1  

   

Selectivity in Organic Chemistry

H3CH

O

CHEMISTRY 215TEXTBOOK

SUPPLEMENT

S 1.1 Overview of Selectivity

A. ChemoselectivityWhen an organic compound contains more than one functional group, the question arises about whether a reaction will take place at one, the other, or both of those groups. For example, the two functional groups in 4-oxopentanoic acid, a ketone and an acid, are both capable of being reduced with lithium aluminum hydride.

O

OH

O

4-oxopentanoic acid

1) LiAlH4

2) acid workupOH

OH

On the other hand, the reaction between 4-oxopentanoic acid and sodium borohydride results in the reduction of the ketone and only the deprotonation of the acid.

1,4-pentanediol

O

OH

O

O

OH

NaBH4

CH3OH

O

Na OH

OH

OH3O

4-hydroxypentanoic acid

When a reagent, such as sodium borohydride, reacts exclusively or predominantly in the competition between two or more functional groups that could give the same reaction, then the reaction is called chemoselective. Sodium borohydride, then, is a more chemoselective reducing agent than lithium aluminum hydride.

  2  

 

Throughout your study of organic chemistry, you have encountered many examples of chemoselectivity. Differences in electrophilic and nucleophilic character can both result in differences in chemoselectivity. Here are a few familiar examples of chemoselectivity.

HO

NH2

O

OO

(CH3CH2)3N

1.0 equivalent

HO

NH

O

O

H2

Pd-C O

H

O

OCH3

OPhMgBr1.0 equivalent1)

2) protonation Ph

O

OCH3

OH

CH3H2

Pd-BaSO4quinoline H3C

When there is no chemoselective method for carrying out a reaction where there could be a competition, chemists often use the protecting group strategy you saw employed in the synthesis of peptides. In the following example, the combination of unprotected alanine with unprotected phenylalanine could give four different dipeptides plus amounts of tri- and tetrapeptide byproducts. Although the protecting group strategy prevents this from happening, it adds extra experimental steps to the procedure. The search for chemoselective methods for carrying out reactions is of ongoing interest because it avoids the need for the time, effort, and additional chemical waste associated with using protecting groups.

H3NO

OHH CH3

H3NO

OHH CH2Ph

+

alanine (Ala) phenylalanine (Phe)

Ala-Ala Ala-Phe

Phe-Ala Phe-Phe

four possible dipeptidesformed with no predictable selectivity

CH3OH cat. H2SO4

H2NO

OCH3

H CH3

Cl OCH2Ph

O

NH

O

OHH CH2PhO

PhH2CO

DCCNH

O

HN

H CH2PhO

PhH2CO

O

OCH3

H3C H

1) H2/Pd-C2) anhydrous HBr

Phe-Ala only

H

H

(CH3CH2)3N

1)

2) adjust pHadjust pH

1)

2)

+

  3  

 

B. RegioselectivityRegioselectivity is the preference for one direction of bond-making, or bond-breaking, when there is a choice, in a chemical reaction. You first encountered this in the electrophilic addition reactions of strong and weak Bronsted acids to carbon-carbon pi bonds (eq. 1). Other examples include the selectivity for opening a bromonium ion intermediate with water (formation of halohydrins) (eq. 2), the preference for ortho, meta, and para substitution in electrophilic aromatic substitution reactions (eq. 3), and the orientation between the diene and dienophile in the Diels-Alder cycloaddition reaction (eq. 4). The regioselectivity for each of these examples is indicated in the formation of the major and minor regioisomer, as shown.

CH2CH3

CH3OH

cat. H2SO4 CH2CH3

CH2CH3

OCH3

OCH3 >

Br2, H2OBr

OH BrOH

>

OCH3

NO2+

H3CONO2

H3CO>

NO2

H3CO

NO2

Br2

FeBr3

H3CO

NO2

H3CO

NO2

BrBr

>

C. StereospecificityStereospecificity is a property associated with a reaction mechanism where the stereochemical outcome of the reaction is dictated by the stereochemistry of the starting material, even when a number of different outcomes are possible. Experimentally, stereospecificity is most easily demonstrated by comparing the outcomes from different stereoisomers of the starting material, to see whether the stereochemistry of the starting material is translated, through the reaction mechanism, into that of the product. Familiar examples of this include the inversion of configuration in bimolecular (SN2) substitution reactions, the preservation of alkene stereochemistry in the formation of epoxides, as well as that of both the diene and dienophile in Diels-Alder cycloaddition reactions. Reactions in which two different stereoisomers of the starting material give the same product stereochemistry (i.e., in cases where different stereoisomers lead to the same reactive intermediate), are non-stereospecific. Unimolecular (SN1) substitution reactions in which either of the stereoisomeric starting materials leads to the same product mixture are a typical example of a non-stereospecific reaction.

