Enantioselective CpRu-catalyzed decarboxylative C-C bond forming reactions

Thesis

Reference

Enantioselective CpRu-catalyzed decarboxylative C-C bond forming reactions

LINDER, David

Abstract

La combinaison du précatalyseur stable à l'air [CpRu(η⁶-C₁₀H₈)] [PF₆] avec des ligands de type pyridine-monooxazoline a permis de développer une nouvelle stratégie pour effectuer des réactions de substitution allyliques avec des conditions expérimentales simples. Cette famille de ligands est apparue particulièrement appropriée pour effectuer l'étude de réactions du type réarrangement de Carroll. Le mécanisme de cette réaction a été étudié et un cycle catalytique raisonnable en a découlé. Une stratégie de double activation par co-catalyse a donc été développée: l'utilisation synergique de sels de magnésium a permis d'effectuer ces réactions à température ambiante et donc de manière plus sélective.

LINDER, David. Enantioselective CpRu-catalyzed decarboxylative C-C bond forming reactions. Thèse de doctorat : Univ. Genève, 2008, no. Sc. 4033

URN : urn:nbn:ch:unige-14791

DOI : 10.13097/archive-ouverte/unige:1479

Available at:

http://archive-ouverte.unige.ch/unige:1479

Disclaimer: layout of this document may differ from the published version.

Département de chimie organique Professeur J. Lacour

Enantioselective CpRu-Catalyzed Decarboxylative C-C Bond Forming Reactions

THÈSE

présentée à la Faculté des sciences de l'Université de Genève

pour obtenir le grade de Docteur ès sciences, mention chimie

par

David LINDER

de

Copenhague (Danemark)

Thèse N° 4033

GENÈVE

Atelier d'impression ReproMail

Dedicated to Dr. Pierre Mangeney.

On the occasion of his retirement.

We want the observed facts to follow logically from our concept of reality. Without the belief that it is possible to grasp the reality with our theoretical constructions, without the belief in the inner harmony of our world, there could be no science.

This belief is and always will remain the fundamental motive for all scientific creation. Throughout all our efforts, in every dramatic struggle between old and new views, we recognize the eternal longing for understanding, […] continually strengthened by the increasing obstacles to comprehension.

Albert Einstein (1879-1955), Leopold Infeld (1898-1968) The Evolution of Physics, 1938, Cambridge University Press

You can get much farther with a kind word and a gun than you can with a kind word alone.

Al Capone (1899-1947)

Les résultats rapportés dans ce manuscrit ont été obtenus dans le cadre d’un travail de thèse réalisé au sein du laboratoire du Professeur Jérôme Lacour, dans le département de chimie organique de l’Université de Genève, du 01 octobre 2004 au 31 octobre 2008.

Je voudrais d’abord exprimer toute ma gratitude au Professeur Jérôme Lacour, pour m’avoir donné l’opportunité de réaliser ce travail de thèse dans son laboratoire, pour la confiance et l’autonomie qu’il m’a accordées ainsi que pour sa patience pendant toutes ces années.

Je désire ensuite remercier le Professeur Antonio Togni (Eidgenössische Technische Hochschule Zürich) et le Docteur Clément Mazet (Université de Genève) pour avoir eu l’amabilité de bien vouloir juger les travaux de thèse rapportés ci-après.

J’exprime aussi toute ma gratitude aux équipes de service d’analyse : RMN (Dr. Damien Jeannerat, André Pinto and Bruno Vitorge), SM (Philippe Perottet and Eliane Sandmeier) et SM-HR (Prof. Gérard Hopfgardner and Nathalie Oudry) pour leur indispensable contribution.

Je voudrais chaleureusement saluer mes collègues, passés et présents, et de tout le département participation active et leur alcophilie partagée. Dans un ordre parfaitement chaotique, j’exprime ma gratitude à Richard, Sam-arche, Benoit, Jej and Simone pour de si nombreuses raisons que je ne peux les détailler ici. Un grand merci à Cédric (a.k.a. Boubou) et à Michael pour leur participation efficace à ces travaux. Le « réfugié politique » remercie Reno, Chloé, Stéphane (x2), Fran et les autres pour leur accueil. Un grand, grand merci à Phan (je suis pas encore devenu comme Niko Brevic…) et à la bande de gros lourds pour les gaming-sessions interminables et les sessions pizza sponsorisées par Feldschlösschen.

“Gracie mille” pour “little V” et à l’autre petite terroriste pour tout et plus encore.

Il me reste à remercier Ankit Sharma, Andrei Badoiù et le Dr. Chloé Bournaud pour leur participation active à la correction de ce manuscrit.

Finalement je tiens à remercier chaleureusement Pierre et Manu qui m’ont tout deux transmis leur enthousiasme pour la recherche et leur saine vision du milieu…

Abbreviations br(s): broad (singlet) s: singlet

d: doublet

dd: doublet of doublet t: triplet

dt: doublet of triplet q: quartet

sept: septet m: multiplet

TLC: Thin layer chromatography Rf: retardation factor

cat.: catalytic amount equiv.: equivalent conv.: conversion C: concentration litt.: literature ref.: reference maj.: major min.: minor

M.p.: melting point ppm: part per million rac: racemic

ent: opposite enantiomer of

Y.: yield

ee: enantiomeric excess dr.: diastereomeric ratio

R.T.: room temperature b: branched regioisomer l: linear regioisomer

Ar: aryl

napht: naphthalene Cp: cyclopentadienyl

Cp*: pentamethyl cyclopentadienyl Cp’: substituted cyclopentadienyl phen: 2,2’-phenantroline

bpy: 2,2’-bipyridine cod: 1,4-cyclooctadiene

BSA: N,O-bis(trimethylsilyl)amide Tol.: toluene

TMS: trimethyl silyl

TBDMS: tert-butyl dimethyl silyl TIPS: triisopropyl silyl

n-Pr: propyl i-Pr: iso-propyl t-Bu: tert-butyl

BDU: Diaza(1,3)bicyclo[5.4.0]undecane Ts: Tosyl

Symbols δ: chemical shift λ: wave length J: coupling constant l: length

tR: retention time T: temperature Units

°C: degree Celsius K: Kelvin

g: gram mg: miligram µl: microliter

mL: milliliter mmol: millimole M: molarity min: minute h: hour

Formation énantiosélective de liaisons C-C par décarboxylation catalysée par des complexes CpRu

L’objectif des travaux de cette thèse est de développer une version asymétrique du réarrangement de Carroll, une réaction qui peut être catalysé par des complexes de ruthénium (Schéma 1) comme décrit par Tunge¹ puis par Lacour.² Bien que le domaine de la substitution allylique soit extrêmement étendu, ce type de réactions catalysées par des complexes de ruthénium est globalement peu décrit dans la littérature.

