Palladium-Catalyzed Tsuji-Trost Allylation of J-Borylated Allyl Acetates

ANNÉE 2013

THÈSE / UNIVERSITÉ DE RENNES 1 sous le sceau de l’Université Européenne de Bretagne

pour le grade de DOCTEUR DE L’UNIVERSITÉ DE RENNES 1 Mention : CHIMIE Ecole doctorale Sciences de la Matière de Rennes

présentée par Krishna Kishore Kukkadapu

UMR 6510 CNRS Chimie et Photonique Moléculaires

UFR Sciences et Propriétés de la Matière

Thèse soutenue à Rennes Gamma-borylated le Jeudi 6 juin 2013 allylic acetates as 3 devant le jury composé de : Véronique BELLOSTA carbon functionalized Professeur –ESPCI / rapporteur units : synthesis and Stéphane PELLET-ROSTAING Chargé de recherche CNRS à l’ICSM-CEA / applications rapporteur Florence MONGIN Professeur à l’Université de Renne1 / / examinateur

Mathieu PUCHEAULT Chargé de recherche CNRS / examinateur

Michel VAULTIER Directeur de recherche CNRS/ / directeur de thèse

Table of contents :

Résumé de la thèse en français 5

Acknowledgements: 22

Abbreviations: 24

General Introduction: 27

PART ͲA 30

Chapter I: Bibliography 30

I. 1. Synthesis &applications of JͲborylated allylic electrophiles: 31

I. 1. i. Synthesis of JͲborylated allylic electrophiles: 31

I. 1. ii. Applications of JͲborylated allylic electrophiles: 33

I. 1. ii. a. In iridium catalysis: 33

I. 1. ii. b. In copper catalysis: 37

I. 1. ii. c. In palladium catalysis: 39

I. 1. ii. d. In Grignard reaction: 41

I. 1. ii. e. In Diels Alder reaction: 42

I. 1. ii. f. In Mitsunobu reaction: 43

I. 1. ii. g. In cyclopropane synthesis: 46

I. 2. Tsuji ͲTrost Allylation: 48

I. 2. i. Stereochemistry in Tsuji ͲTrost allylation: 51

I. 2. ii. Regioselectivity in Tsuji ͲTrost allylation: 52

I. 2. iii. Asymmetric allylic alkylation (AAA): 54

I. 2. iv. Application in natural product synthesis: 58

I. 3. Selectivity issues in palladium catalyzed Tsuji ͲTrost allylation of JͲborylated allyl 61 acetates:

Objectives: 62

Chapter II: Palladium catalyzed Tsuji ͲTrost allylation of JͲborylated allyl acetates 64

II. 1. Synthesis of JͲborylated allyl acetates: 65

II. 2. Reactivity of JͲborylated allyl acetates under palladium catalysis: 67

II. 2. i. Regioselectivity with carbon nucleophiles: 69

II. 2. ii. One pot allylation followed by Suzuki ͲMiyaura cross coupling: 72

II. 2. iii. Application of aone Ͳpot strategy: 74

II. 2. iv. Stereoselectivity: 74

II. 2. v. Regioselectivity with nitrogen nucleophiles: 79

II. 2. vi. One Ͳpot allylation followed by Suzuki ͲMiyaura cross coupling: 83

II. 2. vii. Stereoselectivity: 84

II. 3. Some failure attempts in order to use JͲborylated allylic derivatives: 87

Conclusion: 90

Chapter III: Chemo enzymatic resolution of JͲborylated allylic alcohols in continuous 91 flow systems using ionic liquids &sc CO 2

Introduction: 92

III. 1. Ionic liquids as solvents in Green biocatalysis: 92

III.2. Green biocatalysis in super critical carbon dioxide (sc CO 2): 93

III. 3. Literature data on the mechanism of resolution using Candida Antartica Lipase : 94

III. 4. Kinetic resolution of JͲborylated allylic alcohols in ionic liquids: 96

III. 5. Enzyme activity in Ionic liquids: 98

III. 6. Optimization of kinetic resolution: 100

III.7. Effect of water in kinetic resolution: 102

III.8. Recyclability of ionic liquids: 102

III. 9. Kinetic resolution using continuous flow systems: 103

III. 10. Results and discussion: 104

Conclusion: 107

PART ͲB: Experimental part 108

Compounds synthesized 171

Conclusions and Perspectives 173

6 Juin 2013

Thèse présentée par Mr Krishna Kishore Kukkadapu

Pour l'obtention du grade de Docteur de l'Université de Rennes 1

Résumé de la thèse en français

Introduction générale:

Les boranes vinyliques, les acides boroniques vinyliques et les boronates vinyliques sont des organoboranes où la différence d'électronégativité entre le carbone et le bore est très faible [C (2.55)-B (2.04)] et la liaison entre ces deux atomes est donc peu polaire. Les propriétés caractéristiques du bore permettent de réaliser une grande variété de réactions dans différentes conditions. Beaucoup de groupes de recherche ont exploré les applications synthétiques des organoboranes en synthèse organique. Par exemple les boranes vinyliques peuvent être transformés en les alcènes correspondants par protonolyse, 1 ils peuvent être facilement oxydés avec H 2O2 en présence de base (addition d'un groupe hydroxyle sur la double liaison) pour donner des produits cis-anti Markovnikov. 2 Ils peuvent aussi subir des réactions d'addition pour donner des alcools allyliques, 3 ou des cycloadditions [4+2] pour former deux nouvelles liaisons carbone- carbone via des réactions de Diels-Alder. 4 Les acides

1Brown, H. C.; Zweifel, G. J. Am. Chem. Soc. 1961, 83 , 3834. 2Brown, H. C.; Liotta, R. J. Am. Chem. Soc. , 1979, 101, 96. 3a) Jacob, P.; Brown, H. C. J. Am. Chem. Soc. 1976, 98 , 7832. b) Jacob, P.; Brown, H. C. J. Org. Chem. 1977, 42 , 579. 4a) Matteson, D. S.; Waldbillig, J. O. J. Org. Chem. 1963 , 28 , 366. b) Singleton, D. A.; Martinez, J. P. J. Am. Chem. Soc. 1990, 112, 7423. c) Vaultier, M.; Truchet, F.; Carboni, B. Tetrahedron Lett. 1987, 28 , 4169.

vinylboroniques peuvent être transformés en halogénures vinyliques via une halogénolyse, 5 réagir via une réaction de cyclisation radicalaire utilisant la méthode catalytique de Corey en présence d'un initiateur de réaction radicalaire pour obtenir des diols 1,3- ou 1,4. 6 Ils peuvent participer à des réactions de couplage au palladium de type Suzuki pour former de nouvelles liaisons carbone-carbone. 7 Ils peuvent réagir avec des anhydrides pour donner différentes 8 9 cétones DE -insaturatées via des catalyses au palladium ou au rhodium. Les acides vinylboroniques ont aussi été utilisés pour la formation de nouvelles liaisons carbone-azote, 10 carbone-oxygène, 11 carbone-fluor 12 via des réactions catalysées au palladium ou au cuivre. Les boronates vinyliques ont été employés pour former de nouvelles liaisons carbone-carbone via des couplages de Suzuki- Miyaura. Ils sont employés dans la réaction multicomposant de Petasis 13 pour donner des hétérocycles azotés fonctionnalisés. Ils participent aux réactions de métathèse croisée pour donner des boronates vinyliques hautement fonctionnalisés, 14 ils réagissent facilement avec des carbènes générés à partir de diazos pour donner des cyclopropanes 15 et ceci à travers des catalyses au palladium et au rhodium. Les boronates vinyliques, en réaction avec des oxides de nitrile subissent des réactions de cycloaddition 1,3- dipolaire pour donner des isoxazoles. 16

5Brown, H. C.; Campbell, J. B. J. Org. Chem. 1980 , 45 , 389. 6Batey, R. A.; Smil, D. V. J. Angew. Chem. Int. Ed. 1999, 38 , 1798. 7Suzuki, A.; Miyaura, N. Chem. Rev . 1995, 95 , 2457. 8Yamamoto, A.; Ryuki, K.; Shimizu, I. Helvetica Chimica Acta . 2001, 84 , 2996. 9Frost, C. G.; Wadsworth, K. J. Chem. Commun. 2001, 2316. 10 Tao, C-Z.; Xin, C.; Juan, L.; Guo, Q-X. Tetrahedron Letters. 2007, 48 , 3525. 11 Lam, P. Y. S.; Vincent, G.; Clark, C. G.; Deudon, S.; Jadhav, P. K. Tetrahedron Lett. 2001, 42 , 3415. 12 Takeru, F.; Tobias, R. Org. Lett . 2009 , 11 , 2860. 13 a) Petasis, N. A.; Zavialov, I. A. J. Am. Chem. Soc. 1977, 119, 445. b) Batey, R. A.; Mackay, D. B.; Santhakumar, V. J. Am. Chem. Soc. 1999, 121, 5075. 14 a) Morril, C. ; Grubbs, R. H. J. Org. Chem . 2003 , 68 , 6031. b) McNulty, L.; Wright. Z. J. Org. Chem. 2010, 75 , 6001. 15 a) Fontani, P.; Carboni, M.; Vaultier, M. Tetrahedron Lett. 1989, 30 , 4815. b) Toshiro, I.; Hiroshi, M.; Shinya, N. J. Org. Chem. 1990, 55, 4986. c) Yasutaka, F.; Hideki, A. Org. Lett . 2008, 10 , 769. 16 Bianchi, G.; Cogoli, A.; Grünanger, P. J. Organomet. Chem. 1966, 6, 598.

Les boronates vinyliques ont aussi été utilisés comme nucléophiles en réaction d'allylation 17 avec catalyse au cuivre ou au palladium.

Les transformations précédentes des organoboranes fournissent des précurseurs importants pour la synthèse totale de molécules bioactives complexes qui ont été utilisées dans les domaines de la médecine, de l'agrochimie, des composés pharmaceutiques et de la chimie fine. Les organoboranes peuvent être synthétisés facilement et ceci les rend particulièrement précieux comme intermediaires clés en synthèse organique. Ils peuvent être obtenus par hydroboration d'alcynes à partir d'alkylboranes. 18 Les acides boroniques vinyliques peuvent être synthétisés par une hydroboration d'alcynes avec des alkoxyboranes, suivie d'hydrolyse. 19 Les boronates vinyliques ont été obtenus via des réactifs organométalliques par transmétallation avec le trimethylorthoborate, 20 ou par hydroboration d'alcynes avec des alkoxyboranes.

L'introduction d'une substitution en position allylique sur des boronates vinyliques leur confère un degré élevé de flexibilité vis-à-vis des applications en synthèse organique. De tels boronates vinyliques J-substitués possèdent plusieurs sites réactionnels ce qui permet de les considérer comme des substrats difficiles en ce qui concerne la sélectivité des réactions (spécialement vis-à-vis des réactions catalysées par les métaux. 21 Peu de groupes de recherche ont exploré les applications de dérivés vinyl boroniques J-substitués en synthèse organique via des réactions de Grignard, Mitsunobu, Diels-Alder, ainsi que des cyclopropanations asymétriques et des réactions catalysées par des métaux de transition.

17 a) Whittaker, A. M.; Richard, P. R.; Lalic, G. Org. Lett. 2010, 12 , 3216. b) Ortar, G. Tetrahedron Lett. 2003 , 44 , 4311. 18 a) Brown, H. C.; Zweifel, G. J. Am. Chem. Soc . 1961, 83 , 3834. b) Brown, H. C.; Moerikofer, A. W. ibid , 1963, 85 , 2063. 19 Shyam, K. G.; Brown, H. C. ibid , 1975, 97 , 5249. 20 Miyaura, N.; Suzuki, A. Chem. Rev . 1995, 95 , 2457. 21 Carosi, L.; Hall, D. G. Angew. Chem. Int. Ed. 2007, 46 , 5913.

Différentes méthodes ont été employées pour leur préparation à partir de J-céto vinylboronates par réduction avec des hydrures ou des dérivés du zinc, 22 par hydroboration d'alcools propargyliques avec soit le pinacol borane ou le di-isopinocamphenyl borane suivie par une refonctionnalisation dans ce dernier cas. 23

Dans notre laboratoire, nous avons développé des réactions catalysées au palladium sur des boronates vinyliques J -substitués et nous nous sommes attachés à étudier en particulier les chimio-, régio- and stéréoselectivités lors de la réaction d'allylation.

Cette thèse est divisée en trois chapitres. Le premier chapitre fait une brève revue de la littérature sur la synthèse et la réactivité de dérivés allyliques J-borylés. Dans le second chapitre notre objectif est d'étudier la possibilité de générer des complexes S-allyl palladium à partir d'acétates allyliques et J -borylés puis d'étudier leur réactivité vis-à-vis d'une variété de réactifs nucléophiles (réaction de couplage de Tsuji-Trost 24 ) en mettant l'accent sur les problèmes de chimio-, régio- et stéréo-selectivités. Le troisième chapitre décrit le dédoublement chimio enzymatique d'alcools allyliques J-borylés dans des systèmes à flux continu utilisant des liquides ioniques et du CO 2 supercritique.

Chapitre-I : Synthèse et applications de dérivés allyliques J-borylés:

L’introduction d’un groupe fonctionnel en position allylique sur des boranes vinyliques est très intéressante car elle permettra d’effectuer une grande variété de réactions, compte tenu de la présence de multiples groupes fonctionnels sur ce synthon. Vaultier et al ont décrit la synthèse d’électrophiles allyliques J-borylés en partant d’alcools propargyliques (Schéma 1). 25

22 Jehanno, E.; Vaultier, M. Tetrahedron Lett. 1995 , 36 , 4439. 23 Fortineau, A.-D.; Robert,M.; Gueguan, J.-P.; Carrie, D.; Mortier, J.; Vaultier, M. C. R. Acad. Sci. Serie IIc 1998 , 1, 253. 24 Trost, B. M.; Matthew, L. C. Chem. Rev . 2003, 2921. 25 (a) Fortineau, A. D.; Robert, M.; Gueguan, J. P.; Carrie, D.; Mortier, J.; Vaultier, M. C. R. Acad. Sci. Serie IIc 1998 , 1, 253.

TMSCl, HMDS pinacolborane OH OTMS

R2 o o R2 o R1 0 C to 50 C,16 h R1 CH 2Cl 2, 0 C to rt, 48 h A 70-96%

O O B OTMS citric acid B OH O O R 2 MeOH, rt 1 h R2 R1 R B 41-58% C 47-82% 1

Entrée R 1 R2 Rendement (%) A B C

a H H 96 41 47

b CH3 H 94 58 82

c Ph H 95 4165

d CH3 CH 3 70 50 74

Schéma 1: Alcools allyliques J-borylés via une hydroboration avec le pinacolborane

Des alcools allyliques J -borylés peuvent aussi être synthétisés par une séquence "one-pot" en trois étapes via l’hydroboration de systèmes propargyliques protégés et en utilisant le dicyclohexylborane. 26

Peu d’applications des alcools allyliques J -borylés ont été présentées dans la littérature. Dennis Hall et al ont décrit la préparation d’allylboronates chiraux D-substitutés, à partir de dérivés allyliques J-borylés, via des alkylations allyliques asymétriques par des catalyseurs à 27, 28 l’iridium ou au cuivre portant des ligands chiraux. Des boronates allyliques D-substitués ont été préparés avec de très hautes énantiosélectivités, jusqu’à 93%, et de bons rendements (jusqu’à 87%). Walsh et al ont décrit une allylation chimiosélective catalysée au palladium sur des réactifs bifonctionnels contenant à la fois un acétate allylique et un ester boronique 29 vinylique [Le groupe partant (acetate) est en E du bore]. Il a été montré que seuls des

(b) Berree, F.; Gernigon, N.; Hercouet, A.; Lin, C-H.; Carboni, B. Eur. J. Org. Chem. 2009, 329. 26 Pietruszka, J.; Witt, A. J. Chem. Soc., Perkin Trans . 1 2000, 4293. 27 Peng, F.; Hall, D. G. Tetrahedron Lett . 2007, 48, 3305. 28 Carosi, L.; Hall, D. G. Angew. Chem. Int. Ed. 2007, 46 , 5913. 29 Hussain, M. M.; Walsh, P. J. Angew. Chem., Int. Ed. 2010, 49 , 1834.

produits d’allylation sont obtenus avec une excellente chimioselectivité et des rendements allant de 65 à 92%. Carboni et al ont décrit l’addition de réactifs organométalliques aux boronates vinyliques possédant un group acetal en position J, qui subit un réarrangement allylique en présence d’acides de Lewis pour former des J-alkoxy allyl boronates avec une haute stéréoselectivité, l’isomère E étant très majoritaire. 30

Par une simple oxydation, les alcools allyliques J-borylés donnent des borono-3-acroleines qui ont été employées pour préparer des allylboronates cycliques D-chiraux via des cycloadditions d’hétero Diels-Alder avec des éthers d’enol, catalysées par le complexe chiral Cr III de Jacobsen. 31

Des réactions de Mitsunobu sur des alcools allyliques J-borylés avec des nucléophiles tels que l’acide benzoique, des phénols, des N-tosylamines en présence de triphenylphosphine 32 (PPh 3) et de diethyl azodicarboxylate (DEAD) conduisent aux produits de substitution S N2. Par ailleurs, les alcenylboronates peuvent être employés pour la synthèse de derivés cyclopropaniques optiquement purs en utilisant des auxiliaires chiraux. 33 De plus ces boronates peuvent être oxydés pour obtenir les alcools correspondants.

Chapitre II: Allylation de Tsuji-Trost catalysée au palladium sur des acétates

allyliques J-borylés

Des acétates allyliques J -borylés peuvent présenter des réactivités differenciées vis à vis de complexes metalliques, 34 compte tenu de la présence de plusieurs sites réactionnels dans ces synthons et différents aspects de sélectivité sont donc à considérer dans leurs réactions (Schéma 2).

30 Possémé, F.; Deligny, M.; Carreaux, F.; Carboni, B. J. Org. Chem. 2007 , 72 , 984. 31 (a) Gao, X.; Hall, D. G.; Carreaux, F.; Carboni, B. Chem. Eur. J. 2006, 12 , 3132. (b) Favre, A.; Carreaux, F.; Carboni, B. Eur. J. Org. Chem. 2008, 4900. 32 Berree, F.; Gernigon, N.; Hercouet, A.; Carboni, B. Eur. J. Org. Chem. 2009, 329. 33 Luithle, J. E. A.; Pietruszka, J. J. Org. Chem. 1999 , 64 , 8287. 34 Carosi, L.; Hall, D. G.; Angew. Chem. Int. Ed. 2007, 46 , 5913.

(i) Chimioselectivité : réaction de Tsuji-Trost (a) versus couplage de Suzuki (a 1). 1 (ii) Régioselectivité : attaque en position- J (b) versus position- D ( b ) dans l’allylation de Tsuji-Trost (iii) Stéréoselectivité : stéreorétention (c) versus stéréoinversion (c 1) lors de l’addition nucléophile.

Chemoselectivity Regioselectivity Stereoselectivity

OAc II Nu Nu Pd L2 O (a)O (b)O (c) O B B B B O O O O (a 1) (b1) (c1)

OAc Nu Nu O O PdL 2 B B O O

Schéma 2: Problèmes de sélectivité dans les réactions catalysées au palladium sur des acetates -borylés

Dans ce chapitre notre objectif a été d’étudier la possibilité de générer des complexes

S-allyles palladium à partir d’acétates allyliques J -borylés et d’analyser leur réactivité vis-à- vis d’un certain nombre de réactifs nucléophiles (réaction de couplage de Tsuji-Trost 35 ) en incluant les aspects de chimio-, régio- et stéréo-selectivité.

Une allylation chimio-, régio- et stéréo-selective d’acetates allyliques J-borylés a été développée avec des nucléophiles carbonés, azotés et oxygénés. Une substitution ipso de l’acétate a été obtenue, avec une rétention complète de configuration au niveau du centre chiral, conduisant à des boronates vinyliques J-fonctionnalisés. Ces réactions s’effectuent avec de bons rendements et des excès énantiomériques supérieurs à 99% (Schéma 3).

35 Trost, B. M.; Matthew, L. C. Chem. Rev . 2003, 2921.

Une réaction “one pot” de Tsuji-Trost, suivie par un couplage de Suzuki-Miyaura a été mise au point, conduisant aux produits recherchés avec de bons rendements (Schéma 4).

Il est, en particulier, très difficile de contrôler la régioselectivité de l’allylation quand les deux côtés du complexe S portent des groupes aromatiques (Cas 1, Schéma 5). Cette méthode “one pot” est donc particulièrement utile pour réaliser une allylation sélective sur la position choisie et le boronate intermédiaire peut ensuite être transformé en le groupe aryle choisi (Cas 2, Schéma 5).

Cette procédure “one-pot” offre une alternative intéressante pour contrôler la régioselectivité. La réaction tandem “one pot” Tsuji-Trost allylation / couplage de Suzuki-Miyaura entre l'acétate allylique substitué par un phényle, le dimethyl malonate puis l'iodotoluène, donne le produit désiré avec un rendement de 78%, rendement qui est supérieur à celui obtenu lors du processus en deux étapes (45%). De plus, les boronates vinyliques peuvent être transformés en d’autres groupes fonctionnels. Ils peuvent être activés par une catalyse au cuivre 36 pour obtenir des azides vinyliques avec de bons rendements (Schéma 6).

En utilisant des nucléophiles carbonés nous avons pu introduire de la chiralité par allylation asymétrique de substrats racémiques et en utilisant différents ligands chiraux (Schéma 7).

36 Tao, C.-Z.; Guo, Q.-X. Tetrahedron Lett . 2007, 48 , 3525.

Des dérivés J-borylés et fonctionnalisés ont été obtenus avec de bons rendements (jusqu’à 80%) et des excès énantiomériques allant jusqu’à 78%. Les deux isomères ont été synthetisés à partir de l’acetate racémique en utilisant les ligands chiraux appropriés. De la même manière, l’allylation asymétrique d’acétates allyliques J-borylés a été réalisée avec des nucléophiles azotés. Une allylation de type Trost, suivie en “one pot” d’un couplage de Suzuki-Miyaura, a donné les produits désirés avec des énantioselectivités jusqu’à 63% et des rendements élevés (83-90%) (Schéma 8). Ces réactions s’avèrent complètement chimio-, régio- et stéréo-sélectives.

Conclusion:

Une allylation chimio-, régio- et stereo-selective a été mise au point à partir d’acétates 37 allyliques J -borylés et ceci en utilisant des nucléophiles carbonés, ou azotés. Au bilan, nous avons donc réussi à employer un intermédiaire clé à trois atomes de carbone hautement fonctionnalisé de manière chimio-, régio-, et stéréoselective. Les produits obtenus sont

37 Kukkadapu, K. K.; Ouach, A.; Lozano, P.; Vaultier, M.; Pucheault, M. Org. Lett . 2011, 13 , 4132.

susceptibles d’être employés dans une grande gamme de transformations en utilisant le potentiel de la chimie des boronates.

Chapitre III: Dédoublement chimio-enzymatique d'alcools allyliques J-borylés en système à flux continu, utilisant des liquides ioniques et du CO 2 supercritique.

Les solvants jouent un rôle important pour obtenir de bons résultats dans les réactions de chimie organique. Généralement ces solvants organiques sont volatiles et génèrent des résidus organiques qui ne sont pas acceptables en termes environmentaux et doivent donc être évités. Dans un contexte de chimie verte, 38 le remplacement des solvants dangereux par des solvants avec des effets bénins sur l'environnement est un défi très attractif. Ces problèmes ont conduit les chercheurs à identifier des solvants alternatifs pour remplacer les solvants organiques, comme les fluides supercritiques 39 et les liquides ioniques 40 qui paraissent comme les meilleures alternatives.

Les liquides ioniques sont des sels d'oniums à bas points de fusion et composés seulement d'anions et de cations. Ils sont liquides à, ou en dessous de, 100 °C. Les liquides ioniques ne sont pas volatiles et présentent une tension de vapeur très faible. Ils sont très polaires, recyclables et stables thermiquement jusqu'à 400 °C (donc utilisables à hautes températures). Ils peuvent dissoudre des composés organiques et inorganiques. La synthèse de composés énantioenrichis en utilisant les enzymes comme catalyseurs dans des conditions "sans solvant" relève de la biocatalyse "verte". La grande efficacité catalytique des enzymes dans les liquides ioniques est maintenant bien documentée. 41 Cependant, des solvants organiques sont souvent utilisés pour isoler les produits à partir des liquides ioniques, ce qui constitue un inconvénient pour le développement de procédés verts. L'isolement de produits à partir de milieux de type liquides ioniques par un autre solvant vert comme le CO 2 supercritique ( sc CO 2) est considéré

38 Collins, T. Science 2001 , 291, 48. 39 Noyori, R. Chem. Rev. 1999, 99, 353. 40 Riisager, A.; Fehrmann, R.; Haumann, M.; Wasserscheid, P. Top. Catal. 2006, 40 , 91. 41 Lozano, P. Green Chem. 2010, 12, 555.

comme la stratégie la plus intéressante pour développer des procédés chimiques propres et verts.

Ceci est dû à la capacité du sc CO 2 d'extraire, de dissoudre et de transporter des composés chimiques en phase gazeuse, à savoir le gaz CO 2 comprimé. Dans ce contexte, un système hétérogène peut être utilisé avec succès pour des réactions dans sc CO 2. Des systèmes biphasiques, basés sur des liquides ioniques et sc CO 2 représentent des alternatives intéressantes aux solvants organiques pour le design de procédés propres utilisant des biotransformations en environment non-aqueux et conduisant directement à des produits purs. 42 Les enzymes ne perdent pas leur activité quand elles sont supportées sur un milieu liquide ionique, même à des hautes temperatures. Une telle stabilité des enzymes ainsi que l'emploi du sc CO 2 sont les paramètres clés pour la mise en oeuvre d'un processus de bioconversion vert en flux continu.

Dédoublement cinétique d'alcools allyliques J -borylés dans les liquides ioniques: Andrade et al ont décrit la première application des enzymes comme catalyseurs pour la synthèse énantiocontrôlée de composés contenant du bore par une acetylation énantiosélective (via un dédoublement cinétique catalysé par une enzyme) dans du n-hexane solvant. 43

42 Lozano, P.; Vaultier, M. Green Chem. 2007, 9, 780. 43 Andrade, L. H.; Barcellos, T. Org. lett. 2009, 11, 3052.

Dans un tel dédoublement cinétique d'un composé racéemique, le rendement chimique du procédé sera généralement limité à 50%. Différents types d'alcools secondaires (aromatiques, allyliques, aliphatiques) contenant des boronates ont été acetylés en utilisant ce protocole et de hautes sélectivités (> 98%) ont été obtenues. Dans notre laboratoire, nous nous sommes intéressés à l'étude du dédoublement d'alcools allyliques J-borylés dans des conditions sans solvant (Schéma 9).

