(-)-Huperzine A

 

 

(-)-Huperzine A

Organic Letters, 2012, 14, 4446-4449

R. Ding, B.-F. Sun, G.-Q. Lin

The retrosynthesis of (-)-Huperzine begins with an acid-mediated rearrangement along with dehydration to install the two double bonds.  The conditions for these two transformations took a while to develop as there were other side-reactions occurring as well.  The rearrangement is especially noteworthy since it allows the use of (R)-pugelone as the starting material.  The tertiary alcohol in 10 is formed by ethyl Grignard addition to the ketone 9, which in turn comes by oxidation of diastereomeric alcohols 8.  An elegant Heck-reaction forms the bicyclic structure from 7.  This shows the two parts of the molecule – the “cyclohexene” and the “pyridine” parts – linked through a methylene group.  Thus, alcohol 7 comes by reduction of ketone 6, which is setup to be derived by an enolate addition of ketone 4 on bromide 5.  Compound 4 is derived by a Buchwald-type coupling of Boc amine on enol triflate 3.  The enol triflate 3 is derived from 2, which is easily accessible from (R)-pulegone.

(-)-205B

 

 

(-)-205B

J. Am.  Chem. Soc., 2012, 134, 15237

D. Yang & G. C. Micalizio*

 

The retrosynthesis of (-)-205B, an azatricyclododecene isolated from Dendrobates pumilio, begins with deoxygenation and rearrangement of the double bond of compound 10, which in turn is derived from alcohol 9.  Alcohol 9 is formed by an aza-Sakurai reaction/ring-opening sequence from bicyclic compound 8.  Alkene 8 is derived from ester 7 by a reduction and deoxygenation procedure  Compound 7 comes by a reduction and Horner-Wadsworth-Emmons reaction of reagent 6 with ester 5.  Bicyclic compound 5 is derived from a intra-molecular [2+3] cycloaddition reaction involving the iminium ion formed by the addition of butylglyoxolate with amine-oxide 4.  Compound 4 is formed by oxidation of amine 3, which in turn is derived from a reductive cross-coupling between silane 2 and aldehyde 1.  Overall, the retrosynthesis is derived from two methodologies developed in the Micalizio lab – (a) Ti-mediated reductive cross-coupling between an aldehyde and an allylic alcohol (compound 3 from 1); and (b) intramolecular [3+2] cyclization of a glyoxalate-based homoallylic nitrone (compound 5 from 4).

 

(-)-Huperzine A

(-)-Huperzine A

Organic Letters, 2012, 14, 4446-4449

R. Ding, B.-F. Sun, G.-Q. Lin

The retrosynthesis of (-)-Huperzine begins with an acid-mediated rearrangement along with dehydration to install the two double bonds.  The conditions for these two transformations took a while to develop as there were other side-reactions occurring as well.  The rearrangement is especially noteworthy since it allows the use of (R)-pugelone as the starting material.  The tertiary alcohol in 10 is formed by ethyl Grignard addition to the ketone 9, which in turn comes by oxidation of diastereomeric alcohols 8.  An elegant Heck-reaction forms the bicyclic structure from 7.  This shows the two parts of the molecule – the “cyclohexene” and the “pyridine” parts – linked through a methylene group.  Thus, alcohol 7 comes by reduction of ketone 6, which is setup to be derived by an enolate addition of ketone 4 on bromide 5.  Compound 4 is derived by a Buchwald-type coupling of Boc amine on enol triflate 3.  The enol triflate 3 is derived from 2, which is easily accessible from (R)-pulegone.