[CpRu(η⁶-C10H8)][PF6] (10 mol%) L18f(10 mol%)

THF, 60 °C

O O

O O O

b l

R R R

N

O N

L18f

b:ljusqu'à 99:1 eejusqu'à 87 %

Schéma 1: Réarrangement de Carroll catalysé par un complexe du type CpRu.

Les expériences décrites dans ce manuscrit montrent que la famille des pyridine- monooxazolines est une classe de ligand appropriée pour l’étude du réarrangement de Carroll catalysé par des complexes de type Cp-ruthenium. En particulier le ligand L18f a permis d’obtenir de bonnes réactivités (jusqu’à 20 fois supérieure qu’avec les pyridine-imines), de bonnes régiosélectivités (jusqu’à > 99:1) et de bonnes énantiosélectivités (jusqu’à > 80 %).

Le mécanisme de la réaction a été étudié en détail. Même s’il n’a été possible de caractériser précisément les espèces intermédiaires, les nombreuses expériences ont permis de rassembler suffisamment d’indices non équivoques pour pouvoir proposer un cycle catalytique raisonnable très proche de celui décrit dans la littérature dans le cas des réactions catalysées au

palladium (Schéma 2).

1 Burger, E. C.; Tunge, J. A. Org. Lett. 2004, 6, 2603-2605. Burger, E. C.; Tunge, J. A. Chem. Commun. 2005, 2835-2837.

2 Constant, S.; Tortoioli, S.; Muller, J.; Lacour, J. Angew. Chem. Int. Ed. 2007, 46, 2082-2085. Constant, S.;

Ar O O R

O

Ar [Ru*]

O O R

O

Ar [Ru*]

R O

Ar

CO₂ [Ru*]

Ar R

O

b l

R O

Schéma 2: Cycle catalytique postulé.

Ces résultats mécanistiques ont par ailleurs permis de développer une stratégie de co-catalyse basée sur l’utilisation synergique de sels de magnésium. De meilleures réactivités ont ainsi été obtenues ; permettant de réaliser la réaction à température ambiante et par conséquent d’améliorer sensiblement les sélectivités.

Dans un second temps, le système catalytique développé a été testé dans le cadre de réactions de substitutions allyliques classiques (Schéma 3). Il est apparu dans ces cas que l’utilisation de sels de lithium donne de bons résultats en termes de régiosélectivité (généralement 9:1) pour des réactions de substitutions allyliques sans ajout de base avec une grande variété de prénucléophiles activés. L’ensemble de ces expériences souffre malheureusement du fait que la diastéréosélectivité obtenue pour les produits branchés est médiocre (généralement 1:1) et aucune piste prometteuse ne peut être proposée à ce jour pour contourner ce problème.

[CpRu(η⁶-Napht)][PF₆] (2 mol%) L18f(2.4 mol%) LiOMe (1 mol%) THF, 60 °C

O R' O

O Z Z

b l

R R R

b:ljusqu'à 92:8 r d.de 45:55 à 56:44

Z O

O R'' X

X X

Schéma 3: Réactions de substitution allylique dîtes classiques.

Il a aussi été montré que la même stratégie pouvait être appliquée au réarrangement décarboxylatif de carbonates et carbamates dérivés de l’alcool cinnamique. Le cas des nucléophiles azotés demeure relativement problématique puisque ni la chimiosélectivité (réactions de double alkylation) ni la régiosélectivité n’ont pu être contrôlées de manière satisfaisante. Au contraire, le cas de nucléophiles oxygénés est apparu comme bien plus prometteur puisque de bonnes sélectivités ont pu être obtenues.

La combinaison du précatalyseur stable à l’air [CpRu(η⁶-C10H8)][PF6] avec le ligand L18f a permis de développer une nouvelle stratégie pour effectuer des réactions de substitutions allyliques avec des conditions expérimentales relativement simples. Le ligand L18f est par ailleurs apparu comme particulièrement intéressant non seulement à cause de sa synthèse extrêmement directe, mais aussi du fait que les deux énantiomères de l’aminoalcool dont il est issu sont commerciaux sous forme énantiopure pour un prix relativement modéré ((+)- or (–)- aminoindanol 5g ~ 200 CHF).

De nombreux développements sont actuellement en cours au laboratoire pour évaluer la généralité de ce type de catalyseurs dans le cadre de la substitution allylique.

