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


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.




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


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 Isokidamycin

Total Synthesis of Isokidamycin

B. Michael O’Keefe, Douglas M. Mans, David E. Kaelin, Jr, and Stephen F. Martin

[1] Carbohyd. Res., 19 (1971) 276-280
[2] J. Carbohydrate Chemistry, 2(2), 105-114 (1983)
[3] Aust. J. Chem, 2003, 56, 787 – 794

Dude, this needed some time… Maybe the longest review I ever wrote to date. But Isokidamycin is really a big beasty. Have a look at it:

Scheme 1

The synthesis includes various intermediates and a long linear reaction sequence so I will start right off with the red fragment.

Benzylation of the benzoquinone promoted by silver oxide was followed by monobromination. The second bromine was added with the help of pyridine tribromide, the quinone reduced to the dihydroquinone and selectively monoprotected as the methyl ether.

Scheme 2

For identifying the route to the green fragment I had to dig out some really old papers which are cited by the group. The reconstruction was done as described in the paper but might not be 100% correct. I suppose they started with the dihydropyran shown which is commercially available. Monodeprotection and subsequent tosylation was followed by reductive cleavage of the tosylate and the acetyl protecting groups. Reprotection, hydration of the double bond and azidonation delivered after acetylation the green fragment shown. The hydration/azidonation step goes through a SN2’ reaction in which water (or even hydroxide) pushes out the acetate. Protonation and azide addition on the double bond produces the product.

Scheme 3

The sugar fragment was then coupled under Lewis acid catalysis with furan (d.r. 72 : 28 with respect to the C3 stereocenter) and deprotected under standard conditions to give after chromatographic separation the major C3 epimer shown. Benzylation, azide reduction, Boc-protection and methylation gave the fully protected THP. Functionalization of the furan was accomplished by silylation followed by hydroboration/oxidation to give the terminal alcohol.

Scheme 4

Another interesting THP fragment was isolated from vancomycin (!). By protecting the natural product and heating it in a methanolic solution of HCl, the aminosugar was set free. Some protecting group manipulations furnished the second sugar unit.

It seems to be odd to destroy such an important drug like vancomycin to produce this aminosugar but the author explain this sequence with the extremely long synthesis otherwise needed.

Scheme 5

Now it’s getting interesting. The red and blue halves were combined through a Mitsonobu reaction in pretty high yield. In the presence of BuLi the 1,2-dibromonaphthalene produces an aryne intermediate which undergoes a Diels-Alder reaction with the furan ring. The ether handle was then cleaved off with TBAF and the resulting alcohol methylated.

A really nice way to build up the anthracene ring system.

Scheme 6

The oxacyclic ring was opened with TMSOTf with concomitant cleavage of the Boc protecting group. Reductive amination, TIPS protection of the free alcohol, selective debenzylation, bromination and MOM protection furnished the fully protected anthracene ring system.

Scheme 7

For the next step another intermediate was needed. A Corey-Fuchs alkynylation followed by in situ formylation gave the purple aldehyde shown.

Scheme 8

This aldehyde was added to the anthracene ring through standard conditions and the resulting alcohol oxidized with barium manganate. Addition of diethylamine to the triple bond gave rise to a vinylogous amide which cyclizes under Lewis-acid catalysis which was followed by desilylation.


Scheme 9

Ok, we are approaching the end. Glycosidation of the advanced intermediate with the vancomycin derived aminosugar was only possible in the presence of Sc(OTf)3. During the course the acetyl protecting group was cleaved off so it was reinstalled.

Scheme 10

At last the protecting groups had to be cleaved off. Benzyl group removal was done first with BBr3, the Cbz group was removed in the presence of TMSI which was followed by reductive amination of the free monomethylated amine. The hindered acetate group was cleaved off under standard conditions and the two methyl groups removed oxidatively with cerium sulfate to give isokidamycin.

Scheme 11

Wow… what a damn long and cool synthesis. Only two papers in JACS… I bet some generations of Ph.D. students were needed to get this done.

