Synthesis of Undecachlorosulfolipid A: Re-evaluation of the Nominal Structure

Synthesis of Undecachlorosulfolipid A: Re-evaluation of the Nominal Structure

Christian Nilewski, Nicholas R. Deprez, Thomas C. Fessard, Dong Bo Li, Roger W. Geisser, and Erick M. Carreira

 DOI: http://dx.doi.org/10.1002/anie.201102521

This time I will present to you a real beasty of a molecule. It belongs to the class of the chlorosulfolipids which gained some synthetic interest in the last few years. Their biological profiles combined with the low supply of material drives researchers to produce some quantities for biological evaluation. Nevertheless from a synthetic point of view the development of asymmetric halogenation reactions is a growing field which can be further examined during the synthesis of such complex tasks.

The most complex member of the chlorosulfolipids looks like this:

 Scheme 1

As can be seen from the structure it contains no less than 15 stereocenters of which 9 are contiguous and 9 are chiral chlorine atoms. In the light that only a handful of tactics for asymmetric chlorination reactions are known to date this is an extremely challenging task.

We start off with two precursor molecules whose syntheses are described in the supporting material which I highly recommend for reading because it contains a lot of useful information about NMR analysis of chiral chlorine bearing carbon atoms.

 Scheme 2

 

The first intermediate stems from commercially available (S)-1,2,4-butanetriol 1 which was protected as the acetonide, coupled under Mitsunobu conditions with phenyltetrazolylsulfide which in turn was oxidized to the sulfone. Julia-Kocienski olefination gave a mixture of E/Z-isomers which were isomerized to the major E-isomer under photolytic conditions to give 4.

The more reactive g,d-olefin was dichlorinated with tetraethylammonium trichloride with a d.r. of about 1.8 / 1 which can be further enhanced after epoxidation because of the easier separation of diastereomers. DiBAl-H reduction of the ester was followed by acetylation of the alcohol, stereoselective Sharpless dihydroxylation, and regioselective epoxide formation upon treatment with triflic anhydride. The overall yield of this sequence is only 9 % but during these five steps four of the fifteen stereocenters are formed.

5 was subjected to acetonide cleavage conditions and the resulting diol was protected as the bis-TBS ether of which the primary alcohol was again set free with HF – pyridine to give 6. Oxidation of the terminal alcohol to the aldehyde and Wittig olefination with phosphonium salt 12 gave 13 whose double bond was again dichlorinated to give after deacetylation compound 14.

 Scheme 3

 

Fragment 12 stems from two commercially available building blocks. On one hand ethyl lactate was protected and selectively reduced to aldehyde 7 while on the other hand propanediol was monoprotected and iodinated under Appel conditions to give iodide 8. Diastereoselective alkylation with the lithium reagent derived from 8 then furnished alcohol 9 which in turn was benzylated, and converted after selective monodeprotection into iodide 11 which gave Wittig salt 12 in the presence of triphenylphosphine.

 Scheme 4

 

The second half of the molecule derived from pentanediol. Monoprotection, Ley oxidation and dichlorination with NCS produced aldehyde 15. Next asymmetric alkynylation under Carreira’s conditions gave 16 with excellent enantioselectivity. Semireduction of the alkyne and hydroxy directed epoxidation of the trans-alkene necessitated DMP oxidation of the alcohol because no suitable conditions for selective epoxide opening could be identified. Thus ZrCl4 mediated epoxide opening of 16a and stereoselective reduction of the ketone gave diol 17.

To the end the diol was protected as an acetonide, the TBDPS group removed, the terminal alcohol oxidized, and reacted with Still-Gennari modified HWE reagent A to yield 18.

 Scheme 5

 

Going on with the synthesis ester 18 was successively reduced and the resulting allylic alcohol exposed to Sharpless asymmetric epoxidation reaction conditions. The epoxide was then regioselectively opened to give diol 19. Acetonide formation and debenzylation was followed by Mitsunobu coupling and oxidation to yield sulfone 21.

 Scheme 6

 

Fragments 14 and 21 were coupled under Julia-Kocienski conditions after prior DMP oxidation of the terminal alcohol of 14. Subsequently the epoxide of the intermediate was opened with PPh3Cl2 to give alcohol 22. Stereoselective dichlorination of the double bond then gave 23.

 Scheme 7

 

To the end 23 was debenzylated and the resulting alcohol used as a handle to introduce a double bond with Martin sulfurane. TBS removal and selective esterification with palmitoyl chloride gave protected Undecachlorosulfolipid 25.

Scheme 8

Conversion of 25 into Undecachlorosulfolipid was then accomplished first by sulfate introduction with SO3 in DMF followed by acetonide cleavage with TFA.

