E.

Kwan

Lecture 23: Enolates and CC Bond Formation Enolates and CC Bond Formation
Eugene E. Kwan October 29, 2010. Me Ph OH O R Me Me O

Chem 106

Key Questions 1. How can chiral imide or amide enolates be used to prepare optically active alkanes?
O N O Me

?
HO

Me Bn

N CH3 R'

Scope of Lecture HWE olefination enolate acylation chiral imide alkylation chiral amide alkylation

2. Why do these intermolecular Michael reactions give high diastereoselectivity?

OLi O + Me O Me 78 C THF O Me O Me O

enolates and CC bond formation

intermolecular Michael reactions

-amino acid synthesis

Z enolate
OLi O Me + O 78 C Me THF/HMPA

85%, 95:5 syn:anti

O O Me Me O

the Claisen condensation

enolate tautomerism

E enolate

73%, 13:87 syn:anti

Helpful References 1. "Pseudoephedrine as a Practical Chiral Auxiliary for the Synthesis of Highly Enantiomerically Enriched Carboxylic Acids, Alcohols, Aldehydes, and Ketones." Myers, A.G.; et al. J. Am. Chem. Soc. 1997, 119, 6496-6511. 2. "Intermolecular Michael Reactions: A Computational Investigation." Kwan, E.E.; Evans, D.A. Org. Lett. 2010 doi: 10.1021/ol102017v 3. "Claisen Ester Condensation Equilibria - Model Calculations" Garst, J.F. J. Chem. Educ. 1979, 56, 721-722. 4. "Olefin Synthesis with Organic Phosphonate Carbanions." Boutagy, J.; Thomas, R. Chem. Rev. 1974, 74, 87-99.

3. What are the thermodynamic driving forces behind the Claisen condensation?
O RO Me + RO Me O RO Me O O Me

+ RO H

I thank Professor David A. Evans (Harvard) for the use of some material from Chem 206 for this lecture.

E. Kwan, D.A. Evans

Lecture 23: Enolates and CC Bond Formation

Me N A(1,3) Me O R H Me Me

Chem 106 severe N A(1,3) Me Me interaction

O H R

Diastereoselective Enolate Alkylation Q: How does one alkylate a carboxylic acid derivative diastereoselectively? Overall, the target transformation is:
O HO R

minimized

?
MeI HO

O R Me

ground state: stable but unreactive

transition state: reactive but strained

One solution to this problem is to use a chiral amide auxiliary:

O HO O R* N R* R Me HO R R* N R* O R Me O R

As we will see, these auxiliaries can be cleaved or otherwise converted to a variety of carboxylic acid derivatives including aldehydes. Another advantage of amides is that they form Z-enolates quite selectively. An early advance was made by Evans in the alkylation of prolinol amide enolates (TL 1980 21 4233):

or other carboxylic acid derivatives

HO N

O Me 2 equiv LDA BnBr O N Me Bn aq. HCl

OLi N

OLi Me

Of course, this means that the auxiliary has to be added and then removed. However, one advantage is that the product is less sensitive to epimerization. For example, an -alkyl aldehyde might epimerize, but an -alkyl amide will not because of 1,3-allylic strain. Recall the stereoelectronic requirement for deprotonation: base
R R H O Me

HO

O HO Me Bn

75%, 76% de The amide hydrolysis is facilitated by intramolecular N to O acyl transfer, and then by intramolecular H-bonding:
HO N O Me Bn N H H O O Me Bn

conformation necessary for deprotonation

If R=H, then this is perfectly viable. However, if R is an amide, then A(1,3) strain ensures that the acidic C-H bond remains in the -plane of the amide, preventing deprotonation:
H H O H Me

easily accesses a conformation which can be deprotonated

The diaselectivity of this process depends on: (1) the geometrical purity of the starting enolate; (2) the selectivity of the alkylation itself; and (3) any losses incurred during cleavage of the auxiliary. Here, the problem seems to be the second factor.