Any comments?

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


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.


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?

Total Synthesis of Oidiodendrolides and related Norditerpene Dilactones

Total Synthesis of Oidiodendrolides and related Norditerpene Dilactones

Stephen Hanessian, Nicolas Boyer, Gone Jayapal Reddy, and

Benoıˆt Descheˆnes-Simard


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 (

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?

Asymmetric Synthesis of (+)-Polyanthellin A

Asymmetric Synthesis of (+)-Polyanthellin A

Matthew J. Campbell and Jeffrey S. Johnson


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


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


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


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:


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


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:


But yeah, cool selectivity!! 🙂

Total Synthesis of Cyathin A3 and Cyathin B2

Total Synthesis of Cyathin A3 and Cyathin B2

Part II – Retro schemes from Snider and Trost

As requested (from krest17) here are the two retro schemes from the Snider and Trost groups.

If you are interested in getting further details you find the links to the syntheses in the header.

(I prefer the one from the Trost group, again very cool transition metal chemistry)

Snider’s synthesis :


Trost’s synthesis:


I skipped the details but if you want to we can discuss them here…

Total Synthesis of Cyathin A3 and Cyathin B2

Keunho Kim and Jin Kun Cha



This time two diterpene natural products which were first isolated in the 1970’s by Ayers and co-workers and subjected to a number of total syntheses. If you’re interested, some older syntheses can be found from the Snider and Trost group during which the starting material for this approach was synthesied.
Before you ask why they did another synthesis of these two molecules one should remember the significant biological properties which lay in the stimulation of nerve growth factors and can therefore be used as models for synthetic analogues.
And because it’s another cool approach…

So let’s begin with the retro (I do like paper were they put in their retro… less work for me):


They planned as the key step a Prins-pinacol like tandem reaction (a reaction sequence used extensively by the Overman group) followed by a RCM reaction. The starting cyclopropanol originates from a known ester, synthesised from the Snider group in their earlier approach through a Kulinkovich reaction. This named reaction was new to me but is obviously a very useful manipulation.
So here the first scheme:

Scheme 1


We start with the above mentioned Kulinkovich reaction (the mechanism can be found in detail under the link) followed by TMSCl addition to give the cyclopropanol-TMS ether. This was reacted with dimethoxy-2-bromoethane to give after reductive elimination the intermediate cyclobutanone product. The interesting sequence here is the Prins-pinacol tandem sequence which I will present to you right now:


I suppose that the stereochemistry is fully controlled by the remote methyl group.

Next on a LHMDS induced aldolreaction with two various aldehydes was done followed by a Ti(iPrO)4 catalysed reaction similar to a Turbo-Grignard with the allylbromide shown. The resulting triene was used for a RCM to give the tetracyclic intermediate, ready for the second key step.

Scheme 2


They commenced with a radical thionylation ensued by a PPh3 * Br2 induced Grob fragmentation of the cyclobutanol to give the seven-membered unsatured ketone.
A mechanism is not given so here’s my proposal:


The styrene like double-bond was selectively dihydroxylated, cleaved with lead(IV)acetate and after decarbonylation using Wilkinson’s catalyst, realeased the quarternary methyl group.
Interestingly the PMB group cleavage gave better results than the Ph residue.

The sulfur was then oxidised using Davis oxaziridine and exposed to Pummerer rearrangement conditions (TFAA). This gives a mixture of products which were reacted without separation with acetic anhydride and mercury(II)trifluoroacetate to give in an overall yield of about 65% Cyathin B2.

Scheme 3


This could be converted to Cyathin A3 in 7 steps using standard chemistry which need no further explanation. Here the scheme:

Scheme 4


All in all another cool approach although not very atom economic. My favourites are the two presented key steps and the introduction of the methyl group through the styrene cleavage.
I would be thankful for every comment or suggestion. I’m looking forward to move this page to real .com-domain because it’s difficult to find this page with Google…

And if you’re interested in helping me with publishing reviews please send an eMail to Help is always appreciated…