OH OH OAc OAc (3.0 eq), CAL-B O * O * O B B + B Ionic Liquid, 50 oC, t min O O O (S)-OH (R)-OAc

Schéma 9: Dédoublement cinetique d'alcools allyliques J-borylés avec CAL-B sans solvant. Le dédoublement chimioenzymatique d'alcools allyliques J-borylés par acétylation sélective avec l'acétate de vinyle dans les liquides ioniques a été développé en utilisant Candida Antartica Lipase (CAL-B) comme enzyme à 50 oC. Différents liquides ioniques ont été étudiés en fonction de:

i) Leur longueur de chaine (butyle, octyle, et dodécyle) ii) Le motif cationique: Ammonium: BTMA, TBMA Imidazolium: BMIM Pyrolidinium: BMPy Piperidinium: BMPi

iii) La partie anionique (NTf 2, BF 4, PF 6)

Nous nous sommes donc attachés à optimiser le système catalytique pour avoir des temps de reaction minima, combinés à de bons rendements et de bonnes sélectivités. Les résultats ont été pris sur la base de la formation du produit ( R)-OAc. Différents liquides ioniques ont été testés pour optimiser le dédoublement cinetique. Il faut noter que ces réactions n'ont pas été effectuées sous atmosphère inerte. L'activité enzymatique (présentée en efficacité par milligramme d'enzyme immobilisée utilisée) est un facteur clé pour obtenir un bon dédoublement cinétique. Une activité enzymatique élevée a été trouvée dans le cas des

liquides ioniques contenant NTf 2 par rapport à ceux contenant PF 6 et BF 4. Les rendements faibles obtenus avec les autres liquides ioniques peuvent être dus à la nature hygroscopique de ces derniers conduisant à une absorption d'humidité. La présence d'eau dans le milieu réactionnel peut hydrolyser l'enzyme acetylée en donnant de l'acide acétique, ce qui arrête le processus d'acétylation énantiosélectif. Nos résultats ont démontré une forte activité enzymatique 7.6 (U/mg de IME) pour le liquide ionique [C 12 MIM][NTf 2] (Entrée 3, Tableau 1). Le dédoublement cinétique utilisant les liquides ioniques est réalisé en seulement 2h, alors qu'avec les solvants organiques tels que le n-hexane les temps de réaction sont de 12-14h.

Entrée liquide ionique Activite 'de l' % Rendement a % Rendement a enzyme (%ee a) (%eea) (U/mg IME) at 2 h at 6 h

1. [BMIM][NTf 2] 2.7 45 (>99) 51 (89)

2. [OMIM][NTf 2] 6.3 49 (>99) 50 (>99)

3. [C 12 MIM][NTf 2] 7.6 50 (>99) 50 (>99)

b 4. [BTMA][NTf 2] 2.2 39(>99) 51 (>99)

b 5. [TBMA][NTf 2] 2.4 41(>99) 51 (>99)

6. [BMPy][NTf 2] 2.8 45 (>99) 50 (90)

7. [BMPi][NTf 2] 3.3 48 (>99) 49 (91)

8. [BMIM][PF 6] 3.3 46(88) 49(74)

9. [OMIM][PF 6] 1.8 32(99) 48(99)

10. [C 12 MIM][PF 6] 1.8 40 (99) 49 (85)

11. [BMIM][BF 4] 4.9 44(99) 48(99)

12. [C 12 MIM][BF 4] 1.8 26(99) 29(99) aCette conversion a été évaluée par analyse chromatographique en phase gazeuse sur phase chirale, en se basant sur la formation de l'acétate ( R) au cours de la réaction. bErreur possible sur l'intégration en chromatographie en phase gazeuse sur phase chirale Tableau 1: Activité enzymatique dans les liquides ioniques

Dédoublement cinétique dans des systèmes à flux continu:

Un système à flux continu controlé avec un support hétérogène à 50 0 C a été testé initialement

en utilisant CAL-B et [BMIM][NTf 2] comme support hétérogène (Schéma 10). Un tel procédé ne doit pas générer de sous produit organique et les composés obtenus, après passage à travers le support hétérogène, seront récupérés dans le collecteur. Le sc CO 2 gazeux comprimé sera recyclé vers le cylindre par une condensation. Dans les expériences à l'échelle du laboratoire, ce gaz comprimé sera simplement rejeté dans l'atmosphère.

OH O OAc B CAL ͲB/IL O sc CO 2 produit de départ 50 oC

Résultats et discussion: Les expériences initiales ont visé à l'optimisation du système réactionnel dans des conditions de flux continu et en utilisant un support solide préparé avec CAL-B et [BMIM][NTf 2]. La vitesse de la phase mobile [0.1mL de substrat et 0.9mL de sc CO 2] est de 1mL / min à 100 bar et ceci en maintenant le support hétérogène à 50 0 C. L'activité par gramme d'enzyme utilisée a

été trouvée à 13.3 Pmol/h/g (Tableau 2, entrée 1). Le dédoublement cinétique a été réalisé en continu pendant 8h le premier jour, avec un taux de conversion de 40%. L'activité enzymatique n'a pas changé quand le même support hétérogène a été utilisé une seconde fois pendant une autre opération de 8h le jour suivant, et des résultats identiques ont été obtenus

(Tableau 2, entrée 2). Le troisième jour, nous avons changé la concentration à 12 Pmol/h tout en conservant le même support hétérogène. Cette 3 ème opération a été réalisée pendant 8h. La conversion est restée à 40% alors que l'activité enzymatique a doublé à 26.6 Pmol/h/g (Tableau 2, entrée 3). Cependant, on n'a pas atteint une conversion totale dans ces conditions.

L'étude d'autres liquides ioniques comme [OMIM][NTf2] avec CAL-B comme support hétérogène a par contre donné une conversion complète avec de très bons rendements et des

sélectivités élevées dans des conditions à flux continu (Tableau 2, entrées 4-6). L'activité enzymatique reste la même pendant des temps d'opération longs (jusqu'à 8h) et elle a été trouvée de 9.03 Pmol/h/g (Tableau 2, entrée 4).

Entrée CAL-B Concentration Débit % Conversion Activité durée de sur liquid de l'enzyme réaction ionique ( mol/h) ( L/min) %ee ( mol/ h)

1. [BMIM][NTf 2] 6 0.1 40(99.9) 13.3 8h

2. [BMIM][NTf 2] 6 0.1 40(99.9) 13.3 8h

3. [BMIM][NTf 2] 12 0.1 40(99.9) 26.6 8h

4. [OMIM][NTf 2] 3 0.05 50 (99.9) 9.03 8 h

5. [OMIM][NTf 2] 3 0.05 50 (99.9) 9.03 8 h

6. [OMIM][NTf 2] 6 0.1 50 (99.9) 18.07 8 h

Tableau 2: Dédoublement cinétique en flux continu avec un système sc CO 2/IL Une seconde opération de 8h, à une concentration du substrat de 3 Pmol/h, a donné la même activité enzymatique de 9.03 Pmol / h /g conduisant à un rendement de 50% et une selectivité >99% (Tableau 2, entrée 5). Des études en changeant the flux de substrat de 0.05ml à 0.1ml

(ce qui accroit la concentration à 6 Pmol/h) ont montré que l'activité enzymatique a doublé à 18.07 Pmol/h/g avec un rendement de 50% et une sélectivité >99% (Tableau 2, entrée 6). En conclusion, l'activité enzymatique reste inchangée après 3 jours d'opération en continu et en changeant le flux et la concentration.

Conclusion:

Une acetylation énantioselective d'alcools allyliques J-borylés racémiques par Candida Antarctica Lipase B (CAL-B) et utilisant de l'acétate de vinyle comme donneur d'acyle a permis de préparer des acétates et des alcools allyliques J-borylés avec des rendements élevés (> 99%) et des sélectivités élevées (ee’s > 99%) dans des conditions réactionnelles "sans solvant". Ce dédoublement cinétique très efficace a été réalisé en réacteur à flux continu pendant 3 jours dans un système biphasique liquides ioniques / sc CO 2 sans perte d'activité du système enzymatique. Ceci constitue un exemple d'un procédé réellement "vert" et bénin pour l'environnement.

Conclusions et Perspectives:

Dans la première partie de notre travail de recherche, nous avons mis en œuvre une réaction d'allylation de Tsuji-Trost à partir d'intermédiaires clés hautement fonctionnalisés, à savoir des acétates allyliques J-borylés. Ces réactions ont été réalisées avec un excellent contrôle de la chimio- régio- et stéréo-sélectivité. Nous avons aussi développé une stratégie "one-pot" impliquant d'abord cette allylation de Tsuji-Trost suivie immédiatement de réactions de

Suzuki-Miyaura, et ceci à partir d'acétates allyliques J-borylés. Ces composés ont, en outre, été employés dans des réactions d'alkylation allylique asymétriques conduisant à des dérivés allyliques J-borylés énantioenrichis. Après allylation, tous les composés obtenus pourraient être soumis à une grande variété de réactions mettant à profit la présence du groupe pinacol boronique: par exemple, ils pourraient être employés dans des réactions d'addition 1,4 utilisant des catalyseurs au rhodium; ils pourraient aussi être transformés en dérivés halogénés et ces composés halogénés vinyliques pourraient eux-même être des intermédiaires très utiles pour différentes réactions notamment des couplages catalysés par des métaux de transition. Un autre développement possible de ce travail serait d'étudier cette réaction d'allylation d'acétates allyliques J-borylés en milieu liquide ionique.

Dans la seconde partie de ma thèse nous avons dévéloppé avec succès un procédé de dédoublement cinétique à partir d'un alcool allylique J-borylé, en utilisant une enzyme Candida Antartica Lipase (CAL-B) et des liquides ioniques. De plus nous avons démontré qu'on pouvait réaliser ce dédoublement cinétique d'alcool allylique J-borylé dans un système en flux continu, en utilisant l'enzyme immobilisée sur le liquide ionique comme support et avec du CO 2 super critique. Comme développement ultérieur de ce travail, il serait intéressant de l'étendre à un processus de dédoublement cinétique dynamique à partir de cet alcool allylique J-borylé et en y ajoutant, pour l'étape de racémisation, des composants tels que des zéolithes ou des catalyseurs à base de métaux de transition par exemple. De tels procédés de dédoublements cinétiques dynamiques en flux continu pourraient être étendus ensuite à d'autres alcools allyliques J-borylés. De telles méthodes s'inscrivent parfaitement dans le contexte du développment d'une chimie plus respectueuse de l'environnement.

Acknowledgements:

With great admiration, respect and appreciation, I take this privilege to express my sincere gratitude to my research supervisor Prof. Michel Vaultier, Director of Research, CNRS for his constant encouragement, creative guidance, invaluable and stimulating suggestions, which greatly enhanced my interest in the frontier areas of science. His dedication and passion towards research in chemistry is a great inspiration to my career. It is a great pleasure and privilege for me to work under his guidance for my Doctoral research. I am most thankful for all his invaluable help professionally and personally for spending his valuable time during my tenure.

I would like to thank Dr. Mathieu Pucheault for his support, encouragement and interest throughout every aspect of my research work. I am highly indebted for his valuable suggestions and pain taking efforts in teaching me several skills. Thanks to the group meetings and Mechanistic classes arranged by him which helped me to enlighten my knowledge in chemistry apart from my research work . I am thankful for his helping hand and ideas which helped me to solve many of my research tasks throughout my research period.

I extend my sincere thanks to Dr. Mireille Blanchard-Desce, Director of UMR-6510 for giving me the opportunity to work in her group and to have access for the state of art facilities during my research programme. I would also like to thank Prof. Pedro Lozano, University of Murcia, Spain for his help during my three months research programme in his lab, where i learnt very important process for biocatalysis under continuous flow operation.

Many thanks as well to the staff of UMR-6510 and CRMPO for their help and support during my study. Many thanks as well to Dr. Emilie, Dr. Florence Mongin and to Dr. Floris Chervallier for their fruitful suggestions during weekly joint group meetings.

I also thank the previous and present group members for giving friendly environment in the lab especially Thomas, Nicolas, Katia, Emmanuelle, Aicha, Kevin, Sunitha, Venkat, Shankar, Marina, Cedric, Vivek, Bilal, Jean-Marie and Anne-Claire for their countless support and help during the lab time and greatly enjoyed the foot ball sessions with them

during summer. I also thank my other friends for the lighter moments we shared specially with Ludovic, Yogesh, Eduardo, Sebastien, Elisa, Kassem, Dayaker and Tai. I would also like to thank the students from Pedro laboratory in Spain namely Juana Mari, Berenice for their professional and personal help during my stay in Spain. I would also like to thank other friends Kalyan, Ravi, Deepthi, Kiran, Yalla reddy, Praveen, Pavan reddy, Kesav, Shyam and Sreesailam who joined me for several occasions.

I extend my heartful thanks to my Industry supervisors Dr. Y. Krishna Reddy, Dr. Srinu Guntha and Dr. Srinivasulu Bandaru and Dr. Rajesh Shenoy who helped me to gain research knowledge while working at Albany Molecular Reseearch Inc., India after my Master degree.

This thesis would not have seen the light of the day without the moral support of love and affection from my beloved parents Anjaneyulu, Mahalakshmi and sisters Vani, Jayasri and Jayanthi and brothers-in-laws Madhusudhan rao , Viswesawar rao and Mallikarjuna rao for their incessant encouragement, constant support and understanding.

Financial assistance from UMR 6510 through Egide, France in the form of Fellowship is greately acknowledged. Finally, I thank my Thesis Director Prof. Michel Vaultier for allowing me to submit this work in the form of a thesis and helping me a lot in several aspects. Once again I thank all named and unnamed who have been associated during my part of research work.

Krishna Kishore. Kukkadapu

Abbreviations :

ACN Acetonitrile

Ac 2O acetic anhydride

BF 4 boron tetrafluoride

BMIM 1-butyl-3-methylimidazolium

BMPi 1-butyl-1-methylpiperidinium

BMPy 1-butyl-1-methylpyrrolidinium

Bn Benzyl

(Boc) 2O di- tert -butyl dicarbonate

BTMA butyl-trimethyl-ammonium

Bz Benzoyl

CAL-B Candia antartica lipase – B

Cy 2BH Dicyclohexylborane

C12 MIM 1-dodecyl-3-methylimidazolium

dba dibenzylidene acetone

DCM Dichloromethane

DEAD Diethylazodicarboxylate

DIBAL-H diisobutylaluminium hydride

DMAP 4-dimethylaminopyridine

DME Dimethoxyethane

DMF Dimethylformamide

DMSO dimethyl sulfoxide

Et 2O diethyl ether

GC gas chromatography

HMDS Hexamethyldisilazane

HPLC high pressure liquid chromatography

IL ionic liquid

IME immobilized enzyme

Ipc 2BH Diisopinocampheylborane

[Ir(cod)Cl] 2 iridium(I) chloride 1,5-cyclooctadiene complex dimer

LiAlH 4 lithium aluminum hydride

m-CPBA 3-chloroperbenzoic acid

MOM methoxy methyl ether

m.s. molecular sieves

NaH sodium hydride

NMO N-methylmorpholine- N-oxide

NMR nuclear magnetic resonance

NTf 2 Trifluoromethanesulfonimide

OMIM 1-octyl-3-methylimidazolium

PdCl 2 palladium(II) chloride

Pd 2(dba) 3 tris(dibenzylideneacetone)dipalladium(0)

PF 6 Hexafluorophoshpine

Pd(PPh 3)4 tetrakis(triphenylphosphine)palladium(0)

Pd(OAc) 2 palladium(II) acetate

PMBOH p-methoxybenzyl alcohol

sc CO 2 supercritical carbon dioxide

TBMA tributyl-methyl-ammonium

TBS tert -butyldimethylsilyl chloride

THF Tetrahydrofuran

TMS Trimethylsilyl

TPSCl Chlorotriphenylsilane

General Introduction:

Vinylboranes, vinylboronic acids and vinylboronates are organoboranes where the electronegativity difference between carbon (2.55) and boron (2.04) is low and the bond between them is less polar than usual carbon-metal bonds. The characteristic features of borane allow performing wide range of reactions under different conditions. Several research groups explored the synthetic applications of vinylboranes in organic synthesis. For example, they can be transformed to their corresponding alkenes via protonolysis, 44 can be easily oxidized by hydrogen peroxide in presence of base (addition of hydroxy group at double bond) to result in cis-, anti Markovnikov products. 45 They also participate in addition reactions to give allylic alcohols, 46 they undergo [4+2] cycloaddition reactions to form two new carbon- carbon bonds via Diels-Alder reaction. 47 Vinylboronic acids can be transformed to vinyl halides via halogenolysis, 48 react via boron-tethered radical cyclisation using Corey’s catalytic tributyl-stannane method in presence of radical initiator to afford 1,3- or 1,4-diols, 49 participate in palladium-catalyzed Suzuki cross coupling reactions to give new carbon-carbon 50 51 bond, and react with anhydrides to result in various DE -unsaturated ketones via palladium and rhodium 52 catalysis. Vinylboronic acids were also used for the synthesis of new carbon- nitrogen, 53 carbon-oxygen, 54 carbon-fluorine 55 bonds via palladium and copper catalysis.

44 Brown, H. C.; Zweifel, G. J. Am. Chem. Soc. 1961, 83 , 3834. 45 Brown, H. C.; Liotta, R. J. Am. Chem. Soc. , 1979, 101, 96. 46 a) Jacob, P.; Brown, H. C. J. Am. Chem. Soc. 1976, 98 , 7832. b) Jacob, P.; Brown, H. C. J. Org. Chem. 1977, 42 , 579. 47 a) Matteson, D. S.; Waldbillig, J. O. J. Org. Chem. 1963, 28 , 366. b) Singleton, D. A.; Martinez, J. P. J. Am. Chem. Soc. 1990, 112, 7423. c) Vaultier, M.; Truchet, F.; Carboni, B. Tetrahedron Lett. 1987, 28 , 4169. 48 Brown, H. C.; James, B. C. J. Org. Chem. 1980, 45 , 389. 49 Batey, R.; Smil, D. V. J. Angew. Chem. Int. Ed. 1999, 38 , 1798. 50 Suzuki, A.; Miyaura, N. Chem. Rev . 1995, 95 , 2457. 51 Yamamoto, A.; Ryuki, K.; Shimizu, I. Helvetica Chimica Acta . 2001, 84 , 2996. 52 Frost, C. G.; Wadsworth, K. J. Chem. Commun. 2001, 2316. 53 Tao, C-Z.; Xin, C.; Juan, L.; Guo, Q-X. Tetrahedron Letters. 2007, 48 , 3525. 54 Lam, P. Y. S.; Vincent, G.; Clark, C. G.; Deudon, S.; Jadhav, P. K. Tetrahedron Lett. 2001, 42 , 3415. 55 Takeru, F.; Tobias, R. Org. Lett . 2009 , 11 , 2860.

Vinylboronates were used to synthesize new carbon-carbon bonds via Suzuki-Miyaura cross- coupling reaction under palladium catalysis, participate in Petasis (modified Mannich) multicomponent reaction 56 to give functionalized nitrogen based heterocycles, they undergo olefin cross-metathesis to afford highly functionalized vinylboronate derivatives, 57 readily react with carbene generated from diazo compounds to afford cyclopropane derivatives 58 under palladium and rhodium catalysis. Vinylboronates on treatment with arylnitrile oxides undergo 1,3-dipolar cycloaddition reaction to give isoxazole derivatives; 59 vinylboronates were also used as nucleophiles in allylation 60 with copper and palladium catalysis.

The above transformations of organoboranes provide important precursors for building complex bioactive molecules which were developed as medicine, agrochemicals, pharmaceuticals and fine chemicals. Organoboranes can be easily synthesized and this easy access made them useful key intermediates for organic synthesis. Vinylboranes can be synthesized via hydroboration of alkynes with alkylboranes; 61 vinylboronic acids can be synthesized via hydroboration of alkynes with alkoxyboranes followed by hydrolysis 62 whereas vinylboronates were synthesized from organometallic reagents by transmetallation with trimethylorthoborate, 63 also prepared from hydroboration of alkynes with alkoxyboranes. Grafting a substitution in the allylic position of vinyl boronates confers to these units a high degree of versatility with regard to their use in organic synthesis. J-substitued

56 a) Petasis, N. A.; Zavialov, I. A. J. Am. Chem. Soc. 1977, 119, 445. b) Batey, R. A.; Mackay, D. B.; Santhakumar, V. J. Am. Chem. Soc. 1999, 121, 5075. 57 a) Morril, C. ; Grubbs, R. H. J. Org. Chem . 2003 , 68 , 6031. b) McNulty, L.; Wright. Z. J. Org. Chem. 2010, 75 , 6001. 58 a) Fontani, P.; Carboni, M.; Vaultier, M. Tetrahedron Lett . 1989, 30 , 4815. b) Toshiro, I.; Hiroshi, M.; Shinya, N. J. Org. Chem. 1990, 55, 4986. c) Yasutaka, F.; Hideki, A. Org. Lett . 2008, 10 , 769. 59 Bianchi, G.; Cogoli, A.; Grünanger, P. J. Organomet. Chem. 1966, 6, 598. 60 a) Whittaker, A. M.; Richard, P. R.; Lalic, G. Org. Lett. 2010, 12 , 3216. b) Ortar, G. Tetrahedron Lett . 2003 , 44 , 4311. 61 a) Brown, H. C.; Zweifel, G. J. Am. Chem. Soc . 1961, 83 , 3834. b) Brown, H. C.; Moerikofer, A. W. ibid , 1963, 85 , 2063. 62 Shyam, K. G.; Brown, H. C. ibid , 1975, 97 , 5249. 63 Miyaura, N.; Suzuki, A. Chem. Rev . 1995, 95 , 2457.

vinylboronate derivatives contain multiple reaction sites which make them challenging substrates to obtain selectivity (especially for metal-catalyzed reactions 64 ). Few research groups explored the applications of J-substitued vinylboron derivatives for organic synthesis via Grignard, Mitsunobu, Diels-Alder, asymmetric cyclopropanation and transition metal- catalyzed reactions.

Various methods have been developed for their preparation either from J-keto vinylboronates by reduction with hydride or zinc derivatives, 65 or from hydroboration of propargylic alcohols with either pinacol borane 66 or diisopinocampheylborane followed by a refunctionalization in this last case.

In our lab we developed palladium-catalyzed reaction on J-substitued vinylboronates where we investigated chemo-, regio- and stereoselectivity during allylation reaction. This thesis was divided into 3 chapters.

1. The first chapter describes a brief literature survey on the synthesis and reactivity of J- borylated allylic derivatives.

2. In the second chapter our goal is to study the possibility of generating palladium S- allyl complexes from J-borylated allylic acetates and study their reactivity towards a variety of nucleophilic reagents (Tsuji-Trost coupling reaction 67 ) including chemo-, regio- and stereo-selectivity.

3. The third chapter describes the chemoenzymatic resolution of J-borylated allylic

alcohols in continuous flow systems using ionic liquids & sc CO 2.

64 Carosi, L.; Hall, D. G. Angew. Chem. Int. Ed. 2007, 46 , 5913. 65 Jehanno, E.; Vaultier, M. Tetrahedron Lett. 1995 , 36 , 4439. 66 Fortineau, A.-D.; Robert, M.; Gueguan, J.-P.; Carrie, D.; Mortier, J.; Vaultier, M. C. R. Acad. Sci. Serie IIc 1998 , 1, 253. 67 Trost, B. M.; Matthew, L. C. Chem. Rev . 2003, 2921.

PART ͲA

Chapter I: Bibliography

I.1: Synthesis and applications of J -borylated allylic electrophiles

I.2: Tsuji-Trost allylation

I.3: Selectivity issues in palladium-catalyzed Tsuji-Trost allylation of J-borylated allyl acetates

I. 1. Synthesis & applications of J-borylated allylic electrophiles:

I. 1. i. Synthesis of J-borylated allylic electrophiles:

Vinylboronates J-substituted with leaving group such as acetate has attracted much interest. This highly functionalized three carbon building block bearing boronate is an electron- deficient olefin, which offers synthetic potential for various functional group transformations.

This chapter describes the synthesis and applications of J-borylated allylic systems in organic synthesis. Vaultier et al reported the synthesis of J-borylated allylic eletrophiles starting from propargylic alcohol systems (Scheme 11). 68 Protection of propargylic alcohols as trimethylsilyl derivatives affords 1 in 70-96% yield.

68 (a) Fortineau, A. D.; Robert, M.; Gueguan, J. P.; Carrie, D.; Mortier, J.; Vaultier, M. C. R. Acad. Sci. Serie IIc 1998 , 1, 253. (b) Jehanno, E.; Vaultier, M. Tetrahedron Lett . 1995, 36 , 4439. (c) Berree, F.; Gernigon, N.; Hercouet, A.; Lin, C-H.; Carboni, B. Eur. J. Org. Chem. 2009, 329.

Hydroboration of 1 with pinacolborane results in the formation of TMS protected J-borylated allylic alcohols 2 in 41-58% yield. Deprotection of 2 with citric acid in methanol affords JͲ borylated allylic alcohols 3 in 47-82% yield (Scheme 11). JͲborylated allylic electrophiles can be synthesized from 3 via acetylation.

J-borylated allylic alcohols can also be synthesized by a three step one-pot sequence via hydroboration of protected propargylic systems using dicyclohexylborane, 69 followed by oxidation with trimethylamine oxide, leading to alkenylboronic esters 4. Transesterification of

4 with diols results in the formation of J-substituted pinacolboronate derivatives 5 in 38-60% yields (Scheme 12).

Cy 2BH, DME PG 1O PG 1O PG 1O Me 3NO

o 0 C tort, 2 h BCy 2 rt, 2 h B(OCy) 2 4

Ph Ph HO OMe

PG 1 = Bn 47% HO OMe Ph PG 1O Ph Ph Ph O OMe PG 1 = MOM 38% B OMe 2 h, rt O PG 1 = Bz 60% Ph 5 Ph

Scheme 12: Protected J-borylated allylic alcohols via hydroboration with dicyclohexylborane

Alternatively, J-borylated allylic alcohols were synthesized via direct hydroboration of silyl- or benzyl-protected alkynes 6 with dioxaborolane 7 to give protected J-borylated allylic alcohol derivatives 8 in yields ranging from 30 to 91%. Silyl and benzyl protecting groups did not interfere in the synthesis of corresponding alkenylboronic esters whereas ether, ester and acetal protecting groups failed to give alkenylboronic ester 8 (Scheme 13).

