Total Syntheses of (-)-Acutumine and (-)-Dechloroacutumine

Total Syntheses of (-)-Acutumine and (-)-Dechloroacutumine

Sandra M. King, Nicholas A. Calandra, and Seth B. Herzon

DOI: http://dx.doi.org/10.1002/anie.201210076

Recently the Herzon group dislosed the neat syntheses of (-)-acutumine and (-)-dechloroacutumine. Driven by the interesting biological features (e.g. inhibition of human T-cell proliferation) and the densely functionalized structure the group devised a versatile approach towards both natural products. The common tetrahydroindolone core of the acutumines and the hasubanane alkaloids offered the opportunity to rely to some extend on earlier work on hasubanonine and related congeners.[1] The main steps of the synthesis include the earlier employed lithium acetylide addition to an iminium ion, an intramolecular Hosomi-Sakurai reaction and a nice introduction of an unsaturated ketone.

Scheme 1

The first two fragments are not featured in full detail in the paper so I present them separately. Fragment 5 can easily be accessed in five steps from glucose 1. Acetonide and acetal formation was followed by an Appel reaction and concomitant reductive ring opening to give aldehyde 3. Addition of vinyl Grignard, RCM in the presence of Grubbs-I and oxidation of the alcohol yielded known ketone 5 in good overall yield.

 Scheme 2

The second fragment was synthesized from trimethoxy acetophenone ketal 6 which underwent an interesting reductive ketal cleavage / hydroboration / oxidation procedure to give alcohol 7. Mesylation and S_N2 replacement with sodium azide then furnished 8.

 Scheme 3

 

The following sequence of steps has been used in the synthesis of the hasubanane alkaloids. Oxidative dearomatization of 8 was followed by stereoselective Diels Alder reaction of the less hindered double bond. Finally trimethylphosphine mediated Aza-Wittig reaction produced key intermediate 11.

 Scheme 4

 

Elaboration of ketone 5 began with stereoselective Michael addition of (TMS)₂ in the presence of catalytic Pd(OAc)₂ and subsequent cleavage of the resultant TMS enol ether. Enol triflate formation and Stille coupling produced acetylide 14.

 Scheme 5

Next methylation of the imine and addition of the lithium acetylide of 14 furnished a single diastereomer of 15. The diastereoselectivity in this step is not straightforward to explain. Building a model does not help much because addition seems to occur from the concave site which should be less favored. The group offers an explanation in the paper: “The contrasteric diastereoselectivity in the addition step may be due to unfavorable torsional strain within the pyrrolidine ring in the alternate diastereomer”. For related addition products the group had access to X-ray structures which proved the relative stereochemistry.

Extrusion of TMS-pentadiene under thermal conditions was followed by regioselective hydrostannylation to give 17. TBAF mediated Hosomi-Sakurai reaction proceeded in moderate yield to close the remaining five-membered ring. Metal-halogen exchange with CuCl₂ and deprotection of the diol then yielded 19.

 Scheme 6

 

Introduction of the remaining oxygen functionality proved to be fairly difficult. To the end the group had to rely on a rather steppy but successful approach. Oxidation of the diol to the vicinal diketone was followed by methyl sulfide addition and methylation to give 21. S_N2’ replacement by formic acid and thermally induced Claisen rearrangement and subsequent aminolysis furnished hemiketal 24.

 Scheme 7

With fragment 24 only a few steps were left to complete the endeavor. Oxidation of the hemiketal and succeeding reduction with sodium borohydride gave 25 in good overall yield in excellent diastereoselectivity. In the presence of rhodium and high pressure hydrogen 25 was transformed into acutumine in low yield. In the presence of palladium on charcoal beside the double bond the chlorine could be removed to give dechloroacutumine in good yield.

 Scheme 8

 

Overall a really nice paper which is definitely worth a read.

[1] http://dx.doi.org/10.1002/anie.201102226

Total Synthesis of (±)-Maoecrystal V

Total Synthesis of (±)-Maoecrystal V

Feng Peng and Samuel J. Danishefsky

DOI: http://dx.doi.org/10.1021/ja309905j

Yet another interesting synthesis of Maoecrystal V was just reported from Danishefsky and Peng. Besides the completed total synthesis a first attempt is also featured in this article which might have been successful when the crucial Diels Alder reaction would have given them the correct stereoisomer. After straightforward preparation of precursor A Diels Alder reaction furnished B instead of C. This outcome puts paid to the whole strategy because there is no handle on the C₂-bridge with which the required functionalities could be introduced.

