topic: enantioselective aldol reactions 1 ......effective only for chelating aldehydes. the second...

Update to 2011 Bode Research Group http://www.bode.ethz.ch/

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TOPIC: ENANTIOSELECTIVE ALDOL REACTIONS

1 INTRODUCTION Formation of a new C-C bond with the possibility of forming two new stereocentersà 4 diastereomers. First described in 1848 by Kane and in 1872 Charles-Adolphe Wurtz would go on to describe such products as maintaining the properties of alcohol and aldehyde.

1.1 Types of Enolates Aldols

1.2 Acid and Base Catalysis

1.3 Stereocontrol Elements - Relative configuration: Configuration of the product is determined by enolate configuration. High diastereoselectivity has been achieved through ordered 6-membered transition states.

- Absolute configuration – is controlled by chirality within molecule from: (a) Removable chiral auxiliaries (b) Chiral enolates (c) Chiral catalysts (chiral ligand + metal) (d) Chiral amine catalysis

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

O

R CH3

H+ O

R CH3

H-H+ OH

R CH2

O

R CH3

HO

R

H

CH3ROH

O

R

CH3ROH

-H+

Acid Catalyzed Aldol

O

R CH3-H+ OH

R CH2

O

R CH3O

R

CH3RO

O

R

CH3ROH

Base Catalyzed Aldol

O

HR1

OM

R3R2

O

R3R1

OH

R2

orO

R3R1

OH

R2

Syn Anti

R2

OMetal

R3H

O OMH

R3R2H

R1 R1

OM

R3

O

R2

R1CHO

R1CHOO OMH

R3R2R1

H R1

OM

R3

O

R2

Favored

(E)

H

OMetal

R3R2

O OMR2

R3HH

R1 R1

OM

R3

O

R2

R1CHO

R1CHOO OMR2

R3HR1

H R1

OM

R3

O

R2

Favored

(Z)

Anti Syn

O

HR1

OM

R3

O

R3R1

OHor

O

R3R1

OH


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2 CHIRAL AUXILIARIES 2.1 Diastereoselective Control Syn Evans’ Oxazolidinones: Highly selective towards Z enolates. High diastereoselectivity to yield a single Syn product. Sterics often dominate the most preferred transition state.

Evans, JACS 1981, 103, 2127

Effective only for chelating aldehydes. The second equivalent of titanium is necessary for the diastereoselective control. Chelation overrides steric control, but less as chelating group is further away from carbonyl.

Ghosh, TL ,1997, 38, 7171

2.2 Diastereoselective Control Anti Anti diastereoselectivity is achieved for the aryl sulfonamide indanyls when using one equivalent of titatanium.

Ghosh, TL ,1997, 38, 7171

Evans found that the generation of magnesium enolates with the oxazolidinone auxiliaries would give anti adducts. A closed TS that does not follow the Zimmerman Traxler model is thought to be prevalent. TMSCl does not catalyze the reaction but quenches the aldol adduct.