69 Pietruszka, J.; Witt, A. J. Chem. Soc., Perkin Trans . 1 2000, 4293.

I. 1. ii. Applications of J-borylated allylic electrophiles:

Introduction: Organic chemists explored the interest to use vinylboranes in organic synthesis, and many strategies and applications were developed during these studies on vinylboranes. Major contribution on vinylboranes involves the formation of characteristic new C-C bond. Introducing a functional group at allylic position for vinylboranes brings the interest to perform a variety of reactions because of the multiple functional groups present in this type of molecule.

I. 1. ii. a. In iridium catalysis:

Dennis Hall et al reported a transition metal (TM)-catalyzed enantioselective allylation method for the preparation of chiral D-substituted allylboronates from achiral starting materials (Scheme 14). 70

70 Peng, F.; Hall, D. G. Tetrahedron Lett . 2007, 48, 3305.

This reaction has challenges in regioselectivity between products, 9 and 10 (Scheme 14). Their initial attempts with palladium catalyst along with malonate nucleophile led to mixture of deboronation products 11, 12 and other unidentified materials (Scheme 15).

Iridium-catalyzed asymmetric allylic alkylation (AAA) with malonate as nucleophile and using different chiral monophosphoramidite ligands was studied for regioselectivity. Iridium catalysis led to the formation of branched allylboronates 14 with enantioselectivities up to 84% ee (Scheme 16). The regiochemistry strongly depends on the structure of the chiral phosphoramidite ligands and the size of the boronate groups used during allylation reaction.

Iridium-catalyzed asymmetric allylic alkylations with different ligands in different solvent combinations were studied to optimize the reaction conditions as shown in Table 3. Of all the above mentioned ligands from Table 3, only allylation with 16d in THF solvent was found to give branched type products 14a (Table 3, entry 4) whereas other ligands resulted in the formation of linear products 15a (Table 3, entries 1-3, 5) during asymmetric allylation. Allylation failed with other solvents like ether, dichloromethane and toluene. Use of more polar solvents like DMF, Dioxane and DMSO gave linear products in majority (Table 3,

entries 9-11). Increasing the substitution on the boronate ring resulted in the formation of linear product 15b (Table 3, entry 12) whereas changing the boronate cyclic system to six membered ring gave branched type product as major compound (Table 3, entry 13). Also, it was observed that these products were unstable during isolation, therefore they were readily treated with aldehydes under Lewis acid catalysis to give homoallylic alcohol derivatives 17 with chirality transfer in one-pot. This type of addition between allylboron/crotylboron derivatives to aldehydes is a popular method for stereoselective C-C bond formation (Scheme 17).

The allylboronation proceeds via six-membered chair-like transition state (Mechanism 1). The addition of aldehydes to D -substituted allylboronates of type 18 proceeds with near perfect transfer of chirality to give two diastereomeric products 21 and 22 . These Z and E allylic alcohol products are stereoisomers, and their proportion is highly dependent on the nature of 1 71 the D-substituent (R ) and the structure of the boronic ester. The selectivity between 21 and 22 can be explained in terms of steric and dipolar effects on the two competing Zimmerman- Traxler type transition state structures 19 and 20 . With a non-polar alkyl substituent R 1, steric interactions play a dominant role. Transition structure 19 can be destabilized by steric 1 interactions between a large boronic ester and the pseudo-equatorial D-substituent R . On the other hand, chair-like transition structure 20 features unfavorable allylic interactions due to the pseudo-axial position of the R 1 substituent.

71 (a) Hoffmann, R. W. Pure Appl. Chem . 1988, 60 , 123. (b) Hoffmann, R. W.; Neil, G.; Schlapbach, A. Pure Appl.Chem . 1990, 62 , 1993.

The use of a hindered ester, such as pinacolate, aggravates interactions between R 1 and the dioxaborolane unit in structure 19 , and tends to encourage transition structure 20 leading to mixtures of products 21 and 22 in modest selectivities. 72

I. 1. ii. b. In copper catalysis:

Dennis Hall et al reported copper-catalyzed asymmetric allylic alkylation on J-borylated allylic chloride derivatives using Grignard reagent and a chiral ligand. Enantioenriched D- substituted allylboronates with high level of selectivities (up to 93%) and yields up to 87% were obtained (Scheme 18). 73 AAA using copper catalyst was developed using dichloromethane as solvent with slow addition of Grignard reagent and various phosphoramidite ligands, and various cyclic boronate groups were investigated. The combination of ligand 16e with boronic ester 23d affords optically active D-substituted allylboronate 24d (Scheme 18, entry 5) in 93% ee.

72 Hoffmann, R. W.; Weidmann, U. J. Organomet. Chem. 1980, 195, 137. 73 Carosi, L.; Hall, D. G. Angew. Chem. Int. Ed. 2007, 46 , 5913.

o ligand 16 , CH 2Cl 2, -78 C B(OR) 2 + EtMgBr Cl B(OR) 2 S Et COOCu , 4 h upto 87% yield 23 (CuTC) 24

Ph O O Ph O O B(OR) 2 = B B B B in O O Ph O O Ph 23 a b c d

Entry product ligand %ee

1. 24a 16d 87

2. 24b 16d 52

3. 24c 16d 86

4. 24d 16d 91

5. 24d 16e 93

Scheme 18: Asymmetric allylic alkylation with copper catalyst

The resulting D-substituted allylic boronate reacts with aldehydes in presence of Lewis acid catalyst at low temperature via stereoselective allylation, to give homoallylic alcohol derivative 25 with chirality transfer in 75% yield and 92% selectivity (Scheme 19).

Also, chiral D-substituted allylic trifluoroborate salts were prepared from D-substituted allylic

boronates which have significant potential in carbonyl allylation chemistry. 74 Allylic trifluoroborate salts react with ketones via allylboration to give the homoallylic alcohol 26 containing a quaternary center, in 95% yield with 85% selectivity (Scheme 19).

I. 1. ii. c. In palladium catalysis:

Walsh et al reported palladium-catalyzed chemoselective allylation on bifunctional reagents that contain both allylic acetate and vinylboronate ester groups (Scheme 20). 75 Where the leaving group (acetate) is E-to the boron, this type of substrates were considered to be bifunctional reagents as palladium can catalyze both functional groups i.e., allylic acetate via Tsuji allylation and vinylboronate ester groups via transmetallation. Competitive reactions between Tsuji-Trost and Suzuki could occur for these substrates, but it was observed that only allylation products 27 were formed with excellent chemoselectivity and yields ranging from 65 to 92%.

Nucleophiles like malonates, primary amines and secondary amines successfully underwent chemoselective Tsuji-Trost allylation (Scheme 20).

74 Batey, R. A.; Thadani, A. N.; Smil, D. V. Tetrahedron Lett. 1999, 40 , 4289. 75 Hussain, M. M.; Walsh, P. J. Angew. Chem., Int. Ed. 2010, 49 , 1834.

Allylation between allylic acetate systems that contain pinacolborane substitution (Bpin) and allylic systems without pinacolborane substitution were investigated for regioselectivity. Interestingly, allylation occurred with high regioselectivity at benzylic position affording 28 (Table 4, entries 2 and 3) for allylic systems that contain pinacolborane. Whereas, allylation at the other position was observed affording 29 (Table 4, entry 1) for the allylic system which doesn’t have pinacolborane substituent (regioselectivity 1:9). Therefore, regioselectivity in allylation was quite opposite for the systems which have boron-substitution in S-allyl palladium complex.

Allylations were performed using palladium complex without interference of pinacolborane moiety. Also, since palladium complex catalyzes both allylation and Suzuki reaction, a one- pot tandem allylation followed by Suzuki cross-coupling reaction strategy was developed, to give a variety of 2-arylated allylic amines 30 with yields ranging from 65 to 70% (Schme 21).

Also, allylic substitution followed by oxidation in one-pot provides enol ethers which undergo keto-enol tautomerization to provide D-substituted ketones 31 in 82 to 85 % yields. This type of products were not easy to synthesize by Tsuji-Trost allylation alone (Scheme 22).

I. 1. ii. d. In Grignard reaction:

Carboni et al reported the addition of organometallic reagents to vinylboronates possessing an acetal group in the J-position, which undergo allylic rearrangement in presence of Lewis acid to form J-alkoxy allyl boronates 32 (Scheme 23) with high stereoselectivity and E-isomer as major. 76 The reaction was independent on the nature of the metal and the size of the entering group. Organometallic reagents like n-BuLi, PhLi, BuMgCl react with J-boryl allyllic o derivatives at -78 C to give J-alkoxy allyl boronates in 50-65% yield.

R Bpin OEt RMX, BF 3.Et 2O

o Bpin OEt OEt THF, -78 C, 25 min 32 E/Z > 99:1 50-65%

RMX = n-BuLi, s-BuLi, i-PrMgCl

Scheme 23: Grignard reaction on -boryl alkoxy derivatives

This type of products ( D-substituted J-ethoxy-allylboronates) 32 were difficult to purify, hence they are readily treated with aldehydes via allylboration to result in the formation of homoallylic alcohols 33 in one-pot with 75% yield (Scheme 24).

76 Possémé, F.; Deligny, M.; Carreaux, F.; Carboni, B. J. Org. Chem. 2007 , 72 , 984.

Typical reation mechanism (Mechanism 2) involves the attack of Grignard reagent directly on the boronate moiety to give a tetravalent intermediate, which, on further rearrangement, forms the D-substituted allylic boronate derivative as shown below (1,2-anionotropic shift).

I. 1. ii. d. In Diels Alder reaction:

J-boryl allylic alcohols on simple oxidation provide 3-boronoacrolein which was used to synthesize cyclic D-chiral allylboronate 34 via hetero-Diels-Alder cycloaddition between 3- boronoacrolein and enol ethers, catalyzed by Jacobsen’s chiral chromium (III) catalyst (Scheme 25). 77

CH 3 Bpin Bpin Chromium catalyst + OEt 4 Å m.s., rt, 4 h O OEt N O O Cr Cl 34 O (85%, 96% de) Chromium catalyst Scheme 25: Hetero- [4+2]-cycloaddition of 3-boronoacrolein

77 (a) Gao, X.; Hall, D. G.; Carreaux, F.; Carboni, B. Chem. Eur. J. 2006, 12 , 3132. (b) Favre, A.; Carreaux, F.; Carboni, B. Eur. J. Org. Chem. 2008, 4900.

Stereoselective total synthesis of several styryllactones were achieved efficiently from common intermediate 34 . Further, this intermediate can be oxidized by hydrogen peroxide to give corresponding alcohol 35, which can be readily converted to corresponding acetate 36 which is a useful intermediate in allylic substitution chemistry (Scheme 26).

The cyclic D-chiral allylboronate 34 adds to a variety of aldehydes to give diastereomerically pure products. A three component hetero- [4+2]-cycloaddition between 3-boronoacrolein, enol ethers and aldehydes, catalyzed by Jacobsen’s chiral catalyst, was developed to give D- hydroxy alkyl pyrans 37 in yields ranging from 73 to 92% (Scheme 27). This D-hydroxy alkyl pyran unit shows a broad range of biological properties like antibiotic and anticancer activity.

I. 1. ii. e. In Mitsunobu reaction:

Mitsunobu reaction of J -borylated allylic alcohols with nucleophiles like benzoic acid, phenols, N-tosylamines in presence of triphenylphosphine (PPh 3) and diethyl 78 azodicarboxylate (DEAD) leads to S N2 substitution products (Scheme 28).

78 Berree, F.; Gernigon, N.; Hercouet, A.; Carboni, B. Eur. J. Org. Chem. 2009, 329.

The typical mechanism involves the reaction of triphenylphosphine with DEAD to generate a phosphonium intermediate that converts the allylic alcohol oxygen atom to a leaving group 39 as in classical Mitsunobu reactions (Mechanism 3). Addition of the nucleophile to the boron atom in 39 leads to the borate 40 that rearranges by an anionotropic 1,2-shift to afford D- substituted allylboronates 41 in S N2 manner, anti to the leaving group which is similar to Grignard reaction on J-borylated allylic derivatives.

The resulting Mitsunobu product 38 was used as allylating reagent. A three component one- pot reaction was developed via Mitsunobu followed by allylboration sequences to give ( Z)- homoallylic alcohols 42 (Scheme 29). Different boronates (Scheme 29, entries 1,3,4,5) substituted with alkyl, aryl and allyl were treated with various nucleophiles like benzoic acid, phenols, tosylamides and aldehydes in presence of triphenylphosphine and di- tert -butyl azodicarboxylate to obtain 42 . Substituted enamides or enol benzoates were synthesized in one-pot sequence with a high diastereoselectivity, up to >99%.

Trans -whisky lactone 44 was synthesized using this one-pot strategy by treating J-borylated allylic alcohol with benzoic acid under Mitsunobu conditions followed by allylboration sequence to give intermediate 43. Compound 43 , on treatment with NaOMe followed by oxidation in presence of BF 3.Et 2O, afforded trans -whisky lactone 44 in 57% yield (Scheme 30).

Ruthenium-catalyzed cycloisomerization reaction of enyne derivative 45 was developed by treating a J-borylated allylic alcohol with N-tosyl propargylamine under Mitsunobu conditions to give compound 45 in 69% yield. Ring closing metathesis of 45 with Grubb’s catalyst readily converts 45 to a cyclic diene which, on allylboration with aldehydes, afforded homoallylic alcohol 46 in 36% yield. This protocol was useful to synthesize pyrrolidines with quaternary stereogenic centers of defined stereochemistry (Scheme 31).

I. 1. ii. f. In cyclopropane synthesis:

Cyclopropane rings were useful intermediates in organic synthesis 79 and this strained ring was observed in naturally occurring terpenes, steroids, amino acids, fatty acids, alkaloids, and nucleic acid derivatives. 80 Many cyclopropane-containing non-natural compounds also have important biological activities. Enantiopure cyclopropane 81 derivatives show important biological activity, for example FR-900848 is a potent antibiotic against filamentous fungi, and U-106305 is an inhibitor of cholesteryl ester transfer protein (CETP). Alkenylboronates can be employed for the synthesis of optically pure cyclopropane derivatives 47 using chiral

79 Patai, S.; Rappoport, Z., Eds. The Chemistry of the Cyclopropyl Group ; Wiley: New York. 1987, 1. 80 Faust, R.; Angew. Chem. Int. Ed . 2001 , 40 , 2251. 81 Barrett, A.; Kasdorf, K. Chem. Commun . 1996, 325.

auxiliaries (Scheme 32 ), 82 further this boronate can be oxidized to get corresponding alcohol derivatives.

R OR * CH 2I2, Pd(OAc) 2 R OR 1* B 1 B OR * o OR 1* 1 Et 2O, 0 C, 1 h 47 85-96% dr upto 93:7 Ph Ph Ph HO HO HO CO Pr i OMe HO Ph 2 OR * = 1 OMe HO HO HO CO Pr i Ph HO Ph 2 Ph Scheme 32: Cyclopropanation of chiral alkenylboronates

Chiral J-borylated allylic alcohols were subjected to cyclopropanation via Pd(OAc) 2- catalyzed decomposition of diazomethane afforded diastereomers 48 and 49 in 98% yield (Scheme 33). 82 On the other hand, enantiopure cyclopropylboronic ester 49 was obtained by cyclopropanation of J-borylated allylic alcohol using bis(iodomethyl)zinc as reagent and bis- methanesulfonamide as catalyst. 83

Belactosin A is a Streptomyces metabolite that inhibits the cell cycle progression of human tumour cells, Belactosin A was synthesized using asymmetric cyclopropylamine as a key intermediate (Scheme 34). 84 This cyclopropylamine was synthesized from pure benzoate 50 which was converted into enantiomerically pure trifluoroborate 51 in 90% yield. This was followed by amination, via the dichloroborane, with benzyl azide leading to 52 in 73% yield.

82 Luithle, J. E. A.; Pietruszka, J. J. Org. Chem. 1999 , 64 , 8287. 83 Denmark, S. E.; O’Connor, S. P. J. Org. Chem. 1997, 62 , 3390. 84 Pietruszka, J; Solduga, G. Eur. J. Org. Chem. 2009, 5998.

Boc protection of 52 followed by hydrogenolysis gave intermediate 53 in 86% yield. Boc protection of 53 followed by saponification afforded enantiomerically pure building block 54 in 92% yield. It is the key intermediate for the total synthesis of Belactosin A.

Ph BzO Ph O 1. SiCl 4, Toluene / ACN OMe KHF 2, MeOH BzO B rt, 2 h O Ph 80 oC, 2 d BF K Ph 3 2. BnN , 5 h MeO 3 50 51 90%

BzO 1. (Boc) 2O, Et 3N BzO 1. DMAP, (Boc) 2O, MeOH, 24 h, rt ACN, rt, 15 h NHBn NHBoc 2. Pd/C, H 2, 3 d 2. NaOH, MeOH, 30 min 52 73% 53 86%

HO O O COOH O 8 steps H H N N NBoc 2 2 N H 54 92% O Belactosin A Scheme 34: Application in the synthesis of Belactosin A

I. 2. Tsuji-Trost allylation:

Allylation reactions catalyzed by transition-metal complexes bring a lot of interest and they are used as very powerful tool in organic synthesis for C-C and C-heteroatom bond formation (Scheme 35). 85 Allylation process involves activation of the allylic position by the formation of a S-allyl palladium complex followed by reaction of this ambident electrophile with an anion to result in allyl substituted derivatives. 86

85 Tsuji, J. Tetrahedron Lett. 1965, 4387. 86 Trost, B. M.; Fullerton, T. J. J. Am. Chem. Soc. 1973, 95 , 292.

The reaction mechanism (Mechanism 4) involves in the catalytic cycle first olefin complexation (coordination) with palladium to give a S-complex. The next step is oxidative addition in which the leaving group is expelled to give a S-allyl complex. In the case of soft nucleophiles, nucleophile attacks at proximus or distal carbon atom of the allyl group generating another S-complex by reductive elimination. The palladium detaches from the alkene via dissociation in completion of reaction and can start again the catalytic cycle.

The typical geometry in S-allyl complex for mono-substituted unsymmetrical olefin is shown below (Scheme 36). Between the syn and anti isomers of monosubstituted olefin, syn isomer

is the favoured the geometry because of the less steric hindrance between the R group and ligand (L) in S-complex.

R syn anti (favourable) Pd R Pd (non-favourable) L L L L

Scheme 36: -allyl complex for mono substituted unsymmetrical olefin

Similarly, in case of disubstituted S-allyl complex the syn-syn isomer geometry is favoured when compared to anti-anti isomer due to steric factor. However, in some cases, anti geometry is favoured because of steric hindrance between the substituent in ligand and R group of S-allyl complex (Scheme 37).

The most used leaving groups in allylation reaction are acetates, halides and carbonates at allylic position. When allylic systems substituted with carbonates are subjected to allylation reaction, the alkoxide ion generated during the S-complex formation itself acts as nucleophile during allylation. No base is required and the reaction can be carried without adding base (Scheme 38). 87 Tsuji allylation of 55 with enol carbonate produces 56 wih a quaternary stereogenic center in 96% yield and 88% ee, when chiral ligand (S)-t -Bu-PHOX used as ligand, 56 is a useful building block for synthetic chemistry (Scheme 38).

87 Behenna, D. C. ; Stoltz, B. M. J. Am. Chem. Soc. 2004, 126, 15044.

Many other leaving groups were employed in allylation such as carbamates, sulfones, halides, phosphates and epoxides (Scheme 39).

O OAc OCO 2R OCONHR

Acetates Carbonates Carbamates Oxiranes

OP(O)(OR) 2 Cl NO 2 SO 2R

Phosphates Halides Nitro Sulfones

Scheme 39: Allylic systems used inTsuji-Trost allylation

I. 2. i. Stereochemistry in Tsuji-Trost allylation:

The stereochemistry of this allylation depends on the type of nucleophile used. The S-allyl complex 57 in Tsuji-Trost allylation is formed by S N2 type inversion, and subsequent attack of nucleophile, i.e. either soft or hard nucleophiles, determines the configuration of the product. Soft nucleophiles are those derived from conjugate acids whose pKa<25, like bases generated from dialkyl malonate, E-ketoester, enamine and E-diketone which attack directly on allyl moiety via S N2 reaction to give product 58 with inversion of configuration at this step. Allylation with soft nucleophiles involves a double inversion mechanism which leads to overall retention of product 58a (Scheme 40).

Whereas, reaction with hard nucleophiles follows a different mechanism. Hard nucleophiles are those derived from conjugate acids whose pKa > 20, such as organometallic reagents like Grignard reagent, organozirconium, organozinc and organotin reagents which first attack the metal center in S-complex 57 via transmetallation followed by reductive elimination to give the allylation product 58b with overall inversion of configuration (Scheme 41).

CO 2Me CO 2Me Pd(PPh 3)4 / PPh 3

o OAc MeMgBr, THF, 0 C to rt, 8 h Me 90% (overall inversion) Scheme 41: Stereochemistry of allylation with hard nucleophiles

I. 2. ii. Regioselectivity in Tsuji-Trost allylation:

Symmetrical allylic systems during palladium catalysis do not generate regioselectivity issues, whereas unsymmetrical allylic systems during palladium catalysis have regioselectivity issues. Allylation occurs at less substituted carbon in majority, according to steric effect (Scheme 42). 88

Soft nucleophiles like malonate and morpholine attack the unsymmetrical S -allyl complex at the less substituted carbon in majority to result in allylation products according to steric factor. But hard nucleophiles, like PhZnCl, attack unsymmetrical S-allyl complex at more substituted carbon, and this is due to the fact that hard nucleophile first attacks on palladium in the S-allyl complex via transmetallation. Then the ligand and phenyl group orient for a more stable S-allyl complex (Shown below). After this stable S-complex formation, the phenyl group attacks at adjacent carbon to give the allylated product.

Me iBu Me iBu

Pd Pd Ph 3P Ph Ph PPh 3

-Complex in hard nucleophiles

88 Trost, B. M.; Hung, M. H. J. Am. Chem. Soc . 1984, 106, 6837.

The stereochemical version of allylation in unsymmetrical S-allyl complex is shown below. Soft nucleophiles attack at less substituted carbon with stereoretention in 97% yield as major product, however 3% of the other isomer with stereoretention was formed as minor product in allylation (Scheme 43).

I. 2. iii. Asymmetric allylic alkylation (AAA):

Introducing enantioselectivity 89 in allylation reactions starting from a racemic substrate represents a new dimension to their use in organic synthesis. Ligands play important roles for developing enantioselectivity in allylation reactions, and the chiral information on the ligand is directly responsible for the enantioselectivity. The ability to transform achiral, prochiral, or chiral material to enantiopure material in allylation is termed as asymmetric allylic alkylation (AAA, Scheme 44).

I 1 I PdL* n R R II R R1 R R R R CH 2(CO 2R )2 * * + OAc -OAc CH(CO R'') CH(CO R'') PdL* n 2 2 2 2

Scheme 44: Asymmetric allylic alkylation

Trost et al synthesized different chiral ligands for allylation reaction.90 Most of the chiral ligands are commercially available for various synthetic needs. The most extensively studied example to demonstrate the efficiency of ligand is 1,3-diphenylprop-2-enyl acetate 59.

89 Trost, B. M.; Strege, P. E. J. Am. Chem. Soc. 1977, 99 , 1649. 90 Trost, B. M.; Vranken, D. L. Chem. Rev . 1996, 96 , 395.

However, the results from this system do not necessarily translate into high enantioselectivity for other substrates. Chiral ligands based on nitrogen and phosphines were extensively used for allylation reactions because of the strong binding nature of these ligands to palladium catalyst. A model asymmetric allylic allylation reaction of 1,3-diphenylallyl acetate ( 59 ) under palladium catalysis with malonate nucleophile, under different chiral ligands was studied for enantioselectivities in the product 60 (Scheme 45, Table 5).

OAc MeOOC COOMe MeOOC COOMe Pd(allyl 2Cl 2), ligand* + Ph Ph * Na solvent, reflux Ph Ph 59 60

Scheme 45: Asymmetric allylic alkylation on 1,3-diphenylallyl acetate

Entry ligand % yield % ee

1. L1 98 91

2. L2 83 95

3. L3 86 90

4. L4 68 85

5. L5 86 77

6. L6 89 81

7. L7 85 85

8. L8 97 88

9. L9 99 99

10. L10 56 92

11. L11 92 96

12. L12 80 34

13. L13 81 95

14. L14 89 99

Table 5: Enantioselectivity studies in allylation

Various Chiral ligands used in Tsuji-Trost allylation:

A wide variety of bidentate ligands ranging from bisphosphines 91 (Table 5, entries 3, 4, 12) and bisamines 92 (Table 5, entries 1, 2, 13, 14) are capable of inducing enantioselectivity to give 60 with good yields. Oxazoline ligands 93 during allylation gave 60 with high enantioselectivities up to 99% and yields up to 99% (Table 5, entries 7, 8, 9 and 11). In case of allylation with sodium dimethylmalonate using ligand ( S)-BINAP in THF, a selectivity was observed as low as 34% (Table 5, entry 12). It was improved to 94% when the solvent system changed to dichloromethane. 94 Allylation reaction conditions need to be optimized for each new ligand/substrate/nucleophile/solvent combination in order to find the best efficiency for the reaction.

However, ligands not only introduce chirality into the products but they also influence the regioselectivity during allylation reaction. Simple allylation of optically pure 1-phenyl- p- tolyl-disubstituted allyl acetate 61 with dimethylmalonate affords the products 62 and 63 in 1:1 ratio when triphenylphosphine is used as ligand. The formation of regioisomers can be greatly influenced by the ligands used in the reaction. 95 For instance, using chiral ligands derived from phosphino-dihydrooxazoles ( R)-L 9 and ( S)-L 9 each of the regioisomers 62 and 63 could be obtained in high yield and high enantioselectivity (Scheme 46).

