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

scheme_1_17022013

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

scheme_2_17022013

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

scheme_3_17022013

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

scheme_4_17022013

[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…

Enantioselective Total Synthesis of (+)-Salvileucalin B

Enantioselective Total Synthesis of (+)-Salvileucalin B

Sergiy Levin, Roger R. Nani, and Sarah E. Reisman

DOI: http://dx.doi.org/10.1021/ja110192b

Happy new year fellas… hope you rushed in well.

Today’s molecule is from the past 2010 but a goody! The structure is a bit odd because of the cyclopropane ring breaking the aromatic system of the phthalide. By the way this structure motif is called a norcaradiene ring. Kindly the authors added a retro to the paper so less work for me:

Scheme 1

The authors planned to construct the cyclopropane motif at last by employing a nice copper catalyzed cyclopropanation. The phtalan moiety was constructed through a ruthenium catalyzed cycloisomerization and the chain extended by an Arndt-Eistert homologation.

So here we start from the very beginning.

The alcohol shown was oxidized under standard conditions and reacted with pseudoephedrine to give amide 1.

Scheme 2

The second main fragment was synthesized through a stereoselective alkynylation using a mandelamide ligand and dimethylzinc. The corresponding alcohol was propargylated, desilylated and exposed after mesylation to Finkelstein conditions to give bromide 2.

Next fragment 1 was enolized with LHMDS and reacted with 2 to give triyne 3. The reaction conditions were developed by the Myer’s group (J. Am. Chem. Soc. 1997, 119, 6496-6511), nice paper btw.

Scheme 3

Now it’s getting really cool. The triyne was cyclised to the phthalan ring after deprotection of the TMS group employing TBAF. Really nice but I could not figure out exactly which protocol they followed, nothing is said in the paper or supporting info. If anyone of you has an idea you are welcome to forward me the DOI.

The auxiliary was cleaved off and acid 4 extended by one CH2 under Arndt-Eistert conditions to give 5. The resulting methylester was reacted with the sodium salt of acetonitrile to give a cyanoacetate which was converted to diazo compound 6. Exposing this to a bit of copper(II) for only one minute in a microwave the cyclopropane ring formed in good yield to give 7.

Scheme 4

The ketone was then transformed into the enol triflate. Reduction of the nitrile was not that trivial: the corresponding in situ formed aldehyde underwent a retro-Claisen rearrangement and opened the cyclopropane ring. After some experimentation it was possible to rapidly reduce the nitrile to alcohol 8. Carbonylation under standard conditions furnished lactone 9 which was exposed to Cr(VI) to give a mixture of products containing substantial amounts of (+)-Salvileucalin B.

Scheme 5

Short but very effective. I liked the way how the norcaradiene core was built. And especially the cycloisomerization reaction catched my eye.

Comments?

Development of a Formal [4 + 1] Cycloaddition: Pd(OAc)2-Catalyzed Intramolecular Cyclopropanation and MgI2-Promoted VCP-CP rearrangement

Development of a Formal [4 + 1] Cycloaddition:

Pd(OAc)2-Catalyzed Intramolecular Cyclopropanation of 1,3-Dienyl-Keto Esters and MgI2-Promoted Vinylcyclopropane – Cyclopentene Rearrangement

Rockford W. Coscia, and Tristan H. Lambert

DOI: http://dx.doi.org/10.1021/ja809226x

About half a year ago this interesting paper was published and is still in the list of the most viewed papers of the JACS so I decided to put in my two cents and give you a short overview. The overall reaction looks like this:

Scheme 1

060409_11

As mentioned above the first step is a palladium catalysed cyclopropanation, which is the main investigation in this paper, followed by a vinylcyclopropane/cyclopentene rearrangement (VCP-CP) to give the cis-fused 5/6 ring system.

The first step involves a Mg(ClO4)2 induced enolisation with a simultaneously Pd(II) coordination to the 1,3-diene unit. The formed enol attacks the palladium complex to give the 6-membered ring. After another enolisation a fused cyclopropane is formed with concomitant reduction of the Pd(II) to Pd(0) which is reoxidised with the copper additive. While using Cu(OAc)2 as the oxidant a reductive elimination and a Saegusa type oxidation is observed due to a ligand exchange on the Pd(II) source, which can be overcome by changing the anion from acetate to iPrCO2. The reaction cycle is shown below:

Scheme 2

060409_21

Some compounds which were produced during the investigation are given in the next scheme:

Scheme 3

060409_31

The main drawback with this methodology is the need for a double substituted α-C to increase the yield and to prevent the above mentioned oxidation. Without these substituents the yield dropped to 52% (compound 3) but with complex starting materials the yield is still moderate (compound 4).

With these vinylcyclopropanes in hand a MgI2 induced ring opening/ring closure reaction was used to convert the cyclopropane to a cyclopentene.

The proposed mechanism is shown here:

Scheme 4

060409_41

The Lewis acidic MgI2 attacks the acetyl acetate moiety and releases an iodide. This opens the cyclopropane on reaction with the terminal alkene in a concerted or stepwise manner to give the allyl iodide. A SN2 reaction of the enolate closes the ring again to give this time the thermodynamically favoured cyclopentene. This process gives generally good yields in contrast to the varying yield of the first step.

Some examples were produced to test again the scope of the methodology.

Currently the authors are working on a more general route to 1) extend the strategy to other nucleophilic moieties, 2) remove the need for gem-dimethyl blocking group, and 3) running the two reactions in one pot.

Maybe by using a chiral Lewis acid it should be possible to increase the diastereomeric ratio? In conclusion I think that this methodology has a great potential and I am interested to see its first application in a total synthesis.

Comments?