Evans, JACS , 2002, 124, 394

O N

O O

Me

MeMe

O N

O O

Me

MeMe

OH

RO

BOH

RMe

BuBu

N

O

OMe

Me

n-Bu2BOTf, i-Pr2NEt O N

O OBBu2

MeMe

Me RCHO

>98:2 drR=alkyl, phenyl

Oxazoldinones

75-95% yield

LiOOH

O

Me

OH

RHO

Me(OMe)NHMe3Al

O

Me

OH

RNMe

MeO

O

O

R

NHSp-Tol

OO TiCl4 (2 equiv),

i-Pr2NEt

O

OTiCl3

R

NHSp-Tol

OO

OCl3Ti O

ROTiCl2N

S OO

Me

OBn

BnO(CH2)nCHO

O

O

R

NHSp-Tol

OO

OHOBn

94:6-99-1 drR=alkyl, phenyl

1-3

Aryl Sulfonamide Indanyls

Proposed TS

51-84% yield

O

O

R

NHSp-Tol

OO TiCl4 (1 equiv),

i-Pr2NEt

O

OTiCl3

R

NHSp-Tol

OO

OCl3Ti O

ROTiCl2N

S O

O

Me

R1

O

O

R

NHSp-Tol

OO

OHOBn

99:1 drR=alkyl, phenyll

1-3

83-92% yieldi-BuCHO

Proposed TS

NO

O

Bn

O

Me+ RCHO

MgCl2 (10 mol%)Et3N, TMSCl,

ETOAc71-92%

NO

O

Bn

O

Me

OH

R

7:1-32:1 drR=alkyl, aryl


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2.3 Asymmetric Propionate Aldols Syn With the use of 2 equivalents of titanium, a non-Evans is achieved. The second equivalent of titanium is thought to abstract a chloride that allows chelation to the thiazolidinethione.

Crimmins JACS, 1997, 119, 7883

2.4 Asymmetric Propionate Aldols Anti Norephedrines as auxiliaries- E-enolates are selectively formed and yield the anti products via six-membered TS.

Abiko JOC, 2002, 67, 5250

A chelating substituent on the enolate provides a different mechanistic pathway for the thiazolidinethiones. Z enolate is formed but the anti product is obtained with the use of two equivalents of titanium.

Crimmins OL, 2003, 5, 591

2.5 Asymmetric Acetate Aldols Asymmetric control with acetates is more challenging than with propionates. Increased bulk of thiazolidinethione auxiliary allows for moderate to high diastereoselectivity. This is not possible with Evans’ oxazoldinone auxiliaries.

Phillips OL, 2002, 4, 2253

O N

S O

MeBn

O N

S O

MeBn

OH

RTiCl4 (2 equiv) i-Pr2NEt

RCHO


70-91% yield

TiCl4 (1 equiv) Sparteine O N

S O

MeBn

OH

R

OTiO

H

RMe

N

O


75-95% yield

ClCl

Cl

NN

H

H

S Bn

Ti O

RCHO

N

O

S Bn

R Me

H

non- Evan's Syn

Evan's Syn= Sparteine

ClCl

O

ON SO2MesBn

MePh

Me

1. c-Hex2BOTf (2 equiv), Et3N, -78 oC

2. RCHO

O

ON SO2MesBn

MePh

Me

OH

R

>90% yield>95:5 dr

R=alkyl, alkenyl, phenyl

H

R

ONO

STi

OO

HTi

Bn

O N

S O

Bn

1. TiCl4 (1 equiv) Sparteine

O N

S O

OBn

OH

R

87:13 drR=alkyl

61-84%yield

2. RCHO

O N

S O

Me O N

S O OH

R

1. TiCl4 (1 equiv) (-)-sparteine, NMP(1 equiv)CH2Cl2, 0o C

>85:5 drR=alkyl, alkenyl, phenyl

77-90% yield

Ti ON

O

S

R Me

H

ClCl

MeMe

PhPh 2. RCHO

Me

Me

Ph Ph

MeMe

PhPh

Cl


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3 CHIRAL BORON ENOLATES Enol Boronates Zàsyn aldol and Eà anti aldol. With the use of chiral alkyl boronates, moderate enantioselectivity can be afforded.

Paterson Tetrahedron, 1990, 46, 4663

4 MUKAIYAMA ALDOL REACTION 4.1 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.

O

RMe

OMe

O

Me

RCHO

Me

Me

O BO

Me

H

Me

R

O BO

H

Me

Ipc

Ipc

Ipc

Ipc

BCl = (+)-Ipc2BClO

Me Me

O

MeBOTf= (+)-Ipc2BOTf

OH

R

OH

RMe

Ipc2BClEt3N

CH2Cl2

Ipc2BOTfIPr2NEtCH2Cl2

Me

75-99%

>95:5 d.r.79-91% ee

R=Alkyl, alkenyl, phenylYields much lower for

isopropyl aldehyde

80:20E:Z

selectivityThus not effective for stereocontrol

Me

80:20 d. r


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

4.2 Challenges to Metal Catalytic Enantioselective Mukaiyama Aldol Addition - Background silyl-catalyzed achiral aldol addition

Carreira Tetrahedron Letters 1994, 35, 4323-4326

Bosnich JACS 1995, 117, 4570-4581

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

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

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

Synthetic route to monosaccharides from achiral compounds

Kobayashi Synlett 1993, 911

Guidelines for designing more recent catalysts: (1) Ligands with electron donors. (2) Stabilizing aromatic stacking interactions. (3) Reaction conditions minimize the silyl-catalyzed achiral aldol addition.

