Highly selective aluminium-catalysed intramolecular Prins reaction for l-menthol synthesis

Abstract

An aluminium complex bearing 2-cyclohexyl-6-phenylphenol afforded (5R)-n-isopulegol from (R)-citronellal via the intermolecular Prins reaction with an exceptionally high diastereoselectivity. Using this reaction, L-menthol was obtained with an excellent diastereoselectivity.Intermolecular and intramolecular ene reactions, especially the Prins reaction between carbonyl and olen compounds with Lewis or Brønsted acids, have received great attention. 1 A common application of the Prins reaction is the synthesis of (5R)-isopulegols (2) from (R)-citronellal ((R)-1) (Scheme 1).These are valuable intermediates for the synthesis of Lmenthol (3), one of the most popular fragrances in the world; 2 notably, only (5R)-n-isopulegol (2a) leads to the formation of (3). Hence, a variety of methods has been reported for the diastereoselective cyclisation of citronellal to isopulegol. 3-10 For instance, zinc bromide is used as a catalyst for this cyclisation in an industry process, which provides 2a with 92% of diastereomeric purity. 4a In addition, various other aluminium complexes have been recently proposed as only catalysts that afford (5R)isopulegols with a high diastereoselectivity. 11-14 For instance, tris(2,6-diphenylphenoxy)aluminium complex (ATPH, 4a), 14 which was prepared from triethylaluminium and 2,6-diphenylphenol (5a), has been used to carry out the Prins reaction of citronellal with a diastereoselectivity larger than 99% and 94% selectivity of 2 at 0 C. 11 However, 4a shows the excellent performance in a narrow temperature range. So, it's demanded a catalyst that provides higher reactivity and same diastereoselectivity, in order to apply it to a variety of industrial processes. In this work, we present aluminium catalysts with unprecedented excellent diastereoselectivity for the citronellal cyclisation.Firstly, we prepared tris(2-cyclohexyl-6-phenylphenoxy) aluminium complex (ACPP, 4b) with triethylaluminium and 2cyclohexyl-6-phenylphenol (5b). (R)-Citronellal ((R)-1) gave (5R)n-isopulegol (2a) in the presence of ACPP with 78% conversion, 95% selectivity of (5R)-isopulegols (2) and diastereoselectivity larger than 99% at À20 C while ATPH (4a) afforded 2a with 54% conversion (Scheme 2). A catalyst with such an excellent selectivity and reactivity has never been reported.We next investigated the reactivity of ACPP with a variety of reaction conditions. In particular, 3 mol% of ACPP afforded Scheme 1 Synthesis of L-menthol (3) from (R)-citronellal (1).

Synthesis of (−)‐menthol: Industrial synthesis routes and recent development

“…Diastereoselective cyclization of (+)-citronellal, catalysed by homogeneous aluminium complexes, was explored by Itoh et al from the company Takasago. 91,92 They reported an excellent diastereoselectivity for (−)-isopulegol of 99.5%, with an overall yield of 95% with the 2-cyclohexyl-6-phenylphenol ligand on a 100 g scale. 91 After hydrogenation with Raney-Nickel, (−)-menthol was obtained with 91% yield and 99.5% diastereomeric purity.…”

“…91,92 They reported an excellent diastereoselectivity for (−)-isopulegol of 99.5%, with an overall yield of 95% with the 2-cyclohexyl-6-phenylphenol ligand on a 100 g scale. 91 After hydrogenation with Raney-Nickel, (−)-menthol was obtained with 91% yield and 99.5% diastereomeric purity. High diastereoselectivity of 94% for (±)-isopulegol, with >95% yield for isopulegols has been reported with scandium triflate as homogeneous catalyst.…”

MOF-based heterogeneous catalysis in continuous flow via incorporation onto polymer-based spherical activated carbon supports

“…40 For the cyclisation step, Takasago report the use of a homogeneous tris(2,6-diarylphenoxy)aluminum catalyst offering a benchmark diastereoselectivity towards (−)-isopulegol formation of 99.3%. 49…”

“…40 For the cyclisation step, Takasago report the use of a homogeneous tris(2,6-diarylphenoxy)aluminum catalyst offering a benchmark diastereoselectivity towards (−)-isopulegol formation of 99.3%. 49 Due to the industrial significance of this reaction, it is frequently used to quantify and compare the Lewis acidic catalytic activity of novel catalysts, both homogeneous and heterogeneous, 50 with the use of the more economical racemic equivalent, (±)-citronellal, often preferred. When studying this reaction using a novel Lewis acid catalyst, which is most frequently done in a batch mode of operation, important metrics include the rate of the reaction as well as the selectivity towards the formation of (±)-isopulegols and diastereoselectivity towards (±)-isopulegol formation.…”

Corymbia citriodora: A Valuable Resource from Australian Flora for the Production of Fragrances, Repellents, and Bioactive Compounds

“…As part of their patented process, Takasago make use of aluminum complexes 15a and b to produce selectively pure (-)-2 from (+)-1 by Prins cyclization [50,[52][53][54][55]. A recent improvement of the process was reported by Itoh and coworkers in 2014 [53], whereby a high-performing new aluminum complex 15b was developed and applied to a 100 g (1) scale reaction. The complex was generated in situ from the corresponding 2-cyclohexyl-6-phenylphenol (16) and triethylaluminum (Et 3 Al).…”