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T OTAL S YNTHESIS OF B RYOSTATIN 16 A study in atom economy and chemoselectivity.

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Presentation on theme: "T OTAL S YNTHESIS OF B RYOSTATIN 16 A study in atom economy and chemoselectivity."— Presentation transcript:

1 T OTAL S YNTHESIS OF B RYOSTATIN 16 A study in atom economy and chemoselectivity

2 I NTRODUCTION AND B ACKGROUND Atom Economy Bryostatin background Basic synthetic outline Highlights of synthesis

3 A TOM E CONOMY 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, Awarded the Presidential Green Challenge Chemistry Award in 1998 for his work

4 B ARRY T ROST AND A TOM E CONOMY Goal: to reduce the waste in chemical reactions because unused reactants lead to: Pollution Ineffective use of resources Increase in production costs An example ( % Atom Economy

5 B RYOSTATIN B ACKGROUND Complex macrolactone natural products isolated from Bugula neritina and 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 % yield) Non-renewable source

6 J UST A L ITTLE B IT OF B IOLOGY 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 D IFFICULTIES 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 E FFICIENCY OF B RYOSTATIN S YNTHESIS 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 W HY B RYOSTATIN 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 Explore palladium alkyne-alkyne coupling with ring C Onto the synthesis…



12 O NE P OT R EACTIONS 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




16 A LKYNE -A LKENE C OUPLING R EACTION 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 C HEMOSELECTIVITY OF C OUPLING R XN 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)


19 P ALLADIUM C ATALYZED C ROSS C OUPLING 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 Oxidative addition Ligand association Carbometallation/ Oxidative Coupling Reductive Elimination Pd(OAc) 2

21 C ONCLUSIONS 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 W HAT IS TO C OME 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 F URTHER 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 W E 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 Asymmetric Brown Allylation Making 7 in 11 Steps H. C. Brown and P. K. Jadhav JACS. 1983, 105,

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

28 Proposed T.S. Enatioselective Synthesis of 8 TMS

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

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

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

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

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

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

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 6Vinyl silane

36 Installing conjugated methyl ester 13 14

37 Alkynylation to synthesize 15 Seyferth-Gilbert homologation Mechanism: Deprotonation oxaphosphatane vinyl diazo-intermediatevinyl carbene desired alkyne wiki/Ohira- Bestmann_reaction

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

39 Alkynylation to synthesize 15

40 F ORMATION OF ALCOHOL 4 17, was attained through a separate Trost et 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


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

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

44 Yamaguchi Esterification Mechanism


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 CARBOMETAL LATION

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

49 Baldwin’s Rules For Ring Closure Nomenclature size of the ring being formed 3 membered ring = 3 4 membered ring = 4 etc. geometry of electrophilic atom Sp3 center; then Tet (tetrahedral) Sp2 center; then Trig (trigonal) Sp center; then Dig (digonal) from 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

51 The reaction is carried out under mild conditions yielding an acid sensitive product  Formation of 6 member ring over the 5 member ring  Reaction conditions are almost neutral preventing the isomerization to the 5-exo product  The 6 member ring results in a conjugate system within the ring system

52 Pivalation Reaction

53 Pivalation Reaction Mechanism The reaction to afford the pivalate ester uses large equivalents of Piv 2 O to allow pivalation at the hindered OH

54 POP QUIZ: Why TBAF over HF/Pyridine? POP QUIZ: Why TBAF over HF/Pyridine? And Now For The Finale… A Deprotection

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