Dynamic stereochemistry stereoselectivity


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Dynamic stereochemistry stereoselectivity

  1. 1. DYNAMIC STEREOCHEMISTRY: STEREOSELECTIVE REACTIONS Submitted by: Guided by: Vinit D. Chavhan. Dr. Amit G.Nerkar M.Pharm. Ist Sem. M.Pharm,Ph.D. STES `s Smt.Kashibai Navale College Of Pharmacy, Kondhwa (Bk), Pune- 411048
  2. 2. <ul><li>CONTENTS : </li></ul><ul><li>Dynamic stereochemistry </li></ul><ul><li>Introduction </li></ul><ul><li>Terminologies and classification </li></ul><ul><li>Principles of stereochemistry </li></ul><ul><li>Diastereoselection in acyclic systems </li></ul><ul><li>Diastereoselection in cyclic systems </li></ul><ul><li>Enantioselective synthesis </li></ul><ul><li>Asymmetric amplification </li></ul><ul><li>Conclusion </li></ul><ul><li>References </li></ul>
  3. 3. Dynamic Stereochemistry <ul><li>Effect of stereochemistry on the rate of chemical reactions involving bond making or a bond breaking or conformational transformations involving of interconversion of conforms </li></ul><ul><li>Correlates the stereochemistry of starting material and products in terms of transition states and intermediates . </li></ul>
  4. 4. <ul><li>INTRODUCTION </li></ul>
  5. 5. Thalidomide tragedy: <ul><li>Racemic form of drug was approved in Europe for the treatment of pregnant women suffering from nausea but its use caused severe birth defects. </li></ul>
  6. 6. <ul><li>Prescribed to pregnant woman to alleviate morning sickness </li></ul><ul><li>Chiral drug undergoes rapid enantioconversion </li></ul><ul><li>One enantiomeric form shows sedative and antinausea effect while other shows potent teratogenicity </li></ul>Interconversion of Enantiomers of Thalidomide
  7. 7. <ul><li>Significance of stereochemical integrity of biologically active compounds has received attention </li></ul><ul><li>Today most of the drugs are sold as enantiopure compounds </li></ul>
  8. 8. <ul><li>More than 50% of today’s top-selling drugs including </li></ul><ul><li>Lipitor ( global sales in 2010: $12.66 billion) </li></ul><ul><li>Plavix ( global sales in 2010: $9.4 billion) </li></ul><ul><li>Zocor ( global sales in 2010: $5.276 billion and </li></ul><ul><li>Nexium (global sales in 2010 $5.0 billion) are sold as single enantiomers. </li></ul>
  9. 9. <ul><li>TERMINOLOGIES </li></ul><ul><li>AND </li></ul><ul><li>CLASSIFICATION </li></ul>
  10. 10. <ul><li>Two types of organic reactions: </li></ul><ul><li>Stereo selective reactions: </li></ul><ul><li>Stereo specific reactions: </li></ul><ul><li>STEREOSELECTIVE REACTIONS: </li></ul><ul><li>Single reactant with prostereogenic centre gives two or more stereoisomers in unequal amounts </li></ul><ul><li>Reactant may not be chiral. </li></ul><ul><li>Two stereoisomeric forms of reactant gives the same ratio of products provided that it should not be 50:50 </li></ul>
  11. 11. 4-butyl cyclohexanone 4-butyl cyclohexanol (Trans) 90% 10% (Cis) Stereoselective Re action
  12. 12. Stereospecific Reaction <ul><li>Two stereochemically different reactants gives different stereoisomeric products in unequal amounts </li></ul><ul><li>Reactants can exit as stereoisomers </li></ul><ul><li>Different stereoisomers produces different stereoisomers in different ratio </li></ul>Stereospecific Reaction
  13. 13. <ul><li>All stereospecific reactions are stereoselective but reverse is not true </li></ul>Stereoselective but not stereospecific reaction
  14. 14. <ul><li>Two types of stereoselectivity: </li></ul><ul><li>Substrate stereoselectivity. </li></ul><ul><li>Product stereoselectivity. </li></ul><ul><li>Substrate stereoselectivity: </li></ul><ul><li>Depending upon whether the substrates are enantiomers or diastereomers, it is further classified as: </li></ul><ul><li>Substrate enantioselectivity </li></ul><ul><li>Substrate diastereoselectivity </li></ul><ul><li>Regioselectivity: </li></ul><ul><li>Substrates are capable of reacting at more than one centre but at faster rate than the others . </li></ul>
  15. 15. Regioselective reaction
