Total Synthesis Blog

Today (time to writing posts – at leats!) – some quite simple-looking target: 3-hydroxypipecolic acid. The structure of this target is drawn below (just click on image and enjoy new system of showing pictures on this blog ):

As you can see – it really doesn’t look terrible: two stereocentres and only one ring. It’s hard to believe that only several approaches to such system was developed (authors of paper claim: only four approaches). Let’s say something about biological properties of (2S,3R)-3-hydroxypipecolic acid… Well, structural feature of 3-hydroxypipecolic acid is preasent in many natural and non-natural compounds, for example tetrazomine which was isolated from Saccharothrix mutabilis and exhibiting antitumor activity (3-hydroxypipecolic acid subunit is marked):

The retrosynthesis of (2S,3R)-3-hydroxypipecolic acid is shown below:

(Click on image to enlarge it)

Retrosynthesis is very interesting because of usage of oxazoline moiety to construct stereoselectively piperidine skeleton. Nice way to do such systems, in my opinion. Also synthesis of oxazoline from acyclic precursor looks nice, especially stereochemistry of that reaction. Let’s look at synthesis of 3-hydroxypipecolic acid:

(Click on image to enlarge it)

Compound 3 is converted to oxazoline 4 by treatment palladium(0) complex with triphenylphosphine and K₂CO₃. In my opinion mechanism involves forming π allyl-palladium complex with parallel removal of OAc group. It means that in this step one stereocentre in destroyed (in my opinion of course), but second stereocentre govern stereochemistry of oxazoline ring-closure. Probably K₂CO₃ act as base which can detach hydrogen atom from NH group. Next cyclization occurs. But I can be wrong – Have you got any other suggestions?

4 is then converted to corresponding aldehyde, 5, by ozonolysis. Next, Wittig-Horner reaction is undergone and in that way α,β-unsaturated ester, 6, is formed. 6 can be then saturated by L-Selectride in t-BuOH/THF to form 7. Next hydrogenolysis occurs which produces piperidine skeleton. Other interesting step is selective TBS-deprotection: only primary alcohol group is deprotected, secondary OH group doesn’t react in such (AcOH + H₂O + THF) conditions.

My retrosynthetic approach is shown below… Well… in comparsion with mentioned retrosynthesis, my analysis looks like a little bit… childish

I’ve tride to apply in this case malonic ester-type synthesis… But this is only my try

For more see:

V.-T. Pham et al., Tetrahedron: Asymmetry, 2008, 19, 318.