D. A.

Evans

Olefin Addition Reactions: Part2

! Problems of the Day:
Rationalize the stereochemical outcome of the indicated reaction.

Chem 206

http://www.courses.fas.harvard.edu/~chem206/

Chemistry 206 Advanced Organic Chemistry

Lecture Number 9

Me

N O

MH

Me

H Me N OH R2AlH LiAlH4 97 : 3 28 : 72 H

OH

R. Noyori Bull. Chem. Soc. Japan 47, 2617, (1974)

Olefin Addition Reactions2

! ! Sharpless Epoxidation continued..... Hydrogenation

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 stereoelectronic effects, provide an explanation for the reduced reactivity of olefin B in diene 1.
Cl H RCO3H O 2 favored A 1 Cl H RCO3H B 3 disfavored O Cl H

! Olefin Bromination

! Reading Assignment for week

A. Carey & Sundberg: Part B; Chapter 4 "Electrophilic Additions to CC Multilple Bonds" Hoveyda, Evans, & Fu (1993). Substrate-directable chemical reactions. Chem. Rev. 93: 1307-70 (pdf) J. M. Brown, Angew. Chem. Int. Edit. 26, 190-203 (1987) (Handout)

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 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 trisubstituted olefin.
Me H

Investigation of the early Steps in Electrophilic Bromination through the Study of the Reaction of Sterically Encumbered Olefins R. S. Brown, Accts. Chem. Res. 1997, 30, 131 (handout)
H. Yamamoto et.al, Angew. Chem. Int. Ed. 2005, 44, 4389-4391 (pdf)

TIPSO

H Me H

Me H H O

Al(t-BuO)3

R H Me H O H
" "

Me H O R

t-BuOOH
4 sieves toluene, -20C

HO

HO

D. A. Evans

Friday, October 7, 2005

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 proceeds and provide the stereochemistry (") of the product epoxide along with a stereochemical analysis of the noted face selectivity.

K. A. Beaver, D. A. Evans
Leading References:

Conformational Analysis and Reactivity: Curtin-Hammett Principle

Case 1: "Kinetic Quench"

Chem 206

J. I. Seeman, J. Chem. Ed. 1986, 63, 42-48. J. I. Seeman, Chem Rev. 1983, 83, 83-134. See also Eliel, pp. 647-655

How does the conformation of a molecule effect its reactivity?

Consider the following example:
N Me Me N

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 reflect the initial composition.
[PB] = [PA] [B]o [A]o

13 MeI

13 MeI

!GAB
Energy

!G1

!G2 !G

PB

Do the two different conformers react at the same rate, or different rates? What factors determine the product distribution?

PA

A
Rxn. Coord.

The situation:
Consider two interconverting conformers, A and B, each of which can undergo a reaction resulting in two different products, PA and PB.

In this case, the product distribution depends solely on the initial ratio of the two conformers.
steric hindrance
less stable

Me Me H N O -78C !G = -3.0 kcal/mol (ab initio calculations) Me N

Me
more stable

PA
major

k1

kA kB

k2

PB
minor

(1)

H O
MeBr

We'll consider two limiting cases: (1) The rate of reaction is faster than the rate of conformational interconversion (2) The rate of reaction is slower than the rate of conformational interconversion
If the rates of conformationall interconversion and reaction are comparable, the reactants are not in equilibrium during the course of the reaction and complex mathmatical solutions are necessary. See Seeman, Chem. Rev. 1983, 83 - 144 for analytical solutions.