91 Yamazaki, A.; Morimoto, T.; Achiwa, K. Tetrahedron: Asymmetry 1993, 4, 2287. 92 Gamez, P.; Dunjic, B.; Fache, F.; Lemaire, M. J. Chem. Soc. ,Chem. Commun. 1994, 1417. 93 Vonmatt, P.; Pfaltz, A. Angew. Chem. , Int. Ed. Engl. 1993, 32 ,566. 94 Yamaguchi, M.; Shima, T.; Yamagishi, T.; Hida, M. TetrahedronLett. 1990 , 31 , 5049. 95 Vonmatt, P.; Lloyd-Jones, G. C.; Pregosin, P. S. Helv.Chim.Acta . 1995, 78 , 265.

This shows that ligands can dictate regiochemistry in allylation, however this is applicable only to this substrate, and the results from this system can not be generalized to other substrates. The selectivity is not well documented for the Trost allylation when similar aryl groups were present on both the sides of S-complex, and it is very difficult to control the regioselectivity in allylation when chemically equivalent groups are present on both sides. The Trost allylation products are directly used for the synthesis of many natural products.

I. 2. iv. Application in natural product synthesis:

Helmchen et al reported the synthesis of enantiomerically pure (-)-wine lactone based on a palladium-catalyzed enantioselective allylic substitution with the lithium anion of malonate (Scheme 47). 96

Apart from malonate nucleophiles, E -ketoesters were also used as nucleophiles in palladium- catalyzed allylation by using chiral Trost ligand in the synthesis of (-)-nitramine (Scheme 48). 97

96 Bergner, E. J.; Helmchen, G. Eur. J. Org. Chem . 2000, 419. 97 Trost, B. M.; Radinov, R.; Grenzer, E. M. J. Am. Chem. Soc . 1997, 119, 7879.

Trost et al reported the use of primary alcohols as nucleophiles in palladium-catalyzed allylation by using chiral Trost ligand in the synthesis of (-)-malyngolide (Scheme 49). 98

(+)-Cyclophellitol, an HIV virus inhibitor, was synthesized via palladium-based allylation using carboxylate nucleophile. 99 Pivalic acid was used as oxygen nucleophile in palladium- catalysed allylation using chiral Trost ligand to result in the adduct in 44% yield with 97% ee. This compound was a key intermediate for the synthesis of (+)-Cyclophellitol (Scheme 50).

OAc OAc OH OAc L OAc 7 steps OH Pd 2dba 3-CHCl 3, CH 2Cl 2, 15 HO

OAc Pivalic acid, H 2O, NaOH, rt, 24 h OAc OH O OAc OCO tBu (+)-Cyclophellitol 44%, 97%ee Scheme 50: Tsuji-Trost allylation in the synthesis of (+)-Cyclophellitol

Azides are interesting nucleophiles in allylation for the C-N bond formation, (-)-Epibatidine was synthesized via palladium-catalyzed stereoselective allylation using azide as nucleophile (Scheme 51). 100

98 Trost, B. M.; Tang, W.; Schulte, J. L. Org. Lett . 2000, 2, 4013. 99 Trost, B. M.; Hembre, E. J. Tetrahedron Letters . 1999, 40 , 219. 100 Trost, B. M.; Cook, G. C. Tetrahedron Lett . 1996 , 37 , 7485.

Mori et al used sulfonamides as nucleophiles in allylation reaction for the synthesis of (+)- Tubifoline (Scheme 52). 101

Imide-type nucleophiles were widely used in organic synthesis, Antifungal agent (+)- Polyxamic acid was synthesized using allylation with imide as a key intermediate. 102 Vinyl epoxide on treatment with phthalimide under palladium-catalyzed allylation with chiral ligand

L15 results in the formation of key intermediate with 82% ee and 87% yield, which after several synthetic transformations leads to (+)-Polyxamic acid (Scheme 53).

Allylation is also possible with other metals like Mo, 103 Fe, 104 Ir, 105 Rh 106 and Ru. 107

101 Mori, M.; Nakanishi, M.; Kajishima, D.; Sato, Y. Org. Lett . 2001 , 3, 1913. 102 Trost, B. M.; Krueger, A. C.; Bunt, R. C.; Zambrano, J. J. Am. Chem. Soc . 1996, 118, 6520. 103 (a) Belda, O.; Moberg, C . Acc. Chem. Res . 2004, 37 , 159. (b) Trost, B. M.; Hachiya, I . J. Am. Chem. Soc . 1998, 120, 1104. 104 (a) Plietker, B. Angew. Chem. Int. Ed. 2006, 45 , 1469. (b) Plietker, B. Angew. Chem. Int. Ed . 2006, 45 , 6053. (c) Rushi, T.; Tunge, J. A. Org. Lett., 2009, 11 , 5650. 105 (a) Takeuchi, R.; Kashio, M. Angew. Chm. Int. Ed. 1997, 36, 263.

I. 3. Selectivity issues in palladium-catalyzed Tsuji-Trost allylation of J-borylated allyl acetates:

J-borylated allylic acetates contain many reactive centres, especially when this substrate will be subjected to palladium catalysis (Scheme 54). Palladium can activate the allylic system, as well as the boronate present in the substrate. The activation of allylic system by replacing the acetate functional group, with palladium catalyst to give a S-allyl complex, followed by attack of nucleophile is called the Tsuji-Trost allylation reaction.

(b) Takeuchi, R.; Kashio, M. J. Am. Chem. Soc . 1998, 120, 8647. (c) Bartels, B.; Helmchen, G. Chem. Commun. 1999 , 741. (d) Bartels, B.; Garc õ´a-Yebra, C.; Rominger, F.; Helmchen, G. Eur. J. Inorg. Chem . 2002, 2569. (e) Kanayama, T.; Yoshida, K.; Takemoto, Y. Angew. Chem., Int. Ed. 2003, 42 , 2054. (f) Graening, T.; Hartwig, J. F. J. Am. Chem. Soc. 2005, 127, 17192. (g) Weihofen, R.; Tverskoy, O.; Helmchen, G. Angew. Chem., Int. Ed . 2006, 45, 5546. 106 (a) Evans, P. A.; Nelson, J. D. Tetrahedron Letters , 1998, 39 , 1725. (b) Evans, P. A.; Nelson, J. D. J. Am. Chem. Soc. 1998, 120, 5581. (c) Hayashi, T.; Okada, A.; Suzuka, T.; Kawatsura, M . Org. Lett . 2003, 5, 1713. (d) Evans, P. A.; Leahy, D. K. J. Am. Chem. Soc. 2000, 122, 5012. (e) Evans, P. A.; Robinson, J. E.; Nelson, J. D. J. Am. Chem. Soc. 1999, 121, 6761. 107 (a) Trost, B. M.; Fraisse, P. L.; Ball, Z. T. Angew. Chem. Int. Ed . 2002, 41 , 1059. (b) Morisaki, Y.; Kondo, T.; Take-aki, M. Organometallics , 1999, 18, 4742.

This allylation results in the formation of either branched or linear products, depending on the catalyst/ligand used. For example, palladium majorly gives linear products whereas molybdenum, iron and rhodium give branched products. In the case of iridium-catalyzed allylation, branched-type allylic substrates give branched products whereas linear-type allylic substrates tend to give mixtures. The main challenge in Tsuji-Trost allylation is selectivity.

J-borylated allylic electrophiles can display different reactivities towards metal complexes because of the multiple reaction sites present in these synthons and many selectivity issues can arise from their reaction. Therefore, J-borylated allylic acetates are interesting substrates to study selectivity issues in palladium catalyzed allylation.

Achieving selective palladium-catalyzed allylic substitution on J-borylated allylic derivatives with mild nucleophiles is a much greater challenge and leads “to mixtures of regioisomeric deboronation products and other unidentified materials” as noticed by Hall et al .108 The issue of chemoselectivity was not well documented for the substrates having many reactive sites.

Palladium-catalyzed reaction of J-borylated allylic acetates generate several selectivity issues (Scheme 54). 1. Issue of chemoselectivity between Tsuji-Trost (a) and Suzuki (a 1) reactions

2. Issue of regioselectivity during allylation of unsymmetrical S-allyl complex between 1 J-position (b) and D-position (b ). 3. Issue of stereoselectivity between stereoretention (c) and stereoinversion (c 1) during allylation.

Objectives:

Walsh et al reported palladium-catalyzed chemoselective allylation on E-borylated allylic 109 acetates, where the leaving group (acetate) is E-to the boron. However, the J -borylated allylic acetates offer challenge to perform allylation because of the multiple reactive sites

108 Peng, F.; Hall, D. G. Tetrahedron Lett . 2007, 48 , 3305. 109 Hussain, M. M.; Walsh, P. J. Angew. Chem. Int. Ed. 2010, 49 , 1834.

present in it. Palladium-catalyzed reaction of J-borylated allylic acetates generate chemo, regio and stereoselectivity issues shown in Scheme 54. Therefore, in the second chapter we will be interested in generating a S-complex from J-borylated allylic acetates inorder to study its reactivity in Tsuji-Trost allylation, as well as the chemo, regio and stereoselectivity of the reaction with various nucleophiles.

Chapter II: Palladium-catalyzed Tsuji-Trost allylation of J-borylated allyl acetates

II.1: Synthesis of J-borylated allyl acetates

II.2: Palladium-catalyzed Tsuji-Trost allylation of J-borylated allyl acetates

II. 1. Synthesis of J-borylated allyl acetates:

II. 1. i. From hydroboration of propargylic acetate systems:

25 According to previous reports, J-borylated allylic acetates can be synthesized via hydroboration of TMS-protected propargylic systems with pinacolborane. Deprotection of

TMS-protected J-borylated derivatives with citric acid affords stable J-borylated allylic alcohols in 70-76% yield. Subsequent acetylation with acetic anhydride leads to the final J- borylated allyl acetates in 75-80% yield. In this protocol removal of excess pinacolborane by silica gel chromatography was problematic. Hence, we moved to diisopinocampheylborane

(readily generated from D-pinene by hydroboration with borane-dimethylsulfide complex). Hydroboration was performed on propargylic acetates instead of TMS-protected propargylic alcohols (Scheme 55).

OAc R' THF BH R R' B(Ipc) 2 2 + Me 2S.BH 3 o o R 0 C to rt, 4 h -35 C to rt,16 h OAc

2 (Ipc) 2BH

o O 1. CH 3CHO / 40 C,16 h R' B R O 2. Pinacol / rt, 6 h AcO 64

Entry R R ' 64 Yield (%)

a. H H 64a 75

b. CH 3 H 64b 80

c. Ph H 64c --

d. CH 3 CH 3 64d --

Scheme 55: Hydroboration of propargylic acetates

Hydroboration of propargylic acetates with diisopinocamphenylborane was smoothly carried out from -35 oC to room temperature for 16 h. Refunctionalization of camphenyl derivative with acetaldehyde by refluxing for 16 h resulted in the diethylboronate which was transesterified with pinacol in one pot to give final J-borylated allylic acetates 64a and 64b in 75 and 80% yield respectively. This method was not successful when the R, R’ substituents at allylic position were Ph, H and Me, Me (Scheme 55, entries c and d). Indeed, in this case unseperable complex mixture was obtained, which didn’t show the required product by crude 1HNMR.

Another attempt by direct hydroboration of propargylic acetates with pinacolborane to give J- borylated allyl acetate derivative failed and no product was observed (Scheme 56). In this case starting material was not consumed.

Therefore, a modified method was developed for the preparation of J-borylated allyl acetate derivatives.

II. 1. ii. From hydroboration of propargylic alcohol systems:

Contrary to previous results with propargylic acetates, direct hydroboration of propargylic alcohols to give J-borylated allyl alcohol derivatives was successful with the four substrates. This protocol was more efficient in terms of yield (Scheme 57). Hydroboration of propargylic alcohols with diisopinocampheylborane, followed by refunctionalization with acetaldehyde, and transesterification with pinacol, afforded J-borylated allyl alcohol derivatives 65 in yields ranging from 75 to 80% (Scheme 57, entries a, b, c, d). The J -borylated allyl alcohol

derivatives were acylated to get the final J-borylated allyl acetate derivatives 66 in 85% yields. This protocol was more efficient than previous approaches.

OH R' THF BH R R' B(Ipc) 2 2 + Me 2S.BH 3 o o R 0 C to rt, 4 h -35 C to rt,16 h OH

2 (Ipc) 2BH

O O o Ac O, Et N 1.CH 3CHO / 40 C,16 h R' B 2 3 R' B R O R O 2.Pinacol / rt, 6 h DMAP, CH 2Cl 2 HO o AcO 65 0 C to rt, 2 h 66

Entry R R ' 65 Yield (%) 66 Yield (%)

a. H H 65a 80 66a 85

b. CH 3 H 65b 76 66b 85

c. Ph H 65c 75 66c 85

d. CH 3 CH 3 65d 79 66d 85

Scheme 57: Hydroboration of propargyl alcohols and synthesis of target molecules 66 II. 2. Reactivity of J-borylated allyl acetates under palladium catalysis:

As discussed earlier in Scheme 54, palladium-catalyzed reaction of J-borylated allylic acetates generate many selectivity issues, and our initial attempts on these substrates with palladium catalyst gave interesting results. The allylated branched-type product 67 (Table 6) was observed in good yield, and high regioselectivity under many reaction conditions. Product 68 was not observed although theoretically possible (Table 6). A high yield was observed for 1%

Pd(OAc) 2 and 3% PPh 3 catalytic system (77%, entry 1) when malonate was used as nucleophile. Increase in the ligand amount from 3% to 4% (entry 5) didn’t change the yield. Reactions failed with less ligand loading, i.e. less than 3% (entry 10). Investigation by using N-heterocyclic carbene ligands during allylation was not successful and even failed in t combination with different bases like K 2CO 3, KO Bu and triethylamine (entry 9). Pyridyl-type

ligands gave lower conversion, this might be due to the problem of coardination beween pyridyl ligand and palladium metal (entry 11).

MeO C CO Me MeO C CO Me OAc 1.1mol% [Pd] , n% ligand, 2 2 2 2 THF (or) B(pin) B(pin) B(pin) 2. MeO 2C CO 2Me 67 68 Na (1.1 eq) 3. rt to reflux, 4 h

Entry Catalyst Ligand Yield 67 (%)

1. Pd(OAc) 2 PPh 3(3%) 77

2. PdCl 2 PPh 3(3%) 72

3. [Pd(allyl)Cl] 2 PPh 3(3%) 76

4. Pd(OAc) 2 ---- 0

5. Pd(OAc) 2 PPh 3(4%) 77

6. Pd 2(dba) 3.CHCl 3 PPh 3(2%) 70

7. Pd(dba) 2 PPh 3(2%) 70

8. Pd(PPh 3)4 ---- 75

9. Pd(OAc) 2 NHC-carbene(3%) 0

10. Pd(OAc) 2 PPh 3(1%) 0

11. [Pd(allyl)Cl] 2 Pyridyl Trost(3%) 25

O O NH HN N N N N

(R,R)-DACH- pyridyl Trost ligand NHC-Carbene

Table 6: Optimization of catalytic system for regioselective allylation As expected, the reaction with Pd(II) alone without ligand wasn’t successful [Pd(OAc) 2, Entry 4] and the use of hindered phosphine ligand is required for this reaction. Other catalytic systems like Pd 2(dba) 3 and PdCl 2 along with PPh 3 ligand reacted smoothly to give almost similar yields (~70 %, entries 2 and 7). Catalysts like Pd(PPh 3)4, [Pd(allyl)Cl] 2 gave almost

equal yields to that of palladium(0) generated by reduction of Pd(OAc) 2 with PPh 3 (~75 %, entries 3 and 8). Catalyst loading of 1% is enough to carry out the reaction in good yields. Increased amount of nucleophile to 2 equivalents didn’t change the yield. A typical ratio of catalyst (1%) / ligand (3%) is required for the reaction to be successful. No products of direct transmetallation between boron and palladium were observed.

II. 2. i. Regioselectivity with carbon nucleophiles:

Keeping in view of easy handling, 1% Pd(OAc) 2/3% PPh 3 in THF was selected as catalytic system for allylation reaction using different nucleophiles. Using these optimized conditions, a variety of nucleophiles were tested for their chemo-, and regio-selective allylation and initially the attempts were carried out with enolate-type nucleophiles (Scheme 58).

Firstly, sodium salt of dimethylmalonate (generated by treatment of dimethylmalonate with

NaH) was used as nucleophilic source in the optimized catalytic system. The allylation on S- allyl complex with sterically less crowded substrates (when R, R 1 = H) gave 74% yield with ipso substitution (Table 7, entry 1). A little increase in the steric hindrance from hydrogen to methyl (when R= Me, R 1 =H) didn’t change the position of allylation and gave 77% yield

(Table 7, entry 2). Further increase in crowding from methyl to dimethyl group (when R, R 1 = Me) also resulted in the same type of allylation products in 80% yield (Table 7, entry 3).

Presence of the boron atom in the S-allyl complex drives allylation to J-position irrespective of the nuclophile used. In case of phenyl substituent, a lower 61% yield was obtained (Table 7, entry 4). This is unexpected, considering the traditional outcome of the Tsuji-Trost reaction in the presence of palladium complexes. However, another product 69d’was obtained in 15% yield by direct coupling of boronate moiety with malonate.

E-ketoester (3-oxobutyric acid methyl ester) was tested under these optimized conditions using NaH as base (Table 8). The unsubstituted J-borylated allylic acetate reacted smoothly to give a regioselective allylation product with substitution at J -position in 76% yield (Table 8, entry 1). Methyl and dimethyl substituted J-borylated allylic acetate derivatives underwent allylation reaction with E-ketoester nucleophile, in 80% and 83% yield respectively (Table 8, entries 2 and 3).

1,3-diketones (pentane-2,4-dione) underwent allylation with J-borylated allylic acetate derivatives to give regioselective allylation products at J-position (Table 9). Methyl-

susbstituted derivative in this allylation gave the product in 80% yield (Table 9, entry 1) whereas the dimethyl substituted derivative was obtained in 82% yield (Table 9, entry 2).

Cyanoacetates (methyl 2-cyanoacetate) also reacted efficiently under these allylation conditions, gave regioselective products with substitution at J-position in high yields (Table 10). In case of unsubstituted J-borylated allylic acetate derivatives, a 77% yield (Table 10, entry 1) was obtained. The methyl substituted derivative gave 80% yield (Table 10, entry 2) and the dimethyl substrate gave 79% yield (Table 10, entry 3).

Sterically hindered nucleophiles, such as 2-oxocyclopentanecarboxylic acid methyl ester, successfully underwent allylation reaction to give products with quaternary centers in very good yields. Unsubstituted (when R = H) J-borylated allylic acetate derivatives, in this reaction, gave the allylation product in 79% yield (Table 11, entry 1), whereas methyl

substituted (when R = Me) derivative gave 75% yield of the allylated product (Table 11, entry 2).

Allylation on J-borylated allylic acetate derivatives with aqueous NaCN resulted in J- borylated allylic alcohol derivatives instead of cyano group substitution at J-position. Another nucleophile generated from acetophenone (using NaH and t-BuOK) was not successful in this allylation.

II. 2. ii. One-pot allylation followed by Suzuki-Miyaura cross coupling:

The boronate moiety, present in allylation products after chemo-, and regio-selective allylation of J-borylated allylic acetates, can further be transformed via Suzuki-Miyaura cross coupling for new carbon-carbon bond formation (Scheme 59).

Starting from 70 the cross coupling was performed with phenyl iodide in THF along with 1%

Pd(OAc) 2 and 3% PPh 3 as catalytic system and using aqueous K 2CO 3. In the case of methyl substituent, sequential allylation ( 70a , 77% yield), followed by Suzuki cross coupling ( 71a, 91% yield), led to final product with an overall yield of 70% (Scheme 59, entry 1). Similarly, in the case of phenyl substituent, sequential allylation ( 70b, 61% yield), followed by Suzuki cross-coupling ( 71b, 75% yield), led to final product with an overall yield of 45% (Scheme 59, entry 2).

MeO C CO Me OAc 1.1% Pd(OAc) 2, 3% PPh 3, THF 2 2

R B(pin) 2. MeO 2C CO 2Me R B(pin) Na 70 3. rt to reflux, 4 h

1. Pd(PPh 3)4 1% MeO 2C CO 2Me 70 2. K 2CO 3, ArI, THF R Ar 3. rt to reflux, 6 h 71

Entry R Ar 70 yield (%) 71 yield (%)

1. Me Ph 70a 77 71a 91

2. Ph 4-Me-Ph 70b 61 71b 75

Scheme 59: Sequential allylation followed by Suzuki-Miyaura cross-coupling reaction

The above Suzuki cross-coupling reaction requires Pd(0) catalyst and the same Pd(0) catalyst was used for Tsuji-Trost allylation. Therefore, we were interested in performing Suzuki- Miyaura cross-coupling reaction and Tsuji-Trost allylation in the same pot. The residual palladium(0) after allylation efficiently participated in Suzuki-Miyaura cross-coupling to give double cross-coupled products in one-pot (Table 12).

It was observed that one-pot reaction gave good yields when compared with sequential cross- couplings. In the case of methyl substituent, the yield of one-pot strategy to obtain double cross-coupled product was 75% (Table 12, entry 1). This was more than the yield of sequential cross coupling, 70%. Similarly, dimethyl-substituted J-borylated allylic acetate (R,

R1 = Me) gave the one pot product in 76% yield (Table 12, entry 2) and for unsubstituted J- borylated allylic acetate (R, R 1 = H) this one-pot strategy gave 75% yield (Table 12, entry 3). In case of phenyl substituent the yield of one-pot sequence was 78% (Table 12, entry 4) which was superior to stepwise process where the yield was 45%.

II. 2. iii. Application of the one-pot strategy: In particular, it is very difficult to control the regioselectivity in allylation when both sides of 110 the S-complex is flagged by similar aromatic groups (Case 1). This one-pot method is useful especially to carry out selective allylation at desired position and the resulting boronate can be transformed to the required aryl group (Case 2) using Suzuki-Miyaura cross-coupling reaction (Scheme 60) in high yields.

110 Vonmatt, P.; Lloyd-Jones, G. C.; Pregosin, P. S. Helv.Chim.Acta . 1995, 78 , 265.

After solving the issue of chemo and regioselectivity we focused our studies on the development of stereochemistry and asymmetric allylation (which transforms the racemic material to enantiopure material). Preliminary investigation was carried with allylation of enantiopure J-borylated allylic acetate substrates. The stereochemistry of the products after allylation was studied to establish the absolute configuration.

II. 2. iv. Stereoselectivity:

The ( S)- J -borylated allylic acetate (ee> 99% by Chiral GC) was synthesized in the laboratory by the same route, but starting from commercially available optically pure propargylic alcohol. Allylation was performed on this ( S)-enantiomer using the same optimized conditions, i.e. 1 mol% Pd(OAc) 2 and 3 mol% PPh 3 with 1.1 equivalent of nucleophile (generated from freshly distilled dimethylmalonate on treatment with NaH). The allylation product 73 was obtained in 76% yield with 88% ee (Scheme 61). However, the absolute configuration can’t be assigned directly from this product at this stage. Hence, we were interested to convert 73 to an already existing product in order to establish the absolute configuration. The ambiguity between inversion or retention was solved when >99% ee compound (Table 13, entry 1) was cross-coupled with phenyl iodide using Suzuki reaction in order to measure the specific rotation of 74 (Scheme 61).

OAc MeO 2C CO 2Me 1% Pd(OAc) , 3% PPh , THF O 2 3 O (S) B B O MeO 2C CO 2Me , 4 h, reflux 73 O Na 88%ee, 76%yield (Table 13, entry 4)

MeO C CO Me 2 2 MeO 2C CO 2Me Pd(0), aq. Na 2CO 3 O B PhI, THF, reflux, 6 h (S) Ph 73 O 74

>99%ee D (Table 13, entry 1) Scheme 61: Stereochemistry of allylation

It was observed that 74 has specific rotation [ D]D = -70 ( c 1.8, CHCl 3) which can be compared with existing known compound. From literature, for (S ) product, the specific rotation for 74

111 was observed [ D]D = -51.2 ( c 1.8, CHCl 3), with 80% ee. Hence, the allylation product was assigned with absolute configuration ( S). Therefore, allylation of J-borylated allylic acetate proceeds with retention of configuration which is in agreement with the Tsuji-Trost allylation mechanism. According to Tsuji-Trost allylation, the S-allyl complex was formed by S N2 inversion followed by nucleophilic attack in S N2 inversion manner to result in double inversion product with overall retention of configuration. The high level of selectivity was observed with Trost ligands in allylation. These ligands are sterically crowded and readily form S-complex when treated with allylic acetates.

OAc 1% [Pd(allyl)Cl] 2 0.5%, L 2%, MeO 2C CO 2Me THF O B O (S) MeO C CO Me (S) B O 2 2 Na , 4 h, reflux O

Entry Substrate Ligand % yield % ee

1. ( S)-OAc ( S,S )-DACH phenyl 80 >99 ( S) Trost ligand (L 15 )

2. ( S)-OAc ( R,R )-DACH phenyl 80 >97( S) Trost ligand (L 15 )

3. ( S)-OAc ( R,R ) + ( S,S )-DACH 80 >98 ( S) phenyl Trost ligand(L 15 )

4. ( S)-OAc PPh 3 76 88 ( S)

Table 13: Stereochemical influence of ligands in allylation Matched pair in allylation, i.e. ( S)- J-borylated allylic acetate on allylation using ( S,S)-DACH phenyl Trost ligand, resulted in ( S)-product in 80% yield with ee >99% (Table 13, entry 1, HPLC A ), whereas the same ( S)-OAc on allylation with mismatched pair ( R,R )-DACH phenyl Trost ligand resulted in the same ( S)-product in 80% yield with 97% ee (Table 13, entry 2). It was quite surprising that both the Trost ligands resulted in the same configuration in the product. Therefore, we tested the ( S)-OAc on allylation with racemic mixture of Trost ligands, and the product was obtained with 80% yield and ee > 98% (Table 13, entry 3).

111 Plietker, B. Angew. Chem. Int. Ed . 2006, 45 , 1469.

Hence, the total stereochemical outcome of the reaction was essentially dependent on the substrate.

