Total Synthesis of Branimycin: An Evolutionary Approach

Total Synthesis of Branimycin: An Evolutionary Approach

Valentin S. Enev, Wolfgang Felzmann, Alexey Gromov, Stefan Marchart, and Johann Mulzer

DOI: http://dx.doi.org/10.1002/chem.201200257

As the title suggests this full account features a collection of approaches towards the central core of branimycin. All those who are interested in a great story of evolutionary chemical design really should have a look at the full paper. I will focus in this short write-up only on the longest linear sequence.

Scheme 1

As can be seen from scheme 1 the synthesis focusses mainly on three fragments where green fragment 1 and blue fragment 2 constitute the main part of the molecule. The synthesis of fragment 1 is described in a previous paper but also featured in the following. The evolutionary design is limited to the synthesis of 2 and fragment 3 is commercially available dimethyl malonate.

The first route to allylalcohol 7 started from (R,R)-dimethyltartrate which was protected and reduced to diol 5. Methylation, tosylation, Finkelstein reaction, and reductive acetonide cleavage then furnished 7 in low yield. A more direct access from glycidol 6 is also presented. After methylation of the hydroxy function the epoxide was opened under Corey-Chaykovsky conditions to give 7. TIPS protection and ozonolysis of the olefin produced aldehyde 8.

Scheme 2

Next aldehyde 8 underwent a Marshall reaction with a chiral silylallene to give in high yield and stereoselectivity alkyne 9. Aqueous ammonium chloride was necessary for in situ deprotection of the resulting TMS ether. MOM protection of the alcohol and Schwartz reaction with subsequent iodine quench was used to arrive at vinyl iodide 10. Protection group switch from TIPS to the more convergent cleavage TBS group is straightforward giving green fragment 1.

 Scheme 3

The synthesis of the blue fragment began with Diels Alder reaction between two equivalents of furan and methyl propiolate. With ester 11 in hand the surplus ester group was removed following Barton’s protocol. Saponification and esterification with HPT produced thiohydroxamate ester 12 which loses CO2 under reductive radical reaction conditions yielding 13. Opening of one of the dihydrofurans gives a racemic mixture of alcohols 14 which were in turn protected. The silyl group was used as a handle in a Tamao-Fleming oxidation to introduce the terminal alcohol to give after methylation rac15.

Scheme 4

The next step in the synthesis is an interesting chiral resolution strategy by a “chiral hydride”. This is transferred from a Ni-(R)-BINAP complex with DiBAl-H as the hydride source. Never saw this kind of strategy in a total synthesis before but it is really a pretty neat solution. Although half of the material got lost in this step it provides rapid access to the blue fragment 2. If you are interested in this step you should have a look into this one [1]. So with enantiomerically pure 16 in hand the alcohol was oxidized and the PMB group replaced with a TBS group. After chemo- and stereoselective epoxidation (maybe guided by the methoxy group?) the blue fragment 2 was ready for the crucial coupling step.

 Scheme 5

Metal/halogen exchange of 1 with tBuLi and quench with 2 generated an alcoholate which immediately opens the epoxide in a 5-exo-tet reaction to give 19. This advanced intermediate was protected as a TBS ether and exposed to Cr(VI) which is known to promote allylic oxidation/rearrangement/oxidation to give in the end an unsaturated ketone. An attempted Claisen rearrangement to introduce the side chain did not give any positive results so the group had to pursue a different route. Michael addition of dimethylmalonate, triflation of the ketone, and reduction saved the day giving 21 in good overall yield.

 Scheme 6

Global reduction with LiBEt3H, selective monomethylation and MOM-deprotection produced diol 22. Chemoselective TEMPO oxidation (primary vs. secondary alcohol) to the aldehyde and Pinnick oxidation gave seco-acid 23. Some macrolactonization conditions were screened but the rather old school Corey-Nicolaou reaction proved to be successful to furnish after desilylation branimycin. As can be seen from scheme 7 it was not possible to control the stereochemistry a to the ester functionality. The preceding methylation to differentiate the hydroxy functionalities did not result in any chiral resolution so this stereocenter remains racemic giving at last two diastereomers of branimycin. Nevertheless the absolute of this stereocenter could be unambiguously resolved which remained unclear at the beginning of the story.

