Chemistry of the Double BondChemistry of the Double Bond1. Reactions of the Carbonyl Group1.1 At Carbonyl1.1.1 Reduction (hydride addition)1.1.2 Alkylation1.1.3 Allylation/Propargylation1.2 At αααα-Center (Enolate Chemistry)1.2.1 Alkylation1.2.2 Aldol Reaction1.3 At ββββ-Carbon of Enone1.3.1 Michael (1,4-) Addition2. Reactions of Olefins2.1 Oxidation2.1.1 Epoxidation2.1.2 Dihydroxylation2.1.3 Aminohydroxylation2.2 Reduction

Creation ofCreation of StereocentersStereocenters

Y

X R1R2

Y

XR1

R2

sp2 sp3

prochiral sp 2 center

mirrorXR1

R2

Enantiofacial differentiation

Ph Me

O

Me Ph

O

si re

Hanson J. Am. Chem. Soc. 1966, 88, 2731.Tetrahedron 1974, 30, 3649.

Carbonyl Group Addition ReactionsCarbonyl Group Addition Reactions

O

A B

OH

A BH

OH

A BR

Reduction

H-

R-

C-C bond formation

Difference between A and B determines A.I.If steric, useful only if difference large:

Electronic effects may play a significant role- these are not yet fully understood!

R

RR

R

R

RCH3 H> > > > >

Addition to Carbonyl GroupAddition to Carbonyl Group

OSM

L

OL S

ML

OM

S

Cram Karabatsos Felkin-Anh

All give the same result!Karabatsos and Felkin-Anh consistent with ground state or TS arguments.

R CHO

MeR

MeNu

OH

Nu-

Chemistry of the carbonyl group:Chemistry of the carbonyl group:BürgiBürgi--Dunitz angleDunitz angle

Nu

C OMe

Me C OMe

Me

ππππ∗∗∗∗ C=OππππC=O

107°

Nu

Electrostaticrepulsion

between thenucleophile

and the carbonyl filled ππππ orbital....

...causes the nucleophile to

attack at obtuseangle — theBürgi-Dunitz

angle!

Chemistry of the carbonyl group:Chemistry of the carbonyl group:reactivity boosted by Lewis acidsreactivity boosted by Lewis acids

Nu Nu

C OMe

Me C OMe

Me

BF

F FππππC=O

Electrostatic repulsion between the nucleophile and the carbonyl filled ππππ

orbital....

... is eased if the oxygen can donate electrons to a

powerful electrophile — i.e., a strong Lewis acid

sp2 oxygentwo lone pairs

ππππC=O

Lewis acidBF3

Hydride Reducing AgentsHydride Reducing Agents1 2 3 4 5 6 7 8 9 10

AldehydeKetoneAcid chlorideLactone Complete reduction in 1 hEpoxideEster Reduction takes place in inert solventAcidAcid salt Only partial reduction in 1 htert-AmideNitrile Insignificant reduciton in 1 hNitroOlefin

1 NaBH4 in EtOH2 Li(t-BuO)3AlH3 LiBH44 Al(BH4)35 B2H66 Sia2BH in THF7 9-BBN in THF8 AlH3 in THF9 Li(MeO)3AlH in THF

10 LiAlH4 in THF

Brown, H.C. Chem. Engng. News March 5, 1979, 24.

EnantioselectiveEnantioselective Reduction Reduction -- ReviewsReviewsAsymmetric Synthesis, vol. 2 (Morrison, J.D., Ed.)

Chapter 2Reductions with Chiral Boron Reducing Agents

M.M. Midland

Chapter 3Reductions with Chiral Modifications of Lithium Aluminium Hydride

E.R. Grandbois, S.I. Howard and J.D. Morrison

Chapter 4Reductions with Chiral Dihydropyridine Reagents

Y. Inouye, J. Oda and N. Baba

A Critical Examination of the Relative Effectiveness of Various Reducing Agents for the Asymmetric Reduction of Different Classes of Ketones

H.C. Brown et al. J. Org. Chem. 1987, 52, 5406.