E. Kwan, D.A. Evans

Lecture 23: Enolates and CC Bond Formation

conversion to carboxylic acid derivatives A variety of non-epimerizing conditions are available:
O HO R' H2SO4, reflux (harsh) O H R' R LiAlH(OEt)3 Ph Me or (n-Bu)4NOH t-BuOH/H2O (milder) O R LAB R

Chem 106

Diastereoselective Enolate Alkylation If oxazolidinone imides are used instead, much more selective alkylations can be realized (Evans JACS 1982 104 1737)
O O N Me Me Me O CH3 LDA BnBr O O N Bn Me O CH3

carboxylic acid

92%, >99:1 dr

It has been suggested, but not proven, that lithium is chelated in both the ground and transition states. Various oxazolidinones of different enantiomers are commercially available. However, less activated electrophiles like ethyl iodide are problematic:
O O Ph N CH3 O CH3 NaHMDS EtI O Ph O N Bn Me O CH3

N OH CH3 R' MeLi O Me R' R

HO R'

aldehyde 53% >99:1 dr

alcohol

ketone

(Sodium enolates are more reactive.) Presumably, the increased acidity of imides over amides is responsible for the decrease in reactivity (note that basicity and nucleophilicity are closely related, but not the same--one is thermodynamic and the other is kinetic; see Jaramillo, J Phys Org Chem 2007 20 1050). Myers has developed a solution to this problem involving pseudoephedrine amides (JACS 1997 119 6496):
Me Ph O Me LDA, LiCl n-BuI Ph OH Me O Me N CH3 n-Bu

- LAB: lithium amidoborohydride, formed by LDA + NH3BH3 - the pseudoepherdrine amide is analogous to a Weinreb amide (see next lecture on tetrahedral intermediates) iterative synthesis of 1,3-n-substituted carbon chains
O X* Me A Bn Me A X* Me O Bn Me BnBr X* O Bn Me LAB HO Bn Me PPh3, I2 imidazole

N OH CH3

80%, 99:1 dr
I

etc.

Advantages: (1) compounds are crystalline and can be purified by recrystallization; (2) both enantiomers of psuedoephederine are available; (3) reactions can be done at 0 C; (4) products can be converted to a variety of useful carboxylic acid derivatives; (5) iterative use gives 1,3-n-substituted carbon chains (see below).

The auxiliary is powerful enough to override any inherent "matched" or "mismatched" effects. Myers Synlett 1997 5 457

E. Kwan

Lecture 23: Enolates and CC Bond Formation

are not always available:
CO2R'' R NHCOR' cat.* H2 R CO2R'' NHCOR'

Chem 106

Pseudoephedrine Glycinamide This methodology can be used to synthesize -amino acids (Myers JACS 1997 119 656; JOC 1999 64 3322):
Me Ph OH O LiHMDS LiCl, THF 78 C Me Ph O Br N CH3 NH2 N OLi CH3 NHLi

(3) No protecting groups are required and this sequence works well for a variety of electrophiles. Q: What are the disadvantages of this method? (1) There is no access to -amino acids bearing quaternary stereocenters. These can be obtained using asymmetric Strecker methods (Jacobsen Nature 2009 461 968):
0.5 mol% Ph Br N R H Ph Ph Me N Ph O CF3

pseudoephedrine glycinamide
Me Ph OH O N

The lithium amide is the kinetic product; this does not lead to the desired C-alkylated product.

N CH3

However, equilibration can give the right product:

Me Ph O Me 0 C Ph OLi NH2 N OLi CH3

tBu S
N H N H CF3 HN R CHPh2 CN

N OLi CH3 NHLi Me O NH2

KCN, AcOH, H2O, PhMe, 0 C, 4-8 h

87-90% ee

The hydrocyanate can be hydrolyzed in a similar way:

80%, 93% de (crude) 69%, 99% de (recrystallized)
HN R CHPh2 CN 1. H2SO4, HCl, 2-3 d 2. NaOH, NaHCO3 3. Boc2O, dioxane, 16 g 4. recrystallize R NHBoc CO2H

Ph

N OH CH3

These products can be hydrolyzed without loss of optical purity:

Me Ph O NH2 1. 0.5 M NaOH, reflux 2. Boc2O, dioxane O HO NHBoc

98-99% ee

N OH CH3

The cheap enantiomer of tert-leucine (S) gives the expensive enantiomer (R):
NHBoc NHBoc CO2H NHBoc CO2H

99% de

91%, 99% de

tBu

CO2H

tBuNH2

Q: What are the advantage to this method? (1) Both enantiomers of the auxiliary are cheap. (2) The enamides required for asymmetric hydrogenation (2) The procedure requires dry pseudoephedrine glycinamide (hygroscopic) and glycine methyl ester, which is polymerizable. However, these issues have been worked out.

