A Concise Synthesis of Berkelic Acid Inspired by Combining the Natural Products Spicifernin and Pulvilloric Acid

Christopher F. Bender, Francis K. Yoshimoto, Christopher L. Paradise, and Jef K. De Brabander
DOI: http://dx.doi.org/ja905387r

Hey fellas,

really good stuff was published the last months and it was difficult to make a decision

… so I chose a synthesis from the De Brabander group published in July.

Though total syntheses from the Snider and Fürstner groups were published in 2008 and 2009 respectively there is always room for improvements because it shows some interesting biological activity:

Berkelic acid possesses selective activity against human ovarian cancer cells so a support of synthetic material is needed for further studies. Interestingly the true structure of berkelic acid was unknown until the synthesis from the Snider group in 2009.

Synthesis:

To shorten my review I will focus on the key step but discussions about specific reactions are welcome (I’m still trying to improve my style).

Retro:

The group recognised the fact that berkelic acid might be formed by a DA reaction of the already known compounds spicifernin and pulvilloric acid whose total syntheses were published some years ago.

Synthesis of the red fragment:

A tBu-Valine enamine directed alkylation was followed after hydrolysis by a TiCl₄ promoted aldol reaction giving the required α-β-unsatured ketone. A copper catalysed, anti-selective Michael addition with TMS-butyne, TMS and PMB-ether cleavage then gave the red fragment in good overall yield.

Synthesis of the blue fragment:

A regioselective triflate formation/Suzuki-Miyaura reaction yields the symmetrical bis-hydroxy acid which was protected as the MOM-ether, epoxidized and hydrogenated at the benzylic position to give the racemic alcohol shown. Stereoselective Lipase catalysed acetylation of the R-alcohol and Mitsunobu reaction of the other enantiomer gave the required fully protected dihydroxy benzoic acid. Deprotection and exposure to TEOF/TFA yields the blue fragment through an oxo-Pictet-Spengler reaction again in an overall excellent yield.

Key step:

Combining the 2 fragement in the presence of AgSbF₆ produced berkelic acid methyl ester and additional diastereomers which could be separated after deprotection with (Bu₃Sn)₂O.

Mechanism:

3,5eq of AgSbF₆ were required for the last transformation which can easily be seen from a mechanistic analysis:

The first equivalent produces the exo-methylene tetrahydrofuran, the second equivalent acts as a Lewis acid and oxidises the aromatic ring by cleaving the ethyl acetal. After formation of the required quinone methide the third equivalent catalyses the [4+2] addition yielding berkelic acid as the main diastereoisomer.

Nice work and sorry for the late review; I printed it some months ago but hm… it got lost

Enantioselective Formal Total Synthesis of (+)-Aspergillide C

Joseph D.Panarese and Stephen P.Waters (this review)
DOI: http://dx.doi.org/10.1021/ol902154p

Tomohiro Nagasawa and Shigefumi Kuwahara (last 3 steps)
DOI: http://dx.doi.org/10.1021/ol802803x

Today I will present to you a short formal synthesis of Aspergillide C which makes use of a nice hetero DA followed by a Ferrier-type addition. The last 3 steps were taken from a synthesis published 9 months earlier. You should have a look in it.

I know there’s no KCN-like “never-used-before-in-total-synthesis”-chemistry in it but I were taken with how they accomplished this synthesis in only 9 steps as the longest linear sequence. Efficient and short as expected from a OL paper.

Let’s have a look at the retro:

Scheme 1

(I really like these paper with the retro already in it )

As you can see they started with commercially available starting materials employing a DA, Ferrier alkylation and Pd(II)-catalysed lactonization. After installation of the side chain via Julia-Kocienski and macrolactonization they furnished Aspergillide C as described in the earlier synthesis from Nagasawa and Kuwahara.

Ok, before I forget it: the biological activity is again really interesting as Aspergillide C displays cytotoxicity against mouse lymphocytic leukaemia cells with a LD₅₀ of 2µg/ml (don’t know why they did not use the IC₅₀ value because as far as I know this is more significant…).

Scheme 2

Starting as mentioned above with a hetero DA catalysed by zinc chloride gave the desired γ-pyrone which was stereoselectively reduced under Luche conditions and acetylated. A lithium perchlorate mediated Ferrier-type alkylation followed by Pinnick oxidation furnished the carboxylic acid which was cyclised to the lactone by a Wacker-type oxidation (take a look at the double bond which moves around the ring; nice). Now we have our red fragment in hand.