  16. 16. <ul><li>Product Selectivity: </li></ul><ul><li>Product selectivity refers to cases where a single substrate is capable of giving two or more products but one is formed predominantly </li></ul><ul><li>Depending upon whether the products are enantiomers or diastereomers, it further classified as: </li></ul><ul><li>Product enantioselectivity </li></ul><ul><li>Product diastereoselectivity </li></ul>
  17. 17. <ul><li>Enantioselectivity : </li></ul><ul><li>One of the stereoisomer of the starting material forms two or more enantiomers, in which one enantiomer is formed in excess over the others </li></ul><ul><li>Diastereoselectivity: </li></ul><ul><li>One of the stereoisomer of starting material forms two or more diastereomers, in which one is formed in excess over the others </li></ul>
  18. 18. <ul><li>Asymmetric synthesis and asymmetric induction: </li></ul><ul><li>Reaction in which an achiral unit in an ensemble of substrate molecules is converted into achiral unit in such a manner that unequal amounts of stereoisomers are produced </li></ul><ul><li>Contains both enantioselective and diastereoselective reactions provided that a new chiral centre is created. </li></ul><ul><li>The extent of asymmetry induced at a prochiral centre of the substrate either by the chirality of the reagent or by one or more chiral centres present in substrate molecule itself </li></ul><ul><li>Enantiomeric excess for enantioselective reaction and diastereomeric excess for diastereoselective reaction </li></ul>
  19. 19. <ul><li>Double diastereoselection: </li></ul><ul><li>Reduction of 2-methylcyclohexanone with H-donating reagents </li></ul><ul><li>Ketone exixts in two enantiomeric forms S and R, when reduced with achiral reagent such as Lithium Aluminium Hydride, two diastereomers, a trans (1S,2S from S-ketone and 1R,2R from R-ketone both designated l ) and cis (1R,2S or 1S,2R designated u ) the former predominating </li></ul><ul><li>The substrate is enantiomerically pure and the reducing agent is chiral, either R and S </li></ul><ul><li>With R reagent, the transition state for trans isomer represented bySS-R and with S reagent, other transition state represented by SS-S.Two transition states are diastereomeric and so the asymmetric induction or diastereoselection (de) will be different when the S –ketone (or the R- ketone) is reduced with reagents of opposite chirality </li></ul>
  20. 20. <ul><li>The diastereoselectivity in each combination of the substrate and reagent (SR or SS) considered two contributions: one due to the inherent diastereoface selectivity of reagent and other due to inherent diastereoface selectivity of substrate leading to Double Asymmetric Diastereoselection or Double Diastereoselection </li></ul>
  21. 21. <ul><li>PRINCIPLES </li></ul><ul><li>OF </li></ul><ul><li>STEREOSELECTIVITY </li></ul>
  22. 22. <ul><li>For a reaction to be stereoselective, </li></ul><ul><li>Stereoisomers should formed through diastereomeric transition states </li></ul><ul><li>Due to diastereomeric nature, they would differ in their free energy levels and give products in different amounts </li></ul><ul><li>Difference of 10 KJ/mol at ambient temperature provides preferred isomer about 98% yield </li></ul><ul><li>To make diastereomeric transition states, </li></ul><ul><li>Substrates should have prostereogenic elements, which in turn depends </li></ul><ul><li>on the symmetry or more specifically on the topicity of reacting groups or faces </li></ul><ul><li>Only stereoheterotopic groups and faces on appropriate modification give rise to stereoisomers </li></ul><ul><li>Substrates having diastereomeric ligands gives rise to diastereomeric transition states even with achiral reagent </li></ul>
  23. 23. <ul><li>To create diastereomeric transition states from substrates having enantiomeric faces, they should react with reagents that should be chiral in nature </li></ul><ul><li>Reagents may be catalysts, solvents or the medium </li></ul><ul><li>If the reagent detached from the product at the end of the reaction, the reaction would be enantioselective </li></ul><ul><li>On the other hand, If a chiral moiety remains attached to the product, it would be diastereoselective </li></ul>
