Total Synthesis of Bryostatin 16

1. Total Synthesis of Bryostatin 16 A study in atom economy and chemoselectivity

2. Introduction and Background • Atom Economy • Bryostatin background • Basic synthetic outline • Highlights of synthesis http://www.scientificupdate.co.uk/publications/process-chemistry-articles/982-inventing-reactions-for-atom-economy-.html

3. Atom Economy • Developed by Barry Trost (Stanford) as a way to “foster awareness of the atoms of reactants that are incorporated into the desired product and those that are wasted (incorporated into undesired products)” • Can be used in addition, elimination, substitution, rearrangement, catalytic cycles and many more! • Trost, Barry M., The Atom Economy-A Search for Synthetic Efficiency. Science 1991, 254, 1471-1477 • Awarded the Presidential Green Challenge Chemistry Award in 1998 for his work

4. Barry Trost and Atom Economy • Goal: to reduce the waste in chemical reactions because unused reactants lead to: • Pollution • Ineffective use of resources • Increase in production costs • An example (http://domin.dom.edu/faculty/jbfriesen/chem254lab/atom_economy.pdf) 74.12 121.23 37.94 % Atom Economy

5. Bryostatin Background • Complex macrolactone natural products isolated from Bugulaneritinaand named bryostatin 1-20 • Show anticancer activity and affects memory and cognition • Mode of activity still unknown, and difficult to test • Limited availability- isolated • Low yield from isolation- 18g from 14 tons of bryostatin animal (1.6 x 10-4 % yield) • Non-renewable source

6. Just a Little Bit of Biology • First isolated in 1980 from extracts on bryozoan • Produced by symbiont bacteria on bryozoan larva- protects them from predation and infection • In vivo- act “synergistically” with other cancer drugs to change protein kinase C (PKC) activity • PKC involved in phosphorylation and helps control cell growth and regulate transcription • Increased memory retention of marine slugs by 500% • Now investigated for treatment of Alzheimer’s

7. Difficulties of synthesis • Three problems with synthesis • Substituted tetrahydropyran rings (3!) • Congested trans alkene • Exo-cyclic unsaturated esters • As such, only three Bryostatins (7,2,3) have been synthesized

8. Efficiency of Bryostatin Synthesis • Concise strategy using only 26 steps (36 if you begin with an aldehyde starting material) • Reasons for efficiency: • Tandem reactions (Ru- catalyzed cross couplings followed by Michael Addition) • One-pot reaction forms starting material • Difficult alkyne-alkyne coupling catalyzed by Pd • Further applications available because of “atom-economical and chemoselective approaches”

9. Why Bryostatin 16? • There are 20 varieties of bryostatin, three of which have been synthesized so why 16? • All other bryostatins (except 3, 19, 20) can be achieved with slight alterations to 16, namely double bond 19-20 • Explore palladium alkyne-alkyne coupling with ring C Onto the synthesis…

10. Retrosynthetic Scheme

11. Installation of the trans Alkene

12. One Pot Reactions • A main difficulty of this synthesis is the installation of a highly substituted trans alkene • To avoid problems, this was built into the starting material

13. One Pot Reactions: Stereoselectivity

14. Tandem Reactions

15. Formation of Ring BAlkyne-Alkene Coupling with Michael addition + CpRu(CH3CN)3PF6

16. Alkyne-Alkene Coupling Reaction • Ruthenium catalyzed reaction to form 1,4 dienes • Follows steps: ligand association, carbometallation, β-elimination and ligand dissociation Barry Trost. A Challenge of Total Synthesis: Atom Economy

17. Chemoselectivity of Coupling Rxn • Production of cis-tetrahydropyran driven by several factors • Compatibility of β,γ-unsaturated ketone with six- membered lactone • High reactivity of the unprotected alcohol • Use of correct solvent (Dichloromethane promotes higher conversion and less decomposition)

18. Novel Alkyne-Alkyne Coupling Reactions

19. Palladium Catalyzed Cross Coupling • Pd inserts into alkyne-hydrogen bond, carbometallation* and reductive elimination • Carbometallation- term coined for chemical process in which a metal-carbon bond is inserted into a carbon-carbon π bond • Illustrates a new way to construct macrocycles using carbon-carbon bond formation • Must keep concentrations low (~0.002 M) to avoid formation of dimer side products + Pd(OAc)2

20. Reductive Elimination Pd(OAc)2 Oxidative addition Carbometallation/ Oxidative Coupling Ligand association

21. Conclusions • Synthesis is stereoselective, chemoselective and atom-economical • Installation of trans alkene early in synthesis ensures further selectivity and avoids difficult installation later • Others do this via Julia Olefination or RCM, sacrificing efficiency and selectivity • Using Pd catalyzed ring closure rather, a new and novel carbon-carbon bond formation • Tandem reactions add to efficiency and chemoselectivity

22. What is to Come • Structures 7 and 8 add to form ring B, but they must come from somewhere! • Also, where does 2 come from? Can we buy this?! YES WE CAN!