The mechanism of the Ferrier-type alkylation might look like this:

Scheme 3

Lithium mediated vinylogue elimination of the acetate followed by anti selective addition of the TBS enol ether yields the product shown.

Next the preparation of the Julia fragment:

Scheme 4

They started with the commercially available hexenol which was protected, hydroborated and oxidised to the satured alcohol shown. Thioether formation under Mitsunobu conditions followed by ammonium heptamolybdate oxidation gave the green fragment in high yield.

The 2 fragments were combined after deprotection and diol cleavage of the red fragment under modified Julia-Kocienski conditions (normally it makes use of KHMDS).

Scheme 5

The rest of the synthesis was taken from the earlier published paper.

Hydrolysis, TBS protection and PMB ether cleavage yields the free acid which was cyclised under Yamaguchi conditions. A bit of TBAF then furnished the desired product in good overall yield.

Scheme 6

As mentioned earlier a very short and efficient synthesis again (17% yield over the longest linear sequence starting from protected glyceraldehyde) but hey, it serves the purpose.

I hope you enjoy reading this review though it is a bit shortspoken.

Ok, and next time I will feature a paper with this KCN-like chemistry, promised

Comments?

Total Synthesis of Oidiodendrolides and related Norditerpene Dilactones

Stephen Hanessian, Nicolas Boyer, Gone Jayapal Reddy, and

Benoıˆt Descheˆnes-Simard

DOI: http://dx.doi.org/10.1021/ol901896c

Another sweet paper from the Hanessian group published in August featuring a bunch of nice biological active compounds. Especially Oidiolactone B exhibits an impressive activity against interleukin-1β which could potentially be used for treatment of inflammatory diseases (http://en.wikipedia.org/wiki/Interleukin).

Only a handful of syntheses have been published yet each featuring only one target, this paper disloses the syntheses of 7 members of this class of compounds starting from one common precursor. Pretty amazing I think and very atom economic…

They planned to install the C ring at least and decorating the starting decaline core with some well established methods for example a sweet Reformatzky and Baylis-Hillmann reaction, both a bit underdeveloped in total synthesis.

Scheme 1

So let’s get started with this:

Scheme 2

First some protection and then a nice radical conjugate reduction under Birch conditions quenched with Mander’s reagent to give the methoxycarbonyl side chain in good yield and dr (which is unimportant because it is destroyed in the next step). Triflate formation and Stille like reduction gave them the unsatured ester which was again reduced with single electron transfer as I suppose (or maybe by facial selective hydrogen addition?), followed by alkylation and deprotection. A highly efficient IBX mediated dehydrogenation was followed by deprotection of the ester to give the blue intermediate. Didn’t know the IBX dehydrogenation method, I would have used a Saegusa type reaction but this one seems to be more practical.

With this intermediate in hand they were able to prepare the key intermediate shown above in only 5 more steps:

Scheme 3

A highly efficient phosphine catalysed Baylis-Hillmann reaction with formaldehyde was followed by a bromolactonization to close the D ring lactone through the shown transition state. TES protection and a nice catalytic Reformatzky reaction furnished the key intermediate in an impressive overall yield of 17% over 14 steps.

The biggest problem poses the dehydration to form the exomethylen ester group. This problem was solved employing Burgess reagent to dehydrate the hydroxy function off the ring.

Scheme 4

After having the dehydration problem solved they commenced with HF mediated deprotection/ in situ lactonisation followed by DMDO epoxidation to give Oidiolactone C.

To improve the yield they switched the order of events and got the product in a much better yield. With the epoxidated decaline in hand a mild TES deprotection by CSA, DMP oxidation and strong acid catalysed lactolisation gave then a mixture of epimers of Oidiolactone D.

This was methylated to give Oidiolactone A.

Having these three in hand only 3 more to go:

Scheme 5

Starting with the already employed CSA mediated deprotection and DMP oxidation, followed by Burgess dehydration and acidic lactolisation to give the fourth natural product in this paper. A described access to Nagilactone F through isopropylgrignard addition gave only low yield and moderate diastereoselectivity, so they worked their way through a more commonly isopropylengrignard reaction reaction followed by a modified Wilkinson reduction to give Nagilactone F in a much better yield and diastereoselectivity. Oidiolactone B, the most potent member of this class, was easily accessible by methyl acetal formartion and separation of the desired major isomer.

Overall a nice paper which discloses a bunch of total syntheses in only 4 pages

You are advised to have a look in it. I enjoyed most the smooth preparation of the key intermediate.

Any comments?