Enantioselective CpRu-Catalyzed Decarboxylative C-C Bond Forming Reactions

1. GENERAL INTRODUCTION - 1 -

1.1. PREAMBLE -1-

1.2. ASYMMETRIC CATALYSIS -4-

1.2.1. Birth of the Catalytic Concept - 4 -

1.2.2. Industrial Developments - 4 -

1.3. MODERN APPLICATIONS OF ASYMMETRIC CATALYSIS -5-

1.3.1. Asymmetric Organocatalysis - 5 -

1.3.2. Asymmetric Organometallic Catalysis - 6 -

2. METAL CATALYZED ALLYLIC SUBSTITUTIONS - 7 -

2.1. PREAMBLE -7-

2.2. PALLADIUM CATALYZED ALLYLIC SUBSTITUTIONS -8-

2.2.1. General Mechanism - 8 -

2.2.2. Structure of Metal-Allyl Complexes - 9 -

2.2.3. Enantiodiscriminating Steps - 11 -

2.3. OTHER METAL-CATALYZED ALLYLIC SUBSTITUTIONS -18-

2.3.1. Copper - 18 -

2.3.2. Molybdenum - 19 -

2.3.3. Tungsten - 19 -

2.3.4. Rhodium - 20 -

2.3.5. Iridium - 20 -

2.4. RUTHENIUM-CATALYZED ALLYLIC SUBSTITUTIONS -23-

2.4.1. Early-Stage Developments - 23 -

2.4.2. Ru-Catalysts for Regioselective Allylation of Nucleophiles - 24 -

2.4.3. Asymmetric Allylation of Nucleophiles - 27 -

2.4.4. Ru-catalyzed “Carroll rearrangement” - 28 -

2.5. AIM AND SCOPE OF THE WORK -30-

3. CATALYTIC SYSTEM OPTIMIZATION - 31 -

3.1. PREAMBLE -31-

3.2. OPTIMIZATION OF THE LIGAND -33-

3.2.1. Use and Synthesis of Pymox Ligands - 33 -

3.2.2. Ligand Structure Screening - 34 -

3.3. OPTIMIZATION OF THE REACTION CONDITIONS -36-

3.3.1. Reaction Conditions Screening - 36 -

3.3.2. Synthesis of the Substrates - 37 -

3.3.3. Scope of the Reaction - 38 -

3.3.4. Metal Source Optimization - 40 -

3.4. CONCLUSION -44-

4. MECHANISTIC INSIGHT - 45 -

4.1. PREAMBLE -45-

4.2. MOANALYSIS OF [CPRUL2(η³-ALLYL)]COMPLEXES -45- 4.3. REGIOSELECTIVITY OF THE REACTION IN THE CASE OF UNSYMMETRICALLY

SUBSTITUTED SUBSTRATES -48-

4.7.1. Analysis in Terms of Molecular Orbitals - 48 -

4.7.2. Substituent effect: linear free-energy relations - 50 -

4.4. ENANTIOSELECTIVITY OF THE REACTION -51-

4.7.1. Stereoselectivity at the Ru-centre - 51 -

4.7.2. Rationalization of the enantioselectivity - 55 -

4.5. NATURE OF THE NUCLEOPHILE -59-

4.6. APPROACHES TO CO-CATALYSIS /DUAL-ACTIVATION -65-

4.7. MECHANISTIC RATIONAL -71-

4.7.1. Kinetic Isotope Effects - 71 -

4.7.2. Effect of CO2 - 73 -

4.8. CONCLUSION -74-

5. APPLICATIONS TO “CLASSICAL” ALLYLIC SUBSTITUTION - 76 -

5.1. PREAMBLE -76-

5.2. ACTIVATED C-NUCLEOPHILES -76-

5.2.1. 1,3-Dicarbonyl Prenucleophiles - 76 -

5.2.2. Application of Co-Catalysis - 79 -

5.3. PREFORMED C-NUCLEOPHILES -84-

5.4. UNSTABILIZED NUCLEOPHILES -85-

5.4.1. Unstabilized Ketones - 85 -

5.4.2. Unstabilized Alkynes - 86 -

5.5. HETEROATOMIC NUCLEOPHILES -88-

5.5.1. N-Nucleophiles - 88 -

5.5.2. O-Nucleophiles - 89 -

5.6. CONCLUSION -91-

6. GENERAL CONCLUSION & OUTLOOK - 92 -

6.1. CONCLUSION -92-

6.2. OUTLOOK -93-

7. EXPERIMENTAL PART - 97 -

7.1. GENERALITIES -97-

7.2. SYNTHESIS OF SUBSTRATES OF TYPE 1. -98-

7.3. SYNTHESIS OF PRODUCTS OF TYPE 2. -100-

7.4. CSP-SEPARATION OF PRODUCTS OF TYPE 2. -106-

7.5. GC-SEPARATION OF PRODUCTS OF TYPE 2 AND 3. -107-

7.6. SYNTHESIS OF METAL PRECATALYSTS OF TYPE 4. -107-

7.7. SYNTHESIS OF LIGANDS OF TYPE L18. -108-

7.8. SYNTHESIS OF PRODUCTS OF TYPE 15. -110-

7.9. GC-SEPARATION OF REGIOISOMERS OF 15. -111-

7.10. SYNTHESIS OF CARBAMATES OF TYPE 23. -111-

7.11. SYNTHESIS AND REACTIVITY OF SUBSTRATE 25. -111-

7.12. SYNTHESIS AND REACTIVITY OF CARBONATES 27. -112-

1. General Introduction

How would you like to live in Looking-glass House, Kitty? I wonder if they'd give you milk in there? Perhaps Looking-glass milk isn't good to drink.

Lewis Carroll, Through the Looking-Glass (1871)

1.1. Preamble

The concept of "chirality" is known in chemistry since the 1870's although it took nearly a hundred years before chemists began using this term. In fact, in the first edition of Eliel's

"Stereochemistry of Carbon Compounds" in 1962,¹ the word chiral was not even mentioned, it became prominent in later editions.² In extremely simple terms, chirality corresponds to

"handedness" - that is, the existence of a left / right opposition. For example, left and right hands are mirror images of each other which cannot be superposed and therefore are "chiral".

The term chiral is derived from the Greek name kheir meaning "hand" (Scheme 1-1) and apparently was coined by Lord Kelvin in 1904 when he stated: "I call any geometrical figure, or group of points, chiral, and say it has chirality, if its image in a plane mirror, ideally realized, cannot be brought to coincide with itself". In more modern phrasing, any object or molecule which has no improper axis of symmetry (Sn, n > 0) is thus defined as chiral.

Scheme 1-1: Illustration of chirality with the hands.

The first observation of the macroscopic effects of chirality was made by the French physicist Jean-Baptiste Biot in 1835. He noticed that the plane of polarization of a beam of planar polarized light could be rotated by passing through sugar solutions. In 1848 the French chemist Louis Pasteur provided a new milestone by solving the problems concerning the

1 (a) Eliel, E. L. Stereochemistry of carbon compounds; McGraw-Hill: New York, 1962. (b) Eliel, E. L. Stereochemistry of Carbon Compounds, 1962

nature of tartaric acid. Contrary to samples of the synthetic molecule, which exhibited no optical activity, “natural” tartaric acid, obtained from wine lees, were deviating the plane of polarization of light in one specific direction. By crystallizing sodium ammonium tartrate in the right conditions, Pasteur discovered that some of the obtained crystals were non- superimposable mirror images and that solutions of these exhibited opposite rotations of the plane of polarization. Pasteur correctly deduced that the molecule in question was chiral and could “exist in two different forms that resemble one another as would left- and right-hand gloves”, and the biological source of the compound provided only one type.³

Following Kekule's 1858 postulate that carbon has a valence of four,⁴ van’t Hoff⁵ and Le Bel⁶ independently recognized that four different groups attached to the same carbon atom, arrayed at the corners of a tetrahedron, lead to two different configurations A and Ā called enantiomers (Scheme 1-2).

a

b c

d

a

b c

d

mirror plane mirror plane

(S)

CO₂H

H3C H

NH₂

( R)

CO₂H

CH₃ H H₂N

Scheme 1-2: Models of asymmetric molecules made by van’t Hoff (left), schematic representation of two enantiomeric tetrahedrons (middle) and representation of the two enantiomers of alanine (right).

Many building blocks (amino acids, sugars …), constituting the important families of biologically active molecules (proteins, nucleic acids …), are usually found in nature as a single enantiomer and transfer their properties of chirality to the whole superstructure. These matrices thus have complex three-dimensional structures which are liable to interact differently with the two enantiomers of a molecule. The different interactions can subsequently induce different physiological activities which are particularly important for pharmacologically active molecules (Scheme 1-3).

Due to the constantly growing demand for non-racemic compounds as drugs, agrochemicals, flavours, fragrances and synthetic materials, many efforts have been devoted to developing efficient methods to yield the desired enantioenriched / enantiopure synthetic intermediates.⁷

3 L. Pasteur, Two lectures delivered to the Société Chimique de Paris, Jan. 20^th & Feb. 3^rd, 1860.

4 Kekule, A. Ann. 1858, 154.

5 van't Hoff, J. H. Bull. Soc. Chim. Fr. 1875, 295.

