Selective Organic Synthesis

KD 2390 (9 hp) Christina Moberg

The advent of organic chemistry shaped the world

• Biology is dependent on organic synthesis • Organic synthesis is the foundation for biotechnology, nanotechnology, pharmaceutical industry, and material industry About the course:

• Disposition: lectures, exercises, lab, workshop • Course book: Clayden, Greeves and Warren Organic Chemistry, Oxford University Press, 2012 (ISBN 978-0-19-927029-3) [or Clayden, Greeves, Warren and Wothers: Organic Chemistry, Oxford University Press, 2001 (ISBN 0 19 850346 6)] and distributed material • Examination: oral exam, lab work (lab and workshop compulsory) After the course the student should be able to:

• Describe basic stereochemical concepts • Describe principles for stereoselective synthesis, in particular for enantioselective synthesis

• Explain the stereochemistry observed in chemical reactions • Suggest methods for stereoselective synthesis of simple organic compounds containing stereogenic elements

• Identify suitable reagents for stereoselective transformations • Use retrosynthetic analysis for the construction of synthetic routes for simple organic compounds

• Prepare organic compounds using advanced synthetic methodology

Contents

• Fundamental stereochemical concepts

• Synthetic strategy and principles for stereoselective, in particular enantioselective, chemical transformations

• Transition metal catalysis

• Applications of frontier orbital theory

• Retrosynthetic analysis

• Advanced organic synthesis Marcellin Pierre Eugène Berthelot (1827 - 1907) "La Chimie crée ses objets"

“This is an important point: neither biology nor chemistry would be served best by a development in which all organic chemists would simply become biological such that, as a consequence, research at the core of organic chemistry and, therefore, progress in understanding the reactivity of organic molecules, would dry out. Progress at its core in understanding and reasoning in not only essential for organic chemistry itself, but for life sciences as a whole. Life science needs Organic Chemistry that remains strong.”

Axel Eschenmoser (2008)

“Without the possibility of synthesis on the molecular level, efforts in reconstructing or engineering life are certainly bound to fail”

P. Schwille, Angewandte Editorial 2013 Why are new molecules synthesized?

Verify structure Curiosity Challenge Understand properties Function

Paclitaxel (Taxol) O O H2N NH2 “I can no longer, so to CH3COOH speak, hold my NH Cl + Ag N=C=O CCl4 + CS2 4 chemical water and Camphor must tell you that I Komppa1903 Urea can make urea Wöhler 1828 without needing Acetic acid

a kidney, whether Kolbe 1847 first organic of man or dog; the compound ammonium salt of first C-C bond cyanic acid is urea.” O

H N OMe H H O N Progesterone OH Djerassi 1951 O H Tropinone N Robinson 1917 Quinine …it is in the course of attack of the Woodward & most difficult problems, without Doering 1944 consideration of applications, that new fundamental knowledge is most certainly generated. OH O H NH2 Cedrol H O Stork 1955 -O C N S O 2 CN NH2 NH N N NH + O N OAC 2 3 O Co O CO2H H N N

H2N O Cephalosporin O Woodward 1966 O NH2 N NH N HO Vitamin B12 O H Eschenmoser & O O P O Woodward 1973 O OH

O

OH OH Erythronolide O OH Corey 1978 O OH OH H N 2 O O O OH OH OH HO OH OH

OH CH3 HO OH OH OH OH OH OH HO OH O O CH3 OH OH O OH OH HO N N H H OH OH OH OH HO O H3C HO OH OH O CH3 OH O H3C HO CH OH OH 3 O OH OH OH OH HO OH OH

Palytoxin Kishi 1994 Vancomycin Nicolau 1998 Därför säger nu Herren så: “Härav skall du förnimma att jag är Herren: Brevetoxin B se, med staven som jag håller i min hand vill jag slå på vattnet i Nilfloden, och då skall det förvandlas till blod.