(racemic) (racemic)

eq. 1

eq. 2

eq. 3

eq. 4

  4  

     

D. StereoselectivityStereoselectivity describes the distribution of stereosiomeric products derived from a starting material in which no stereospecificity is involved because there is no related stereochemical information in the starting material and/or because the stereochemical information is lost during the course of the reaction mechanism. Often, there are two aspects of stereoselectivity that can be described: enantioselectivity and diastereoselectivity. As the names of these terms imply, enantioselectivity refers to the degree to which one enantiomer forms relative to the other, while diastereoselectivity refers to the degree to which a diastereomer is formed relative to other diastereomers that might form.

BrH3C

Ph H NaSCH3H3CS

CH3

PhHBr

H3C

H Ph NaSCH3H3CS

CH3

HPh

H3C

H Ph

CH3

ClO

OOH

H3CH Ph

CH3

O

(racemic)H

H3C Ph

CH3

ClO

OOH

HH3C Ph

CH3

O

(racemic)

OCH3

CH3

CH3

O

OCH3+

OCH3

CO2CH3

CH3CH3

(racemic)

OCH3

CH3H3C

O

OCH3+

OCH3

CO2CH3

CH3CH3

(racemic)

CH3

H

OHCH3

CH3

H

CH3

OH

OR

HBr

HBr

CH3

H

CH3

CH3

H

BrCH3

CH3

H

CH3

Br

+

80%

20%common intermediateduring SN1 mechanism

non-stereospecific: gives the same distribution of products, regardless of which starting material is used

Examples of Stereospecific Reactions

Example of a Non-Stereospecific Reaction

inversion inversion

H

H

H

H

  5  

   

H3C

H Ph

CH3

ClO

OOH

H3CH Ph

CH3

O

(racemic)OCH3

CH3

CH3

O

OCH3+

OCH3

CO2CH3

CH3CH3

(racemic)

CH3

H

OHCH3

HBrCH3

H

BrCH3

CH3

H

CH3

Br

Stereoselectivity (enantioselectivity and diastereoselectivity) can also be described in some, but not all, of the previous examples:

BrH3C

Ph H NaSCH3H3CS

CH3

PhH SN2 substitution reactionstereospecific (inversion of configuration)no aspect of stereoselectivity to consider

epoxidation reaction of an alkenestereospecific (alkene stereochemistry translates)no enantioselectivity (1:1 racemic mixture)no aspect of diastereoselectivity to consider

Diels-Alder cycloadditionstereospecificno enantioselectivity in either (racemic)high diastereoselectivity (due to endo transition state)

OCH3

CO2CH3

CH3CH3

(racemic)

>

SN1 substitution reactionnon-stereospecificno aspect of enantioselectivity80:20 diastereoselectivity

Carbonyl addition reactions are one of the most highly studied areas of stereoselectivity. These versatile, carbon-carbon bond forming reactions are important for chemists who strive to build new molecules with high degrees of selectivity, such as in the preparation of new pharmaceutical agents. For example, camptothesin is a drug that was discovered in the bark of Camptotheca, or “Happy Tree,” whose bark and stem are used for anti-cancer treatment in Traditional Chinese Medicine. Water-soluble derivatives of camptothesin have been approved by the FDA for the treatement of ovarian, lung, and colon cancer. The laboratory synthesis of camptothesin requires a chemist to think about the stereoselective formation of the single, tertiary alcohol stereocenter.

NN

O

O

OOHcamptothesin

NO

O NO

O

O

O

OO

O

O

+

preparation of the chiral tertiary alcohol of camptothesin (after protonation) using a diastereoselective reaction where a chiral ester attached to the ketone undergoing nucleophilic addition

Li

major (80%) minor (20%)alcohol epimer of the starting material gives the same result

PhPh

chiral ester

Li

chiral tertiary alcohol of camptothesin

  6  

 

To understand why the camptothesin example works, one needs to consider the conformation of the molecule containing the ketone that undergoes addition. In a molecule with no stereocenters, the two faces of a ketone are equally accessible, and the reaction demonstrates no stereoselectivity (i.e., gives a racemic mixture).

Ph

O 1) CH3Li

2) H3O Ph

HO CH3

(racemic)C

O

CH2CH3PhCH3 CH3

Ph

H3C OH

Ph

HO CH3

In contrast with this case, the ketone in the following bicyclic molecule has two quite different faces because of the other stereocenters in the molecule. The convex face of the pi bond is more accessible than the concave face, because the pathway to the concave face is sterically hindered by the other ring.