E. Kwan

Lecture 23: Enolates and CC Bond Formation

Chem 106

Pseudoephedrine Glycinamide This example serves to illustrate how enolate-based reactions can be optimized. Here is the optimized sequence compared with the unoptimized one. Direct alkylation of pseudoephedrine glycinamide hydrate is targeted, as it is an air-stable, free-flowing, and crystalline solid (Myers, JOC 1999 64 3322):
O MeO NH2HCl

The improved procedure uses an extra equivalent of base to remove the water, rather than dehydrating the glycinamide in a previous step:
Me Ph OH O 3.2 equiv LiHMDS, 3.2 equiv LiCl RX Me Ph O N CH3 NH2H2O N OH CH3 NH2H2O

free-base and distill

O MeO NH2

Access to Quaternary Stereocenters Although there is no reported way to use this approach to make -amino acids, it is possible to do the Myers alkylation with tetrasubstituted enolates (JACS 2008 130 13231). The enolate geometry has been established by trapping:
iPr

polymerizable
Me Ph NH OH CH3

LiOtBu, THF; H2O, crystallize

Me Ph OH

O Me

1. LDA, LiCl, 0 C 2. DMPU, (iPr)2SiCl2 40 C

Ph Me

O Si iPr O N CH3 Me Me

LiOMe, LiCl; H2O

Me Ph O

N CH3 Me

N OH CH3 NH2H2O

pseudoephedrine glycinamide hydrate (stable)

19:1 Z isomer Presumably, deprotonation occurs through a conformation which incurs considerable 1,3-allylic strain. It is unclear if aggregates are involved. However, the other epimer gives the opposite enolate geometry:
iPr Me O Me 1. LDA, LiCl, 0 C 2. DMPU, (iPr)2SiCl2 40 C Ph Me O Si iPr O N CH3 Me Me

The old procedure dries the hydrate azeotropically (84 wt% MeCN/16% water; bp=76 C; 80% PhMe/20% water; bp=84 C)
Me Ph OH O azeotropic drying in MeCN; PhMe Me Ph OH Me Ph O NH2 O N CH3 NH2

Ph

N OH CH3 Me

N CH3 NH2H2O

1:15 E isomer

1.95 equiv LiHMDS, 6 equiv LiCl, THF, 0 C RX

N OH CH3 R

E. Kwan

Lecture 23: Enolates and CC Bond Formation

O

Chem 106
O + H (+) R R O O O OH

Access to Quaternary Stereocenters The behavior of these enolates is different on alkylation, too:
Me Ph O LDA, LiCl; BnBr N OH CH3 Me Me OH Ph Me N Bn Me O Me

aldol
(+) O

O () O () +

Michael

(+)

O () (+) (+)

19:1 Z isomer
Me Ph O

fast, selective

95%, 10:1 dr 1 h at 40 C
Me O Me Me Bn Ph OH

What are the relative thermodynamics of these reactions? One must consider the reactions before quenching:
O M + H R R O O OM

LDA, LiCl; BnBr N OH CH3 Me Me

1:15 E isomer

slower less selective

89%, 1:5 dr 4.5 h at 40 C

Overall, an aldol reaction replaces a weak C=C bond (the enolate's) with a stronger CC bond (the red bond). The same thing happens in a Michael reaction:
OM + O O OM

The selectivity for the top alkylation decreases over the course of the reaction from 19:1 at 65% conversion to 10:1 at full conversion, suggesting that some equilibration to the E enolate may be occurring. With an excess of enolate relative to alkyl bromide, higher selectivities are observed. However, the reason for the differences in selectivity is unclear. Another way to generate the enolates is via conjugate addition. Again, enolates are alkylated from a common diastereoface:
Me Ph OH O 1. MeLi, LiCl 2. RLi 3. R'X Me Ph OH N R' Me O R

ketone enolate

type of enolate preserved

ketone enolate

On bond strength alone, this replacement should be worth about 20 kcal/mol. However, one must also consider acidity differences. The ketone to ketone Michael reaction shown produces an enolate of the same type, so there is no difference. What about the aldol reaction?
O M + H R R O O OM

