Catalytic Asymmetric Synthesis of Cyclohexanes by Hydrogen Borrowing Annulations

Abstract

Hydrogen borrowing catalysis serves as a powerful alternative to enolate alkylation, enabling the direct coupling of ketones with unactivated alcohols. However, to date, methods that enable control over the absolute stereochemical outcome of such a process have remained elusive. Here we report a catalytic asymmetric method for the synthesis of enantioenriched cyclohexanes from 1,5‐diols via hydrogen borrowing catalysis. This reaction is mediated by the addition of a chiral iridium(I) complex, which is able to impart high levels of enantioselectivity upon the process. A series of enantioenriched cyclohexanes have been prepared and the mode of enantioinduction has been probed by a combination of experimental and DFT studies.

Asymmetric Guerbet Reaction to Access Chiral Alcohols

“…Herein, we disclose that by employing aN oyori Ru-diamine-diphosphine catalyst, well-known in asymmetric hydrogenation, enantiomerically enriched chiral alcohols could be produced from the cross coupling of racemic secondary alcohols with primary benzylic alcohols,providing the first examples of asymmetric Guerbet reaction. Thecatalysis disclosed also adds anew transformation to the asymmetric "borrowing hydrogen" reactions [10] reported by Nishibayashi, [7] Williams, [11] Oe, [12] Adolfsson, [8] Zhao, [13] Beller, [14] Quintard, [15] Zhou, [16] Popowycz, [17] Donohoe [9] and Dydio. [18] It proceeds via an interesting cooperative Ru-catalyzed hydrogen autotransfer and base-catalyzed isomerization process (Figure 1d).…”

“…I nstead, racemization was observed in the presence of ak etone and base without 3a [Eq. (9)], suggesting that the racemization may proceed via abase and carbonyl intermediate through aMPV-type mechanism. [25] As this MPV-type hydrogen transfer is sensitive to steric hindrance, [25] the racemization of sterically bulky products would be slow,w hich fits well with the experimental results.…”

“…[5] Alarge number of catalysts have been reported to catalyze this transformation to give racemic alcohol products (Figure 1b). [6] In related studies, Nishibayashi, [7] Adolfsson, [8] Donohoe [9] and their co-workers showed that enantioenriched alcohol [7,8] or ketone [9] products could be obtained in the cross coupling of ketones with alcohols using chiral Ru or Ir catalysts (Figure 1c). However, asymmetric cross coupling of two alcohols remains elusive.…”

Control of Absolute Stereochemistry in Transition‐Metal‐Catalysed Hydrogen‐Borrowing Reactions

“…[52] Donohoe and coworkers recently reported that pentamethylacetophenone 137 can undergo ahighly enantioselective hydrogen-borrowing annulationw ith diols 138 to synthesize enantioenricheds ubstituted cyclohexanes 139 (Scheme 34). [54] It is thought that the enantiodeterminings tep involves iridium hydride mediated reductiono facyclic enone intermediate via transition state TS-3.T he cyclic nature of the enonei ntermediate enforces a single alkene geometry,t hereby enabling highly enantioselective reduction to form acyl-cyclohexane products such as 139 a-139 b.T he Donohoe group had previously shown that enantiopure g-substituted 1,5-diols react withoutr acemization, [52c,d] and it was found that by matching or mismatching the chiral ligand complex diastereomerically enriched products such as 139 c could be synthesizedi nv ery high yield and diastereoselectivity.…”

“…Moreover, the Ph* group can readily be converted to a wide range of functional groups (e.g., esters, amines, acids and alcohols) by retro‐Friedel–Crafts acylation . Donohoe and co‐workers recently reported that pentamethylacetophenone 137 can undergo a highly enantioselective hydrogen‐borrowing annulation with diols 138 to synthesize enantioenriched substituted cyclohexanes 139 (Scheme ) . It is thought that the enantiodetermining step involves iridium hydride mediated reduction of a cyclic enone intermediate via transition state TS‐3 .…”