D. A.

Evans Olefin Addition Reactions: Part–2 Chem 206

! Problems of the Day:

http://www.courses.fas.harvard.edu/colgsas/1063 Rationalize the stereochemical outcome of the indicated reaction.

N M–H N H Me N OH
Me Me
O
Chemistry 206 OH H

R. Noyori R2AlH 97 : 3
Advanced Organic Chemistry Bull. Chem. Soc. Japan 47, 2617, (1974) LiAlH4 28 : 72

Lecture Number 9 Problem 579. The following publication (J. Org. Chem. 1991, 56, 5553) reported the
surprisingly selective olefin epoxidation illustrated below. In this reaction, olefin B in 1
was found to be much less reactive than olefin A. Using your knowlege of
Olefin Addition Reactions–2 stereoelectronic effects, provide an explanation for the reduced reactivity of olefin B in
diene 1.
Cl H Cl H Cl H
! Curtin-Hammett Principle RCO3H
A
RCO3H
B
O
2 1 3 O
favored disfavored
! Hydrogenation
Problem 313. Overman and co-workers recently reported the indicated selective
epoxidation in conjunction with a synthesis of briarellins A and E, a new family of
diterpenes (JACS 2003, 125, 6650). It should be noted that the Al(t-BuO)3/(t)-BuOOH
! Reading Assignment for week reagent system is both highly diastereoselective and site selective. It is also relevant to
the mechanism of the reaction that the ring-trisubstituted olefin lacking an allylic oxygen
substituent would normally be more prone to epoxidation with a peracid than the acyclic
A. Carey & Sundberg: Part B; Chapter 4 trisubstituted olefin.
"Electrophilic Additions to C–C Multilple Bonds"
Me H
Hoveyda, Evans, & Fu (1993). Substrate-directable chemical reactions. Me Al(t-BuO)3 R Me
Chem. Rev. 93: 1307-70 (pdf) TIPSO H H t-BuOOH H H
Me H H Me H
O 4 Å sieves O R
J. M. Brown, Angew. Chem. Int. Edit. 26, 190-203 (1987) (Handout) O
"
toluene, -20˚C "

H
H. Yamamoto et.al, Angew. Chem. Int. Ed. 2005, 44, 4389-4391 (pdf)
HO HO
Part. Provide a general mechanism illustrating how the Al(t-BuO)3/(t)-BuOOH
reagent epoxidizes olefins. Three-dimensional drawings are recommended.
Part B. Provide a general mechanism illustrating how the above epoxidation
Friday, proceeds and provide the stereochemistry (") of the product epoxide along with a
D. A. Evans October 6, 2006 stereochemical analysis of the noted face selectivity.
 A Brief Introduction to the Curtin-Hammett Principle

J. I. Seeman, J. Chem,Ed. 1986, 63, 42-48 The Curtin-Hammett Principle and the Winstein-
Holness Equation

J. I. Seeman, Chem. Rev. 1983, 83, 84-134. Effect of Conformational Change on Reactivity in
Organic Chemistry. Evaluations, Applications, and Extensions of Curtin-Hammet-Winstein-
Holness Kinetics
Curtin–Hammett Conditions

k1 kA k2
Curtin–Hammett Principle PA A B PB
slow kB slow
fast
“The product composition, PA vs PB is not
solely dependent on relative proportions of
!!G‡
the conformational isomers in the substrate;

it is controlled by the difference in standard

Gibbs energies (ΔΔG*) of the respective !G1‡ !G2‡
!GAB‡
transition states.”

Energy
!G° PB
The C-H principle may be extended to A
rapidly interconverting diastereomers, or PA B
constitutional isomers as well.

Chem 206, D. A. Evans major

Rxn. Coord. minor
D. A. Evans Curtin–Hammett Conditions: Conformer Populations vs Product Ratios Chem 206

"Curtin–Hammett Conditions" Case 2: Less stable conformer leads to the minor product.

k1, k2 << kA, kB: If reaction rates are much slower than the rate of
interconversion, (!GAB‡ is small relative to !G1‡ and !G2‡),
then the A/B ratio is constant throughout the course of the rxn.
k1 kA k2
PA A B P (1)
slow kB slow B
!!G‡
fast

Case 1: Less stable conformer leads to the major product.