Scheme 1

With this result in hand the group started a study which then turned out be the starting point of their revised synthesis. In the first step readily accessible precursors 1 and 2 where joined together in moderate yield. Global reduction with DIBAL-H and selective oxidation of the allylic alcohol gave 4 which was acylated with D and converted to TBS enol ether 5. Under almost identical conditions as for the synthesis of B this time Diels Alder product 6 was obtained after TBAF mediated desilylation and base induced desulfinylation. Epoxidation of the unsaturated lactone double bond was followed by MgI₂ facilitated opening of the epoxide with formation of the corresponding a-iodo alcohol. Dehalogenation was accomplished with Bu₃SnH to give 7.

 Scheme 2

Next the cyclohexadiene ring was functionalized. Stereoselective epoxidation with mCPBA and subsequent opening under acid catalysis furnished tetrahydrofurane 9. Acetylation of the alcohol and reduction of the ketone yielded an inseparable mixture of diastereomers which proved to be inconsequential because the alcohol will be transformed into a sp² center during the synthesis.[1] MOM-protection and deacetylation gave homoallylic alcohol which could be epoxidated again to epoxide 12. Oxidation and acetic anhydride assisted opening of the epoxide was followed by conjugate addition of phenyl thiol and reduction of the ketone to give thioether 14. Desulfination with Raney-Ni and elimination of the alcohol furnished at last enol ether 15. Though the functionalization of the cyclohexadiene ring seems to be pretty steppy the transformations could be executed in overall acceptable yield.

Scheme 3

To the end of the synthesis mainly the remaining methyl groups have to be introduced. Therefore again an epoxidation was used to functionalize the enol ether double bond. Note the overall inversion of the stereogenic center comparing 14 and 16. Under Lewis acidic conditions the epoxide was opened to ketone 16 in a Rubottom-type oxidation. Then a rather cool approach for the introduction of a gem-dimethyl group was utilized. First the ketone was transformed to an exomethylene group in the presence of Lombardo’s reagent. A Simmons-Smith cyclopropanation converts the double bond into the spiro-cyclopropane 17 which was opened under hydrogenolytic conditions after deprotection and adjustment of the oxidation states of the appendant alcohols. Chemoselective methylenation of the less hindered ketone was accomplished again in the presence of Lombardo’s reagent and followed by acid catalyzed migration of the double bond. Saegusa oxidation, epoxidation with TFDO and Lewis acid assisted opening of the ketone produced Maoecrystal V.[2]

Scheme 4

[1] Though the following purification steps were of course be affected.

[2] I know that this piece of work is not a pretty recent one anymore but I really wanted to cover this nice synthesis. I am really busy these days. Hopefully this changes within the next weeks because there are a lot of nice papers out. I hope you guys are still enjoying my posts and thanks for still visiting my blog…

Total Synthesis of (±)-Communesin F via a Cycloaddition with Indol-2-one

Johannes Belmar and Raymond L. Funk

 DOI: http:// dx.doi.org/10.1021/ja307277w

It has been some time since my last entry. I was very busy with moving to the US and starting my master’s thesis. But as you can see after about 12 weeks I am back. I chose a rather short synthesis but there is still some work to be covered within the next weeks which should result in much more detailed write-ups.

The communesins are known to the synthetic community for quite a while and were the targets of extensive research and synthetic studies. The current paper utilized some nice methodology developed by the group and published in an earlier synthesis of perophoramidine. [1]

The synthesis begins with the union of azide 1 and bromooxindole 2. Because their initially reported conditions did not give any product at all it was found that the reaction proceeded smoothly in the presence of substoichiometric amounts of silver carbonate yielding 3. After tosylation the mixture was exposed to methanolysis to produce the backbone structure 4 of communesin F. Methylation with Meerweins’s salt, hydrogenolysis of the azide with subsequent Boc-protection and detosylation furnished amide 5.

 Scheme 1

The bromine was then used as a handle to introduce the prenyl sidechain with a Heck reaction to give an intermediate allylic alcohol. In the presence of mercury salts a cyclization took place constructing the crucial seven-membered amine ring. Deprotection of the amine under mild conditions using TBSOTf was followed by amide formation with some help from trimethylaluminium. The second side-chain was introduced in the usual sequence of deprotonation and subsequent alkylation with iodoacetonitrile.

 Scheme 2

The last ring was closed in a straightforward manner. Reduction of the nitrile to the aldehyde and the amide to the hemiaminal gave tetrahydrofuran 9. Reductive amination and acetylation finally produced communesin F in an overall yield of 6.7 %.

Scheme 3

The mechanism of the key step is pretty straightforward but nevertheless a nice one. After tosylating the oxindole nitrogen the resulting amide can be cleaved by methoxide to give an anilide anion which undergoes intramolecular attack on the indolenine 2 position to close the ring.

Scheme 4

[1] J. Am. Chem. Soc. 2004, 126, 5068

Yeah… that is it for the moment. I found some new interesting stuff to write-up, so I promise I will be up to date from now on J