Och fiskarna i floden skola dö, och floden skall bliva stinkande, så att egyptierna skola vämjas vid att dricka vatten ifrån floden.” 2:a Mosebok 7:17-18 Maitotoxin

Isolated 1971 from ciguateric fish (svart kirurgfisk)

LD50: 50 ng/kg - 1 mg can kill 1 million mice 98 stereogenic centers

11 rings 26 stereogenic centers Structure determination - O NH You need to know which 2 O O CN NH2 N N molecule to synthesize NH2 Co O H N N

H2N O O O NH2 N NH HO N O H Vitamin B12 O Dorothy Crowfoot Hodgkin 1956 O P O O OH Nicolau 2006

Epothilone A (anticancer)

R O S

N OH O

O OH O Discodormelide

HO

O O OH O NH2 OH O

OH

first isolated in 1990 from the Caribbean marine sponge Discodermia dissoluta! Erythromycin (antibiotic) Malaria

Malaria kills two children every minute

OMe N OH H N Strategy

Retrosynthesis

S HO N O

O OH O epothilone C

and methodology: chemoselectivity regioselectivity stereoselectivity yield

Chirality - Asymmetric synthesis

A compound which is not identical to its mirror image is chiral A chiral compound is not identical to its mirror image

A compound which is identical to its mirror image is not chiral A compound which is not chiral is identical to its mirror image S-(-)-limonene R-(+)-limonene HO OH N N H3C O O CH3

Muskarin ”Lorsqu’il se forme un corps dissymmétrique dans une réaction ou l’on n’a mis en présence les uns des autres que des corps symmetriques, il y aura formation dans la meme proportions des deux isomères de symétrie inverse… Il n’en est pas nécessairement de meme composés dissymétriques formés en présence de corps actifs euxmemes ou traversés de la lumière polarisée circulairement…” J.-A. LeBel 1874

E OH HO N N O CH3 H3C O

t OCH3 H3C CH3

N S N HN OCH3

OCH3 H3C CH3 OCH3 H C CH O 3 3 N S N O N S N HN OCH3 HN OCH3 O O

H2N NH2 OH Aspargine HO O H H O H2N NH2

bitter taste sweet taste

Cl OH 1-Chloro-2,3- HO Cl HO H propanediol H OH poison pharmaceutical

O O

N O Thalidomide O N NH HN O O O O

teratogenic

CO H CO H HS 2 HS 2 NH Penicillamine NH 2 2 Pharmaceutical against artrite poison In 2006, 80% of small-molecule drugs approved by FDA were chiral and 75% were single enantiomers.

The field of asymmetric synthesis is expanding rapidly. Cl O Cl O O CN O Cl O N H

S-Metolachlor herbicide

Largest asymmetric metal-catalyzed process in the world (via hydrogenation of the imine using an Ir catalyst) Classification of isomers

Stereoisomers Constitutional Isomers

Enantiomers Diastereomers Stereogenic center

Interchange of two ligands at a stereogenic center leads to a stereoisomer.

H H * * Cl F Br Br Cl F

For the tetrahedral carbon atom the interchange leads to an enantiomer

F F This is not necessarily the case F * Cl F * Cl for molecules with other Cl F geometries F Cl

A stereogenic center may or may not be chiral, but all chiral centers are stereogenic. Diastereomers

HO HO

CHO CHO H OH H Me H HO H Me Et Me H OH H OH N N Et H OH H OH Me H OH H OH

CH2OH CH2OH Chiral?

NH2 Me Me N H2N Me NH2 Me

Me Me H MeO Me H Me OMe Chiral (or stereogenic) elements

H H

• Chiral (stereogenic) F F Cl Cl Br Br center NO 2 NO O N NO2 2 2 O2N NO2 HO2C S • Chiral (stereogenic) O2N CO2H

HO2C CO2H O2N axis CO2H HO2C CO2H CO2H

Me (H2C)4 Me • Chiral (stereogentic) OH HO plane O O Br Exercise

Racemic 2-(1-hydroxyethyl)pyridine reacts with OH

POCl3 to yield a phosphoric ester, OP(OR)3. 1 Describe the methyl part of the H NMR spectrum N O of the product mixture, assuming a statiscial ratio OH P RO OR of isomers RO N Exercise

Draw all stereoisomers of the anhydride 1. Which isomers are chiral? Are there any symmetry elements? The optical rotation of two of the isomers approaches zero after standing at room temperature. Which are these isomers? Explain the phenomenon.