If reaction rates are much slower than the rate of

interconversion, (!GAB‡ is small relative to !G1‡ and !G2‡), !G1‡ !G2‡
!GAB‡
then the A/B ratio is constant throughout the course of the rxn.

Energy
!G° PB
A
!!G‡
PA B
major
minor

!G1‡ !G2‡ Rxn. Coord.

!GAB‡
Energy

Curtin - Hammett Principle

!G° PB
A
The product composition is not solely dependent on
PA B
minor relative proportions of the conformational isomers in the
substrate; it is controlled by the difference in standard
major
Gibbs energies (!!G‡) of the respective transition states.
Rxn. Coord.
D. A. Evans Curtin–Hammett Derivation Chem 206

Case 2: Curtin-Hammett Conditons To relate this quantity to !G values, recall that !Go = -RT ln Keq or
k1, k2 << kA, kB: If the rates of reaction are much slower than the rate of
Keq = e–!G°/RT, k1 = e–!G1‡/RT, and k2 = e–!G2‡/RT. Substituting this
interconversion, (!GAB‡ is small relative to !G1‡ and !G2‡), then the ratio of A into the above equation:
to B is constant throughout the course of the reaction.
[PB] k2 e-!G2/RT
= Keq = (e-!G°/RT) = e-!G2/RTe-!G°/RTe!G1/RT (4)
[PA] k1
k1 kA k2 (1) e-!G1/RT
PA A B PB
slow kB slow Combining terms:
fast
[PB] [PB]
!!G‡ = e–(!G2 + !G°–!G1)/RTor = e–!!G/RT
[PA] [PA]

!G1‡ !G2‡ Where !!G‡ = !G2‡+!G°-!G1‡

!GAB‡
Energy

Curtin - Hammett Principle: The product composition is not solely

!G° PB
A dependent on relative proportions of the conformational isomers in the
PA B substrate; it is controlled by the difference in standard Gibbs energies
of the respective transition states.
major minor
Rxn. Coord.

The Derivation: Within these limits, we can envision three scenarios:

d[P ] d[PB]
Using the rate equations dtA = k1[A] and dt
= k2[B] we can write: • If both conformers react at the same rate, the product distribution will be
the same as the ratio of conformers at equilibrium.
d[PB] k2[B] k2[B]
= or d[PB] = d[PA] (2)
d[PA] k1[A] k1[A] • If the major conformer is also the faster reacting conformer, the
product from the major conformer should prevail, and will not reflect the
[B] equilibrium distribution.
Since A and B are in equilibrium, we can substitute Keq =
[A]
• If the minor conformer is the faster reacting conformer, the product
ratio will depend on all three variables in eq (2), and the observed product
k [PB] k distribution will not reflect the equilibrium distribution.
d[PB] = 2 Keq d[PA] Integrating, we get = 2 Keq (3)
k1 [PA] k1
This derivation implies that you could potentially isolate a product
When A and B are in rapid equilibrium, we must consider the rates of which is derived from a conformer that you can't even observe in the
reaction of the conformers as well as the equilibrium constant when ground state!
analyzing the product ratio.
 D. A. Evans Non-Curtin-Hammett–Conditions Chem 206

"Non-Equilibrating Conformers"
k1, k2 >> kA, kB: If the rates of reaction are faster than the rate of
interconversion, A and B cannot equilibrate during the course of the
reaction, and the product distribution (PB/PA) will simply reflect the
initial equilibrium composition.

[PB] [B]o
=
[PA] [A]o !GAB‡
Energy

!G2‡
!G1‡ PB
!G°
PA A B

Rxn. Coord.