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*XnR

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 oCEtS

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 OSnO

R

HOTfTf

H3CCHO

OSiMe3

OPh

BnO

Sn(OTf)2 +

NMe

10-20 mol%

HN

SnO, AcCN -78 oCH3C

O

OPh

OH

OBn

ligand

ligand =

cat. OsO4.NMO

acetone-H2O / 0oC

OH

OBnOO

H3CHO

dr = 97:3 92 %ee

4

5 1. DIBALH, DCM, -78 oC2. Pd-C/H2, MeOH

O

OHOH

OH

CH3 OH

L-fucose


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4.4 Silyl ketene acetals, thioester-derived silyl ketene acetals as nucleophiles 4.4.1 Syn - Chiral (acyloxy)borane (CAB) complexes of tartrate-derived ligands by Yamamoto

Yamamoto Synlett 1991, 439

α,β-Unsaturated aldehydes reveal excellent diastereo- and enantioselective due to the π interaction. Reaction with aliphatic aldehyde resulted in slight reduction of optical and chemical yields. 4.4.2 Anti - Chiral BINOL and Zr(IV) complexes by Kobayashi

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

Synthesis of Khafrefungin

Kobayashi JOC 2001, 66, 5580

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

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.

H

O+

MeOPh

OTMS

OPh

OOH

Me

O

I

O

I

ZrOt-Bu

Ot-Bu

10 mol%

n-PrOH, H2OMe

IMe

I

dr = 80:20 99 %ee

H3C(H2C)9 OOH

O

OH

OH

O

MeMe

O

MeMeMe

OH

Me

OH

Khafrefungin


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4.4.3 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

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

Carreira JACS 1994, 116, 8837

Carreira, Kvaerno Classics in stereoselective synthesis p.133-134

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

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 O

OOSiR3

Si-trap

OMe

O

R

OSiR3

Ti OO

O

Si-shuttleL3 L3

OMe

O

R

OSiR3 TiL3O

O

O

+

A


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Synthesis of Phorboxazole A

Smith JACS 2001, 123, 10942

- Complex of chiral Bis(oxazolidine) (BOX) or bis(oxazoline) (PYBOX) and metals by Evans

Evans JACS 2000, 122, 10033

Evans ACIE 1997, 36, 2744 2.4.4 Ketones as electrophiles - Evans developed a family of chiral bis(oxazolidine) (BOX) and bis(oxazoline) (PYBOX) complexing with different metals as catalysts for enantioselective Mukaiyama aldol addition. Diverse stereo outcomes can be obtained based on the metal and ligand used in the complex. 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). Broad range of nucleophiles: thioester-derived ketene acetals, ketene acetals, ketone-derived enolates. Chiral Bis(oxazolidine) (BOX) or bis(oxazoline) (PYBOX) and Cu(II) complexes

Evans JACS 1997, 119, 7893

ON

O

H

OPMB

OBn

OTMS

A (2 mol%)O

N

OPMB

OBn

OOTMS

99 %eeO

N

Me

O

Me

H

N

O

O

OH

H

15

15

O H

O

O HOHO

OMe

HMe

BrMeO

HO

Phorboxazole A

ON

O

H St-Bu

OTMS 10 mol% ON

St-Bu

OOH

94 %ee O

N

Me

O

Me

H

N

O

O

OH

H

15

15

O H

O

O HOHO

OMe

HMe

BrMeO

HO

Phorboxazole BPh

+

NSn

N

O OMe Me

Ph PhTfO OTf

Ph

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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Chiral Bis(oxazolidine) (BOX) or bis(oxazoline) (PYBOX) and tin(II)

Evans JACS 1997, 119, 10859

Chiral Bis(oxazolidine) (BOX) or bis(oxazoline) (PYBOX) and scandium(III)

Evans OL 2002, 4. 3379

- Complex of Cu(I)fluoride and chiral Taniaphos ligand by Shibasaki Examples of effective catalyzed enantioselective aldol addition involving 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

4.5 Enol ethers as nucleophiles 4.5.1 Syn - Chiral (acyloxy)borane (CAB) complex of tartrate-derived ligands by Yamamoto.

