catalytic enantioselective 1,2 additions-2012 pn - eth … · topic: catalytic enantioselective 1,2...

Update to 2012 Bode Research Group http://www.bode.ethz.ch/

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Topic: Catalytic Enantioselective 1,2 Additions

1 ENANTIOSELECTIVE KETONE REDUCTION 1.1 Catalytic asymmetric metal hydride reduction Corey developed the chiral oxazaborolidine catalysts, which are impressively effective in the reduction of a wide variety of aromatic, unsaturated, and cyclic ketones with high enantioselectivities. The catalysts can be used in reduction of a variety of functionalized ketones.

Corey ACIE 1998, 37, 1986

1.2 Catalytic asymmetric hydrogenation [RuCl2{P{C6H5)3}3] is a great catalyst for hydrogenation of terminal olefin but very inactive for reaction of carbonyl compounds. In the presence of 1 equivalent of ethylenediamine and 2 equivalents of KOH with respect to ruthenium, [RuCl2{P{C6H5)3}3] selectively hydrogenates carbonyls.

Noyori ACIE 2001, 40, 40 1.2.1 Hydrogenation of functionalized ketones BINAP-Ru-catalyzed hydrogenation of functionalized ketones -Chelation of Ru atom to carbonyl and/or heteroatom to form 5- or 6-membered ring is important in stereo-differentiation.

Noyori JACS 1988, 110, 629

OH

CH3BH3

O

CH3

99 %ee

N BO

Ph PhH

Me

OBr OHBr

BH3

N BO

Ph PhH

nBu

95 %ee

CH3Ar

O

BH3

N BO

Ph PhH

nBu CH3Ar

OH

O

c-hexH BH3

N BO

Ph PhH

CH2TMS

OH

c-hexH

98 %ee

97 %ee

O

4 atm H20.2% [RuCl2(P(C6H5)3)3]

6:1 (CH3)2CHOH/toluene28 °C

OH

Additive t [min] C=C:C=O

NH2(CH2)2NH2 + KOH(Ru:diamine:KOH = 1:1:2

150

10

250:1

1:1500

Aliphatic series Aromatic series

X

H

X

CH3

X = O, CH2KC=O/KC=C = 450

X = O, CH2KC=O/KC=C = 1500

R

O

C X

R

O

C CY

H2(S)-BINAP!Ru

H2(S)-BINAP!Ru

H2(R)-BINAP!Ru

H2(R)-BINAP!Ru

R

OH

C X

R

OH

C CY

R

OH

C X

R

OH

C CY

X, Y = carbonyl oxygen or heteroatom

PPh2

PPh2

RuX2


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Noyori JACS 2000, 122, 6510 Carbonyl selective hydrogenation of unsaturated aldehydes and ketones using RuCl2(phosphane)n-1,2-diamine-KOH

Noyori JACS 1995, 117, 10417 1.2.2 Hydrogenation of simple ketones

Zhang ACIE 1998, 37, 1100

1.3 Catalytic asymmetric transfer hydrogenation Hydride transfer from the H-donors can occur through two mechanisms: - Direct H-transfer (metal-templated concerted process) Metal acts as a template for the concerted shift of hydride from H-donor to acceptor.

Hydrogen donors

Gladiali Chem. Soc. Rev. 2006, 35, 226

NMe2

O

P

PRu

Ar2

Ar2

Cl

Cl NH2

H2N

i-PrH

OMe

OMe

Ar = 3,5-Me2C6H3

H2, 96%Substrate:catalyst = 10000:1

NMe2

OH

97.5% ee

NHMe•HCl

O

CF3

>99% ee(R)-Fluoxetine

P

PRu

Ph2

Ph2

Cl

Cl NH2

H2N

i-PrH

OMe

OMe

O1, KOH, H2

OH

99.6%, (90% ee)

O

Me

1, KOH, H2 OH

Me100%, (91% ee) 1

R R 11

OH2

[Rh(cod)Cl]2,PennPhos

2,6-lutidine, MeOH R R 11

OH(S) P

Me

MeP

Me

Me

PennPhos

Me Me

O

Me Me

O

Me Me

Me

O

Me

O

Me Me

O

Me

Me

48

75

94

106

96

96

66

99

90

51

75

85

84

92

94

ketone Time, h yield, % ee, % ketone Time, h yield, % ee, %

R R'

O+

H

O

MeMe

MLnO

H

O

LnM

RR'

MeMe

O

R HR'

MLn

+Me

O

Me

- Cyclic transition state- Typical of non-transition metals- Example: Meerwein-Ponndorf-Verley reaction

R1 R2

X+

Me Me

OH chiral cat.

R1 R2

XH+

Me Me

O

Isopropanol

- Reversible process- To shift the equilibrium toward product, IPA is usually used as solvent.

Formic acid and its salts

R1 R2

X+ HCOOH + NEt3

chiral cat.

R1 R2

XH+ CO2

- Irreversible process due to the release of CO2


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1.3.1 Reduction of simple ketones

Noyori JOC 2001, 66, 7931

1.3.2 Reduction of functionalized ketones

Ikariya Tetraheron 2004, 60, 7411

Noyori JACS 1997, 119, 8738

2 ENANTIOSELECTIVE C=O ADDITIONS -Nucleophilic addition of organometallic reagents to aldehydes and ketones is one of the most popular methods for construction of C-C bonds. -Development of enantioselective addition of organometallic reagents to carbonyls is attractive and immense research has been described. 2.1 Catalytic enantioselective C=O additions of dialkylzinc 2.1.1 Catalyzed by DIAB -Dialkylzinc addition to C=O is historically well known and is one of the most successful examples in enantioselective additions. -Noyori’s camphor-derived β-amino alcohol (−)-DIAB was the first chiral ligand that can mediate dialkylzinc addition to aldehyde in a highly catalytic enantioselective fashion.

Noyori JACS 1986, 108, 6071 and JACS 1995, 117, 4832 -The mechanism of diethylzinc addition has been studied extensively.