"Non-Equilibrating Conformers"

Me Me A Dramatic case from Merck

N N

less stable more stable CF3

OH
slow O conditions
Li CF3
H2SO4 NH
fast H2SO4 fast
NH

H + Me Me + H
N N OMe
Me Ph –78°C: low ee OMe
minor product major product
–78°C RT –78°C: er = 50:1
N OLi

The rates of protonation are much faster than the rates of conformation JACS 1998, 120, 2028-2038
interconversion
 K. A. Beaver, D. A. Evans Some Curtin-Hammett Examples Chem 206

Tropane alkylation is a well-known example. Enantioselective Lithiation:

N
Me Me
N N i-Pr2N O
H i-Pr2N O N
less stable more stable Li
s-BuLi (-)-Sparteine
Me
Me

13 Me–I
faster 13
Me–I slower Because sparteine is
chiral, these two
(-)-Sparteine complexes are
13Me + Me Me + 13Me diastereomeric and
N N have different
major product minor product properties.
i-Pr2N O i-Pr2N O
Li•sparteine Li•sparteine

Me
Me
The less stable conformer reacts much faster than the more stable
conformer, resulting in an unexpected major product!

JOC 1974 319 faster Cl

slower

i-Pr2N O
Oxidation of piperidines: i-Pr2N O
Me
Me
N N Me
Me3C Me3C Me
less stable more stable
H Keq = 10.5 H
82 - 87% ee

slower k1 H2O2 k2 faster

Enantioselectivities are the same, regardless of whether or not the starting material is
Me O– chiral, even at low temperatures. Further, reaction in the absence of (-)-sparteine
results in racemic product.
N+ N
Me3C O– Me3C + Me

H H Note that the two alkyllithium complexes MUST be in equilibrium, as the

minor product Ratio: 5 : 95 major product enantioselectivity is the same over the course of the reaction. If they were not
equilibrating, the enantioselectivity should be higher at lower conversions.

When the equilibrium constant is known, the Curtin-Hammett derivation This is a case of Dynamic Kinetic Resolution: Two enantiomeric alkyl
can be used to calculate the relative rates of reaction of the two lithium complexes are equilibrating during the course of a reaction with an
conformers. Substituting the above data into [PB]/[PA] = k2K/k1, the ratio electrophile.
k2/k1 ~ 2.
Note that in this case, the more stable conformer is also the faster reacting conformer! Beak, Acc. Chem. Res, 1996, 552
Tet. 1972 573
Tet. 1977 915
K. A. Beaver, D. A. Evans Reactions Involving Interconverting Isomers Chem 206

The Curtin-Hammett treatment can be extended to ANY case where different

products are formed from two rapidly intereconverting starting materials,
whether they are conformers, tautomers or isomers.

kA "It was pointed out by Professor L. P. Hammett in 1950 (private

k1 k2
PA A B PB communication) that ..."
kB
major minor
David Y. Curtin, 1954

Stannylene ketals provide an efficient way to acylate the more hindered site of 1,2-diols.
" Because Curtin is very generous in attributing credit, this is
O Ph O O sometimes referrred to as the Curtin-Hammett principle rather
Cl
SnBu2 Cl than the Curtin principle."
O
O2N
O2N
Louis Plack Hammett, 1970

Ph OCOAr Ph Ph OSnBu2Cl
O
Ar
OSnBu2Cl
OSnBu2Cl O OCOAr Curtin - Hammett Principle: The product composition
more stable less stable is not solely dependent on relative proportions of the
Ratio 2:1 conformational isomers in the substrate; it is controlled
Ar= p-NO2C6H4 by the difference in standard Gibbs energies of the
TMS-Cl faster slower TMS-Cl respective transition states.

Ph OCOAr Ph OTMS

Product Ratio 22:1

OTMS OCOAr
THE TAKE-HOME LESSON:

The two stannyl esters are in equilibrium at room temperature, and the Never assume that the most stable conformation of a
more stable isomer is initially formed more slowly. The stannyl esters are compound is the most reactive. It may be, but then
allowed to equilibrate before quenching with TMS-Cl, which reacts more again, it may not.
rapidly with the less hindered primary alkoxystannane.