H

H3CCH3

H O

1) CH3Li

2) H3O

CH3

HHO CH3

diastereoselective formationof the major product

O

CH3

H3C

convexface attack

CH3

HH3C

OHconcaveface attack

The camptothesin example, then, requires a more complex analysis of how the conformation of the large dimethylphenylmethyl group creates steric hindrance, and blocks one direction of the addition pathway for the carbonyl carbon. This is a drawing of the model used by the researcher who did the work. Note how the back pi face of the ketone (away from your view) is blocked by the phenyl ring, so the attack into the carbonyl comes preferentially onto the front face, as shown here.

O

O

O

Li

O

O

O

LiNO

O

Li

N

O O

In the remaining sections, we will detail some examples of how diastereoselectivity has been designed into reactions to control the stereochemical outcomes of various substitution, addition, and acylation reactions.

steric hindrancefor concaveface

preferred, less hindered pathwayfrom convex face

  7  

   

S 1.2 Alkylation Reaction of Chiral Enolates

A. Preparation of Chiral Amide Enolates. Evans Oxazolidinones.As with carbonyl addition reactions, the nucleophilic reactions of enols and enolates are among the most commonly used methods to prepare new carbon-carbon bonds. Starting with an enolate, the four types of carbon-atom electrophiles that you have encountered represent a diverse set of options for building new molecules.

Problem S.1 Predict the diastereoselectivity for each of the following reactions, and draw the major product.

OH

H

(a)

1) PhMgBr

2) H3O(b)

PhH

H

CH3

H2

Pd-C

CH3

H

(c)

ClO

OOH CH3

H

(d)

Br2, CH3OH

(e)

PhH

H

CH3

1) BH3

2) H2O2, NaOH

(f) product from part (c)1) PhMgBr

2) H3O

OLiPhCH2Br

O

CH2Ph

OO

O1)

2) workup

enolatealkylation

Michaelreaction

(conjugateaddition)

OPh

O

H

1)

2) workup

OH

Phaldolreaction

(addition)

Claisenreaction

(acylation)

Ph

O

OCH3

1)

2) workup

O O

Ph

(substitution)

  8  

 

In those examples, note that the enolate alkylation (substitution) reactions are not enantioselective; that is, the reaction results in the formation of a racemic mixture because the enolate is achiral. The reaction with the enolate can take place equally well from either face of the pi bond.

OLi O

HBr

Ph Br

Ph

Br

Ph

OCH2Ph

H

OH

CH2Ph

By definition, enantioselective reactions can occur when diastereomeric transition states are created. For example, the biological reduction of methyl ketones using NADH with the enzyme phenylacetaldehyde reductase produces secondary alcohols with (S)- configuration. Although 1-phenylethanone is achiral, the environment of the enzymatic active site is chiral, and the 1-phenylethanone is situated in the active site with high selectivity, exposing only one of its pi faces to the NADH reducing agent.

O

CH3N

R

O

NH2

HH

NADH

BH OH

CH3

H H

CH3

HO

95-100% 0-5%

+

because the active site is chiral, the other orientation of the ketone would represent a geometry that is diastereomeric with respect to the one shown here; thus, this enantioselective reaction relies on diastereoselective conditions

Diastereoselective conditions are also created when there is at least one pre-existing stereocenter in the molecule (see earlier examples, such as the following organometallic addition reaction from page 6).

CH3

H O

1) CH3Li

2) H3O

CH3

HHO CH3

CH3

HCH3

OH

+

major isomer minor isomer

  9  

   

Strategically, then, chemists who want to develop enantioselective reactions often think about the transformation they want to carry out, and then consider how to create a molecular unit that is called a chiral auxiliary. Like a protecting group, the chiral auxiliary is incorporated into a molecular structure to create a temporary diastereoselective condition where only an enantioselective one existed previously. The general scheme for using a chiral auxiliary is shown here.

H3CO

O 1) LDA2) PhCH2Br

H3CO

O

H3CO

O

CH2Ph CH2Ph

+

Examples of a non-enantioselective reaction

H3CO

O

Generic use of a chiral auxiliary to give an enantioselective outcome through a diastereoselective process

Ochiral N

H

chiral N

1) LDA2) PhCH2Br

O

chiral N

O

chiral NCH2Ph CH2Ph

enantiomers (50:50)

diastereomers (X%:Y%; NOT 50:50)

removal of chiral auxiliary

e.g., hydrolysis (H2O / H2SO4)

HO

O

HO

O

CH2Ph CH2Ph

+

enantiomers (X%:Y%, NOT 50:50)

Chiral members of a class of molecules called oxazolidinones have been used successfully as chiral auxiliaries to prepare chiral enolates. Professor David Evans (Harvard University) has contributed greatly to the development of this method, and so these are often called the Evans oxazolidinones. The oxazolidinone is first deprotonated and then it is acylated.

