Voacangalactone

Voacangalactone

Organic Letters 2012, 14, 5800

M. Harada, K. N. Asaba, M. Iwai, N. Kogure, M. Kitajima, and H. Takayama*

The retrosynthesis of Voacangalactone A begins with the reduction of keto-amide group in 17 to reveal the amine functionality.  Compound 17 was prepared by cyclization of the keto-ester on the deprotected amine, which in turn came by acylation of oxalyl chloride on indole 16.  The indole ring was closed by using Utimoto’s protocol employing NaAuCl₄.2H₂O as the oxidant on alkyne 15, which was prepared by a Sonogashira reaction between 2-iodo-4-methoxyaniline and alkyne 14.  Here, CuSO₄ was used as the copper source – no doubt reduced to Cu(I) by Na-ascorbate.  I had never seen being used in Sonogashira reaction, but this is referenced from the work of Bag, S. S. et al. Org. Chem. 2011, 76, 2332–2337.  Going further back, the alkyne 14 was prepared from alcohol 13 using standard transformations.  Compound 13’s precursor was iodo-alcohol 12, which came from acid 11.  Acid 11 was prepared by an iodo-lactonization-hydrolysis sequence on diester 10.  This is a really nice step as it establishes the lactone-ring elegantly and also allows differentiation of the oxidation states of the pendant carbon.  The bicyclic-amine 10 was closed by alkylating Cbz-amine 9.  Compound 9 is a penta-substituted cyclohexene and thus it is not surprising that an asymmetric Diels-Alder reaction was used to prepare it.  Its immediate precursor is the chiral auxiallary containing intermediate 8, which comes by a Diels-Alder reaction between dimethyl 2-methylenemalonate and diene 7.  This Diels-Alder reaction is between an electron-rich diene and an electron-deficient dienophile.  No wonder, it even goes at room temperature.  It is also completely regioselective – again due to the relative electronics of the reactants.  The absolute stereochemistry is driven by the chiral auxiallary.  This is the key step of this synthesis.  The diene was prepared by a Cu-mediated amination of vinyl-iodide 5.  Adjustment of the carbon oxidation states meant that 5 came from conjugated ester 4, which came from aldehyde 3 by a Wittig reaction.  Aldehyde 3 was prepared by reduction-oxidation sequence on acid 2, which was prepared by decarboxylation/hydrolysis of diester 1.  Diester 1 was prepared by alkylation of diethyl ethylmalonate.

 

Overall, a really nice synthesis.

 

 

 

 

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.