MeBr

Me Me N minor product O Me H

Me Me N O H Me

major product

While enolate conformers can be equilibrated at higher temperatures, the products of alkylation at -78 C always reflect the initial ratio of enloate isomers. Padwa, JACS 1997 4565

K. A. Beaver, D. A. Evans
Case 2: Curtin-Hammett Conditons

Curtin - Hammett: Limiting Cases

Chem 206

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

To relate this quantity to !G values, recall that !Go = -RT ln Keq or Keq = e-!G/RT, k1 = e-!G1/RT, and k2 = e-!G2/RT. Substituting this into the above equation:
[PB] [PA] = k2 k1 Keq = e-!G2/RT e-!G1/RT (e-!G/RT) = e-!G2/RTe-!G/RTe!G1/RT

PA

slow

slow

PB

(1)

(4)

fast
!!G

Combining terms:
[PB] [PA]

= e-(!G2 + !G-!G1)/RT or

[PB] [PA]

e-!!G/RT

!G1

!GAB

!G2

Where !!G = !G2+!G-!G1

PB

Energy

A
PA

!G

Curtin - Hammett Principle: The product composition is not solely dependent on relative proportions of the conformational isomers in the substrate; it is controlled by the difference in standard Gibbs energies of the respective transition states.
minor

major

Rxn. Coord.

The Derivation:
d[PB] d[P ] Using the rate equations dt A = k1[A] and dt = k2[B] we can write:
d[PB] d[PA] = k2[B] k1[A]

Within these limits, we can envision three scenarios: If both conformers react at the same rate, the product distribution will be the same as the ratio of conformers at equilibrium. If the major conformer is also the faster reacting conformer, the product from the major conformer should prevail, and will not reflect the equilibrium distribution. 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 distribution will not reflect the equilibrium distribution. This derivation implies that you could potentially isolate a product which is derived from a conformer that you can't even observe in the ground state!

or

d[PB] =

k2[B] k1[A]

d[PA]

(2)

Since A and B are in equilibrium, we can substitute Keq =

k2 k1

[B] [A]
(3)

d[PB] =

Keq d[PA]

Integrating, we get

[PB] [PA]

k2 K k1 eq

When A and B are in rapid equilibrium, we must consider the rates of reaction of the conformers as well as the equilibrium constant when analyzing the product ratio.

K. A. Beaver, D. A. Evans
Tropane alkylation is a well-known example.
N Me Me N

Some Curtin-Hammett Examples

Enantioselective Lithiation:

Chem 206

less stable

more stable

i-Pr2N

O H Me

i-Pr2N

Li Me

s-BuLi

(-)-Sparteine

faster

13 MeI

13 MeI

slower (-)-Sparteine
13Me

13Me

+ Me N

Me + N

major product

minor product

i-Pr2N

Because sparteine is chiral, these two complexes are diastereomeric and have different properties.
Lisparteine Me

Lisparteine Me

i-Pr2N

The less stable conformer reacts much faster than the more stable conformer, resulting in an unexpected major product!
JOC 1974 319

faster
i-Pr2N
O

Cl

slower
i-Pr2N

Oxidation of piperidines:
Me N N Me3C H

Me Me

Me

less stable

Me3C

more stable
82 - 87% ee

Keq = 10.5 k1
Me N+ O

slower

H2O2

k2 faster
O Me3C H N + Me

Enantioselectivities are the same, regardless of whether or not the starting material is chiral, even at low temperatures. Further, reaction in the absence of (-)-sparteine results in racemic product. Note that the two alkyllithium complexes MUST be in equilibrium, as the enantioselectivity is the same over the course of the reaction. If they were not equilibrating, the enantioselectivity should be higher at lower conversions.

Me3C

minor product

Ratio: 5 : 95

major product

When the equilibrium constant is known, the Curtin-Hammett derivation can be used to calculate the relative rates of reaction of the two conformers. Substituting the above data into [PB]/[PA] = k2K/k1, the ratio k2/k1 ~ 2.
Note that in this case, the more stable conformer is also the faster reacting conformer!

