Corallopyronin A and Myxopyronin B

 

Corallopyronin A and Myxopyronin B

Angew. Chem. Int. Ed. 2012, 51, 11381

A. Rentsch and M. Kalesse*

http://onlinelibrary.wiley.com/doi/10.1002/anie.201206560/abstract

 The retrosynthesis of corallopyronin begins with removal of protecting groups (OTBS, and OCH2OTBS) and oxidation of the alcohol in 19 to the corresponding ketone.  The OCH₂OTBS group is called tert-butyldimethylsiloxylmethyl group or SOM and was used for differentiating two hydroxyl groups earlier in the synthesis.  Secondary alcohol 19 is prepared by connecting fragments “A” and “B” by an alkylation reaction that used LiTMP as the base. 

Fragment “A” has a terminal conjugated aldehyde on the right-hand-side that is installed by reduction of the corresponding ester to the alcohol followed by oxidation to the aldehyde.  The left-hand-side of fragment “A” has a terminal propene that is formed by reacting acetaldehyde with the sulfone formed by the oxidation of intermediate 18.  Compound 18 is prepared by a Mitsunobu reaction between phenyltetrazole thiol 17 and terminal alcohol 16.  The TBS-protected secondary chiral alcohol of 16 is formed by using (-)-DIPCl as the chiral reduction agent upon ketone 15.  This reduction gave the product with 95% ee and the absolute stereochemistry was confirmed by making the corresponding Mosher’s esters.  Ketone 15 is formed by reacting zincate 12 with aldehyde 14 followed by Swern oxidation of the resulting alcohol.  Aldehyde 14 comes by a selective oxidative cleavage of the more electron-rich alkene in 13.  Finally, compound 13 is prepared from Gerinol by an oxidation and Wittig protocol.  The zincate intermediate 12 was prepared in an interesting fashion from bromo-boronate 11 by treatment with dimethylzinc.  In turn, compound 11 is prepared from bromo-alkyne 10, which I presume comes from butynol. 

Fragment “B” has a terminal vinyl carbamate group on the right-hand-side.  Since vinyl-amines are unstable, a Curtius-rearragement is used to prepare this functionality.  This gives us acid 9 as the precursor, which is prepared from aldehyde 8 by a Horner-Wadsworth-Emmons reaction of phosphonate ester 8 with aldehyde 7.  Aldehyde 7 is prepared from TBS protected alcohol 6, which came from protected alcohol 5.  Here, we see the installation of the SOM group to differentiate the terminal (TBS protected) alcohol from the hydroxyl group on the enol-form of the diketoester.  Pyrone 5 comes from the rearrangement of ketone formed by the oxidation of 4.  Compound 4 is prepared by the signature reaction of the Kalesse group – “the Vinylogous Mukaiyama Aldol Reaction” (VMAR).  Thus, the reaction of aldehyde 3 with the vinylogous-silyl-ketene-acetal 3 generates the desired product 4.  Compound 2 is prepared from beta-(-)-citronellene by (a) selective oxidative-cleavage of (R)-3,7-dimethylocta-1,6-diene; (b) reduction of the aldehyde to the alcohol; and (c) protection of the alcohol as TBS ether.

In this paper, the authors have also described the completion of the synthesis of a related natural product – Myxopyronin B.  Retrosynthetically, it involves the combination of Fragment “B” with aldehyde 22 (followed by oxidation and the removal of SOM protecting group).  Aldehyde 22 is derived from ester 21, which in turn, comes by an oxidation-Wittig sequence on alcohol 20.  Alcohol 20 is prepared by the attack of nBu-cupurate (prepared by reacting nBuLi with BrCu(SMe₂)) on ethyl butynoate – an example of nBuLi being used as the reagent with the “nBu” portion getting installed on the molecule.

Overall, an excellent piece of work from the Kalesse group which includes the signature “VMAR” (i.e. Vinylogous Mukaiyama Aldol Reaction).  Other interesting features include the Curtius reaction which installs the sensitive vinylcarbamate group, SOM groups that allows for the differentiation of hydroxyl groups, selective oxidative cleavage of electron-rich alkenes in presence of electron-deficient alkenes, liberal use of easy-to-perform oxidations and reductions, use of (-)-DIPCl to establish the desired “R” configuration, using easily available chiral starting materials "geraniol" and "beta-(-)-citronellene", and finally, the use of buffered HF.pyridine in THF/pyridine to remove the silyl protecting groups.  The fact that all this was done by a single chemist makes it even more commendable!

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.

 

 

 

 

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.