NO

OH

CH(CH3)2

CH3CH2CH2CH2LiNO

O

CH(CH3)2

Li

deprotonation

Cl

O

acylationNO

O

CH(CH3)2

O

Acylation of a chiral oxazolidinone

Some examples of Evans oxazolidinone chiral auxiliaries

NO

OH

CH(CH3)2

NO

OH

CH2Ph

NO

OH

CH2Ph

NO

OH

CH3Ph

+

  10  

 

Deprotonation of the acylated oxazolidinone creates a chiral enolate. A great deal is known about the structure of these enolates. Two diastereomers of the enolate are possible, called the (Z)-enolate and the (E)-enolate.

NO

O

CH(CH3)2

OLDA

NO

O

CH(CH3)2

OLi

NO

O

CH(CH3)2

OLi

(Z)-enolatefavored

(E)-enolatedisfavored

B. Reaction of Chiral Amide Enolates.The enolate is a highly organized and rigid structure because of the internal complexation with the lithium ion. When this enolate reacts with alkylating agents (electrophiles for substitution reactions), a high level of diastereoselectivity in the reaction outcome is observed.

NO

O

CH(CH3)2

OLi

(Z)-enolate

PhCH2BrNO

O

CH(CH3)2

O

NO

O

CH(CH3)2

O

CH2Ph CH2Ph+

+

99% 1%The origin of the diastereoselectivity in these reactions is based on the rigid “bicyclic” nature of the (Z)-enolate, where the isopropyl group on the oxazolidinone ring provides an effective steric hindrance for substitution, thus raising the activation energy and slowing down the reactions on that pi face of the enolate.

NO

OO

Li

H

CH2CH3

H

Ph

Br

Ph

Br

NO

O

CH(CH3)2

O

CH2Ph

NO

O

CH(CH3)2

O

CH2Ph

minor productpathway includessteric hindrance withthe isopropyl group

major productpathway is on the pi face opposite to the isopropyl group

The rate of formation of the (Z)-enolate is faster than the (E)-enolate because the transition state leading to the (Z)-enolate minimizes interactions between the ethyl and isopropyl groups seen in the (E)-enolate. In the (Z)-enolate, the alkyl group at the β-carbon is cis to the smaller oxygen atom substituent and trans to the larger oxazolidinone group. The overall structure of the enolate is also quite rigid because the lithium ion forms a 6-membered complex between the enolate oxygen atom and the carbonyl group of the oxazolidinone.

  11  

     

After the substitution reaction has been performed, the diastereomeric major and minor products can be separated. The chiral oxazolidinone auxiliary, having done its job, is a relatively good leaving group, and so it can now be removed in a number of different nucleophilic (acyl transfer) reaction. A few examples of removing the chiral auxiliary are shown here using reactions that should be familiar from Chapters 15 and 21.

NO

O

CH(CH3)2

O

CH2Ph

PhCH2O LiPhH2CO

O

CH2Ph

1) LiAlH4

2) H3O

OH

CH2Ph

LiOH followedby protonation

HO

O

CH2PhN

O

CH2Ph

CH3NHOCH3

H3CO

CH3

NaSCH3

H3CS

O

CH2Ph

Problem S.2 Draw the major product of the following diastereoselective reactions.

(a)NO

O

CH(CH3)2

O

Ph1) LDA2) CH3CH2I (b)

NO

O

CH3

O

Ph1) LDA2) PhCH2Br

Ph

(c)NO

O

CH2Ph

O1) LDA2) PhCH2Br (d)

NO

O

CH2Ph

O1) LDA2) PhCH2Br

Weinreb amide(can be used to prepare ketones)

  12  

     

Problem S.3 Complete the following reaction sequences.

NLiO

O

CH(CH3)2

HO

O SOCl2

A B

NLi

CBr

DE1) LiAlH4

2) work-up

A

N

F

Problem S.4 Outline a reaction sequence that can accomplish the following enantioselective transformations.