O

O

O

1 AB-spectrum

http://micro.magnet.fsu.edu/electromag/java/nmr/abspectrum/ Karplus’ equation

J. Chem. Phys. 1959, 30, 11 J. Am. Chem. Soc. 1963, 85, 2870 How to get chiral enantioenriched molecules?

• The chiral pool • Separation of enantiomers • Kinetic resolution (dynamic kinetic resolution) • Stereoselective synthesis

”Life depends on chiral recognition, because living systems interact with enantiomers in decisively different manners” (R Noyori) Paul Walden

The Chiral Pool - Kirala poolen

(R)-Hydroxy- Isobutyric acid

(S)-Malic acid (äppelsyra-E296)

Inhibits leukocyte adhesion to endothelial cells

Cyclamenol A (2001) OH COOH HOOC OH

OH COOH HOOC OH Asymmetric synthesis: De novo synthesis of a chiral substance from an achiral precursor such that one enantiomer predominates over the other.

Molecules which contain at least one chiral element: lack of agreement; use

Stereoselective synthesis Enantioselective synthesis Diastereoselkective synthesis Methods for stereoselective (asymmetric) synthesis

–Diastereoselective reaction with chiral substrate –Use of chiral auxiliary –Use of chiral reagent –Asymmetric catalysis •Chiral metal catalyst Catalysis has a key role to •Enzymatic catalysis play in the development of Green Chemistry - not only

•Catalytic antibodies for replacement of old •Organocatalysis stoichiometric reactions, but also for the development of new reactions. Chiral induction in catalytic reactions

O Enantiotopic faces Ph Ph

Ph X Enantiotopic groups X (-)-Menthol 20 000 ton/year

N N OH 98% ee 100% ee

TOF = 50 000 Enzymatic hydrolysis

CO2CH3 pig liver CO2H 1. BH3 O esterase 2. H+ CO2CH3 CO2CH3 O Examples of additions to enantiotopic faces

O HO H R1 H H2 H2 R1 R1 R2 R1 R2 cat "M" R2 cat "M" R2 hydrogenation hydrogenation O 1 Ph SiH Ph2HSiO H R ROOH O 2 2 R1 1 2 R1 R2 R R cat "M" R2 cat "M" R2 hydrosilylation epoxidation

R1 O XCN NC OX ox HO OH R1 1 2 1 2 R R cat "M" R R R2 cat "M" R2 hydrocyanation dihydroxylation OH O O O- + 1 1 R R 2 R R2 aldol condensation Catalytic cycle Catalytic hydrogenation E

Naproxen

t H3C CH2 H H CH3 COOH COOH COOH H3C H3C H3C

O O O Bonding in transition metal complexes

Octahedral complex Square planar complex

L L L L L L L L L L Square planar Rh(I) complex Two coordination sites available for the olefin

L L Rh S The Dewar-Chatt-Duncanson model olefin metal

M

Pd(II)

olefin metal

M

Pd(O) Determination of stereochemistry

COOR COOR COOR COOR H NHCOR NHCOR NHCOR NHCOR H

Diastereomeric complexes

Chiral ligands

OMe

P P P P

MeO

(R,R)-DIPAMP (S,S)-CHIRAPHOS

O O H H

P P P P

(R,R)-DIOP (aR)-BINAP Conformation (S,S)-Chiraphos

Me P Rh P Me RO2C NHCOCH3

H RO2C NHCOCH3 Rh(I)-olefinkomplex

P P P P P P P P

Re P P

P P P P P P P P

Si

=

RO2C NHCOCH3 Curtin Hammet principle

E

COOR COOR NHCOR NHCOR

COOR COOR H NHCOR NHCOR H Preparation of L-Dopa

OMe OMe Rh(COD)2BF4 OAc L* OAc HO NH2

CO2H H2, MeOH HO 3 bar, 50 °C L-DOPA HO2C NHCOMe HO2C NHCOMe sub/cat>10 000 96% ee, 100% after recryst

