Electron Rich Substituents have lone pairs (OR, NR2, SR, SO2R)Electron Poor Substituents: SiR3 (electropositive)

Based solely on electrostatic considerations

Mick DartEvans Group SeminarTues. Jan. 18, 1994

1. Diels Alder reactions2. Halogenation and related electrophilic additions3. Reactions of allylsilanes4. Hydroborations5. Osmylations

Diastereoselective Attack ofElectrophiles on Chiral Olefins

D. Jones, J. C. S. Chem. Comm. 1980, 739.

■ Other dienophiles also give adducts derived from endo addition syn to the hydroxyl

anti

syn

DienophileX

SynAnti

Electron RichElectron Poor

Hehre's Proposal:

■ Opposite diastereofacial selectivity is observed with acrolein.

(73%)

■ Stereocontrol: A(1,3) strain

Trost, J. Org. Chem, 1989, 54, 2271-2274.

Diastereoselective Diels–Alder Reactions: Chiral Dienes

Diastereoselection 91 : 9

Diastereoselection >95 : 5

Kahn & Hehre, J. Am. Chem. Soc. 1987, 109, 663-666.

(99%)PhN

O

O O

O

Me

H

H

O

NPh

Me

OHH

HOH

O

H

H

Me

H

O

H

R

X

H

Me

Me

OH O

O

OO

O

O

Me

Me

OHH

H OH

Me

01-Diels-Alder 3/19/02 2:03 PM

Also see A. Kozikowski, J. Am. Chem. Soc. 1987, 109, 5167-5175.

Allylic Ether

Allylsilane

Favored diene conformers in reactions with acetylenic dienophiles

Dienophile

■ Rationalization for diastereofacial selectivity:

Fleming, JCS Perkin Trans I, 1989, 2023-2030.

Diastereoselective Diels–Alder Reactions: Chiral Dienes

Diastereoselection 82 : 18

Diastereoselection 12 : 88R. Franck, J. Am. Chem. Soc. 1988, 110, 3257

Dienophile

Dienophile Dienophile

Dienophile

PhH, rt

PhH, 60 °C

10 days

2 days

(96%)

(90%)

2 days

PhMe, 100 °C

Dienophile

Dienophile

Dienophile

R. Franck, J. Am. Chem. Soc. 1988, 110, 3257 Diastereoselection 27 : 73

Diastereoselection >99 : 1Fleming, JCS Perkin Trans I, 1989, 2023-2030.

PhMe, 100 °C

2 days

(72%)

(62%)

See Houk & Co-workers Science, 1986, 221, 1108-1117.

anti

outsideinside

Dienophile

Me

H SiMe2Ph

Me

PhN

O

O

NPh

O

O

H SiMe2Ph

Me

MeH

HH

NPh

O

O

H OSiMe3

Me

MeH

HHH H

HMe

Me

OSiMe3H

O

O

NPh

SiMe2Ph

Me

H H

HMe

Me

Me

SiMe2PhH

O

O

NPh

O

O

PhN

Me

OSiMe3H

Me

HMe

H Me

OSiMe2 Me

HMe3SiOMe

Me

Me H

OSiMe3H

Me

PhMe2Si Me

Me

Me3SiO H

Me

Me

OSiMe3H

Me

Me

H OSiMe3

Me CO2Me

CO2Me

CO2Me

CO2Me

CO2Me

CO2Me

CO2Me

CO2Me

H SiMe2Ph

Me

Me

Me

H

H Me

SiMe2Ph

CO2Me

CO2Me CO2Me

CO2Me

Me

H OSiMe3

Me

Me

H H

MeH

Me

Me

OSiMe3H

SiMe2Ph

H

Me

Me

SiMe2PhH

Me

CO2Me

CO2Me

CO2Me

CO2MeH

SiMe2Ph

H

Me

SiMe2PhH

Me

Me

PhMe2Si

Me

02-Diels-Alder 3/19/02 1:59 PM

A preference for "inside alkoxy"is observed in these cyclizations

BA

low yield due to δ-lactone formation

Gauche A is now moredestabilizing than gauche B

+

I2, HOH/THF

HCO3–

Ratio >95 : 5 (49%)

+A B

How can the above results be rationalized?

