MAKING COMPLEX MOLECULES

Hermann Emil Fischer Germany (1852-1919)

Fischer achieved the first synthesis of the first truly complicated organic molecules, the sugar molecule D-glucose in 1890.

The Nobel Prize in Chemistry 1902

H

C

C OH

C HHO

C OHH

C OHH

CH2OH

O H

D-Glucsoe

Fischer’s work on the total synthesis of D-glucose is regarded as the catalyst for the development of synthetic organic chemistry in the 20th century.

Sir Robert Robinson United Kingdom (1886-1975)

The Nobel Prize in Chemistry 1947

O I Br

Br

Br

Br

NMe2

NMe2

Br Br Br

NMe2 NMe NMe Br

NMeOH

HNMe ONMe

H

OH

( II )

CHO

CHO

+ H2NMe +

COOH

COOH

O NMe O

COOH

COOH

NMe O

Willstatter’s synthesis of tropine

Robinson’s synthesis of tropinone in 1917

The Robinson’s synthesis of tropinone was hailed as revolutionary. This was to look at the target molecule and try to imagine how the molecule could be constructed from simpler chemical units.

Sir Christopher Kelk Ingold (1893-1970)

Mechanism?

Sir Derek H. R. Barton (1918-1998)

The Nobel Prize in Chemistry 1969"for their contributions to the development of the concept of conformation and its application in chemistry"

Conformational Analysis

1H NMR spectrum of cyclohexane-d11 at different temperature

H

DD

D

D

D

D

DD

DD

D

D

DD

DD

D

D

D

D

H

Robert Burns Woodward

Quinine (1944)anti-malarial drug

Vitamin B12 (1973)

Strychnine (1954) pesticide

Some of the Complex Molecules Made by Woodward

“There is excitement, adventure, and challenge, and there can be great art in organic synthesis.” - Woodward

Corey, Elias James1928–, b. Methuen, Mass., grad. Massachusetts Institute of Technology (B.S. 1948, Ph.D. 1951). In 1990, he was awarded the Nobel Prize in Chemistry.

Some prostaglandins affect human blood pressure at concentrations as low as 0.1 microgram per kilogram of body weight. Substances that inhibit prostaglandin synthesis may be useful in controlling pain, asthma attacks, and anaphylactic shock and in reducing the clotting ability of blood.

Prostaglandins

“The organic chemist is more than a logician and strategist; he is an explorer strongly influenced to speculate, to imagine, and even to create.” - Corey

Retrosynthetic Analysis by Corey

Retrosynthetic analysis (or retrosynthesis) : the process of mentally breaking down a molecule into starting materialsRetrosynthetic arrow: an open-ended arrow, , used to indicate the reverse of a synthetic reactionSynthon: idealized fragments resulting from a disconnection. Synthons need to be replaced by reagents in a suggested synthesis

Retrosynthetic analysis for violet oil component

Synthesis of violet oil component

Organic Synthesis: 1. Carbon-Carbon Bond Formation2. Functional Group Interconversion

Enantioselectivity

Some Physical Properties of the Stereoisomers of Tartaric Acid

Louis Pasteur Chemist

1822-1895

“Chance favors only prepared mind.” -Louis Pasteur

Louis Pasteur was born on December 27, 1822 in Dole, in the region of Jura, France.

Resolution of enantiomersin 1848

Twenty years later, J. H. van’t Hoff and J.-A. Le Bel independently explained the origins of enantiomers based on the tetrahedral nature of carbon bonding.

Resolutiondiastereomeric salts seperation by selective crystallization or some other means

Once separated, acidification of the two diastereomeric salts with strong acid gives pure enantiomers and recover the chiral amine.

