Synthesis of 10-Carbonyl and 10-Carboxylic Derivatives of para-Mentha-1,8-Diene-5,6-Diol

Abstract

The synthesis of 10-carbonyl and 10-carboxylic derivatives of para-mentha-1,8-diene-5,6-diol (1) that exhibited high anti-Parkinson's activity was described. The synthesis of these compounds was an important programmatic component in a study of the metabolism of 1.Our previous discovery [1, 2] that (4S,5R,6R)-para-mentha-1,8-diene-5,6-diol (1) exhibited high anti-Parkinson's activity stimulated further studies of it. The absolute configuration of 1 affected its anti-Parkinson's activity [1]. It was important to include all functional groups (double bonds and hydroxyls) in the molecule [3]. Metabolism studies represent a key phase of pharmacokinetic investigations. As a rule, mass spectra of monoterpenoids are very difficult to relate reliably to their structures without mass spectrometric data of the pure compounds, which makes it necessary to synthesize them.According to literature data on the metabolism of para-menthane monoterpenoids [4][5][6][7], the formation of products from methyl hydroxylation and further oxidation to carbonyl compounds were expected. We synthesized earlier hydroxyderivatives 2 [8] and 3 [9]. The methods for synthesizing these and other similar alcohols were recently reviewed by us in detail [10].The goal of the present work was to synthesize 10-carbonyl and 10-carboxylic derivatives of 1. The first task was to prepare 2-[(1S,5R,6R)-5,6-dihydroxy-4-methylcyclohex-3-enyl]acrylaldehyde (3). The simplest approach seemed to involve oxidation of triol 2. However, its reaction with MnO 2 formed reaction mixtures with <30% of target aldehyde 3 according to PMR and GC-MS data.We used bromide 4 as a key intermediate in the synthesis of triol 2 [8]. Also, bromides are known to be capable of transforming into the corresponding aldehydes via alkylation of nitro compounds followed by Nef hydrolysis [11,12] or Kornblum oxidation by 14]. However, instead of the expected reaction with EtNO 2 , 4 underwent an intramolecular heterocyclization to form bicyclic product 5 in quantitative yield (Scheme 1). We prepared previously 5 in 15% yield via the reaction of 4 with n-BuLi [8]. Thus, the newly found version for performing the intramolecular cyclization turned out to be much more effective. Kornblum oxidation of 5 via reaction with DMSO in CCl 4 formed a complicated product mixture with total contents of identified 3 and 5 of <7%. 1) N. N. VorozhtsovOH OH 1 3 5 9 7 OH OH OH OH OH O 1 2 3

The First Synthesis of (4S,5R,6R)‐5,6‐Dihydroxy‐4‐(prop‐1‐en‐2‐yl)cyclohex‐1‐ene‐1‐carboxylic Acid

“…It should be noted that the presence of severalf unctional groups of comparable reactivity and three asymmetric centers in 1 causes considerable difficulties in planningand performing its transformations [7] [8].However,previously,wesuccessfully synthesizedanumber of derivatives of 1 (triols 2 [9]a nd 3 [10], and lactone 4 [11])t hat can be considered as possible metabolites. Theaim of this work was the synthesis of carboxylic acid 5.…”