MeO Ph P L* =

P Ph MeO

RuCl2-BINAP-diamine-catalyzed reduction of ketones

Nonlinear effects

Enantioselective reductions and oxidations Epoxide Reactions

OH OH

OH OH Cl OH

SR NH2

O O O CO2CH3 O O

O leukotriene -C1 erythromycin (macrolide antibiotic) O

dispalure (pheromone) Sharpless Epoxidation

• Enantioselective epoxidation of allylic alcohols • Reagents involved are – Tert-butyl hydroperoxide (oxidant) – Titanium tetraisopropoxide (Lewis acid) – (+) or (-) dialkyl tartrate (source of chirality) • Double bond adjacent to the OH bearing C is epoxidized Sharpless Epoxidation

R2 R3 i t Ti(O Pr)4, BuOOH O OH D-(+)-diethyl tartrate, CH Cl , -20 °C R1 R2 R3 2 2

OH i t Ti(O Pr)4, BuOOH R2 R3 R1 O L-(-)-diethyl tartrate, CH2Cl2, -20 °C OH R1 Model for predicting the product

(-)-Tartrate

OH

(+)-Tartrate R'O2C OR HO OR E CO Et RO O O 2 Ti(O-i-Pr)4 + 2 2 Ti Ti EtO2C O O OR O OH O OR' R'O (R = i-Pr, R' = Et,

E = CO2Et) R'O2C O n-C H OR 7 15 OH E RO O O Ti Ti O O O + t-BuOOH C H O 7 15 O E t-Bu R'O HO H O n-C H O = 7 15 OH H C7H15 Taxol Synthesis

i Ti(O Pr)4 1. RuCl3 tBuOOH NaIO O 4 O (+)-DET 2. CH N OH 2 2 OMe Ph OH Ph Ph O O

Me3SiN3 N3 O PhO NH O PhCOCl H2/Pd Ph OMe Ph OMe OCOPh OH Ligands for Asymmetric Dihydroxylation

Dihydroquinidine (DHQD) Dihydroquinine (DHQ) Model for predicting the product

OsO4(DHQD)

RS RM

RL H

OsO4(DHQ) Methathesis Nobel price in Chemistry 2005 “för utveckling av metates-metoden inom organisk syntes”

Yves Chauvin Robert H. Grubbs Richard R. Schrock Institut Français du California Institute of Massachusetts Institute of Pétrole Technology (Caltech) Technology (MIT) Rueil-Malmaison, France Pasadena, CA, USA Cambridge, MA, USA b. 1930 b. 1942 b. 1945 Mekanismen kan beskrivas som en pardans

H [M] C H H [M] C H [M] H H C C C C C H3C H H C H H H H3C H H H 3 C C H H Metates, mekanism

Fürstner: Synthesis of Balanol

Large scale production

Cross-metathesis (CM) for preparation of propene

H [M] C H + H2C CH2 2

O H O [M] C OH OH H + +

H2C CH2

Cross-metathesis (CM) for cleavage of oleic acid

Fuel of the future? Ring opening polymerization (ROMP)

H [Ru] C H n

H [Ru] C H

n

Bulletproof plastics (stops 9-mm bullets)

“Unbreakable” baseball racket Asymmetric Ring-Closing Metathesis (ARCM)

Desymmetrization of a meso-Substrate with a chiral Metathesis catalyst.

Kiely, A. F.; Jernelius, J. A.; Schrock, R. R.; Hoveyda, A. H. J. Am. Chem. Soc. 2002, 124, 2868-2869 Enantioselective methathesis reaction Stille couplings Stille couplings Sonogashira couplings Metal Catalyzed Asymmetric Allylic Alkylations (AAA)

M, Nu OX Nu

M = Pd, Mo, Ir, W, Cu, Ni, Pt, Ru, Rh, Co, Fe X = COCH3, COOR, PO(OR)2

C-C, C-O, C-N, C-S bond formation HistoryO O O OEt OEt OEt Na H OEt OEt OEt Cl O O O First allylic alkylation: Pd Pd + Cl N O