  24. 24. Principle of Stereoselectivity
  25. 25. <ul><li>DIASTEREOSELECTION </li></ul><ul><li>IN </li></ul><ul><li>ACYCLIC SYSTEMS </li></ul>
  26. 26. <ul><li>Similar to aldol reaction but here –OM of the enolate being replaced by – CM or – CB </li></ul><ul><li>Diastereoselectivity depends upon geometry of allyl derivatives </li></ul><ul><li>Proceed through chair like transition state produced by E- and Z- allyl compounds with metal or boron coordinated to carbonyl oxygen </li></ul>Addition of allylmetal and allylboron compounds to carbonyl:
  27. 27. <ul><li>E-allyl produces anti product and Z-allyl produces syn product </li></ul><ul><li>Two attacks may possible: one between like (Re-Re or Si-Si) faces and other between unlike (Re-Si or Si-Re) faces </li></ul><ul><li>Ideally in transition states R group of the aldehyde should orients itself pseudo equatorial so that there will no 1,3 – diaxial strain between R group and one of the ligands of the boron </li></ul><ul><li>In E-allyl compounds, during attack between like faces Re-Re or </li></ul><ul><li>Si-Si while in Z-allyl compounds, during attack between Si-Re or Re-Si the above condition observed </li></ul>
  28. 28. <ul><li>Enantioselective synthesis: </li></ul><ul><li>Allylboranes or allylboronic esters with chiral ligands are especially efficient for inducing high asymmtry at the carbinol carbon </li></ul><ul><li>Optically active tartaric esters of allylicboronic acid used because its two faces are homotopic and induce symmetry in the same direction </li></ul><ul><li>Homoallyl alcohols are obtained with 71-87% ee </li></ul>
  29. 29. <ul><li>Diastereoselective synthesis: </li></ul><ul><li>If either or both of the aldehyde and allyl derivative contain chiral centres, diastereomers are formed with varying degree of stereoselectivity. </li></ul><ul><li>S-2-Methylbutanal reacts with (-)-phenylboranediol-E-crotylboronate </li></ul><ul><li>to give mainly (92%) the anti,syn isomer </li></ul>
  30. 30. Diastereoselective Reaction: Aldol Reaction <ul><li>Valuable C-C bond forming reaction </li></ul><ul><li>Creates two new stereocentres from achiral starting material and forms four stereoisomers </li></ul><ul><li>Syn or anti diastereomers produced each as a pair of enantiomers </li></ul><ul><li>Takes place via highly ordered transition states known as Zimmerman- Traxler transition state. </li></ul>
  31. 31. <ul><li>Diastereoselectivity achieved by employing enolate of desired stereochemistry </li></ul><ul><li>Enolate formed from ketone and a base by deprotonation </li></ul><ul><li>Two possible conformations cis or(Z)-enolate and trans or(E)-enolate </li></ul><ul><li>Steric interaction between R1 and R2 predominating cis (Z)-enolate </li></ul>
  32. 32. <ul><li>Results below demonstrate stereoselectivity influenced by the size of R </li></ul><ul><li>Z-enolates gives 2,3-syn aldols while E- enolates give the </li></ul><ul><li>2,3-anti aldols </li></ul>
  33. 33. <ul><li>Achiral aldehyde and achiral enolate with two enantiotopic faces </li></ul><ul><li>(Re and Si) reacts in two modes: </li></ul><ul><li>Unlike mode: </li></ul><ul><li>Combination takes place between Si and Re (or Re and Si) faces of the reactants leads to a syn diastreoisomer </li></ul>
  34. 34. <ul><li>Like mode: </li></ul><ul><li>Combination takes place between Re and Re (or Si and Si) faces of the reactants leads to an anti diastereoisomer </li></ul>
  35. 35. Achiral aldehyde and achiral enolate: <ul><li>Two diastereomers are formed, their relative amounts being determined by the diastereoface selectivity of the enolate </li></ul><ul><li>The dibutylboron enolate derived from an amide containing a chiral centre </li></ul><ul><li>The reaction proceeds with high diastereoselection and with higher enantioselection and the product on hydrolysis yields 3-hydroxy-2-methylcarboxylic acid of high purity </li></ul>Aldol Syn Diastereoselection