This is a case of Dynamic Kinetic Resolution: Two enantiomeric alkyl lithium complexes are equilibrating during the course of a reaction with an electrophile. Beak, Acc. Chem. Res, 1996, 552

Tet. 1972 573 Tet. 1977 915

K. A. Beaver, D. A. Evans

Mechanism of Asymmetric Hydrogenation

P Rh S S MeO2C NHAc

Chem 206

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

Ph

[L2Rh]+

MeO2C

NHAc

coordination
MeO2C NH HN

coordination
CO2Me P Ph O Me Me Rh P

Ph

Ph

> 95% ee Enantioselectivities are generally very high when the ligand is a chelating diphosphine. (ee's are given for S,S-CHIRAPHOS)

P Rh P Ph O

minor

major

When a chiral ligand is used, there are two diastereomeric complexes which may be formed:
MeO2C NH P HN P Ph O Me Me Ph O Rh P CO2Me

hydrogen addition
MeO2C P

faster

slower

hydrogen addition
CO2Me

NH Ph O Me Me

HN Ph O

P P Rh H H

Rh P

H Rh P H

minor complex 1
H2

major complex
(NMR, X-Ray) H2

fast

slow

migration
P

+S

+S

migration

MeO2C

NHAc

R
Ph

MeO2C

NHAc

H Rh P S O Me

S
Ph

CH2Ph CO2Me R NH

PhH2C MeO2C S S HN

P H Rh P O Me

observed product
Observations: Complex 2 is the only diasteromer observed for the catalyst-substrate complex (1HNMR, X-Ray crystallography) in the absence of hydrogen 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

reductive elimination

-L2RhS2

-L2RhS2

reductive elimination

MeO2C

NHAc

These observations may be explained using the Curtin - Hammett Principle

R
Ph

S
Ph

> 95% ee

Halpern, Science, 217, 1982, 401

D. A. Evans
The Sharpless Epoxidation
OR RO O V O O ! RO HO V O O ! R O+ RDS

Sharpless Epoxidation (V+5)

Chem 206

! The literature precedent: Sheng, Zajecek, J. Org. Chem. 1970, 35, 1839
OR RO O V O O !
OH

TBHP 80 oC
O " OH OH O "

Catalyst
ROOH

VO(acac)2 Mo(CO)6

4:1 1:1

ROH OR RO O V OR O ! HO

! Next step: Sharpless, Michaelson JACS 1973, 95, 6136

OH OH Me

HO

O !

VO(acac)2 TBHP
Me Me OH

Me O "

Regioselection 20:1

Me Me

80 C

Aldrichimica Acta, 12, 63 (1979)

OH

Mo(CO)6 TBHP 80 C
O "

Stereoselection 98:2 (90 % yield)

OC2C3C4 = 41 The Sharpless estimate: ~50

Relative Rates (Diastereoselectivities) for the Epoxidation of Cyclohexene Derivatives JACS 1973, 95, 6136
t-BuOOH
HO HO

t-BuOH

Substrate
O

krela,b (diastereoselectivityc ) peracid

1.00

Mo(CO)6
1.00

VO(acac)2
1.00

2 1 3 RO 4 O

tBu O V O tBu O O

OR V O O-OtBu

OH

0.55 (92 : 8)
OAc

4.5 (98 : 2)

>200 (98 : 2)

0.046 (37 : 63) 0.07 (40 : 60)

O O
OH

--

Chem 3D Transition State

slow

RO V O O

0.42 (60 : 40)

11.0 (98 : 2)

10.0 (98 : 2)

a,b The relative rate data apply only to a given column.

Values in parenthesis refer to the ratio of syn:anti epoxide.

D. A. Evans
! Allylic Alcohols:

Epoxidation of Acyclic Alcohols

OH OH
Reagent

Chem 206

OH
+

Me

OH
Reagent

Me O "

OH Me
threo +

Me

OH Me
erythro

Me

Me

Me

Me

O !

Me

Me

O !

Me

" O

! Estimate ~ 120 40-50

Reagent

Ratio 95 : 5 71 : 29 84 : 16
R1

Reagent m-CPBA t-BuOOH / VO(acac)2 t-BuOOH / Mo(CO)6

Ratio 64 : 36 29 : 71 62 : 38 64 : 36
OH

m-CPBA t-BuOOH / VO(acac)2 t-BuOOH / Mo(CO)6

OH H Me H Me C Me C OH H

t-BuOOH / (t-BuO)3Al
OH R2 SiMe3
t-BuOOH
VO(acac)2

OH R1

! RCO3H Transition States: ! ~ 120 TSmajor

H Me CH C

! O R1

R2 SiMe3

R1

O !