Yamamoto JACS 1991, 113, 1041

Synthesis of cheimonophyllal

Tadano JOC 2002, 67, 6690

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 %

O

MeOO

MeMe

St-Bu

OTMS

NO

N N

O

ScTfO OTf

Ph Ph10 mol% MeO

St-Bu

O

Me

OHMe

Odr = 92:8 93 %ee

+

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

Hi-Pr

O

Me

OTMS

OPri

OPri

O

OO B

O

CO2H O

H20 mol%

then BzCl

O

Me

OBz

i-Pr

OMe

HOOH

H

H CHOO

i-Pr

(+)-Cheimonophyllaldr = 10:1 99 %ee


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

Mikami JACS 1993, 115, 7039

Broad scope of enolates (esters, thio-esters, ketone-derived enolates) 4.5.2 Anti Enantioselective aldol addition of enolates to aldehyde catalyzed by BINAP/Silver(I) complex by Yamamoto

Yamamoto JOC 2003, 68, 5593

4.5.3 Acetate 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 Tetrahedron Letters 1992, 33, 6907

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

AgOO

H

R3

H

R1Si(OMe)3F

PP*

R2 AgOO

H

R3

R1

HSi(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 MeOHR

hydrogen bonding

facial blocking

+

H

Ph H

O OTMS

+ OMe

NH

N BO

Ts n-Bu

20 mol %Ph

OOH

H

OMeTFA O

OPh

H

100 % yield 82 %ee


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4.6 Dienolates as nucleophiles Addition reactions of dienolates and aldehydes lead to four-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

Carreira JACS 1995, 117, 12360

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

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

Synthesis of Leucascandrolide Carreira JOC 2003, 68, 9274

Evans JACS 2008, 130, 16295

OTi

NO

t-Bu

t-Bu

OO

O

2 mol%

t-Bu

Br

A

Ph H

OO O

+OTMS

MeMe

then TFAO

O O

MeMe

OH

Ph 99 %ee

Bu3Sn H

OO O

+OTMS

MeMeent-A

A

O O

O

MeMe

Bu3Sn

OTMS

92 %ee

O O

O

MeMe

Bu3Sn

OTMS

92 %ee

OH

Me

OO

HO

HO

77

3

3

15

15

11

11

Macrolactin A

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

O

OTMS

Me H

OOEt

O

+

NSn

N

Et EtO O

TfO OTf

DCM, -78 oC

10 mol% O

OEt

O

O

Me

OHdr >50:1 95 %ee 94%yield

(+) azaspiracid-1


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5 LEWIS BASES ON TRICHLOROSILYL ENOLS A metalloenolate 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.

. 5.1 Achiral Methyl Ketone derived Trichlorosilyl Enols

Denmark JACS, 2000, 122, 8837

5.2 Achiral Ethyl Ketone trichlorosilyl enols

Denmark JOC, 2003, 68, 5045

5.3 Chiral Methyl Ketone derived trichlorosilyl enols Double diastereoselection with the use of chiral catalyst and chiral enolate. Matched case here involves the use of the (R,R) phosphoramide catalyst, whereas the (S,S) gives very low syn selectivity. TBS protection of alcohol is necessary to prevent chelation and lower diastereoselection.

Denmark, JACS, 2000, 122, 8837

**

O**

OXnM Lewis BasePromoter O MXn

O MXnLB

O

RO MXn

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

OSiCl3 O

Ph+

NP

NMe

Me

Me

Me

O

N

5 mol %

CH2Cl2, -78 oC O OH

Ph85% yield

73:1 syn/antiOTBSOTBS

Me MeH


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5.4 Ethyl Ketone trichlorosilyl enols Diastereoselectivity for these mostly dependent dependent on enolate configuration. The (R,R) and (S,S) phosphoramide catalysts give similar diastereoselectivities.

