Organocatalytic Entry to Chiral Bicyclo[3.n.1]alkanones via Direct Asymmetric Intramolecular Aldolization

Abstract

[reaction: see text] The facile stereoselective syntheses of endo-8-hydroxybicyclo[3.3.1]nonan-2-one and endo-7-hydroxybicyclo[3.2.1]octan-2-one, featuring an alpha-amino acid catalyzed intramolecular aldolization of sigma-symmetric substrates, are described. A high enantioselectivity and a high catalytic efficiency have been exhibited by (4R,2S)-tetrabutylammonium 4-TBDPSoxy-prolinate in the aldolization of 3-(4-oxocyclohexyl)propionaldehyde to give highly enantiomerically enriched (1S,5R,8R)-8-hydroxybicyclo[3.3.1]nonan-2-one.

Highly Diastereo‐ and Enantioselective Direct Aldol Reactions of Aldehydes and Ketones Catalyzed by Siloxyproline in the Presence of Water

“…The cissiloxy-d-proline 8 was prepared according to the literature procedure. [34] Catalyst screening: The aldol reaction of benzaldehyde (1 equiv) and cyclohexanone (5 equiv) was performed using 10 mol % of the organocatalyst in the presence of water (18 equiv) for 18 h at room temperature. The results for the organocatalysts investigated are summarized in Table 1.…”

“…[34] While trans-4-hydroxy-l-proline is inexpensive, its enantiomer, trans-4-hydroxy-d-proline, is very expensive. Therefore, either enantiomer of the aldol product may be easily synthesized by judicious choice of either trans-siloxyl-proline 7 or cis-siloxy-d-proline 8, both of which are available from the same inexpensive starting material.…”

Primary Amino Acid Lithium Salt-Catalyzed Asymmetric Michael Addition of Carbon Nucleophiles to Enones

“…Therefore, cyclohexane was chosen as a solvent for further investigations. 100 72 9 2 MeOH 100 62 4 3 MeCN 11 11 59 4 AcOEt 24 24 68 5 THF 27 22 68 6 CH 2 Cl 2 41 28 68 7 Toluene 60 45 65 8 Cyclohexane 94 69 70 a The reaction was carried out with 2a (0.6 mol), 3a (0.5 mmol) and 1a (0.15 mmol) in a solvent (1 mL) at 25 °C for 72 h; We then synthesized various siloxy amino acids and their alkali metal salts from L-serine, L-threonine (Thr) and L-tyrosine (Tyr) to perform a catalyst screen in cyclohexane (Table 2) [33][34][35][36][37][38][39][40]. Since L-serine derived catalyst 1a gave better results in both yield and enantioselectivity of 4a than did Thr(O-TBS)-OLi (1b) and Tyr(O-TBS)-OLi (1c), L-serine was selected as a basic amino acid and used for further modification of the catalyst ( Table 2, entries 1-3).…”

2.07 The Aldol Reaction: Organocatalysis Approach

“…Interestingly, opposite enantiopreferences are found in the transformation of 79 to (S)-81 with cis-siloxy proline 82. 43 Enantiopurity of the bicyclic aldol (S)-81 is increased up to 99% ee after recrystallization. A stereocontrolled synthesis of (−)-CP55,940 (83), a potent cannabinoid receptor agonist, has been attained by employing this organocatalytic asymmetric aldol reaction.…”