Asymmetric Reductions with Organoborane ReagentsM.M. Midland Chem. Rev. 1989, 89, 1553.

EnantioselectiveEnantioselective Reductions Reductions -- DarvonDarvon

O

O

O

H

H

HOOLiAlH4, Darvon

> 95 % yield> 98 %ee Asteriscanolide

P.A. Wender J. Am. Chem. Soc. 1988, 110, 5904.

NMe2OH

Ph

PhDarvon

Cohen JOC 1980, 45, 582.

EnantioselectiveEnantioselective Reductions Reductions -- DarvonDarvon

NMe2OH

Ph

PhDarvon

Cohen JOC 1980, 45, 582.

1) LiAlH4, Darvon

quant yield> 98 %ee

O

OSiR3

BMPO

OSiR3 O

O

O

O H2) NaH, PMBBr

(+)-Sterepolide

B.M. Trost Angew. Chem., Int. Ed. Engl. 1989, 28, 1502.

Hydride Reduction Hydride Reduction -- Chiral AuxiliariesChiral Auxiliaries

B B B

Alpine boraneM.M. Midland

JOC 1984, 49, 1316.

Eapine boraneH.C. Brown

JOC 1990, 55, 6328.

Prapine boraneH.C.Brown

JOC 1990, 55,6328.

BH

Eapine hydrideH.C. Brown

THAS 1990, 1, 433.

BH

OBn

Li NB-EnantrideM.M. Midland

JOC 1991, 56, 1068.

Li Li

BCl

2

H.C. BrownJOC 1985, 50, 5446.JOC 1986, 51, 3394.

BH

S. MasamuneJACS 1986, 108, 7402, 7404.

H2NPh

OH

Ph

S. ItsunoJOC 1984, 49, 555.

OAl

O

OEt

H

R. NoyoriJACS 1984, 106, 6709.

Ph NH

O2S

NH

Ph

K.B. SharplessJOC 1984, 49, 3861.

NH OH

PhPh

E.J. CoreyJACS 1987, 109, 7925.

NH

H

HHO Ph

E.J. CoreyTHL 1989, 30, 5547.

NH HN

T. MukaiyamaChem. Lett. 1984, 2071.

Catalytic CBS ReductionCatalytic CBS Reduction

O

OCO2Et

OH

OCO2Et

N BO

Me

PhPhH

94 % yield93 %ee

OOH

OHOAc

O

OH

H

25 mol-%65 mol-% BH3

.THF

Forskolin

Corey, E.J.; da Silva Jardine, P. Tetrahedron Lett. 1989, 30, 7297.

Catalytic CBS ReductionCatalytic CBS Reduction

Corey, E.J.; da Silva Jardine, P. Tetrahedron Lett. 1989, 30, 7297.

N BO

Me

PhPhH

99 % yield94 %ee

10 mol-%60 mol-% BH3

.THF

Cl

O

Cl

OH

NH

O

CF3

Me

.HCl

Fluoxetine hydrochlorideProzac (Eli Lilly)

Catalytic CBS ReductionCatalytic CBS Reduction

O

RL RS

OH

RL RS

BH3.THF 60 mol-%

10 mol-% cat (R=H,Me)

O

R H R H

OHD2H-catecholborane

150 mol-%

30 mol-% cat (R=Bu)

-126 ºC, 3.5 h12 examples

82.2-97.8 %ee 6 examples82-95 %ee

N BO

H NpNp

R

Np = β-naphthyl

Catalyst

Corey, E.J.; Link, J.O. Tetrahedron Lett. 1989, 30, 6275.

