Frontalin : origin and synthesis
by Gérard Dupuis and Nicole Berland
Lycée Faidherbe - LILLE

Also available : CHIME Version

What is frontalin ?

Frontalin, first isolated by G. Kinzer [1], play an important role as volatile signal in sytems of chemical communication among many insect species. This is an aggregation pheromone of a beetle population in the scolitidae family :

Dendroctonus adjunctus Blandford ; Dendroctonus brevicomis ; Dendroctonus frontalis Zimmermann ; Dendroctonus ponderosae Hopkins ; Dendroctonus pseudotsugae Hopkins ; Dendroctonus terebrans (Olivier).

Among these insects, the Dendroctonus frontalis Zimmermann beetle called Southern Pine Beetle (SPB) is the most destructive to pines forest in the southeastern United States.

Photo by USDA forest Service

This picture representes an adult Dendroctonus frontalis Zimmermann beetle. Its length is from 2 to 4 mm and its color varies from brown to black.
The insect attacks pines, makes drills in the bark. The resin flows from these drills and the tree dies.

The molecule of frontalin

Frontalin contains two asymmetric centers. K. Mori [7], [8] has shown that the absolute configuration of the biologically active species is (1S, 5R).

(-)-frontalin, the structure of which shown left, is a tricyclic molecule with an acetal linkage.
C1 : (S) (O > C7 > C2 > CH3)
C5 : (R) (O6 > O8 > C4 > CH3)
Its name in the international nomenclature is :
Because of the rigidity of tricyclic system, only 2 enantiomeric stereoisomer exist : (-)-frontalin and (+)-frontalin.

(-)-Frontaline with link to pdb file

The left picture represents the (-)-frontalin molecule in spacefill representation mode. You can save the molecule file with the right mouse button. You will be able to see the molecule without connection with a visualization program like RasMol.

Biological aspect : mechanism of tree colonization

Pinene with link to pdb file Verbenol with link to pdb file Verbenone with link to pdb file Endobrevicomine with link to pdb file





You can save the molecule file with the right mouse button. You will be able to see the molecule without connection with a visualization program like RasMol.

The complete biosynthetic pathway for frontalin is not yet known. A possible way is the transformation of isoprenoid compounds which is regulated by the enzyme HMG-CoA reductase.
On account of the difficulty to isolate these natural products and of the importance of chemical mediators, several chemists have realized the synthesis since about thirsty years. The first strategies have rested on the racemic synthesis and more recently they rest on the enantioselective synthesis of (-)-frontalin.

Retrosynthetic analysis

The retrosynthetic analysis is shown below :

Since (-)-frontalin (F) can be viewed as being formed by internal acetalization of the dihydroxyketone (T). This precursor contains only one asymmetric center (1S). Although frontalin contains two asymmetric carbon. The configuration at C5 is dictated by the (1S) center during the formation of the acetal linkage.

Synthesis of racemic frontalin

Enantioselective synthesis of the (-)-frontalin

A number of enantioselective syntheses of both (+) and (-)-frontalin have been reported. Three exemples will be given here.


The authors would like to thank Dr. L. Delaude (University of Liège).


[1] G. W. Kinzer; A. F. Fentiman T. F. Page; R. L. Foltz; J. P. Vite; G. B. Pitman Nature 1969, 221, 447.
[2] P. A. Bartlett et J. Myerson, J. Org Chem, 1979, 44, 1625.
[3] P. A. Bartlett et al, J. Chem Ed, 1984, 61, 816-817.
[4] M. C. Trinth, J-C Florent et C. Monneret, J. Chem. Soc. Chem. Comm. 1987, 615.
[5] M. C. Trinth, J-C Florent et C. Monneret ; Tetrahedron, 1988, 44, 6633.
[6] Sharpless asymmetric dihydroxylation : J. A. Turpin; L. O. Weige; Tetrahedron Lett. 1992, 33, 6563.
[7] K. Mori Total Synhesis of Natural products; Ap Simon, J. Ed., John Wiley & Son : New York 1992; Vol. 9 and Vol. 4.
[8] K. Mori Tetrahedron 1975, 31, 1381.


[9] Synthesis of frontalin using a Chiral Silyl Ether
[10] TP Université de Liège
[11] Frontalin Project Home Page

Biosynthesis of frontalin in the Jeffrey Pine Beetle
Biosynthesis of bark beetle aggregation pheromones
Enzymatic and microbial hydrolyse of epoxydes
Asymmetric hydrolysis of epoxydes

Biological aspects
Attractive and inhibitory pheromones produced in the bark beetle Dendroctonus Brevicomis
Chemical ecology of the Southern Pine Beetle
SPB Update. Utilisation de la verbenone
The Southern Pine Beetle


For educational purpose - No commercial use

Page created by Gérard Dupuis - Lycée Faidherbe LILLE
This site was last updated December 2000