6 Le Bel, J. A. Bull. Soc. Chim. Fr. 1874, 337.

7 (a) Halpern, J.; Trost, B. M. Proc. Nat. Acad. Sci. U.S.A. 2004, 101, 5347-5347. (b) Trost, B. M. Proc. Nat. Acad. Sci.

(S)

NH O O N O O

(R)

NH O O N O

O

N(S)

H HN

(S)

H(R)

N N H

(R)

MeO

(S) OH

O MeO

(R)

OH O

(R) O HN

OH

O

(S)

NH OH

Thalidomide Ethambutol

Naproxen Propanolol

OH OH

OH

OH effective against

morning sickness

teratogenic

treats arthritis pain

causes liver poisoning

treats tuberculosis

causes blindness

adrenoceptor antagonist local anesthetic local anesthetic

Scheme 1-3: Both enantiomers of selected drugs and their respective physiological effects.

Historically, enantioenriched compounds were synthesized by manipulating, through successive chemical transformations, an optically active precursor often generated from nature’s chiral pool or by separating the two enantiomers of a racemic mixture by the use of an enantiopure agent. Both these approaches suffer from potentially severe drawbacks: the former requires stoichiometric amounts of a suitable precursor and often leads to tortuous synthetic routes to overcome nature’s rather specific structural scaffold, while the yield of the desired enantiomer for the latter is limited to a maximum of 50 %, unless a suitable epimerization reaction is simultaneously at play.

The strategy consisting in using a chiral auxiliary (generally derived from the chiral pool) as asymmetry inducing agent also suffers from the same drawbacks. However, one must notice the importance of this strategy in total synthesis, since certain functions, with already established configurations, can act as intramolecular asymmetry inducers (diastereoselective synthesis). On the other hand, asymmetric catalysis, in which each molecule of chiral catalyst, by virtue of being continually regenerated, can yield many molecules of chiral product, has significant potential advantages over these older procedures. Nature is the biggest user of asymmetric catalysis: living systems use enzymes to perform the stereoselective synthesis of their building blocks with very high fidelity. Enzymes exploit hydrogen bonding between the active site and substrate, together with non-bonding dipole-dipole, electrostatic, and steric interactions, to orient the substrate and stabilize the transition state, leading to high levels of stereoselectivity.

1.2. Asymmetric Catalysis

Catalysis is the process by which the rate of a chemical reaction is increased by the action of a substance (catalyst) which remains unchanged in nature at the end of the reaction.

1.2.1. Birth of the Catalytic Concept

It is the Swedish chemist Jöns Jacob Berzelius who first described the concept of “catalytic power” in 1835.⁸ This he defined as follows: “The catalytic force actually appears to consist in the ability of substances to arouse the affinities dormant at this temperature by their mere presence and not by their affinity and so as a result in a compound substance [where] the elements become arranged in another way such that a greater electrochemical neutralization is brought about”. Though he was not the first to use the word catalysis, as it was already in use in Andreas Livbavius’s Alchemy in 1597, he was the first to crystallize the concept with help of the separate experiments of Kirchhoff, Thénard, Davy, Döbereiner and Mitscherlich (1811-1834). Most of these early catalytic experiments dealt with the reaction of gaseous reagents at the surface of noble metal wires. In 1909 Ostwald received a Nobel Prize in recognition of his work on catalysis and for his investigations into the fundamental principles governing chemical equilibria and rates of reaction leading to a new definition: “catalysts are substances which change the velocity of a reaction without modification of the energy factors of the reaction”.⁹ This year, Ertl recived the Nobel Prize “for his studies of chemical processes on solid surfaces” showing the on-going validity of the concept.

1.2.2. Industrial Developments

Prior to the Second World War the chemical industry was mainly coal-based with a strong emphasis on production of ammonia, nitric acid, hardened fat and methanol synthesis. In the 50s the rapid expansion of the petrochemical industry (based on oil and natural gas) resulted in the production of new fuels and synthetic materials and to the growing significance of catalyzed processes as selective oxidations and hydroformylations. Major advances have been made among which one can focus on the Ziegler-Natta catalysis, steam reforming with NiK2Al2O3, catalytic cracking with zeolites, low pressure methanol synthesis and metallocene catalysis among many others.¹⁰ Today some 80 % of chemical processes use catalysts whose whole sell price corresponds to less than 1 % of their generated revenue. However, despite the

8 Roberts, M.W. Catalysis Lett. 2000, 67, 1-4.

9 Nobel Lectures, Chemistry 1901-1921, Elsevier Publishing Company, Amsterdam, 1966.

wide investments by both governments and industry, catalytic enantioselective industrial processes remain quite rare compared to other processes yielding achiral or racemic products.

1.3. Modern Applications of Asymmetric Catalysis

In this section only selected examples of applications for asymmetric catalysis will be briefly discussed in an attempt to show the width of the scope of synthetic catalytic methodologies.

1.3.1. Asymmetric Organocatalysis

The first example of an asymmetric organocatalyzed reaction¹¹ dates back to 1912 with the report of Bredig of the effect of alkaloids on the addition of HCN onto benzaldehyde.¹² The yield was modest but the product was optically active and its optical activity of opposite sign when using quinine or quinidine as catalyst.

NH CO₂H H

O

OBn OH

OBn

OH NO2

Ph

R¹ R² O

ONHPh

H N

NH CO2Bn

CO₂Bn O

H

O OH

H3C O

NO₂ NHAr

α-oxyaldehyde OH

dimerization up to 99 %ee

Intermolecular Michael reaction

up to 23 %ee α-aminooxylation

up to > 99 %ee

α-amination up to 96 %ee Mannich reaction up to > 99 %ee Intermolecular

cross-aldol reaction up to 97%ee

As catalyst

Scheme 1-4: Selected (S)-proline catalyzed reactions.

However the field did not really develop until the 70s and the Hajos-Parrish-Eder-Sauer- Weichert reaction: a proline catalyzed intramolecular aldol reaction.¹³ Since that time, proline (and its derivatives) has become a versatile and widely used catalyst providing the desired products with high selectivity (Scheme 1-4).¹⁴

11 For recent reviews on organocatalysis see : (a) Shi, Y. Acc. Chem. Res. 2004, 37, 488-496. (b) Chem. Rev 2007, 107, (whole issue 12). (c) Enantioselective Organocatalysis, Dalko, P.I. Ed.;Wiley-VCH: Weinheim Germany, 2007.

12 (a) Bredig Ber. 1908, 41, 752. (b) Bredig Biochem. Zeit. 1913, 46, 7.

13 (a) Eder Angew. Chem. Int. Ed. Engl. 1971, 10, 496-497. (b) Hajos J. Org. Chem. 1974, 39, 1615-1621.