Chamberlin, J. Am. Chem. Soc. 1983, 105, 5819-5825.

K2CO3MeOH

Epoxidation Ratio = 3 : 97Lactonization Ratio = 96 : 4

t-BuOOHVO(acac)2

Gauche B is more destabilizing than gauche A

+

Ratio96 : 4 (85%)

HCO3–

I2, HOH/THF

+

R = H

R = Me

A(1,2) strain

95 : 5 49

■ Kinetic conditions: 3 equiv I2, aq Na2CO3, Et2O, 0 °C

■ Protection of the hydroxyl group (TBS or Ac) does not affect selectivity

■ Iodolactonization of allylic alcohols

75 : 25 9 : 91

(cis : trans)

NIS, CHCl3, 25 °C3 equiv I2, MeCN, O °C

KineticThermodynamic

Conditions

Bartlett, J. Am. Chem. Soc. 1978, 100, 3950-3952.

Iodolactonization

Yield (%)SelectivityMajor ProductSubstrate

85

7481

4194

66

R = HR = Me

95 : 5

87 : 1390 : 10

93 : 7

77 : 2342 : 58

R = HR = Me

Chamberlin, J. Am. Chem. Soc. 1983, 105, 5819-5825.

■ Bartlett's "thermodynamic conditions" produced complex mixtures

I

HO

OO

OO

HO

IMe

Me

R

R

Me OH

HO

O

-O2CCH2

HO H

O

C HCH

Me

HO

I

Me

O H

HO

O

II

O

HO

HO

C

IH

OH

CMe

H

R

R

Me

H

HO

CH2

Me

OH

Me

-O2C

O

RO

OH

MeHO

O

O

HO

OH

OH

HO

OO

I

Me

O

Me

I

O

Me

HO

O

O

OO

Me

OH

Me

RO

O

-O2CCH2

HO

Me

Me

HO H

CMe

CH

Me

I

O Me

HO

O

I I

O

HO

MeO

Me

HO

C

I

CMe

HMe

H

CH2-O2C

O

MeO

Me

OH

Me

Me

IH

I

HO

O

OOMe

OH

Me

MeO

O

O

O

OH

O

I

Me

03-Iodolactonization 3/19/02 2:00 PM

■ Place the medium size group (–OH) outside and the small group (–H) inside

■ Other conditions: I2, THF/phosphate buffer; I2, THF, aq Na2CO3 provide 1,3–diols in very high selectivity

Model for Stereoinduction?

minormajor

Gauche B is more energetically destabilizing than gauche A

I2, AgOAc+ +

–OAc AcO–

BA

AB

H2O

++I2, AgOAc

Gauche A is now more destabilizing than gauche B

OH2

Ratio 80 : 20 perfect regioselectivity

HCO3–

I2, HOH/THF Poor regioselectivity affordsa mixture of products

Evans, Kaldor, Jones, J. Am. Chem. Soc. 1990, 112, 7001.

Chamberlin, Tetrahedron 1984, 40, 2297-2302.

Diastereoselection 96 : 4

I2, THFaq KH2PO4

Cytovaricin Synthesis

■ High selectivities are also observed with allylic ethers (OMe, OBn, OTBS)

■ Prevost conditions: 2 equiv I2, 2 equiv AgOAc, THF, –78 →0 °C

94 : 6

98 : 2

95 : 5

80 : 20

78

90

85

Substrate Major Product Selectivity Yield (%)

Iodo diol formation from allylic alcohols

■ Analysis: D. A. Evans, Chem. 115, Lecture 23, Dec. 16, 1993

HO H

R

CH

H

OAc

I

OH

R'R

OH

CMe

I

R'

HO H

R

CMe CH

H

I

I

Me

OH

Me

OH

Bu

Bu Me

R

Me

OH

TIPSO

Me

Bu

OH

Me

OH

Me

OAc

R

Bu

R'

OH

I

OH OH

Bu I

Me

OAc

C C

IH

OH

Me

OH

Bu

OAc

OH

Me

R RHO

OH

R

OH

OH

Me

I

OH

R

Me

Me

Bu

Bu

OH

I

I

I

I

Me MeHO

OAc

TIPSO

OH

R'

HH

R

HO

C C

IHO

HHR'

R

H

04-Iododiol formation 3/19/02 2:00 PM

■ "The presence or absence of an internal nucleophile acts to determine the stereochemical outcome of the reaction by modifying the nature (timing) oftransition state.