Denmark OL, 2001, 3, 2202

6 DIRECT CATALYTIC ENANTIOSELECTIVE ALDOLS These involve the in situ generation of enolates (donor) in the presence of an aldehyde (acceptor), circumventing the use of preformed enolates and decreasing waste. Often substoichiometric catalysts amounts of catalyst can be used.

6.1 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

6.2 Lanthanum and Barium Binols as Bifunctional Catalysts (Donor and Acceptor Activation) These catalysts serve as both lewis (lanthanum or barium) acid and bronsted base catalysts (lithium binaphthoxides or binols). Proceed with exogenous base.

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

OTBS

HOOSiCl3

Me O

H Ph

NP

NMe

Me

Me

Me

O

N

CH2Cl2, -78 oC MeO

PhOTBS Me

OHRelative

Internal

87% yieldRelative d.r. 16:1 syn/antiInternal d.r. >50:1 syn/anti

+

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

O**

OR1

R2

ALO

OMH

O

HOR1

R2

OMH

OLA

R2O

R2O

OMH

OLA

R1

HOOM

H

OLA

R2

**

O

OH

R1


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

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

Shibasaki JACS, 2001, 123, 2466

6.3 Dinuclear Zinc Prophenols as Bifunctional 6.3.1 Direct aldols with acetone(enantioselectivity lower for alpha unbranched aldehydes)

Trost OL, 2001, 3, 2497

6.3.2 Chelation of alpha hydroxyl ketone increases reactivity of donor and allows close to equimolar equivalents with respect to aldehyde(highly syn selective).

Trost JACS, 2001, 123, 3367

6.3.3 Mild conditions allow for use of ynones as substrates for aldol, used in the total synthesis of dephosphofostriecin.

Trost, JACS, 2004, 126, 2660

O

Ph Me

O

R+

OO Ba

OO

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 PhPhPh

PhEt

O

Me Me

O

R+

O

Ph

OH

RR=alkyl, phenyl

78-94% ee59-89%

48 h10-15equiv

4 A MS, THF 5 oCH

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

MeMe

ON NZnZn

OO PhPhPh

PhEt

O

Me

O+

O OH

99% ee58-67%4-17 hSlight excess

4 A MS, THFTBS

MeOEtEtO

3 mol%

TBS OEtMe

EtO OO

OH

Me OH

OH OH

dephosphofostriecin

H


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7 CHIRAL AMINE CATALYSIS In Nature:

Trost Chem. Soc. Rev. 2010, 39, 1600

Early 1970s, Hajos-Parrish-Eder-Sauer-Wiechert reaction

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

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

PO OH

OOO O

PO OH

NOO O

Lys229

Ser271

PO OH

HNOO O

Lys229

Ser271

PO

O

OO

OHO

H

Lys107

PO

NOO O

Lys229

Ser271 H

Lys107

OP

OR

OH

OH

OH

O

O O

R = OPO32-

type I aldolase

OOH

OH

OH

PO

O

O

H3C

O O

O

Me NHCO2H

3 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 NHCO2H

30 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

-O2C

O

O

Me

ON H

OO

H H

Hajos Model

Me O

N OHN

CO2-H

Agami model(two-proline mech.)

MeO

OO H

NO

OH

H

Swaminathan Model

(crystal surface)O

ON

O

OH

Me

Houk Model

intramolecular

CH3HR

ON

O

OH

intermolecular


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Hajos JOC 1974, 39, 1615

Agami JACS 1986, 108, 2353 Swaminathan Tetrahedron Asymmetry 1999, 10, 1631

Houk JACS 2003, 125, 2475 List Acc. Chem. Res. 2004, 37, 548

Seebach&Eschenmoser Helv. Chim. Acta 2007, 90, 425

Discussion on mechanism: Houk ACIE 2004, 43, 5766 List PNAS 2004, 101, 5839 Blackmond Bioorg. Med. Chem. Lett. 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