14 (a) Mannich reaction: List, B.; Pojarliev, P.; Biller, W. T.; Martin, H. J. J. Am. Chem. Soc. 2002, 124, 827-833. (b) α- Amination: List, B. J. Am. Chem. Soc. 2002, 124, 5656-5657. (c) α-Aminoxylation: Zhong, G. Angew. Chem. Int. Ed. 2003, 42, 4247-4250; Brown, S. P.; Brochu, M. P.; Sinz, C. J.; MacMillan, D. W. C. J. Am. Chem. Soc. 2003, 125, 10808-10809;

Bøgevig, A.; Sunden, H.; Córdova. A. Angew. Chem. Int. Ed. 2004, 43, 1109-1112. (d) Michael addition: List, B.; Pojarliev,

1.3.2. Asymmetric Organometallic Catalysis

The major advantage of asymmetric organometallic catalysis resides in the use of the reactivity of organometallic species in order to obtain reactions that are sometimes not accessible via classical organic chemistry. In addition, in the case of homogeneous catalysis, the use of soluble catalysts, by their easier synthesis, opens up perspectives for “rational”

structural modifications of both ligand and metal to reach improved activity and selectivity.

The first example of an enantioselective reaction catalyzed by an organometallic complex was reported by Nozaki and Noyori for styrene cyclopropanation with a phenol-imine/copper complex.¹⁵ In the last 40 years tremendous advances in this field have been made and which can be emphasized by the Nobel prizes in 2001 of Knowles and Noyori¹⁶ “for their work on chirally catalyzed hydrogenation reactions” and of Sharpless¹⁷ “for his work on chirally catalyzed oxidation reactions”. Asymmetric homogeneous catalysis has now become a versatile tool for the modern chemist as exemplified by the synthesis of (–)-salicylihamlamide by Fürstner which is strongly based on organometallic catalysis for several key steps.¹⁸ The field has also expanded to industrial applications (Scheme 1-5).¹⁹ For instance, Novartis has developed the synthesis of (S)-metolachlor by an asymmetric iridium catalyzed hydrogenation process (herbicide, 10000 tons/year)²⁰ and Takasago uses an enantioselective rhodium catalyzed allylic amine isomerization for the synthesis of (–)-menthol (2000 tons/year).²¹

OH NEt₂

NEt₂ [Rh-(S)-BINAP]⁺

(-)-menthol 97.6%ee

ton 400000 tof 1300 h^-1 N

O

H2, [Ir-xyliphos]

acid, I2

HN O

80%ee, ton >1000000, tof 180000 h^-1

OH O

HN O

OH [Pd] cat.

[Cu] cat.

[Ru] cat.

[Ru] cat.

[Ru] cat.

[Pd] cat.

[Cr]

Fürstner's synthesys of (-)-salicylihalamide

Ciba-Geigy/Novartis (S)-metolachlor synthesis

Takasago (-)-menthol synthesis

Scheme 1-5: Fürstner’s synthesis of (–)-salicylihamlamide and selected industrial catalytic processes.

F.; MacMillan, D. W. C. Angew. Chem. Int. Ed. 2004, 43, 2152-2154. (f) Cross-aldol reaction: Northrup, A. B.; MacMillan, D. W. C. J. Am. Chem. Soc. 2002, 124, 6798-6799.

15 (a) H. Nosaki, H. Takaya, S. Moriuti, R. Noyori, Tetrahedron 1968, 24, 3655-3669. (b) H. Nosaki, S. Moriuti, H. Takaya, R. Noyori, Tetrahedron Lett. 1966, 22, 5239-5243.

16 (a) Knowles, W. S. Angew. Chem. Int. Ed. 2002, 41, 1998-2007. (b) Noyori, R. Angew. Chem. Int. Ed. 2002, 41, 2008- 2022.

17 Sharpless, K. B., Angew. Chem. Int. Ed. 2002, 41, 2024-2032.

18 A. Fürstner, T. Dierkes, O. R. Thiel, G. Blanda, Chem. Eur. J. 2001, 7, 5286-5298.

19 Blaser, H. U.; Studer, M. Chirality 1999, 11, 459-464. Blaser, H. U. Chem. Commun. 2003, 293-296.

20 (a) Spindler, F.; Pugin, B. (Ciba-Geigy A.-G., Switzerland). (b) Pat. 87-810435256982, 1988. Spindler, F.; Pugin, B.;

Jalett, H.-P.; Buser, H.-P.; Pittelkow, U.; Blaser, H.-U. Chemical Industries (Dekker) 1996, 68, 153.

2. Metal Catalyzed Allylic Substitutions

If knowledge can create problems, it is not through ignorance that we can solve them.

Isaac Asimov (1920-1992)

Enantioselective metal catalyzed allylic substitution and rearrangement reactions constitute too wide a field to be exhaustively described in this chapter. This introduction will thus mainly focus on enantioselective metal catalyzed reactions of non-symmetrically substituted substrates with an emphasis on palladium and ruthenium as metal sources. It will only highlight a few selected historical results or important breakthroughs. The addition of carbon nucleophiles will be primarily stressed but can not be exclusively treated in this overview.

However, many more detailed reviews have been published in the recent years with a much broader scope of substrates, metal sources and nucleophiles.^1,2,3

2.1. Preamble

Transition metal catalyzed allylic substitutions are widely used in organic synthesis.⁴ Indeed, the allylic moiety combined with a stereogenic center is an important intermediate in many organic syntheses as the remaining carbon-carbon double bond allows a large variety of functionalisations.⁵ Starting either from branched or linear substrates, a common π-allyl (or σ,π-) metal-complex is formed (Scheme 2-1) onto which a nucleophile is liable to add in the

1 The enantioselective allylic substitutions have been widely studied. For reviews, see: (a) Frost, C. G.; Howarth, J.; Williams, J. M. J. Tetrahedron: Asymmetry 1992, 3, 1089-1122. (b) Trost, B. M.; Van Vranken, D. L. Chem.

Rev. 1996, 96, 395-422. (c) Johannsen, M.; Jørgensen, K. A. Chem. Rev. 1998, 98, 1689-1708. (d) Pfaltz, A.;

Lautens, M. In Comprehensive Asymmetric Catalysis, Vol 2; Jacobsen, E. N.; Pfaltz, A.;Yamamoto, H., Eds.;

Springer: Berlin Germany, 1999, 833–884. (e) Trost, B. M.; Lee, C. B. In Catalytic Asymmetric Synthesis II;

Ojima, I., Ed.; Wiley-VCH: Weinheim Germany, 2000, 593-650. (f) Trost, B. M. Chem. Pharm. Bull. 2002, 50, 1. (g) Trost, B. M.; Crawley, M. L. Chem. Rev. 2003, 103, 2921-2944. (h) Lu, Z.; Ma, S. M. Angew. Chem. Int.

Ed. 2008, 47, 258-297.