■ Onium ion formation is rate determing in the addition reactions■ π–complex cyclizes if R contains a Nu and its formation is rate determining

For a review of the halogenation reaction see: Andy Ratz, Evans Group Seminar,Synthetic and Mechanistic Review of Electrophilic Halogenation, May 7, 1992.

For a review of elctrophilic induced olefin cyclization reactions see:G. Cardillo & M. Orena, Tetrahedron 1990, 46, 3321.

■ "Facial preferences in electrophilic addition reactions are not invariant with respect to the location of the transition state along the reaction coordinate."

Chamberlin & Hehre, J. Am. Chem. Soc. 1987, 109, 672-677.

-

I2

I2

OH2

cis : trans 95 : 5

ratio 99 : 1

I2

I2

H2O

■ A complete turnover in olefin diastereofacial selectivity is observed when adding internal and external nucleophiles

Chamberlin & Hehre's Rationalization

For electrophiles that react via onium intermediates (I2, Br2, Hg(OAc)2, PhSeCl),the major diastereomer from electrophile-induced cyclization is opposite to thatobserved in the analogous intermolecular electrophilic addition.

General Observation:

■ Analysis of the stereoselectivity of electrophilic addition to chiral olefins:

1. Relative abundances of conformational minima2. Relative reactivities of the available forms3. Stereoselectivies of the individual conformers

■ Change in diastereoselectivity is a consequence of a change in the rate-limiting step

● Addition reactions: Formation of an onium ion intermediate(subsequently trapped by a Nu from the medium)

● Cyclization reactions: Intramolecular attack on a ππππ–complex (not an onium ion)

+

+

Nu

Nu

Disfavored π–complex

Favored π–complex Disfavored iodonium ion

Favored iodonium ion

Cyclization product

Addition product

Favored ground-state conformer

More reactiveground-state conformer

Hehre's Analysis

Houk: Argument for the "inside alkoxy effect" in π–complex formation

OO

HO

OH

MeBu

OH

I

Me

IH

I

OH

Bu Me

OH

HI

Me

HO

OO

Bu

HHO

OH

Bu Me

Me

OH

HO

O

OO

Me

OH

H

I2

H

O

O

H

H

R

H

OH

Me Me

OH

H

R

H

I

HO

Me

Me

IH

OH

MeBu

OH

I

Me

HR

HO

H

H H H

H

H

HO

R

H

MeMe

H

R

HO

H

H H

H

OH

RH

MeI

I2

05-Iodolact/Hehre 3/19/02 2:00 PM

D. A. Evans, Chem. 115, Lecture 23, Dec. 16, 1993

Diastereoselective Functionalization of (E) Allylic Alcohols

■ Halogenation

■ Oxymercuration

■ Hydroboration

■ Sulfenylation

At least 3 major productsH2O2

ThexylBH2

Ratio = 99 : 1 (40%)

PhS–Cl

Me2ZnTiCl4

+

Ratio = 50 : 50 (77%)

Me2ZnTiCl4

PhS–Cl

+

Reetz, Angew. Chem. Int. Ed. 1987, 26, 1028-1029.

minormajor

Gauche B is more energetically destabilizing than gauche A

syn : anti = 80 :20Chamberlin, Tetrahedron 1984, 40, 2297-2302.

Hg(OAc)2

I2, AgOAc

+ +

–OAc AcO–

BA

Hg(OAc)2

R'OH

Oxymercuration of Acyclic allylic alcohols:

NaBH4

R R'OH Ratio

-Et HOH 76 : 24

yield

65%72%93 : 07MeOH-Et

-Ph HOH 88 : 12 66%

70%98 : 02HOH-tBu

Giese, Tet. Lett. 1985, 26, 1197

Hg(OAc)2

NaBH4

HOH

Hg(OAc)2

syn

syn : anti = 77 : 23

O-acetate participation will turn over the stereochemical course of the rxn

Iodohydroxylation of thesesubstrates is not regioselective

+

+ +

+

FavoredDisfavored

■ Hehre's model could be invoked to explain turnover in π–facial selectivity

O

H RL

CH

C

n-Bu

OH

Me

OAc

I

OH

H

H

Hg

X

R'