Ar R

O

RuN

NPh

Ph

Ts

HH

Cl

Rn

Ar R

OH

Me

OH

Me

H3CO

OHOH

>99 %yield98 %ee

>99% yield97 %ee

>99 % yield91 %ee

HCOOH-(C2H5)3N

Ar

OY

NH2

RhNPh

Ph

Ts

Cl

HCO2H - N(C2H5)3Ar

YOH

Y

ClOCH3NO2OHCN

%yield

9992939395

%ee

9694959798

R1

O

R2R1

OH

R2NH2

RhNPh

Ph

Ts

Cl

MeMe

Me

IPA

R1

PhPhPhn-Bu

R2

MeiPr

c-HexMe

%yield

>9998>9970

%ee

97999898

O

H Et2Zn

Me

NMe2OH

Me Me

(!)-DIAB, 2 mol %

98%

OHMe

99% eeMechanism of catalyic process:

Me

NMe2

OH

ZnEt2

Me

Me2N

OZnEt ZnEt2

Me

Me2N

OZnEt

ZnEtEt

H

O

Me

Me2N

OZn

ZnEtEt

Et HO

Me

Me2N

OZn

Et

ZnO

EtEtMe

Me2N

OZn

Et

ZnO

EtEt

OEt

ZnEt

n


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-Noyori proposed that the active species is the monomeric zinc complex rather than its dimeric complex. -Positive nonlinear effect was observed in these reactions.

2.1.2 Catalyzed by Ti-TADDOL -Ti-TADDOL is a great catalyst for dialkylzinc addition to aldehyde, and very high ees were obtained. -Not many dialkylzinc reagents are commercially available. Seebach developed a method that can generate dialkylzinc (other than diethylzinc) in situ from the corresponding Grignard reagent.

Seebach ACIE 1991, 30, 1008 2.1.3 Catalyzed by C2-Symmetric disulfonamide and Ti(Oi-Pr)4 The combination of C2-Symmetric disulfonamide and Ti(Oi-Pr)4 gives very reactive catalyst that can facilitates the addition of higher organozinc homologues to aldehydes.

Ohno Tetrahedron 1992, 48, 5691 2.2 Enantioselective Grignard additions -Grignard addition to carbonyls is one of the most reliable methods of forming C-C bonds. Grignard reagents are, however, so reactive that their fast background reaction via uncatalyzed pathway would greatly diminish the enantioselectivity. Grignard reagent has been considered unsuitable for asymmetric alkylation. 2.2.1 Chiral ligands used in enantioselective Grignard additions There are a wide variety of chiral ligands that have been used to induce enantioselectivity. Only a few papers report high enantioselectivities and also these methods require non-ideal conditions such as very low temperature (<-100 °C) and stoichiometric quantity of chiral ligands.

Luderer Tetrahedron: Asymmetry 2009, 20, 981; Seebach Tetrahedron 1994, 50, 6117 2.2.2 Catalytic enantioselective alkylation of aldehydes with Grignard reagent -So far there’s no catalytic enantioselective Grignard addition. -Harada’s organotitanate derived from Grignard reagent, DPP-binol and Ti(OiPr)4 adds to aldehydes catalytically and enantioselectively (an indirect way of doing catalytic enantioselective Grignard addition). -This system works very well with aromatic aldehydes, alkyl- and aryl- Grignards. -The titanate is generated at -78 °C by adding Grignard reagent to Ti(OiPr)4.

2 RCH2MgX ZnCl2 (RCH2)2Zn MgX2

OO

MgX2• OO

precipitate, filtered out

H

O OTi

O

O

OO

O O

OPhPh

Ph PhPh Ph

Ph Ph

0.15 eq cat1.2 eq Ti(OCHMe2)4

Me

OH

69%95% ee cat

OTIPS

i) Et2BHii) Et2Zn

OTIPSZn

2

NHSO2CF3

NHSO2CF3

Ti(Oi-Pr)4PhCHO

77% OTIPS

OH

Ph>96% ee

RMgXR1

O

Hor

R2

O

R1

chiraladditive* OH

R1R R

HO

R2

R1

Me

MeO OMe

Me(Cohen, Wright 1953)

O

O

OMgX

O

O

(Inch 1969)

NN

OR

OR(Seebach 1969)

NN

(Nozaki 1971)

N N

LiO(Mukaiyama 1979)

NNPh

PhPh

Ph

(Tomioka 1987)

O

OMg

(Noyori 1988)

O

O

Me

Me

Ar

OHAr

Ar

OHAr

Ar = Ph, 2-naphth(Seebach 1994)


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Harada ACIE 2008, 47, 1088; CEJ 2008, 14, 10560; Bull. Chem. Soc. Jpn. 2010, 83, 19

-Da reported a similar indirect way of doing catalytic enantioselective Grignard addition. -Catalytic asymmetric addition was achieved by deactivating Grignard reagents through chelation with bis[2-(N,N-dimethylamino)ethyl]ether (BDMAEE). -In this carbonyl addition reaction, MgBr2 and MgBr(OiPr) are formed. These Lewis acids promote the background reaction to form the racemic product and thus lower the enantioselectivity of the process. Addition and chelation of DBMAEE to the in situ generated MgBr2 and MgBr(OiPr) suppress their activity and so the asymmetric catalytic additions can be highly enantioselective. -The catalytically active specie is also a titanate. -Reaction can be run at room temperature.

Da OL 2009, 11, 5578 2.3 Catalytic enantioselective alkyne addition

2.3.1 Boron alkynilide addition to aldehydes -Corey’s boryl acetylides gives good yields and enantioselectivities.

Corey JACS 1994, 116, 3151 2.3.2 Alkylzinc-mediated enantioselective alkynylation of aldehyde

H

O

[nBuMgCl + Ti(OiPr)4]

DPP-binol (2 mol %),Ti(OiPr)4 (1.4 eq),CH2Cl2, 0 °C, 3 h

OH

90% (96% ee)

Ph

PhOHOH

DPP-binol

RMgX + Ti(OiPr)4 ! R"Ti(OiPr)4•MgXTitanate

R2

O

HR1MgBr

(S)-BINOL, Ti(OiPr)4,

THF/TBME R1

OH

R2

R1 R2 yield, % ee, %

2-MeO-C6H4

1-naphth

thiophene-2

cyclohexyl

Ph

iBu

iBu

iBuiBu

n-pentyl

86

93

35

27

53

97

98

94

98

90

4-MeO-C6H4 Me2C=CHCH2CH2 50 92

NO

NBDMAEE

NBr

Mg

O

Br

N NBr

Mg

O

OiPr

N

Ph SnBu3

Me2BBr, !78 °Ctoluene Ph BMe2

NH

BO

n-Bu

Ph

Ph1)

2) O

OH

Ph

90% (96% ee)

Mechanism:

NB

O

n-Bu

Ph Ph

R2

Me2B

H R1

O

HN B

O

H

R

HR2

B R1

O

H

MeMe

NB

O

n-Bu

Ph Ph

H

Me2BO

R2H

R1

++

O

HR1

R2

Me2Zn (3 eq),(S, S) 1 (10 mol %),Toluene, 4 °C

OH

Me

N

OHPhPh

N

HO PhPh

(S, S)-1

R1

OH

R2

R1 = NO2, H, C4H4(2-binaphth), furyl, OCH3

R2 = Ph, TMS, -CH2OCH3, -CO2Et

O

H CO2Me

Me2Zn (3 eq),(S, S) 1 (10 mol %),Toluene, 4 °C

Ph

OH

CO2MePh

92% (95% ee)

(68-99% ee)

!-hydroxy-",#-acetylenic esters areextremely versatile synthetic intermediates


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-Many amino alcohol-zinc complexes have shown the activity for catalyzed alkynylation of aldehydes. -Trost’s ProPhenol catalyst is commercially available, which works well with aromatic and α,β-unsaturated aldehydes with high yields and ees.