Synthesis of One Enantiomer using a Chiral Auxiliary

OH

Ochemical steps

Put auxiliary on

Ochemical steps

OH

O

OH

O

NH2 NH2

Both handed forms of product(racemic mixture; 1:1 mixture of enantiomers)

OH

O

OH

O

NH2

take auxiliary offO

NH2

HN O

O

Chiral Auxiliary :[ ]

Asymmetric Synthesis

The Nobel Prize in Chemistry 1979"for their development of the use of boron- and phosphorus-containing compounds, respectively, into important reagents in organic synthesis"

Hebert C. Brown (1912- )

Me

Me

OMe

Me

OHIpc2BCl

B-Cl

Me

Me

OH

is not formed

Ipc2BCl

2

Synthesis of an Enantiomer using a Chiral Reagent

Asymmetric Synthesis

MeO

CO2H

'Flat' precursor

MeO

CO2H

HMe

Hydrogen

Naproxen anti-inflammatory drug

Ru

oooo

Synthesis of an Enantiomer using a Chiral Catalyst

Asymmetric Synthesis

[Ru-(S)-BINAP], 135 atm H2

PPh2

PPh2

92% yield, 97%ee

Synthesis of an Enantiomer using a Chiral Catalyst

Asymmetric Synthesis

OHOH

Allyl alcohol

Oxidant

Glycidol

O

Ti

oooo

OH

OHOxidant

'Flat' precursor Product formed with superb selectivity

oooo

Os

TBHP (t-BuOOH), Ti(OPri)4

L-(+)-DET

The anticancer drug, Taxol

Synthesis: K. C. Nicolaou at The Scripps Research Institute Robert Holton at Florida State University

Acid-Base Chemistry

C

CCA H

CB X

C

C

Organometallic Chemistry

CY MCY H

C M

C M

relatively stable complex

CC C C C

unstable species

stable(neutral)

Carbon Species

carbanion radical carbene carbocation

Organometallic CompoundsOrganometallic Compounds

1. Stabilize unstable organic compounds

C

C C

C

H

H

H

H

cyclobutadiene

C

C C

CH

H

H

H

iron complex

Fe

CO

COOC

- strained, unstable- does not exist at normal temperatures and pressures- reacts with itself to form larger ring

- stable- well-behaved and easily-manipulated- readily seperated- a convenient source of cyclobutadiene

2. Change characters of organic compounds

Benzene

C

CC

C

CCH

H

H

H

H

H

chromium complex

Cr

CO

COOC

CCC

C CC

H H

HH

H H

- surrounded by a cloud of negative electrons- prefer to interact with positively-charged molecules- reacts with itself to form larger ring

- Cr(CO)3 sucks away electrons from benzene- prefer to interact with negatively-charged molecules

3. organometallic complexes: useful templates (as reagents)

C

C

H

H

(OC)3Co

(OC)3Co

CH2

CH2

C

O

HC

HC CH2

CH2

C

O

Pauson-Khand Reaction: 1970s

- useful method for the synthesis of cyclopentenone

OO

H2C CH2

CO

Co2(CO)8

O

O

O

O

Taylorione

Application to the synthesis of complex molecules

taylorione: synthesis by Williams Kerr in 1990s

4. Catalyze Reactions: efficiency

R

R

R

R

CH2

CH2+

olefin metathesis

catalyst

in early 1990s, Bob Grubbs at California Institute of Technology

Olefin metathesis

- for some time had been used for synthesis of polymers but had been overlooked by organic chemists

- alkenes are one of the most important building block- abundant in nature's chemicals: vitamin A, quinine, chlorophyll- manmade organic chemicals: pharmaceuticals, perfumes, flavoring

Ru C

PCy3

PCy3

Cl

Cl H

H

P

[Ru] CH

H

active catalyst

PCy3

H3C

H3C

CH3Mes =

catalysts for olefin metathesis: many catalysts based on organometallic reagents "Ru", "Mo", "W"

Grubbs's catalyst Ru

Ph

PCy3

PCy3

Cl

ClRu

PhPCy3

Cl

Cl

NNMes Mes

Olefin Metathesis

[Ru] CH

H C CH

H

R

H

C C HH

R

H

[Ru] CH

H

C CH

H

H

H

CR H

[Ru]

C CH

H

R'

H

C C HR'

R

H

[Ru] CH

H

C CH

R'

R

H

R

R

R

R

CH2

CH2+

[Ru] CH

H

mechanism

Olefin Metathesis

O

O O

HO

OTBS

N

S

O

O O

HO

OTBS

N

S

CH2Cl2

15 mol%

rt, 8h

50% + 35% (E -isomer)

O

O O

HO

OH

N

S

Epothilone A

Osimple starting material

Ring-Closing Olefin Metathesis