  36. 36. <ul><li>Chiral aldehydes and achiral enolates: </li></ul><ul><li>Number of diastereomers formed by addition of an achiral enolate increases to four but aldol syn stereoselection for z-enolates reduces it to two: syn, syn and syn, anti </li></ul>Diastereoface selectivity chiral aldehydes
  37. 37. <ul><li>Chiral aldehydes and chiral enolates: </li></ul><ul><li>Eight pairs of diastereomers are possible if the chiral components are taken as racemates which reduced to only two </li></ul><ul><li>If the chirality of the two components fixed a completely syn configuration assumed at C-2 and C-3 centers </li></ul><ul><li>If the two exixting chiral centres work synergistically, the stereoselectivity will be reduced </li></ul><ul><li>The diastereoface stereoselectivities of the S-aldehyde and S-enolate thus cooperate with each other in forming the isomer but neither gets its way in forming the isomer which explains the predominant product.In cross combination i.e. S-aldehyde and R-enolate, the two stereoselectivities work in opposition giving a very low diastereoselection It also follows that the stereochemically non-cooperative reactants so that if the racemic aldehyde is allowed to react with the racemic enolate </li></ul>
  38. 38. <ul><li>Condenstion would occur almost exclusively between R and R and between S and S components and very little of cross combination would take place. </li></ul>
  39. 39. <ul><li>Addition of nucleophiles to carbonyl compounds: </li></ul><ul><li>Most common method to generate a new c-c bond </li></ul><ul><li>Achiral carbanion on addition to carbonyl compound having enantiotopic or diastereotopic faces gives rise to stereoisomers </li></ul><ul><li>1,2-Asymmtric induction: </li></ul><ul><li>If the chiral centre present adjacent to a carbonyl group, nucleophillic addition based on either the open chain model or the cyclic or chelate model </li></ul><ul><li>Stereoselectivity not achieved through open chain model except when R is bulky but chelate model can give high stereoselectivity depending upon extent of chelation which in turn determined by nature of chelating group, metal and solvent </li></ul>
  40. 41. <ul><li>High diastereoselectivity achieved in Grignard reactions and hydride additions with substrates (III) which do not contain a chelating group but have a bulky trimehyl sillyl moiety as part of L group </li></ul><ul><li>Syn compound is obtained in over 99% yield while when it is oxdised to ketone (IV) and reduced with hydrides, anti diastereomer obtained exclusively </li></ul><ul><li>Substrate used for stereoselective synthesis of both syn-anti diastereomer of methylhomoallyl alcohol </li></ul><ul><li>If one of the adjacent endocyclic atom is chelating, a highly diastereoselective addition to the exocyclic ketone may occur </li></ul><ul><li>The bicyclic chiral adjuvant (v) from (+)-pulegone gives lithium derivative obtained entirely the equatorial diastereomer </li></ul><ul><li>Resulting ketone (VI) undergoes Grignard addition to give exclusively the alcohol (VII) according to chelate model </li></ul>
  41. 42. <ul><li>Clevage of the oxathine leads to the α -hydroxyaldehyde (VIII) to give tert.alcohol, glycol and hydroxy acid may obtained in 90-99% enantiomeric purity </li></ul><ul><li>Double transfer of chirality –first occurs at C-2 of the chiral adjuvant (lithiation) and second transfer occurs during Grignard addition. </li></ul>
  42. 43. <ul><li>1,3-Asymmetric induction: </li></ul><ul><li>When the carbonyl group is two bonds away from the chiral centre, </li></ul><ul><li>asymmetric induction particularly in reaction with metal hydrides is low </li></ul><ul><li>More than 90% Diastereoselectivity reported in the addition reaction of chiral β -alkoxyaldehydes using titanium reagents through the chelated six-centred chair like model </li></ul><ul><li>Alkyl group transferred from the β - face rather than from the α - face of the chelated ring </li></ul>
