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

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

Scalable Total Synthesis of (-)-Berkelic Acid Using a Protecting-Group-Free Strategy

Scalable Total Synthesis of (-)-Berkelic Acid Using a Protecting-Group-Free Strategy[1]

Francisco J. Fananás, Abraham Mendoza, Tamara Arto, Baris Temelli, and Felix Rodriguez

 DOI: dx.doi.org/10.1002/anie.201109076

Berkelic acid is a rather old target to the synthetic community and three total syntheses have been published to date. Interestingly the material provided by synthesis produced contradictory biological results compared to earlier studies. So besides showing the power of their methodology the group planned to provide enough material for refined studies.

 Scheme 1

As can be seen from scheme 1 the group planned to construct almost the whole framework in one single step after disconnection of the side. It should be noted that the group has some experience with this kind of cascade transformations of which they can rely on. Nevertheless instead of employing palladium catalysts the group turned their attention to silver catalysis. With this cascade reaction in mind they hoped that the stereogenic methyl group would control the stereoselectivity of the whole transformation.

The three key building blocks were prepared in a straightforward manner. Starting from commercially available butynol 1 the hydroxy functionality was mesylated and replaced by diethylmalonate to give after complete reduction diol 2. Starting from ester 3 the second fragment was prepared by triflation of the least hindered hydroxy group followed by Suzuki cross coupling with the trifluoroborate of heptyne. Hydroxy-directed reaction with formaldehyde and subsequent oxidation produced ester 4. The last building block stems from dimethyl malate which was doubly alkylated in the first place. Then the a-hydroxy ester was used for a periodate cleavage followed by cyanohydrin formation which was catalyzed by PNPCl.[2]

 Scheme 2

 

Combination of the red fragment 2 and orange fragment 4 was accomplished in the presence of 5 mol% silver(II). Subsequent hydrogenation of the resulting double bond yielded 7 in good yield and diastereoselectivity favoring the desired one. Appel reaction under standard conditions was followed by cyanohydrin alkylation and unmasking of the ketone to give protected Berkelic acid 9. Small amounts of Berkelic acid can be produced in good yield by selective saponification of the more active ester. This was only done when material was needed for testing or analysis as the natural product is a short-lived compound.

 Scheme 3

 

The mechanism of the cool key step is presented below. On one hand the red fragment underwent a 5-exo-dig cyclization thus desymmetrizing the propanediol moiety to give after protodemetallation a tetrahydrofuran ring. On the other hand the carbonyl of the orange fragment underwent a 6-endo-dig cyclization. Supported by keto-enol tautomerism of the hydroxy functionality an ortho-quinone methide is formed. Michael addition of the enol ether from the red fragment onto the quinone methide was followed by acetal formation by the phenol. Hydrogenation of the newly formed double bond then gave intermediate 7.[3]

 Scheme 4

 

[1] I was pointed to the title which says “[…] protecting-group-FREE strategy”… I am not particularly sure how they got the title but I see almost two protecting groups: the TES-cyanohydrin and one of the methyl esters. Maybe the title refers to the neat cascade reaction in which no protecting groups are necessary…

[2] It is the first time I ever saw this reagent in action. It is usually used for halogenation reactions. The cited paper in this step found that in the presence of PNPCl the cyanohydrin formation is much faster which was ascribed to an activation of the carbonyl oxygen by the high oxophilicity of phosphorous.

[3] At first sight one might think of a Diels-Alder reaction. But brief examination of the stereochemistry on the newly formed pyran ring shows that only a stepwise mechanism can form this particular anti-substitution pattern.

Addendum: If you are interested in earlier studies of the group you should have a look into these two papers

Big THX to Bobby for proofreading.

Synthesis of Dragmacidin D via Direct C-H Couplings

Synthesis of Dragmacidin D via Direct C-H Couplings

Debashis Mandal, Atsushi D. Yamaguchi, Junichiro Yamaguchi, and Kenichiro Itami

DOI: http://dx.doi.org/10.1021/ja209945x

I thought about writing this review a few months ago but never found the time to get it done. But here it is and I hope you enjoy this cool paper as I did. I am a big fan of “flat” chemistry and C-H activation so naturally this piece had to be reviewed. Dragmacidin D itself shows some promising activity in the treatment of neurodegenerative diseases like Alzheimer’s or Parkinson’s disease. Only one total synthesis has been published by the Stoltz group in 2002 so there is still room for improvement. Retrosynthetically the group planned to stick all parts together via C-H activation/C-C coupling reactions.

 Scheme 1

The “sticky” –positions are marked in blue. As can be seen from this picture almost all crucial bonds can be formed through C-H activation (except the iodide).