Scheme 9

With a few µg of Undecachlorosulfolipid A in hand the group compared the analytical data of their lab work to the reported data and noticed that the compounds were not identical. Especially the assignment of the ester bearing hydroxy group caused some problems. It was assumed that the stereochemistry should be R instead of S.

Well… nevertheless congratulations to the group to get this synthesis to work. Hopefully there will be a full account of this work showing all their tactics.

THX to Bobby for proofreading!
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Asymmetric Synthesis of (+)-Polyanthellin A

Asymmetric Synthesis of (+)-Polyanthellin A

Matthew J. Campbell and Jeffrey S. Johnson

DOI: http://dx.doi.org/10.1021/ja904136q

Hell yeah, back from the grave…

It took some time but now it’s finished: this time featuring a very cool asymmetric synthesis of the natural product Polyanthellin A. I do remember an extremely effective synthesis from Overman in this class of natural products a few years ago employing his oxy-Cope/Mannich-tandem reaction. In this paper the attention is less methodical nature and more focussed on the target itself.

Whatsoever let’s get started:

If you’re interested in the biology of this little metabolite take a look in the original report in Natural Products (ref. 7)…

First the retro:

polyanthellin A_160909

The key step in this synthesis features an asymmetric formal [3+2] cycloaddition starting from the 2 fragments which I will call from now on the red and the blue one.

This paper is full of interesting chemistry, too much for this little review, so I will focus only on the key aspects. If you’re interested we can discuss the reactions I did not picture in full detail later in the comments.

The blue fragment was synthesised starting from commercially available methallyl alcohol:

Scheme 1

scheme_1_160909

Sharpless asymmetric epoxidation creates the only stereocenters in this fragment, followed by an epoxide opening from a copper catalysed allylation. Chemoselective tosylation, Kolbe-Schmitt-nitrile synthesis, TMS protection and DIBAL-H reduction furnished the blue fragment in an overall acceptable yield (the solvent is choice is odd, I would have taken THF)…

Synthesis of the red one needed some more attention but in the end makes use of a bunch of quite efficient stereoselective methods. And here it comes:

Scheme 2

scheme_2_160909

First a more or less standard Michael addition catalysed by Prolinol-derivative (1) and catechol ester (2) to give the 1,5-diketone in high yield. A Wittig reaction with titanated allyldiphosphine yields the required Z-allyl side chain which was followed by methylcarboxylation using Mander’s reagent furnishing the functionalized malonester. Diazotransfer and subsequent carbene inserton catalysed by (3) into the nearer double bond gives in the end the red fragment ready for the formal [3+2] cycloaddition.

Now the key step: After an extensive screening of catalysts the authors found this bulky aluminium based Lewis-acid catalyst giving the best results. The complete scheme looks like this:

Scheme 3

scheme_3_160909

However they needed 3eq of the blue fragment but this gives them the core structure in a very good yield and stereoselectivity. A metathesis employing Grubbs II closes the ring ensued by Krapcho decarboxylation, a sequence of hydroboration/TPAP oxidation and another Wittig reaction completes this scheme.

Because there are no mechanisms in this paper I created this one for the [3+2] cycloaddition:

mechanism_160909

First a Lewis-acid catalysed cyclopropane opening gives the stabilised allyl cation and the enol ester which in turn attacks the carbonyl in an aldol fashion followed by ring closure from the enolate oxygen. Or a more concerted cyclization?

Ok, nevertheless only a few more steps to go:

Scheme 4

scheme_4_160909

Simple iodo etherification, oxymercuration and global reduction yields the naked Polyanthellin which was acetylated to give the desired product.

To my surprise the JACS paper is only 2 pages long… I would have expected the paper to be at least 4 to 6 pages long to show how they employed the specific methods cause some of them a really rare. That’s why I prefer the Angewandte papers: they feature almost the complete synthesis in detail, which is not always useful but gives you a better insight into the planning and realization of such a complex synthesis.

Ok, that’s it from my site, any comments?

___________________________________________________________________________________________

To the selectivity in the iodoetherfication:

I made this nice little 3D model with ChemDraw which might explain the differentiation. The cyclohexane-methylen group is blocked from equatorial attack by the hydroxy functionality cause the cyclononane ring forms a twist boat whereas axial attack is blocked as usual by  1,3 axial strain.  Or the access to the other methylen group is much easier as we’re dealing with a more convex shape of the molecul in this area. Here is what I mean: the green ring marking the blocked methylen-group, the red ring marking the attacked one:

iodoetherfication

But yeah, cool selectivity!! 🙂

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…