Total Synthesis of Jiadifenolide

Total Synthesis of Jiadifenolide

Ian Paterson,* Mengyang Xuan, and Stephen M. Dalby*

DOI: http://dx.doi.org/10.1002/anie.201404224

As promised months ago here is the write-up of the second Jiadifenolide synthesis published this year. The main features of this synthesis from the Paterson group consist of a boron-aldol reaction and a neat SmI2 mediated radical cyclization. Though a racemic synthesis (like in the good old days) this route provides an efficient and highly selective access to Jiadifenolide.

The synthesis started with Luche reduction of cyclopentenone 1 which in turn was treated with mCPBA followed by TBS protection to give oxirane 2. In the presence of BF3 the epoxide rearranged to the corresponding ketone with excellent diastereocontrol. HWE reaction, LiAlH4 reduction and acylation then delivered allyl acetate 5. Silylketene acetal formation and subsequent heating in benzene resulted in Ireland-Claisen rearrangement to yield after another LiAlH4 reduction alcohol 6 in moderate yield. Hydrolysis of the TBS ether and global Swern oxidation finally furnished 7.

Scheme 1

 scheme_1_17102014

The remaining carbon skeleton was attached utilizing the boron enolate of lactone 8 followed by TES protection. Upon treatment with samarium diiodide the last quaternary center was formed giving tricycle 10 in good yield. A possible transition state is depicted below. Deprotection and PCC oxidation then delivered ketone 11. The hydroxyl group at the ring junction was then introduced by a Rubottom oxidation, the ketone subsequently reduced and protected. All that remained was dihydroxylation of the double bond, oxidation to the pyruvate and deprotection of the TES group to complete the synthesis.

 

Scheme 2

 scheme_2_17102014

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A Concise Total Synthesis of (-)-Maoecrystal Z

A Concise Total Synthesis of (-)-Maoecrystal Z

Jacob Y. Cha, John T. S. Yeoman, and Sarah E. Reisman

DOI: http://dx.doi.org/10.1021/ja2073356

Recently I stumbled onto this excellent paper from the Reisman group. While reading the paper I wondered if I ever reviewed one of their total syntheses because of the very appealing tactics employed by the group. By checking my archive I found the review of salvileucalin B … Nevertheless here is another excellent piece of work from this young research group featuring the total synthesis of Maoecrystal Z.

The retro is shown below.

Scheme 1

 

Some functional group manipulations led to a diol which was disconnected with respect to a radical cyclization cascade of the corresponing bisaldehyde. This in turn derived from a spirocyclic precursor which can easily be synthesized from a known cyclohexane derivative.

Though the paper starts from 3 the synthesis of this intermediate can be found in two older publications. The synthesis begins with the condensation of methylmalonate and mesityl oxide followed by conversion of one of the resulting ketones into a vinyl chloride with PCl3 and reduction of this into cyclohexanone 1. Wittig olefination, mild ester hydrolysis and resolution with (R)-phenylethylamine gave acid 2. Esterification with diazomethane and reduction with LAH then gave (-)-γ-cyclogeraniol 3 in good overall yield.

Scheme 2

 

Going on with the synthesis the alcohol was silylated and the exo methylene group epoxidized with mCPBA. Now to the first key step of the synthesis: a nice lactone formation through a radical promoted cyclization employing a protocol devised by the Gansäuer group. The mechanistic details are discussed at the end. According to the paper the use of the trifluoroethyl ester was required in contrast to the normally employed ordinary alkyl esters.

 Scheme 3

With fragment 5 in hand the group turned their attention onto the synthesis of alkylating agent 9. Pentenoic acid was reacted with pseudoephedrine, and alkylated under Myer’s conditions to give 8 in high yield and dr. Reductive removal of the auxiliary and Appel iodinaton then gave 9.

 Scheme 4

 

Both fragments were combined via enolization of 5 with LDA in the presence of HMPA followed by the addition of 9. Next a double bond was introduced through selenation/selenoxide elimination. Global desilylation with H2SiF6 and Dess-Martin oxidation then gave bisaldehyde 11. This cyclizes with some help from SmI2 (Kagan’s reagent) to give 12 in good yield. Remarkably during this process two new rings and four stereocenters were formed in a highly selective manner. Again the mechanistic rationale is discussed later in this review.