 Scheme 7

Sorry for the long delay of posting but I am really busy with finishing my exams and planning my move to the US.

 

[1] http://dx.doi.org/10.1016/S0040-4020(97)10211-3

 

Total Synthesis of Tulearin C

Total Synthesis of Tulearin C

Konrad Lehr, Ronaldo Mariz, Lucie Leseurre, Barbara Gabor, and Alois Fürstner

 DOI: http://dx.doi.org/10.1002/anie.201106117

Tulearin C is at first sight a rather simple polyketide natural product. Only seven stereocenters of which only four are contiguous and none of them is quaternary. Nevertheless no useful route to this compound has been established to date despite some potential antiproliferative action against human leukaemia cell lines.

The group around Fürstner built their synthesis upon a RCAM (ring-closing alkyne metathesis) with subsequent trans-selective hydrosilylation/protodesilylation to get the trans alkene. This critical feature was the major problem of earlier approaches which relied on a trans selective RCM which instead gave a mixture of trans and cis alkenes of virtually 2 : 1.

 Scheme 1

 

Breaking down the molecule into two halves the group reduced the problem to the common starting unit 1. This glutarate monoester is available in large quantities from dimethyl-3-methylglutarate.

Desymmetrizing saponification of one of the ester groups with a pig liver esterase (PLE) and further enhancing ee by crystallization of the crude acid with cinchonidine gave ester 1. You should have a look in the SI how they did this interesting saponification. After formation of the lithium salt the ester was reduced to the alcohol and cyclized to give lactone 2. Wittig reaction then furnished dichloride 3 which was reacted with excess methyl lithium to give alcohol 4 and after DMP oxidation aldehyde 5.

The key transformation of this scheme is detailed at the end.

Scheme 2

Aldehyde 5 then underwent stereoselective alkynylation under Carreira’s conditions to give diyne 6. Regioselective reduction of the internal alkyne and quench with iodine was followed by silylation of the free alcohol. The excellent regiocontrol can be ascribed to the alcohol function which guides the Red-Al to the correct end of the triple bond. Palladium catalyzed methylation and subsequent desilylation then furnished the green fragment. Direct introduction of the methyl group in the hydrometallation step with Red-Al did not produce any product at all.

Scheme 3

As mentioned above the synthesis of the second fragment commenced with key intermediate 2. Claisen reaction with ethyl acetate and reduction of the resulting dicarbonyl compound gave diol 9. Protection of the primary alcohol was necessary to get the following methylation done. MOM-protection of the secondary alcohol produced ester 10. After desilylation of the TBDPS group an Appel reaction of the free alcohol furnished iodide 11

Scheme 4

The second half of the red fragment was synthesized from butynol. Hydrozirconation with Schwartz’ reagent in the presence of DiBAl-H and iodine quench was followed by triflation and alkynylation to get iodide 12.

Scheme 5

Both parts were combined by first generating the alkylzinc species from 11 which underwent a Negishi coupling with iodide 12. Sharpless dihydroxylation and subsequent MOM cleavage was followed by global TBS protection and saponification of the ester grouping.

Scheme 6

Esterification of 15 with 8 was accomplished with EDC in almost quantitative yield. RCAM with catalyst C was done in toluene in excellent yield although some heating was necessary. Trans-selective hydrosilylation gave lactone 17 from which the siloxy group was removed with AgF. TBS removal under standard conditions then produced Tulearin C.

Scheme 7

And here are the details concerning the formation of key fragment 4. It is some kind of Grob fragmentation and I would compare it to the well known Eschenmoser fragmentation. Two possible reaction pathways are shown in the paper of which the left one is preferred.

As can easily be seen from the scheme the first step is a metal-halogen exchange to give a carbenoid-like carbon atom. The next step might on the one hand be an intramolecular E2-reaction to give the acetylenic chloride which undergoes another metal-halogen exchange and subsequent alkylation with in situ formed MeCl (blue arrows).

Or alternatively the vinyl-lithium species is alkylated with in situ formed MeCl before the second chloride atom undergoes a metal-halogen exchange and further fragmentation (green arrows).

Independent of the intermediates the same product is formed in good yield. In the original paper some applications of this transformation are shown and a detailed investigation of the mechanism and further application are underway. Also two examples are shown in which allenes instead of alkynes are formed.