Indole 1 was carboxylated to block the 3 position of the indole which would normally undergo iodination in the presence of NIS. Removal of the carboxyl group after halogenation gave indole 3. Tosylation was accomplished under standard conditions yielding the first coupling partner 4. Thiophene boronic acid 5 was oxidized to the corresponding alcohol to furnish after TIPS protection coupling partner 6. In the presence of PdII and silver(I) as the re-oxidant thiophene 7 formed in good yield on a gram scale. Desilylation and reductive desulfuration with Raney-Ni was followed by global deprotection and double MOM-protection to produce ketone 8. [1]

 Scheme 2

Next the 3 position of the indole moiety was again functionalized. This time pyrazine N-oxide was used in the presence of PdII to give 9. A TFAA mediated Polonovski-Potier rearrangement gave pyrazinone 10 which was used in a Friedel-Crafts-like acylation with 6-bromoindole to furnish 11 in good yield. Bromination of the ketone was accomplished via the TMS-enolate and NBS mediated bromination yielding 12. In the presence of Boc-guanidine Dragmacidin D was formed after deprotection.

 Scheme 3

 

Short and very efficient I would say. The only drawback might be that Dragmacidin D is formed in both enantiomeric forms. I was wondering how much silver the group stores in their laboratories J.

[1] Really a nice method to introduce the side chain on the indole. The net result is the reaction of an umpoled ketone with the aromatic ring.

Asymmetric [C + NC + CC] Coupling Entry to the Naphthyridinomycin Natural Product Family: Formal Total Synthesis of Cyanocycline A and Bioxalomycin β2

Asymmetric [C + NC + CC] Coupling Entry to the Naphthyridinomycin Natural Product Family: Formal Total Synthesis of Cyanocycline A and Bioxalomycin β2

Philip Garner, H. Umit Kaniskan, Charles M. Keyari, and Laksiri Weerasinghe

DOI: http://dx.doi.org/10.1021/jo200553g

Sorry for the long delay but I was a bit busy with my relocation. This piece of work was published a few weeks ago and deals with some interesting chemistry. I am not very familiar with this unusual [3 + 2] or formal [2 + 2 + 1]-cycloaddition reaction.

Let’s take a look at the retro:

Scheme 1

 

They make use of some old school and some modern chemistry. The bicyclic moiety is accessible by a Strecker reaction. A Pictet-Spengler reaction was used to produce the tetrahydroisoquinoline ring using starting material from a lactamization step. The proline-like motif in turn was formed through this odd cycloaddition step.

 Scheme 2

The aromatic part of Cyanocycline A was synthesized using some well known chemistry. Starting from anisol 1 a Friedel-Crafts acylation and subsequent Baeyer-Villiger oxidation formed 2. Regioselective bromination and saponification yielded phenol 3 which was protected as the benzyl ether 4.

Now to the first cool chemistry used in this paper: a stereoselective Grignard reaction with a D-serine-derived nitrone. The mechanistic rationale is explained at the end of this review. Hydroxylamine reduction was accomplished under Clemmensen conditions followed by Cbz-protection of the free amine to give 6. Acetonide removal and Dess-Martin oxidation then gave aldehyde 7.

Scheme 3

 

Next the formal [3 + 2]-cycloaddition is used to make three more stereocenters. Condensation of 7 with amine 8 was followed by the addition of silver acetate and methyl acrylate to give 10. Again the mechanism is discussed later on. Removal of both Cbz-groups and benzyl-groups forms the lactam ring and subsequent protection of the pyrrolidinyl nitrogen with Cbz gave 11. Boc-deprotection with TFA and a Pictet-Spengler reaction in acetic acid produced after benzylation of the free alcohol 12.

Scheme 4

 

Reduction of the Cbz group to a methyl group and cleavage of the chiral auxiliary with LAH in the presence of the amide worked fine. Oxidation of the terminal alcohol of 13 and subsequent Strecker reaction with TMSCN formed 14. Thioamide formation with Lawesson’s reagent and reductive desulfuration then gave imine 15.

 Scheme 5

Heating 15 in MeOH with some equivalents of ethylene oxide in a sealed tube formed 16. Selective debenzylation was accomplished with boron trichloride followed by benzoquinone formation with Mn3+ to give Cyanocycline A.

Scheme 6

And for those who want to know how the key steps might work, here is the mechanistic rationale. First the Grignard reaction:

Scheme 7

The authors explain the outcome of the reaction with an open transition state in which the Grignard reagent attacks the least hindered face of the nitrone. This is probably stabilized by a magnesium ion (when Grignard reagents are used). The reaction proceeds with high diastereoselectivity.

The second key step is somewhat more complicated. First the amide undergoes an imine formation with the aldehyde. Next one of the glycine protons is lost in the presence of silver which forms a tight complex with the imine nitrogen. The result is a positive charge on the nitrogen and a negative charge on one of the two vicinal carbon atoms. Moreover the silver cation forms a second complex with the acrylate which undergoes the cycloaddition and attacks the 1,3-dipole from the least hindered face to give 10.

