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

CONTENTS: Dynamic stereochemistry Introduction Terminologies and classification Principles of stereochemistry Diastereoselection in acyclic systems Diastereoselection in cyclic systems Enantioselective synthesis Asymmetric amplificationConclusion References

Dynamic StereochemistryEffect of stereochemistry on the rate of chemical reactions

involving bond making or a bond breaking or conformational transformations involving of interconversion of conforms

Correlates the stereochemistry of starting material and products in terms of transition states and intermediates.

INTRODUCTION

Thalidomide tragedy:

Racemic form of drug was approved in Europe for the treatment of pregnant women suffering from nausea but its use caused severe birth defects.

Prescribed to pregnant woman to alleviate morning sickness

Chiral drug undergoes rapid enantioconversionOne enantiomeric form shows sedative and antinausea

effect while other shows potent teratogenicity

Interconversion of Enantiomers of Thalidomide

Significance of stereochemical integrity of biologically active compounds has received attention

Today most of the drugs are sold as enantiopure compounds

More than 50% of today’s top-selling drugs including Lipitor ( global sales in 2010: $12.66 billion) Plavix ( global sales in 2010: $9.4 billion) Zocor ( global sales in 2010: $5.276 billion and Nexium (global sales in 2010 $5.0 billion) are sold as single

enantiomers.

TERMINOLOGIES AND

CLASSIFICATION

Two types of organic reactions: Stereo selective reactions: Stereo specific reactions:

STEREOSELECTIVE REACTIONS: Single reactant with prostereogenic centre gives two or more

stereoisomers in unequal amounts Reactant may not be chiral.Two stereoisomeric forms of reactant gives the same ratio of

products provided that it should not be 50:50

4-butyl cyclohexanone 4-butyl cyclohexanol (Trans) 90% 10% (Cis)

Stereoselective Reaction

Stereospecific ReactionTwo stereochemically different reactants gives different

stereoisomeric products in unequal amountsReactants can exit as stereoisomersDifferent stereoisomers produces different stereoisomers in

different ratio

Stereospecific Reaction

All stereospecific reactions are stereoselective but reverse is not true

Stereoselective but not stereospecific reaction

Two types of stereoselectivity: Substrate stereoselectivity. Product stereoselectivity.Substrate stereoselectivity: Depending upon whether the substrates are enantiomers or

diastereomers, it is further classified as: Substrate enantioselectivity Substrate diastereoselectivityRegioselectivity: Substrates are capable of reacting at more than one centre but at

faster rate than the others.

Regioselective reaction

Product Selectivity: Product selectivity refers to cases where a single substrate is capable

of giving two or more products but one is formed predominantly Depending upon whether the products are enantiomers or

diastereomers, it further classified as: Product enantioselectivity Product diastereoselectivity

Enantioselectivity:One of the stereoisomer of the starting material forms two or

more enantiomers, in which one enantiomer is formed in excess over the others

Diastereoselectivity:One of the stereoisomer of starting material forms two or

more diastereomers, in which one is formed in excess over the others

Asymmetric synthesis and asymmetric induction: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

Contains both enantioselective and diastereoselective reactions provided that a new chiral centre is created.

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

Enantiomeric excess for enantioselective reaction and diastereomeric excess for diastereoselective reaction

Double diastereoselection:Reduction of 2-methylcyclohexanone with H-donating reagents 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

The substrate is enantiomerically pure and the reducing agent is chiral, either R and S 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

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

PRINCIPLES OF

STEREOSELECTIVITY

For a reaction to be stereoselective, Stereoisomers should formed through diastereomeric transition statesDue to diastereomeric nature, they would differ in their free energy

levels and give products in different amountsDifference of 10 KJ/mol at ambient temperature provides preferred

isomer about 98% yield To make diastereomeric transition states, Substrates should have prostereogenic elements, which in turn

depends on the symmetry or more specifically on the topicity of reacting

groups or faces Only stereoheterotopic groups and faces on appropriate modification

give rise to stereoisomers Substrates having diastereomeric ligands gives rise to diastereomeric

transition states even with achiral reagent

To create diastereomeric transition states from substrates having enantiomeric faces, they should react with reagents that should be chiral in nature

Reagents may be catalysts, solvents or the medium If the reagent detached from the product at the end of the reaction,

the reaction would be enantioselective On the other hand, If a chiral moiety remains attached to the

product, it would be diastereoselective

Principle of Stereoselectivity

DIASTEREOSELECTION IN ACYCLIC SYSTEMS

Similar to aldol reaction but here –OM of the enolate being replaced by – CM or – CB

