Upload
john-dominic
View
257
Download
3
Tags:
Embed Size (px)
DESCRIPTION
Total Synthesis of Bryostatin 16 has been given...
Citation preview
TOTAL SYNTHESIS OF BRYOSTATIN 16A study in atom economy and chemoselectivity
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
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
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
BRYOSTATIN BACKGROUND
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 10-4 % yield) Non-renewable source
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
Three problems with synthesis Substituted tetrahydropyran rings (3!) Congested trans alkene Exo-cyclic unsaturated esters
As such, only threeBryostatins (7,2,3) have been synthesized
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?
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…
RETROSYNTHETIC SCHEME
INSTALLATION OF THE TRANS ALKENE
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
ONE POT REACTIONS: STEREOSELECTIVITY
TANDEM REACTIONS
FORMATION OF RING BALKYNE-ALKENE COUPLING WITH MICHAEL ADDITION
+
CpRu(CH3CN)3PF6
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
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)
NOVEL ALKYNE-ALKYNE COUPLING REACTIONS
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
Oxidative addition
Ligand association
Carbometallation/Oxidative Coupling
Reductive Elimination
Pd(OAc)2
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
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!
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!
In 3 easy steps, we have the final material needed to form Bryostatin 16
Now for some mechanisms…
Building the Core
Asymmetric Brown Allylation
Making 7 in 11 Steps
H. C. Brown and P. K. Jadhav JACS. 1983, 105, 2092-2093
Enatioselective Synthesis of 8
Halogen-metal exchange
α,β-unsaturated aldehyde
Proposed T.S.
Enatioselective Synthesis of 8TMS
Enatioselective Synthesis of 8
Allenic alcohol Homopropargylic alcohol
In aqueous mediaM=In(I), R=bulky group
In organic solventM=In(III), R=small group
M. J. Lin, T. P. Loh, JACS, 2003, 125, 43, 13042-13043
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
Synthesis of Cis-tetrahydropyran 6
Ruthenium catalyzed tandem alkene-alkyne coupling/Michael addition
Ligand association
Oxidative coupling
Reductive Elimination
1,2- deinsertion/ β elimination
Synthesis of Cis-tetrahydropyran 6
Ruthenium catalyzed tandem alkene-alkyne coupling/Michael addition
Synthesis of Cis-tetrahydropyran 6
Ruthenium catalyzed tandem alkene-alkyne coupling/Michael addition
6
One step synthesis of 13
• Bromination of exo-cyclic vinyl silane• Acid catalyzed transesterificiation/methyl ketalization/desilylation all in one event
13
6 12
AB
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
Installing conjugated methyl ester
13
14
Alkynylation to synthesize 15
Seyferth-Gilbert homologation
Mechanism:
Deprotonation oxaphosphatane
vinyl diazo-intermediatevinyl carbene desired alkyne
http://en.wikipedia.org/wiki/Ohira-Bestmann_reaction
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
Alkynylation to synthesize 15
FORMATION 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 etherStep 2: Removal of the acetonideStep 3: Selective protection of alcohol with TBS
!!!THE SYNTHESIS OF BRYOSTATIN 16!!!
DRUM ROLL PLEASE…
A ring
B ring
Trans alkene
C ring formation
Macrocylization
Pivalation
A whole lot of deprotection!
Synthesis Progress Thus Far
A Yamaguchi esterification between the carboxylic acid 5 andthe alcohol 4.
Esterification Reaction
Yamaguchi Esterification Mechanism
Deprotection (removal of PMB) to form macrocyclization precursor 3
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
Alkyne Coupling Mechanism
CARBOMETALLATION
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
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 http://en.wikipedia.org/wiki/Baldwin%27s_rules
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
Proposed Gold catalyzed 6-endo-dig cyclization mechanism
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
Pivalation Reaction Mechanism
The reaction to afford the pivalate ester uses large equivalents of Piv2O to allow pivalation at the hindered OH
POP QUIZ: Why TBAF over HF/Pyridine?
And Now For The Finale… A Deprotection