N CH3 Me

The Michael Reaction isopropanol pKa: acetone pKa: In terms of "charge affinity," the Michael reaction is a vinylogous 29.3 26.5 form of alkylation. Compared to the aldol reaction, it forms 1,5rather than 1,3- dioxygenation patterns: Because the starting material is a bit more acidic than the product, there is a bit of a penalty: by this estimate, 4 kcal/mol O O O at room temperature. However, these penalties do not + R X alkylation R () (+) represent an insurmountable barrier: (+)

E. Kwan, D.A. Evans

Lecture 23: Enolates and CC Bond Formation

Chem 106

The Michael Reaction A perfectly reasonable Michael reaction is between a -ketoester enolate and an ,-unsaturated ester acceptor:
OM O + OR OR CO2R OR O O OM

Mechanism of the Michael Reaction What is the mechanism of the Michael reaction? It depends on what the enolate actually looks like. We can imagine a number of possible tautomers:
O Li Li O O Li

ester enolate new enolate is less stable t-butyl acetate ethyl acetoacetate pKa=30.3 pKa=14.2 In this case, the revised estimate is 20 + 22.5 = +2.5 kcal/mol at room temperature. Of course, these crude analyses do not account for further proton transfers, solvation, etc. In fact, in the above reaction, a downstream proton transfer converts the ester enolate back to a -ketoester enolate: energy
O OM OR CO2R OM OM O + OR OR O CO2R O OR

-ketoester enolate

1-(O) syn
O

1-(O) anti vs. "true" 3 uses p orbital on Li

1-(C)

Li

O Li

ion pair - Li is attracted to negative charge on carbon This gives rise to several possible mechanisms:
O Li O Li O Li O

all O-bound, open TS

O O Li O Li

all O-bound, closed 8-membered TS

O O OLi

O- to C- bound, closed 6-membered TS This means that the overall thermodynamic barrier is unaffected, but the kinetic barrier is raised. This explains why, ester enolate Michael reactions can occur at 78 C, but -ketoester enolate Michael reactions require elevated temperatures and harsher bases.
O O Li Li O O OLi

C- to O- bound, closed 6-membered TS

E. Kwan, D.A. Evans

Lecture 23: Enolates and CC Bond Formation

Li O

Chem 106 B3LYP/6-31g(d)

Mechanism of the Michael Reaction Q: Could these six-membered transition states explain the highly stereoselective nature of these reactions? Some computational studies have suggested that enolates are the energy minimum for lithioimines (Collum JACS 2006 128 6939). This is a serial solvation study, in which an increasing number of Me2O ligands is coordinated to lithium:
3

+19.9 +15.4
O

Me

+S
O Li Me

LiS

G (kcal/mol)

Me

Li Me

i-Pr

B3LYP/6-31g(d)

+4.7 +3.6
O Me LiS

+S
Me

LiS2

+17.0 +8.5
i-Pr Me N Li

S3Li

i-Pr

+1.0 +0.6
O Me LiS2

+S
Me

LiS3

+S
SLi Me N i-Pr

Me

G (kcal/mol)

+8.3 +8.2
i-Pr S2Li Me N LiS3

0.0

C-O-Li bond angle Li Li O Li 60 H O 120 H O 180

+4.0 +S +0.3
i-Pr Me N LiS

i-Pr

Me

+S H
N LiS2

+0.8 0.0
i-Pr Me

C-C-O-Li dihedral angle Li Li O 30 O H 150

However, a similar serial solvation study on acetone does not show the same trend (top right). How can we be sure that we have checked every possible structure? A systematic search in the gas phase suggests that the 3 structure is the energy minimum for lithioacetaldehyde (next page, MP2/6-31G*, Anslyn OL 2006 8 3461).

