Isonitramine

 

 

Isonitramine

Organic Letters 2012, 14, 852

Y. Park, Y. J. Lee, S. Hong, M. Lee, H. Park*

The retrosynthesis of isonitramine begins with the unmasking of the amine (from the amide) and the alcohol (from the ketone).  The diphenylmethyl protection on amine 11 was removed by hydrogenation and amide 10 was reduced by lithium aluminum hydride reduction.  Amide 10 was prepared by the stereoselective reduction of the ketone group in 9 by Dibal-H.  The Al coordinates on the side containing the amide oxygen while delivering the hydride ion, thus giving the R configuration on secondary alcohol in 10.  Ketone 9 was derived by decarboxylation of ketoester 8, which is the Robinson annulation product of diester 7.  At this stage, there is a protecting group interchange in 6.  Compound 6 is derived by xanthate group removal from 5, which in turn is coming from the radical addition of xanthate and “ethylacetate anion” across the carbon-carbon double bond in 4.  Compound 4 is prepared from bromide 3 (because the non-brominated version did not give high ee).  The synthesis of compound 3 is what drives this synthesis – the “phase transfer catalyst” driven asymmetric allylation of alpha-tertbutoxycarbonyllactam compound 2.  A chiral PTC is used which gives the product is highly stereoselective fashion, but it required the 2-bromoallyl bromide instead of allyl bromide.  This is an example of the utility of “Br” as a masked “H” to improve stereoselectivity.  Compound 2 is prepared by installing the butoxycarbonyl group on valerolactam.

I noticed that all but 2 steps had >90% yield (and those two were also >85%)!!  Although most steps are fairly standard, but I still find it very impressive – especially when considering the messy “tin chemistry” and the final two reduction steps.  

 

(-)-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).

 

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.

 

(rac)-Trigonoliimine B

Reference: T. Buyck, Q. Wang, J. Zhu Org. Lett. 2012, 14, 1338