HO

O O

(a)

(b)

(a)

(b) NO

O

CH3Ph

O(CH3)2NH

G1) LiAlH4

2) work-upH

(c) NO

O

CH3Ph

ONaOCH2CH3

I1) CH3Li (excess)

2) H3O work-upJ

H2N

O

HO

O

  13  

     

S 1.3 Addition Reactions of Aldehydes and Ketones with Organometallic Compounds

A. CyclohexanonesCarbonyl addition reactions of aldehydes and ketones with organometallic compounds are among the most useful reactions for forming carbon-carbon bonds, and so they have been studied extensively for their stereoselectivities. The addition reactions of 4-substituted cyclohexanones allow chemists to study the diastereoselective preference for axial versus equatorial attack by various nucleophiles.

Typical organometallic reagents, such as organolithium compounds and Grignard reagents, show a preference for equatorial over axial attack.

(H3C)3C

H

O

(H3C)3C

H

OH

CH(CH3)2

(H3C)3C

H

CH(CH3)2

OH

1) (CH3)2CHMgI

2) H3O82

18

The usual model used to explain the equatorial preference is that a nucleophile’s trajectory for axial attack is hindered by the atoms and groups bonded in the other axial positions on that same side of the molecule. In contrast, the trajectory leading to the group in the equatorial position is not blocked by any groups.

(H3C)3C

H

OH

H

Nu

Nu

trajectory for nucleophilic addition that leads to the axial attack needs to pass through the space occupied by other axial groups

trajectory for nucleophilic addition that leads to the equatorial attack does not pass through space occupied by other groups or atoms

The diastereoselectivity trends for hydride reducing agents is more complicated than that for organometallic reagents. The following table summarizes some of the key experimental results. The general observations are (1) some hydride reagents are considered “small,” and the steric hindrance of the groups along the axial attack trajectory does not play a role. and (2) some hydride reagents with highly branched groups are “large,” shifting the diasteroselectivity to favor the equatorial attack.

diastereoselectivity

  14  

   

(H3C)3C

H

O

(H3C)3C

H

OH

H

(H3C)3C

H

H

OH

97

3

These results suggest that there is an intrinsic preference for nucleophilic attack along the axial trajectory for small reagents, and that this is overcome when the size of the nucleophilic reagent increases.

For the addition to the carbonyl group along the axial trajectory, the oxygen atom is pushed downward, moving away from any eclipsing interaction with the equatorial C-H bond. During the nucleophilic attack along the equatorial trajectory, on the other hand, the carbonyl group must eclipse the equatorial C-H bond, thus raising the activation energy.

Diastereoselectivities for hydride reducing agents with 4-(tert-butyl)cyclohexanone

[H]

hydride [H] reducing reagents

H B

3

K

+

92

8

H B

3

Li

28

72

H Al

2

NaBH4

LiAlH(OC(CH3)3)3

LiAlH4

21

79

8

92

“large” “small”

OH

H

(H3C)3C

H

OHequatorial

Haxial

(H3C)3C

Hpoint of view

OH

H

(H3C)3C

H

O

H

H

(H3C)3C

H

NuNu

OH

H

(H3C)3C

HNu

O

H

H

(H3C)3C

H

OH

H

(H3C)3C

H

Nu

Nu

Nu

lower energy pathfor small reagents:no axial collisions, no CH/CO eclipsing

higher energy pathfor small reagents:no axial collisions, CH/CO eclipsing

axialadditionproduct

equatorialadditionproduct

The model used to explain these results requires you to visualize the geometry of the carbonyl group relative to the equatorial hydrogens on the α-carbon. In particular, as viewed using a modifed Newman projection, the carbonyl group lies slightly below the equatorial α-hydrogen.

  15  

     

Thus, when the nucleophilic reagent is “large,” the axial interactions that take place along the axial attack trajectory raise the energy of activation for the axial attack pathway above that of the equatorial pathway, and then the equatorial pathway becomes favored.

OH

H

(H3C)3C

H

O

H

H

(H3C)3C

H

Nu

Nu

OH

H

(H3C)3C

HNu

O

H

H

(H3C)3C

H

OH

H

(H3C)3C

H

Nu

Nu

Nu

higher energy pathfor large reagents:axial collisions, no CH/CO eclipsing

lower energy pathfor large reagents:no axial collisions, CH/CO eclipsing

axialadditionproduct

equatorialadditionproduct

HH

H H

Problem S.5 Explain the following diastereoselectivities relative to their 4-(tert-butyl)cyclohexanone counterparts.