2 For reviews on ligands see: (a) Dai, L. X.; Tu, T.; You, S. L.; Deng, W. P.; Hou, X. L. Acc. Chem. Res. 2003, 36, 659-667. Hayashi, T. Acc. Chem. Res. 2000, 33, 354-362. Helmchen, G.; Pfaltz, A. Acc. Chem. Res. 2000, 33, 336-345. McManus, H. A.; Guiry, P. J. Chem. Rev. 2004, 104, 4151-4202. Desimoni, G.; Faita, G.;

Jorgensen, K. A. Chem. Rev. 2006, 106, 3561-3651. Trost, B. M.; Machacek, M. R.; Aponick, A. Acc. Chem.

Res. 2006, 39, 747-760.

3 For reviews on applications see: (a) Braun, M.; Meier, T. Angew. Chem. Int. Ed. 2006, 45, 6952-6955.

Graening, T.; Bette, V.; Neudorfl, J.; Lex, J.; Schmalz, H. G. Org. Lett. 2005, 7, 4317-4320. Trost, B. M. J. Org.

Chem. 2004, 69, 5813-5837. Tunge, J. A.; Burger, E. C. Eur. J. Org. Chem. 2005, 1715-1726.

4 (a) B. M. Trost and C. Lee, in Catalytic Asymmetric Synthesis, ed. I. Ojima, Wiley-VCH, New York, 2nd Ed, 2000, 593–649; (b) A. Pfaltz and M. Lautens, in Comprehensive Asymmetric Catalysis I-III, ed. E. N. Jacobsen, A. Pfaltz and H. Yamamoto, Springer, Berlin, 1999, 833–884.

5 (a) Söll, H. In Houben-Weyl, 4th ed. Vol. V, 1b; Thieme: Stuttgart, 1972, 946. (b) Comprehensive Organic Synthesis, Vol. 4; Trost, B. M.; Fleming, I., Eds.; Pergamon: Oxford, 1991, Chap. 4. (c) Comprehensive Organic Synthesis, Vol. 7; Trost, B. M.; Fleming, I., Eds.; Pergamon: Oxford, 1991, Chap. 3.

least substituted position, yielding in the linear regioisomer (l), or the more substituted position, giving the branched regioisomer (b). Mono-substituted allylic substrates have drawn attention the last years because the control of the regioselectivity of the reaction in favor of the branched chiral product remained challenging. Recent developments have provided methodologies where the substitution of the substrate, the nature of the metal and its ligands play a crucial role: the fact that only catalytic amounts of the transition metal are required and the possibility of tuning the reactivity by means of suitable ligands have definitely contributed to the success of this methodology.

R LG

R LG

[M]

R

[M] R

R Nu Nu^-

LG^- π-allyl intermediate

Nu

b

l b

l

Scheme 2-1: General scheme for transition metal catalyzed allylic substitutions.

2.2. Palladium catalyzed allylic substitutions

One of the most documented,^1,6 and historically the first, metal used for allylic substitutions is palladium. This reactivity was discovered by Tsuji⁷ and thoroughly developed by the group of Trost since the seventies.⁸ This paragraph will thus set the basis for the analysis of mechanistic issues which are common to most of the metal-catalyzed allylic substitutions.

2.2.1. General Mechanism

The reaction, which general course is outlined in Scheme 2-2, starts with the complexation of the allylic substrate onto an unsaturated Pd(0) species. Allylic acetates and carbonates are the most widely used substrates due to the ease of the ionisation that allows the formation of a π- allyl complex through oxidative addition. These Pd(II) π-allyl complexes can then isomerize via a π−σ−π rearrangement before the addition of the nucleophile and finally decomplexation of the product to regenerate the active Pd(0) species. The general catalytic cycle of the Pd- catalyzed asymmetric allylic substitution thus offers at least four opportunities for

6 (a) Tenaglia, A.; Heumann, A. Angew. Chem. Int. Ed. 1999, 38, 2180-2184. Agrofoglio, L. A.; Gillaizeau, I.;

Saito, Y. Chem. Rev. 2003, 103, 1875-1916.

7 (a) Tsuji, J.; Shimizu, I.; Minami, I.; Ohashi, Y.; Sugiura, T.; Takahashi, K. J. Org. Chem. 1985, 50, 1523- 1529. Tsuji, J.; Takahashi, H.; Morikawa, M. Tetrahedron Lett. 1965, 4387.

8 (a) Trost, B. M. Tetrahedron 1977, 33, 2615-2649. Trost, B. M. Acc. Chem. Res. 1980, 13, 385-393. Trost, B.

M.; Murphy, D. J. Organometallics 1985, 4, 1143-1145. Trost, B. M.; Strege, P. E. J. Am. Chem. Soc. 1977, 99, 1649-1651. Trost, B. M.; Verhoeven, T. R. J. Am. Chem. Soc. 1980, 102, 4730-4743.

enantiodiscrimination (see section 2.2.3). In some instances, the stereochemistry of the incoming nucleophile can also be set in the same step providing a fifth possibility.

[Pd⁺] Pd

L' L

R LG

R'

R LG

R' [Pd]

R R'

R R'

[Pd⁺]

LG^- Nu^-

R ∗ R' Nu [Pd]

R' R ∗

Nu [Pd]

or R ∗ R'

Nu R'

R ∗ Nu

or

Coordination Decoordination

Nucleophilic Addition

Oxidative Addition

Isomerization

Scheme 2-2: General scheme for transition metal catalyzed allylic substitutions.

2.2.2. Structure of Metal-Allyl Complexes

Furthermore, to gain insight into the nature of the stereodetermining event, one needs to determine the structure of the lowest energy diastereomeric transition states. However, this is not experimentally easy since only the ground state metal-olefin or metal-π-allyl complexes can, in some cases, conveniently be observed by X-ray crystallography⁹, mass spectrometry¹⁰ or NMR spectroscopy.¹¹ Though information concerning the structure of olefin complexes remains scarce,¹² many X-ray structures of metal-π-allyl complexes have been studied.⁹ However the influence of the ligands on the environment of the metal and more importantly its changes during the course of the reaction remain difficult to predict with certainty. Thus the crucial information about the exact structure of the lowest energy transition state is most

9 (a) Allured, V. S.; Kelly, C. M.; Landis, C. R. J. Am. Chem. Soc. 1991, 113, 1-12. Chan, A. S. C.; Pluth, J. J.;

Halpern, J. J. Am. Chem. Soc. 1980, 102, 5952-5954. Fiaud, J. C.; Aribizouioueche, L. J. Chem. Soc. Chem.

Commun. 1986, 390-392. Hayashi, T.; Yamamoto, A.; Ito, Y.; Nishioka, E.; Miura, H.; Yanagi, K. J. Am. Chem.