7.1 Progress 7.1.1 Aldehyde electrophiles

NH

CO2H

N CO2H

CH3

CH3HR

ON

O

OH

R

N CO2HOH

H3C CH3

O

H2O

R H

O

H2O

R CH3

OH O

NH

CO2H

N CO2-

CH3H3C

N CO2-

H3C CH3

O

H2OH2O

CH3

O

N O

H3C CH3

H O

N CO2H

CH3

N OCH3

H O

Electrophile

EE

Electrophile

Mechanism proposed by List et al. Mechanism proposed by Seebach et al

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

H3C CH3

O

H

O+

R

NH

NH

O

OH

PhPh

20 mol%

R CH3

OH O

R

4-NO2Ph4-BrPh4-MePh2-ClPh

naphthyl

% yield

6677488393

%ee

9390848584

Wu JACS 2003, 125, 5262

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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Cross-aldol of aldehydes

MacMillan ACIE 2008, 47, 3568

Cross-trimerizations

Cordova ACIE 2005, 44, 1343 & MacMillan Science 2004, 1752

7.1.2 Activated Ketone electrophiles

Zhao Tetrahedron Letters 2006, 47, 3383 & Jorgensen Chem. Comm. 2002, 620 8 Other Classes of Aldols 8.1 Reformatsky Reaction

Reformatsky Berichte der Deutschen Chemischen Gesellschaft, 1887, 20, 1210

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

H3C Cl

MeO

H3C

H3C

H OH

O O

OHH3C OH

CH3

MeO

O

B

C

callipeltoside C

H

O

R1

+ H

O

R2

NH

CO2H

10 mol%H R2

O

R1

OH NHCO2H

10 mol%

H

O

CH3

O OHR2

MeOH

R1

R2

Etc-hexylBnOMe

% yield

294139

% ee

99>99>99

R1

MeMe

BnO

Two-step polyketide synthesis

Sugar synthesis

H

O

OBn

NH

CO2H

10 mol%H

OBnO

OBn

OH

+

O OH

OBnOH

BnO

BnO

51 % dr 4:1 98 %ee

41 % 98 %ee

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

O

R1 R2

OX R3

MSolvent

+R2

O

R3

R1HO

X= Cl, Br, IM= Zn, In, SmII, TiIII, Fe, Co, Sn...

Classical Reformatsky


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8.1.1 Enolates with a CF3 α to an ester or amide are often unstable, but they work well in Reformatsky reactions.

Ishihara TL, 2006, 8, 1129

8.1.2 The Indium tends to yield E enolates and can provide high diastereoselectivity in the formation of β-lactones.

Baba OL, 2006, 8, 3029

8.2 Ketene Aldehyde Cycloadditions Acyl halides can be transformed to the corresponding ketenes in the presence of base. With a chiral lewis base and a lewis acid, asymmetric aldols can be mediated to give β-lactones.

Nelson JACS, 2004, 126, 5352

NO

O O

Br

CF3

Bn

+Ph

O ZnAlEt3 NO

O O

Bn

OH

CF3CF387.5%

yield

96% d.r.

H

O

Br

+Ph

OIn

TolueneO

O

67%yield

99% d.r.

EtO Ph

OH PhHOPh

O

EtOOH

PhOHPh

O

Cl Me+

O

Ph

10 mol%TMSq

30 mol%LiClO4Et3N

N

OMe

N

OTMS

TMSQ

N

OMe

N

OTMS

TMSq

OO

PhMe

OO

PhMe80%yield

96% d.r.99% ee

78%yield

96% d.r.99%ee

10 mol%TMSQ

30 mol%LiClO4Et3N

H

O

Cl Me

O

Me

Et3N NR3 **O

R3H2N

O

R3H2N

M

Me

O

Ph

O OM

M

Me

HPh

NR3**

O OMMe

HPh

NR3**

OO

PhMe

Me

H

H

topic: enantioselective aldol reactions 1 ......effective only for chelating aldehydes. the second...

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