However there was 6% of the starting material that underwent racemization in case of PPh 3 (Table 13, entry 4), this could probably be due to 4h of reaction time which is sufficient for the S-complex to racemise during the reaction. The racemization could be due to S-V-S isomerisation which proceeds through a bond rotation in ( S-allyl)Pd complex (shown in Figure 2). 112

112 Kleimark, J.; Norrby, P-O. Top. Organomet. Chem . 2012, 38 , 65.

Asymmetric allylic alkylation (AAA) where the nonchiral or prochiral material was converted to chiral material during allylation was studied using J-borylated allylic acetates. Allylation with malonate as nucleophile along with several Trost ligands were investigated and the enantioselectivity was studied, starting from racemic J-borylated allylic acetates. The chiral ligands used in AAA of J-borylated allylic acetates are shown below:

Asymetric allylic alkylation with ( S,S)-DACH phenyl Trost ligand instead of triphenylphosphine resulted 80% yield with 78% ee (Table 14, entry 1) of ( S)-product, whereas the ( R,R)-DACH phenyl Trost ligand gave 80% yield with 72% ee of other enantiomer ( R)-product (Table 14, entry 2). Increase in ligand steric crowding from phenyl to naphthyl group, i.e. ( R,R)-DACH naphthyl Trost ligand in allylation, increased the yield up to 84% but resulted in a drastic decrease in enantioselectivity, 54% (Table 14, entry 3). Further increase in steric crowding from naphthyl to a modified diamine chiral ligand ( R,R)-ANDEN phenyl Trost ligand gave the other enantiomer ( S) with very good yields up to 85% but with tremendous decrease in selectivity, 30% (Table 14, entry 4) was obtained. Overall, increase in the steric hindrance of ligand decreased the enantioselectivity, and the simplest ligand turned out to give the best selectivities. The nitrogen-based pyridyl ligand, i.e. ( R,R)-DACH pyridyl

Trost ligand in this allylation, gave a low 25% yield and a very poor selectivity of 11% ee (Table 14, entry 5).

The boronate moiety obtained after allylation obtained can be transformed to other functional groups. For instance, Chan-Lam-Evans coupling of vinylboronates on treatment with sodium azide under copper catalyst affords efficient C-N bond formation to result in the J- functionalized vinyl azide 75 in 78% yield (Scheme 62).

In short, a chemo-, regio-, and stereo-selective allylation on J-borylated allylic acetates was achieved with carbon nucleophiles. A further study of allylation was studied on J-borylated

allylic acetates using nitrogen and oxygen based nucleophiles as the products can be useful bulding blocks.

II. 2. v. Regioselectivity with nitrogen nucleophiles:

Palladium-catalyzed reaction of J-borylated allylic acetates generate chemo-, regio- and stereo-selective issues. Allylation with nitrogen nucleophiles was investigated to confirm a general strategy for selective substitutions in J-borylated allylic acetates (Table 15). Preliminary experiments were carried out on the optimization of catalytic system using aniline as nucleophile. The branched-type products (Table 15, product 76 ) were obtained with high regioselectivity in good yields, and the other product 77 was not observed although theoretically possible. 1% [Pd(allyl)Cl] 2 and 3% PPh 3 system was found to give high 76% yield (Table 15, entry 3).

Ph Ph OAc 1.1mol% [Pd] , n% ligand, NH NH THF (OR) B(pin) B(pin) B(pin) 2. PhNH 2 (1.1eq), rt to reflux, 76 77 THF, 4 h

Entry Pd source Ligand (n%) Yield 76 (%)

1. Pd(OAc) 2 PPh 3 (3%) 70

2. PdCl 2 PPh 3 (3%) 65

3. [Pd(allyl)Cl] 2 PPh 3 (3%) 76

4. Pd(OAc) 2 ---- 0

5. Pd(OAc) 2 PPh 3 (4%) 70

6. Pd 2(dba) 3.CHCl 3 PPh 3 (2%) 70

7. Pd(dba) 2 PPh 3 (2%) 70

8. Pd(PPh 3)4 ---- 70

Table 15: Optimization of the catalytic system for nitrogen nucleophiles Carbene and nitrogen-based ligands were not efficient in this catalytic system, in the case of

carbon nucleophiles. Hence, those ligands were not tested in allylation with nitrogen nucleophiles. The most efficient catalytic system in allylation with malonate nucleophiles was found to be 1% Pd(OAc) 2 and 3% PPh 3 but in aniline allylation it resulted in a yield of 70% (Table 15, entry 1). Further increase in the ligand amount up to 4% didn’t change the yield

(Table 15, entry 5). As expected, palladium(II) catalyst alone i.e., Pd(OAc) 2, failed in this allylation (Table 15, entry 4). A low yield of 65% in this allylation was observed when the reaction was catalyzed by 1% PdCl 2 and 3% PPh 3 (Table 15, entry 2). Allylation with other catalytic systems like Pd(dba) 2 and Pd(PPh 3)4 gave yields similar to that of Pd(OAc) 2 (Table 15, entries 6 and 7). The optimized conditions in allylation with aniline on J-borylated allylic acetates was found to be 1% [Pd(allyl)Cl] 2 and 3% PPh 3. Therefore, this optimized catalytic system was used for extension studies. Only THF was used as solvent in all these allylations (Scheme 63).

Aniline was used as nucleophile with other substituted J-borylated allylic acetates derivatives. Studies were done by increasing the steric hindrance at J-position with different alkyl groups. The dimethyl-substituted derivative gave a high yield, 77% (Table 16, entry 3) on allylation.

The unsubstituted derivative reacted equally well to give a yield of 75% (Table 16, entry 1), whereas the methyl-substituted derivative resulted in a yield of 76% (Table 16, entry 2).

Aqueous sodium azide was successfully employed as nucleophile in allylation with J- borylated allylic acetates, using the optimized condition of 1% [Pd(allyl)Cl] 2 and 3% PPh 3. The unsubstituted derivative resulted in an excellent yield of 85% (Table 17, entry 1), while the methyl-substituted derivative gave a yield of 81% (Table 17, entry 2) and further increase in steric hindrance from methyl to dimethyl resulted in a yield of 80% (Table 17, entry 3).

OAc R 1. [Pd(allyl)Cl] 1%, PPh 3% HN 1 2 3 R R B(pin) + p- Anisidine 1 2. THF, rt to reflux, 4h R B(pin) 78

Entry R R 1 78 yield(%)

1. H H 78g 76

2. Me H 78h 73

3. Me Me 78i 78

Table 18: p-Anisidine as nucleophile p-Anisidine was also found to be a good nucleophile in this allylation, and the unsubstituted derivative gave a yield of 76% (Table 18, entry 1,). A little increase in steric hindrance by

methyl substitution resulted in a yield of 73% (Table 18, entry 2), whereas the disubstituted derivative gave a yield of 78% (Table 18, entry 3).

Several nitrogen nucleophiles such as pyrrolidine, aq. NH 4OH, allyl amine, succinimide, phthalimide, TMSN 3, TsNH 2, Bn 2NH, 4-nitroaniline, benzamide, tert -butyl carbamate, benzyl carbamate and heterocyclic bases such as imidazole, pyrrole and purine were not reactive, even in presence of added bases like NaH, t-BuOK under this catalytic system. Investigation of the allylation for a J-borylated allylic acetate, where phenyl group was presented at the allylic position, with aqueous sodium azide as nucleophile resulted in a direct coupling of nucleophile with boronate (Scheme 64).

Thus, a chemo-, and regio-selective allylation was obtained with nitrogen nucleophiles on J- borylated allylic acetates. The boron moiety presented in the products of allylation can be conveniently converted to other functional groups, like Suzuki-Miyaura, which involves a new C-C bond formation.

II. 2. vi. One- pot allylation followed by Suzuki-Miyaura cross coupling:

Palladium(0) presented after allylation was effectively catalyzing the Suzuki-Miyaura cross- coupling in a one-pot sequence (Table 19) to give double cross-coupled products. The dimethyl substrate resulted in an yield of 72% (Table 19, entry 2), whereas the methyl substrate resulted in 77% yield in a one pot reaction (Table 19, entry 1).

The boronate obtained after allylation can also be transformed to other functional groups like azide 81 via Chan-Lam-Evans cross-coupling with copper catalysis. This involves the treatment of vinylboronates with sodium azide in presence of copper catalyst like CuSO 4 in MeOH to yield J-functionalized vinyl azide in 80% yield (Scheme 65).

II. 2. vii. Stereoselectivity:

Palladium-catalyzed asymmetric allylation was studied, using nitrogen-based nucleophiles, on

J-borylated allylic acetate. Stereochemistry at J-position in allylation was assigned in comparison with already reported material. 113 Here, we performed allylation, followed by Suzuki-Miyaura cross-coupling in one-pot in order to establish the enantioselectivitiy (Table 20).

113 Plietker, B. Angew. Chem. Int. Ed . 2006, 45 , 6053.

Enantiomerically pure ( S)- J-borylated allylic acetate was subjected to one-pot allylation followed by Suzuki-Miyaura cross-coupling using 1% [Pd(allyl)Cl] 2 and 3% PPh 3, and resulted in ( S)- J-functionalized product in 76% yield and with 25% ee (Table 20, entry 4).

The specific rotation for 99% ee, (Table 20, entry 1) was found to be [ D]D = -120 ( c 1.0,

CHCl 3), and the product was assigned with configuration ( S) by comparison with the reported

(S)- J - functionalized product. From literature, for ( S) product, the specific rotation [ D]D = -4.6

(c 1.0, CHCl 3), this indicates an 83% ee]. Therefore a double inversion product was obtained during allylation, hence in agreement with the regular Tsuji-trost allylation mechanism. The influence of ligands on the stereochemistry during allylation of enantiomerically pure substrate with aniline as nucleophile was investigated. Matched pair in allylation, i.e. ( S)- J- borylated allylic acetate in combination with ( S,S)-DACH phenyl Trost ligand, gave the ( S)- product in 83% yield with >99% ee (Table 20, entry 1, HPLC B ), whereas the same ( S)- J- borylated allylic acetate on allylation with mismatched pair ( R,R)-DACH phenyl Trost ligand resulted in the same ( S)-product in 82% yield with 98% ee (Table 20, entry 2). So both Trost ligand enantiomers resulted in the same configuration for the product. Therefore, we were interested to test ( S)- J-borylated allylic acetate on allylation with a racemic mixture of Trost ligands and the product was obtained with 81% yield and ee>98% (Table 20, entry 3). Hence,

the total stereochemical outcome of the product in allylation with aniline is dependent on the substrate.

The higher level of selectivity in allylation was observed with Trost ligands. These ligands are sterically crowded and readily form stable S-complex when treated with allylic acetates. In case of PPh 3 ligand the starting material underwent racemization (Table 20, entry 4). The racemization in case of PPh 3 ligand could be due to bond rotation in ( S-allyl)Pd complex via S -V-S isomerisation (shown in Figure 2) considering 4 h of reaction time.

Racemic J-borylated allylic acetate was converted via asymmetric allylation to chiral J- borylated allylic synthons. Asymmetric allylation of J-borylated allylic acetates with ( S,S)- DACH phenyl Trost ligand resulted in 83% yield with 30% ee (Table 21, entry 1) of ( S)- product, whereas ( R,R)-DACH phenyl Trost ligand gave 83% yield with 63% ee of the other enantiomer ( R)-product (Table 21, entry 2). Increase in the ligand steric hindrance from phenyl to naphthyl group, using ( R,R)-DACH naphthyl Trost ligand, increased the yield up to 87% but the enantioselectivity was dropped to 5% (Table 21, entry 3). Further increase in steric hindrance, from naphthyl to a modified diamine chiral ligand, ( R,R)-ANDEN phenyl Trost ligand, gave the products in excellent yield of 90% but the enantioselectivity was very low 8% (Table 21, entry 4).

1. [Pd(allyl)Cl] 0.5%, L 3% OAc 2 NHPh THF B(pin) * Ph rac -OAc 2. PhNH 2 (1.1 eq), rt to reflux, 4 h 3. PhI, aq. Na 2CO 3, 6 h

Entry Substrate Ligand % yield % ee

1. rac -OAc ( S,S )-DACH phenyl 83 30 ( S) Trost ligand (L 15 ) 2. rac -OAc ( R,R )-DACH phenyl 83 63 ( R) Trost ligand (L 15 ) 3. rac -OAc ( R,R )-DACH naphthyl 87 5 ( R) Trost ligand (L 16 ) 4. rac -OAc ( R,R )-ANDEN phenyl 90 8 ( R) Trost ligand (L 17 ) 5. rac -OAc ( R,R )-DACH pyridyl 0 0 Trost ligand (L 18 )

Table 21: Asymmetric allylation with aniline, followed by Suzuki Miyaura in one pot Nitrogen-based pyridyl ligand, i.e. ( R,R)-DACH pyridyl Trost ligand, failed to give products (Table 21, entry 5). Sterically crowded ligands gave very poor selectivities, although excellent yields. The simple ligands gave good selectivities.

Chemo- and regio-selective allylation was also successful with J-borylated allylic acetates using oxygen nucleophiles and the products were obtained in 74% yield using 1mol%

Pd(OAc) 2 and 3mol% PPh 3 as catalytic system (Scheme 66).

II. 3. Some failure attempts of J-borylated allylic derivatives:

Here we indicate some reactions that we attempted but failed to give the desired product.

1. Trost allylation on trifluoroborate salts using aqueous sodium azide as nucleophile, under palladium (0) catalyst (Scheme 67).

This reaction was carried out with THF as the solvent and it was observed that the reaction has solubility problem and no product obtained. Hence we studied other solvents like acetone,

DMF and THF/H 2O. We also investigated the addition of base K 2CO 3 but all these attempts failed to give the desired product.

2. Haibo et al reported a palladium-catalyzed decarboxylative cross-coupling of aryl potassium aryltrifluoroborates with D-oxocarboxylic acids in the presence of K 2S2O8, resulting in the formation of aryl ketones as shown below (Scheme 68). 114

A similar reaction was attempted with J-substituted vinyl trifluoroborates on treatment with with D-oxocarboxylic acids in presence of K 2S2O8, but this reaction wasn’t successful to give the J-substituted D,E-unsaturated systems (Scheme 69).

114 Mingzong, L.; Cong, W.; Haibo, G. Org. Lett . 2011 , 13 , 2062.

3. Meike et al reported a Friedel-Crafts alkylation at room temperature with calcium and lithium salts (Lewis acid) as catalysts. Allylic alcohol on treatment with resorcinol dimethyl ether, under lithium or calcium Lewis acid catalyst, results in the formation of alkylated product (Scheme 70). 115

This type of Friedel-Crafts alkylation was attempted on J-borylated allylic alcohol but no alkylated product was observed even after 48 h of reaction time, and the starting material was completely unreactive for this catalytic reaction (Scheme 71).

4. Grubb’s et al reported a 1,3-isomerization of allylic alcohols via rhenium oxo catalysis 116 using O 3ReOSiPh 3 as catalyst, under very mild conditions in 30 min (Scheme 72).

115 Meike, N.; Matthias. J. M. Angew. Chem., Int. Ed. 2010, 49, 3684. 116 Morrill, C.; Grubbs, R. H. J. Am. Chem. Soc. 2005, 127, 2842.

A similar 1,3-isomerization of allylic alcohol was studied using J-borylated allylic alcohol under same conditions as mentioned, but it was observed that only the starting material was present after 30 min reaction time. The prolonged reaction times like 1h, 2h, 4h, 8h and 24h resulted in the same starting material only, and no isomerized product was isolated (Scheme 73).

Conclusion:

A chemo-, regio-, and stereo-selective allylation was achieved on J-borylated allylic acetates using carbon, 117 and nitrogen nucleophiles. Overall, we have managed to use a highly functionalized three-carbon building block in a chemo-, regio-, and stereoselective manner. The resulting products could be used in a large variety of transformations taking advantage of further reactions of the pinacol boronate moiety.

117 Kukkadapu, K. K.; Ouach, A.; Lozano, P.; Vaultier, M.; Pucheault, M. Org. Lett . 2011, 13 , 4132.

Chapter III: Chemo enzymatic resolution of J-borylated allylic alcohols in continuous flow systems

using ionic liquids & sc CO 2

Introduction:

Organic solvents play an important role in organic chemistry to get a successful chemical reaction. In majority these organic solvents are volatile and generate organic waste which were not environmentally acceptable and should be avoided. In green chemistry 118 replacing hazardous solvents with environmentally benign solvents is highly attractive. These problems led to identify alternative solvents like supercritical fluids 119 and ionic liquids 120 which are considered as best alternatives for organic solvents.

III. 1. Ionic liquids as solvents in green biocatalysis:

Ionic liquids attracted great attention as green solvent and were used in large number of chemical transformations. 121 Ionic liquids are low-melting onium salts composed solely of anions and cations that are liquids, at or below 100 °C. The combination of bulky organic cations and inorganic or organic anions counterparts lowers the lattice energy thereby melting point is diminished for the resulting salts. 122 Ionic liquids differs from molten salts like sodium chloride (which are high-melting salts). Ionic liquids are non-volatile, exhibit very low vapor pressure. They are highly polar, recyclable and thermally stable up to 400 °C (safe to use at high temperatures) and can dissolve organic and inorganic materials. Many reactions have been reported using ionic liquid media like Friedel-Crafts reaction, 123 olefin metathesis, 124 hydrogenation, 125 hydroformylation, 126 etc. Ionic liquids are green solvents and very good alternatives for organic solvents. Synthesis of enantioenriched products using enzyme catalysts under organic solvent free media is called green biocatalysis. Green biocatalysis in ionic liquids attracted the interest of scientists to perform different reactions for

118 Collins, T. Science 2001 , 291, 48. 119 Nayori, R. Chem. Rev. 1999, 99, 353. 120 Riisager, A.; Fehrmann, R.; Haumann, M.; Wasserscheid, P. Top. Catal. 2006, 40 , 91. 121 Wasserscheid, P. Ionic Liquid in Synthesis : Wiley VCH , 2007 . 122 Hamaguchi, H-O.; Ozawa, R. Adv. Chem. Phys. 2005, 131, 85. 123 Ross, J.; Xiao, J. Green Chem. 2002, 4, 129. 124 Yao, Q.; Zhang, Y. Angew. Chem., Int. Ed. 2003, 42 , 3395. 125 Obert, K.; Roth, D.; Ehrig, M.; Schoenweiz, A.; Assenbaum, D.; Lange, H.; Wasserscheid, P.; Appl. Catal., A 2009, 356, 43. 126 Hamza, K. ; Blum, J. ; Eur. J. Org. Chem. 2007, 4706.

green chemistry development. It is a highly effective approach for pollution prevention. Minimising the formation of side products and the design of new methodologies for obtaining pure products are becoming challenging problems. Enzyme catalysis in ionic liquids can solve this up to certain extent. The high catalytic efficiency of enzymes in ionic liquids is now well documented. 127

However, organic solvent was often used to isolate products from ionic liquids, which is a drawback for green process development. Alternative strategies were reported in literature like membrane technology developed for isolating ( S)-ibuprofen from ( rac )-ibuprofen. 128

Isolation of products from ionic liquid media by another green solvent such as sc CO 2 is considered to be the most interesting strategy for developing a clean & green chemical process.

III.2. Green biocatalysis in supercritical carbon dioxide (sc CO 2):

Supercritical carbon dioxide (sc CO 2) brings the attention of scientists regarding its use as green solvent in continuous flow systems. This is due to its ability to extract, dissolve and transport the chemicals in gas phase. It is a compressed CO 2 gas. Hence, a heterogeneous system can be successfully employed for reactions in sc CO 2. Biphasic systems based on ionic liquids and supercritical carbon dioxide ( sc CO 2) represent interesting alternatives to organic solvents for designing continuous clean bio transformations in non-aqueous environment that 129 directly provide pure products. The reaction with sc CO 2 under heterogeneous medium was successfully carried out for many synthetic transformations like kinetic resolution, 130 dynamic kinetic resolution 131 and other synthetic reactions. 132 The enzyme immobilized on ionic liquid support (IME) was used as solid support and the substrate along with sc CO 2 used as mobile

127 Lozano, P. Green Chem. 2010, 12, 555. 128 Branco, L. B.; Crespo, J. G.; Afonso, C. A. M. Chem. Eur. J. 2002, 8, 3865. 129 Lozano, P.; Vaultier, M. Green Chem. 2007, 9, 780. 130 Tomoko, M.; Kazunori, W.; Tadao, H.; Kaoru, N.; Yoshitaka, A.; Yukihiro, Misumi.; Shinichiro, I.; Takao, I. Chem. Commun. , 2004, 2286. 131 Lozano, P.; Diego, T. D.; Mira, C.; Montage, K.; Vaultier, M.; Iborra, J. L. Green Chem. 2009, 11 , 538. 132 (a) Huabin, X.; Tao, W.; Youyuan. D.; J. Supercrit. Fluids , 2009, 49 , 52. (b) Firas, Z.; Lasse, G.; Peter, S. S.; Alexei, L.; Walter, L. Chem. Commun. , 2008, 79.

phase. The reactor was filled with IME, known concentration of substrate was pumped through the reactor using controlled flow of sc CO 2. The reaction occurs on solid support with very less residence time, the products after passing through the heterogeneous support will be collected at the collection chamber and the compressed sc CO 2 gas is recycled back to the cylinder by condensation process using back pressure (Picture 1). Enzymes tend to lose their activity when heated because of denaturation . But enzymes on ionic liquid support don’t lose their activity even at high temperatures. The stability of enzyme on ionic liquid support along with sc CO 2 even at high temperatures are key parameters for carrying out integral green bioprocess in continuous operation.

III. 3. Literature data on the mechanism of resolution using Candida Antartica Lipase (CAL-B or Novozyme-435):

The enantioselectivity in acetylation of enzyme (CAL-B or Novozyme-435) is due to the oxyanion active site (Picture 2). It’s a tetrahedral coordinate geometry obtained by the hydrogen bonding interactions of Ser-His-Asp triad. 133 The spatial arrangement of hydrogen- bond donors in the active site lowers the free energy of the transition state. The oxyanion is stabilized by two backbone amide hydrogen atoms and the side-chain hydroxyl group of

133 Anders, M.; Kar, H.; Mats, H. J. Am. Chem. Soc . 2001, 123, 4354-4355.

Thr40. The transition state of trans-esterification proceeds through an oxyanion and this active site introduces the enantioselectively in acetylation.

A typical enantioselective acetylation (Mechanism 4) involves the interaction of acylating agent to the active site of Ser-His-Asp protein, A, and a tetrahedral intermediate, B, is formed. The alcohol part of the ester leaves and an acyl enzyme is formed, C. A second tetrahedral intermediate, D, is formed after nucleophilic attack by a second alcohol. The newly formed ester leaves, completing the catalytic cycle.

Mechanism 4: Reaction mechanism of trans -acetylation Lozano et al reported an efficient kinetic resolution of racemic 1-phenylethanol in continuous flow process by selective acetylation of benzylic alcohols on treatment with CAL-B (Scheme 74), affording the products in equal yields with high selectivity. 134 The racemic 1-

134 Lozano, P.; Diego, T. D.; Carrié, D.; Vaultier, M. Chem. Comm. 2002, 692.

phenylethanol reacts with CAL-B and only the ( R)-OH converts to ( R)-OAc whereas ( S)-OH remains unreacted for this catalytic system.

III. 4. Kinetic resolution of J-borylated allylic alcohols in ionic liquids:

Andrade et al 135 reported the first application of enzymes as catalysts for synthesizing enantiopure boron compounds via enantioselective acetylation (Enzyme-catalyzed kinetic resolution) in n-hexane as solvent. Kinetic resolution being used for separating the two enantiomers of a racemic mixture, the chemical yield of the process will be limited to 50%. Various types of aromatic, allylic and aliphatic secondary alcohols containing boronates were acetylated using this protocol. High enantioselectivities, more than 98%, were obtained.

In our laboratory we were interested to investigate the kinetic resolution of J-borylated allylic alcohols under solvent free media (Scheme 75). Furthermore, we wanted to apply this

135 Andrade, L. H.; Barcellos, T. Org. lett. 2009, 11, 3052.

knowledge to continuous flow reactor with sc CO 2 in order to develop continuous kinetic resolution of J-borylated allylic alcohols.

OH OH OAc OAc (3.0 eq), CAL-B O * O * O B B + B Ionic Liquid, 50 oC, t min 50% 50% O O O (+,-)- rac OH (S)-OH (R)-OAc

Scheme 75: Kinetic resolution of -borylated allylic alcohols under solvent free media with CAL-B

Chemoenzymatic resolution of J-borylated allylic alcohols by selective acetylation with vinyl acetate in ionic liquids was developed using CAL-B as enzyme at 50 oC. Preliminary experiments were focused on optimising the catalytic system in different ionic liquids. Various ionic liquids were screened based on their chain length (butyl, octyl, and dodecyl), anionic counterpart (NTf 2, BF 4, PF 6), and cationic counterpart: Ammonium (BTMA & TBMA), Imidazolium (BMIM), Pyrrolidinium (BMPy), Piperidinium (BMPi).

The reaction mixture samples were injected into chiral GC to study the reaction profile at different reaction times. The relative conversion of racemic alcohol with respect to time to obtain enantiopure products was plotted in graph to find enzyme activity in ionic liquids. The ionic liquids used in kinetic resolution are shown below:

III. 5. Enzyme activity in Ionic liquids:

In kinetic resolution (Scheme 75), enzyme acetylates only ( R)-OH to ( R)-OAc. The only product formed is ( R)-OAc whereas the ( S)-OH present in the racemic mixture remains unreactive, hence products obtained in this reaction were ( S)-OH and ( R)-OAc. But after prolonged reaction times under enzyme catalysis we observed that ( S)-OH can also be acetylated to ( S)-OAc in minor yields (~3-5%). Therefore, we focused to optimize the catalytic system with less reaction time, high yield and good selectivity. Here the results were taken based on the ( R)-OAc product formation. Various ionic liquids were screened for optimisation of kinetic resolution. It is to be noted that these reactions were performed under non-inert conditions. Enzyme activity (efficiency per milligram quantity of immobilized enzyme used) is the key factor to obtain kinetic resolution. Enzyme activity is the rate at which resolution occurs, the more enzyme activity results more efficient catalytic system.

A chemoenzymatic enantioselective acetylation was performed on J-borylated allylic alcohol (0.01g, 0.05mmol) with vinyl acetae (0.015 mL, 0.15mmol) in 0.485 mL of ionic liquid using 0.01 g of CAL-B enzyme at 50 oC. This reaction was monitored using different ionic liquids and the results were plotted in graph between time and rate of conversion and the reaction was monitored at regular intervals of time (15 min, 30 min, 1h, 2h, 4h, 6h, 8h, 24h).

Calculation of enzyme activity for [BTMA][NTf 2] ionic liquid:

The enzyme activity was calculated from [BTMA][NTf 2] ionic liquid reaction profile (kinetic resolution) by plotting the reaction progress with respect to time in minutes (Graph 1).