Oxazaborolidine Oxazaborolidine Reduction: Reduction: RationalizationRationalization

N BO

PhPhH

H

N BO

PhPhH

HBH3

N BO

PhPhH

OH2B

RL

RSH

N BO

PhPhH

OH2B

RL

RSH

H

HOBLn

RL

RSHH2O

BH3.THF

BH3.THF

OH

RL

RSH

Asymmetric Reduction: BINALAsymmetric Reduction: BINAL--HH

O

OAl

OEt

H O

OAl

OEt

HLi Li

(S)- BINAL-H (R)- BINAL-H

X

O

X

OHBrI(n-Bu)3Sn

>95>95>90

969798

% yield % eeX300 mol-% (S)-BINAL-H

THF

X R

O

X R

OH

(S)-BINAL-H

THF

c-C6H11c-C6H11CH2n-BuC(Me)2CH2

969495

% eeR

50-76 % yield

Asymmetric Reduction: BINALAsymmetric Reduction: BINAL--HH

O

OAl

OEt

H O

OAl

OEt

HLi Li

(S)- BINAL-H (R)- BINAL-H

O OH

300 mol-% (S)-BINAL-H

THF

100 mol-% (S)-BINAL-H

THF

65 % yield94 %ee

87 % yield, 84 % ee(with methoxy-BINAL-H)

O

O

O

HO

BINALBINAL--H: Transition State H: Transition State ModelModel

O

OAl

OEt

H O

OAl

OEt

HLi Li

(S)- BINAL-H (R)- BINAL-H

Al

OLi

O

H

H

AlO

Li

O

O

O

R'

RR

O

O

R' R

RS

S

favored unfavored because ofbinaphthyl/R' repulsion

H

BINALBINAL--H: H: Enantioface Enantioface DifferentiationDifferentiation

O

OAl

OEt

H O

OAl

OEt

HLi Li

(S)- BINAL-H (R)- BINAL-H

favored unfavored

Al

OLi

OH

R

Un

R'

O

O

Al

OLi

OH

Un

R

R'

O

Oπ

S R

Effect of Methyl Group on the Effect of Methyl Group on the Enantioselectivity in BINALEnantioselectivity in BINAL--H ReductionH Reduction

R

O

O

R

O

R

O

R

R

OH

OH

R

OH

R

OH

RR

S

S

S

(S)-BINAL-H

(S)-BINAL-H

(S)-BINAL-H

(S)-BINAL-H

Me n-alkyl

95 %ee 98-100 %ee

79 91

84 90

R in 24 %ee!!!

R

Noyori, R.; Tomino, I.; Yamada, M.; Nishizawa, M. J. Am. Chem. Soc. 1984, 106, 6717.

Kinetic Discrimination in BINALKinetic Discrimination in BINAL--H H Reduction of a Prostaglandin Reduction of a Prostaglandin

Intermediate Intermediate

CO2Me

O

TBSO TBSO

CO2Me

HO

TBSO TBSO

BINAL-H

rel rate 9α:9β

(R)-BINAL-H >130 99:1(S)-BINAL-H 1 95:5

9

Suzuki, M.; Yanagisawa, A.; Noyori, R. J. Am. Chem. Soc. 1988, 110, 4718.

INTERNAL AIINTERNAL AI

O

CO2Me

OHPh

O

CO2MePh

OB

H

OAcAcO

CO2Me

OHPh

OH

Turnbull, M.D. et al. Tetrahedron Lett. 1984, 25, 5449.

Chelation controls selectivity

(Saksena, A.K.; Mangiaracina, P. Tetrahedron Lett. 1983, 24, 273.)

StereocontrolledStereocontrolled ReductionReduction

PMBOOH

OAc

OPMBPMBO O

PMBOOH

OAc

OPMBPMBO OH

NaBH(OAc)3

HOAc, MeCN, rt

Saksena Tetrahedron Lett. 1983, 24, 273.Turnbull Tetrahedron Lett. 1984, 25, 5449.

Evans, D.A. J. Am. Chem. Soc. 1988, 110, 3560.Prestwich J. Am. Chem. Soc. 1991, 113, 9885.