Trost JACS 2006, 128, 8 2.3.3 Titanium-catalyzed zinc acetylide addition to aldehydes -Pu found that BINOL and Ti(O-iPr)4 catalyzed alkynylzinc addition to aldehydes. -High temperature was required in the first step and caused decomposition of some functional alkynes. -Subsequent reports showed that addition of HMPA allows the reaction to run at r.t. and tolerates more functional groups. -High yields and ees were obtained with aromatic, aliphatic and α,β-unsaturated aldehydes.

Pu Adv. Synth. Catal. 2009, 351, 963; PNAS 2004, 101, 5417; OL 2002, 4, 4143 2.3.4 Metal-catalyzed addition of terminal acetylenes to aldehydes -Additions of in situ generated metal alkynilide to aldehyde were achieved with catalytic amount of metal salt.

Carreira JACS 2001, 123, 9687

Shibasaki JACS 2005, 127, 13760

2.4 Catalytic enantioselective allylations 2.4.1 Diasteroselectivity of allylating reagents

Carreira C5.3, 5.6, 5.8

2.4.2 Catalytic enantioselective addition of allylic silanes and stannanes These allylations are most efficiently achieved by the combination of Lewis acid and allyl trialkylsilanes and trialkylstannanes (type II allylating agents). 2.4.2.1 Chiral acyloxy borane (CAB)-catalyzed Yamamoto achieved the first example of chiral Lewis acid-catalyzed enantioselective allylation of aldehydes in 1991 using CAB catalysts.

Ph1. Et2Zn (1.2 eq), toluene refulx2. Ti(O-i-Pr)4 (1.5 eq) OH

OH(S)-BINOL (20 mol %)O

Ph HDCM, 4 h, r.t.

(2,2 eq)Ph

Ph

OH

77% (96% ee)

R1 H

O+ H R2

Zn(OTf)2 (20 mol%)Et3N (50 mol%)

ligand (22 mol%)toluene, 60 ˚C R1

OH

R2(R1 : aliphatic) yield upto 91%

upto 99% eeHO

Ph Me

NMe2

R1 H

O+ H R2

InBr3 (10 mol%)(R)-BINOL (10 mol%)Cy2NMe (50 mol%)

CH2Cl2 (2.0 M), 40 ˚C R1

OH

R2(R1 : aliphatic, aromatic) yield upto 95%

upto 99% ee

type

I

II

III

M

-SiR3 or SnR3

Cr, Ti, or Zr

product

anti from (E)syn from (Z)

stereospecific additionthrough 6-membered TS

anti

open TS

rapid isomerization of allylic reagents

MMeR H

OR

OH

MeR

OH

Me

syn

synanti

+ +

-B(OR)2

SiMe3R1R2

R H

O cat. (20 mol %),EtCN, !78 °C

R

OH

R1

R2

R

H

O

H

R1

R2

TMSCAB

R

H

O

R1

H

R2 CAB

TMS

<anti syn


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Yamamoto Synlett 1991, 561; JACS 1993, 115 11490 2.4.2.2 Titanium/BINOL-catalyzed -Titanium/BINOL-catalyzed allylation is one of the most extensively studied chiral Lewis acid-catalyzed allylations.

Tagliavini/Umani-Ranchi JACS 1993, 34, 7001; Keck JACS 1993, 34, 8467 BINOL/Ti(IV) catalysts are relatively weak Lewis acids, and not very effective to promote reaction with allylic

silanes, which are less nucleophilic and toxic. Carreira found that reactivity is enhanced when using TiF4 in place of Ti(O-iPr)4.

Carreira ACIE 1996, 35, 2363; JOC 2001, 66, 6410 2.4.3 Catalytic enantioselective allylboration -Allylboration has the advantages that the reaction is stereospecific and highly diasterospecific. -If Lewis acid can catalyze allylboration without interfering the chair-like 6-membered cyclic transition state, the reaction would allow a catalytic, enantioselective, regiospecific and diastereospecific approach to chiral homoallylic alcohol. Chiral diol- SnCl4 Catalyzed

Hall JACS 2008, 130, 8481

OO

BHO

O

OOi-Pr

Oi-Pr COOH

OO

BO

O

OOi-Pr

Oi-Pr COOH CF3

CF31 2 H Me Ph 2 99 88

55461PhHHH Me Ph 1 68 82

8695/5361C3H7EtMeMe Et Ph 1 74 97/3 96

ee, %syn/antiyield, %cat.RR2R1

!

!

!

SnBu3R

O

H

(S)-BINOL (20 mol %),TiCl2(O-i-Pr)2 (20 mol %)

CH2Cl2, 4! MS R

OH

SnBu3R

O

H

(R)-BINOL (20 mol %),Ti(O-i-Pr)4 (10 mol %)

CH2Cl2, 4! MS R

OH

(a)

(b)

R cat. temptime,

hyield,

%ee, %

PhPh(E)-PhCH=CH(E)-PhCH=CHc-C6H11c-C6H11

ababab

rtrtrtrt

0 °C"20 °C

48324432446

9685

777559

85

828989859383

H O Ar

O O

Me Me

SiMe3

(S)-BINOL (10 mol %),TiF4 (5 mol %)

97%O Ar

OOH

MeMe91% ee

OMe

S

NMe

O

O

O

R

MeMe

OHMe

OHMe

R = H, Epotilone AR = Me, Epotilone B

BO

OR1

HO OHR R

(R,R)-Vivol (5 mol %)SnCl4 (5 mol%)

R = cyclooctyl

Na2CO3 (0.2 eq),toluene, !78 °C

6-8 h

R

OH R1

R

O

H

R1 aldehyde yield, % ee, %

O

HH

TBSO

O

H

H3CH

O

H

OF3C

CF3

H

O

TBDPSO

O

H

H

H

H

H

CH3

99

98

90

99

99

99

95

95

95

94

71

92

R1 aldehyde yield, % ee, %


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Chiral Bronsted acid-catalyzed

Antilla JACS 2010, 132, 11884 First catalytic enantioselective allylboration and crotylation of ketones

Shibasaki JACS 2004, 126, 8911 2.4.4 Catalytic enantioselective allylation with allylic halides -In situ generation of allylic organometallic reagents from allylhalides and metals is synthetically advantageous because it does not require the preparation, isolation and handling of toxic or sensitive reagents. -Chromium catalyzed enantioselective addition of allylic halide to aldehydes using chiral salen ligand gives high ees for aromatic and aliphatic aldehydes.

