Clavosolide A

Clavosolide A

Organic Letters 2012, 14, 5614

G. Peh and P. E. Floreancig*

The retrosynthesis of clavosolide A beings with the dimerization of the hydroxyl-acid unit 11 by using the classical Yamaguchi cyclization (trichlorobenzoyl chloride, DMAP, toluene, 65 °C).  Advanced intermediate 11 was produced from 10 in three steps – first stereoselective reduction of the ketone in the presence of Corey’s boraxazoline chiral catalyst established the “S” configuration on the hydroxyl; then the TIPS group was removed under acidic conditions, which was followed by oxidation of the free primary alcohol selectively (over the secondary alcohol) to the corresponding acid by using bleach.  Intermediate 10 was prepared by a glycosidation reaction of sugar 9 with the secondary alcohol obtained by the reduction of the ketone group of 8.  It is interesting to note that reduction of ketone 8 was stereoselective in favoring the formation of the equatorial hydroxyl group only.  Compound 8 was prepared from enol-ether 7 by using DDQ and lithium perchlorate.  This oxidative cyclization is an offshoot of methodology that has been developed in the author’s laboratories during the past few years.  Compound 7 was prepared by alkylation of alcohol 5 with mesylate 6, followed by ruthenium catalyzed O-acetylation of the acetylinic bond.  Alcohol 5 was prepared from a zinc-mediated coupling between mesylate 4 and aldehyde 3 using conditions developed by the Marshall group.  Acetylene-mesylated 6 was prepared by Negeshi propargylation procedure on ketone 2, which in turn was prepared cyclopropanation of chloro-alkene 1.  This cyclopropanation procedure gives trans products selectively and proceeds via a conjugate addition step followed by enolate trapping.  (See JACS, 2010, 132, 14349). EXTRA: compound 1 was prepared by reacting allyl chloride with acetyl chloride!

Thus, in this synthesis, the cyclopropanation step was performed right in the beginning and all subsequent transformations kept the ring intact.  Also interesting was the oxidative cyclization step to prepare the pyran ring (7 to 8). 

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.