E. Kwan, D.A. Evans

Lecture 23: Enolates and CC Bond Formation

(b) 180
160

Chem 106

Mechanism of the Michael Reaction Lithioacetaldehyde (MP2/6-31G* enthalpy, gas phase):

(a) 180
160

Lithioacetone (M05-2X/6-31G* energy, 3 dimethyl ethers):

electronic energy (kcal/mol)
1.4

Li-O-C-C dihedral angle (degrees)

140 120 100 80 60 40 20 0 60 80 100 120 140 160 180

Li-O-C-C dihedral angle (degrees)

enthalpy (kcal/mol)
1.4 2.8 4.2 5.6 10 15 20 35

140 120 100 80 60 40 20 0 60 80 100 120 140 160 180

2.8 4.2 5.6 10 15 20 35

global min.: -0.4 kcal/mol Li-O-C angle (degrees)

Li-O-C angle (degrees)

gas phase: 3-bound enolate

Li

Conclusion: Lithium enolates are exclusively O-bound in etheral solutions.

E. Kwan, D.A. Evans

Lecture 23: Enolates and CC Bond Formation

Chem 106

Stereochemical Course of Michael Reactions Assuming an open transition state, here are the numbers for this prototypical Michael reaction (M05-2X/6-31G*, three dimethyl ether ligands on lithium, denoted as S):
OLi + Me Me S O S Li S O O Me free energy (kcal/mol) Si Me Re Me H +3.1 Me Li S O Re Si s-trans TSs Me Me O O OLi

How do the computations perform for reactions which have actual selectivities which can be compared against?
OLi O Me Z enolate OLi O Me + 78 C Me THF/HMPA O Me 73%, 13:87 syn:anti + O Me 78 C THF O Me 85%, 95:5 syn:anti O Me O O Me O

+4.0 +3.7 Me S Li S O O Me

Me

E enolate

+3.3

s-cis TSs

Here is the scheme for the Z enolate (the E enolate gives similar results):
+13.8 Re s-trans transition states S R O O Me Me Li S O R

S O Li S O -13.6 E enolate Me O +9.0 S Li O Me S Me O -19.9 Z enolate Li S O Me 0.0 S +6.3

Si Si

+0.0 S S Li O O Me starting materials

Me

s-cis transition states

16
+0.6 Re 1,2-anti

favored TS
-11.5 -12.0 E enolate products

S S Li O O O Me Me

1,2-syn

The four transition states represent the enone reacting in an s-cis or s-trans fashion with either diastereoface of the enolate. For this relatively unhindered system, there is little preference for any particular geometry. Note that s-cis transition states lead to Z enolates and s-trans transition states lead to E enolates. Kwan and Evans OL 2010 ASAP

1,2-syn
starting materials (Z enolate) 1,2-anti

-22.8
-24.0

Z enolate products

E. Kwan, D.A. Evans

Lecture 23: Enolates and CC Bond Formation

Here is the favored transition state for the Z enolate:
O O Me 85%, 95:5 syn:anti Me O

Chem 106

Stereochemical Course of Michael Reactions Here are the predictions vs. the real results:
OLi O Me Z enolate + O Me 78 C THF

predicted: +4.9 kcal/mol experimental: +1.1 kcal/mol

OLi O Me + O 78 C Me THF/HMPA O Me 73%, 13:87 syn:anti O Me O

E enolate

predicted: -4.5 kcal/mol experimental: -0.7 kcal/mol Why are the selectivities too high? (1) The calculations are just wrong. (2) The calculations are OK, but there is leakage through open transition states. (3) The calculations reflect the instrinsic selectivity of geometrically pure enolates, but the enolates in the flask are not geometrically pure:
O Me O Me Me O Me OLi Me O OLi Me

Here is the disfavored transition state for the E enolate. The s-cis requirement gives rise to a substantial steric interaction:

LDA/THF: 91:9 LDA/HMPA/THF: 16:84 Where do the computed selectivities come from? The s-cis preference reflects the unfavorability of having a trans double bond in an eight-membered ring.