The enzyme activity was found by multiplying the slope of Graph 1 with the concentration

(Pmol) of the substrate per mg of enzyme used. In case of [BTMA][NTf 2] ionic liquid the slope from this graph was found to be 0.44. The concentration of the substrate used was 50.51

Pmol per 10 mg of enzyme.

Slope x Pmol of substrate Enzyme activity = mg of enzyme used

Enzyme activity in 0.44 x 50.51 = = 2.2 U/mg of IME [BTMA][NTf ] 2 10

The enzyme activity in [BTMA][NTf 2] was found to be 2.2 U/mg of IME. Similarly, enzyme activity was calculated for other ionic liquid reactions to optimise the reaction conditions.

III. 6. Optimisation of kinetic resolution:

A high enzyme activity was found in case of NTf 2-based ionic liquids, compared to PF 6 and

BF 4 ionic liquids. Kinetic resolution in NTf 2-based ionic liquids having ammonium as cationic counterpart like [BTMA] and [TBMA] ions showed similar enzyme activity of 2.2 and 2.4 respectively with conversion upto 40% at 2 h and 51% at 6 h of reaction time with a selectivity >99% (Table 22, entries 4 and 5). Changing the cationic counter ion of the ionic liquid from ammonium to imidazolium by using [BMIM][NTf 2] showed an increased enzymatic activity to 2.7, with conversion upto 45% with 99% selectivity were obtained at 2 h, and 51% conversion at 6 h with selectivity of 89% were obtained (Table 22, entry 1). By increasing the chain length of imidazolium ionic liquid from butyl to octyl by using

[OMIM][NTf 2], enzyme activity increased to 6.3 with 49% conversion at 2 h and 50% conversion at 6 h with selectivity of 99% (Table 22, entry 2). Further increase in chain length from octyl to dodecyl by using [C 12 MIM][NTf 2] gave a high enzymatic activity of 7.6 with 50% conversion and selectivity >99% (Table 22, entry 3).

Other cationic counter ions based on pyrrolidinium [BMPy] and piperidinium [BMPi] showed low enzymatic activities of 2.8 and 3.3 respectively with moderate conversion of 45% and 48% at 2 h with 99% selectivity, the selectivity was further decreased to 90% at 6 h (Table 22, entries 6 and 7).

Ionic liquid based on BF 4 anionic counterpart, [BMIM][BF 4], showed enzyme activity of 4.9 with a conversion of 44% at 2 h and 48% conversion at 6 h with 99% selectivity (Table 22, entry 11). Increasing chain length from butyl to dodecyl by using [C 12 MIM][BF 4] reduced the enzyme activity to 1.8 and the conversion was very poor, 26% at 2 h and 29% at 6 h (Table 22, entry 12).

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Entry Ionic liquid Enzyme activity % Conversion a %Conversion a (U/mg IME) (%ee) at 2 h (%ee) at 6 h

1. [BMIM][NTf 2] 2.7 45 (>99) 51 (89)

2. [OMIM][NTf 2] 6.3 49 (>99) 50 (>99)

3. [C 12 MIM][NTf 2] 7.6 50 (>99) 50 (>99)

b 4. [BTMA][NTf 2] 2.2 39 (>99) 51 (>99)

b 5. [TBMA][NTf 2] 2.4 41 (>99) 51 (>99)

6. [BMPy][NTf 2] 2.8 45 (>99) 50 (90)

7. [BMPi][NTf 2] 3.3 48 (>99) 49 (91)

8. [BMIM][PF 6] 3.3 46 (88) 49 (74)

9. [OMIM][PF 6] 1.8 32 (99) 48 (99)

10. [C 12 MIM][PF 6] 1.8 40 (99) 49 (85)

11. [BMIM][BF 4] 4.9 44 (99) 48 (99)

12. [C 12 MIM][BF 4] 1.8 26 (99) 29 (99) aThis conversion was evaluated from chiral GC based on the ( R)-OAc formation in the reaction b Possible integration error in chiral GC

Table 22: Enzyme activity in ionic liquids

Ionic liquids based on PF 6 anionic counter part gave a poor conversion. In case of

[BMIM][PF 6], the enzyme activity was found to be 3.3 with 46% conversion and poor selectivity (88%) at 2 h whereas the conversion was increased to 49% but tremendous drop in selectivity was observed, 74% at 6 h (Table 22, entry 8). Increasing the chain length from butyl to octyl decreased the enzyme activity from 3.3 to 1.8 with a conversion of 32% at 2 h, whereas it is 48% at 6 h with selectivitiy up to 99% (Table 22, entry 9). Using further increased chain lengths from octyl to dodecyl resulted in enzyme activity of 1.8 with a conversion of 40% at 2 h, and 49% at 6 h with selectivity of 85% (Table 22, entry 10). The low yields may be due to the hygroscopic nature of these ionic liquids which tend to absorb

101

moisture and the presence of water in reaction medium might hydrolyze the acetylated enzyme to acetic acid and thereby enantioselective acetylation process was arrested.

From the above results, high enzymatic activity of 7.6 (U/mg of IME) was found for

[C 12 MIM][NTf 2] ionic liquid. Kinetic resolution using ionic liquids occurs in 2 h, faster than with organic solvents like n-hexane for which the reaction time was 12-14 h.

III.7. Effect of water in kinetic resolution:

A study has been conducted to know the effect of added water on the reaction profile. The ionic liquid [OMIM][NTf 2] was tested under the reaction conditions of Scheme 75 and it was observed that increased amount of water decreased the product formation (From Table 23). The conversion, when no water was added at 30 min, was 36% which was decreased to 25% when 2 PL of water was added, and the conversion did not reach 50% even at 8 h of reaction.

Amount of water 0 PL 2 PL 4 PL 6 PL 8 PL added

%of ( R)-OAc 36% 25% 15% 10% 8% formed at 30 min

%of ( R)-OAc 50% 42% 36% 25% 20% formed at 8 h

Table 23: Reaction profile by the addition of water

A further amount of added water to 8 PL gave less conversion (only 8% conversion was observed at 30 min which reached to 20% after 8 h). This could be due to hydrolysis of acetylated enzyme which stops the chemoenzymatic kinetic resolution. Therefore it was necessary to perform the reaction in ionic liquids under water free conditions.

III.8. Recyclability of ionic liquids:

After solving the issue of low conversion we were interested to study the recyclability of the catalytic system. Recyclability test was studied using [C 12 MIM][NTf 2] ionic liquid as in

102

Scheme 32. After 1 st reaction cycle the products were extracted from the reaction media using n-hexane or ethyl acetate (3 times each) and the same media (which contains the ionic liquid and enzyme) was used for the second reaction cycle. It was observed that the second reaction cycle showed the same productivity (Table 24) in 50% yield and selectivity >99% after 2 h and 6 h. The enzyme activity remains unchanged for two consecutive reactions, therefore we were interested to make use of this catalytic system as a heterogeneous solid support for continuous flow systems.

III. 9. Kinetic resolution using continuous flow systems:

Enzymes can be immobilized 136 (IME) on solid supports while keeping their activity and stability. Then, fixed-bed reactors can be used for heterogeneous enzymatic catalysts using ionic liquid/ sc CO 2 mixtures as solvent in continuous flow systems allowing for the synthesis of products in very good yields and selectivities. The main advantages of sc CO 2 are its ability to extract, dissolve and transport chemicals. Enzyme behaviour in sc CO 2 and ionic liquids, as well as the phase behaviour of ionic liquids/ sc CO 2, are key parameters for carrying out integral green bioprocess in continuous operation.

136 González-Sab õғn, J.; Gotor, V.; Rebolledo, F. Tetrahedron Asymmetry 2002, 13 , 1315.

103

Firstly, the enzyme was immobilised on ionic liquid using acetonitrile as solvent and the acetonitrile was removed by evaporation. This solid support was used in a continuous flow reactor (Picture 4). This continuous flow reactor was operated using sc CO 2 as solvent, which is a compressed gas, and the flow was controlled using a pressure regulator. The substrate was diluted in hexane (for a typical lab-scale experiment) connected with pump to control the flow rate of substrate. A controlled flow system having heterogeneous support at 50 oC was experimented initially using CAL-B and [BMIM][NTf 2] as heterogeneous support (Scheme 76). This total operation will not result in any organic waste, the products after passing through the heterogeneous support will be collected at the collection chamber and the compressed sc CO 2 gas will be recycled back to the cylinder by condensation process using back pressure. In normal lab-scale experiment, this compressed gas after collecting the product was left to the atmosphere.

OH OAc OAc CAL ͲB/IL * O * O B + B sc CO 2 O O (S)-OH 50 oC products (R)-OAc

III. 10. Results and discussion:

Initial experiments were focused to optimize the reaction system under continuous flow systems using solid support made of CAL-B and [BMIM][NTf 2], with a total flow rate of

1mL/min of mobile phase (0.1 mL substrate and 0.9mL of sc CO 2) at 100 bars while maintaining the heterogeneous support at 50 OC. The enzyme activity under continuous flow

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systems was calculated by multiplying concentration with percentage of conversion of the product per gram of enzyme used.

For example, in the first continuous flow reaction, the substrate concentration was 6 Pmol/h, whose conversion rate was found to be 40% using 0.18 g of enzyme on solid stationary phase.

The enzyme activity per gram of enzyme used was found to be 13.3 Pmol/h/g (Table 25, entry 1). The kinetic resolution was done continuously for 8 h in a day and a 40% conversion was observed. Enzyme activity didn’t change when the same heterogeneous support was used for the second time of another 8 h operation (Table 25, entry 2). However, the full conversion was not reached but we observed reproducibility. Changing the concentration to 12 Pmol/h, while keeping same heterogeneous support for 3 rd time operation of 8 h, was done. Here, the concentration was doubled but still the conversion remains 40% whereas the enzyme activity was doubled to 26.6 Pmol/h/g (Table 25, entry 3). However, the full conversion was not reached.

Therefore, to increase the conversion rate, another ionic liquid where the enzyme activity was better than with [BMIMNTf 2] ionic liquid was studied (from Table 25). Investigation by other ionic liquid [OMIM][NTf 2] along with CAL-B as heterogeneous support resulted in very good yields with high selectivity under continuous flow operation. The total flow rate of mobile phase is 1 mL/min (0.05 mL of substrate and 0.95 mL of sc CO 2) at 100 bars pressure and heterogeneous support was maintained at 50 oC. The continuous flow operation using 3

Pmol/h concentration gave the products in good conversion of 50% with high selectivity of >99% (Graph 2) after 8 h of continuous operation.

105

In the continuous flow reaction using [OMIM][NTf 2], the substrate concentration was 3 Pmol/h, whose conversion rate was found to be 50% using 0.16 g of enzyme on solid stationary phase.

The enzyme activity remains the same for very long operation times. Upto 8 h, it was found to be 9.03 Pmol/h/g (Table 25, entry 4). Another day of operation for 8 h with 3 Pmol/h concentration of the substrate gave the same enzymatic activity of 9.03 Pmol/h/g with 50% conversion and >99% selectivity (Table 25, entry 5). By changing the flow rate from 0.05 mL to 0.1 mL of substrate (which increases the concentration to 6 Pmol/h) it was observed that the enzymatic activity was doubled to 18.07 Pmol/h/g with a conversion of 50% and selectivity of >99% (Table 25, entry 6). Therefore, enzyme activity remains the same after 3 days of continuous operation by changing flow rate and concentration.

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Entry CAL-B Concentration Flow Rate %Conversion Enzyme Time of on Ionic ( L/min) & activity operation liquid ( mol/ h) %ee ( mol/h)

1. [BMIM][NTf 2] 6 0.1 40 (99.9) 13.3 8 h

2. [BMIM][NTf 2] 6 0.1 40 (99.9) 13.3 8 h

3. [BMIM][NTf 2] 12 0.1 40 (99.9) 26.6 8 h

4. [OMIM][NTf 2] 3 0.05 50 (99.9) 9.03 8 h

5. [OMIM][NTf 2] 3 0.05 50 (99.9) 9.03 8 h

6. [OMIM][NTf 2] 6 0.1 50 (99.9) 18.07 8 h

Table 25: Kinetic resolution in continuous flow under sc CO 2/IL system

Conclusion:

Candida Antarctica Lipase B (CAL-B)-mediated enantioselective acetylation of J-borylated racemic allylic alcohols using vinyl acetate as acyl donor led to almost enantiomerically pure

J-borylated allylic acetates and alcohols in high yields (> 99%) and high selectivities (ee>99%) under solvent free media. This highly efficient kinetic resolution was done in continuous flow systems for 3 days. Thus on a long term basis the ionic liquids/ sc CO 2 biphasic system is efficient and working without the loss of activity of the enzymatic system. This constitutes an example of a truly environmental benign green process.

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PART-B

Experimental

108

General Procedures. All reactions were carried out using oven-dried glassware under Argon atmosphere or unless specified. Ether, THF, hexanes, pentane, and toluene, distilled from Na /

Benzophenone; DMF, benzene, CH 2Cl 2, and CHCl 3, distilled from CaH 2; Ethyl acetate, Heptane and acetone, simple distillation; stored over molecular sieves. All reagents were purchased from Sigma-Aldrich, Acros chemicals or Alfa Aesar and used without further purification unless specified. Analytical thin layer chromatography (TLC) was carried out using 0.25 mm silica plates purchased from Merck. Eluted plates were visualized using

KMnO 4 stain or anisaldehyde stain. Silica gel chromatography was performed using 230–400 mesh silica gel purchased from Merck.

NMR spectra were recorded on standard 300 MHz FT spectrometers instrument Bruker FT 1 NMR (AVANCE 300) which referenced to the residual solvent signals ( H: CDCl 3, 7.26 ppm; acetone-D5, 2.05 ppm, CD 3OD, 3.31ppm, D 2O, 4.79 ppm, CD 3CN, 1.94 ppm, DMSO, 2.25 13 ppm; C: CDCl 3, 77.0 ppm; acetone-D6, 29.9 ppm, CD 3OD, 49 ppm, CD 3CN, 1.32 ppm and 118.26 ppm, DMSO, 39.52 ppm) and recorded at 20-25 0C on a Bruker FT NMR instrument

(AVANCE 300). NMR spectra are reported as chemical shifts in G values in ppm relative to calibrated CDCl 3. Splitting patterns are abbreviated as follows: singlet (s), doublet (d), triplet (t), quartet (q), multiplet (m), doublet of doublet (dd), triplet of doublet (td), doublet of triplet (dt). Determination of enantiomeric excesses was carried out using Waters HPLC 600 controller and pumps, equipped with a 2996 Photodiode Array Detector. Unless specified, chromatographic conditions used for enantiomers separation were: - Chiralpak AS-H 250mm column and Chiralpak AD-H 250mm columns - 90/10 n- hexane / iPrOH mixture as mobile phase at 1mL/ min flow rate.

High-resolution mass spectra (HRMS) were recorded using a Waters-MicroMass analytical LCT (ESI) spectrometer and obtained from the CRMPO analysis center at the University of Rennes1.

Kinetic resolution was determined by GC using E-DEX 110 Cyclodextrin Supelco chiral column. Optical rotations were measured by using a Perkin- Elmer model 141 polarimeter. Solution of compounds was prepared in spectroscopic grade solvent.

109

Chapter-II Experimental:

II. 1. i. Synthesis of J -borylated allyl acetates from hydroboration of propargylic acetates (Scheme 55):

In a dried schlenk 26 mmol of freshly distilled Į-pinene was added to 26 mmol of o BH 3.THF in 20 mL dry THF at 0 C slowly for a period of 10 min and slowly warmed to rt for 4 h. A white suspension of diisopinocampheylborane observed which was cooled to -35 oC, 26 mmol of propargylic acetate derivative was slowly added for a period of 30min allowed to warm to rt, stirred for 5 h at rt and 260 mmol of freshly distilled acetaldehyde was added at 0 oC and heated the reaction at 45 oC for 12 h. Distilled off the excess acetaldehyde and 26 mmol of pinacol was added at rt and stirred for another 5 h. The solvent was removed and the residue was purified on silicagel column chromatography.

Acetic acid 3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-allyl ester (64a):

O AcO B O

Yield : 4.40 g (75% ) 1 H NMR (300 MHz, CDCl 3) G 6.61 (td, 1H, J = 4.67 Hz, J = 18.1 Hz), 5.66 (td,1H, J = 1.8 Hz, J = 18.1 Hz), 4.65 (dd, 2H, J = 1.81 Hz, J = 4.67 Hz), 2.05 (s, 3H), 1.23 (s, 12H);

13C NMR (75 MHZ, CDCl 3) G 11 BNMR (CDCl 3) G .

110

Acetic acid 1-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-allyl ester (64b):

OAc O B O

Yield : 4.98 g (80%)

Rf 0.60 (Heptane/Ethyl acetate (5:1)). 1 H NMR (300 MHz, CDCl 3) G 6.42(dd, 1H, J = 4.7Hz, J = 18.1Hz), 5.45 (dd,1H, J= 18.1 Hz, J= 1.6 Hz), 5.25-5.35 (m, 1H), 1.94 (s, 3H), 1.19 (d, 3H, J = 6.6 Hz), 1.15 (s,12H); 13 C NMR (75 MHz,CDCl 3) G 170.1, 151.1, 83.0, 71.2, 24.7, 21.1, 19.5; 11 BNMR (CDCl3) G .

II. 1. ii. Hydroboration of propargylic alcohols and synthesis of target molecule 66 (Scheme 57):

In a dried schlenk 26 mmol of freshly distilled Į-Pinene was added to 26 mmol of BH 3.THF in 20 mL dry THF at 0 oC slowly for a period of 10 min and slowly warmed to rt for 4h. A white suspension of diisopinocampheylborane observed which was cooled to -35 oC, 26 mmol of propargylic alcohol derivative was slowly added for a period of 30 min allowed to warm to rt, stirred for 5 h at rt and 260 mmol of freshly distilled acetaldehyde was added at 0 oC and heated the reaction at 45 oC for 12 h. Distilled off the excess acetaldehyde and 26 mmol of pinacol was added at rt and stirred for another 5 h. The solvent was removed and the residue was purified on silicagel column chromatography to give J-borylated allylic alcohol derivatives.

(E)-3-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-prop-2-en-1-ol (65a):

111

O HO B O

Yield: 3.82 g (80%)

Rf 0.45 (Heptane/Ethyl acetate (1:1)). 1 H NMR(300 MHz, CDCl 3) G 6.61 (dd, 1H, J = 18.1 Hz, J = 4.9 Hz), 5.58 (dd, 1H, J = 1.5 Hz, J = 18.1 Hz), 4.30 (dd, J = 4.0 Hz, J = 1.8 Hz, 2H), 1.27 (s, 12H); 13 C NMR (75 MHz, CDCl 3) G 11 B NMR (96 MHz, CDCl 3) G 29.0.

(E)-4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-but-3-en-2-ol (65b):

OH O B O

Yield: 3.90 g (76%)

Rf 0.45 (Heptane/Ethyl acetate (1:1)). 1 H NMR (300 MHz, CDCl 3) G 6.61 (dd, 1H, J = 18.1 Hz, J = 4.9 Hz), 5.58 (dd, 1H, J = 1.5 Hz, J = 18.1 Hz), 4.30-4.40 (m, 1H), 2.29 (br, 1H), 1.28 (s, 12H), 1.24 (d, J = 5.6 Hz, 3H); 13 C NMR (75 MHz, CDCl 3) G 156.46, 83.48, 69.68, 24.89, 22.77; 11 B NMR (96 MHz, CDCl 3) G 29.9.

(E)-1-Phenyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-prop-2-en-1-ol (65c):

OH O Ph B O

112

Yield: 5.33g (75%)

Rf 0.45 (Heptane/Ethyl acetate (1:1)). 1 H NMR(300 MHz, CDCl 3) G 7.40-7.29 (m, 5H), 6.79 (dd, 1Hz, J = 18.0 Hz, J = 5.2 Hz), 5.78 (dd, 1Hz, J = 18.0 Hz, J = 1.5 Hz), 5.28 (dd, 1Hz, J = 5.2 Hz, J = 1.5 Hz), 2.12 (s, 1H), 1.28 (s, 12H); 13 C NMR (75 MHz, CDCl 3) G 11 B NMR (96 MHz, CDCl 3) G 29.0.

(E)-2-Methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-but-3-en-2-ol (65d):

OH O B O

Yield: 4.13 g (79%)

Rf 0.45 (Heptane/Ethyl acetate (1:1)). 1 H NMR(300 MHz, CDCl 3) G 6.75 (d, 1H, J = 18.3 Hz), 5.65 (d, 1H, J = 18.3 Hz), 1.65 (s, 1H), 1.32 (s, 6H), 1.29 (s, 12H); 13 C NMR (75 MHz, CDCl 3) G 160.5, 83.1, 72.0, 26.6, 24.4; 11 B NMR (96 MHz, CDCl 3) G 29.0.

Acetylation of J-borylated allylic alcohol derivatives (Scheme 57):

In a dried schlenk introduced 0.182 mol of DMAP, 1.82 mmol of J-borylated allylic alcohol and 3.01 mmol of triethyl amine in 3mL of dry THF at 0 oC and stirred for 45 min then added o 1.99 mmol of Ac 2O slowly for a period of 5 min at 0 C, stirred at rt for 2 h. Diluted the reaction mass with diethyl ether (50 mL) washed with 1N HCl (50 mL x 3 times) followed by sat. NaHCO 3 (50 mL x 3 times) dried over MgSO 4 and the residue was purified by silica gel column chromatography to give the J-borylated allylic acetate derivative in 80% yield.

(E)-Acetic acid 3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-allyl ester (66a):

113

O AcO B O

Yield: 0.35 g (85%)

Rf 0.45 (Heptane/Ethyl acetate (1:1)). 1 H NMR (300 MHz, CDCl 3) G 6.61 (td, 1H, J = 4.67 Hz, J = 18.1 Hz), 5.66 (td,1H, J = 1.8 Hz, J = 18.1 Hz), 4.65 (dd, 2H, J = 1.81 Hz, J = 4.67 Hz), 2.05 (s, 3H), 1.23 (s, 12H);

13C NMR (75 MHz, CDCl 3) G 11 BNMR (CDCl 3) G .

(E)-Acetic acid 1-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-allyl ester (66b):

OAc O B O

Yield: 0.37 g (85 %)

(E)-Acetic acid 1-phenyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-allyl ester (66c):

OAc O Ph B O

114

Yield: 0.46 g (85%)

Rf 0.45 (Heptane/Ethyl acetate (1:1)). 1 H NMR(300 MHz, CDCl 3) G 7.31-7.36 (m, 5H), 6.70 (dd, 1H, J = 4.8 Hz, J = 18.0 Hz), 6.31 (d, 1H, J = 4.8 Hz), 5.67 (dd, 1H, J = 18.0 Hz, J = 1.7 Hz), 2.13 (s, 12H), 1.27 (s, 12H); 13 C NMR(75 MHz, CDCl 3) G 169.8, 149.3, 138.3, 128.5, 128.4, 128.2, 127.3, 83.4, 24.8, 24.7, 21.1; 11 B NMR (96 MHz, CDCl 3) G 29.2.

(E)-Acetic acid 1,1-dimethyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-allyl ester (66d):

OAc O B O

Yield: 0.39 g (85%)

Rf 0.45 (Heptane/Ethyl acetate (1:1)). 1 H NMR(300 MHz, CDCl 3) G 6.52 (d, 1H, J = 18.0 Hz), 5.51 (d, 1H, J = 18.0Hz), 2.01 (s, 3H), 1.61 (s, 6H), 1.22 (s, 12H); 11 B NMR (96 MHz, CDCl 3) G 29.0.

Typical experimental for Tsuji-Trost allylation using carbon nucleophiles (Scheme 58):

In a dried schlenk reactor, were dissolved the boronate (1eq), Pd(OAc) 2 (1 mol %) and PPh 3 (3 mol%) in 2 mL of anhydrous THF. In another schlenk reactor, to a solution of NaH (60% suspension in oil, 1.1 eq) washed with 2 mL dry ether was added freshly distilled dimethyl malonate at 0 oC (1.1 eq). After 1h at room temperature, the malonate salt was added to the palladium-boronate mixture at RT. After 4 h under reflux, the reaction mixture was concentrated, dissolved in CH 2Cl 2 (20 mL/mmol). This organic solution was washed with water (10 mL/mmol), brine (2 x 10mL/mmol), dried over MgSO 4, and concentrated under reduced pressure. The residual oil was purified by silica gel column flash chromatography.

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(E)- 2-[3-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-allyl]-malonic acid dimethyl ester (69a):

O B O O O O

Yield : 97 mg (74%), colorless oil

Rf 0.52 (Heptane/Ethyl acetate (1:1)). 1 H NMR (300 MHz, CDCl 3) G 6.56 (m, 1H), 5.52 (td, 1H, J = 1.5 Hz, J = 17.9 Hz), 3.72 (s, 6H), 3.53 (t, 1H, J = 7.5 Hz), 2.76 (dt, 2H, J = 1.5 Hz, J = 6.3 Hz), 1.24 (s, 12H); 13 C NMR (75 MHz, CDCl 3) G 169.1, 148.5, 83.1, 52.5, 50.5, 34.4, 24.6; 11 B NMR (96 MHz, CDCl 3) G 29.4; HRMS (ESI) [M + Na +]/z calcd. 321.1485, found 321.1487.

(E)- 2-[1-Methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-allyl]-malonic acid dimethyl ester (69b):

O B O O O O

Yield: 100 mg (77%), colorless liquid

Rf 0.52 (Heptane/Ethyl acetate (1:1)). 1 H NMR (300 MHz, CDCl 3) G 6.54 (dd, 1H, J = 7.4 Hz, J = 17.9 Hz), 5.50 (d,1H, J = 17.9 Hz), 3.72 (s, 3H), 3.68 (s, 3H), 3.35 (d, 1H, J = 9.1 Hz), 3.05-2.97 (m, 1H), 1.24 (s, 12H), 1.09 (d, 3H, J = 6.8 Hz); 13 C NMR (75 MHz, CDCl 3) G 168.5, 168.4, 153.9, 83.1, 56.8, 52.3, 52.2, 39.3, 24.7, 17.4; 11 B NMR (96 MHz, CDCl 3) į 28.8; HRMS (ESI) [M + Na +]/z calcd. 335.1641, found 335.1644.