R2 SiMe3

TSminor

Oshima, Tetrahedron Lett. 1982, 23, 3387.

R2 Bu Me
OH

Yield 84 % 70 %

Ratio 99 : 1 99 : 1

H C5H11

OH
t BuOOH

! V(+) Transition States: ! ~ 45

HO

Me C H Me H
EtO OEt OH

O O Me Me

VO(acac)2 60 %

! O
EtO OEt OH

O O Me Me

only isomer

TSmajor

H Me

H Me

C HO

H TSminor H

t-BuOOH

O EtO OEt O Me Me

VO(acac)2 60 %

! O
EtO OEt

O O Me Me

only isomer

Me Me

OH
Reagent

Me Me O !

OH Me
threo +

Me Me O !

OH Me
erythro

Depezay, Tetrahedron Lett. 1978, 19, 2869.

Me

Me HO OH
Boeckman, JACS 1977, 99, 2805.

t-BuOOH
VO(acac)2 60 % HO

O ! Me OH

Diastereoselection = 7 : 1

K. Oshima & Coworkers Tetrahedron Lett. 1980, 21, 1657, 4843. K. B. Sharpless & Coworkers Tetrahedron Lett. 1979, 20, 4733.

Reagent m-CPBA

t-BuOOH / VO(acac)2 t-BuOOH / Mo(CO)6 t-BuOOH / (t-BuO)3Al

Ratio 95 : 5 86 : 14 95 : 5 100 : 0

Me

NHCONHPh Ph

m-CPBA
CH2Cl2, 0 C 75 %

Me O !

NHCONHPh Ph
+

Me O !

NHCONHPh Ph

Roush, J. Org. Chem. 1987, 52, 5127.

Diastereoselection = 95 : 5

D. A. Evans

Epoxidation of Acyclic Homoallylic Alcohols

Anti diastereomer
OH O ! R2 R1 Me OH O ! R2 R1 Me + R1

Chem 206

Homoallylic Alcohols (Mihelich, JACS 1981, 103, 7690)

t-BuOOH
VO(acac)2 90 % O ! OH Me Me + Me Me O ! OH

OH R2 Me

t-BuOOH
VO(acac)2

OH Me Me

Control Elements
A(1,3) Strain Directed Rxn
H H Me H O L HV

Diastereoselection > 400 : 1

L' O R O H ! Me HO Me Me

R1 C6H13 Me
O !

R2 Me

Yield 92 % 97 %

Ratio 104 : 1 > 400 : 1

i-Pr

Syn diastereomer
OH R2 R1 Me O ! OH R2 R1 Me + R1 Me

t-BuOOH
VO(acac)2

O !

OH R2

OH Me Et

t-BuOOH
VO(acac)2

O ! Et

OH Me +

O !

OH Me

R1 C6H13 Me Me
OH

R2 Me Me C5H11
OH Me Me C5H11

Yield 73 % 70 % 81 %

Ratio 70 : 1 85 : 1 16 :1
OH Me Me C5H11

Et

Diastereoselection 12 : 1

Control Elements
Directed Rxn
Me

H O

L HV

L' O R O ! H Et Me

OH

! O
Me

O !

t-BuOOH
VO(acac)2

! O
+

Me
Et

C5H11

E. D. Mihelich & Coworkers J. Am. Chem. Soc. 1981, 103, 7690.

Diastereoselection = 211 : 1

Epoxidation of Homoallylic Alcohols with TBHP, VO(acac)2

Prediction
H R2 O R1 H L HV L' O R H L O R1 HV

Substrate
L' O R O H ! Me
Me Me OH Hex R OH Me OH

Product
OH Me OH Me Me OH Hex

Selectivity
! O
2:1

! H O
Me

Anti should be more diastereoselective than syn

R2 H

! O

4.6 : 1

Anti diastereomer

Syn diastereomer

! O

1.4 : 1

R = (CH2)7CO2Me

D. A. Evans

Epoxidation of Acyclic Homoallylic Alcohols

Chem 206
R AcOH iPr O Me Et OH !