Diastereoselectivity depends upon geometry of allyl derivatives Proceed through chair like transition state produced by E- and Z-

allyl compounds with metal or boron coordinated to carbonyl oxygen

Addition of allylmetal and allylboron compounds to carbonyl:

E-allyl produces anti product and Z-allyl produces syn productTwo attacks may possible: one between like (Re-Re or Si-Si) faces

and other between unlike (Re-Si or Si-Re) faces 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

In E-allyl compounds, during attack between like faces Re-Re or Si-Si while in Z-allyl compounds, during attack between Si-Re or

Re-Si the above condition observed

Enantioselective synthesis: Allylboranes or allylboronic esters with chiral ligands are especially

efficient for inducing high asymmtry at the carbinol carbon Optically active tartaric esters of allylicboronic acid used because its

two faces are homotopic and induce symmetry in the same direction Homoallyl alcohols are obtained with 71-87% ee

Diastereoselective synthesis: If either or both of the aldehyde and allyl derivative contain chiral

centres, diastereomers are formed with varying degree of stereoselectivity.

S-2-Methylbutanal reacts with (-)-phenylboranediol-E-crotylboronate to give mainly (92%) the anti,syn isomer

Diastereoselective Reaction: Aldol Reaction

Valuable C-C bond forming reactionCreates two new stereocentres from achiral starting material and

forms four stereoisomers Syn or anti diastereomers produced each as a pair of enantiomers Takes place via highly ordered transition states known as

Zimmerman- Traxler transition state.

Diastereoselectivity achieved by employing enolate of desired stereochemistry

Enolate formed from ketone and a base by deprotonation Two possible conformations cis or(Z)-enolate and trans or(E)-

enolate Steric interaction between R1 and R2 predominating cis (Z)-

enolate

Results below demonstrate stereoselectivity influenced by the size of R

Z-enolates gives 2,3-syn aldols while E- enolates give the 2,3-anti aldols

Achiral aldehyde and achiral enolate with two enantiotopic faces (Re and Si) reacts in two modes: Unlike mode:Combination takes place between Si and Re (or Re and Si) faces of

the reactants leads to a syn diastreoisomer

Like mode:Combination takes place between Re and Re (or Si and Si) faces of

the reactants leads to an anti diastereoisomer

Aldol Syn Diastereoselection

Achiral aldehyde and achiral enolate:

Two diastereomers are formed, their relative amounts being determined by the diastereoface selectivity of the enolate

The dibutylboron enolate derived from an amide containing a chiral centre

The reaction proceeds with high diastereoselection and with higher enantioselection and the product on hydrolysis yields 3-hydroxy-2-methylcarboxylic acid of high purity

Chiral aldehydes and achiral enolates: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

Diastereoface selectivity chiral aldehydes

Chiral aldehydes and chiral enolates:Eight pairs of diastereomers are possible if the chiral components are

taken as racemates which reduced to only two If the chirality of the two components fixed a completely syn

configuration assumed at C-2 and C-3 centers If the two exixting chiral centres work synergistically, the

stereoselectivity will be reduced 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

Condenstion would occur almost exclusively between R and R and between S and S components and very little of cross combination would take place.

Addition of nucleophiles to carbonyl compounds: Most common method to generate a new c-c bond Achiral carbanion on addition to carbonyl compound having

enantiotopic or diastereotopic faces gives rise to stereoisomers 1,2-Asymmtric induction: 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

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

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

Syn compound is obtained in over 99% yield while when it is oxdised to ketone (IV) and reduced with hydrides, anti diastereomer obtained exclusively

Substrate used for stereoselective synthesis of both syn-anti diastereomer of methylhomoallyl alcohol

If one of the adjacent endocyclic atom is chelating, a highly diastereoselective addition to the exocyclic ketone may occur

The bicyclic chiral adjuvant (v) from (+)-pulegone gives lithium derivative obtained entirely the equatorial diastereomer

Resulting ketone (VI) undergoes Grignard addition to give exclusively the alcohol (VII) according to chelate model

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

Double transfer of chirality –first occurs at C-2 of the chiral adjuvant (lithiation) and second transfer occurs during Grignard addition.

1,3-Asymmetric induction:

When the carbonyl group is two bonds away from the chiral centre, asymmetric induction particularly in reaction with metal hydrides

is low More than 90% Diastereoselectivity reported in the addition

reaction of chiral β-alkoxyaldehydes using titanium reagents through the chelated six-centred chair like model

Alkyl group transferred from the β -face rather than from the α- face of the chelated ring

1,4-Asymmtric induction:Asymmetric inductiom is low to moderte

98% asymmrtric induction has been observed when (-) 8-phenylmenthyl glyoxylate used as substrate

The bulky phenyl group blocks one diastereoface of the carbonyl group effectively

A carbonyl group separated by more than three bonds from the chiral centre does not show much stereoselectivity in nucleophilic reactions.