  43. 44. <ul><li>1,4-Asymmtric induction: </li></ul><ul><li>Asymmetric inductiom is low to moderte </li></ul><ul><li>98% asymmrtric induction has been observed when (-) 8-phenylmenthyl glyoxylate used as substrate </li></ul><ul><li>The bulky phenyl group blocks one diastereoface of the carbonyl group effectively </li></ul><ul><li>A carbonyl group separated by more than three bonds from the chiral centre does not show much stereoselectivity in nucleophilic reactions. </li></ul>
  44. 45. <ul><li>Stereoselecive transformations of C=C bond: Hydroboration: formation of an alcohol: </li></ul><ul><li>Hydroboration of olefin takes place in a syn fashion which on deboronation gives an alcohol </li></ul><ul><li>If a double bond adjacent to chiral centre, addition takes place to less hindered diastereotopic face </li></ul><ul><li>Hydroboration of the terminal double bond in the ester, disiamyl borane reacts from side anti 4-methyl giving 4,6-syn product </li></ul><ul><li>predominantly (87%) </li></ul>
  45. 46. <ul><li>Perhydroxylation: formation of a vicinal diol: </li></ul><ul><li>Several methodes of hydroxylation available giving 1,2-glycols </li></ul><ul><li>Iodine and silver salt similarly goes through a cyclic iodinium ion followed by neighbouring group participation to give an anti glycol </li></ul><ul><li>If a reaction carried out under moisture, the intermediate acylium ion hydrolysed and syn glycol results </li></ul>
  46. 47. <ul><li>Osmiun tetroxide oxidation giving syn glycols complementary to each other in the sence that they show opposite diastereoselectivity in the final product </li></ul><ul><li>The former gives Sterically less hindered syn glycol whereas latter the Sterically more hindered syn glycol </li></ul><ul><li>The first ring intermediate in both reactions is formed on the less hindered α -side but since oxidation takes place through one more cyclic intermediate, stereoselectivity is ultimately reserved </li></ul>
  47. 48. <ul><li>DIASTEREOSELECTION </li></ul><ul><li>IN </li></ul><ul><li>CYCLIC SYSTEMS </li></ul>
  48. 49. <ul><li>Nucleophillic addition to cyclic ketones: </li></ul><ul><li>Two possibilities can be possible: Stereoselective formation of equatorial alcohols and stereoselective formation of axial alcohols </li></ul><ul><li>Formation of axial alcohols: </li></ul><ul><li>Secondary axial alcohols are less stable, therefore must be formed under kinetic control using bulky reagents to approach the carbonyl group from the less hindered equatorial side </li></ul><ul><li>Following trialkylborane reagents are highly stereoselective in this respect </li></ul>
  49. 50. <ul><li>Results of reduction of five substituted cyclohexanones with just of such reagents are: </li></ul>Cyclohexanones (substituents) Li (s-Bu) 3 BH (XXIV) Li (Siam) 3 BH (XXV) IsOB-OAICl 2 (XXV) 4-t-Bu 96.5 99.0 92.0 4 - Me 90.0 98.0 90.0 3 - Me 94.5 99.0 92.0 2 - Me 99.3 99.0 98.0 3,3,5-Me 3 99.0 99.0 98.0
  50. 51. <ul><li>Formation of equatorial alcohols: </li></ul><ul><li>The thermodynamically more stable equatorial alcohols are best prepared by dissolving metal reduction of cyclohexanones </li></ul><ul><li>Reduction with t-butylmagnesium chloride using methylalumino derivative of bis-(2,6-Di-butyl-4-methylphenoxide) and </li></ul><ul><li>Reduction with fluorenyloxyaluminium dichloride which go through radical intermediates </li></ul>
  51. 52. <ul><li>Catalytic hydrogenation: </li></ul><ul><li>Used for reduction of C=C bonds with high stereoselectivity depending upon nature of solvents, catalysts and the substitution pattern </li></ul><ul><li>Substrate adsorbed with its less hindered face toward the catalyst surface and addition of hydrogen takes place from that side in a cis fashion </li></ul><ul><li>CH 2 OH,CHO, and CO 2 H groups show haptophilic effect meaning they remain anchored on the catalyst surface sufficiently long to allow hydrogen to add on the same molecular face rather than opposite side </li></ul><ul><li>In hydrogenation of the tetrahydrofluorene derivatives when R= CH 2 OH, proximofacial addition of hydrogen takes place giving 95% of the cis product But when R=CONH 2 no haptophilic effect operates and distofacial addition is preferred </li></ul>
