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…