Lecture 1c

Asymmetric Synthesis

Assigned Reading• Hanson, J. J. Chem. Educ. 2001, 78(9), 1266 (including supplemental

material).• Larrow, J.F.; Jacobsen, E.N. Org. Synth. 1998, 75, 1. • Cepanec, I. et al. Synth. Commun. 2001, 31(19), 2913.• Flessner, T.; Doye, S. J. Prakt. Chem. 1999, 341, 436. • McGarrigle, E.M.; Gilheany, D.G. Chem. Rev. 2005, 105(5), 1563.• Schurig, V.; Nowotny, H.P. Angew. Chem. Int. Ed. Engl. 1990, 29(9), 939. • Sharpless, B. Angew. Chem. Int. Ed. Engl. 2002, 41, 2024.• Katsuki, T. Coord. Chem. Rev. 1995, 140, 189.• Kunkely, H.; Vogler, A. Inorg. Chem. Comm. 2001, 4, 692.• Trost, B. PNAS 2004, 101, 5348• Yoon, J.W.; Soon, W.L.; Shin, W. Acta Cryst .1997, C53, 1685.• Yoon, J.W.; Yoon, T.; Soon, W.L.; Shin, W. Acta Cryst. 1999, C55, 1766.

Why Asymmetric Synthesis?• Chirality plays a key role in many biological systems i.e.,

DNA, amino acids, sugars, terpenes, etc.• Many commercial drugs are sold as single enantiomer

drugs because often only one enantiomer (eutomer) exhibits the desired pharmaceutical activity while the other enantiomer is inactive or in many cases even harmful (distomer)

• (*) These drugs are isomerized in vivo

Drug R-enantiomer S-enantiomer

Thalidomide Morning sickness Teratogenic*

Ibuprofen Slow acting Fast acting*

Prozac Anti-depressant Helps against migraine

Naproxen Liver poison Arthritis treatment

Methadone Opioid analgesic NMDA antagonist

Dopa Biologically inactive Parkinson’s disease

N

O

O

* NHO

O

COOH

HO

HO

NH2

OH

O

L-DOPA

History of Asymmetric Synthesis I• 1848: Louis Pasteur discovers the chirality of sodium

ammonium tartrate • 1894: Hermann Emil Fischer outlined the concept of

asymmetric induction• 1912: G. Bredig and P.S. Fiske conducted one of the

first well documented enantioselective reactions (addition of hydrogen cyanide to benzaldehyde in the presence of quinine with 10 % e.e.)

• 1960ties: Monsanto uses transition metal complexes for catalytic hydrogenations i.e., Rh-DIPAMP for L-dopa (Parkinson disease, 95 % e.e.)

• 1980ties : R. Noyori developed hydrogenation catalyst using rhodium or ruthenium complexes of the BINAP ligand

PP

OCH3

OCH3

(R,R)-DIPAMP

(R)

PPh2

PPh2

(R)-BINAP

History of Asymmetric Synthesis II• 1980: T. Katsuki and K.B. Sharpless develop chiral epoxidation of allylic

alcohols (90 % e.e., but moderate yields!)

• They attribute the high selectivity to the in-situ formation of a chiral, dinuclear Ti-complexes• The alkene is tied to the reaction center by the allylic

hydroxyl function• This places the peroxide function in close proximity

to the alkene function• The reaction is usually carried out at low temperatures (-20 oC),

is very sensitive towards water and require up to 18 hours to complete• The yields are moderate (77 % for the reaction above) due to the increased water

solubility of the products

HOH

HOH

1. (+)-DET,Ti(iOPr)4

2. TBHP

O

HOH

O+

geraniol (2S, 3S)major

(2R, 3R)minor

O OTi

OiPr

E

OTi

O

E

O

O

O

tBu

RR

R

EiPr O

E=COOEt

OEtO

History of Asymmetric Synthesis III

• Example: Sharpless epoxidation is used to prepare (+)-disparlure, a sex pheromone, that has been used to fight Gypsy moths through mating disruption (note that the (-) enantiomer is a deterrent and reduces trap captures)

• The Sharpless epoxidation is also used to obtain intermediates in the preparation of methymycin and erythromycin (both macrolide antibiotic)

• The Nobel Prize in Chemistry in 2001 was awarded to three of the pioneers in the field: K. B. Sharpless, R. Noyori, W. S. Knowles

OH1. (+)-DETTi(OiPr)42. TBHP

OHO

> 98% ee

O

(+)-disparlure

O

H3C

OH

HO

CH3

OH

CH3

CH3

O

H3C

H3CH2C

H3C

O

O O

OHO

N(CH3)2

CH3

O

OCH3

CH3OH

CH3

How do Chemists control Chirality?