Soc. 1989, 111, 6301-6311. Lloyd-Jones, G. C.; Pfaltz, A. Zeit. Naturforsch. 1995, 50b, 361-367. Rappe, A. K.;

Casewit, C. J.; Colwell, K. S.; Goddard, W. A.; Skiff, W. M. J. Am. Chem. Soc. 1992, 114, 10024-10035. Togni, A.; Rihs, G.; Pregosin, P. S.; Ammann, C. Helv. Chim. Acta 1990, 73, 723-732. Trost, B. M.; Breit, B.; Peukert, S.; Zambrano, J.; Ziller, J. W. Angew. Chem. Int. Ed. Engl. 1995, 34, 2386-2388. Von Matt, P.; Lloyd-Jones, G.

C.; Minidis, A. B. E.; Pfaltz, A.; Macko, L.; Neuburger, M.; Zehnder, M.; Ruegger, H.; Pregosin, P. S. Helv.

Chim. Acta 1995, 78, 265-284.

10 Muller, C. A.; Pfaltz, A. Angew. Chem. Int. Ed. 2008, 47, 3363-3366.

11 Zalubovskis, R.; Bouet, A.; Fjellander, E.; Constant, S.; Linder, D.; Fischer, A.; Lacour, J.; Privalov, T.;

Moberg, C. J. Am. Chem. Soc. 2008, 130, 1845-1855.

12 Hodgson, M.; Parker, D.; Taylor, R. J.; Ferguson, G. J. Chem. Soc. Chem. Commun. 1987, 1309-1311.

often only postulated. Still, much information can be gathered to rationalize the different mechanistic theories.

2.2.2.1. ηηηη³-ηηηη¹-ηηηη³ isomerization

One crucial aspect of palladium catalyzed allylic substitution reactions is that, during the course of the reaction, ligands may dissociate, re-associate, exchange and/or change in conformation and geometry. This state of dynamic equilibrium is key to the selectivities observed.

R' R

H H H B

A R R'

H

H H

B A

R R' H

H H

η³-η¹

A B

R H H C-C rotation

R'

B A

R' H

H

R H

η³-η¹

syn anti

anti,syn-exo syn,sy n-endo

Pd-C rotation

A B A B

R' R H

H

syn,sy n-exo η³-η¹ H

syn syn

path a

pathb

: Metal A,B: ligands

1

1

1

1 1

1

3 3

3

3

3

3

Scheme 2-3: η³-η¹-η³ isomerization and nomenclature of a π-allyl complex.

An important nomenclature needs to be introduced at this point: (i) the substituents of a π- allyl are named anti and syn according to their position respective to the central allylic substituent (Scheme 2-3), (ii) the π-allyl is named exo or endo when the central allylic substituent is pointing respectively opposite or towards the concave face of the metal complex. On the time scale of a typical alkylation reaction, the syn and anti substituents in a palladium π-allyl complex can exchange hundreds of times faster than the alkylation.

Two possible isomerization pathways have been shown. In the first case (path a) the ligands of the palladium and the substituents of the π-allyl fragment keep the same relative configuration (bold substituents remain on the same side). This has two consequences: the bold R group exchanges position from syn to anti and the conformation of the π-allyl changes from endo to exo but C¹ and C³ globally remain at the same position. The stereospecificity of this isomerization was shown by Togni and collaborators in the case of an allyl-palladium Josiphos complex.¹³ On the time scale of the nOe experiments, the carbon trans to the dicyclohexylphosphino group (C¹) always remains in the same position (Scheme 2-4).

13 Breutel, C.; Pregosin, P. S.; Salzmann, R.; Togni, A. J. Am. Chem. Soc. 1994, 116, 4067-4068.

η η η

η³-ηηηη¹ ηηηη¹-ηηηη³

Rotation around C-C bond PPh2

PCy₂

Fe Pd P

Ph2

PCy₂

Fe Pd P

Ph₂ PCy2

Fe Pd

nOe nOe

1

1 3 3

1 3

Scheme 2-4: Dynamics of a Josiphos palladium π-allyl complex.

Another type of isomerization is an apparent rotation of the π-allyl which involves a rotation around the metal-carbon single bond in the η¹ complex. In this case there is no anti/syn isomerization of the allyl substituents but an overall rotation of the allyl fragment occurs (bold substituents on opposite sides – Scheme 2-2, path b). Helmchen has shown that this mechanism takes place in the isomerization of (phosphinoaryl)oxazoline (Phox) palladium diphenylallyl complexes (Scheme 2-5).¹⁴

O N PPh₂ Pd

η ηη

η³-ηηηη¹ ηηηη¹-ηηηη³

Rotation around Pd-C bond

1 3

Ph Ph

O N PPh₂ Pd 1

3

Ph Ph O N PPh₂

Pd

1 3

Ph Ph

Scheme 2-5: Dynamics Phox palladium π-allyl complex.

This isomerization can also occur through pseudorotation of the ligands with the participation of a coordinating counterion¹⁵ or by decoordination of one of the other ligands of the metal.¹⁶

2.2.3. Enantiodiscriminating Steps

LG

Coordination on enantiotopic faces

of the olefin

M M

LG LG

Oxidative addition on enantiotopic leaving groups

M M

Isomerization to enantiotopic faces

of theπ-allyl

M

Nu^-

Addition of nucleophile on enantiotopic termini

of theπ-allyl

M

-O

Allylation on enantiotopic faces

of the nucleophile

I II III IV V

Scheme 2-6: Sources for Enantiodiscrimination in metal-catalyzed allylic substitutions.

2.2.3.1. Enantiofacial Complexation and Ionization (I)

The complexation of the olefin to the metal is the first potential source of stereoselection.

Indeed, unless the olefin is symmetrically substituted, the complexation of the olefin to the

14 Sprinz, J.; Kiefer, M.; Helmchen, G.; Huttner, G.; Walter, O.; Zsolnai, L.; Reggelin, M. Tetrahedron Lett.

1994, 35, 1523-1526.

15 (a) Andersson, P. G.; Harden, A.; Tanner, D.; Norrby, P. O. Chem. Eur. J. 1995, 1, 12-16. (b) Gogoll, A.;

Ornebro, J.; Grennberg, H.; Bäckvall, J. E. J. Am. Chem. Soc. 1994, 116, 3631-3632. (c) Hansson, S.; Norrby, P.

O.; Sjogren, M. P. T.; Akermark, B.; Cucciolito, M. E.; Giordano, F.; Vitagliano, A. Organometallics 1993, 12, 4940-4948.

16 (a) Albinati, A.; Kunz, R. W.; Ammann, C. J.; Pregosin, P. S. Organometallics 1991, 10, 1800-1806. (b) Churchil, M. R.; O'Brien, T. A. J. Chem. Soc. A 1970, 206.

metal will yield a planar chiral complex. The stability of such metal complexes is very much depending on the electronic and steric properties of the olefin.¹⁷ For example electron withdrawing groups on the olefin will enhance the stability of the complex (due to better π- back-bonding from the metal into the lower LUMO of the allylic ligand) whereas bulky groups will destabilize the complex via unfavorable steric interactions.