Stereoselecive transformations of C=C bond: Hydroboration: formation of an alcohol:

Hydroboration of olefin takes place in a syn fashion which on deboronation gives an alcohol

If a double bond adjacent to chiral centre, addition takes place to less hindered diastereotopic face

Hydroboration of the terminal double bond in the ester, disiamyl borane reacts from side anti 4-methyl giving 4,6-syn product

predominantly (87%)

Perhydroxylation: formation of a vicinal diol: Several methodes of hydroxylation available giving 1,2-glycols Iodine and silver salt similarly goes through a cyclic iodinium ion

followed by neighbouring group participation to give an anti glycol If a reaction carried out under moisture, the intermediate acylium

ion hydrolysed and syn glycol results

Osmiun tetroxide oxidation giving syn glycols complementary to each other in the sence that they show opposite diastereoselectivity in the final product

The former gives Sterically less hindered syn glycol whereas latter the Sterically more hindered syn glycol

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

DIASTEREOSELECTION IN CYCLIC SYSTEMS

Nucleophillic addition to cyclic ketones: Two possibilities can be possible: Stereoselective formation of

equatorial alcohols and stereoselective formation of axial alcohols Formation of axial alcohols: 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

Following trialkylborane reagents are highly stereoselective in this respect

Results of reduction of five substituted cyclohexanones with just of such reagents are:

Cyclohexanones (substituents)

Li (s-Bu)3 BH (XXIV)

Li (Siam)3 BH (XXV)

IsOB-OAICl2

(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-Me3 99.0 99.0 98.0

Formation of equatorial alcohols:The thermodynamically more stable equatorial alcohols are best

prepared by dissolving metal reduction of cyclohexanones Reduction with t-butylmagnesium chloride using methylalumino

derivative of bis-(2,6-Di-butyl-4-methylphenoxide) andReduction with fluorenyloxyaluminium dichloride which go through

radical intermediates

Catalytic hydrogenation:Used for reduction of C=C bonds with high stereoselectivity depending

upon nature of solvents, catalysts and the substitution pattern Substrate adsorbed with its less hindered face toward the catalyst surface

and addition of hydrogen takes place from that side in a cis fashionCH2OH,CHO, and CO2H 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

In hydrogenation of the tetrahydrofluorene derivatives when R= CH2OH, proximofacial addition of hydrogen takes place giving 95% of the cis product But when R=CONH2 no haptophilic effect operates and distofacial addition is preferred

Alkylation:Generally alkylation leads to axially alkylated product through chair

like transition state Alkylation at a carbon already having a substituent is often more

stereoselective In the synthesis of steroids, side chain at C-10 in the intermediate

introduced by cyanoeyhylation, unnatural isomer with CH3

occupaying the equatorial position

In the later synthesis, alkylation sequence reversed and methylation gave the natural isomer,

In the synthesis of dehydroabietic acid, the steric factor controlled the stereochemistry of alkylation of the dienolate derived from a similarly substituted cyclohexanone

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

Diastereoselective oxidation:Highly stereoselective epoxidation of allylic or homoallylic cyclic

alcohols with t-butylhydroperoxide catalysed by vanadium or molybdenum

In epoxidation of 7β-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

Stereoselective formation of a double bond:Diols can be converted into corresponding olefinic compounds

stereoselectivityApplicable to both acyclic and cyclic diolsZ- cyclooctene on hydroxylation with peroxy acids converted into diol

which on reaction with thiophosgene gives the cyclic thiocarbonate which on treatment with triethyl phosphite or better with 1,3-

dimethyl-2-phenyl-1,3-dioazo-2-phospholidinegives E- cyclooctene with complete stereoselectivity

Stereoselective cyclisation of polyenes: 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

Terminal double bond of a polyene chain preferentially epoxidised which on acid catalysis genrates an oxonium ion which sets up a guided concerted cyclisation

ENANTIOSELECTIVE SYNTHESIS

Reduction with chiral hydride donors: Number of chiral reagents which reduce prochiral ketones and α-

deuterated aldehydes by the transfer of hydrogen MPV Reduction of isohexyl methyl ketone with S-2-butanol 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 an excess of 2-octanol Asymmetric induction in the reaction is however very low

Sterically hindered Grignard reagents: 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

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

Bornyloxyaluminium dichlorides: in modified MPV reduction,(-)-isobornyloxy and (-)-

bornylaluminium dichlorides are used to reduce variety of carbonyl compounds with enantioselection ranging from 30-90%