(a)

(b)

(H3C)3C

H

O (H3C)3C

H

OH

H (H3C)3C

H

H

OH+CH3

HCH3

H

CH3H2) H3O

BH

3Li

79% 21%

O

H3C

H3C

HCH3 NaBH4

CH3OHH3C

H3C

HCH3

OH

HH3C

H3C

HCH3

H

OH+

60% 40%

Problem S.6 The diastereoselectivities for both of these reactions is 86:14. In one case, the endo alcohol is preferred, while in the other, the exo alcohol is preferred. What is the major product from each case, and what is the explanation for the selectivity?

ONaBH4

CH3OHO

NaBH4

CH3OHH3C

H3C CH3(a) (b)

  16  

 

B. Carbonyl Compounds with α-Stereocenters: The Cram Chelate ModelAcyclic carbonyl compounds with α-stereocenters give diastereoselective reactions, but the models for understanding the selectivity are less obvious than those for cyclic compounds because the acyclic compounds are conformationally mobile rather than being rigid. The following examples provide some typical outcomes.

O

HH3C H

1) PhMgBr

2) H3O OH

HH3C H

Ph

20%

Ph

HH3C H

HO

80%

+

O

CH3

H3C H1) LiAlH4

2) H3O H

CH3

H3C H

HO

75%

OH

CH3

H3C H

H

25%

+

During the 1950s, chemists began developing models for explaining and predicting the diastereoselectivity in these addition reactions. One of these, still used today, is called the Cram Chelate model. The word “chelate” comes from a Greek root that means “claw,” and it describes the way in which a molecule with multiple Lewis basic sites can coordinate with a metal ion. The formation of (Z)- and (E)-enolates from the N-acyl oxazolidinones, shown previously (p. 10), is an example of forming a lithium ion chelate. These types of intramolecular complexations provide relatively rigid conformations that often prove to be useful for predicting reaction outcomes.

H

O

PhPhO CH3 1) LiAlH4

2) H3O

H

H

PhPhO CH3

HO

28%

H

OH

PhPhO CH3

H

72%

+

NO

O

CH(CH3)2

OLDA

NO

O

CH(CH3)2

OLi

NO

O

CH(CH3)2

OLi

(Z)-enolatefavored

(E)-enolatedisfavored

+

  17  

 

 

When the α-carbon contains an atom that can form a good chelate, the diasteroselectivity from the addition of organometallics and hydride reducing agents follows from an analysis of a chelate. Functional groups that are good Lewis bases form good chelates, such as alcohols, ethers, amines, thiols, and thioethers. The third example from the previous page (p. 16) is representative.

H

O

PhPhO CH3 1) LiAlH4

2) H3O

H

H

PhPhO CH3

HO

28%

H

OH

PhPhO CH3

H

72%

+

The Cram Chelate Model

H

O

PhPhO CH3

PhO

O

PhH3C H

Li

the preferred conformationfor forming a chelate withthe lithium ion eclipses thecarbonyl group with the ether group

nucleophilicattack anti tomethyl group(favored)

nucleophilicattack syn tomethyl group(disfavored)

SS

SR

PhO

O

Ph

H3C H

Li

HS

S 72%

28%

B. Carbonyl Compounds with α-Stereocenters: The Non-Polar and Polar Felkin-Anh Models

In general, an alcohol group will be deprotonated by the organometallic and/or hydride reducing agent, and so the alkoxide forms a strong chelate. Reagents that use divalent cations, such as Zn+² and Mg+², can also enhance the strength of the chelate.

Although the Cram Chelate model works well for predicting diastereoselectivity when one of the groups at the α-carbon can chelate a metal ion, predicting the outcome from other cases did not get sorted out until the 1980s, when chemists developed two important models for predicting the diastereoselectivity in these other addition reactions. There are two Felkin-Anh models.The non-polar Felkin-Anh model: the three groups at the α-carbon do not include electronegative atoms, and they are ranked according to size (sterics). The preferred conformation for the reaction places the largest of the three groups perpendicular to the sp² plane of the carbonyl group, and the medium-sized group closer to the carbonyl oxygen.The polar Fekin-Anh model: one of the three groups at the α-carbon is a non-chelating electronegative atom (e.g., a halogen). The preferred conformation for the reaction places the electronegative atom perpendicular to the sp² plane of the carbonyl group, and the medium-sized group closer to the carbonyl oxygen.

PhO

O

H

H3C H

Li

PhSH2

R

  18  

 

O

HH3C H

1) PhMgBr

2) H3O OH

HH3C H

Ph

20%

Ph

HH3C H

HO

80%

+

At the beginning of this section (p. 16), the following result was shown.