R % ee σ

4-O2N-PhCO 22 0.78 4-CN-PhCO 60 0.63

PhCO 76 0.00

4-H3C-PhCO 80 -0.17 4-H3CO-PhCO 90 -0.27

Table 2-1: Examples of enantioselective complexation and ionization.

This question was investigated by Fiaud et al. (Table 2-1) for the palladium-catalyzed allylic alkylation of esters using BINAP as chiral ligand.¹⁸ The selectivity of the process was found to be very sensitive to the reaction conditions and the nature of the leaving group in particular:

enantioselectivities in this system were found to approximately linearly correlate with the electronic properties of the leaving benzoate group (Hammett σ value). There is no direct evidence for selective complexation as direct source of enantioselection in metal catalyzed allylic substitutions; but since the olefin-complex serves as precursor to the ionization step, these two sources of selectivity cannot be considered separately.

2.2.3.2. Ionisation of Enantiotopic Leaving Groups (II)

Type II asymmetric induction depends on the ability of the catalyst to promote differential ionization of enantiotopic leaving groups. As shown in Scheme 2-6 (II), the metal coordinates to the face of the olefin opposite to the leaving groups and the oxidative addition can then occur with departure of one of the two enantiotopic leaving groups. Many ligands have been used but the most successful family is based on a combination of 2- (diphenylphosphino)benzoic acid (DPPBA)¹⁹ and enantiopure diols or diamines possessing a C2-symmetry; this allows many straightforward variations (Scheme 2-7). Two cases can be

17 (a) Tolman, C. A. J. Am. Chem. Soc. 1974, 96, 2780-2789. (b) White, D.; Coville, N. J. Adv. Organomet. Chem.

1994, 36, 95.

18 (a) Fiaud, J. C.; Legros, J. Y. J. Org. Chem. 1990, 55, 4840-4846. (b) Legros, J. Y.; Fiaud, J. C. Tetrahedron 1994, 50, 465-474.

19 (a) Hoots, J. E.; Rauchfuss, T. B.; Wrobleski, D. A. Inorg. Synth. 1982, 21, 175-179. (b) Jeffery, J. C.;

Rauchfuss, T. B.; Tucker, P. A. Inorg. Chem. 1980, 19, 3306-3316. (c) Rauchfuss, T. B. J. Organomet. Chem.

1978, 162, C19-C22.

t-Bu OR

NaCH(CO2Me)2 4 mol% Pd(dba)2 4 mol% (R)-BINAP

dioxane, RT

t-Bu t-Bu

CO2Me MeO2C

CO2Me CO2Me

major minor

distinguished: (a) asymmetric induction onto symmetrically 1,3-disubstituted olefins (Table 2-2)²⁰ or (b) asymmetric induction onto symmetrically 1,1-disubstituted olefins (Table 2-3).²¹

O X P

Ph Ph

O X

P Ph Ph

NH2

H2N

Ph H2N

Ph NH2

H2N NH2

O O

O O O O

L*

X X

=

L1 L2 L3 L4

Scheme 2-7: DPPBA based chiral ligands for Pd-catalyzed asymmetric allylic substitutions.

n Ligand % yield % ee 1 L1 100 (+)-64

1 L2 97 (+)-78

1 L3 91 (–)-79

1 L4 94 (–)-88

2 L1 82 97

3 L1 82 95

Table 2-2: Examples of intramolecular asymmetric induction onto symmetrically 1,3-disubstituted olefins.

R R’ NaNu % yield % ee

Ph CH3 NaCH3C(CO2CH3)2 92 95 i-Pr CH3 NaCH3C(CO2CH3)2 93 95 CH3 CH3 NaCH3C(CO2CH3)2 99 92 CH3 C2H5 NaCH3C(CO2CH3)2 99 92 CH3 CH3 NaCH3C(SO2Ph)2 99 67

Table 2-3: Examples of asymmetric induction onto symmetrically 1,1-disubstituted olefins.

20 (a) Trost, B. M.; Sudhakar, A. R. J. Am. Chem. Soc. 1987, 109, 3792-3794. (b) Trost, B. M.; Sudhakar, A. R.

J. Am. Chem. Soc. 1988, 110, 7933-7935. (c) Trost, B. M.; Vanvranken, D. L. J. Am. Chem. Soc. 1990, 112, 1261-1263.

21 (a) Trost, B. M.; Lee, C. B.; Weiss, J. M. J. Am. Chem. Soc. 1995, 117, 7247-7248. (b) Trost, B. M.;

Vercauteren, J. Tetrahedron Lett. 1985, 26, 131-134.

R H

OCOR' OCOR'

2.5 mol% (dba)₃Pd₂CHCl₃ 7.5 mol%2

NaNu THF R.T.

R H

OCOR' Nu O

O O

TsHN NHTs O

2.5 mol% (dba)3Pd2CHCl3 7.5 mol%L*

THF R.T.

O N O Ts

n n

2.2.3.3. Enantiofacial Isomerization of πππ-Allyl Complexes (III) π

H H A B

Nu

B A

Nu B A

Nu B A

Nu A B

Nu

A B

Nu B A

Nu B A

Nu

H H

H H A B

Nu

A B

Nu B A

Nu B A

Nu

H H H

H H

H

syn,syn syn,syn anti ,syn ant i,syn anti,anti anti ,anti

LG LG

B A

or

endo

exo

C1-symmetric

Scheme 2-8: Some of the possible complexes of unsymmetrical π-allyl systems and nucleophile attacks.

If both terminal positions of the allyl fragment are disymmetrically substituted and the ligands are not C₂-symmetric, a complex situation with up to 16 equilibrating π-allyl complexes²² occurs (Fig 2-8). In addition for each case, two different trajectories of the nucleophile can be envisaged depending on the terminus of attack as shown in Scheme 2-9.²³

NaCH(CO2Me)2 [{η³-C3H5Pd(dba)}2]

L10 THF 40°C

OAc MeO

MeO

MeO

OMe MeO

O O

O O

MeO OMe

N PPh2

Fe

L10 PPh2 OH

OH

44 % yield; 95 %ee 56 % yield; 80 %ee

Scheme 2-9: Example of dissymmetrically substituted diaryl allylic acetate.

In this case, the result implies that each enantiomer of the starting material is the precursor of one of the regioisomeric products and that racemization of neither starting material nor the reactive intermediate is occurring. This example is however misleading since the regiocontrol remains a general problem for Pd-catalyzed allylic substitution with dissymmetrical substrates since the more hindered position is generally inaccessible for nucleophilic attack as shown in

22 With C2-symmetric ligands or symmetrically substituted allylic subtrates the situation becomes much simpler.

23 Hayashi, T.; Yamamoto, A.; Hagihara, T.; Ito, Y. Tetrahedron Lett. 1986, 27, 191-194.