O

R

H

C

Hg

X

H

HC

H

RL

O

R

OH OH

R

R

C

Hg

RL

H

HCH

OR'

HgOAc

OR'

R

H

Me

OH

X

C

HgH

X

CH

H

OH

OH

H

n-Bu

R' HO

RL

OH

RL

HgOAcHgOAc

Me

OH

OR'n-Bu

RL

HO

OH

OH

OH

RL

OR'

HgOAc

O

R

OR

Me

MeRL

OR

Et

OR

RL

Me

OR

HO

OBz

H

OH

EtMe

OBzOBz

Et

CH

CH

Me

Hg

X

RR R'

OH

I

OAc

C C

IH

S

Ph

C

H

CEt

H

H

MeO

Me

Me

Me

SPh

Me

TBSO

Et

OMe

Me

Me

OTBS

Me

TBSO

Me

SPh

Me

Me

MeO

Me

SPh

Et

Me

Me

OH

R'

HH

R

HO

C C

IHO

HHR'

R

H

n-Bu

06-Oxymercuration 3/19/02 2:01 PM

Scott J. Miller Evans Evening Seminar, "The Chemistry ofAllylsilanes and the β Silicon Effect," Dec 11, 1990, p 45.

Path A Path B

Paddon-Row, Rondan, and Houk JACS 1982 104, 7162.

+ +

El+ El+

■ If A = H, then Path B can compete

■ If A ≥ Me, then Path A dominates due to A(1,3) strain

Stereochemical Model For Electrophilic Attack on Allylsilanes

Model assumes: 1. Electrophilic attack anti to the silyl moiety2. The silyl group is the "large" substituent

Electrophilic Attack on Allylsilanes

mCPBA

MeiPrPH

61 : 39>95 : 05 89 : 11

R Ratio

RatioR

58 : 42>95 : 05 91 : 09

MeiPrPH

AlMe3

OsO4

MeiPrPH

34 : 66 67 : 33 92 : 08

R Ratio

CH2I2

■ Epoxidation

■ Cyclopropanation

■ Osmylation

The products on the leftcorrespond to attack by Path A

■ Larger R groups result in higher selectivity

■ The size of R is more important in locking the substrate into the conformation leading to Path A than in shieldieng the El+

Fleming, JCS Perkin Trans I, 1992, 3303-3308.

El

C

R

SiR3R'

A

HR

PhMe2Si

MeR

SiR3

C H

H

C

El

CR'

H R

SiR3

CHA

R'

R

El

R R'

Me R

A

Me

PhMe2Si

C H

PhMe2Si

O O

PhMe2SiPhMe2Si

MeRMeRR

R

HR

SiR3

CH

Me

PhMe2Si

PhMe2Si

MeR

C A

R Me R Me

PhMe2Si

R'

PhMe2Si

OH

OH

OH

OH

A El A

A

R R'

SiR3

R'

07-Allylsilanes 3/19/02 2:01 PM

K. N. Houk, M. N. Paddon-Row, & Co-workers, Tetrahedron 1984, 40, 2257-2274.

Assume OH (OR') = Rm and results are consistent with the model

W. C. Still & J. C. Barrish, J. Am. Chem. Soc. 1983, 105, 2487.

BH3•THF

9–BBN

H2O2

OR'

OHOHOTMSOAcOH

nBuiPrnBunBunBu

92 : 08 96 : 04 91 : 09 88 : 12 42 : 58

SelectivityR

R2BH

M. M. Midland & Co-workers, J. Am. Chem. Soc. 1983, 105, 3725.

H2O2

R2BH

Dave Evans, Chem 115, Lecture 22, Dec 14, 1993

BH3

H2O2H2O2

■ A turnover in diastereofacial selectivity is sometimes observed using BH3

Favored product fordialkyl borane reagents

H2O2H2O2

R2BH

WorseBad

■ Hydroboration of allylic alcohols (ethers)

Selectivity

50 : 50 80 : 20 93 : 07 96 : 04

BH3•DMSThexylBH29–BBN(Chx)2BH

Diastereoselective Hydroboration Examples

A Model for Diastereoselective Hydroborations

OH

Me

RM

OH RL

R

OR'