The Non-Polar Felkin-Anh Model (H/alkyl/aryl)

The Polar Felkin-Anh Model (non-chelating eN)

RM

RL

RS

O

R

the largest of the three groups (RL) is perpendicular to the plane of the carbonyl, and the medium group (RM) is closer to the carbonyl oxygen atom due to more favorable sterics

RM

RL

RSO

R

RM

RS

RL

R

O RM

RS

RL

R

ONupreferred conformationleading to the transitionstate: the nucleophile approaches away from RLand along the path of RS

RL

eN

RS

O

R

the non-chelating electronegative atom group (eN) is perpendicular to the plane of the carbonyl, and the largest of the two groups (RL) is closer to the carbonyl oxygen atom due to more favorable sterics

RL

eN

RSO

R

RL

RS

eN

R

O RL

RS

eN

R

ONupreferred conformationleading to the transitionstate: the nucleophile approaches away from eNand along the path of RS

Because the α-carbon has no electronegative atoms of any kind, the non-polar Felkin-Anh models would apply. The phenyl group would be RL, the methyl group would be RM, and the hydrogen atom would be RS. The conformation leading to the formation of the major isomer needs to be visualized from the point of view used in the model and the drawing needs to preserve the proper stereochemistry of the starting material.

CH3

H

Ph

H

O

Ph

R R RR S

Ph

CH3

H

Ph

H

OH3O

H

OHPh CH3

H PhRS

predictedmajorpathway

observedmajordiastereomer

Ph

O

HH3C H

R

view

Nu Nu

non-preferredconformation:the nucleophile is hindered alongits path to addition

non-preferredconformation:the nucleophile is hindered alongits path to addition

  19  

   

CH2CH3

O

H3CHCl

1) LiAlH4

2) H3O

In the next example, there is a non-chelating electronegative atom group (Cl) present at the α-carbon. The polar Felkin-Anh model would be used to predict which of these two is the major diastereomer.

H3CH2C

H

Cl

CH3

O

H

H3CH2C

Cl

H CH3

H

OH3O

H3CH2C

CH3HCl

HOH

R

R

predictedmajorpathway

predictedmajordiastereomer

view

CH2CH3

HO

H3CHCl

H

CH2CH3

H

H3CHCl

OH+R R R

R S

CH2CH3

O

H3CHCl

R

In summary, you have been introduced to three models for predicting the diastereoselectivity when the α-carbon of a carbonyl group is a stereocenter.

If the stereocenter does not contain electronegative atoms, then the non-polar Felkin-Anh model for only hydrocarbon groups is used.

Problem S.7 Predict the major diastereomer resulting from each of the following reactions.

(a) (b)O CH2CH3

OH

1) Zn(BH4)2

2) H3O

CH3

O

H3CHPh

1) CH3CH2MgBr

2) H3O

(c) (d)

CH3

O

PhOCH3H

1) CH3MgBr

2) H3O

O

HCl

CH3H

1) CH3Li

2) H3O

If the stereocenter contains a non-chelating electronegative atom, then the polar Felkin-Anh model is used.

If the stereocenter contains a chelating electronegative atom, then the Cram Chelate model is used.

95% 5%

  20  

 

S 1.4 Aldol Addition Reactions of Aldehydes with Boron Enolates

A. Preparation of Boron EnolatesThe stereoselectivity of enolate formation is based on a combination of thermodynamic and kinetic effects. In the following series, for example, the identity of the group on the carbonyl carbon influences the outcome. Ketones are generally the starting materials in these studies because aldehydes undergo reactions with themselves so readily during the attempted preparation of enolates.

H3CH2C CH2CH3

O LDA OLi

H3CH2C CH3

H

OLi

H3CH2C H

CH3

+

(Z)-enolate (E)-enolate

(H3C)2HC CH2CH3

O LDA OLi

(H3C)2HC CH3

H

OLi

(H3C)2HC H

CH3

+

(H3C)3C CH2CH3

O LDA OLi

(H3C)3C CH3

H

OLi

(H3C)3C H

CH3

+

30 : 70

60 : 40

>99 : <1

These results are generally interpreted in the following way. The conformation in which the deprotonation takes place holds the α-hydrogen parallel to the p-orbitals of the pi bond. The resulting steric effects dictates the favorable comformation.

OR

H

H CH3

OR

H

H3C H

base

OR

HCH3

OR

H3CH

(Z)-enolate (E)-enolate

as “R” increases in size, this conformer becomes increasingly less stable due to unfavorable steric interaction with the methyl group

  21  

   

Boron enolates are prepared by combining dialkylboranes bearing a leaving group on the boron atom with the requisite ketone, and in the presence of a tertiary organic base. A simplified version of this reaction is given here. The timing of the steps is thought to be variable.