  52. 54. <ul><li>Alkylation: </li></ul><ul><li>Generally alkylation leads to axially alkylated product through chair like transition state </li></ul><ul><li>Alkylation at a carbon already having a substituent is often more stereoselective </li></ul><ul><li>In the synthesis of steroids, side chain at C-10 in the intermediate introduced by cyanoeyhylation, unnatural isomer with CH 3 occupaying the equatorial position </li></ul>
  53. 55. <ul><li>In the later synthesis, alkylation sequence reversed and methylation gave the natural isomer, </li></ul>
  54. 56. <ul><li>In the synthesis of dehydroabietic acid, the steric factor controlled the stereochemistry of alkylation of the dienolate derived from a similarly substituted cyclohexanone </li></ul><ul><li>Alkylating agent (ethyl bromoacetate) from β -side in chair-like transition state effectively blocked by a 1,3-synaxial interaction with 10- Me and desired product is keto-ester transformed into dehydroabietic acid </li></ul>
  55. 57. <ul><li>Diastereoselective oxidation: </li></ul><ul><li>Highly stereoselective epoxidation of allylic or homoallylic cyclic alcohols with t-butylhydroperoxide catalysed by vanadium or molybdenum </li></ul><ul><li>In epoxidation of 7 β -hydroxycholest-5,6-ene, vanadium coordinates with both the allylic OH and t-Bu-O-OH and oxygen transferred to double bond almost completely from the side cis to allylic OH </li></ul>
  56. 58. <ul><li>Stereoselective formation of a double bond: </li></ul><ul><li>Diols can be converted into corresponding olefinic compounds stereoselectivity </li></ul><ul><li>Applicable to both acyclic and cyclic diols </li></ul><ul><li>Z- cyclooctene on hydroxylation with peroxy acids converted into diol which on reaction with thiophosgene gives the cyclic thiocarbonate </li></ul><ul><li>which on treatment with triethyl phosphite or better with 1,3-dimethyl-2-phenyl-1,3-dioazo-2-phospholidinegives E- cyclooctene with complete stereoselectivity </li></ul>
  57. 59. <ul><li>Stereoselective cyclisation of polyenes: </li></ul><ul><li>In cyclisation of the monocyclic teraene, the allylic carbinol carbon in the cyclopentene ring forms a carbonium ion which triggers the cyclisation, with two inner double bonds (with E geometry ) undergoing addition at both ends in a fashion so that the correct relative configuration is attained in the product and then converted into progesterone </li></ul><ul><li>Terminal double bond of a polyene chain preferentially epoxidised which on acid catalysis genrates an oxonium ion which sets up a guided concerted cyclisation </li></ul>
  58. 60. <ul><li>ENANTIOSELECTIVE </li></ul><ul><li>SYNTHESIS </li></ul>
  59. 61. <ul><li>Reduction with chiral hydride donors: </li></ul><ul><li>Number of chiral reagents which reduce prochiral ketones and α -deuterated aldehydes by the transfer of hydrogen </li></ul><ul><li>MPV Reduction of isohexyl methyl ketone with S-2-butanol </li></ul><ul><li>Two transition states possible (TS-1 and TS-2) and the one (TS-2) with larger groups on the opposite sides of the plane preferred giving </li></ul><ul><li>an excess of 2-octanol </li></ul><ul><li>Asymmetric induction in the reaction is however very low </li></ul>
  60. 63. <ul><li>Sterically hindered Grignard reagents: </li></ul><ul><li>Sterically hindered Grignard reagents instead of undergoing nucleophilic addition transfer a β -H to a carbonyl function and chirality can be induced in the alcohols if hydrogen is transferred from chiral centre </li></ul><ul><li>Reagents like S-2-phenylmagnesium chloride for reduction of isopropyl is enantioselective while phenyl ketone and Trialkylaluminium and dialkylzinc for the reduction of ketones provides low enantioselectivity </li></ul>
  61. 64. <ul><li>Bornyloxyaluminium dichlorides: </li></ul><ul><li>in modified MPV reduction,(-)-isobornyloxy and (-)-bornylaluminium dichlorides are used to reduce variety of carbonyl compounds with enantioselection ranging from 30-90% </li></ul>
  62. 65. <ul><li>Chiral trialkylboranes: </li></ul><ul><li>B-(3 α -pinanyl)-9-borabicyclononane easily prepared from 1,5-cyclooctadiene,borane and α - pinene are efficiently reducing agents and reduces aliphatic, allylic and aromatic aldehydes and α , β -unsaturated ketones </li></ul>