PMBOPMBO

OOAc

OB

HOAcAcO

OBMP

INTERNAL AIINTERNAL AI

Evans, D.A. et al J. Org. Chem. 1991, 56, 761.

H B OMeOOC R

OAc

AcO

O

O B OMeOOC R

Et

Et

H-

axial attack

via

diastereoselection 12:1

diastereoselection 9:1

82 %

Et2BOMe, NaBH4

82 %

Me4NHB(OAc)3

O OHMe

MeOOTIPS

OH

O OHMe

MeOOTIPS

OH

O O OHMe

MeOOTIPS

StereoselectiveStereoselective ReductionReduction

Kishi, Y. J. Am. Chem. Soc. 1991, 113, 9693.

O

O O

H

Ph

O

OMe

HO

O O

H

Ph

OH

OMe

HO

O O

H

Ph

OH

OMe

H

NaBH4 0 1

LiAlH4

L-selectride

BH3.THF

ZhBH4)2

NaBH3CN

NaBH3CN/CeCl3

NaBH(OAc)3/CeCl3

0

0

0

1

1

1

1

1

1NaBH4/CeCl3

1

3

3

5

2

1

12

OO

O OMe

PhO

BINAPBINAP--RuRu Ketone ReductionKetone Reduction

R C

OY

R C

OHY

R C

OHY

(R)-BINAP-Ru

H2, X=Cl, Br, I

(S)-BINAP-Ru

H2, X=Cl, Br, I

R C

OC

R C

OHC

R C

OHC

(R)-BINAP-Ru

H2, X=Cl, Br, I

(S)-BINAP-Ru

H2, X=Cl, Br, I

Y Y

Y = heteroatom, C = sp2 or achiral sp3 carbon

Y

NMe2

O O

SEt

O O

R R

O O

O OH

OHO

RNMe2

O

O Br

O CO2H

96 %ee

93 %ee

94-100 %ee

98 %ee

92 %ee

93-96 %ee

92 %ee

92 %ee

Representative ketones

Noyori R, Chem. Soc. Rev. 1989, 18, 187.

Catalytic Asymmetric Catalytic Asymmetric ReductionReduction

O OH

98.2 %

O OH

30 g19.7 mg catalyst1.2 mg en4 mg KOH4 atm H2200 mL iPrOH

29.4 g

NH2

NH2Asymmetric version:

BINAP and 70 - 98 %eeRuCl2.(PPh3)3 catalyst to substrate ratio:1: 5000

Catalytic Asymmetric Catalytic Asymmetric ReductionReduction

2.2 mg cat

H2 (45 atm)iPrOH, 30 oC, 48h100% conversion

80 %ee

cat=

O OH

PP

RuNH2

H2NCl

Cl

Ph

Ph

Tol2

Tol2

Noyori, R. Angew. Chem,., Int. Ed. Engl. 1988, 37, 1703.

TON > 1,000,000similar catalyst, 99 %ee, TON > 100,000

Carbonyl Reduction ReactionsCarbonyl Reduction Reactions

nC5H11

O

nC5H11

OH

nC5H11

OHO

nC5H11

O

Alpine borane

NH2 NH-K+

KAPA

1) n-BuLi

2) CO23) H2 - Lindlar

Midland, M.M. Tetrahedron Lett. 1984, 40, 1371.

Carbonyl Reduction ReactionsCarbonyl Reduction Reactions

OH

HO2C

OMeN

OMeO

Me OMe

O

OMe

OH

OMeMO

PhOMeM

OPh

via

1) MeO(Me)NH.HCl Et3N, pyBOP 81%2) MeI, Ag2O 88 %

MeC=CLi

89%

K-selectride -100 ºC 72 %

D'Aniello, F.; Mann, A.; Taddei, M. J. Org. Chem. 1996, 61, 4870-1.Takahashi, T. et al. Tetrahedron Lett. 1985, 26, 4463, 5139.