RL

RM

Me

B

H

B

HHH

Me

RM

Me

C

H

RL

H

CMe

C

Me

OR'

RL R ROHRM

H

OR'

Me

OH

H

H

RL

RM H

CMe

C

C

B B H

H

H

Me

HRM

RL

RMRL

RM

Me

R RR R

Me

RM

RL RLOH

RM

Me

OH

H

H

H

CCH

H Me

H

RL

Me

H

H

MeMe

H

H

MeH H

OH

HMe

H

H

MeOH

08-Hydroboration Models 3/19/02 2:01 PM

I. Paterson & J. ChannonTetrahedron Lett., 1992, 33, 797-800.

BH3•THF unexpectedly provided theanti isomer in high selectivity

5

synanti

74%89%

yield

95 : 05>95 : 05

9-BBNBH3•THF

anti : syn

anti : syn

9-BBNBH3•THF

85 : 15 05 : 95

yield

70%84%

anti syn

80%99%

yield

82 : 1817 : 83

(Chx)2BHBH3•DMS

anti : syn

synanti

The sense of asymmetric induction is completely turnedover in Andy's reaction when using R2BH↔BH3

■ Erythronolide synthesis: Annette Kim

Diastereoselection 93 : 7

THF, 0 °C→rt 12 h

3 ThexylBH2

■ Lonomycin synthesis: Andy Ratz

Diastereoselective Hydroborations

BH3•DMS

(85%)

Diastereoselection > 95 : 5 (anti)

9-BBN

(60%)

Diastereoselection 92 : 8 (syn)

Nakata, Tatsuta & Co-workers, Bull. Chem. Soc. Jpn., 1992, 65, 2974.

Diastereoselective Hydroborations

BH3•THF

BH3•THF

Diastereoselection 92 : 8 (anti)

R = H Diastereoselection 6.8 : 1 (anti)Diastereoselection 6.6 : 1 (anti)R = OBn

K. MoriTetrahedron 1979, 32, 1979.

Oikawa & Co-workersTetrahedron Lett., 1983, 19, 1987.

■ Anti–selective hydroborations with borane

A 2:1 mixture of the lactol:lactone was obtained. This mixture wasoxidized to the keto-lactone in 73% overall yield from the olefin.

Me

OH

MeH

O

Me

Me

OMe

Me

OMe

Me

XP O OH

OH

OH

OBn

OH

Me OBn

OH

Me

O

Me

OH

XP

Me

OMe

Me

OMeMe

O

HMe

OH

Me

Me

OH

MeH

O

MeOMe

Me

OMe

Me

XP O

O

Et

OH

Me

O

Me

TBSO

Me Me

TBSO

Me

Me

Et

OHO O OH

Et

Me

O

Me

TBSO

Me

OH

OH

Me OBn

OH

Me

OH

OH

Me

OH

OBnMe

OBn

OH

OBn

MeMe

OH

OBnMe

OBn

OBn

OH

Me

OH OH OH

OHOHOH

Me

OH

OBn

OBn

Me OBn

OH

Me Me

OBn

OH

OBn

Me OBn

OH

Me

OH

Me

O

O

OO

MeMe

Me

Me O

BnO R

MeMe

OO

Me

RBnO

OH

OMe

Me

O

O

OH

09-Hydroboration-2 3/19/02 2:02 PM

RhLn

Rh cat

CB

Evans & Fu JOC 1990, 55, 2280 and Evans, Fu, Anderson JACS 1992, 114, 6679.

■ Olefin↔catalyst complexation is the stereochemistry-determining step

■ Olefin binding to metal is irreversible for 1,1-disubstituted allylic alcohol derivatives

Stereochemical Model

RhLn

The Catalyzed Hydroboration

■ Complexation involves back-donation from a filled metal d orbital→π*C=C

■ The EWG (alkoxy substituent) is aligned perpendicular to the olefin (π→σ*C—O)

■ This stereoelectronic interaction lowers the energy of π*

■ The small group is placed "inside", the most sterically congested site

CB

Rh cat

syn anti

antisyn

9-BBN

El+

9-BBN

El+

The uncatalyzed variant:Complementary diastereoselectivity for the catalyzed and

uncatalyzed reactions is observed for a wide range of substrates.