R

O

CH2CH3

R’2B-LG

R”3N R

O

CH2CH3

BLG

R’R’

R”3N

R

OBLG

R’R’

H

CH3R

OB

R’R’

H

CH3

- LG

OR

H

H CH3

OR

H

H3C H

base

OBR’2R

HCH3

OBR’2R

H3CH

(Z)-boron enolate (E)-boron

enolate

when the complexed boron group is turned towards the α-carbon, it creates a large steric effect that can make this conformation more stable

The stereochemical outcome is observed to depend on a subtle combination of the alkyl groups on the boron, on the identity of the leaving group, and on the base that is used.

BR’2

LGBR’2

LG- LG

OR

H

H CH3

OR

H

H3C H

base

R’2BLG

R’2B

LG

- LG

R

O

CH2CH3

BOSO2CF3

N

OR

BCl

N

R

OBR2

H

CH3 R

OBR2

CH3

H

(Z)-boron enolate

(E)-boron enolate

B Cl

OR

BOSO2CH3

N

The complexation between the boron and the oxygen creates another source of stereochemistry and potential steric interference, partially providing an explanation for why the (E)-enolate can form.

N

  22  

   

B. Aldol Addition Reactions of Boron Enolates: Zimmerman-Traxler modelThe reactions between (Z)- and (E)-boron enolates with aldehydes give aldol reactions with highly predictable diastereoselective outcomes. The (Z)-boron enolate gives a racemic mixture of what is called the “syn” product, while the (E)-boron enolate gives a racemic mixture of what is called the “anti” product.

R

OBR2

H

CH3

R

OBR2

CH3

H

(Z)-boron enolate

(E)-boron enolate

H

O

R’

H

O

R’

R

O

CH3

R’

OH

R

O

CH3

R’

OH

+

“syn”aldol product

R

O

CH3

R’

OH

R

O

CH3

R’

OH

+

“anti”aldol product

A simple look at the curved-arrow mechanism provides a useful overview of the reaction. The boron enolates, because they carry the open shell boron atom, creates an excellent opportunity for the oxygen atom of the aldehyde’s carbonyl group to complex, thereby creating a highly organized transition state structure by bringing the reactants together.

R

O

CH3

BR R

H

O

R’ R

O

CH3

BR R

OR’

H R

O

CH3

R’

OBR2

R

O

CH3

R’

OH

workup

R

O

CH3

B

R R

O

R’H

δ δ

  23  

 

R

OBR2

H

CH3

R

OBR2

CH3

H

(Z)-boron enolate

(E)-boron enolate

H

O

R’

H

O

R’

R

O

CH3

R’

OH

R

O

CH3

R’

OH

+

“syn”aldol product

R

O

CH3

R’

OH

R

O

CH3

R’

OH

+

“anti”aldol product

In 1957, Zimmerman and Traxler proposed that a chair-like transition state could be used to explain the (Z)-enolate-to-syn and (E)-enolate-to-anti diastereoselectivity.

O

BO

R

RH

CH3

R

R’

H

O

BO

R

RH

CH3

R

H

R’

favored: R’ in pseudo-equatorial position disfavored: R’ in pseudo-axial position

O

BO

R

RH

CH3

R

R’

H

R

O

CH3

R’

OH

H

H

R

O

CH3

R’

OH

O

BO

R

RH3C

H

R

R’

H

O

BO

R

RH3C

H

R

H

R’

favored: R’ in pseudo-equatorial position disfavored: R’ in pseudo-axial position

O

BO

R

RH3C

H

R

R’

H

R

O

H

R’

OH

H3C

H

R

O

CH3

R’

OH

(Z)-boron enolate

(E)-boron enolate

  24  

   

Using a specific example, then, the Zimmerman-Traxler model explains the observed stereochemical outcome, whereby the (E)-boron enolate is correlated with the formation of the anti diastereomer of the aldol reaction product.

O

BOH3C

H

H

O B Cl2

(CH3CH2)3N

OB

2 H

O1)

2) workup

O

CH3

OH

+ enantiomer

O

BOH3C

H

H

Problem S.8 Predict the major product(s) resulting from each of the following reactions. Provide the Zimmerman-Traxler transition state model for your prediction.

(a)

O B Cl2

H

O1)

2) workup

OCH3

Ph

(b)O

(CH3CH2)3N

H

O1)

2) workup

N2

BCl

Problem S.9 Provide a diastereoselective method to prepare the following aldol reaction products.

O

Ph

OH(a) O

Ph

OH(b)

(racemic) (racemic)