 Scheme 5

 

Protection of the free hydroxy groups with acetic anhydride catalyzed by TMSOTf furnished lactone 13. To the end ozonolysis of the terminal olefin, exo-methylene introduction with Eschenmoser’s salt and selective mono-deprotection produced Maoecrystal Z in moderate yield. The major problem the end of the synthesis posed was the selective acetylation of 12. Acetylation was not possible under various conditions without rearrangement processes or different monoacetylation products.

 Scheme 6

 

As promised here is the mechanistic understanding of the lactonization process: reductive opening of the epoxide gave a tertiary radical which attacks the acrylic acid ester. The resulting ester then cyclizes spontaneously under the reaction conditions.

 Scheme 7

 

The latter cyclization of the bisaldehyde can be explained with the scheme shown below. As usual SmI2 produces a ketyl radical from the less sterically hindered carbonyl functionality. 6-endo-trig cyclization closes the first ring and provides an enoyl radical which is reduced by a second equivalent of SmI2 to give the corresponding enolate. Aldol reaction with the remaining aldehyde closes the second ring to give 12.

 Scheme 8

Very nice work… And very straightforward. I really like the two key steps because of their efficiency and their rareness.

THX to Bobby for proofreading.

Catalytic Enantioselective Total Syntheses of Bakkenolides I, J, and S: Application of a Carbene-Catalyzed Desymmetrization

Catalytic Enantioselective Total Syntheses of Bakkenolides I, J, and S: Application of a Carbene-Catalyzed Desymmetrization

Eric M. Phillips, John M. Roberts, and Karl A. Scheidt

DOI: http://dx.doi.org/10.1021/ol100938j

“The bakkanes are a large class of sesquiterpene natural products containing a characteristic cis-fused 6,5-bicyclic core”. They possess a wide variety of biological activity for example antifeedant effects, platelet aggregation inhibition and presumably some activity against various cancer cell lines. Some total syntheses were published to date but this one catched my eye because of the nice methodology presented here. As you might know, NHC (N-heterocyclic carbene) catalyzed reactions can be used in analogy to nature’s TPP-catalyzed aldol reactions, e.g. in the Strecker reaction. Further examples are the use of NHC’s as ligands in metathesis reactions, Suzuki- and Buchwald-cross couplings or, as presented here, in an enantioselective synthesis of β-lactones.

It’s a rather short synthesis but with two cool key steps presented separately. First the three guys which were synthesized:

Scheme 1

As you can see with the core of Bakkenolide S in hand the remaining two are easily made.

The synthesis starts off with a Tsuji-Trost reaction giving them the allylic alcohol which was oxidized with BAIB in the presence of TEMPO to the unsatured aldehyde (why didn’t they use manganese dioxide?). This was cyclised to the β-lactone employing the group’s own chemistry with a good yield and excellent enantio- and diastereoselectivity.

Scheme 2

The mechanism looks like this:

Scheme 3

As in the Strecker reaction the NH-carbene (in situ produced with Hünig’s base) attacks the aldehyde and forms after loss of the α-proton an unsaturated enolate. This is re-protonated with enol formation and reformation of the positively charged NH-ligand. Subsequent enantio- and diastereoselective aldol reaction gave the tertiary alcohol which reacts with the strongly activated ketone to give the β-lactone under catalyst recovery. NICE…

With the key intermediate in hand the group removed the lactone in the presence of silica gel to give the olefin and carbon dioxide. Dioxolane formation was followed by stereoselective boronation/oxidation to the alcohol followed by deprotection of the ketone and TBS ether formation. Wittig reaction to the terminal olefin and isomerization with Crabtree’s catalyst gave the trisubstituted internal alkene.