JOC 1996, 5257

K. A. Beaver, D. A. Evans Mechanism of Asymmetric Hydrogenation Chem 206

P S MeO2C NHAc
The asymmetric hydrogenation of prochiral olefins catalyzed by
Rh
Rhodium is an important catalytic process.
S,S P S Ph

coordination coordination
MeO2C NHAc [L2Rh]+ MeO2C NHAc
CO2Me
MeO2C
NH HN
Ph Ph P P
> 95% ee Rh minor major Rh
Ph Ph
P P
O O
Enantioselectivities are generally very high when the ligand is a chelating Me
Me
diphosphine. (ee's are given for S,S-CHIRAPHOS)

When a chiral ligand is used, there are two diastereomeric complexes which hydrogen hydrogen
addition faster slower addition
may be formed:
MeO2C CO2Me MeO2C CO2Me
NH HN P NH HN P
P P
Rh H P
* Ph Ph Rh
* Rh Ph Ph Rh
P P
O O P H
Me O O
Me major complex H
minor complex 1 2
Me Me H
(NMR, X-Ray)

H2 fast slow migration +S +S migration

H2

P CH2Ph P
PhH2C
MeO2C NHAc H CO2Me MeO2C
MeO2C NHAc H
R Rh R S Rh
S P S S P
Ph
Ph O NH HN O
observed product
Me Me
Observations:

• Complex 2 is the only diasteromer observed for the catalyst-substrate complex

(1HNMR, X-Ray crystallography) in the absence of hydrogen reductive -L2RhS2 reductive
-L2RhS2 elimination
elimination
• The enantioselectivity is strongly dependant on the pressure of H2, and
degrades rapidly at higher hydrogen pressures
• The observed enantiomer is exclusively derived from the minor complex 2 MeO2C NHAc MeO2C NHAc
R S
These observations may be explained using the Curtin - Hammett Principle
Ph Ph
> 95% ee Halpern, Science, 217, 1982, 401
D. A. Evans Diastereoselective Hydrogenation: Introduction Chem 206

The Hydrogenation Reaction Polar functional groups may play a role in controlling the diastereoselectivity
of the hydrogenation process;
Review article: J. M. Brown, Angew. Chem. Int. Edit. 26, 190-203 (1987) (handout) however, the control elements were not well-defined.

CHMe2 CHMe2
! General Mechanism
M
M
R
M(0) +
R
C C R R C C R C C R O H2, Pd-C O
H H H H only isomer
H H
H H
CH3 CH3
H
H H H M H M H however CHMe2 CHMe2
M(0) + R C C R R
R C C R C C R
H H H H H H OH
H2, Pd-C OH
trans:cis = 55:45
Historically, primary stereochemical control designed around analysis of H H
steric environment in vicinity of C=C. CH3 CH3

However, the influence of polar effects was documented

J. E. McMurry & Co-workers, Tetrahedron Lett.. 3731 (1970)

O CO2Et O CO2Et
H
O H2 Pd-C O HO
10% Pd-C
EtOH H H
H2 N
H
Steric Control
OMe OMe
H
HO H
sole product
LiAlH4 trans : cis H OH
Pd(0) Pd(II) 85 : 15 N

H
O CH2OH O CH2OH HO
O
O H2 Pd-C O H H
5% Pd-Al2O3 N
EtOH Directed ?
H H2
12 : 1
OMe OMe H
OH

trans : cis Y. Kishi & Co-workers, J. Am. Chem. Soc. 102, 7156 (1980)
Thompson, J.Org. Chem. 36, 2577 (1971) 5 : 95
D. A. Evans Diastereoselective Hydrogenation: Introduction-2 Chem 206

The first rational attempt to identify those FGs which will direct the reaction Cationic Hydrogenation Catalysts
H

O H2, 5% Pd-C O
CH3O CH3O Rh
– BF
R O R O 4
–
Ph2P PPh2 Ir PF6
10
Py PCy3
R cis : trans (CH2)n
Schrock & Osborne, R. Crabtree
CH2OH 95 : 5 J. Am. Chem. Soc. 91, 2816 (1969) J. Organomet. Chem. 168, 183 (1979)
CHO 93 : 7
CN 75 : 25
COONa 55 : 45
18 : 82 S S S S = solvent
COOH S
15 : 85 H2 – BF H2
COOMe 14 : 86 Rh 4
Ph2P PPh2 H Rh PPh2
COMe 10 : 90
CONH2 H
(CH2)n
Ph2P
Rh(+I): d8 16-e– 18-e–
H. Thompson & Co-workers, J. Am. Chem. Soc. 95, 838 (1973)

The first rational attempt to associate catalyst with substrate:

Mechanism of Hydrogenation Cationic Rhodium-(I) Catalysts.