Bishomoallylic Alcohols (Kishi, Tet. Lett. 1978, 19, 2741)

R

Epoxidation & Cyclization of Bishomoallylic Alcohols

Et VO(acac)2 R Et O ! iPr OH Me

OH Me Et CHMe2

t-BuOOH, VO(acac)2
C6H6, RT

O ! Me Et

OH CHMe2
iPr OH Me

diastereoselection ~ 9 : 1
H H R O Et Et H V Me O ! O R R OH O !
Me

The Kishi Lasalocid Synthesis (JACS 1978, 100, 2933)

Me OH O Me H Et

A
Me
HO CO2H Me Me Me Et VO(acac)2 TBHP AcOH Et H O

B
Me

OH Et

Et

A
Ar O Et

OH Me Et Me CHMe2

t-BuOOH, VO(acac)2
C6H6, RT

O ! Me Et Me

OH CHMe2

Ar

OH

Diastereoselection 8:1
OH ! Et Me

Ar = p-MeOPh

Me

diastereoselection ~ 20 : 1
H Et Me Me R O H V Me O ! O R OH R O ! Et Me
Me O OH Me A O Me

Evans X-206 Synthesis JACS 1988, 110, 2506.

Me OH H B O OH Me C O OH OH Me D Me H E O O F Me OH Me O Et OH

2nd stereocenter is reinforcing

Me

OH Me Et Me CHMe2

t-BuOOH, VO(acac)2
C6H6, RT

O ! Me Et Me

OH
Me O N O O OBn Me OH Et VO(acac)2 TBHP C6H6, RT XN OBn HOAc O Me O OH

CHMe2

Ph

O ! Et

diastereoselection ~ 6 : 1

Me H R O

Et Me H V Me O ! O R OH R O ! Et Me

diastereoselection 20 : 1 (89 %)

XN OBn

D O

Et Me OH !

A New Enantioselective Epoxidation Reaction

H. Yamamoto et.al, Angew. Chem. Int. Ed. 2005, 44, 4389-4391

D. A. Evans

Diastereoselective Hydrogenation: Introduction

The Hydrogenation Reaction

Chem 206

Review article:

J. M. Brown, Angew. Chem. Int. Edit. 26, 190-203 (1987) (handout)

Polar functional groups may play a role in controlling the diastereoselectivity of the hydrogenation process; however, the control elements were not well-defined.
CHMe2 CHMe2 H2, Pd-C O

! General Mechanism
M

M C R H R C H C R H H H H

M(0) +

R C H

C R H

R C H

only isomer
CH3

CH3

H C C R H

M(0) +

M R H C C

H R H R C H

H C R H

however

R H

CHMe2 OH H CH3

CHMe2 H2, Pd-C H CH3 OH

Historically, primary stereochemical control designed around analysis of steric environment in vicinity of C=C. However, the influence of polar effects was documented

trans:cis = 55:45

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

O O CO2Et O CO2Et
HO H H H

H2 Pd-C EtOH

10% Pd-C
H OMe

OMe

H2
HO H H OH H

Steric Control
sole product

LiAlH4

Pd(0)
O O CH2OH

Pd(II)
O

trans : cis 85 : 15

CH2OH
O

HO H

H H

H2 Pd-C EtOH

O H

5% Pd-Al2O3 H2
OMe
OH H

Directed ?
12 : 1

OMe

Thompson, J.Org. Chem. 36, 2577 (1971)

trans : cis 5 : 95

Y. Kishi & Co-workers, J. Am. Chem. Soc. 102, 7156 (1980)

D. A. Evans

Diastereoselective Hydrogenation: Introduction-2

Cationic Hydrogenation Catalysts

Chem 206

The first rational attempt to identify those FGs which will direct the reaction
H O CH3O R O H2, 5% Pd-C CH3O
10

O R O

Rh Ph2P
(CH2)n

BF 4

PPh2 Py

Ir

PF6

R CH2OH CHO CN COONa COOH COOMe COMe CONH2

cis : trans 95 : 5 93 : 7 75 : 25 55 : 45 18 : 82 15 : 85 14 : 86 10 : 90

PCy3

Schrock & Osborne, J. Am. Chem. Soc. 91, 2816 (1969)