Umani-Ronchi ACIE 1999, 38, 3357; Pure App. Chem. 2001, 73, 325 2.4.5 Catalytic enantioselective transfer hydrogenative allylation and crotylation -Krische reported allylation and crotylation under hydrogenative condition, where non-activated substrates such as allylic acetate and butadiene were utilized as nucleophiles.

Krische JACS 2008, 130, 14891; Org. Process Res. Dev. 2011, 15, 1236

BO

OR

OH

R

O

H

(R)-TRIP-PA (5 mol %)toluene, -30 °C

R yield, % ee, %

Ph

4-NO2C6H4

4-MeOC6H4

PhCH3

BnOCH2

c-C6H11

99

98

95

93

92

98

98

98

98

93

79

73

OP

O O

OH

i-Pr i-Pr

i-Pr

i-Pr

i-Pr i-Pr(R)-TRIP-PA

OB O

OH

R H

P

O

OO

O

*

++

Proposed TS

R

O

R' B O

O

CuF2•2H2O (3 mol %)(R,R)-iPr-DuPHOS (6 mol %)

La(OiPr)3 (4.5 mol %)

DMF, !40 °C, 1 hR

R'

OH

substrate yield, % ee, %

CH3

O

H3C

CH3

O

89

87

84

90

P

P

iPr

iPr

iPr

iPr

DuPHOS

substrate yield, % ee, %

CH3H3C

CH3

O

H3C

CH3

OH3C

H3C

99

98

91

84

ClR H

O

N

t-Bu OH

t-Bu

N

t-BuHO

t-BuCrCl3 (10 mol %), Mn, TMSCl, CH3CN

(10 mol %)

1)

2) HCl, THF R

OH

R yield, % ee

Ph

c-C6H11

PhCH2CH2

67

42

45

84

90

77

OH

+ AcO

[Ir(cod)Cl]2 (2.5 mol%)(R)-Cl,MeO-BIPHEP (5 mol%)

Cs2CO3 (20 mol%)m-NO2BzOH (10 mol%)

THF, 100 ˚CPh

OH

Phy. 72%91% ee

MeOMeO

Cl

Cl

PPh2PPh2

[Ir3+]

OH

R

[O]

O

R

[Ir3+]

OH

Rredox neutral process


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Krische Science 2012, 336, 324

3 ENANTIOSELECTIVE ALDOL REACTIONS 3.1 Types of aldol reactions

3.2 Mukaiyama aldol reaction 3.2.1 Background and mechanism The crossed aldol reaction between a silyl enolate and a carbonyl compound in the presence of Lewis acid is referred to as a Mukaiyama aldol reaction.

Mukaiyama Chem. Lett. 1973, 1011

Mechanism: - Diastereoselection. - Stereochemical outcome is explained by open-transition model, based on steric- and dipolar effects.

Ph

OH+

RuH2(CO)(PPh3)3 (5 mol%)dppf (5 mol%)

chiral acid (10 mol%)THF, 95 ˚C Ph

OH

y. 86%dr. 8:1 (anti:syn)90% ee (major)

Me4( equiv)

Me

Me Me

MeOO P O

OH

R1

O

Me

O

R2

+R1

O OH

R2

Methyl Ketone Aldol

R1

O O

R2

+R1

O OH

R2

Ethyl Ketone Aldol

Me Me

R1O

O

Me

O

R2

+R1O

O OH

R2

Acetate Aldol

Propionate Aldol

H

H R1

O OH

R2Me

syn anti

R1O

O O

R2

+R1O

O OH

R2Me Me

H R1O

O OH

R2Me

syn anti

++

H

OSiCl3

Ph H

OO

Ph

OH

+

O

Ph

OH1. TiCl4 RT

2. H2O 63% 19%

OSiCl3

Ph H

OO

Ph

OH

+

O

Ph

OH1. TiCl4 RT

2. H2O 63% 19%

R1 H

OMX4

R1 H

O MX3 O

R3

Me3Si

R2

X

R1 R3

O O

R2

X3M

R1

OH

R2

O

R3

X Me3SiX

H2O

R1

O

HR2 H

TMSO R3

H O

R1R2 H

TMSO R3O

H

R1LALAHR2

TMSO R3

R1

O

HH R2

R3 OTMSH O

R1H R2

R3 OTMSO

H

R1LALAR2H

R3 OTMS

LA

LA

A B C

D E F

anti

syn

When R2 is small and R3 is large.transition state A is most favored and leads to anti-diastereomer.

When R2 is large and R3 is small.transition state D is most favored and leads to syn-diastereomer.


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Mahrwald Chem. Rev. 1999, 99, 1095-1120

3.2.2 Challenges to metal-catalyzed enantioselective Mukaiyama aldol Reaction - Background achiral silicon-catalyzed aldol addition

Carreira TL 1994, 35, 4323; Bosnich JACS 1995, 117, 4570

- Anti vs Syn (in aldol reaction with substituted silyl enolates)

3.2.3 Historic enantioselective Mukaiyama aldol addition The first enantioselective catalytic Mukaiyama aldol addition

Mukaiyama, Kobayashi Chem. Lett. 1990, 129, 1455

3.2.4 Silyl ketene acetals, thioester-derived silyl ketene acetals as nucleophiles 3.2.4.1 Syn - Chiral (acyloxy)borane (CAB) complexes of tartrate-derived ligands by Yamamoto

Yamamoto Synlett 1991, 439

With an aldehyde capable of chelating to a Lewis acid, there is a reversal of the normal high anti-selectivity - syn-selectivity- was observed.

H

OR2 H

TMSO R3

LAOBn

H

OH R2

R3 OTMS

LAOBn

syn (favored) anti

Chiral Metal-Catalyzed

R

O

H

M*Xn

R

O

H

M*XnOSiR3

OEt R!!

OM*Xn

OEt

OSiR3

MXn R!!

OSiR3

OEt

O

R3SiX

R

O

OEt

OR3Si

Achiral Silicon-Catalyzed

R

O

H

R3SiX

R

O

H

SiR3 OSiR3

OEt R

OR3Si

OEt

OSiR3

X X

Rac

R3SiX

Rac

R!!

