Frontalin is an aggregation pheromone of the Southern Pine Beetle.
It possesses an interesting tricyclic structure containing an
acetal linkage. The synthesis is a five step process with the
ring construction occurring in the last step by an acid catalyzed
reaction on an acyclic precursor. The initial reaction is formation
of a tosylate which is displaced by an anion formed from acetoacetate.
After elimination of the beta-keto acid, the alkene is epoxidized
to give the precursor to frontalin.
The table below lists the chemicals that we will have available for this project. If you need something that is not on this list, consult with the mentor for your project. Also note the "Amount/group" column. This is the total amount of material available for each group to use on the project.
| Reagent | Source | Amount/group | Location | Comments |
|---|---|---|---|---|
| p-Toluenesulfonyl chloride | Aldrich Cat. # 24,087-7 |
15 g | TA room | |
| 1,4-Diazabicyclo[2.2.2]octane (DABCO) | Aldrich Cat. # D2,780-2 |
15 g | TA room | |
| 3-methyl-3-butene-1-ol | Aldrich Cat. # 12,940-2 |
8 mL | TA room | |
| Sodium ethoxide 21 wt% solution in denatured ethyl alcohol |
Aldrich Cat. # 23,055-3 |
10 mL | TA room | Last year we tried to use solid sodium ethoxide purchased from Aldrich with limited success. This year I am ordering the sodium ethoxide as a 21% solution in ethanol. Alternately, you may try forming the sodium ethoxide by adding sodium metal to absolute (i.e., 100%) ethanol. (Consult with your instructor for a proper procedure.) |
| Ethyl acetoacetate | 5 g | TA room | ||
| 3-chloroperoxybenzoic acid (MCPBA) | Aldrich | 5 g | Fridge |
| Lab Day | Name | |
|---|---|---|
| Monday | Karen Ecklebe | kecklebe@ups.edu |
| Monday | Trina Blair | tblair@ups.edu |
| Tuesday | Linnea Erickson | lerickson@ups.edu |
| Tuesday | Brian Weiderman | bweiderman@ups.edu |
| Wednesday | LTeri Longworth | tlongworth@ups.edu |
| Wednesday | Lindsey Koepke | lkoepke@ups.edu |
| Thursday | Melissa Krick | mkrick@uswest.net |
| Thursday | Tomoko Kiyonaga | tkiyonaga@ups.edu |
| Friday | Doug Young | dyoung@ups.edu |
| Friday | Sera Yee | syee@ups.edu |
Step 1: Tosylation
For the past few years we have used a modified procedure for the tosylation. This modified procedure uses TsCl with DABCO as a base. This eliminates the need to use pyridine (which is rather stinky). I have included information from the original article below.
This could be a much better procedure for tosylation since it avoids the use of pyridine!
Hartung, J.; Hunig, S.; Kneuer, R.; Schwarz, M.; Wenner, H. "1,4-Diazabicyclo[2.2.2]octane (DABCO) - an Efficient Reagent in the Synthesis of Alkyl Tosylates or Sufenates" Synthesis 1997, 1433-1438.
Abstract: The bicyclic tertiary amine 1,4-diazabicyclo[2.2.2]octane (DABCO) is a promising substitute not only for the widely used but hazardous and hygroscopic base pyridine in the synthesies of alkyl tosylates 3 but also for triethylamine in the preparation of alkyl sulfenates 4 from sterically hindered alcohols 2. In several provided examples the substrates 2 were completely converted into the desired products, e.g. the respective tosylates 3, which minimized subsequent separation processes. The current protocol points, in a number of cases, to nonchlorinated solvents as good alternatives to chloroform or dichloromethane and offers a workup procedure for a larger scale reaction which relies on the removal of the side products by filtration instead of the traditional extratction method using several aqueous washings.
In the general procedure they note that TsCl was recrystallized from cyclohexane.
Synthesis of O-Esters (3,4); General Procedure:
A round-bottom flask was charged with a solution of DABCO (2.24 g, 20 mmol, 10 mL of anhydrous solvent) and alcohol 2 (10 mmol) and was stoppered with a drying tube (CaCl2). The mixture was cooled to 0 C (ice bath). The respective acid chloride (in our case, tosyl chloride, 15 mmol, neat) was added in small portions over a period of 5 min which was paralleled by the formation of a precipitate. The slurry was stirred for 1h at 0 C and after removal of the ice bath until all starting alcohol 2 has been consumed [14-24 h for tosylates 3, tosylation studies using primary alcohols (not shown in Table 1) indicate that these substrates are converted to the respective tosylates within 1-3 h. It is advantageous to work up these mixtures immediately rather than allowing an extention of the reaction period to 24 h.]. The mixture was filtered and the precipitate was repeatedly washed with t-BuOME (total volume of 50 mL). The filtrate was extracted with 2 M HCl (2 x 20 mL), with 5% NaHCO3 (20 mL) and with H2O (20 mL). The organic phase was dried (MgSO4 and concentrated in vacuo. The oily to solid residues were purified by column chromatography (silica gel) using the given eluent.
Notes and Suggestions