Carbonyl addition reactionsCarbonyl addition reactions

O O

O

R*O

O

OHMeHO

O

OHMeMeMgI

Et2O/PhH

86 %

KOH

Atrolactic acid69 % ee

OPh

O

OR

OPh

OR

HO R'

R'MgBr

90-98 % ee

Dauben, W.G.; Prelog, V. Helv. Chim. Acta 1953, 36, 325.

Whitesell, J.K. Chem. Commun. 1982, 888.Chem. Commun. 1983, 802.

Carbonyl Addition ReactionsCarbonyl Addition Reactions

H

O

Li SiMe3

NMe

N

HOOH

SiMe3-123 oC

92 %ee

Mukaiyama, T. J. Am. Chem. Soc. 1979, 101, 1455.

Asymmetric CarbonylAsymmetric CarbonylAlkylationAlkylation

RCHO + Et2ZnR Me

OH

RCHO cat yield (%) config (% ee)

123233223

-9790

1004790857882

R (86)R (98)S (92)R (92)S (82)S (94)R (99)R (99)S (75)

Ph

Ph(CH2CH2)

4-MeOC6H4PHCH=CHC5H11C6H13

NB

OMe

H

NH

TfTf

HN

OHHN

NMe

H

Brown, H.C.Tetrahedron Lett. 1989, 30, 5551.

Ohno, M.Tetrahedron Lett. 1989, 30, 7095.

Tanaka, K.Chem. Commun. 1989, 1700.

AlkylationAlkylation ((PhCHO PhCHO + Et+ Et22Zn)Zn)

NB

OMe

H

NH

TfTf

HN

OHHN

NMe

H

Brown, H.C.Tetrahedron Lett. 1989, 30, 5551.

95 % ee (R)

Ohno, M.Tetrahedron Lett. 1989, 30, 7095.

98 % ee (S)

Tanaka, K.Tetrahedron Lett. 1989, 30, 1700.

92 % ee (R)

OHHN

Tanaka, K.Tetrahedron Lett. 1989, 30, 1700.

97 % ee (R)

Noyori, R.J. Am. Chem. Soc. 1989, 111, 4028.

99 % ee (S)

Ph

Ph

OHNMe2

NMeH

Tanaka, K.Tetrahedron Lett. 1989, 30, 1700.

88 % ee (S)

OHHN

Tanaka, K.Tetrahedron Lett. 1989, 30, 1700.

93 % ee (R)

NMe

Corey, E.J.Tetrahedron Lett. 1987, 28, 5233.

95 % ee (S)

MeN Me

HO Ph

NMe OH

PhPh

Soai, K.J. Am. Chem. Soc. 1987, 109, 7111.

99 % ee (S)

OH

HN

Allylation (PhCHO)Allylation (PhCHO)

Ph

NBr

N

Ph Ph

SO2TolTolO2SO

OB O

NB

SO2Me

OB

OPriO2C

PriO2CB

B

TMS

B2

CoreyJACS 1989, 111, 5459.

94 %ee (R)

Hoffmann, R.W.Ber 1981, 114, 375.

Reetz, M.Chem. & Ind. 1988, 663.

Roush, W.R.JACS 1985, 107, 8786.

87 %ee (S)

Masamune, S.JOC 1987, 52, 4831.

88 %ee (S)

Masamune, S.JACS 1989, 111, 1892.

96 %ee

Brown, H.C.JACS 1983, 105, 2092.

94 %ee

Reagent Control in Double Reagent Control in Double StereodifferentiationStereodifferentiation

S,S-reagent

R,R-reagent

Allyl-MgCl

99.5 %0.5 %

1.9 %98.1 %

44.9 %55.1 %

Reagent

R,R-reagent

+

TiO

O

OO

PhPh

PhPh

ON

BOC

OH

ON

BOC

OH

ON

BOC

H

O

Duthaler, R.O. et al. J. Am. Chem. Soc. 1992, 114, 2321.