O

OEt

OMXn-1

R

O

H EtS

OTMS

Me

Sn(OTf)2 + NMe

10-20 mol%

C2H5CN, -78 oC EtS

O

RMe

OH

R

PhTol

CrotylOctylc-Hex

Yield

7775768071

syn : anti

93 : 789 : 1196 : 4

100 : 0100 : 0

ee

909193

>98>98

HN

N NMe OSn

O

R

HOTfTf

!,"-unsaturated aldehydes reveal excellent diastereo- and enantioselectivities due to the π- π interactions. Reaction with aliphatic aldehyde resulted in slight reduction of optical and chemical yields.

R1

OR2

OSiMe3+ R

O

H R

OH

R1

COOR2

OPri

OPri

O

OO B

O

CO2H O

H20 mol%

H

O

RH R1

Me3SiO OR2

B*Ln

H

O

RR1 H

Me3SiO OR2

B*Ln

<

anti syn

OB

OO

OHO2C

O

O

H

i-PrO

i-PrO

yield (%)

835797

d.r

79:2165:3596:4

% ee

928897

R1

Me

R2

Ph

R

Phn-propyl

n-pent-1-enyl


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3.2.4.2 Anti - Chiral BINOL and Zr(IV) complexes by Kobayashi

Kobayashi JACS 2000, 122, 5403; JACS 2002, 124, 3292

3.2.4.3 Acetate Mukaiyama aldol addition Like chiral auxiliaries, metal catalysts have also had difficulties in obtaining high enantioselectivity in acetate aldol additions (acetate derived nucleophiles). - Chiral oxazaborolidine complex generated from Cα-alkylated α-amino acids by Masamune

Masamune JACS 1991, 113, 9365

- BINOL and Ti(IV) complexes by Keck and Mikami

BINOL/TiClx(OTf)y catalyzes acetate aldol addition with excellent yields and enantioselectivity. Broad scope of aldehydes including simple aldehydes and functionalized aldehydes such as trifluoroacetadehyde, chloroacetaldehyde, benzyloxyacetaldehyde, ethyl glycolate…

Mikami JACS 1993, 115, 7039, JACS 1994, 116, 4077; Synlett 1995, 1057

Ph H

O

OPh

OTMS Ph OPh

OOH

Me

O

I

O

I

ZrOt-Bu

Ot-Bu

10 mol%

n-PrOH, H2O

dr = 95:5 99 %eeMe

OPh

OTMS

Me

dr = 93:7 98 %ee

R1

O

HR2

R3 OTMS

LA

R1

O

HTMSO R3

LAR2

< R1 R3

OOH

R2 Syn-adduct

R1

O

HR2

R3 OTMS

LA

R1

O

HTMSO R3

LAR2

< R1 R3

OOH

R2 Anti-adduct

The asymmetric environment around zirconium center iscrowded with the bulky iodine on BINOL -> interaction between alkyl group of aldehyde and LA becomes more severe.

Me

iPr

NHSO2Ar

CO2H

BH3•THF

Me

iPr OB

NTs

O

HMe H

O

Me

iPr OB

NTs

O

H

OTMS

St-Bu

Me

MeOTMS

OPh

Me St-Bu

OOH

Me OPh

OOH

Me Me

92 %ee

>98 %ee!, !'-disubstituted glycine

20 mol%

BnOH

O

St-Bu

OTMS+

St-BuBnO

OTMSO

96 %ee

> 98%ee

(R)-BINOL/TiCl2(Oi-Pr)25-20 mol%

(S)-BINOL/Ti(Oi-Pr)420 mol%

F3C H

O

St-Bu

OTMS+

ClH

O

St-Bu

OTMS+

(S)-BINOL/TiCl2(Oi-Pr)25 mol%

(R)-BINOL/TiCl2(Oi-Pr)25-20 mol%

F3C St-Bu

OTMSO

St-BuCl

OTMSO

96% ee

91 %ee


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- Complex of Ti(IV), tridentate Schiff base and di tert-butylsalicylic acid by Carreira


Carreira, Kvaerno Classics in stereoselective synthesis p.133-134 - Complex of chiral Cu(II)-Pyridine Bis(Oxazoline) (PyBOX) complex by Evans

Evans JACS 2000, 122, 10033; ACIE 1997, 36, 2744

3.2.4.4 Ketones as electrophiles - Evans developed a family of chiral BOX complexs with different metals as catalysts for enantioselective Mukaiyama aldol reactions. Bidentate chelation leads to the formation of a square pyramidal complex and the re aldehyde enantioface is shielded -> High level of diastereoselectivity and enantioselectivity. The requirement of chelation limits the scope of electrophiles (α-alkoxyacetaldehydes, pyruvates, glycolates, α-diketones, 5-formyloxazoles). Chiral Cu(II)/tert-Bu-BOX complex

Evans JACS 1997, 119, 7893

Chiral Sn(II)/Ph-PyBOX complex

Ph H

O

OMe

OTMS+ Ph

OH

OMe

O

OTi

NO

t-Bu

t-Bu

OO

O

2 mol%

then TBAF98 %ee

The carboxylate in the catalyst structure traps the electrophilic silyl group after the addition of the enoxy silane to aldehyde,thus precluding any silyl-catalyzed background reactions.The silyl carboxylate is then activated towards intramolecular silyl transfer.

t-Bu

Br

OMe

O

R

OTi OO

OSiR3

Si-trap

OMe

O

R

OSiR3

Ti OOO

Si-shuttleL3 L3

OMe

O

R

OSiR3 TiL3O

O

O

+

A

St-Bu

OTMS

H

OOBn +

NO

N N

O

Cu

Ph Ph

2+

2 SbF6

0.5 mol%

t-BuS

OOBn

OHO

O

AcO

Me OH

Me

OAcMe

O

O

OMeO

HO

O

MeOH

HOHO

HO

Me

OHHO

O

O

Spongistatin 299 %ee

MeOMe

O

O MeSt-Bu

OTMS

+

NCu

N

O OMe Me

t-Bu t-Bu

2+

2OTf-

10 mol% MeOSt-Bu

O

O

OHMe

Me

d.r = 94:6 96 %ee

N NO O

MeMe

CuO OMe OMe

t-Bu

H

H

t-Bu

Nu (si face)


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Evans JACS 1997, 119, 10859

- Complex of Cu(I)fluoride and chiral Taniaphos ligand by Shibasaki Examples of effective catalyzed enantioselective aldol reactions with simple ketone acceptors are scarce due to the attenuated reactivity of ketones and reversibity of their aldol addition. Stereocontrol is also challenging.

Shibasaki JACS 2006, 128, 7164

3.2.5 Silyl enol ethers as nucleophiles 3.2.5.1 Syn - Chiral (acyloxy)borane (CAB) complex of tartrate-derived ligands by Yamamoto.