Tsuji, J.; Takahashi, H.; Morikawa, M. Tetrahedron Lett. 1965, 4387

First catalytic reaction:

Pd(acac) OR 2 NEt + HNEt2 2 PPh R = H, OCOMe 3 OH

OH and gave the same product

Atkins, K. E.; Walker, W. E.; Manyik, R. M. Tetrahedron Lett. 1970, 3821 History, contd O O

O EtO OEt Cl OEt OMe + Na Pd Pd P First asymmetric reaction Cl OEt O 24% ee, corrected for 80% optical purity of ligand! optical yield

Trost, B. M.; Dietsche, T. J. J. Am. Chem. Soc. 1973, 95, 8200

SO2Ph Na CO2CH3 CO2CH3 CO2CH3 First catalytic asymmetric reactions OEt O + + Pd(PPh ) + L* Pd AcO OAc 3 4 L L

CO2CH3 CO2CH3

H3CO2C H3CO2C “ Optical yields of this magnitude for carbon-carbon SO Ph L* = (+)-DIOP bond forming reactions at normal temperatures 2 (70-80 °C) in a catalytic process are among the highest seen and suggest this approach as an exciting solution to asymmetric induction in carbon- OAc carbon bond forming reactions.” CO2CH3 "Pd-L*" L* = (+)-DIOP 46% ee

Trost, B. M.; Strege, P.E. J. Am. Chem. Soc. 1977, 99, 1649 Asymmetric Allylic Alkylations, AAA

M, Nu Nu Nu OR Nu Nu

R = OAc, OCOOMe, OPO(OEt)2 M = Pd, Mo, W, Ir, Rh, Co, F, Ru, Ni, Pt, Cu

stereoselectivity regioselectivity

The selectivity is a function of many factors: • The metal ion • The ligand • The nucleophile • The substituents of the allyl system

Stereochemistry

L L R L 1 R1 R2 R1 R2 R2 L X stabilized Nu Nu- nucleophile net retention

R1 L R1 R2 R2 L unstabilized Nu Nu nucleophile net inversion Sources of enantiodiscrimination in transition metal catalyzed allylic alkylations

X X X enantiotopic faces enantiotopic enantiotopic faces of the olefin leaving groups of the allyl

Nu

Nu- enantiotopic faces of the nucleophile enantiotopic termini of the allyl Sources of enantiodiscrimination in transition metal catalyzed allylic alkylations

enantiotopic termini of the allyl Nu

Nu-

H H

Nu Nu Enantioface exchange

LB

LA R R R R R1 = R2: 1 2 1 2 R R X X H H

regiochemistry of nucleophilic attack enantiodetermining

LB R1 R2 LA R1 R2 R1 R2 R1 = R2: H H R1 R2 X X L LA B H H

enantioface exchange required for enantioselective reaction R1 R2 R1 R2 Nu Nu Syn-anti isomerization

L B LB L A LA R R 1 2 R1 H H H H R2

Apparent allyl rotation

LB LB

LA LA H H R1 R2 H H R1 R2 Prediction of enantioselectivity

favored N P N P Nu Nu

Nu Nu

N P N P

Exothermal reaction Endothermal reaction “Trost ligand”

Pd PPh2 Ph2P P P

NH HN LINKER LINKER O O

CHIRAL SCAFFOLD Trost’s ligand in catalytic reactions symmetric substrate

3 [Pd(η -C3H5)µ-Cl]2, L* OCOOEt Nu Nu

regiochemistry of nucleophilic attack enantiodetermining

MeO OH 1 min, 96% yield, 95% ee O O L* = NH HN O

PPh2 Ph2P NH 4 min, 79% yield, 97% ee

O

O O 1.5 min, 83% yield, >95% ee MeO OMe

Bremberg, U.; Larhed, M.; Moberg, C.; Hallberg, A. J. Org. Chem. 1999, 64, 1082 Enantiotopic leaving groups