Scheme 8

Nice chemistry don’t you think? And a really complex target. Comments?

And thx to Bobby for proofreading 😉

Total Synthesis of Bryostatin 1

Total Synthesis of Bryostatin 1

Gary E. Keck, Yam B. Poudel, Thomas J. Cummins, Arnab Rudra, and Jonathan A. Covel

DOI: http://dx.doi.org/10.1021/ja110198y

[1] http://doi:10.1016/j.tetlet.2006.09.094, Tetrahedron Letters 47 (2006) 8267–8270

[2] http://dx.doi.org/10.1021/ol050511w, ORGANIC LETTERS, 2005, 2149-2152

As promised here is my first review of the month:

I finished almost all of my exams so I decided to review this huge contribution to the field of organic and total synthesis. Although some members of the family of the Bryostatins were readily synthesized the total synthesis of Bryostatin 1 has never been disclosed to day. And here it is:

Scheme 1

O yeah, what a beauty J The current paper deals only with the last 24 steps so a closer look in the literature and supporting information unveiled the remaining “few” steps. If you want to read more stuff about the whole story you should have a look in the many references mentioned in the original paper.

So what’s it all about with these Bryostatins? As mentioned in the paper Bryostatin 1 for example exhibits some action against diabetes, stroke, cancer and Alzheimer’s disease. It is assumed that this action is a result of the strong interaction with protein kinase C isozymes. Again, more details can be found in the references.

I will start my review with the syntheses of some key fragments which are later used in the main paper mentioned above.

The blue fragment was available in four simple steps from ester 16: Allylation was followed by a Wohl-Ziegler bromination, a modified Williamson ether synthesis and simple saponification of the ester to give acid 1.

Scheme 2

The second half was synthesized starting from isobutyl lactate 34. BOM-protection and DiBAl-H reduction gave aldehyde 35. Stereoselective allylation, PMB-protection and ozonolysis furnished aldehyde 36 which in turn was allylated to give fragment 2 in about 80% overall yield.

Scheme 3

Fragment 1 and 2 were combined under standard Esterification conditions to give 3. The olefin was extended by a three step protocol involving oxidative boronation, Parrikh-Doering oxidation and Wittig methylenation to furnish 4. This underwent a nice Rainier metathesis reaction, which I presented to you last month, to close the pyran ring and gave 5. Epoxidation with MMPP (a more soluble substitute for the more familiar mCBPA) and in situ opening of the epoxide with methanol was followed by Ley oxidation and aldol condensation with methyl glyoxalate to give ketone 7.

Scheme 4

Luche reduction of the ketone and immediate trapping of the alcohol with acetic acid anhydride produced 8. TBS cleavage with HF and Ley oxidation with TPAP yielded aldehyde 9 which was reacted with homoallyl alcohol 10 in the presence of TMSOTf to give 11.

Scheme 5

The synthesis of the green fragment is discussed next before we move on with the synthesis.

Ester 20 was alkylated and isomerized with tBuOK to give 22. Complete DiBAl-H reduction gave alcohol 23 which was deprotonated / mesylated / stannylated in a one pot reaction to give 24.

Scheme 6

The second half of the fragment was synthesized starting with aldehyde 25. A stereoselective Mukaiyama aldol reaction was followed by PMB-protection of the free alcohol to give 26. Deprotection of the silylated alcohol and Parrikh-Doering oxidation was followed by another nice substrate controlled Mukaiyama aldol reaction to give 28. Silylation, dihydroxylation and lead mediated diol cleavage (Criegee oxidation) gave 29.

Scheme 7

Next Me2AlCl mediated allylation of aldehyde 29 with allyl stannane 24 gave alcohol 30 as a single diastereomer. Acetylation and PMB-cleavage under standard conditions was followed by ozonolysis to give 32. The hemiacetal was converted to a full acetal with methanol / CSA while the TBS group was cleaved off, the free alcohol oxidized and allylated to give the red / green fragment 10.

Scheme 8

The BPS-group (better known as TBDPS) was cleaved off with HF, the thiolester hydrolysed in the presence of H2O2 and the free alcohol trapped as the TES ether 12. PMB-cleavage was followed by Yamaguchi macrolactonization to give lactone 13 whose exo-methylene group was dihydroxylated and oxidized to ketone 14.

Scheme 9

The ketone was used to introduce the last ester group by employing a HWE-reaction with Fuji’s chiral phosphonate A to give 15. Selective acetate cleavage, esterification and global deprotection with LiBF4 then produced Bryostatin 1 as a single diastereomer.

Scheme 10

Man, what a long synthesis but extremely cool. Hope you enjoyed reading this and hopefully you have some suggestions and comments for me… It really took me some time to get an overlook and find all the widespread papers.

Bis die Tage…

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

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:

retro_051109

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:

scheme_1_051109

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:

scheme_2_051109

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:

scheme_3_051109

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:

mechanism_051109

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 🙂