Defining Pathways of Anaerobic Alkane Oxidation: Synthesis of Enantiomers of 4‐Methylalkanoic Acids and (2‐Methylalkyl)malonic Acids

Abstract

The coenzyme A (CoA) esters of 4‐methylalkanoic acids are pivotal intermediates in metabolism of alkanes by anaerobic bacteria found in O2‐deprived environments. A generic method for synthesis of either (R)‐ or (S)‐acid in high enantiomeric purity from enantiomers of methyl 3‐hydroxy‐2‐methylpropionate is described for (R)‐ and (S)‐4‐methyloctanoic acid and (R)‐4‐methyldodecanoic acid. In a typical procedure silyl‐protection of methyl (S)‐3‐hydroxy‐2‐methylpropionate was followed by reduction of the ester to a primary alcohol, which was tosylated. Cu(I)‐catalysed cross‐coupling of the tosylate with propylmagnesium chloride followed by deprotection, tosylation and base‐induced reaction with di‐t‐butyl malonate, gave di‐t‐butyl (R)‐(2‐methylhexyl)malonate. Microwave heating of the diester in 2,2,2‐trifluoroethanol gave a 42 % overall yield of (R)‐4‐methyloctanoic acid, which was shown to be the enantiomer derived by metabolism of hexane by proteobacterium Aromatoleum sp. HxN1. Deprotection of the diester with trifluoroacetic acid gave (R)‐2‐(2‐methylhexyl)malonic acid, which is the biological precursor of (R)‐4‐methyloctanoic acid (via CoA esters).

Recent advances in the synthesis of insect pheromones: an overview from 2013 to 2022

“…Fig. 7 shows the methyl-branched pheromones of Tenebrio molitor (Col., Tenebrionidae): (R)-156, [124][125][126][127][128] Oryctes rhinoceros (Col., Dynastidae): 157, [128][129][130][131] Kheper nigroaeneus (Col., Scarabaeidae): (R)-158, 126,128,132 Oryctes rhinoceros (Col., Dynastidae): 159, 133 Euproctis pseudoconspersa (Lep., Erebidae): 160, 134,135 Miltochrista calamina (Lep., Erebidae): (5R,7R)-161 136,137 palm weevils (Col., Curculionidae): (4S,5S)-162 and (4S,5S)-163, 138 Rhynchophorus ferrugineus (Col., Dryophthoridae): 164, 165, 133,139 Scolytus multistriatus (Col., Curculionidae): 166, 140 Sitophilus granarius (Col., Dryophthoridae): 167, 141 Diabrotica longicornis (Col., Chrysomelidae): (2S,8R)-168, 142,143 Bicyclus spp. (Lep., Nymphalidae): 169, 144 Cryptothelea variegata (Lep., Psychida): (3R,13R,3 ′ S)-170, 145,146 Eurytoma maslovskii (Hym., Eurytomidae): (2S,10R)-171, (2S,8S)-and (2S,8R)-172, 147 Pellaea stictica (Hem., Pentatomidae): 173, 148,149 Edessa meditabunda (Hem., Pentatomidae): 174, 150 Trichogramma turkestanica (Hym., Trichogrammatidae): 175, 151 Margarodes prieskaensis (Hem., Margarodidae): 176, 177.…”