Anti Syn

9-BBN

9-BBN

9-BBN

75

72

67

Si(t-Bu)Me2

3 : 9795 : 5

95 : 5

96 : 4

R Conditions Anti : Syn

H50 : 50

15 : 85

68

65

77

Yield (%)

THF

20 °C

The Catalyzed vs Uncatalyzed Hydroboration Reactions

Rh(PPh3)3Cl / CB

Rh(PPh3)3Cl / CB

Rh(PPh3)3Cl / CBSi(t-Bu)Ph2

Evans, Fu, & Hoveyda JACS 1988, 110, 6917 and JACS 1992, 114, 6671.

K. Burgess & Co-workers, J. Org. Chem. 1991, 56, 1020-1027

i-Pr

Me

OR OR

Me

i-Pr i-Pr

R

HR'O

C MeCH

HR

Me

OR'

OR'

Me

R

Me

OR

OH

CH

HCMe

OH

HR'O

R

R

Me

OR'

OHOH

OH OH

OR'

Me

R

R'O

H R

CMe CH

H

R

Me

OR'

OR'

Me

RCH

HC Me

H R

OR'

10-Cat Hydroboration 3/19/02 2:02 PM

E. Vedejs & C. McClure JACS, 1986, 108, 1094.

synanti

synanti

Vedejs Model

OsO4

X = SR, SO2R, SiR3X = OTBS, OAC

OsO4

Kishi Model

OsO4

OsO4

34 : 6622 : 7833 : 6761 : 3962 : 38

selectivity

PhMe2SiPhSO2PhSTBSOAcO

X

(E) Olefins

(z) Olefins

(E) Olefins

(z) Olefins

■ Vedejs argues that hyperconjugative effects are not importantbecause both EDG and EWG provide the same sense of induction

■ Addition occurs anti to the allylic heteroatom functionality

X

PhMe2SiPhSO2PhSTBSOAcO

selectivity

78 : 2280 : 2083 : 1762 : 3870 : 30

OsO4

Diastereoselective Osmylations

James Barrow, Evans Group Seminar, "Osmium Mediated Dihydroxylation:Mechanism and Application" April 21, 1993.

Kishi & Co-workersTetrahedron Lett., 1983, 24, 3943 and Tetrahedron, 1984, 40, 2247.

Acetates give lower selectivity

■ Allylic oxygen protecting group: H, Bn, SiR3, acetonides→all work well

Works for both (Z) and (E) allylic ethers (alchols)OsO4 attacks anti to the allylic oxygen substituentArrange olefin in the stable ground state conformer

■ Kishi's Empirical Model:

OsO4

OsO4

OsO4

X

MeOBn

selectivity

60 : 4081 : 19

50 : 5086 : 14

selectivity

MeOBn

X

Diastereoselective Osmylations

OsO4

Me

OH

Me

X

OH

X Me

H

C HCH

BnO

OH

XR

OH

OH

BnO

BnO

CMe

HC

OH

RX

OH

H

Me

BnO

OH

XX

H

Me

OH

Me

Me

X

OH

OH

OH

Me

OH

Me

C(Me)H

(H)MeC H

HCH2OBn

OBn

X

Me

Me

Me

OH

Me

H

XX

OHMe

C HCMe

H

X

OH

Me

CMe

HCH

MeX

H

Me

11-Osmylations 3/19/02 2:02 PM

Houk, JACS, 1986, 108, 2754.

■ Oxygen avoids "outside" position to avoid repulsiveelectrostatic interactions with the incoming OsO4

anti

syn

OsO4

OsO4

"inside alkoxy"

Houk Model: Staggered transition states

Vedejs model breaks downor iPr, Ph > Me2PhSi

synanti

syn

OsO4

Fleming, JCS Perkin Trans I, 1992, 3303-3308.

RatioR

34 : 66 67 : 33 92 : 08

MeiPrPH

OsO4

Diastereoselective Osmylations

PhMe2Si

MeR R Me R Me

PhMe2Si PhMe2Si

OH

OH

OH

OH

H

PhMe2SiR

CH CH

Me

CMe

HCH

HXO

R

R

HXO

C HCH

Me

OH

OH

OH

OH

XO

XO

MeR

MeR

12-Osmylation 3/19/02 2:02 PM