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(E)- 2-[1,1-Dimethyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-allyl]-malonic acid dimethyl ester (69c):

O B O O O O

Yield: 102 mg (80%), white amorphous solid

Rf 0.45 (Heptane/Ethyl acetate (1:1)). 1 H NMR (300 MHz, CDCl 3) G 6.72 (d, 1H, J = 18.2 Hz), 5.45 (d, 1H, J = 18.2 Hz), 3.67 (s, 6H), 3.41 (s, 1H), 1.25 (s, 12H), 1.22 (s, 6H); 13 C NMR (75 MHz, CDCl 3) G 168.1, 159.0, 83.1, 59.9, 52.0, 40.1, 24.7, 24.5; 11 B NMR (96 MHz, CDCl 3) G 28.6; HRMS (ESI) [M + Na +]/z calcd. 349.1798, found 349.1799.

(E)- 2-[1-Phenyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-allyl]-malonic acid dimethyl ester (69d):

MeOOC COOMe

O B O

Yield: 95mg (61%), colorless oil

Rf 0.49 (Heptane/Ethyl acetate (1:1)). 1 H NMR(300 MHz, CDCl 3) į 7.28-7.19 (m, 5H), 6.71 (dd, 1H, J = 17.8 Hz, J = 7.4 Hz), 5.50 (dd, 1H, J = 1.2 Hz, J = 17.8 Hz), 4.21 (ddd, 1H, J = 7.4 Hz , J = 1.0 Hz, J = 11.3 Hz), 3.92 (d, 1H, J = 11.3 Hz), 3.73 (s, 3H), 1.22 (s,12H) ; 13 C NMR (75 MHz, CDCl 3) į 168.0, 167.1, 151.5, 139.0, 128.6, 128.2, 127.1, 83.2, 56.7, 52.6, 52.3, 51.1, 24.7, 24.7; 11 B NMR (96 MHz, CDCl 3) į 28.6;

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HRMS (ESI) [M + Na +]/z calcd. 397.1798, found 397.1799.

(E)- 2-Acetyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pent-4-enoic acid methyl ester (69e):

O B O O O O

Yield: 95mg (76%), colorless oil

Rf 0.52 (Heptane/Ethyl acetate (1:1)). 1 H NMR (300 MHz, CDCl 3) G 6.53 (m, 1H), 5.51 (td, 1H, J = 1.5 Hz, J = 17.9 Hz), 3.73 (s, 3H), 3.62 (t, 1H, J = 7.3 Hz), 2.71 (dt, 2H, J = 1.5 Hz, J = 7.6 Hz), 2.23 (s, 3H), 1.24 (s, 12H); 13 C NMR (75 MHz, CDCl 3) G 202.1, 169.5, 148.8, 83.2, 58.2, 52.5, 33.7, 29.2, 24.7; 11 B NMR (96 MHz, CDCl 3) G 28.6; HRMS (ESI) [M + Na +]/z calcd. 305.1536, found 305.1537.

(E)- 2-Acetyl-3-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pent-4-enoic acid methyl ester (69f):

O B O O O O

Yield: 99 mg (80%), colorless oil

Rf 0.50 (Heptane/Ethyl acetate (1:1)). 1 H NMR (300 MHz, CDCl 3) G 6.53 (dq, 1H, J = 7.4 Hz, J = 17.9 Hz, J = 2.3 Hz, J = 15.6 Hz), 5.49 (dd, 1H, J = 3.1 Hz, J = 17.9 Hz), 3.72 (s, 1.5H), 3.67 (s, 1.5H), 3.44 (dd, 1H, J = 2.3 Hz, J = 9.7 Hz), 3.08-3.00 (m, 1H), 2.23 (s, 1.5H), 2.18 (s, 1.5H), 1.24 (d, 12H, J = 1.3 Hz), 1.07(dd, 3H, J = 3.6 Hz, J = 6.7 Hz ); 13 C NMR (75 MHz, CDCl 3) G 202.3, 168.9, 154.1, 83.2, 65.1, 52.3, 39.2, 29.6, 24.7, 17.6;

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11 B NMR (96 MHz, CDCl 3) G 28.9; HRMS (ESI) [M + Na +]/z calcd. 319.16927, found 319.1695.

(E)- 2-Acetyl-3,3-dimethyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pent-4-enoic acid methyl ester (69g):

O B O O O O

Yield: 102 mg (83%), white crystals

Rf 0.51 (Heptane/Ethyl acetate (1:1)). 1 H NMR (300 MHz, CDCl 3) G 6.75 (d, 1H, J = 18.2 Hz), 5.45 (d, 1H, J = 18.2 Hz), 3.68 (s, 3H), 3.51 (s, 1H), 2.19 (s, 3H), 1.26 (s, 12H), 1.22 (s, 3H), 1.19 (s, 3H); 13 C NMR (75 MHz, CDCl 3) G 202.4, 168.8, 159.1, 83.1, 67.1, 51.9, 40.5, 31.5, 25.0, 24.7, 24.2; 11 B NMR (96 MHz, CDCl 3) G 28.6; HRMS (ESI) [M + Na +]/z calcd. 333.1849, found 333.1848.

(E)- 3-[1-Methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-allyl]-pentane-2,4-dione (69h):

O B O O O

Yield: 93 mg (80%), colorless liquid

Rf 0.48 (Heptane/Ethyl acetate (1:1)). 1 H NMR (300 MHz, CDCl 3) G 6.43 (dd, 1H, J = 7.6 Hz, J = 17.9 Hz), 5.47 (dd, 1H, J = 1.0 Hz, J = 17.9 Hz), 3.64 (d, 1H, J = 10.4 Hz), 3.14-3.06 (m, 1H), 2.18 (s, 3H), 2.11 (s, 3H), 1.23 (s, 12H), 0.99 (d, 1H, J = 6.6 Hz);

119

13 C NMR (75 MHz, CDCl 3) G 203.4, 153.8, 83.2, 74.8, 39.6, 29.9, 24.7, 17.7; 11 B NMR (96 MHz, CDCl 3) G 29.5; HRMS (ESI) [M + Na +]/z calcd. 303.1743, found 303.1747.

(E)- 3-[1,1-Dimethyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-allyl]-pentane-2,4- dione (69i):

O B O O O

Yield: 95 mg (82%), white crystals

Rf 0.51 (Heptane/Ethyl acetate (1:1)). 1 H NMR (300 MHz, CDCl 3) G 6.75 (d, 1H, J = 18.2 Hz), 5.43 (d, 1H, J = 18.2 Hz), 3.75 (s, 1H), 2.16 (s, 6H), 1.27 (s, 12H), 1.16 (s, 6H); 13 C NMR (75 MHz, CDCl 3) G 203.6, 159.1, 83.2, 75.3, 41.4, 32.4, 24.7, 24.6; 11 B NMR (96 MHz, CDCl 3) G 29.2; HRMS (ESI) [M + Na +]/z calcd. 317.1900, found 317.1901.

(E)- 2-Cyano-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pent-4-enoic acid methyl ester (69j):

NC B O O O O

Yield: 90 mg (77%), colorless liquid

Rf 0.50 (Heptane/Ethyl acetate (1:1)). 1 H NMR (300 MHz, CDCl 3) G 6.59 (m, 1H), 5.68 (m, 1H), 3.83 (s, 3H), 3.64 (m, 1H), 3.09 (m, 0.6H), 2.80(m, 1.4H), 1.28(s, 12H);

120

13 C NMR (75 MHz, CDCl 3) G 166.1, 145.8, 116.0, 83.3, 53.4, 37.4, 31.6, 24.7; 11 B NMR (96 MHz, CDCl 3) G 29.5; HRMS (ESI) [M + Na +]/z calcd. 288.1383, found 288.1385.

(E)- 2-Cyano-3-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pent-4-enoic acid methyl ester (69k):

NC B O O O O

Yield: 93 mg (80%), colorless liquid

Rf 0.50 (Heptane/Ethyl acetate (1:1)). 1 H NMR (300 MHz, CDCl 3) G 6.55 (dd, 1H, J = 6.7 Hz, J = 17.9 Hz), 5.62 (d, 1H, J = 17.9 Hz), 3.81 (s, 1.5H), 3.79 (s, 1.5H), 3.59 (dd, 1H, J = 5.6 Hz, J = 21.8 Hz), 3.06-2.97 (m, 1H), 1.27 (d, 12H, J = 1.0 Hz), 1.23(d, 3H, J = 6.7 Hz); 13 C NMR (75 MHz, CDCl 3) G 165.8, 151.3, 115.0, 83.4, 53.4, 43.5, 40.1, 24.7, 17.8; 11 B NMR (96 MHz, CDCl 3) G 29.1; HRMS (ESI) [M + Na +]/z calcd. 302.1539, found 302.1542.

(E)- 2-Cyano-3,3-dimethyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pent-4-enoic acid methyl ester (69l):

NC B O O O O

Yield: 91 mg (79%), white crystals

Rf 0.51 (Heptane/Ethyl acetate (1:1)). 1 H NMR (300 MHz, CDCl 3) G 6.61 (d, 1H, J = 18.1 Hz), 5.56 (d, 1H, J = 18.1 Hz), 3.76 (s, 3H), 3.43 (s, 1H), 1.29 (s, 3H), 1.27 (s, 12H), 1.26 (s, 3H);

121

13 C NMR (75 MHz, CDCl 3) G 165.1, 155.5, 115.3, 83.4, 52.9, 48.0, 41.1, 24.9, 24.7, 24.1; 11 B NMR (96 MHz, CDCl 3) G 29.0; HRMS (ESI) [M + Na +]/z calcd. 316.1696, found 316.1698.

(E)- 2-Oxo-1-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-allyl]- cyclopentanecarboxylic acid ethyl ester (69m):

O O O O B O

Yield: 106 mg (79%), colorless liquid

Rf 0.51(Heptane/Ethyl acetate (1:1)). 1 H NMR (300 MHz, CDCl 3) į 6.46 (m, 1H), 5.51 (td, 1H, J = 1.3 Hz, J = 17.7 Hz ), 4.17 (q, 2H, J = 7.1 Hz), 2.82 (dddd, 1H, J = 1.3 Hz, J = 6.8 Hz, J = 14.1 Hz), 2.45 (m, 4H), 1.99 (m, 3H), 1.24 (m, 15H) ; 13 C NMR (75 MHz, CDCl 3) į 214.2, 170.5, 147.7, 83.1, 61.4, 59.6, 39.6, 37.8, 32.0, 24.6, 19.4,14.0 ; 11 B NMR (96 MHz, CDCl 3) į 29.4; HRMS (ESI) [M + Na +]/z calcd. 345.1849, found 345.1848.

(E)- 1-[1-Methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-allyl]-2-oxocyclopentanecarboxylic acid ethyl ester (69n):

O O O OEt B O

Yield: 105 mg (75%), colorless liquid

122

Rf 0.51(Heptane/Ethyl acetate (1:1)). 1 H NMR (300 MHz, CDCl 3) į 6.45 (dddd, 1H, J = 6.9 Hz , J = 1.6 Hz, J = 17.9 Hz), 5.50 (dddd, 1H, J = 1.3 Hz, J = 3.1 Hz, J = 17.9 Hz), 4.20 (m, 2H), 3.24 (m, 1H), 2.50 (m, 2H), 2.17 (m, 1H), 1.95 (m, 3H), 1.28 (m, 15H), 1.02 (dd, 3H, j = 6.8 Hz, j = 14.7 Hz) ; 13 C NMR (75 MHz, CDCl 3) į 214.2, 169.7, 153.3, 83.1, 64.7, 61.5, 43.0, 39.0, 28.3, 24.7, 19.7, 14.8, 14.0; 11 B NMR (96 MHz, CDCl 3) į 28.8; HRMS (ESI) [M + Na +]/z calcd. 359.20057, found 359.2005.

Typical one-pot reaction experimental procedure (Table 12):

To a dried argon filled Schlenk 0.416 mmol of gamma-borylated allylic acetate, 2.1 ȝmol of

Pd(OAc) 2 and 6.3 ȝmol of PPh 3 were dissolved in 2mL of anhydrous THF and stirred for 1 h at RT. In another Schlenk freshly distilled 50 ȝL (0.457 mmol) of dimethyl malonate were added at 0 oC to a solution of 18 mg of NaH (0.458 mmol, 60% in oil washed with 2 mL of anhydrous Et 2O). After 1 h at RT, the solution was added at RT to the boronate-palladium complex mixture. After 4 h under refluxing THF, 0.63mmol of aryliodide and a degassed saturated aqueous solution of K 2CO 3 (0.63 mmol) were added to the reaction mixture at room temperature. After 6 h under refluxing conditions, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in CH 2Cl 2 (10 mL), washed with water (5 mL), brine (2 x 5 mL). Organic phases were dried over MgSO 4 and purified by silica gel column flash chromatography.

(E)-dimethyl 2-(4-phenylbut-3-en-2-yl)malonate(72a):

Yield: 87 mg (75%), colorless liquid

123

13 C NMR (75 MHz, CDCl 3) G 168.6, 137.0, 131.1, 130.7, 128.4, 127.3, 126.2, 57.7, 52.4, 37.7,18.4; HRMS (ESI) [M + Na +]/z calcd. 285.1102, found 285.1105.

(E)- 2-(1,1-Dimethyl-3-phenyl-allyl)-malonic acid dimethyl ester (72b)

O O

Yield: 87 mg (76%), colorless liquid

Rf 0.51(Heptane/Ethyl acetate (1:1)). 1 H NMR (300 MHz, CDCl 3) į 7.37-7.20 (m, 5H), 6.47 (d, 1H, J = 16.2Hz), 6.39 (d, 1H, J = 16.2Hz), 3.69 (s, 6H), 3.45 (s, 1H), 1.34 (s, 6H) ; 13 C NMR (75 MHz, CDCl 3) į 168.2, 137.4, 136.5, 128.4, 127.4, 127.1 126.2, 60.9, 52.0, 38.6, 25.5.; HRMS (ESI) [M + Na +]/z calcd. 299.1259, found 299.1256.

(E)- 2-(3-Phenyl-allyl)-malonic acid dimethyl ester (72c):

O O

Yield: 77 mg (75%), colorless liquid

Rf 0.51(Heptane/Ethyl acetate (1:1)). 1 H NMR (300 MHz, CDCl 3) į 7.34-7.21 (m, 5H), 6.50 (d, 1H, J = 15.7Hz), 6.18-6.08 (m, 1H), 3.74 (s, 6H), 3.55 (t, 1H, J = 7.5Hz), 2.83-2.78 (m, 2H) ; 13 C NMR (75 MHz, CDCl 3) į 169.2, 136.9, 132.9, 128.4, 127.3, 126.1, 125.3, 52.5, 51.7, 32.2.

124

(E)- 2-(1-Phenyl-3-p-tolyl-allyl)-malonic acid dimethyl ester (72d):

MeOOC COOMe

Yield: 109 mg (78%), colorless liquid

Rf 0.51 (Heptane/Ethyl acetate (1:1)). 1 H NMR (300 MHz, CDCl 3) į 7.31-7.0 (m, 9H), 6.47 (d, 1H, J = 15.7 Hz), 6.30 (dd, 1H, J = 8.5 Hz, J = 15.7 Hz), 4.27 (dd, 1H, J = 10.8 Hz, J = 8.6 Hz), 3.95 (d, 1H, J = 10.9 Hz), 3.69 (s, 3H), 3.51 (s, 3H), 2.30 (s, 3H); 13 C NMR (75 MHz, CDCl 3) į 168.3, 167.9, 140.4, 137.5, 134.1, 131.8, 129.3, 128.8, 128.1, 128.0,127.2, 126.4, 57.8, 52.7, 52.6, 49.3, 21.3.

(S,E )-2-[1-Methyl-3- (4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-allyl]-malonic acid dimethyl ester (73):

MeOOC COOMe

B O O

Yield: 100 mg (77%)

Rf 0.52 (Heptane/Ethyl acetate (1:1)). 1 H NMR (300MHz, CDCl 3) G 6.54 (dd, 1H, J = 7.4 Hz, J = 17.9 Hz), 5.50 (d,1H, J = 17.9 Hz), 3.72 (s, 3H), 3.68 (s, 3H), 3.35 (d, 1H, J = 9.1 Hz), 3.05-2.97 (m, 1H), 1.24 (s, 12H), 1.09 (d, 3H, J = 6.8 Hz); 13 C NMR (75 MHz, CDCl 3) G 168.5, 168.4, 153.9, 83.1, 56.8, 52.3, 52.2, 39.3, 24.7, 17.4;

125

11 B NMR (96 MHz, CDCl 3) į 28.8; HRMS (ESI) [M + Na +]/z calcd. 335.1641, found 335.1644.

(S,E)-2-(1-Methyl-3-phenyl-allyl)-malonic acid dimethyl ester (74):

MeOOC COOMe

Yield: 77 mg (75%), pale yellow solid

Rf 0.65(Heptane/Ethyl acetate (1:1)) 1 H NMR (300 MHz, CDCl 3) G 7.34 (m, 5H), 6.48 (s, 1H, J = 15.8 Hz), 6.16 (dd, 1H, J = 18.2 Hz), 3.75 (s, 3H), 3.67 (s, 3H), 3.42 (d, 1H, J = 8.9 Hz), 3.16 (m, 1H), 1.20 (d, 3H, J = 6.7 Hz); 13 C NMR (75 MHz, CDCl 3) G 168.6, 137.0, 131.1, 130.7, 128.4, 127.3, 126.2, 57.7, 52.4, 37.7,18.4; HRMS (ESI) [M + Na +]/z calcd. 285.1102, found 285.1105.

( E)- 2-(3-Azido-1-methyl-allyl)-malonic acid dimethyl ester 75 (Scheme 62):

NaN 3 (32 mg, 0.48 mmol) and CuSO 4 (0.2 mmol) were placed in an oven-dried roundbottomed flask. Subsequently methanol (3mL) and ( E)-2-[1-Methyl-3- (4,4,5,5- tetramethyl-[1,3,2]dioxaborolan-2-yl)-allyl]-malonic acid dimethyl ester (0.1 g, 0.32 mmol) were added. After 4 h at room temperature, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in CH 2Cl 2 (10 mL), washed with water (5 mL), brine (2 x 5 mL). Organic phases were dried over MgSO4 and purified by silica gel column flash chromatography affording 75 as colorless liquid.

126

MeOOC COOMe

Yield : 58 mg (78%), colorless liquid

Rf 0.51( Heptane/Ethyl acetate (1:1)). 1 H NMR (300 MHz, CDCl 3) į 6.00 (d, 1H, J = 13.9 Hz), 5.30 (dd, 1H, J = 13.4 Hz, J = 9.1 Hz), 3.72 (s, 3H), 3.70 (s, 3H), 3.29 (d, 1H, J = 8.7 Hz), 3.00 (m, 1H), 1.10 (d, J = 6.8 Hz, 3H); 13 C NMR (75 MHz, CDCl 3) į 168.5, 168.4, 128.2, 121.0, 57.7, 52.6, 52.5, 34.8, 18.7; HRMS (ESI) [M + Na +]/z calcd. 250.08038, found 250.0805.

Typical experimental for allylic substitution reaction using nitrogen nucleophiles (Scheme 63):

To a dried argon filled shlenk introduced the boronate (1 eq), Pd(allyl)Cl] 2 (0.5 mol%) or Pd(OAc) 2 (1 mol%) and PPh 3 (3 mol %) were added in 2 mL dry THF and stirred for 1 h at rt, Nucleophile (1.1 eq) was added to the boronate palladium complex mixture at rt and refluxed for 4 h, reaction compiles and the crude was concentrated and separated between (10 mL) DCM and (5 mL) water, washed the organic layer with brine (2 x 5 mL), dried over

MgSO 4, purified by silica gel column flash chromatography to get the respective yields which were described below. (E)-N-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)allyl)aniline (78a):

NH H O H B O

Yield: 86 mg (75%), colorless oil

127

Rf 0.58 (Heptane / Ethyl acetate (1:1)). 1 H NMR (300 MHz, CDCl 3) į 7.18-7.13 (m, 2H), 6.72-6.58 (m, 4H), 5.72 (d, 1H, J = 18.0 Hz), 3.87 (dd, 2H, J = 1.6 Hz, J = 4.6 Hz), 1.26 (s, 12H); 13 C NMR (75 MHz, CDCl 3) į 150.0, 147.8, 129.1, 117.4, 112.8, 83.2, 47.5, 24.7; 11 B NMR (96 MHz, CDCl 3) į 28.4; HRMS (ESI) [M + Na +]/z calcd. 282.16413, found 282.1643. (E)-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)but-3-en-2-yl)aniline (78b):

NH O B O

Yield: 80 mg (76%), colorless liquid

Rf 0.65 (Heptane / Ethyl acetate (1:1)). 1 H NMR (300 MHz, CDCl 3) į 7.16 (m, 2H), 6.68-6.54 (m, 4H), 5.66 (d, 1H, J = 18.0 Hz), 4.05-4.00 (m, 1H), 1.32 (d, 3H, J = 6.7 Hz), 1.25 (s, 12H); 13 C NMR (75 MHz, CDCl 3) į 155.4, 147.2, 129.1, 117.1, 113.1, 83.2, 51.9, 24.7, 21.2; 11 B NMR (96 MHz, CDCl 3) į 28.9; HRMS (ESI) [M + Na +]/z calcd. 296.17978, found 296.1797.

(E)-N-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)but-3-en-2-yl)aniline (78c):

NH O B O

Yield: 87 mg (77%), white amorphous solid

R f 0.61(Heptane / Ethyl acetate (1:1)). 1 H NMR (300MHz, CDCl 3) į 7.11-7.06 (m, 2H), 6.78- 6.60 (m, 4H), 5.64 (d, 1H, J = 18.3 Hz), 1.38 (s, 6H), 1.26 (s, 12H);

128

13 11 C NMR (75 MHz, CDCl 3) į 160.2, 146.3, 128.6, 117.1, 115.4, 83.1, 55.4, 27.9, 24.7; B

NMR (96 MHz, CDCl 3) į 28.9; HRMS (ESI) [M + Na +]/z calcd. 310.19543, found 310.1955.

(E)- 2-(3-Azido-propenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (78d):

N H 3 O H B O

Yield: 79 mg (85%), colorless oil

R f 0.58 (Heptane /Ethyl acetate (1:1)). 1 H NMR (300MHz, CDCl 3) į 6.60-6.50 (m, 1H), 5.74 (td, 1H, J = 1.6 Hz, J = 17.9 Hz), 3.86 (dd, 2H, J = 1.4 Hz, J = 5.3 Hz), 1.26 (s, 12H); 13 C NMR (75 MHz, CDCl 3) į 144.9, 83.4, 54.2, 24.7; 11 B NMR (96 MHz, CDCl 3) į 29.1. HRMS (ESI) [M + Na +]/z calcd. 232.12281, found 232.1232.

(E)- 2-(3-Azido-but-1-enyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (78e):

N3 O B O

Yield: 76 mg (81%), colorless oil

Rf 0.60 (Heptane / Ethyl acetate (1:1)). 1 H NMR (300 MHz, CDCl 3) į 6.53 (dd, 1H, J = 6.2 Hz, J = 17.9 Hz), 5.68 (d, 1H, J = 17.9 Hz), 4.08-3.99 (m, 1H), 1.32 (d, 3H, J = 6.8 Hz), 1.29 (s, 12H); 13 C NMR (75 MHz, CDCl 3) į 150.2, 83.5, 60.4, 24.7, 19.2; 11 B NMR (96 MHz, CDCl 3) į 29.7;

129

HRMS (ESI) [M + Na +]/z calcd. 246.13898, found 246.1392.

(E)- 2-(3-Azido-3-methyl-but-1-enyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (78f)

N3 O B O

Yield: 75 mg (80%), white amorphous solid

Rf 0.63 (Heptane / Ethyl acetate (1:1)). 1 H NMR (300 MHz, CDCl 3) į 6.56 (d, 1H, J = 18.1 Hz), 5.64 (d, 1H, J = 18.1 Hz), 1.34 (s, 6H), 1.28 (s, 12H); 13 C NMR (75 MHz, CDCl 3) į 154.2, 83.4, 62.7, 25.8, 24.7; 11 B NMR (96 MHz, CDCl 3) į 29.7; HRMS (ESI) [M + Na +]/z calcd. 260.15463, found 260.1548.

(E)- (4-Methoxy-phenyl)-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-allyl]-amine (78g):

NH H O H B O

Yield: 97 mg (76%), colorless oil

Rf 0.62 (Heptane / Ethyl acetate (1:1)). 1 H NMR (300MHz, CDCl 3) į 6.77-6.73 (m, 3H), 6.57 (dd, 2H, J = 9.0 Hz, J = 6.6 Hz), 5.71 (td, 1H, J = 1.8 Hz, J = 18.0 Hz), 3.82 (dd, 2H, J = 1.8 Hz, J = 4.7 Hz), 3.73 (s, 3H), 1.26 (s, 12H); 13 C NMR (75 MHz, CDCl 3) į 152.0, 150.3, 142.0, 114.8, 114.0, 83.2, 55.7, 48.4, 24.7; 11 B NMR (96 MHz, CDCl 3) į 28.9;

130

HRMS (ESI) [M + Na +]/z calcd. 312.17469, found 312.1748.

(E)- (4-Methoxy-phenyl)-[1-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)- allyl]-amine (78h):

NH O B O

Yield: 93 mg (73%), colorless liquid

Rf 0.59 (Heptane / Ethyl acetate (1:1)). 1 H NMR (300MHz, CDCl 3) į 6.77–6.72 (m, 2H), 6.63–6.53 (m, 3H), 5.64 (dd, 1H, J = 18.0 Hz, J = 1.4 Hz), 3.98-3.93 (m, 1H), 3.74 (s, 3H), 1.31 (d, 3H, J = 6.7 Hz), 1.26 (s, 12H); 13 C NMR (75 MHz, CDCl 3) į 155.8, 151.9, 141.4, 114.6, 83.1, 55.7, 52.9, 24.7, 21.2; 11 B NMR (96 MHz, CDCl 3) į 28.9; HRMS (ESI) [M + Na +]/z calcd. 326.19034, found 326.1905.

( E)- [1,1-Dimethyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-allyl]-(4-methoxy- phenyl)-amine (78i):

NH O B O

Yield: 97 mg (78%), white amorphous solid

R f 0.59 (Heptane / Ethyl acetate (1:1)). 1 H NMR(300MHz, CDCl 3) į 6.77-6.61 (m, 5H), 5.59 (d, 1H, J = 18.3 Hz), 3.73 (s, 3H), 1.32 (s, 6H), 1.27 (s, 12H);

131

13 C NMR (75 MHz, CDCl 3) į 160.6, 152.7, 140.0, 118.7, 114.1, 83.1, 55.9, 55.6, 27.8, 24.7; 11 B NMR (96 MHz, CDCl 3) į 28.4; HRMS (ESI) [M + Na +]/z calcd. 340.20599, found 340.2062.

