Total Synthesis Blog

Today, in the end of the year , some new total synthesis – (+)-Kalafungin. The structure of this target is shown below:

(+)-Kalafungin was isolated for the first time in 1968 from Streptomyces tanashiensis fungi and it exhibits some antibiotic properties. Retrosynthesis of that target is shown below:

As you can see, there are some interesting conversions in the retrosynthetic plan. In my opinion tandem Michael-Dieckmann and intramolecular tranesterification steps are very tricky (and look very very nice ). Also undergone isomerisation and oxidation by atmospheric oxygen have great synthetic utility.

The whole synthesis was completed as shown below:

Transformation of starting material, (S)-aspartic acid (1) starts with diazotization of amine group followed by exchanging diazonium group to bromine (with inversion of configuration – S_N2 mechanism). Next reduction of carboxylic groups occurs and converting of bromohydrine to corresponding epoxide can be completed. By treatment TBSCl on such epoxy-alcohol, TBS-protected epoxy-alcohol 2 is formed.

Transformation of 2 to 4 (throug epoxide-ring opening) is undergone under standard conditions. Cyclization of 4 to lactone 5 occurs in the presence of methanolic solution of sodium methoxide. This is very interesting step. I’ve wondered a lot about mechanism of thar conversion… I’ve published my try on the next page, I think it can be possible (I hope so).

Next, we have second interesting step in that synthesis. Tandem Michael-Dieckmann reaction ! Nice! My own mechanism of that step is also drawn on the next page. I just wonder about acidity of hydrogen atom in methyl group in 6. Nice way to complete substituted anthracene-like systems, by the way.

Conversion of 7 to 8 includes Grignard addition to carbonyl group of lactone an deprotection of TBS, That’s interesting that phenolic -OH group can be present while Grignard addition occurs

8 is then oxidized by NBS and cerium-ammonium nitrate (CAN) to form 9. Then methoxy group in 9 is deprotected to OH on the presence of Lewis acid, AlCl₃. Next, side chain is oxidized to carboxylic group and then, in the presence of atmospheric oxygen, oxidation and lactonizaton take place. The last step in which (+)-kalafungin, 13, is formed, occurs in the presence of sulfuric acid.