Helioporin C
Organic Letters 2012, 14, 5996
W. Lorsberg, S. Werle, J.-M. Neudorlf, H.-G. Schmalz*
The retrosynthesis of helioporin C begins with oxidation of
the allylic hydroxyl group in 15
thus generating the sensitive a,b-unsaturated
ketone in the last step. These
conjugated unsaturated species are very reactive and can sometime lead to
unnecessary side reactions and it is wise to leave their formation towards the
end. The hydroxyl group of 15 was formed by the addition of the
vinylic Grignard reagent 14 on
aldehyde 13. The aldehyde functionality was formed by a
TBS deprotection followed by oxidative cleavage of the diol by using periodic
acid from 12. The chiral methyl group on 12 was installed by a stereoselective reduction
of alkene 11 by a hydrogenation
procedure that used an Iridium-based chiral catalyst developed by Pfaltz. Alkene 11
came by an ene-reaction between alkene 9
and TBS-protected glycolaldehyde using dimethylaluminum chloride. Compound 9
was prepared by a Friedel-Crafts-type cyclization procedure on 8, again using dimethylaluminum
chloride as the catalyst. These two
steps are really interesting as they use the same reagent! But, more importantly, the relative geometry
(syn) is established in this step
with moderate selectivity (4:1).
Compound 9 was not separable
from its diastereoisomer and was therefore carried on into the next step where
the undesired isomer was separable.
Compound 8 was prepared by an
alkyl-Suzuki-reaction (not often seen!)
between 9-BBN-derivative of alkene 6
and vinyl iodide 7. The hydroboration protocol is well
established and so this is a reliable disconnection strategy. Alkene 6
was prepared in extremely high yields and selectivity by a stereoselective
methylation/elimination procedure that used a chiral catalyst derived from (S,S-TADDOL) and used the cuparate as the
attacking species. Chloride 5 was installed by a unique oxidative
chlorination step, which I had never seen before, from allylic alcohol 4.
Alcohol 4 was prepared by a
nucleophilic attack by aryl-lithium derived from bromide 3, which in turn was prepared from dimethoxy compound 2.
The bromo-group on 2 was
installed by brominating commercially available 1,2-dimethoxy-3-methylbenzene.
There are three chiral centers in this molecule and two of
these were installed by using chiral-catalysts.
Both of these steps gave the product in very high selectivities and that
is a take-home message from this synthesis. Finally, they have also prepared Helioporin E, from intermediate 15 by using methanesulfonic acid at very low temperatures (not drawn).
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