( E)- (3-Azido-propenyl)-benzene (79)

Yield: 44 mg (83%), colorless oil

Rf 0.68 (Heptane / Ethyl acetate (1:1)). 1 H NMR (300MHz, CDCl 3) į 7.42-7.26 (m, 5H), 6.68 (d, 1H, J = 15.7 Hz), 6.29-6.20 (m, 1H), 3.96 (d, 2H, J = 7.3 Hz); 13 C NMR (75 MHz, CDCl 3) į 135.9, 134.5, 128.6, 128.1, 126.6, 122.3, 53.0. Typical experimental procedure for one-pot reaction (Table 19):

To a dried argon filled Schlenk 0.416 mmol of gamma-borylated allylic acetate, 2.1 ȝmol of

Pd(OAc) 2 and 6.3 ȝmol of PPh 3 were dissolved in 2mL of anhydrous THF and stirred for 1 h at RT. Nucleophile (1.1 eq) was added to the boronate palladium complex mixture at rt and refluxed for 4 h. After 4 h under refluxing THF, 0.63 mmol of aryliodide and a degassed saturated aqueous solution of K 2CO 3 (0.63 mmol) were added to the reaction mixture at room temperature. After 6 h under refluxing conditions, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in CH 2Cl 2 (10 mL), washed with water (5 mL), brine (2 x 5 mL). Organic phases were dried over MgSO 4 and purified by silica gel column flash chromatography.

(E)- (1-Methyl-3-phenyl-allyl)-phenyl-amine (80a):

132

Yield: 72 mg (77%), colorless liquid

R f 0.59 (Heptane / Ethyl acetate (1:1)). 1 H NMR (300MHz, CDCl 3) į 7.26-7.03 (m, 6H), 6.62-6.44 (m, 4H), 6.14 (dd, 1H, J = 5.8 Hz, J = 15.9 Hz), 4.05 (m, 1H), 1.30 (d, 3H, J = 6.6 Hz), 13 C NMR (75 MHz, CDCl 3) į 147.2, 136.9, 133.0, 129.2, 129.1, 128.4, 127.2, 126.2, 117.2, 113.3, 50.7, 21.9. (E)- (1,1-Dimethyl-3-phenyl-allyl)-phenyl-amine (80b):

Yield: 66 mg (72%), white amorphous solid

Rf 0.59 (Heptane / Ethyl acetate (1:1)). 1 H NMR (300MHz, CDCl 3) į 7.41-7.23 (m, 5H), 7.13- 7.08 (m, 2H), 6.75 (dd, 3H, J = 7.8 Hz, J = 16.5 Hz), 6.57 (d, 1H, J = 16.2 Hz), 6.44 (d, 1H, J = 16.2 Hz), 1.49 (s, 6H) ; 13 C NMR (75 MHz, CDCl 3) į 137.9, 137.2, 128.8, 128.5, 127.9, 127.2, 126.3, 117.7, 115.8, 100.0, 68.0, 54.6, 28.7. (E)- (3-Azido-1-methyl-allyl)-phenyl-amine 81(Scheme 65):

NaN 3 (17 mg, 0.28 mmol) and CuSO 4 (5 mg, 0.1 mmol) were placed in an oven-dried round bottomed flask. Subsequently methanol (3 mL) and (E)- [1-Methyl-3-(4,4,5,5-tetramethyl- [1,3,2]dioxaborolan-2-yl)-allyl]-phenyl-amine (0.05 g, 0.18 mmol) were added. After 4h at room temperature, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in CH 2Cl 2 (10 mL), washed with water (5 mL), brine (2 x 5 mL). Organic

133

phases were dried over MgSO 4 and purified by silica gel column flash chromatography affording 30 mg of 81 as a colorless liquid.

Yield: 30 mg (80%), colorless liquid.

R f 0.69 (Heptane / Ethyl acetate (1:1)). 1 H NMR (300MHz, CDCl 3) į 7.22 (t, 2H, J = 8.5 Hz), 6.76 (t, 1H, J = 7.3 Hz), 6.61 (d, 2H, J = 7.6 Hz), 6.13 (dd, 1H, J = 13.4 Hz, J = 1.0 Hz), 5.41 (dd, 1H, J = 13.5 Hz), 4.07 (m, 1H), 1.35 (d, 3H, J = 6.6 Hz); 13 C NMR (75 MHz, CDCl 3) į 146.8, 129.2, 127.3, 122.6, 117.6, 113.3, 48.4, 22.2. HRMS (ESI) [M + Na +]/z calcd. 211.1044, found 211.1102.

(E)- 4,4,5,5-Tetramethyl-2-(3-phenoxy-but-1-enyl)-[1,3,2]dioxaborolane (82):

O O B O

Yield: 85 mg, (74%), colorless liquid

Rf 0.65 (Heptane / Ethyl acetate (1:1)). 1 H NMR (300MHz, CDCl 3) į 7.24-7.21 (m, 1H), 6.92-6.85 (m, 3H), 6.69 (dd, 1H, J = 4.9 Hz, J = 18.2 Hz), 5.71 (dd, 1H, J = 1.4 Hz, J = 18.2 Hz), 4.85-4.81 (m, 1H), 1.44 (d, 3H, , J = 6.5 Hz), 1.25 (s, 12H); ); 13 C NMR (75 MHz, CDCl 3) į 157.9, 152.9, 129.3, 120.5, 115.6, 83.3, 74.8, 24.7, 20.8; 11 B NMR (96 MHz, CDCl 3) į 28.8. HRMS (ESI) [M + Na +]/z calcd. 297.1632, found 297.1631. Chiral ligands used in allylation:

134

O O O O NH HN NH HN

PPh Ph P 2 2 PPh 2 Ph 2P

(R,R)-DACH- Phenyl Trost Ligand (R,R)-L1 (R,R)-DACH-Naphthyl Trost (R,R)-L2

Ph 2P O O PPh 2 NH HN HN O O HN N N

(R,R )-DACH- Pyridyl (R,R )-ANDEN- Phenyl Trost Trost Ligand ( R,R )-L4 (R,R )- L3

135

HPLC-1( 69b)

136

HPLC-2 (Table 13, entry 4)

137

HPLC-3 (Table 13, entry 1)

138

HPLC-4 (Table 13, entry 2)

139

HPLC-5 (Table 13, enry 3)

140

HPLC-6 (Table 14, enry 1)

141

HPLC-7 (Table 14, entry 2)

142

HPLC-8 (Table 14, entry 3)

143

HPLC-9 (Table 14, entry 4)

144

HPLC-10 (Table 14, entry 5)

145

HPLC-11( 78b)

146

HPLC-12 (Table 20, entry 1)

147

HPLC-13 (Table 20, entry 2)

148

HPLC-14 (Table 20, entry 3)

149

HPLC-15 (Table 21, entry 1)

150

HPLC-16 (Table 21, entry 2)

151

HPLC-17 (Table 21, entry 3)

152

HPLC-18 (Table 21, entry 4)

153

HPLC-19 (Table 20, entry 4)

154

Chapter-III Experimental:

Typical experimental procedure for kinetic resolution in ionic liquids (Scheme 75):

To J-borylated alcohol (0.01 g, 0.05 mmol) were added vinylacetate (0.015 mL, 0.15 mmol) and 10mg of CAL-B in ionic liquid (0.485 mL) at rt and heated the reaction at 50 oC. The reaction was monitored at regular intervals of time (15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, 24 h) with different ionic liquids and the results were plotted in graph with rate of conversion vs Time of reaction.

OH OH OAc OAc (3.0 eq), CAL-B O * O * O B B + B Ionic Liquid, 50 oC, t min 50% 50% O O O (+,-)- rac OH (S)-OH (R)-OAc

Scheme 75: Kinetic resolution of -borylated allylic alcohols under solvent free media with CAL-B

[rac -OH] = racemic alcohol (starting material)

[IS] = Internal standard (Butyl Buterate)

[R-Product] = Final product- [ R-OAc]

[R-OH] = [R-OH] (which was not formed)

[S-OH] = Final product-[ S-OH]

[S-Product] = [S-OAc] (which was not formed)

[VA] = vinyl acetate

[Vr] = Total volume of the reaction

IME = Immobilized enzyme

24 ( S)-OH [ ǩ]D = +11.8 ( c 1.0, MeOH)

24 ( R)-OAc [ ǩ]D = +42.5 ( c 1.0, MeOH)

155

Reaction profile in [BTMA][NTf 2] ionic liquid:

The progress of the reaction was monitored by Chiral-GC. The racemic J-borylated allylic acetate was separated in chiral GC with the retention time of isomers tS = 25.3; tR = 25.5 (Picture 5).

The reaction was monitered by comparing with authentic ( S)-OAc (synthesized in laboratory) retention time whose absolute configuration was already known, tS = 25.3 (Picture 6).

The chemoenzymatic resolution was successfully carried on J-Borylated allylic alcohol in ionic liquids. A typical reaction profile was shown below (Picture 7) where the only compound formed during the reaction was ( R)-OAc whose retention time is tR = 25.5 and no peaks were observed at 25.3.

156

Chemoselective acetylation can be carried successfully in ionic liquids, However, the resolution of racemic alcohol in chiral-GC under different conditions by changing various columns and temperatures wasn’t successful. Therefore, to obtain the exact percentage of conversion for racemic alcohol a calibration was plotted by taking an internal standard (IS) as butyl butyrate (3 rd parameter) to know the exact conversion of racemic alcohol to pure ( S)- OH. As enantiomerically pure isomer ( S)-OAc is available (prepared synthetically), hence a comparison was done w.r.to this isomer.

Calibration curve: The equal concentration of the rac-OH (0.05 mmol) and ( S)-OAc (0.05 mmol) were mixed in 10 mL of toluene (mother solution, MS). Different concentration samples were prepared from this MS using standard concentration of IS and toluene. The correction factor was obtained by plotting a graph with conc vs area of the two substrates. In all these samples the concentration of rac -OH is same as that of ( S)-OAc (Table 26).

Sample MS Toluene IS Final [rac -OH] [S-OAc] (PL) (PL) P L) volume (Pmol/mL) (Pmol/mL) P L) 1. 100 300 100 500 1.0 1.0

2. 150 250 100 500 1.5 1.5

3. 200 200 100 500 2.0 2.0

4. 250 150 100 500 2.5 2.5

157

5. 300 100 100 500 3.0 3.0

6. 350 50 100 500 3.5 3.5

7. 400 0 100 500 4.0 4.0

These 7 samples were injected in GC (same conditions used for the reaction monitoring). The chiral GC areas observed for same internal standard concentration shown in Table 27.

[IS] [S-OAc] [Rac-OH] Sample A-OH A-S-OAc A-IS (Pmol/mL) (Pmol/mL) (Pmol/mL) 1. 121565 177941 1636903 15 1.0 1.0 2. 189332 261633 1608050 15 1.5 1.5 3. 259268 353723 1608770 15 2.0 2.0 4. 337548 453942 1661121 15 2.5 2.5 5. 414080 550208 1667355 15 3.0 3.0 6. 465811 624893 1628294 15 3.5 3.5 7. 561627 735411 1841803 15 4.0 4.0 A calibration was done with internal standard to the concentrations of rac-OH and S-OAc, and also to the areas from GC. (The concentrations and areas were divided with respective concentration of Internal standard and areas from GC, Table 28)

A-(S)-OAc A rac -OH [S-OAc] / [rac -OH] Sample / A-IS / A-IS [IS] / [IS] 1 0.108 0.074 0.066 0.066 2 0.162 0.117 0.1 0.1 3 0.219 0.161 0.133 0.133 4 0.273 0.203 0.166 0.166 5 0.329 0.248 0.2 0.2 6 0.383 0.286 0.233 0.233 7 0.399 0.304 0.266 0.266

From this calibrated values a plot of racemic alcohol concentration vs its area with respect to internal standard gives the exact correction factor for the concentration of rac -OH.

158

[rac-OH]/[IS] = m x (A R-S-OH/A IS) [Where m = slope of this graph] [rac-OH] = [IS] x m x. (A R-S-OH/A IS) = 15 x 0.832 x (A R-S-OH/A IS) [rac-OH] = 12.48 x (A R-S-OH/A IS)

Similarly, a plot of S-OAc concentration vs its area with respect to internal standard gives the exact correction factor for the concentration of S-OAc.

[S-OAc] / [IS] = m . (A S-OAc / A IS) [Where m = slope of this graph] [S-OAc] = [IS] x m . (A S-OAc / A IS) = 15 x 0.635 (A S-OAc / A IS) [S-OAc] = 9.525 (A S-OAc / A IS)

This correction factor was used for ( S)-OAc product. Since this isomer is completely pure (>99%) the same correction factor can be used for pure ( R)-OAc product during the reaction w.r.to the 3 rd parameter (i.e., internal standard).

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[R-OAc] = 9.525 (A R-OAc / A IS).

Calibrated correction factors with internal standard: [rac -OH] = 12.48 (A R-S-OH/A IS) [S-OAc] = 9.525 (A S-OAc / A IS) [R-OAc] = 9.525 x (A R-OAc / A IS)

These correction factors were used while calculating the GC conversion of racemic alcohol to (S)-OH and ( R)-OAc.

A model GC chromatogram of reaction profile in [BTMA][NTf 2] at 2h:

From this GC – the areas were calibrated with internal standard a model calculation was shown below:

GC- GC- GC-Area of GC-Area of [rac -OH] c [R-OAc] c Area of Area of [rac -OH] [R-OAc] = 12.48 x = 9.52 x [VA] [IS] [rac -OH] [R-OAc] / /[IS] [IS] 73887 1467136 190689 159682 1.622 1.036

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Example : At 2 h reaction time in [BTMA][NTf 2] the GC-area were calibrated.

[rac -OH] C = calibrated area with respect to internal standard = 12.48 x [ rac -OH] / [IS] = 1.622

[R-OAc] c = calibrated area w.r.to internal standard = 9.525 x [ R-OAc] / [IS] = 1.036 Therefore, Correction in the area of [ rac -OH] = 1.622 / (1.622 + 1.036) = 61% Therefore, Correction in the area of [ R-OAc] = 1.036 / (1.622 + 1.036) = 39% Since the initial percentage of [ R-OH] and [ S-OH] in Racemic mixture is 50/50. Therefore the area of [ R-OH] remaining = 50-[ R-OAc] = 50 – 39 = 11% Area of [ S-OH] = 50-[ S-OAc] = 50-0 = 50%. In this reaction profile [R-OH] [S-OH] [R-OAc] [S-OAc] 11% 50% 39% 0%

Same calibration was done for each chromatogram using correction factor to know the exact % of conversion and were shown in graph. Kinetic resolution in ionic liquids using CAL-B: (Scheme 75) Typical reaction conditions: Ionic liquid volume [IL] = 0.485 mL Vinyl acetate volume [VA] = 0.15 mL

Racemic alcohol substrate [ rac -OH] = 10 mg (50.51 Pmol) CAL-B enzyme = 10 mg (IME) The reaction was monitored with Chiral GC and the reaction profiles in ionic liquids were shown in graphical representation at each interval of time for ex: 15 min, 30 min, 1h, 2h, 4h, 6h, 8h, and 24h respectively. From this graph the enzyme activity was calculated.

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1. Reaction profile in [BMIM][NTf 2]: (Table 22, entry 1)

Enzyme activity in [BMIM][NTf 2] = slope x Pmol of [ rac -OH] / mg of IME = (0.544 x 50.51) / 10 = 2.74 U / mg of ,0(

Reaction profile in [OMIM][NTf 2] : (Table 22, entry 2)

Enzyme activity in [OMIM][NTf 2] = (1.255 x 50.51) / 10 = 6.33 U / mg of IME

Reaction profile in [C 12 MIM][NTf 2] : (Table 22, entry 3)

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Enzyme activity in [C 12 MIM][NTf 2] = (1.51 x 50.51) / 10 = 7.63 U/mg of IME

Reaction profile in [BTMA][NTf 2] : (Table 22, entry 4)

Enzyme activity in [BTMA][NTf 2] = (0.44 x 50.51) /10 = 2.26 U/mg of IME

5. Reaction profile in [TBMA][NTf 2] : (Table 22, entry 5)

Enzyme activity in [TBMA][NTf 2] = (0.48 x 50.51) /10 = 2.45 U/mg of IME

6. Reaction profile in [BMPy][NTf 2] : (Table 22, entry 6)

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Enzyme activity in [BMPy][NTf 2] = (0.56 x 50.51) /10 = 2.83 U/mg of IME

7. Reaction profile in [BMPi][NTf 2] : (Table 22, entry 7)

Enzyme activity in [BMPi][NTf 2] = (0.65 x 50.51) /10 = 3.31 U/mg of IME 8. Reaction profile in [BMIM][PF ] : (Table 22, entry 8) 6

Enzyme activity in [BMIM][PF 6] = (0.69 x 50.51) /10 = 3.34 U/mg of IME 9. Reaction profile in [OMIM][PF ] : (Table 22, entry 9) 6

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Enzyme activity in [OMIM][PF 6] = (0.37 x 50.51) /10 = 1.87 U/mg of IME

10. Reaction profile in [C MIM][PF ] : (Table 22, entry 10) 12 6

Enzyme activity in [C 12 MIM][PF 6] = (0.36 x 50.51) /10 = 1.86 U/mg of IME 11. Reaction profile in [BMIM][BF ] : (Table 22, entry 11) 4

Enzyme activity in [BMIM][BF 4] = (0.98 x 50.51) /10 = 4.97 U/mg of IME

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12. Reaction profile in [C MIM][BF ] : (Table 22, entry 12) 12 4

Enzyme activity in [C 12 MIM][BF 4] = (0.36 x 50.51) /10 = 1.82 U/mg of IME Enzymatic Resolution in Continuous flow reactors: (Scheme 76)

Experimental procedure: Vinyl acetate (3 mmol) and rac-OH (1 mmol) were dissolved in 50 mL of hexane in a flask and pumped under controlled flow (0.1 mL / min) through the stationary phase which was filled with CAL-B on ionic liquid as a heterogeneous support. A controlled flow (0.9 mL / min) with 100 bar pressure of scCO 2 was used as mobile phase.

Heterogeneous support (stationary phase) preparation for CAL-B / [BMIM][NTf 2]: (Table 25, entry 1)

100 mg of [BMIM][NTf 2] and 200 mg of CAL-B were mixed in 2 mL ACN solvent and the solvent was evaporated to get the enzyme coated with ionic liquid of 300 mg mixture. The stationary phase was prepared by 270 mg of this mixture. The amount of enzyme present in the stationary phase = (270 / 300) x 200 = 180 mg = 0.18 g.

1st Cycle: [ rac -OH] = 1 mmol, [VA] = 3 mmol were mixed in 50mL of hexane

Total flow rate = 1 mL /min ( sc CO 2 = 0.9 mL and Substrate = 0.1 mL). Concentration of [ rac -OH] = 1 mmol = 1 x 10 -3 mol / Lt, Amount of Substrate = 0.1 mL / min = 0.1 x 10 -3 Lt / min, Substrate flow rate per min during reaction = Concentration x Amount of Substrate -3 -3 = 1 x 10 x 0.1 x 10 mol / min = 0.1 Pmol/min

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Substrate flow rate per hour = 60 x 0.1 Pmol/min = 6 P mol/min The conversion from GC was plotted in graph below:

The % of conversion observed from graph to form ( R)-OAc = 40% (from graph)

The overall productivity per hour = 6 x 0.4 = 2.4 Pmol/ h. Note: 0.18g of enzyme was presented in the stationary phase.

The enzyme activity per gram of CAL-B in [BMIM][NTf2] in continuous flow system = 2.4/0.18 = 13.33 Pmol/h/g of enzyme.

2nd Cycle (Table 25, entry 2): [ rac -OH] = 1 mmol, [VA] = 3 mmol were mixed in 50mL of hexane, the same stationary phase and same flow rate 0.1 mL /min was used for the second cycle for another 8h. It was observed the same percentage of conversion (40%) and the enzyme activity didn’t changed remains same 13.33 Pmol/ h/ g of enzyme.

3rd Cycle (Table 25, entry 3): [ rac -OH] = 2 mmol, [VA] = 6 mmol were mixed in 50mL of hexane The same stationary phase was used but the concentration was doubled.

Total flow rate = 1 mL/min ( sc CO 2 = 0.9 mL and Substrate = 0.1 mL). Concentration of [rac-OH] = 2 mmol = 2 x 10 -3 mol/Lt, Amount of Substrate = 0.1 mL/min = 0.1 x 10 -3 Lt/min,

Substrate flow rate per min during reaction = Concentration x Amount of Substrate PL/min -3 -3 = 2 x 10 x 0.1 x 10 mol/min = 0.2 Pmol/min Substrate flow rate per hour = 60 x 0.2 Pmol/min = 12 P mol/min

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The conversion from GC was plotted in graph below:

The % of conversion observed from graph to form ( R)-OAc = 40% (from graph)

The overall productivity per hour = 12 x 0.4 = 4.8 Pmol/h. Note: 0.18g of enzyme was presented in the stationary phase.

The enzyme activity per gram of CAL-B in [BMIM][NTf2] in continuous flow system = 4.8/0.18 = 26.66 Pmol/h/g of enzyme.

Heterogeneous support (stationary phase) preparation for CAL-B / [OMIM][NTf 2]: (Table 25, entry 4)

100mg of [OMIM][NTf 2] and 200 mg of CAL-B were mixed in 2 mL ACN solvent and the solvent was evaporated to get the enzyme coated with ionic liquid of 300 mg mixture. The stationary phase was prepared by 250 mg of this mixture. The amount of enzyme present in the stationary phase = (250/300) x 200 = 166 mg = 0.166 g.

1st Cycle: [ rac -OH] = 1 mmol, [VA] = 3 mmol were mixed in 50 mL of hexane

Total flow rate = 1 mL /min ( sc CO 2 = 0.95 mL and Substrate = 0.05 mL). Concentration of [ rac -OH] = 1 mmol = 1 x 10 -3 mol/Lt, Amount of Substrate = 0.05 mL /min = 0.05 x 10 -3 Lt/min, Substrate flow rate per min during reaction = Concentration x Amount of Substrate -3 -3 = 1 x 10 x 0.05 x 10 mol/min = 0.05 Pmol/min Substrate flow rate per hour = 60 x 0.05 Pmol/min = 3 P mol/min The conversion from GC was plotted in graph below:

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The % of conversion observed from graph to form ( R)-OAc = 50% (from graph)

The overall productivity per hour = 3 x 0.5 = 1.5 Pmol/h. Note: 0.166 g of enzyme was presented in the stationary phase.

The enzyme activity per gram of CAL-B in [OMIM][NTf 2] in continuous flow system = 1.5/0.16 = 9.03 Pmol/h/g of enzyme.

2nd Cycle (Table 25, entry 5): [ rac -OH] = 1 mmol, [VA] = 3 mmol were mixed in 50 mL of hexane, the same stationary phase and same flow rate 0.05 mL was used for the second cycle for another 8 h. It was observed the same percentage of conversion (50%) and the enzyme activity didn’t changed, it remains same 9.03 Pmol/h/g of enzyme.

3rd Cycle (Table 25, entry 6): [ rac -OH] = 1 mmol, [VA] = 3 mmol were mixed in 50 mL of hexane, the same stationary phase was used but the substrate flow was doubled.

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Total flow rate = 1 mL /min ( sc CO 2 = 0.9 mL and Substrate = 0.1 mL). Concentration of [ rac -OH] = 1 mmol = 1 x 10 -3 mol/Lt, Amount of Substrate = 0.1 mL /min = 0.1 x 10 -3 Lt/min,

Substrate flow rate per min during reaction = Concentration x Amount of Substrate PL/min -3 -3 = 1 x 10 x 0.1 x 10 mol/min = 0.1 Pmol/min Substrate flow rate per hour = 60 x 0.1 Pmol/min = 6 P mol/min The conversion from GC was plotted in graph below:

The % of conversion observed from graph to form ( R)-OAc = 50% (from graph)

The overall productivity per hour = 6 x 0.5 = 3 Pmol/h. Note: 0.166g of enzyme was presented in the stationary phase.

The enzyme activity per gram of CAL-B in [OMIM][NTf 2] in continuous flow system = 3/0.16 = 18.07 Pmol/h/g of enzyme.

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Compounds Synthesized:

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Conclusion & Perspectives:

In the first part of our research we have developed a chemo, regio-, and stereoselective Tsuji-Trost allylation reaction starting with highly functionalized building

blocks, the J-borylated allylic acetates. We also developed a one-pot strategy of Tsuji- Trost allylation, followed by Suzuki-Miyaura reactions, using J-borylated allylic acetates. Further, J-borylated allylic acetates were employed for asymmetric allylic alkylation to give enantioenriched J-borylated allyl derivatives. The resulting products, after allylation, could be subjected to a wide range of reactions using the pinacol boronate moiety: for example it could be employed in 1,4-addition reactions using rhodium catalysts, it could be subjected to halogenolysis since the resulting vinyl halide derivatives could be, as well, useful key intermediates for various synthetic transformations and transition metal catalyzed cross couplings. As an extension to this work, it would be interesting to test such a Tsuji-Trost allylation 137 reaction of J-borylated allylic acetates in ionic liquids.

In the second part we successfully developed a kinetic resolution process for a J- borylated allylic alcohol, by using an enzyme, Candida Antartica Lipase (CAL-B),

along with ionic liquids. Further, we developed this kinetic resolution of a J-borylated allylic alcohol in continuous flow systems using immobilized enzyme (CAL-B) on

ionic liquid support, along with sc CO 2. As an extension to this work, it would be interesting to perform a dynamic kinetic resolution process in continuous flow systems in combination with components for the racemization step such as zeolites or transition metal catalysts, for instance. Further, such enzyme-mediated kinetic

dynamic resolution process in continuous flow systems could be extended to other J- borylated allylic alcohols. Such new technologies are perfectly in line with a development of a sustainable chemistry.

137 Liao, M-C, Duan, X-H, Liang, Y-M. Tetrahedron Lett . 2005, 46 , 3469.

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ANNEXE 2 (Modèle dernière page de thèse)

VU : VU :

Le Directeur de Thèse Le Responsable de l'École Doctorale

(Nom et Prénom)

VU pour autorisation de soutenance

Rennes, le

Le Président de l'Université de Rennes 1

Guy CATHELINEAU

VU après soutenance pour autorisation de publication :

Le Président de Jury,

(Nom et Prénom)

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