• Chiral pool: optically active compounds that can be isolated from natural sources (i.e., amino acids, monosaccharides, terpenes, etc.) and can be used as reactants or as part of a chiral catalyst or a chiral auxiliary• The TADDOL, DIOP and the Chiraphos ligand have tartaric acid as

chiral backbone

• Enzymatic process: very high selectivity, but it needs suitable substrates and well controlled conditions• The Lipitor synthesis requires halohydrin dehalogenase, nitrilase, aldolase• The reduction of benzil using cryptococcus macerans leads to the formation of

(R,R)-hydrobenzoin (dl:meso=95:5, 99 % e.e.)

• Chiral reagent: it exploits differences in activation energies for alternative pathways

• Chiral auxiliary: it is a chiral fragment that is temporarily added to the molecule to provide control during the key step of the reaction and is later removed from product

How do Chemists control Chirality?

• By manipulating the energy differences in transition states (DDG‡)

• Bottom line• The higher the energy difference in the transition states is the higher

the selectivity will be at a given temperature• The lower the temperature, the more selective the reaction will be at

a given difference in transition energy

0 10 20 30 40 50 60 70 80 90 1000

2000

4000

6000

8000

10000

12000

14000

16000

Difference of Activation Energy required vs. the Ratio of Enantiomers

173

273

298

373

K

‡ (

/)

DDG

Jmol

RT

G

eK

‡

T\DDG‡

4000 J

173 16.1

273 5.8

298 5.0

373 3.6

Chiral Reagent

• Example: Enantioselective reduction of aromatic ketones using BINAL-H

• The enantioselectivity for the reaction increases from R=Me (95 %) to R=n-Bu (100 %) but decreases for R=iso-Pr (71 %) and R=tert.-Bu (44 %) due to increased 1,3-diaxial interactions in the six-membered transition state

O

OAl

H

OEt LiAl

EtO Li OH

R

Runsat.

O

O

(R)-BINAL-H Transition state ofBINAL reduction

(n-C3H7)

O

(n-C3H7)

HO H (R)

78% yield, 100 % e.e.

(n-C3H7)

H OH

64% yield, 100 % e.e.

(S)

Chiral Auxiliary I• Evans (1982): Oxazolidinones for chiral alkylations

• The oxazolidinone is obtained from L-valine (via a reduction to form L-valinol, which is reacted with either urea or diethyl carbonate under MW conditions)

• The iso-propyl group in the auxiliary generates steric hindrance for the approach from the same side in the enolate (the high-lighted atom is the one which is deprotonated)

• Chiral auxiliaries• The auxiliary has to be close to reaction center, but not slow down the

reaction significantly or change the structure in the transition state• The auxiliary should be easily removed without loss of chirality• It should be readily available for both enantiomers

ON

OO 1. Li(N(i-C3H7)2)

2. PhCH2Br

ON

OO

ONH

O

Cl

O

CH2PhPhH2CO

O

CH2Ph

(4S)-(-)-4-isopropyl-2-oxazolidine

>99% e.e.92% yield

LiOCH2Ph

Front view

Side view

Chiral Auxiliary II

• In 1976, E. J. Corey and D. Enders developed the SAMP and RAMP approach that uses cyclic amino acid derivatives ((S)-proline for SAMP, (R)-glutamic acid for RAMP) and hydrazones to control the stereochemistry of the product.

• Below is an example for the use of SAMP in an asymmetric alkylation reaction. • The condensation of SAMP with a ketone affords an E-hydrazone• The deprotonation with LDA leads to the enolate ion that undergoes

alkylation from the backside • The chiral auxiliary is removed by ozonolysis

R'R''

O N

OCH3

NH2 R'R''

NN

OCH3 R'R''

NN

OCH3

R

1. LDA2. RX R'

R''

O

R

O3

"SAMP"

Chiral Catalyst

• In Chem 30CL, a chiral catalyst is used to form a specific enantiomer of an epoxide

NH2

NH2 HOOC

HOOC

OH

OH

+

H2O/AcOH

NH3+

NH3+ -

OOC

-OOC

OH

OH

OH

CHO

2

2 K2CO3

N

N

OH

OH

N

N

O

O

1. Mn(OAc)2*4 H2O

2 Air

3. LiCl

Mn Cl

R3

R1 R2

R4

NaOCl

R3

R1 R2

R4

O