Yamamoto JACS 1991, 113, 1041

- BINOL and Ti(IV) complexes by Keck and Mikami

Mikami JACS 1993, 115, 7039

Broad scope of enolates (esters, thio-esters, ketone-derived enolates) 3.2.5.2 Anti Enantioselective aldol addition of enolates to aldehyde catalyzed by BINAP/Silver(I) complex by Yamamoto

O

MeOO

MeMe

St-Bu

OTMS

NO

N N

O

SnTfO OTf

Ph Ph10 mol% MeO

St-Bu

O

Me

MeHO

O

dr = 99:1 99 %ee yield = 94 %

Me

O

OMe

OTMS

Me+

HO Me

OMe

O

Me

CuF(PPh3)3•2EtOH (2.5 mol%)ligand 4 mol%

FePCy2

Cy2P

Bu2N

liganddr = 86:14 94 %ee

OPri

OPri

O

OO B

O

CO2H O

H20 mol%Ph H

O

MeEt

OTMS

Et

OTMSMe

Ph Et

OH

Me

O

dr = 94:6 96 %ee

dr = 93:7 94 %ee

OSiMe3Me

H CO2Me

O

OO

TiCl

Cl

5 mol%

CH2Cl2, 0 oC

Me

OSiMe3Me

Me

MeO

CO2MeMe

OH58 %

54%

d.r 98:2 99 %ee

d.r 98:2 99 %ee

OHOH

(R)-BINOL

OSi(OMe)3

+Ph H

O (R)-BINAP, AgOTf, KF, 18-crown-6O

Ph

OH

PAr2PAr2

(R)-BINAPt-BuO

OSi(OMe)3Me +

Ph H

O (R)-BINAP, AgOTf, KF, 18-crown-6t-BuO Ph

O

Me

OH


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Yamamoto JOC 2003, 68, 5593

3.2.5.3 Methyl ketone Mukaiyama aldol aditions - Another class of amino acid derived N-sulfonamide oxazaborolidines by Corey. Effective catalyst with a variety of aldehydes. The existence of hydrogen bonding between the catalyst and aldehyde contributes much to the significant facial differentiation.

Corey TL 1992, 33, 6907

3.2.6 Dienolates as nucleophiles Additions of dienolates to aldehydes lead to 4-carbon subunits in one step, which facilitates the synthesis of polyketides. - Complex of Ti(IV), tridentate Schiff base and di tert-butylsalicylic acid as catalyst


Synthesis of Macrolactin A Carreira ACIE 1998, 37, 1261 - Bisphosphine Cu(I) complex

Carreira JACS 1998, 120, 837; ACIE 1998, 37, 3124

Synthesis of Leucascandrolide Carreira JOC 2003, 68, 9274 3.3 Lewis bases on trichlorosilyl enol ethers A metal-enolate is activated by a chiral Lewis base. This activated complex is much more reactive than the free enolate species. Association and activation of the aldehyde allows for a closed transition state. Enolate geometry is transferred directly to the diastereoselectivity of the products.

AgOO

HR3

H

R1 Si(OMe)3F

PP *

R2 AgOO

HR3

R1

H Si(OMe)3F

PP *

R2

anti synE Z

Ph H

O

n-Bu

OTMS NH

N BO

Ts n-Bu

O

20 mol %Ph n-Bu

OOH

90 %ee yield = 100%

HN

NB

O SO

O

O MeOH

R

hydrogen bonding

facial blocking

+

H

OTi

NO

t-Bu

t-Bu

OO

O

2 mol%

t-Bu

Br

A

Ph H

O O O+

OTMS

MeMe

then TFAO

O OMeMe

OH

Ph 99 %ee

Me H

O O O

OTMS

MeMe

+O O

O

MeMe

Me

OHO O

Me

OMe

O

O

NOHN

OMeO

Me

Me

O

O

Leucascandrolide A

(R)-Tol-BINAPCu(OTf)2

then TFA91 %ee


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.

. 3.3.1 Methyl ketone derived trichlorosilyl enol ethers

Denmark JACS, 2000, 122, 8837

3.3.2 Ethyl ketone derived trichlorosilyl enol ethers

Denmark JOC, 2003, 68, 5045

3.4 Direct catalytic enantioselective aldol reactions These involve the in situ generation of enolates (donor) in the presence of an aldehyde (acceptor), circumventing the use of preformed enolates and decreasing wastes. 3.4.1 Ito’s Au(I) catalyst First example of a direct asymmetric catalysis by Ito and coworkers. Gold(I) catalyzed the reaction between α-cyanoacetate and an aldehyde to yield trans oxazolines. These lead trans products and do not have great scope beyond the use of α-cyanoacetate.

Ito JACS, 1986, 108, 6405

3.4.2 Lanthanum and barium binols as bifunctional catalysts (dual activation of donor and acceptor) These catalysts serve as both lewis (lanthanum or barium) acid and bronsted base catalysts (lithium binaphthoxides or binols). Proceed with exogenous base.

**

O**

OXnM Lewis Base

Promoter O MXn

O MXnLB

O

RO M

Xn

LB

**

O MXnLB

**O

R

O

R

R

More reactivethan freeenolate

Closed6-membered

TS

Rapid Turnover

HH

OSiCl3

Me

O

Ph+

NP

NMe

Me

O

N

10 mol %

CH2Cl2then

sat. NaHCO3Me

O OH

Ph92% yield84% ee

H

OSiCl3

Me

O

Ph+

NP

NMe

Me

Me

Me

O

N

10 mol %

CH2Cl2 O OH

Ph

77% yield11.5:1 syn/anti94% ee for syn

Me Me MeH

O

MeO CN +O

R O N

PhO

OMe

PAu

PFe

PhPh

PhPh

LL

MeMeN N O

CH2Cl286-97% yield

R=alkyl, alkenyl, aryltrans:cis= 54:46-93:7

81-94% ee

H


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Shibasaki’s first catalysts were barium- and lanthanide-based and could provide moderate to high ees for methyl ketones. Reaction times were long and large excess of ketone was necessary.

