Aspercyclides A & B

Aspercyclides A  & B

Organic Letters 2012, 14, 4290-4292

T. Yoshino, I. Sato*, M. Hirama

The retrosyntheses of Aspercyclides A and B begin with a common advanced intermediate 8.  For aspercyclide A (which has an aldehyde group), the hydromethyl in 8 is first oxidized using manganese oxide and the benzylether is deprotected using boron trichloride.  For aspercyclide B (which has the hydroxymethyl group), the benzylether group is deprotected using boron trichloride.  Thus, with one advanced intermediate, they are able to get two natural products.  Intermediate 8 is prepared by a very interesting selective oxidative phenol-aryl bonding.  There are two phenolic groups present in 7 (the precursor to 8) and only one of them is oxidized and undergoes a ring-closure reaction with the other aryl ring.  The authors explain this chemo-selectivity on the relative electron richness of the two phenols.  One has alkyl substituents, while the other has a carbonyl group on it – the more electron rich phenol (with alkyl substituents) gets oxidized and reacts with the other.  They even did a side experiment where they took two phenols – one with alkyl groups and the other with carbonyl.  Only the one with the alkyl groups reacts with phenyl iodoacetate!  Very nice!! Moving along backwards, intermediate 7 comes by a slightly convoluted protection/deprotection series of steps, but it again has some interesting selectivity.  Intermediate 7 has the hydroxymethyl group protected as the TBS ether and with two open phenol groups.  All three were initially protected as TBS ether, but the two phenol hydroxyl groups were deprotected selectively by TBAF (i.e. TBAF left the hydroxymethyl TBS ether intact!)  Their precursor was formed by the acetonide deprotection of 6.  Intermediate 6 comes by esterification reaction between alcohol 4 and methyl ester 5.  Compound 4 was derived from a Heck reaction between alkene 3 and aryl iodide 2.  Alkene 3 was prepared by attack of butyl anion (from nBuLi) on epoxide formed by the Sharpless epoxidation (and the benzyl ether protection) on penta-1,4-dien-3-ol.  Also interesting are the preparation of intermediates 5 and 2 from a common precursor – 1.  Thus compound 5 is prepared by palladium catalyzed methyl zinc  substitution on iodide 1, whereas compound 2 is prepared by deprotection of the acetonide in 1, followed by reduction of the acid to the alcohol and the re-formation of the acetonide ring. 

Overall, this is a very neat synthesis and has some very interesting selective transformations (selective TBS ether deprotection & selective phenolic oxidative cyclization).  

 

(-)-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.

(-)-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.