23. Further down the line • We now have structure 5, but this isn’t the final product just yet! • Addition to 4 gives the final product. But WAIT! Where did 4 come from? +

24. We made it of course! • In 3 easy steps, we have the final material needed to form Bryostatin 16 Now for some mechanisms…

25. Building the Core

26. Making 7 in 11 Steps Asymmetric Brown Allylation H. C. Brown and P. K. Jadhav JACS. 1983, 105, 2092-2093

27. Enatioselective Synthesis of 8 Halogen-metal exchange α,β-unsaturated aldehyde

28. Enatioselective Synthesis of 8 TMS Proposed T.S.

29. Enatioselective Synthesis of 8 In aqueous media M=In(I), R=bulky group In organic solvent M=In(III), R=small group Allenic alcohol Homopropargylic alcohol M. J. Lin, T. P. Loh, JACS, 2003,125, 43, 13042-13043

30. Synthesis of Cis-tetrahydropyran 6 Ruthenium catalyzed tandem alkene-alkyne coupling/Michael addition • Chemoselectivity is demonstrated by the high compatibility of a β,γ- unsaturated ketone, a six-member lactone, an unprotected allylic alcohol, a PMB ether, and two different silyl ethers. • DCM was found to be the optimal solvent

31. Synthesis of Cis-tetrahydropyran 6 Ruthenium catalyzed tandem alkene-alkyne coupling/Michael addition Reductive Elimination Ligand association 1,2- deinsertion/ β elimination Oxidative coupling

32. Synthesis of Cis-tetrahydropyran 6 Ruthenium catalyzed tandem alkene-alkyne coupling/Michael addition

33. Synthesis of Cis-tetrahydropyran 6 Ruthenium catalyzedtandemalkene-alkyne coupling/Michael addition 6

34. One step synthesis of 13 12 6 B A 13 • Bromination of exo-cyclic vinyl silane • Acid catalyzed transesterificiation/methyl ketalization/desilylation all in one event

35. One step synthesis of 13 • Used in either radical substitution or electrophilic addition • Convenient source of Br+ (brominium ion) • Easier and safer to handle than bromine N-Bromosuccinimide • Highly regioselective reaction with electrophiles • (silicon is replaced by the electrophile) • Stereochemistry of the alkene is retained 6 Vinyl silane

36. Installing conjugated methyl ester 14 13

37. Alkynylation to synthesize 15 Seyferth-Gilbert homologation Mechanism: Deprotonation oxaphosphatane http://en.wikipedia.org/wiki/Ohira-Bestmann_reaction desired alkyne vinyl carbene vinyl diazo-intermediate

38. Alkynylation to synthesize 15 Bestmann modification in situ generation The Ohira-Bestmann modification gives terminal alkyne in high yield, and allows the conversion of base-labile substrates such as enolizablealdehydes, which would tend to undergo aldol condensation under the Seyferth-Gilbert conditions.

39. Alkynylation to synthesize 15

40. Formation of alcohol 4 17, was attained through a separate Trostet al venture into the synthesis of a bryostatin analogue. Trost, B. M., Yang, H., Thiel, O. R., Frontier, A. J. & Brindle, C. S. Synthesis of a ring-expanded bryostatin analogue. J. Am. Chem. Soc. 129, 2206–2207 (2007) Step 1: Formation of the PMB ether Step 2: Removal of the acetonide Step 3: Selective protection of alcohol with TBS

41. DRUM ROLL PLEASE… !!!The Synthesis of Bryostatin 16!!!

42. A ring B ring Trans alkene C ring formation Macrocylization Pivalation A whole lot of deprotection! Synthesis Progress Thus Far

43. Esterification Reaction A Yamaguchi esterification between the carboxylic acid 5 and the alcohol 4.

44. Yamaguchi Esterification Mechanism

45. Deprotection (removal of PMB) to form macrocyclization precursor 3

46. Macrocyclization: Palladium Catalyzed Alkyne-Alkyne Coupling • Extensive Experimentation: ligand type, ratio and solvent choice • Low concentrations are necessary to prevent the polymerization of the product • High dilution chemistry executed in this step

47. Alkyne Coupling Mechanism CARBOMETALLATION

48. Formation Of The C Ring: 6-endo-dig cyclization 73% yield reported Gold catalyst used to evade the formation of 5-exo and 6-endo isomers which would occur if a palladium catalyst was used

49. Baldwin’s Rules For Ring Closure • Nomenclature • size of the ring being formed • 3 membered ring = 3 • 4 membered ring = 4 etc. from http://en.wikipedia.org/wiki/Baldwin%27s_rules • geometry of electrophilic atom • Sp3 center; then Tet (tetrahedral) • Sp2 center; then Trig (trigonal) • Sp center; then Dig (digonal) • where displaced electrons end up • Exo: if the displaced electron pair ends up out side the ring being formed • Endo: if the displaced electron pair ends up within the ring being formed JOC 1977, 42 , 3846

50. Proposed Gold catalyzed 6-endo-dig cyclization mechanism