Scheme 8

As usual exceptionally good stuff from the Fürstner group.

And big thanx to Bobby for proofreading.

Total Synthesis of (+)-Condylocarpine, (+)-Isocondylocarpine, (+)-Tubotaiwine and (-)-Actinophyllic Acid

Total Synthesis of (+)-Condylocarpine, (+)-Isocondylocarpine and (+)-Tubotaiwine

Connor L. Martin, Seiichi Nakamura, Ralf Otte, and Larry E. Overman

DOI: http://dx.doi.org/10.1021/ol102709s


Total Synthesis of (±)- and (-)-Actinophyllic Acid

Connor L. Martin, Larry E. Overman, and Jason M. Rohde

DOI: http://dx.doi.org/10.1021/ja100178u

This review summarizes two very interesting papers published more or less recently by the Overman group (he is still my favourite… ). I decided to combine both papers because a common intermediate was used to make all  four natural products and its synthesis makes use of some uncommon in situ Umpolung chemistry.

The first schemes were reproduced from the JACS paper while the last two schemes came from the OL paper.

Scheme 1

Starting with Boc-protected GABA 1 the free acid was transformed into the Weinreb amide and alkylated with a vinyl-Grignard to get 2. Enantioselective reduction of the resulting ketone with high ee was accomplished by using catalyst A in the presence of hydrogen (Noyori’s catalyst). Ozonolysis of the double bond and trapping of the alcohol and resulting aminal with acetic anhydride furnished piperidine 4.

The second main fragment was obtained in two steps from di-tert-butylmalonate. Deprotonation and acylation gave compound 6 which formed indole 7 after reduction of the nitro group with Pd on charcoal in the presence of vanadate.

Scheme 2

Then it is getting more interesting: the blue and red fragment were combined by using a bit of scandium triflate to form 8 with great diastereoselectivity. Reductive removal of the acetyl protecting group and Swern oxidation of the resulting free alcohol produced ketone 9. Next my favourite reaction of the whole paper was employed: first a double deprotonation of the ketone and the malonate and then combination of the two carbanions to form the critical bicyclic ring system. Although the yield is moderate it proceeds with high dr. [Fe(DMF)3Cl2][FeCl4] was prepared from dehydrated iron(III)chloride and DMF by simply mixing the reagents. Finally addition of vinyl-Grignard under Luche conditions to the ketone forms lactone 11.

Scheme 3

Going on with the synthesis the lactone and the remaining ester group were reduced to get bis-alcohol 12. At this stage Overman makes use of his almighty aza-Cope/Mannich reaction.

The t-Bu- and Boc-groups were cleaved off in the presence of dilute acid before formalin was added. For clarity I added the main stages of the following events:

First a Schiff base formed from formaldehyde and the secondary amine. This underwent an aza-Cope rearrangement (or some sort of Prins-reaction) with the allyl alcohol to form 13b. The newly formed enol then attacks the rearranged Schiff base in a Mannich reaction to give (-)-Actinophyllic acid 14 as its hydrochloride.

Scheme 4

Finally to the paper mentioned first. Starting from key intermediate 10 the ketone was reduced, the Boc group removed and the malonate decarboxylated/transesterified to give amine 15. Reductive amination with the dithioacetal aldehyde shown was followed by a DMTSF mediated alkylation to give 17. Reductive desulfuration with Raney Ni and oxidation of the remaining alcohol under Albright/Goldman conditions (Swern-oxidation) furnished 18.

Scheme 5

Wittig reaction of the keto group then produced (+)-condylocarpine (and (-)-isocondylocarpine respectively) which was reduced in the presence of platinum oxide to give (+)-tubotaiwine.

Scheme 6

Nice… I had the schemes finished a few days ago but also had to write my last serious exam so … What do you think? Any comments?

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…

Asymmetric Construction of Rings A-D of Daphnicyclidin-Type Alkaloids

Asymmetric Construction of Rings A-D of Daphnicyclidin-Type Alkaloids

Travis B. Dunn, J. Michael Ellis, Christiane C. Kofink, James R. Manning, and Larry E. Overman

DOI: http://dx.doi.org/10.1021/ol902373m

It’s finished… took me some weeks to complete this review but here it is: a sweet “towards”-total synthesis from the Overman group.