E. Kwan, D.A. Evans

Lecture 23: Enolates and CC Bond Formation

Chem 106

The Claisen Condensation "Claisen Ester Condensation Equilibria - Model Calculations" Garst, J.F. J. Chem. Educ. 1979, 56, 721-722. Not to be confused with the Claisen rearrangement, the Claisen condensation refers to the acylation of an enolate with a carbonyl group. What are the thermodynamics of this process? Is strong base needed? Fundamentally, one must consider a number of competing equilibria, shown below for the generic self-condensation of an ester. Here is the overall reaction:
O RO Me + RO Me O RO Me O O Me

If we assume the pKa's of isopropanol and tert-butyl propiponate in water (16.5 and 24.5, respectively) are representative, then this equilibrium is disfavored by (24.5-16.5)x1.4 = 11 kcal/mol. If the reaction is performed in an aprotic solvent, we can assume that pKa's in DMSO are representative (29.3 vs. 24.5), and the equilibrium is favored by 4.8 kcal/mol. With a stronger base like tritylsodium, the equilibrium is favored in both solvents (pKa = 31.5 in water or 30.6 in DMSO). To summarize:
O RO Me + OM O

M B

RO Me Me

B H

+ RO H

base = alkoxide in water (+11 kcal/mol) base = alkoxide in DMSO (5 kcal/mol) base = tritylium in water (15 kcal/mol) base = tritylium in DMSO (6 kcal/mol) The second step involves the actual Claisen step:
OM RO Me + RO Me O RO Me O O Me +

In terms of bond strengths, and ultimately, free energies, the products are less stable than the reactants (estimate: +10 kcal/mol based on a fragement-based method). This may be due to the loss of resonance energy in one ester or the increased polarity of the products. Whatever the reason, it is not surprising that for straight chain ethyl esters, the removal of ethanol drives the reaction to completion, raising yields from 40% to 80% (Hauser Org. Reac. 1942, 1, 266). Note that unlike the aldol reaction, which can be done in either acid or base, the Claisen reaction must be done in base. The overall reaction is really the sum of three components. The first is the deprotonation of the ester by a base B with a metal counterion M: Step 1: Enolization
O RO Me + OM

RO M

This produces the -ketoester product as well as an alkoxide. Finally, a proton transfer is possible:
O RO Me O Me + O OM Me Me

RO M

RO

+ RO H

M B

RO Me

B H

The overall effect of these two steps combines the intrinsic thermodynamics of the Claisen condensation itself (+10 kcal/ mol) with the thermodynamics of forming a more stable enolate. Q: The pKa of ethyl acetoacetate is 11 in water and 14.2 in DMSO. What are the expected free energy changes for steps two and three in water and DMSO?

Of course, this produces an enolate and the conjugate acid of the base. Many Claisen condensations are done in hydroxylic solvents like methanol with bases like sodium methoxide.

E. Kwan, D.A. Evans

Lecture 23: Enolates and CC Bond Formation

Therefore, the reaction is affected by three factors:

Chem 106

The Claisen Condensation Q: The pKa of ethyl acetoacetate is 11 in water and 14.2 in DMSO. What are the expected free energy changes for steps two and three in water and DMSO? Step 2: Claisen Condensation
OM RO Me + RO Me O RO Me O O Me +

(1) the initial favorabilty of ester deprotonation; (2) the intrinsic cost of forming of a -ketoester; and (3) the eventual favorability of proton transfer So the reaction is favored by having a base which is strong enough to deprotonate the ester. Even then, one needs a stoichiometric amount of base (the reaction is not really "catalytic") because the product is more acidic than the starting material. Thus, one uses stronger basse like potassium hydride (Brown Synthesis 1975 326) or forcing conditions (continual removal of ethanol). One can also imagine a scenario in which the product has no enolizable protons:
O O Me Me + O + Me Me Me

RO M

Step 3: Proton Transfer

O RO Me O Me + O OM Me Me

RO M

RO

+ RO H

The sum of these steps is:

OM RO Me + RO Me O RO Me O OM Me

2 RO + RO H

M B

RO

B H

pKa(ester) = 24.5 in water pKa(ketoester) = 11 in water 30.3 in DMSO 14.2 in DMSO (1) The "bond energy component" is +10 kcal/mol. (2) The "acidity component" is (11-24.5)x1.4 = -18.9 kcal/mol in water and (14.2-30.3)x1.4 = -22.5 kcal/mol in DMSO. (3) Thus, we predict G = -3.5 kcal/mol in water and -12.5 kcal /mol in DMSO for steps two and three.
0

In this case, one loses the benefit of the third step. For alkoxide in water, the new estimate is 10+11=+21 kcal/mol, which is unsurmountable. For example, this reaction is done with KH in THF (pKa ~ 36), and does not work with alkoxide in water:
O O O O Me Me Me O