Scheme 4

Reduction of the alkene, de-silylation and DMP-oxidation then furnished the ketone shown. Deprotonation was accomplished with LDA, the resulting enol reacted with Mander’s reagent and the methyl ester transesterified with propargyl alcohol. The prepended isomerization of the terminal olefin proved to be necessary because direct reduction under various conditions didn’t produce the expected product.

The following step presents again a nice methodology which I will present to you separately.

Originally the group planned to produce the δ-lactone via a Conia-ene reaction (http://www.organic-chemistry.org/namedreactions/conia-ene-reaction.shtm) but this attempt was unsuccessful. Nevertheless by reacting the propargyl ester with Mn3+ the lactone was formed in very good yield with excellent diastereoselectivity.

Reduction of the ketone and subsequent isomerization of the lactone then produced Bakkenolide S.

Scheme 5

The mechanism of the lactone formation might be this one:

Scheme 6

First a SET oxidation by manganese to give the strongly stabilized radical which reacts after rotation of the ester group with the alkyne moiety to give the 5-exo-dig radical.

Further info about this kind of reactions can be found here: Chem. Rev. 1996, 96, 339-363

To the end, ester formation with the corresponding acid chloride gave Bakkenolide I and J.

Scheme 7

Overall a nice synthesis in which a lot of interesting methodology was employed. If you’re interested in further reactions catalyzed by this NHC’s have a look in the references.

THX for reading my stuff J

_______________________________________________________________________________________

I received a question on the isomerization step so here’s the mechanism for this transformation:

Scheme 8

The TBAF acts as a base and deprotonates the alcohol. This undergoes a retro aldol reaction followed by bond rotation of the latone and reverse aldol reaction to give the final product.

Synthesis of the Monomeric Unit of the Lomaiviticin Aglycon

Synthesis of the Monomeric Unit of the Lomaiviticin Aglycon

K. C. Nicolaou, Andrea L. Nold, and Hongming Li

DOI: http://dx.doi.org/10.1002/anie.200902509

Hello again,

it took some time to get this post done but I was again busy learning some mathematics and physical chemistry… Boring stuff…

But nevertheless here it is: the nice KCN approach to the relatively new class of Lomaiviticins A and B which structures reminds me somewhat of a class of compounds reviewed by Paul: http://totallysynthetic.com/blog/?p=1520

So what’s it all about with this class of compounds? As usual they exhibit an impressive activity against cancer cell lines through a novel type of action which is currently under investigation. They’re acting through cleavage of the DNA in cancer cells. Interesting stuff but let’s get started with the chemistry:

(As you can see I almost got my ChemDraw installed and it’s great… much better than this shitty ISIS Draw)

Lomaiviticin

In this publication we’re dealing as mentioned above with the monomeric units of these two condensed polycycles. The retro is short and straightforward:

retro

First the blue fragment:

They started with the readily available aldehyde which was debenzylated with AlCl3, oxidised to the p-quinone which was protected as the SEM-ether after reduction to give the blue fragment:

Scheme 1

scheme_1

The synthesis of the red fragment is also very short. Readily available ethyl-cyclohexenone was exposed to a Sharpless asymmetric dihydroxylation and protected as the acetonide. A Saegusa oxidation furnished a new double bond which is regioselectively iodinated:

Scheme 2

scheme_2

Now comes the interesting part: The union of the two fragments and the formation of the remaining five membered ring containing the unusual diazo-cyclopentadiene motif. Starting with an Ullmann coupling followed by a benzoin condensation using Rovis catalyst gives the almost finished product.

Scheme 3

scheme_3

They had some problems with the benzoin condensation in first instance by using this catalyst and a different naphthalene unit cause it lead to the formation of the Stetter product. This problem could be overcome by using the shown starting material under the same conditions.

Next a SmI2 induced hydroxyl transposition gives the almost functionalised intermediate. Again they had some problems with their own standard protocol http://pubs.acs.org/doi/abs/10.1021/ja074297d from an older synthesis, so they modified and studied this reaction extensively and got good results with the following reaction sequence:

Scheme 4

scheme_SmI2

Very cool stuff but I were wondering if they didn’t try to transpose the hydroxyl group through a chrome(VI) induced allylic oxidation followed by chemoselective reduction of the resulting ketone. Nevertheless a very effective reaction protocol.

