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What is frontalin ?

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.

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).

Biological aspect : mechanism of tree colonization

• Initial attack
  The aggregation mechanism of these insects isn't perfectly known but it seems that the volatil compounds producted by the trees attract some female insects (the main constituant of the volatil compounds is a monoterpene called a-pinene). The females create a mixture of (-)-frontalin, trans-verbenol and verbenone. These products have to effect to attract a lot of other male and female insects. The trans-verbenol and the verbenone intensify the attracted character of (-)-frontalin.
  

• Mass attack
  After the initial attack and during three or five days, males and females reproduce and continue to produce (-)-frontalin, trans-verbenol and verbenone. When a concentration threshold of the two last substances is obtained, these ones inhibit the (-)-frontalin and then stop the aggregation.

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

• The P. A Bartlett, J. Myerson route [2], [3].
  

  

  

  The key reaction is the opening of epoxyd catalysed by an acid with the participation of a neighbouring carbonyl group.

  

Enantioselective synthesis of the (-)-frontalin

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

• Utilisation of a chiral substrate as starting material.

  M. C. Trinth, J-C Florent, C. Monneret [4], [5] used a derivative of lactose as chiral substrate.

  

  

  

  

• Utilisation of chiral silyl ether as an auxiliary to control stereoselective processes.
  M. Trzoss and S. Bienz [9] investigate the utilisation of a silyl ether as a protective and stereochemically directing group.

  First step is the preparation of the a-siloxyketone (2).

  

  p facial selectivity under the influence of the chiral (tert-butyl)(methyl)(benzyloxymethyl)silyl group is not very high. The addition of Grignard reagent G to a-siloxyketone (2) leads with only low stereoselectivity to the alcohols (3/3') (60 : 40) precursors of frontalin F.

  

  

• Utilisation of Sharpless asymmetric dihydroxylation.
  J. A. Turpin, L. O. Weige [6] used the adaptation of ligand accelerated catalytic asymmetric dihydroxylation. AD-mix a is a mixture of 1,4-bis-dihydroquinine phtalazine ligand (DHQ)₂PHAL, potassium ferricyanide, potassium carbonate and potassium osmate. This reagent makes the oxydation protocol exceptionally simple.

  

  This methodology gives frontalin with 60-70 % ee.

Bibliography

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

Biosynthesis
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 aspect
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