R. Crabtree J. Organomet. Chem. 168, 183 (1979)

S H2 Ph2P Rh

S
BF 4

S H2 S H Rh H Ph2P

S = solvent

PPh2
(CH2)n

PPh2

H. Thompson & Co-workers, J. Am. Chem. Soc. 95, 838 (1973)

Rh(+I): d8

16-e

18-e

The first rational attempt to associate catalyst with substrate:

CH2OK (Ph3P)3RhCl MeO H2 100 psi 50 C, C6H6 H MeO CH2OH

Mechanism of Hydrogenation Cationic Rhodium-(I) Catalysts. S = solvent

S S Rh Ph2P PPh2 CH2=CH2 S Rh Ph2P CH3CH3 H2
(S)

S PPh2

cis : trans >98 : 2

CH2ORh(PPh3)3

Reductive Elimination
H

(+S)

Oxidative Addition
H S PPh2

Rxn Catalytic in Rh (4 mol%)

H2C
MeO

S Rh PPh2

Rh

Ph2P

Ph2P

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

D. A. Evans

Diastereoaselective Hydrogenation: Cationic Catalysts

D. A. Evans & M. M. Morrissey JACS 106, 3866 (1984)
OH OH
H2

Chem 206

Mechanism of Hydrogenation Cationic Rhodium-(I) Catalysts.

S 2H2 Ph2P + PPh2 Rh
BF 4

S Rh
BF 4

S H2 S H Rh PPh2
CH3

+2 S

CH2Cl2

Ph2P

PPh2

CH3

S = solvent

16-e_
P P H2 HA Rh HB H C H H

18-e

H Ph2P

Catalyst

Mol% Catalyst 17.5 3.5 20.0 2.5

H2 Pressure 15 psi H2 375 psi H2 15 psi H2 15 psi H2

trans:cis (Yield) 200 : 1 (89%) 300 : 1 (95%) 50 : 1 (82%) 150 : 1 (85%)

Rh(DIPHOS-4)+
OH

R2 CH2

OH

Ir(pyr)PCy3
C R2 H

P Rh P P R2 CH3 OH P Rh CH3 H R2 OH

Which hydrogen migrates ??

CH3

OH

Rh + H2

OH CH3 CH3

CH2OH
Rh + H2

CH2OH

65 : 1

CH3 19 : 1

H C H
Me H Me

Rh(DIPHOS-4)+ H2 1000 psi CH2Cl2

Excessive Steric Hindrance

Me H Me Me

A potential stereoelectronic effect

P P HA Rh HB H C H H OH C R2 H P
Me H Me CO2H

Me

P HB Rh

H Me Me

OH Me
}

OH Me

HA

HA H H

R2

+ H

Retigeranic Acid Me
Rh + H2

OH Me Me

Me

H Me

OH

75 : 1 (95%)

That H atom lying parallel to the pi-system (HA) should migrate preferentiallyif the dihydride is an intermediate.

Rh(DIPHOS-4)+ H2 800 psi THF 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

O X Ir(pyr)Pcy3+ H2 Me
CO2Me Ir(pyr)Pcy3+ CO2Me

Chem 206

Polar functional groups other than OH may also direct the process
CO2Me Rh(DIPHOS-4)+ H2C H2 CH3 CO2Me

O X X OMe NC4H8 Me Diastereoselection 55:45 99:1

diastereoselection 91 : 9

O X CH3 Ir(pyr)Pcy3+ H2 CH3 X CH3

X OMe

Diastereoselection 99:1 >99:1

CH3

H2

CH3

diastereoselection 89:11

CH3

NC4H8

Ir(pyr)Pcy3+ H2 Me

A.G. Schultz and P.J. McCloskey, J. Org. Chem., 1985, 50, 5907.

diastereoselection >99:1
H Me
OCH3 15 psi H2 Ir(pyr)Pcy3+ CH3 R.H. Crabtree and M.W. Davis, J. Org. Chem., 1986, 51, 2655. OCH3

