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Total Synthesis of Bryostatin 16. A study in atom economy and chemoselectivity. Introduction and Background . Atom Economy Bryostatin background Basic synthetic outline Highlights of synthesis

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total synthesis of bryostatin 16

Total Synthesis of Bryostatin 16

A study in atom economy and chemoselectivity

introduction and background
Introduction and Background
  • Atom Economy
  • Bryostatin background
  • Basic synthetic outline
  • Highlights of synthesis

atom economy
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
barry trost and atom economy
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 (



37.94 % Atom Economy

bryostatin background
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
just a little bit of biology
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
difficulties of synthesis
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

efficiency of bryostatin synthesis
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”
why bryostatin 16
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…

one pot reactions
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
alkyne alkene coupling reaction
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

chemoselectivity of coupling rxn
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)
palladium catalyzed cross coupling
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


Reductive Elimination


Oxidative addition


Oxidative Coupling

Ligand association

  • 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
what is to come
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?!


further down the line
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?


we made it of course
We made it of course!
  • In 3 easy steps, we have the final material needed to form Bryostatin 16

Now for some mechanisms…


Making 7 in 11 Steps

Asymmetric Brown Allylation

H. C. Brown and P. K. Jadhav JACS. 1983, 105, 2092-2093


Enatioselective Synthesis of 8

Halogen-metal exchange

α,β-unsaturated aldehyde


Enatioselective Synthesis of 8

In aqueous media

M=In(I), R=bulky group

In organic solvent

M=In(III), R=small group

Allenic alcohol



M. J. Lin, T. P. Loh, JACS, 2003,125, 43, 13042-13043


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

Synthesis of Cis-tetrahydropyran 6

Ruthenium catalyzed tandem alkene-alkyne coupling/Michael addition

Reductive Elimination

Ligand association

1,2- deinsertion/ β elimination

Oxidative coupling


Synthesis of Cis-tetrahydropyran 6

Ruthenium catalyzed tandem alkene-alkyne coupling/Michael addition


Synthesis of Cis-tetrahydropyran 6

Ruthenium catalyzedtandemalkene-alkyne coupling/Michael addition



One step synthesis of 13






  • Bromination of exo-cyclic vinyl silane
  • Acid catalyzed transesterificiation/methyl ketalization/desilylation all in one event

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


  • Highly regioselective reaction with electrophiles
  • (silicon is replaced by the electrophile)
  • Stereochemistry of the alkene is retained


Vinyl silane


Alkynylation to synthesize 15

Seyferth-Gilbert homologation




desired alkyne

vinyl carbene

vinyl diazo-intermediate


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.

formation of alcohol 4
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

A ring

B ring

Trans alkene

C ring formation



A whole lot of deprotection!

Synthesis Progress Thus Far


Esterification Reaction

A Yamaguchi esterification between the carboxylic acid 5 and

the alcohol 4.


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

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


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)
  • 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

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

Pivalation Reaction Mechanism

The reaction to afford the pivalate ester uses large equivalents of Piv2O to allow pivalation at the hindered OH


And Now For The Finale… A Deprotection

POP QUIZ: Why TBAF over HF/Pyridine?