Shibasaki TL, 1998, 39, 5561; ACIE, 2003, 36, 1871

Lanthanum provides moderate anti and syn selectivity complimentary to enamine catalysis (favors anti adducts)

Shibasaki JACS, 2001, 123, 2466

3.4.3 Dinuclear zinc prophenols as bifunctional catalyst

Trost JACS, 2001, 123, 3367

3.5 Chiral amine-based catalyst Early 1970s, Hajos-Parrish-Eder-Sauer-Wiechert reaction

O**

OR1

R2

ALO

OMH

O

HOR1

R2

OMH

OLA

R2O

R2O

OMH

OLA

R1

HOOM

H

OLA

R2

**

O

OH

R1

O

Ph Me

O

R+

OO Ba O

O

X

X

DME, -20oC

X=Binol-Me

=(R)BaB-M

5 mol%

O

Ph

OH

RR=alkyl, phenyl

50-70% ee

77-99%

O

Ph Me

O

R+

O

Ph

OH

RR=alkyl, phenyl

52-91% ee

43-90%3-12 days

OO Ln

OO

O OLi

LiLi = (R)LLB

20 mol%

HH

O

Ph

O

R+

O

Ph

OH

R

R=alkyl, phenyl2:1-5:1 anti:syn90-95% ee anti

78-92%OH Me

10 mol% (R)LLB9% KHMDS

20 mol% H2O-50oC

2 equiv

H

MeMe

ON NZnZn

OO PhPh

PhPh

Et

O

Me

O

R+

O

Ph

OH

R

R=alkyl, phenyl4:1-100:0 syn:anti

86-98% ee

65-97%48 h1.5 equiv

4 A MS, THF, -55--35oCOH

MeMe

ON NZnZn

OO PhPh

PhPh

O O

Ar HR

O

OHH


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Eder ACIE 1971, 83, 496; Hajos JOC 1974, 39, 1615

Pioneering findings by List, Barbas III: Proline-catalyzed enantioselective intermolecular aldol addition

Barbas III JACS 2000, 122, 2395

3.5.1 Mechanism of proline-catalyzed aldol addition Different proposed mechanisms and models for transition state

Discussion on mechanism: Houk ACIE 2004, 43, 5766 List PNAS 2004, 101, 5839 Blackmond BMCL 2009, 19, 3934 Trost Chem. Soc. Rev. 2010, 39, 1600

Limitations of Proline-catalyzed aldol addition - Relatively large amount of proline (20-30mol%) - Large amount of ketones - Low enantioselectivity with aromatic aldehydes

3.6 Progress 3.6.1 Aldehyde as electrophiles

H3C

O O

O

Me NH

CO2H3 mol%

DMF, 20hO

OMe

OH

H3C

OMe

O NH

CO2H3 mol%

DMF, 72h

Me

OH

O

O

93 %ee 74 %eeHajos-Parish Ender-Sauer-Wiechert

H3C CH3

O

H R

O NH

CO2H30 mol%

DMSO H3C R

O OH+

% yield

6268945497

%ee

6076697796

R

phenylp-nitrophenylo-chlorophenyl

naphthylisopropyl

H3C

O O

O

Me

O

OMe

OHn n

-H2O

O

OMe

n

H3C CH3

O

H R

O

H3C R

O OH+

(S)-Proline

(S)-Proline

O

R1

O

R3 (S)-ProlineHO R3O

R1

R2 R2

H3C CH3

O

H

O

CH3

CH3

20 mol%

(L)-Proline10-20 mol%

H3C

O OH

CH3

CH3

34 %yield 73 %ee

1. TBSCl, imidazole

2. KHMDS

Cl NTfTf

OTf OTBS

CH3

CH3

OTBS

CH3

CH3

SnBu3Pd(PPh3)4

TBAF, THFOH

CH3

CH3(S)-Ipsenol

+

List OL 2001, 3, 573

H3COH

O

+ H R

O (L)-Proline20 mol%

H3C R

O

OH

OH

anti

R

c-hexylisopropylphenyl

naphthyl

% yield

60628362

dr

>20:1>20:1

1:13:1

%ee

>99>998079

NO H

O OHR

HHO H N

O HO O

HHO H

HR

anti syn(favored)

Barbas III JACS 2001, 123, 5260


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3.6.2 Cross-aldol reactions of aldehyde

MacMillan ACIE 2008, 47, 3568

3.6.3 Activated ketone electrophiles

Zhao TL 2006, 47, 3383; Jorgensen Chem. Comm. 2002, 620 4 ENANTIOSELECTIVE C=N ADDITIONS 4.1 Comparision of C=O and C=N bonds

4.2 Enantioselective Mannich reactions 4.2.1 Silyl ketene acetals and thio-derived silyl ketene acetals - The first catalytic enantioselective Mannich reations was reported by Kobayashi in 1997 - This system is restricted to imines with N-aryl and a chelating group for two-point binding to the catalyst.

H

O

OTIPS

NH

CO2H

H

O

OTIPSOTIPS

OH

DMF, 40h, 5 oC

O

TIPSOCH3

O

HO

H3C

OMe

Cl3C NH

H

O

CH3

+ H

O

CH3

NH

CO2H

H

O

MeMe

OH1.10 mol%

DMF, 40h, 5 oCOPMB OPMB

dr 12:1 48 %yeildFelkin:anti Felkin >19:199 %ee

O

OTBSCh3

OMeHHO

H3C CO2MeB

CB

O

O

H3CCl

MeO

H3C

H3C

H OH

O O

OHH3C OH

CH3

MeO

O

B

C

callipeltoside C

EtO2C

O

H3C CH3

O

NO2

+NH

CO2HCH3

OEtO2C OH

O2N

79 % yield 75 %ee

EtO2C CO2Et

O

+ H

O

CH3aldehyde donor

NH

CO2H

EtO2C H

O

CH3

OHEtO2C90 % yield90 %ee

ketone donor

R H (R')

O

R H (R')

NR''

C=X bond energy(kcal/mol)

173-181 143

Polarization ! +0.51 +0.33

- Reduced electrophilicity of the C=N bond

- Tendency of enolization to form enamine rather than 1,2-addition

Ph H

N

HO

OTMS

SEt

OO

ZrOO

Br

Br

Br

Br5-10 mol%

NMI 5-30 mol%, DCM Ph SEt

ONH

OH

78 %yield 88 %ee


19

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wor

k is

lice

nsed

und

er a

Cre

ativ

e C

omm

ons

Attr

ibut

ion-

Non

Com

mer

cial

-Sha

reA

like

4.0

Inte

rnat

iona

l Lic

ense

.

Kobayashi JACS 1997,119, 2060

- Jacobsen developed chiral ureas and thioureas functioning as chiral hydrogen-bond donors.

