Stereoselective Synthesis of Limonene‐Based Chiral 1,3‐Amino Alcohols and Aminodiols

Abstract

An unexpected ring‐closing reaction of an α,β‐unsaturated carboxylic acid, derived from (R)‐ and ‐(S)‐limonene, in the presence of trifluoroacetic anhydride (TFAA) resulted in bicyclic α‐methylene ketones and their hydroxylated analogues in a stereoselective intramolecular acylation reaction. The reaction was studied in detail, and was optimised for both compounds. The addition of secondary and primary amines to both keto alkenes followed by in‐situ reduction of the resulting aminoketones with sodium borohydride gave new bicyclic terpenoid secondary and tertiary 1,3‐amino alcohols and aminodiols with excellent diastereoselectivities. Regioisomeric aminodiols were prepared stereoselectively from the unsaturated 1,3‐amino alcohols by hydroboration with Me2S·BH3/H2O2.

Regio‐ and Stereoselective Synthesis of Bicyclic Limonene‐Based Chiral Aminodiols and Spirooxazolidines

“…Chiral bicyclic aminodiols were prepared from commercially available (−)‐limonene ( 1 ) starting with regioselective hydroxylation to afford allylic alcohol 2 . The resulting allylic alcohol was oxidized to aldehyde 3 , which was then converted into carboxylic acid 4 by applying a literature method . Intramolecular acylation of isoperillic acid ( 4 ), performed by using earlier methods, resulted in bicyclic methylene ketone 5 as a single product (Figure ).…”

“…THF and toluene were dried with Na wire. ( S )‐Isoperillyl alcohol ( 2 ), ( S )‐ p ‐mentha‐1,8‐dien‐9‐al ( 3 ), ( S )‐ p ‐mentha‐1,8‐dien‐9‐oic acid ( 4 ), and (1 S ,5 S )‐4‐methyl‐7‐methylenebicyclo[3.2.1]oct‐3‐en‐6‐one ( 5 ) were prepared according to literature procedures, and all spectroscopic data were similar to those reported …”

Chiral high‐performance liquid and supercritical fluid chromatographic enantioseparations of limonene‐based bicyclic aminoalcohols and aminodiols on polysaccharide‐based chiral stationary phases

“…Bicyclic 1,3‐aminoalcohols ( 1–3 ), 1,3,5‐aminodiols ( 4 ) and 1,3,6‐aminodiols ( 5 ) (Figure ) were prepared from commercially available (−)‐( S )‐ and (+)‐( R )‐limonene in five steps according to a recently reported method (Le Minh et al, ) and all of the physical and chemical properties of the enantiomeric pairs of 1–5 were identical to those reported. Limonene was regioselectively hydroxylated and the resulting allylic alcohol was oxidized to isoperillic acid in two steps.…”

“…Intramolecular acylation of isoperillic acid resulted in methylene ketones. Aza‐Michael addition of secondary and primary amines on methylene ketones followed by NaBH 4 ‐mediated reduction furnished aminodiols and 1,3‐aminoalcohols in highly stereoselective reactions (Le Minh et al, ).…”

“…Additionally, aminoalcohols and aminodiols are known to be excellent building blocks for the synthesis of noteworthy heterocyclic compounds. The synthesis of new, limonene‐based chiral bicyclic 1,3‐aminoalcohols and aminodiols ( 1 – 5 ) (Figure ) from commercially available (−)‐( S )‐ and (+)‐( R )‐limonene has recently been reported (Le Minh, Fülöp, & Szakonyi, ).…”