CH2OK CH2OH S = solvent

S S
(Ph3P)3RhCl CH2=CH2 S
S Rh PPh2 Rh PPh2
H2 100 psi H
MeO 50 °C, C6H6 MeO
Ph2P Ph2P
cis : trans
>98 : 2 H2
Reductive CH3–CH3 Oxidative
Elimination (+S)
(–S)
Addition
CH2O–Rh(PPh3)3
H
H
S
H S H Rh PPh2
Rxn Catalytic in Rh (4 mol%) Rh PPh2
H2C
MeO Ph2P
Ph2P

Thompson & Coworkers, J. Am. Chem. Soc. 97, 6232 (1974)

D. A. Evans Diastereoaselective Hydrogenation: Cationic Catalysts Chem 206

D. A. Evans & M. M. Morrissey JACS 106, 3866 (1984)

Mechanism of Hydrogenation Cationic Rhodium-(I) Catalysts.
OH OH
S S S
S H2
2H2 – BF H2
Rh 4
CH2Cl2
H Rh PPh2 CH3 CH3
+2 S Ph2P PPh2
– BF H
Rh 4
+ Ph2P
Ph2P PPh2 Catalyst Mol% Catalyst H2 Pressure trans:cis (Yield)
S = solvent 16-e_ 18-e–

17.5 15 psi H2 200 : 1 (89%)

P Rh(DIPHOS-4)+
P 3.5 375 psi H2 300 : 1 (95%)
+
HA Rh OH 20.0 15 psi H2 50 : 1 (82%)
H2 HB Ir(pyr)PCy3
R2
OH H 2.5 15 psi H2 150 : 1 (85%)
C C R2
CH2 H H H

P Which hydrogen OH OH CH2OH

Rh + CH2OH
Rh migrates ?? Rh +
P P
H2
H2
CH3 CH3 CH3 CH3
+ 65 : 1
19 : 1
P Rh OH Rh(DIPHOS-4)+ H2 1000 psi CH2Cl2
R2 CH3 H
OH
C
CH3 H H Excessive Steric Hindrance
R2 Me
Me H Me Me
H
A potential stereoelectronic effect Me
OH OH
Me H H
CO2H Me Me
P P Me Me } Me
P P
+ Retigeranic Acid
HA Rh OH HB Rh Me Me
+ H
HB HA HA O
H R2 Rh +
C C R2 H2 75 : 1 (95%)
H H H H OH OH
H
H Me Me
Me Me
That H atom lying parallel to the pi-system (HA) should Rh(DIPHOS-4)+ H2 800 psi THF
migrate preferentiallyif the dihydride is an intermediate.
THF is important to success of rxn to buffer the Lewis acidity of the catalyst which
causes elimination of ROH under normal conditions
D. A. Evans Diastereoselective Hydrogenation: Cyclic Substrates Chem 206

Polar functional groups other than OH may also

direct the process O O

CO2Me CO2Me X X Diastereoselection

Ir(pyr)Pcy3+ X
Rh(DIPHOS-4)+ OMe 55:45
diastereoselection
H2 91 : 9 H2 99:1
H2C CH3 NC4H8
Me Me

CO2Me CO2Me
X Diastereoselection
O O
Ir(pyr)Pcy3+
diastereoselection CH3 CH3 OMe 99:1
X Ir(pyr)Pcy3+ X
H2 89:11 CH3 CH3
CH3 CH3 NC4H8 >99:1
H2

A.G. Schultz and P.J. McCloskey, J. Org. Chem., 1985, 50, 5907.
O N O N
Ir(pyr)Pcy3+
diastereoselection
H2 >99:1
Me Me OCH3
H 15 psi H2 OCH3
Ir(pyr)Pcy3+
J.M. Brown and S.A. Hall, J. Organomet. Chem., 1985, 285, 333. diastereoselection
>99:1
CH3 CH3
Me O Me O
H H
N Ir(pyr)Pcy3+ N R.H. Crabtree and M.W. Davis, J. Org. Chem., 1986, 51, 2655.
diastereoselection
H2 >99:1
H N H
N H
H O O
H H
CONC4H8 CONC4H8
15 psi H2
CH2OMe CH2OMe Ir(pyr)Pcy3+
N N diastereoselection
Ir(pyr)Pcy3+ >99:1
CH3 O CH3 O
CH3 CH3
diastereoselection CH3 CH3
H2 >99:1
A.G. Schultz and P.J. McCloskey, J. Org. Chem., 1985, 50, 5907.

