enzymes, is necessary. [7] As such, conformationally rigid metal-organic frameworks (MOFs) are not suitable as artificial enzymes because they have few induced-fit properties to adapt dynamics in transition states. [8] A chiral supramolecular catalyst (4 a) was readily prepared in situ from three components, which included 10 mol % of chiral (R)-3,3'-bis(5,5-dimethyl-2-oxido-1,3,2-dioxaphosphorinan-2-yl)-BINOL (5 a; BINOL = 1,1'-bi(2-naphthol)), [9] 10 mol % of 3,5-bis(trifluoromethyl)phenylboronic acid (6 a), and 20 mol % of tris(pentafluorophenyl)borane (7), by taking advantage of the typical preparation of boron BINOLates [10] (Scheme 1). Intermolecular acid-base coordinate bonds in the two P=O···B(C 6 F 5 ) 3 moieties [11] are critical for the design of conformationally flexible complex 4 a; compound 7 acts as a bulky functional group to form a ch...

Brønsted Acid/Lewis Base Hybrid Complexes

“…However, as a working model to explain the anomalous stereoselectivity, a chiral, narrow, and deep cavity is assumed due to the six bulky C 6 F 5 moieties. In this regard, theoretical calculations for a 28b-41 complex with the B3LYP/6-31G* method supported that the two non-covalent P¼O···B(C 6 F 5 ) 3 moieties have a syn-conformation (48) on one hand and an anti-conformation (49) on the other hand [102] (Fig. 7).…”

“…They expected that this acid-base activation system, in particular with possible bulkiness based on the C 2 -symmetric chiral BINOL moiety, might be applicable to the design of novel conformationally flexible chiral supramolecular catalysts. In such a situation, Ishihara developed a new type of conformationally flexible, highly active, chiral supramolecular catalyst based on well-designed single-molecule components [102,103]. A chiral supramolecular catalyst (41) was readily prepared in situ from three components, including 10 mol% of chiral (R)-3,3 0 -bis (5,5-dimethyl-2-oxido-1,3,2-dioxaphosphorinan-2-yl)-BINOL (42), 10 mol% of 3,5-bis(trifluoromethyl)phenylboronic acid (43), and 20 mol% of tris(pentafluorophenyl)borane (44) [102] (Scheme 8).…”

“…In such a situation, Ishihara developed a new type of conformationally flexible, highly active, chiral supramolecular catalyst based on well-designed single-molecule components [102,103]. A chiral supramolecular catalyst (41) was readily prepared in situ from three components, including 10 mol% of chiral (R)-3,3 0 -bis (5,5-dimethyl-2-oxido-1,3,2-dioxaphosphorinan-2-yl)-BINOL (42), 10 mol% of 3,5-bis(trifluoromethyl)phenylboronic acid (43), and 20 mol% of tris(pentafluorophenyl)borane (44) [102] (Scheme 8). Since the arylboronic acid 43 is usually allowed at hydrolysis equilibrium with the triarylboroxin 46 (Eq.…”

“…Among the possible transition states, a si-face attack would be disfavored due to enantio-face control by a C 6 F 5 group. In a possible transition state (TS)-50, an endo-approach inside the cavity via a re-face attack would be relevant, while an exo-approach via a re-face attack (TS-51) would be unlikely because of the bulkiness of another C 6 F 5 group [102] (Fig. 8).…”

“…To demonstrate other anomalous endo-selective Diels-Alder reactions, the reactions between 27 and α-haloacroleins, which usually provided exo-adducts as major products (Scheme 10), were examined [102]. Electron-deficient α-haloacroleins are extremely reactive, and thus their enantioselective DielsAlder reactions have been especially limited.…”