Jacobsen JACS 2002, 124, 12964

The catalysts can tolerate the Lewis basic substrates like heteroaromatic aldimines. - Chiral Bronsted acid: BINOL-derived phosphoric acids as catalysts

Akiyama ACIE 2004, 43, 1566

Terada JACS 2004, 43, 1566; TL 2007, 48, 497

4.2.2 Silyl enol ethers - BINAP derived metal complex of transition metals – Ag(I), Cu(I), Pd(II), Ni(II)

OZr

N

HPh

O

O

OO

*

*

H

OZr

N

Ph

O

O

O*

*

H

TMSOCOSEt

ZrOO

OO* *

SEt

OTMS

OH

N

Ph SEt

OSiR3

OH

NH

Ph SEt

O

HO

N

HR1

Catalytic cycle

N

NBoc

HOi -Pr

OTBDMSt-Bu t-Bu

HO

N

NH

NH

SN

BnO

Me t-Bu

5 mol%

i-PrO N

O NBoc

99 %yield 98 %ee

Ph H

N

HO

+Me

OEt

OTMS

PhCO2Et

HN

Me

HO

87:13 dr 96 %ee

OO

POOH

10 mol%

NO2

NO2

4-(!-Naphth)-C6H4

OO

4-(!-Naphth)-C6H4

POOH

2 mol%Br

H

NBoc

+Me Me

O O

Br

Ac

Ac

NHBoc

96 %yield 98 %ee

PO

O

O

O

HR

R

O

N

Ph

O


20

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und

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Cre

ativ

e C

omm

ons

Attr

ibut

ion-

Non

Com

mer

cial

-Sha

reA

like

4.0

Inte

rnat

iona

l Lic

ense

.

Lecka JACS 1998, 120, 4548; JOC 1998, 63, 6090

- Chiral binuclear cationic Pd(II) complex

Sodeoka JACS 1998, 120, 2474

- Chiral phosphine Ag(I) complex

Snapper&Hoveyda JACS 2004, 126, 3734

4.2.3 Direct catalytic enantioselective Mannich reactions - Direct Mannich reactions have been explored with both metal catalysts and organocatalysts more intensively than aldol variants possibly due to the lack of retro reactions, which are normally problematic in aldol reaction. - List succeeded in using acetaldehyde as nucleophiles in direct Mannich reactions.

List Nature 2008, 452, 453

4.3 Enantioselective Strecker reactions - Jacobsen reported one of the first catalytic, asymmetric variants of Strecker reaction, using chiral urea as a catalyst. The hydrogen bonding between imine and catalyst is responsible for the induction of chirality.

OEt

ON

Ts

Ph

OTMS

PP

MLn

ArAr

ArAr

2-10 mol%

THF or DCM-80 oC - 0 oC OEt

OHN

Ts

Ph

O

MLn

AgSbF6Pd(ClO4)2CuClO4

Ni(SbF6)2

%yield

95919189

%ee

90809896

OEt

ON

Ts

Ph

OTMS

PP

CuClO4

ArAr

ArAr

2-10 mol%

THF or DCM-80 oC - 0 oC OEt

OHN

Ts

Ph

O

Me Me

86 %yield 98%ee dr 25:1

Highly anti diastereoselectivity regardless of the geometry of enol silanes

NM

O

EtO H

TsP P

*

Bidentate chelation

Ph

OTMS

iPrO2C

NPMP

P

PPd

Ar Ar

Ar Ar

O

OPd

P

P

ArAr

ArAr 2 BF4-

Ph

O

CO2iPr

NHPMP

5 mol %

DMF 95 % yield 90 %ee

PdP P

*

N O

CO2iPr

PMP

Ph

MeO

H2N+ RCHO + Me

OTMS

PPh2

NHN

OOMe

Me Et

1 (5 mol %)AgOAc (5 mol%)

1R Me

OArHN R

n-C10H21Cyi-Bu

%yield

605341

%ee

929494

Enantioselective synthesis of (-) Sedamine

MeO

H2N+

+Ph

OTMS

MeO

OCHO

5 mol% 15 mol% AgOAc

MeO

O Ph

OArHN

>98 %ee

PhI(OAc)2, HOAC, MeOH;10 % HCl; 20% aq. Na2S2O3;Na2CO3, DCM NMe

Ph

O

O 1. DIBAL-H; LAH2. CH2O, MeCNNaCNBH3, AcOH NMe

Ph

OH

(-) Sedamine 40 % overall yield

Me H

O+

Ph H

N Boc

MeCN, 0 ˚C

(S)-proline (20 mol%)

Ph

HNBoc

H

O

y. 54%>98% ee


21

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ativ

e C

omm

ons

Attr

ibut

ion-

Non

Com

mer

cial

-Sha

reA

like

4.0

Inte

rnat

iona

l Lic

ense

.

Jacobsen OL 2000, 6I, 867; JACS 2002, 124, 10012; Nature 2009, 461, 968

- Peptidic Schiff base ligand and Ti(IV) complexes

Hoveyda JACS 2001, 123, 11594

- Lanthanide based catalysts

Shibasaki TL 2004, 45, 3147

4.4 Catalytic enantioselective additions of other nucleophiles - The first catalytic enantioselective alkyl zinc addition to C=N using chiral amidophosphine Cu(II) complex

Tomioka JACS 2000, 122, 12055

A range of aromatic N-sulfonylaldimines participated in the addition and products were obtained in high ees. - Chiral Rh(II) diene complexes for arylation of N-sulfonylimines

Hayashi JACS 2004, 135, 13584

R CH3

N+ HCN R Me

CNBnHNBn

BnHN N

HNHO

O

N

tBu

HO

tBu OCOtBu

R

Php-NO2Php-CH3OPh

tBu

% yield

97quant

9898

%ee

90938870

BnHN N

HNHO

O

N

tBu

HO

tBu OCOtBuR Me

NBn

Cl

N

Ph PhCl

ClOH

NHN

ONHBu

O

OtBu10 mol%

10 mol% Ti(Oi-Pr)4, 2 equiv TMSCN2 equiv i-PrPH, PhMe

Cl

HN

Ph Ph

CNH

85 %yield >99 %ee

O

NHN

OH

H

ONH

O

Cl

ClTi

O O

N Ar

HH

C N H

N

N

Me

PO

PhPh

+ TMSCN Me

N

HNNCPO

PhPh

Me

N

NHBocMeO2C

F

FHO

OHO

PPh

OPh

Gd(OiPr)3 10 mol%

DMP 10 mol%

DMP=2,6-dimethylphenol

i) conc. HClii) MeOH, SOCl2iii) Boc2O

84 %yield 99 %ee

ON

H

SO2Me

+ Et2Zn

NPPh2

PhPh

t-Bu O 1.3 mol%

Cu(OTf)2 (1 mol%)O

HN

Et

SO2Me

93 %ee

H

NS

O

O

Me

+ (PhBO)3

Ph

Ph (3 mol%)

[RhCl(C2H4)2]2 (3 mol%)KOH / H2O, 60 oC

HNS

O

O

Me

96 %yield 98%eeCl Cl

catalytic enantioselective 1,2 additions-2012 pn - eth … · topic: catalytic enantioselective 1,2...

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