J.M. Brown and S.A. Hall, J. Organomet. Chem., 1985, 285, 333.
Me O N N H O H Ir(pyr)Pcy3+ H2 H Me O N N H O
CONC4H8 CH3

diastereoselection >99:1

diastereoselection >99:1

N CH3

CH2OMe O CH3 Ir(pyr)Pcy3+ H2 CH3

CH2OMe O CH3

15 psi H2 Ir(pyr)Pcy3+

CONC4H8

diastereoselection >99:1
CH3

diastereoselection >99:1

CH3

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

Acyclic Allylic Alcohols
P P + Rh H P H Rh C R1 + OH H2 C CH2R2 H R2 Me OH R1

Chem 206
P
+

OH R2 CH2 R1 P

P + Rh H

OH H2 CH2R2 H R2 Me R1

P H

Rh C R1

OH C

anti > 93 : 7

favored
OH R2 CH2 P P + Rh R1

anti
OH P R2 CH3 R1 P + Rh P R2 H

P Rh C R1 OH C CH3 H H2 R2 Me
+

OH R1

H H

H C P Rh P C + OH

R1 CH2R2 H2 R2 Me

OH R1
OH R CH2 Me O N O O Me Ph H2 Rh(DIPHOS-4)+ R Me

syn > 91 : 9
OH COXn Me

disfavored

syn

D
P P R2 H OH R2 Me P P + Rh H C P Rh P C + OH R1 Me H2 R2 Me OH R1 R1 Rh C R1 + OH C CH3 H OH H2
OH O

anti

low pressure
P P + Rh
Me N Me Me O O Ph OH R Me Me COXn

favored

R2 Me

R1

H2 Rh(DIPHOS-4)+

syn

syn

Anti : Syn Ratio

Hydroxy-Olefin R = CH3 15 psi H2 25 : 75 (23%) 52 : 48 (35%) 71 : 29 (-) 13 : 87 (6%) 12 : 88 (8%) 21 : 79 (-) 640 psi H2 93 : 7 94 : 6 93 : 7 9 : 91 8 : 92 6 : 94

R2 H

R = (CH3)2CH R = Ph R = CH3

disfavored

anti
T

R = (CH3)2CH R = Ph

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

D. A. Evans
Homoallylic Alcohols
P P + Rh R

Diastereoselective Hydrogenation: Acyclic Substrates

Evans, Morrissey Tetrahedron Lett. 26 6005 (1985)
OH H C CH2 C Me P Rh P O+ H Me H H2 R Me Me

Chem 206

The Premonensin Synthesis

HO O HO C Me Me Me OH O Me OH Me Me Et Me O Me

favored
OH R Me Me

syn

disfavored
P P + Rh

P R Me

P H O+ Rh CH2 C Me C H H

OH H2 R Me Me

EtO2C Me HO Me Me H2 Rh +

Me EtO2C HO Me Me

Catalyst
Rh(DIPHOS-4) + Rh()(BINAP) + Rh(+)(BINAP) +

Ratio
85 : 15 65 : 35 98 : 2 (90%)

anti A(1,3) destabilization

Evans, DiMare, JACS, 1986, 108, 2476)

HO Me Me

OTBS

HO Me Me

OTBS
Me

The Ionomycin Synthesis

Me OH OH Me Me O Me Me CH3O2C ! Me Me Me H2 OH Rh(DIPHOS-4)+ Me CH3O2C ! Me Me Me OH Me H O Me H O Me OH

A
HO Me Me HO

syn

OTBS Me Me

HOOC Me

! Me

B Olefin A A B

OTBS

anti

Catalyst (H2 Pressure) Rh(DIPHOS-4)+ (1000 psi) Ir(pyr)PCy3+ (15 psi, 2.5 mol%) Rh(DIPHOS-4)+ (1000 psi)

syn : anti 95 : 5 73 : 27 9 : 91

Diastereoselection: 94 : 6 (93%)
with Dow, Shih, Zahler, Takacs, JACS 1990, 112, 5290
}