  63. 66. <ul><li>NADH models: </li></ul><ul><li>Coenzyme NADH is highly enantioselective hydride donor </li></ul><ul><li>A few mimics containing dihydronicotinamide moiety have been prepared e.g. La and Lb </li></ul><ul><li>The reagents reduce a number of ketones in the presence of magnesium perchlorate with high enantioselection </li></ul>
  64. 67. <ul><li>Chiral metal hydride complexes: </li></ul><ul><li>Lithium aluminum hydride and sodium borohydride have been modified by replacing one or more H atoms by organic chiral molecules with different functionalities and used for enantioselective reduction of ketones </li></ul><ul><li>Chiral auxillaries include 2,2’-dihydroxy-1,1’-binaphthyl,N-methylephedrine </li></ul>
  65. 68. <ul><li>Enantioselective catalytic hydrogenation: </li></ul><ul><li>Heterogenous catalysis: </li></ul><ul><li>Tartaric acid –modified raney nickel can be used to reduce methyl acetoacetate to methyl R-3-hydroxy in 88% enantiomeric excess </li></ul><ul><li>Chiral adjuvants can be used such as α -ketoacids are condensed with chiral amines i.e. S- α -aminobenzylamine and the resultant Schiff base hydrogenated to give α -amino acids with moderate enantioselection </li></ul>
  66. 69. <ul><li>Homogenous catalysis: </li></ul><ul><li>Chiral phosphorus-complex rhodium catalysts prepared either with a chiral phosphorus containing chiral organic auxillaries </li></ul><ul><li>Following catalysts are used for enantioselective reduction of N-acetyl (benzoyl) enamines </li></ul><ul><li>N-acetylaminoacrylic acid reduced with them in 56,79 and 95% ee respectively </li></ul>
  67. 70. <ul><li>Sharpless Enantioselective Epoxidation </li></ul><ul><li>Converts achiral allylic alcohol into chiral epoxide </li></ul><ul><li>Remarkable stereoselection achieved by Sharpless and Katsuki (1980) using titanium-catalysed epoxidation with tartaric acid as chiral ligand </li></ul><ul><li>Allyl alcohol treated with t-butylhydroperoxide in presence of titanium isopropoxide and optically active diethyl tartarate </li></ul><ul><li>Creates two contiguous stereocentres with predictable stereochemistry, depending on which enantiomer of DET used </li></ul><ul><li>Incorporation of enantiomerically pure tatarate esters makes reaction highely enantioselective </li></ul>
  68. 72. Displacement of two isopropoxy groups of titanium complex by two hydroxyl groups of tartarate ester Remaining isopropoxyl groups replaced by hydroxyl groups of peroxide and allylic alcohol respectively Mechanism of Sharpless Enantioselective Epoxidation
  69. 74. <ul><li>Enatioselective synthesis via hydrazones: </li></ul><ul><li>Diastereoselective hydrogenation of cyclic hydrazones: </li></ul><ul><li>α - amino acids in 96-99% e can be prepared through diastereoface selective hydrogenation of chiral cyclic hydrazones </li></ul><ul><li>In next reaction, hydrogenation takes place from the side opposite to methyl and the product on hydrogenolysis affords α -amino acids </li></ul><ul><li>Both enantiomers of the indoline-amine prepared </li></ul>
  70. 76. <ul><li>Alkylation of chiral hydrazones: </li></ul><ul><li>S-1-amino-2-methoxymethylpyrrolidine and its enatiomer can be used for enantioselective alkylation of aldehydes and ketones </li></ul><ul><li>Derived hydrazone from 3- pentanone on treatment with lithium diisopropylamide gives complex in which lithioum coordinated to both the carbanionic centre and methoxyl group </li></ul><ul><li>Alkylating reagent approaches from the proximofacial side and gives product </li></ul>
  71. 77. <ul><li>Enantioselective alkylation through oxazolines: </li></ul><ul><li>Efficient and versatile method for enantioselective synthesis of substituted aliphatic acids through alkylation of chiral oxazolines which serve as a masked carboxylic group </li></ul><ul><li>The oxazoline on lithiation forms the complex with lithium held below the plane of the ring by methoxyl group </li></ul><ul><li>Alkylation takes place from the side of lithium giving alkylated product which on hydrolysis affords S-acid in 72-82% ee </li></ul><ul><li>In another approach, the oxazoline converted into the 2-vinyl derivative which undergoes Michael addition to give the β -alkylated product, again with very high diastereoselection, which on hydrolysis affords 3,3-disubstituted propionic acids in 92-98% ee </li></ul>
