(-)-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.

(-)-KAITOCEPHALIN

 

 

(-)-KAITOCEPHALIN

Organic Letters, 2012, 14, 1644-1647

K. Takahashi, D. Yamaguchi, J. Ishihara, S. Hatakeyama*

The retrosythesis of (-)-Kaitocephalin begins with unmasking all the acid groups by oxidizing phenyl and carbon-carbon double bonds while the amino and alcohol groups are also simultaneously generated by deprotecting the oxazolidone ring of 14.  This is very rarely seen in total syntheses as people generally shy away from such strong oxidations towards the end of the synthesis.  So, keeping a benzene ring and carbon-carbon double bonds are “masked acids” is a useful disconnection.  Compound 14 predictably comes from acid chloride 13 and deprotected form of amine 12.  Compound 12 is formed by a stereoselective intramolecular C-H amination in 11 mediated by a Rh catalyst.   This is a neat way of establishing a crucial stereocenter.  Compound 11 comes from protected alcohol 10.  Compound 10 is generated by an intramolecular addition of a carbamate on cyclic sulfamate 9, which comes from another stereoselective intramolecular C-H amination of sulfonamide 8.  This step is very similar to the preparation of 12 from 11 – sulfonyl versus and carbonyl and also a different ligand is used in the Rh catalyst.  Compound 8 comes from protected alcohol 7, which in turn is prepared by a Overman rearrangement reaction of alcohol 6.  This step establishes the quaternary spiro stereocenter.  Compound 6 is formed by a Suzuki reaction between alkyl boronate ester and vinyl iodide 5.  This comes from protection-deprotection of alcohol 4 whose precursor is ketone 3.  Ketone 3 comes from the iodination of 2, which is derived from alcohol 1, by an enzyme-mediated stereoselective oxidation.

 

(-)-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).

 

(+)-Sch 725680

(+)-Sch 725680

Organic Letters, 2012, 14, 4303-4305

Toshifumi Takeuchi et al.

The retrosynthesis of (+)-Sch725680, begins with disconnecting the ester bond, thus giving acid chloride 13 and alcohol 10 as the main components.  Alcohol 10 comes from an hydroxyl addition on to a carbon-carbon triple bond in alkyne 9.  (Synthetically this is accomplished by just acidic treatment of the in-situ generated alcohol on the conjugated triple bond).  Compound 9 comes from an Aldol-condensation of ketone 8, which is generated by (a) alkyne lithium addition on aldehyde 6,; (b) methyl lithium attack on Weinreb amide portion of the molecule and finally,; (c) oxidation of the alcohol formed to the ketone functionality by using PCC.  Compound 6 comes by ring-opening of lactone 5 by N, O-dimethylhydroxylamine hydrochloride and oxidation of the primary alcohol.  The protected alcohol 5 comes from diol 4, which is formed by a cyclization of terminal alcohol on the chiral auxiliary 3.  Compound 3 is generated by a titanium mediated aldol reaction of imide 1 with aldehyde 2.

 

 

 

 

(-)-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.

Organic Letters, 2012, 14, 2078

J. P. Lajiness, W. Jiang, D. L. Boger

This paper describes the synthesis of (+)-spegazzinine, isolated from Aspidosperma chakensis in 1956.  From a synthetic point of view, there are 4 attached rings – two of which are spiro bound, 5 contiguous chiral centers – 3 of which are quaternary.  Boger’s group had developed a powerful methodology to construct the core of this molecule back in 2002, where 1,3,4-oxadiazoles undergo a intramolecular Diels-Alder reaction with a dienophile.  The resulting adduct loses nitrogen and undergoes a 1,3-dipolar cycloaddition reaction with an indole ring to furnish 3 atteched rings with upto 6 chiral centers formed stereoselectively around the central ring in a single step.  (See: JACS, 2002, 124, 11292).  The synthesis of (+)-spegazzinine is thus an extension of that methodology.

 



In the case of (+)-spegazzinine, the vinyl ether in not present, instead of the ester – there is an alcohol group, the aryl ring in indole is substituted with a hydroxyl group, and lastly, instead of the amide – there is an amine.

Retrosynthetically, (+)-spegazzinine is prepared by the reduction of the corresponding amide 9, since the amide is essential for the [4+2]/[3+2] cascade.  The hydroxyl group in 9 comes from a cyano hydrin in 8, which is produced by ring-opening (“reduction”) of 7.  Compound 7 is derived from the ester 6 – which is the key intermediate produced by the [4+2]/[3+2] cascade.  Its precursor, 5 has the 1,3,4-oxadiazole ring and the alkene group, which is in turn made by coupling the appropriate acid chloride with amine 4.  The oxadiazole ring is made by the hydrazide 3, which comes from activated amine 1.

The next retrosynthesis is of (-)-okilacomycin D, whose synthesis was recently completed by Thomas Hoye's group in Univ. of Minnesota.  The most interesting feature of the synthesis is the intra molecular Diels Alder reaction in the penultimate step to create the spiro tetranoate portion of the molecule.