Frontalin is a naturally occurring organic compound. It is a

terpenoid The terpenoids, also known as isoprenoids, are a class of naturally occurring organic compound, organic chemicals derived from the 5-carbon compound isoprene and its derivatives called terpenes, diterpenes, etc. While sometimes used interchangeabl ...

and

acetal In organic chemistry, an acetal is a functional group with the connectivity . Here, the R groups can be organic fragments (a carbon atom, with arbitrary other atoms attached to that) or hydrogen, while the R' groups must be organic fragments n ...

that functions as a

pheromone A pheromone () is a secreted or excreted chemical factor that triggers a social response in members of the same species. Pheromones are chemicals capable of acting like hormones outside the body of the secreting individual, to affect the behavio ...

in bark beetles and elephants.

Occurrence

Frontalin acts as an insect pheromone in bark beetles of the genus '' Dendroctonus'', including '' Dendroctonus frontalis'' (''Southern Pine Beetle'') and '' Dendroctonus brevicomis'' (''Western Pine Beetle''), as well as the '' Mountain Pine Beetle''. The biologically active form is predominantly (-)-frontalin. However, (+)-frontalin also occurs in some cases. In ''Dendroctonus frontalis'', the female mainly produces (-)-frontalin, the male mainly (+)-frontalin. In '' Dendroctonus rufipennis'' the distribution is reversed. In addition to its role in insect pheromones, frontalin also serves as a pheromone in Asian elephants. It is secreted by adult male elephants during musth, with secretion levels increasing with age. It signals mating readiness, particularly attracting females who are also in the receptive phase of their sexual cycle.

Biosynthesis

Unlike many

s in bark beetles, which are derived from

terpene Terpenes () are a class of natural products consisting of compounds with the formula (C5H8)n for n ≥ 2. Terpenes are major biosynthetic building blocks. Comprising more than 30,000 compounds, these unsaturated hydrocarbons are produced predomi ...

s present in host plants, frontalin does not follow this pathway. The

biosynthesis Biosynthesis, i.e., chemical synthesis occurring in biological contexts, is a term most often referring to multi-step, enzyme-Catalysis, catalyzed processes where chemical substances absorbed as nutrients (or previously converted through biosynthe ...

in '' Dendroctonus jeffreyi'' and other species of the genus was studied using isotope labeling. The biosynthesis is believed to originate from

acetate An acetate is a salt formed by the combination of acetic acid with a base (e.g. alkaline, earthy, metallic, nonmetallic, or radical base). "Acetate" also describes the conjugate base or ion (specifically, the negatively charged ion called ...

, with geranyl pyrophosphate and 6-methyl-6-hepten-2-one being probable intermediates.

Synthesis

Both enantiomers of frontalin can be synthesized starting from the ester of 8-phenylmenthol with

pyruvic acid Pyruvic acid (CH3COCOOH) is the simplest of the keto acids, alpha-keto acids, with a carboxylic acid and a ketone functional group. Pyruvate, the conjugate acid, conjugate base, CH3COCOO−, is an metabolic intermediate, intermediate in several m ...

. The alcohol component acts as a chiral auxiliary. In the presence of lithium perchlorate, methylmagnesium bromide can be added to the reactant. The resulting hydroxy group can then be reacted with the Cornforth reagent (pyridinium dichromate), followed by the addition of a Grignard compound derived from 5-bromo-2-methylpent-1-ene. Reduction with lithium aluminum hydride removes the chiral auxiliary, yielding a diol. Subsequent reaction with

ozone Ozone () (or trioxygen) is an Inorganic compound, inorganic molecule with the chemical formula . It is a pale blue gas with a distinctively pungent smell. It is an allotrope of oxygen that is much less stable than the diatomic allotrope , break ...

and reductive work-up with dimethyl sulfide produces (-)-frontalin. By reversing the order of the Grignard reagents, i.e., adding methylmagnesium bromide second, (+)-frontalin can be obtained. An alternative synthetic route begins with a Diels-Alder reaction between 3-buten-2-one and methacrylic acid methyl ester. The methyl ester can be reduced to a hydroxymethyl group using lithium aluminum hydride. Oxymercuration with mercury(II) acetate, followed by treatment with

potassium hydroxide Potassium hydroxide is an inorganic compound with the formula K OH, and is commonly called caustic potash. Along with sodium hydroxide (NaOH), KOH is a prototypical strong base. It has many industrial and niche applications, most of which utili ...

/ sodium borohydride, hydroxylates the double bond and allows for direct cyclization to frontalin.{{citation, author=Bradford P. Mundy, Rodney D. Otzenberger, A. Richard DeBernardis , date=August 1971 , doi=10.1021/jo00815a048 , issue=16 , pages=2390 , periodical=The Journal of Organic Chemistry , title=Synthesis of frontalin and brevicomin , volume=36

References

Methyl compounds Oxygen heterocycles Tetrahydropyrans Dioxolanes Heterocyclic compounds with 2 rings