The compounds to be made are Daphnicyclidin A – D whose biological profile is poorly studied yet.

The crude extracts of the plant are used in Chinese folk medicine… so some biological effect could be expected.

Retro:

The paper skips the last 2 stages which I painted in grey so a full account could be expected in the near future.

I think the retro does not need some comment, questions should being answered in the following schemes… so let’ get started.

Blue fragment:

First a nice DA reaction developed by the MacMillan group formed the cyclohexene carbaldehyde was followed by a stereoselective methylation under conditions described by Woodward. TBDPS protection, Saegusa-like oxidation and TBS enol ether formation completes the first part in overall great yield and e.r..

Red fragment:

Hydroxybenzamide was oxidised with periodate to give in situ nitrosocarbonylbenzene which undergoes a hetero-DA in acceptable yield and diastereoselectivity. The crude mixture was used in the next step, a Mo(CO)6 induced cleavage of the N-O bond and deprotection. to yield the cyclohexenone shown. Conjugate addition of DMPS-lithium and epimerization of the benzoylamide was followed by de-benzoylation/reduction, alkylation and Swern oxidation to give the red fragment ready for the crucial aza-Cope/Mannich-reaction sequence developed by Overman some years ago.

Green fragment:

After some efforts to tune the reaction conditions for the introduction of the side chain, a premixed solution of the ketone with CeCl3 and LiCl was treated with the iodie and t-BuLi giving the alcohol in good yield. Some silver nitrate then induced the key transformation, the aza-Cope-Mannich reaction, forming 2 of the 6 rings required.

2 different approaches were employed to form the fused pyrrolidine rings which will be presented in 2 schemes:

Scheme 1

The first approach starts with TBDPS deprotection, mesylation of the delivered alcohol, which directly undergoes SN2 displacement, and double debenzylation. The free alcohol was tosylated, followed by Grignard addition of allylmagnesium chloride on the ketone. Treatment of the tosylate ester with the p-nitrophenyl selenide anion and subsequent oxidation with mCPBA yielded the required terminal bis-olefin. Grubbs II then did the job and closed the fourth ring ready for further transformations.

Scheme 2

A Grignard addition under Lewis acid conditions starts this sequence off. Grubbs II closed again the seven membered ring in excellent yield. Alcohol transposition with thionyl chloride and DMP oxidation (if I remember right CrO3 should do the same job in one step?) gave the α-β-unsatured ketone. TBDPS deprotection and mesylation/in situ ring closing yielded a structure similar to the one in the scheme before.

Yeah, I really appreciate the work from Overman’s groups. He’s really one of the best chemists alive. What do you think?

Stereoselective Phosphine-Catalyzed Synthesis of Highly Functionalized Diquinanes

Stereoselective Phosphine-Catalyzed Synthesis of HighlyFunctionalized Diquinanes

Jonathan E. Wilson, Jianwei Sun, and Gregory C. Fu

DOI: http://dx.doi.org/10.1002/anie.200905125

While reviewing a nice paper from Overman I found this sweet one from Greg Fu and decided to present this to you first.

What we got here is a subsequent investigation of a procedure already published by Tomita et al. featuring a novel Baylis-Hillmann-like cyclization cascade:

The blue compounds represent the paper from Tomita et al., the red ones the paper featured in this review.

The reaction sequence is induced by the addition of about 20 mol% of tributylphopshine in a DCM/ethyl acetate mixture at room temperature to the starting material.

First a Michael addition of the phosphine to the alkyne yields an allenyl enolate which rapidly tautomerizes to an α-β-unsatured enolate. Next a Michael addition to the unsatured ester gives an ester enolate which reacts with the vinyl phosphine cation to from an ylide. This in turn yields after some tautomerization and catalyst regeneration the product:

The diastereoselectivity can easily be seen from the transition state:

Having established the right reaction conditions the group prepared some derivatives with the yields varying from 54% up to 89% respectively. Also the first formed 5 membered ring could be expanded to a 6 membered one without significant loss in yield.

And some studies towards further reactions of the produced diquinanes were employed featuring a Grignard reaction, Luche-reduction and Pd catalysed hydrogenation all in excellent diastereoselectivity:

Attempts to develop enantioselective reaction conditions by using a chiral phosphine gave very promising results:

On balance a nice reaction with some potential in natural product synthesis. What do you think?