Chiral trialkylboranes:

B-(3α-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

NADH models: Coenzyme NADH is highly enantioselective hydride donor A few mimics containing dihydronicotinamide moiety have been

prepared e.g. La and Lb The reagents reduce a number of ketones in the presence of

magnesium perchlorate with high enantioselection

Chiral metal hydride complexes: 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

Chiral auxillaries include 2,2’-dihydroxy-1,1’-binaphthyl,N-methylephedrine

Enantioselective catalytic hydrogenation:Heterogenous catalysis:Tartaric acid –modified raney nickel can be used to reduce methyl

acetoacetate to methyl R-3-hydroxy in 88% enantiomeric excess

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

Homogenous catalysis:Chiral phosphorus-complex rhodium catalysts prepared either with a

chiral phosphorus containing chiral organic auxillaries Following catalysts are used for enantioselective reduction of N-

acetyl (benzoyl) enamines N-acetylaminoacrylic acid reduced with them in 56,79 and 95% ee

respectively

Sharpless Enantioselective Epoxidation Converts achiral allylic alcohol into chiral epoxide Remarkable stereoselection achieved by Sharpless and Katsuki (1980)

using titanium-catalysed epoxidation with tartaric acid as chiral ligandAllyl alcohol treated with t-butylhydroperoxide in presence of titanium

isopropoxide and optically active diethyl tartarateCreates two contiguous stereocentres with predictable

stereochemistry, depending on which enantiomer of DET used Incorporation of enantiomerically pure tatarate esters makes reaction

highely enantioselective

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

Enatioselective synthesis via hydrazones: Diastereoselective hydrogenation of cyclic hydrazones:

α- amino acids in 96-99% e can be prepared through diastereoface selective hydrogenation of chiral cyclic hydrazones

In next reaction, hydrogenation takes place from the side opposite to methyl and the product on hydrogenolysis affords α-amino acids

Both enantiomers of the indoline-amine prepared

Alkylation of chiral hydrazones: S-1-amino-2-methoxymethylpyrrolidine and its enatiomer can be

used for enantioselective alkylation of aldehydes and ketones Derived hydrazone from 3- pentanone on treatment with lithium

diisopropylamide gives complex in which lithioum coordinated to both the carbanionic centre and methoxyl group

Alkylating reagent approaches from the proximofacial side and gives product

Enantioselective alkylation through oxazolines:Efficient and versatile method for enantioselective synthesis of

substituted aliphatic acids through alkylation of chiral oxazolines which serve as a masked carboxylic group

The oxazoline on lithiation forms the complex with lithium held below the plane of the ring by methoxyl group

Alkylation takes place from the side of lithium giving alkylated product which on hydrolysis affords S-acid in 72-82% ee

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

Miscellaneous enantioselective syntheses: Phase transfer catalysis: Phase transfer catalysts such as crown ethers, ammonium salts,and

phosphonium compounds gives rise to enantioselection Enantioselective alkylation of a2-phenyllindanone catalysed by benzyl

cinchoninium cation 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

Intermolecular aldol condensation: S-proline catalysed cyclisation of the cyclopentan-1,3-dione to the

bicyclic ketone in 93% ee

Michael addition:Michael addition in presence of chiral amines show various degree of

enantioselectivity

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

Polymer –bound chiral catalysts: Polymer catalysed catalysts can be used for enantioselective reactions 1R,2S- ephedrine with chloromethylated polystyrene to give the

basic catalyst which promotes asymmetric addition of dialkyizinc to aldehydes

ASYMMETRIC AMPLIFICATION

Ultimate method of asymmetric synthesis in which the ee of the product far exceeds the ee of the chiral auxillary used

Benzaldehyde on reaction with diethylzinc under the catalysis of some Sterically constrained chiral amino alcohols gives 1-phenylpropanol in high optical purity

The use of the amino alcohol with 10.7% optical purity furnished 1-phenylpropanol of 82% enantiotopic purity

Required amino alcohols may be prepared by enantioselective reduction of the corresponding amino ketones

CONCLUSION

Dynamic stereochemistry correlates with the stereochemistry studies of any rate process, through the transition state and intermediate.

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.

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.

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.

REFERENCES

1) Stereochemistry of Organic Compounds, D. Nasipuri, New Age publications, 383-418.

2) Dynamic Stereochemistry of Chiral Compounds: Principles and Applications, Christian Wolf, Royal Society of Chemistry Publishing House,1-4.

3) Stereochemistry Conformation and Mechanism, P.S. Kalsi, New Age Publications, 114.

4) Stereochemistry of carbon compounds, Ernest L. Eliel, Tata McGraw-Hill publishing Company limited, 434-436

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