At least they installed the diazo motif by forming the hydrazone with TsNHNH2 and oxidised it using Dess-Martin-periodinane which also cleaved the SEM-groups to give the expected quinone system. Reduction and subsequent acetylation, followed by SEM-ether cleavage with TMSOTf, oxidation using CAN and hydrolysis furnished the final product.

Scheme 5

scheme_4

This is a really short and effective approach to this exciting class of compounds, hopefully followed by the condensation of the monomers. Even though it is a typical KCN publication the extensive colouring is missing… Maybe he forgot it? Or they omitted it for clarity…

Suggestions are as usual welcome…

Enantioselective Total Synthesis of (-)-Napyradiomycin A1 via Asymmetric Chlorination of an Isolated Olefin

Enantioselective Total Synthesis of (-)-Napyradiomycin A1 via Asymmetric Chlorination of an Isolated Olefin

Scott A. Snyder, Zhen-Yu Tang, and Ritu Gupta

DOI: http://dx.doi.org/10.1021/ja9014716

Hello again! It’s almost a month ago since my last post so I decided to dig out this short synthesis with some nice new chemistry in it as mentioned in the headline.

This time an interesting halogenated natural product (chosen to demonstrate their powerful method) with only 3 stereocenters of which 2 were captured by chlorine. This class of Napyradiomycins exhibit antibacterial activity against methicillin- and vancomycin-resistant strains and some anti tumour activity (some infos about MRSA can be found here: http://en.wikipedia.org/wiki/Antibiotic_resistance).

Only one total synthesis is known which yielded only a racemic mixture of Napyradiomycin A1 so here comes the second one. The retro looks like this:

Scheme 1

1_0705091

They planned to use the isolated olefin for their asymmetric chlorination, install the alcohol and rearrange it to build up the allylic chain on the benzoquinone ring system. It was further planned to cyclise the bis-unsatured chain to get Napyradiomycin B4 but these results will be presented in a follow up publication.

The basis of the synthesis is flavion which was synthesised earlier by other groups in a relatively long 8 step reaction sequence. They shortened it by heating the sulfonic acid salt in an alkali fusion and let the air do the rest.

Scheme 2

2_070509

The resulting flavion was reacted with methyl crotonaldehyd under acid catalysis to give the ABC-ring system via a tandem Knoevenagel/6-π-electrocyclization followed by protection of the non-conjugated hydroxy function. The resulting tetrahydropyran fused ring system was exposed to the chlorination conditions which yielded the expected product in 87% yield with 93% e.e. after crystallisation. The conjugated chlorine was changed to an acetate with retention of configuration and after protection of the other hydroxy function and acetate cleavage, the second key intermediate was readily prepared.

The key step in this scheme is the asymmetric chlorination of the olefin:

4 eq of the previously synthesised ligand were reacted in THF with BH3 and AcOH. After solvent removal, the intermediate was added in THF, followed by chlorine which was bubbled through the solution. A transition state was formulated which look like this:

Scheme 33_070509

Details can be found in the supporting information. Then they installed the hydroxy function with retention of configuration:

Scheme 4

4_070509

The adjacent carbonyl function may act as an electron pair acceptor throughout the whole addition/elimination reaction. The in situ formed SmI2 acts as a Lewis acid and removes selectively the acetyl protecting group.

The second half of the synthesis starts with a Johnson-Claisen rearrangement followed by a conjugate reduction with KHBPh3 as the reducing agent. It’s the first time I met a reagent for this kind of reduction without making use of a copper containing reagent.

After ester reduction and re-oxidation with Dess-Martin periodinane the resulting aldehyde was used for a Wittig-olefination.

The second chlorine was introduced stereoselectively with NCS and the protecting groups cleaved with MgI2 and PPTS to give enantiomerically pure Napyradiomycin A1.

Scheme 5

5_070509

The supporting information also features a synthesis of the ligand used in the asymmetric chlorination if you’re interested in trying it by yourself.

So that’s it for the moment. Suggestions are welcome.