2 h, rt >95%

This reaction also takes advantage of the changes in pKa on going from water to THF. An alternative strategy uses Lewis acids to lower the pKa of the starting ester (Tanabe JACS 2005 127 2854). Crossed Claisen reactions are possible:
O R O R OH TiCl4 Bu3N OMe NaH Cl3CCOCl R R O O O CCl3 OTiLn OMe O CH2Cl2 MeO Me Me Me O

(4) The overall reaction with alkoxide must also take into account the free energy of deprotonation. The overall standard free energy changes are +7.5 kcal/mol (water) and -11.5 kcal/mol in DMSO. (5) If trityl anion is used, the the energy change becomes -18.5 kcal/mol (water) and -18.5 kcal/mol (DMSO).

E. Kwan, D.A. Evans

Lecture 23: Enolates and CC Bond Formation

O RO Li O O OMe RO Li O CN OMe RO

Chem 106
O O OMe

Alternatives for -Dicarbonyl Synthesis As rosy as this thermodynamic analysis is, the truth is that the performance of the crossed Claisen reaction is not terrific, partly because esters are not very electrophilic. Unfortunately, if acyl chlorides or carbonates are used, O-acylation is seen. In this section, three alternatives to this are presented.
O O RO Li O O R RO R O O R

NC

The intermediate must be stable, since only one equivalent of base is required. Therefore, the tetrahedral intermediate must be stable. If it weren't stable, then either the product malonate or H-CN would quench any unreacted enolate. Clearly, the tetrahedral intermediate is stabilized by chelation, but so is the intermediate in a regular Claisen:
O RO Li O
CN

+
Cl

+
RO

O-acylation product (undesired)

C-acylation product (undesired)

Chelation and Carbon Dioxide In Rathke's solution to this problem (JOC 1985 50 4877), the pKa of the ester is lowered by Lewis acid coordination, and then deprotonated by an amine. This is called "soft enolization" and will be discussed in detail in Lecture 24. The electrophile is carbon dioxide:
O R OMe MgCl2 NEt3 OMgLn R OMe

OMe

more stable than

O RO

Li

O
OMe

A big part of the difference must be the leaving group abilities of cyanide vs. methoxide (DMSO pKa's: 12.9 vs. 27.9). Based on this, one might conclude that cyanide is the better leaving group than methoxide. These are thermodynamic arguments. What do the kinetic data say? Stirling has reported (JCS Chem. Commun. 1975 940) the rates of E1cb elimination:
PhO2S X PhO2S
+

O C O

+ X

Mg O RO O O RO O O OH

This does not agree with the thermodynamic data: cyanide leaves slower.

log (k/kOPh) R= PPh3 +4.4 R=OMe -3.9 R=CN < -7

The magnesium also serves to protect the final product from decarboxylation. The product can then be alkylated to produce a stable -ketoester. The Mander Reagent -Ketoacids are unstable, so it is desirable to access the product directly. Mander has introduced (TL 1983 24 5425) methyl cyanoformate, which combines with lithium enolates to give exclusively C-acylated products:

Based on these rate data, one would conclude that the tetrahedral intermediate partitions to alkyl cyanide, since methoxide is apparently a better leaving group. However, the requirements of E1cb reactions, which go through carbanions, may be quite different from these reactions, which go through oxyanions.

E. Kwan

Lecture 23: Enolates and CC Bond Formation

The stereochemical rationalization is as follows:
MO
EWG

Chem 106
P(O)(OR)2 H H R OM O P(OR)2 EWG

The Roskamp Reaction This clever reaction avoids the problems of condensation entirely (Roskamp JOC 1989 54 3258):
O O + R H N N H OtBu SnCl2 R O H Cl Sn O OtBu N2 R O O OtBu

