Enantioselective Total Synthesis of (-)-Napyradiomycin A1 via Asymmetric Chlorination of an Isolated Olefin

Enantioselective Total Synthesis of (-)-Napyradiomycin A1 via Asymmetric Chlorination of an Isolated Olefin

Scott A. Snyder, Zhen-Yu Tang, and Ritu Gupta

DOI: http://dx.doi.org/10.1021/ja9014716

Hello again! It’s almost a month ago since my last post so I decided to dig out this short synthesis with some nice new chemistry in it as mentioned in the headline.

This time an interesting halogenated natural product (chosen to demonstrate their powerful method) with only 3 stereocenters of which 2 were captured by chlorine. This class of Napyradiomycins exhibit antibacterial activity against methicillin- and vancomycin-resistant strains and some anti tumour activity (some infos about MRSA can be found here: http://en.wikipedia.org/wiki/Antibiotic_resistance).

Only one total synthesis is known which yielded only a racemic mixture of Napyradiomycin A1 so here comes the second one. The retro looks like this:

Scheme 1


They planned to use the isolated olefin for their asymmetric chlorination, install the alcohol and rearrange it to build up the allylic chain on the benzoquinone ring system. It was further planned to cyclise the bis-unsatured chain to get Napyradiomycin B4 but these results will be presented in a follow up publication.

The basis of the synthesis is flavion which was synthesised earlier by other groups in a relatively long 8 step reaction sequence. They shortened it by heating the sulfonic acid salt in an alkali fusion and let the air do the rest.

Scheme 2


The resulting flavion was reacted with methyl crotonaldehyd under acid catalysis to give the ABC-ring system via a tandem Knoevenagel/6-π-electrocyclization followed by protection of the non-conjugated hydroxy function. The resulting tetrahydropyran fused ring system was exposed to the chlorination conditions which yielded the expected product in 87% yield with 93% e.e. after crystallisation. The conjugated chlorine was changed to an acetate with retention of configuration and after protection of the other hydroxy function and acetate cleavage, the second key intermediate was readily prepared.

The key step in this scheme is the asymmetric chlorination of the olefin:

4 eq of the previously synthesised ligand were reacted in THF with BH3 and AcOH. After solvent removal, the intermediate was added in THF, followed by chlorine which was bubbled through the solution. A transition state was formulated which look like this:

Scheme 33_070509

Details can be found in the supporting information. Then they installed the hydroxy function with retention of configuration:

Scheme 4


The adjacent carbonyl function may act as an electron pair acceptor throughout the whole addition/elimination reaction. The in situ formed SmI2 acts as a Lewis acid and removes selectively the acetyl protecting group.

The second half of the synthesis starts with a Johnson-Claisen rearrangement followed by a conjugate reduction with KHBPh3 as the reducing agent. It’s the first time I met a reagent for this kind of reduction without making use of a copper containing reagent.

After ester reduction and re-oxidation with Dess-Martin periodinane the resulting aldehyde was used for a Wittig-olefination.

The second chlorine was introduced stereoselectively with NCS and the protecting groups cleaved with MgI2 and PPTS to give enantiomerically pure Napyradiomycin A1.

Scheme 5


The supporting information also features a synthesis of the ligand used in the asymmetric chlorination if you’re interested in trying it by yourself.

So that’s it for the moment. Suggestions are welcome.


Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out / Change )

Twitter picture

You are commenting using your Twitter account. Log Out / Change )

Facebook photo

You are commenting using your Facebook account. Log Out / Change )

Google+ photo

You are commenting using your Google+ account. Log Out / Change )

Connecting to %s

%d bloggers like this: