AP Chem
Poison Dart Frogs
Dendrobates azureus
Poison dart frogs are frogs from the family Dendrobratidae. There are no confirmed cases of poison
from any of these frogs being used to tip a dart but they’re still called poison dart frogs. It is unclear
whether the frogs produce the poisons they are known for or if they acquire the toxins from their diet.
Regardless, the frogs are fascinating and beautiful as are the molecules related to them.
Most poison dart type frogs are native to the Americas but some are from Madagascar. All of these
frogs are small and most are brightly colored. Most are endangered by habitat loss. The frogs’ fame (or
infamy) comes from the fact that the poison could have been used to tip darts used for hunting by
Native Americans. While the biology of the frogs is interesting we’ll focus on the chemistry.
Mantella baroni, a frog native to Madagascar
Mantella pulchra
One toxin utilized by frogs is pumiliotoxin 251D. This molecule is bicyclic, that is, it has 2 rings. It turns
out that 5 and 6 membered rings are the most stable so they are the most commonly found. The
molecule also has a 6 carbon side chain. There is a tertiary amine, an alcohol, and an alkene. There are
also 3 chiral carbons. Some frogs convert this molecule to allopumiliotoxin 267A which is more toxic.
Pumiliotoxin251D
Allopumiliotoxin267A
Epibatidine is of interest because it is a general anesthetic. Unfortunately it causes intestinal distress in
patients. The molecule has an aromatic ring with a nitrogen. This part of the molecule is similar to the
molecule pyridine so we call this part of epibatidine a pyridine moiety.
Epibatidine
Pyridine
Histrionicotoxin is interesting because the two rings only share one carbon atom. Alkynes are relatively
uncommon in natural products but it has two alkyne groups.
Histrionicotoxin
Batrachotoxin is a much more complex molecule than the others we’ve looked at. The 4 rings on the
left side of the structure are the structure that is the basis of steroids. Steroids are common in
biochemistry so it makes sense for Nature to choose a steroid as the basis of a molecule.
Batrachotoxin
Below are some pictures of these amazing animals:
Questions:
1.
2.
3.
4.
5.
6.
7.
What functional groups are present in histrionicotoxin?
What functional groups are present in batrachotoxin?
Identify all the rings present in batrachotoxin. Tell how many of each element are in the ring.
Which nitrogen atom in batrachotoxin is more basic? Explain.
Tell whether epibatidine is less or more basic than pyridine. Explain.
Which nitrogen in epibatidine is more basic? Explain.
Show the product that results when batrachotoxin undergoes hydrolysis.
8. Show the product that results when batrachotoxin undergoes saponification.
9. Propose a synthesis of pumiliotoxin 251D from this precursor (alkene)
10. Propose a synthesis of allopumiliotoxin 267A from this precursor (alkene)
Answers:
1. Alcohol, alkene, ester, ether, amine,
2. Alcohol, amine, alkene, alkyne
3. 6,6,6, nad 5 carbons for the 4 steroid rings.
5-membered pyrrole moiety ring
7-membered ring with N and O
6-membered ring with ehter O
4. One of the nitrogens is a tertiary amine, the other is a pyrrole nitrogen. (Google pyrrole) Look
closely at the pyrrole moiety. It has 4 sp2 carbons with conjugation. If the pyrrole N is sp3 it’s
just a molecule. If the pyrrole N is sp2 then the lone pair on the N can participate in the
conjugation, putting 6 electrons in the conjugated pi system. If n=1 then 4n+2 = 6 so 6 electrons
is aromatic. These 2 electrons are delocalized into the conjugated pi system and are not very
basic. To have them bond with an H+ would mean the molecule is no longer aromatic.
5. The secondary amine N is sp3 and the pyridine N is sp2. Sp2 is more electronegative than sp3 so
the secondary amine should be more basic. Add this to the fact that there is an electronegative
atom (Cl) adjacent to the pyridine N and it is clear that the secondary amine N is more basic.
6. See 5
7. Hydrolysis will break the ester bond and produce a carboxylic acid and an alcohol.
8. Saponification will break the ester bond and produce the salt of a carboxylic acid and an alcohol.
9. We’ll ignore the basicity of the N for now. We’ll add H+ and H2O and do an addition.
Conveniently, there is a methyl group for us that makes the carbon it is attached to more
substituted than the other carbon of the alkene group. We’ll ignore the possibility that the
other alkene could also react for now.
10. We’ll ignore the N and the other alkene for now. We could add permanganate or osmium
tetroxide to make a diol. The problem is the diol would be cis. We need the OH groups on
opposite sides of the molecule. The way to do this is to make the epoxide, then open it with
hydroxide. There is a name reaction that would give us the product we want, the Prevost
reaction.