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 rac-15.

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

 

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 Isokidamycin

B. Michael O’Keefe, Douglas M. Mans, David E. Kaelin, Jr, and Stephen F. Martin
DOI: http://dx.doi.org/10.1021/ja107926f

[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 S_N2’ 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.

Cool…

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?