A.G. Schultz and P.J. McCloskey, J. Org. Chem., 1985, 50, 5907.
D. A. Evans Diastereoselective Hydrogenation: Acyclic Substrates Chem 206

Acyclic Allylic Alcohols P OH

OH P +
+ P Rh OH
P P Rh H2 R2 R1
R2 R1
P + OH H
P Rh OH C C CH2R2 Me
+ CH2 H
P Rh H2 R1 H
R2 R1 anti > 93 : 7
H
favored C C CH2R2 Me
H R1 H
anti P
OH +
OH OH
P P Rh OH
R2 R1 +
R2 R1 P Rh R2 R2 R1
C C CH3 H2
CH2
CH3 H R1 H Me

H R1 syn > 91 : 9
P H OH
+ C C CH2R2
P Rh H2
H OH O Me
R2 R1 OH
disfavored +
P Rh OH H2 COXn
Me Ph
R N Rh(DIPHOS-4)+ R
P
syn
CH2 Me O Me Me
D O anti

low pressure
P
P + OH
+ P Rh OH OH O Me OH
P Rh H2 H2
R2 R1 Rh(DIPHOS-4)+ COXn
favored R2 Ph R
R N
C C CH3 Me Me Me
H R1 H syn
Me Me O syn
OH O
T
R2 R1
Anti : Syn Ratio
Me Hydroxy-Olefin 15 psi H2 640 psi H2

R = CH3 25 : 75 (23%) 93 : 7
P H R1 OH
R2 D
+ C C Me R = (CH3)2CH 52 : 48 (35%) 94 : 6
P Rh H2
H R2 R1
disfavored + R = Ph 71 : 29 (-) 93 : 7
P Rh OH Me

anti R = CH3 13 : 87 (6%) 9 : 91

P
T
R = (CH3)2CH 12 : 88 (8%) 8 : 92
D. A. Evans & M. M. Morrissey JACS 106, 3866 (1984)
R = Ph 21 : 79 (-) 6 : 94
D. A. Evans Diastereoselective Hydrogenation: Acyclic Substrates Chem 206

Homoallylic Alcohols Evans, Morrissey Tetrahedron Lett. 26 6005 (1985) The Premonensin Synthesis

P OH HO
R H Me Me
+ H2 Me
P Rh C C H
R O
Me OH OH Me
favored P Rh C Me
CH2 Me Me
O+ HO O
P Et O
OH H Me Me
syn Me Me
R

Me Me Catalyst Ratio
P H EtO2C Me
OH
O+ Rh(DIPHOS-4) + 85 : 15
disfavored P Rh CH2 H2
H2 Me Me EtO2C Me
R Rh + Rh(–)(BINAP) + 65 : 35
P R HO HO
C C H Me Me
+ Me Me Me Rh(+)(BINAP) + 98 : 2 (90%)
P Rh Me H
anti
A(1,3) destabilization Evans, DiMare, JACS, 1986, 108, 2476)

HO OTBS HO OTBS The Ionomycin Synthesis

Me Me Me Me
Me Me
A syn OH OH
Me
O O O
Me H Me H Me
HO HO OTBS HOOC ! Me Me OH
Me O
Me Me
OTBS anti Me Me Me
B

Me
Olefin Catalyst (H2 Pressure) syn : anti H2
CH3O2C !
OH
Rh(DIPHOS-4)+
A Rh(DIPHOS-4)+ (1000 psi) 95 : 5 Me Me Me Me
CH3O2C !
A Ir(pyr)PCy3+ (15 psi, 2.5 mol%) 73 : 27 OH
Me Me Me
Rh(DIPHOS-4)+ (1000 psi) 9 : 91 Diastereoselection: 94 : 6 (93%)
B
with Dow, Shih, Zahler, Takacs, JACS 1990, 112, 5290
}