t otal s ynthesis of b ryostatin 16 a study in atom economy and chemoselectivity

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



Ligand association

Oxidative coupling

Reductive Elimination

1,2- deinsertion/ β elimination



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


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

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

t otal s ynthesis of b ryostatin 16 a study in atom economy and chemoselectivity

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