O R + H

ratedetermining step
MO
EWG

equilibration via epimerization is possible

P(O)(OR)2
R

It proceeds via a formal 1,2-hydrogen shift. Yields are good to excellent and the reaction works on sensitive substrates. However, it will not produce mono- or di-alkyl substitution at the active methylene of the -ketoester. The Horner-Wadsworth-Emmons Reaction "Olefin Synthesis with Organic Phosphonate Carbanions." Boutagy, J.; Thomas, R. Chem. Rev. 1974, 74, 87-99. Myers, A.G. et al. "Horner-Wadsworth-Emmons Olefination." Chem 215 Handout. http://www.chem.harvard.edu/groups/ myers/page8/page8.html (accessed October 2010). One of the most important reactions involving doubly stabilized carbanions is the HWE reaction:
O RO O + P OMe OMe O H R
base

EWG M

O P OMe OMe OM O P(OR)2 R EWG OM O P(OR)2 R EWG

OM O P(OR)2 R EWG

EWG

E olefin

selectivitydetermining step
R EWG

Z olefin

O RO2C R + HO P OMe OMe

(1) Rate-determining and selectivity-determining addition of the stabilized enolate to the aldehyde is occurring. (2) Interconversion of the intermediates can occur through epimerization (this is impossible for a substituted HWE reagent), but not through retro-carbonyl addition.

E olefin This is a very reliable reaction. The product is a phosphate, which is water soluble and can be easily removed by extraction. (3) The overall selectivity depends on the selectivity of the initial In contrast, the Wittig reaction produces triphenylphosphine addition and the lifetime of the intermediates. oxide, which must be removed by chromatography. Q: How are stabilized phosphonates prepared? How does the reaction work? Studies show that the addition of the phosphonate anion is rate-limiting. A mesomerically Q: How can reagents be chosen to optimize E/Z selectivity? electron withdrawing group is required to avoid the formation of stable -hydroxyphosphonates: Q: What are good reaction conditions?

E. Kwan, D.A. Evans

Lecture 23: Enolates and CC Bond Formation

Chem 106

The Horner-Wadsworth-Emmons Reaction Michaelis-Arbusov Reaction There are number of possible preparations, but this is the most common. It starts from an -bromo carbonyl compound:
O O Br O P(OMe)3 O MeO P O CH3 MeO Br MeO O O P OMe OMe

Anything that will increase the reversibility of the reaction will favor the E isomer: (1) higher reaction temperatures (2) DME vs. THF (3) potassium vs. sodium or lithium The Still-Gennari Modification (TL 1983 24 4405)
O RO O O + P OCH2CF3 H R OCH2CF3 KHMDS, 18-cr-6 THF, 78 C R RO2C

However, yields are typically moderate (60-70%), often because a substantial amount of the methyl dimethyl phosphonate forms. The Ando Modification (JOC 1998 63 8411) What is the source of this side reaction? This is a more recent improvement that gives higher selectivities O O and uses phenol-based starting materials: P(OMe)
3

O Br

Me

P OMe OMe

O RO

This occurs because methyl bromide is generated during the reaction. Alkylation of trimethyl phosphite with acyl -bromide occurs at a rate that is competitive with alkylation with methyl bromide: Br
OMe P OMe MeO H3C Br Me MeO P O CH3 MeO O P Me OMe OMe

O P OPh OPh

O + H R

NaH, THF THF, 78 to 10 C

R RO2C

The use of 2-tert-butylphenoxy phosphonates gives even higher Z:E selectivities (Touchard Eur JOC 2005 9 1790). Epimerizable Aldhydes The Masamune-Roush conditions avoid the epimerization problems caused by strong base and are suitable for making E or Z olefins (TL 1984 25 2183):
O RO O P OR OR O + H R LiCl, DIPEA MeCN, rt RO2C R

This can be reduced, but not completely eliminated, with the use of triethyl phosphite instead. E vs. Z Selectivity These olefinations are very versatile: Stabilized Wittig: E olefins Unstabilized Wittig: Z olefins (E possible with Schlosser mod.) Stabilized HWE: E olefins (phosphonate OR with R=alkyl) Z olefins (Still-Gennari: R=CH2CF3 or Ando: R=OAr)

Patterson has also reported the use of barium hydroxide for epimerizable aldehydes (Synlett 1993 774). A more recent modification comes from the Myers group (OL 2005 7 4281):
O RO O P OR OR O + H R
n-BuLi, HFIP

DME, 14 C

RO2C

Lithium hexafluoroisopropoxide is a very weak base and gives higher E selectivities than other conditions without epimerization.