  72. 79. <ul><li>Miscellaneous enantioselective syntheses: </li></ul><ul><li>Phase transfer catalysis: </li></ul><ul><li>Phase transfer catalysts such as crown ethers, ammonium salts,and phosphonium compounds gives rise to enantioselection </li></ul><ul><li>Enantioselective alkylation of a2-phenyllindanone catalysed by benzyl cinchoninium cation </li></ul><ul><li>The quinuclidine ring lies behind the plane of the indanone enolate permitting π - interaction between the benzyl group of the catalyst and the 2-phenyl group and at the same time 9-OH provides a directive handle through H-bonding so that back side approach of the alkylating agent is effectively prohibited and S-(+)-2- methyllindanone formed </li></ul>
  73. 80. <ul><li>Intermolecular aldol condensation: </li></ul><ul><li>S-proline catalysed cyclisation of the cyclopentan-1,3-dione to the bicyclic ketone in 93% ee </li></ul>
  74. 81. <ul><li>Michael addition: </li></ul><ul><li>Michael addition in presence of chiral amines show various degree of enantioselectivity </li></ul><ul><li>Thus α , β -unsaturated amides derived from ephedrine on Grignard addition and subsequent hydrolysis afford 3,3-disubstituted propionic acids in 79-99% enantiomeric excess </li></ul>
  75. 82. <ul><li>Polymer –bound chiral catalysts: </li></ul><ul><li>Polymer catalysed catalysts can be used for enantioselective reactions </li></ul><ul><li>1R,2S- ephedrine with chloromethylated polystyrene to give the basic catalyst which promotes asymmetric addition of dialkyizinc to aldehydes </li></ul>
  76. 83. <ul><li>ASYMMETRIC </li></ul><ul><li>AMPLIFICATION </li></ul>
  77. 84. <ul><li>Ultimate method of asymmetric synthesis in which the ee of the product far exceeds the ee of the chiral auxillary used </li></ul><ul><li>Benzaldehyde on reaction with diethylzinc under the catalysis of some Sterically constrained chiral amino alcohols gives 1-phenylpropanol in high optical purity </li></ul><ul><li>The use of the amino alcohol with 10.7% optical purity furnished 1-phenylpropanol of 82% enantiotopic purity </li></ul><ul><li>Required amino alcohols may be prepared by enantioselective reduction of the corresponding amino ketones </li></ul>
  78. 85. <ul><li>CONCLUSION </li></ul>
  79. 86. <ul><li>Dynamic stereochemistry correlates with the stereochemistry studies of any rate process, through the transition state and intermediate. </li></ul><ul><li>Today many biologically active compounds, for example pharmaceuticals, agrochemicals, flavors, fragrances, and nutrients, are chiral and more than 50% of today’s top-selling drugs are sold as single compounds. </li></ul><ul><li>The significance of the stereo chemical integrity of biologically active compounds has received increasing attention and the investigation of the stereo dynamic properties of chiral molecules has become an integral part of modern drug development. </li></ul><ul><li>As we are dealing with chemistry, we have to develop such auxillaries, reagents and catalysts which can incorporate it’s stereoselectivity in our reactions to make it as stereoselective. </li></ul>
  80. 87. <ul><li>REFERENCES </li></ul>
  81. 88. <ul><li>1) Stereochemistry of Organic Compounds, D. Nasipuri, New Age publications, 383-418. </li></ul><ul><li>2) Dynamic Stereochemistry of Chiral Compounds: Principles and Applications, Christian Wolf, Royal Society of Chemistry Publishing House,1-4. </li></ul><ul><li>3) Stereochemistry Conformation and Mechanism, P.S. Kalsi, New Age Publications, 114. </li></ul><ul><li>4) Stereochemistry of carbon compounds, Ernest L. Eliel, Tata McGraw-Hill publishing Company limited, 434-436 </li></ul>
  82. 89. <ul><li>THANK YOU </li></ul>