ex: O O O O O X X NHTs TsHN N O Ts enantiotopic leaving groups

O O O O

ligand PPh2 Ph2P PPh2 Ph2P

P P side view P P

RO OR RO OR preferred motion

Complexes with phosphineoxazoline

O

N PPh2 Complexes with phosphineoxazoline

R O R O R O R O N P N P N P N P Pd Pd Pd Pd

R O R O R O R O N P N P N P N P Pd Pd Pd Pd Regioselectivity

R OAc

Nu Nu R or R Nu Nu Mo Pd R

OAc Isomerization

OCO2Me OCO2Me

Ph Ph 1 ent-1

"Fast" reacting "Slow" reacting enantiomer enantiomer

Mo kR Mo

Ph Ph kS

NaCH(CO2Me)2 k1 k3 NaCH(CO2Me)2

MeO C CO Me MeO2C CO2Me 2 2

Ph Ph

2 ent-2

Fast equilibrium: kR and kS >> k1, k2 Synthesis of (R)-baclofen

O

O OH O O OMe

H MgBr Cl OMe "Mo"

Cl Cl Cl

MeOOC COOMe COOMe COOH

NaCl 1. O3 NH2

Cl DMSO/H2O Cl 2. NH4 OAc Cl NaCNBH3

Homogeneous cat: 160 °C, 6 min, 78% yield, b:l 26:1, 96% ee Polymeric cat: 160 °C, 30 min, 76% yield, b:l 25:1, 89% ee

Belda, O.; Moberg, C. Org. Lett. 2003, 5, 2275-2278. Synthesis of Tipranavir

OH MeO2C CO2Me OCO2Me 10 mol% Mo(CO)6 L*, 180 °C, 20 min, mw O O O ONa O HN S O NO2 NO2 Ph MeO OMe 92% yield, 94% ee HIV protease inhibitor CF O O 3 L* = NH HN

R PPh2 Ph2P R R = H, OMe

First enantioselective Ir-catalyzed allylation

NaCH(COOCH3)2 MeO2C CO2Me 1/2 [Ir(COD)Cl] /L* CO2Me R OAc 2 + R R * CO2Me

R = Ph 95 : 5 91% ee L* = O R = 4-(MeO)Ph 99 : 1 95% ee

N P CF3

CF3

Takeuchi and Kashio had demonstrated the high regioselectivity using an achiral catalyst

Janssen, J. P.; Helmchen, G. Tetrahedron Lett. 1997, 38, 8025-8026. Memory effect

OAc NaCH(COOCH3)2 MeO2C CO2Me 1/2 [Ir(COD)Cl]2/L* Ph P(OPh)3 Ph 91% ee 51% ee

memory of stereochemistry of starting material: σ−π isomerization is slow

retention of configuration - shown to be double inversion

and give no product, while

H AcO OAc H OAc does Nickel catalysts have been used for allylations using stabilized as well as non- stabilized nucleophiles. Good selectivities have been obtained only in a few cases.

L L R L 1 R1 R2 R1 R2 R2 L X stabilized Nu Nu- nucleophile net retention

R1 L R1 R2 R2 L unstabilized Nu Nu nucleophile net inversion Cu-catalyzed AAA

R R2Zn Cl CuOTf, L*

R regioselectivity yield (%) ee (%)

L* = O Et 93:7 74 86 P N iPr 97:3 94 88 O

Van Zijl, A. W.; Arnold, L. A.; Minnard, A. J.; Feringa, B. L. Adv. Synth. Catal. 2004, 346, 413-420. Summary

Pd catalysts have been most deeply explored. High enantioselectivity with different types of allylic substrates. React wide a wide range of nucleophiles.

Mo and W and catalysts show different regioselectivity. Higher enantioselectivity with Mo.

Ir catalysts show the same regiochemistry as Mo and W. React wide a wider range of nucleophiles.

Rh: regiochemistry of starting allylic substrate largely conserved during reaction

Ru catalysts less explored, but seem to have promising properties.

Ni catalysts have been used for allylations using stabilized as well as non- stabilized nucleophiles. Good selectivities have been obtained only in a few cases.

Cu catalysts react with non-stabilized nucleophiles with high enantioselectivity.

THE END