Stereoselective Synthesis Novartis.pptx

1

Introduction to Stereoselective Organic Synthesis

Introduc)on to Stereoselec)ve Organic Synthesis Ph Me H "H("

O O O Me

N

Bu H

B

O

H

O R Me

Bu

O

R H

RO O

N H Me

O O

RO2C OR O CO2R O Ti Ti O O

RO

◾ Advanced Organic Chemistry: Parts A and B, Francis A. Carey, Richard J. Sundberg ◾ Organic Chemistry, Jonathan Clayden, Nick Greeves, Stuart Warren, Peter Wothers ◾ Stereochemistry of Organic Compounds, Ernest L. Eliel, Samuel H. Wilen ◾ Selecvated/carbonyl considered/to/be/ largest/group

RS O M

R RM

Donald J. Cram, Nobel Prize with Jean-‐Marie Lehn and Charles J. Pederson, 1987 Nu RL R

RS

torsional/strain not/considered OH

RM

Cram, D. J.; Elhafez, F. A. A., J. Am. Chem. Soc., 1952, 74, 5828 Different model put forward by Karabatos in 1967; Karabatsos, G. J. J. Am. Chem. Soc. 1967, 89, 1367


Acyclic Stereocontrol – aZack on aldehydes and ketones with α-‐stereocentres The Bürgi-‐Dunitz trajectory ◾ Cram’s rule assumes that the nucleophile approaches perpendicular to the plane of the carbonyl group. ◾ In the 1970s two crystallographers, Hans-‐Beat Bürgi and Jack D. Dunitz, determined the trajectory of axack on a carbonyl group by analysis of the X-‐ray structures of a number of cyclic amino ketones. ◾ The Burgi-‐Dunitz angle is approximately 107 ° -‐ close to the tetrahedral angle. ◾ Axack along the Burgi Dunitz trajectory maximises overlap of the nucleophile HOMO with the LUMO of the carbonyl group (π* orbital).

Nu&

N

O

R' R

107 ° O

Bürgi, H.B.; Dunitz, J.D.; Lehn , J.M., G. Wipff, Tetrahedron, 1974, 30, 1563.

58

59


Acyclic Stereocontrol – aZack on aldehydes and ketones with α-‐stereocentres

◾ Felkin-‐Anh Model – most widely used and accepted model for addi)on of nucleophiles to α-‐chiral aldehydes and ketones Assump-ons: ◾ Transi)on states are all reactant-‐like rather than product like. ◾ Torsional strain considera)ons are dominant hence staggered transi)on state conforma)ons are dominant. ◾ Reac)ve conforma)on has the largest group perpendicular to the plane containing the carbonyl group RC=O. ◾ The nucleophile approaches along the Burgi-‐Dunitz trajectory ~107° for best overlap with the C=O π* orbital. RL O RM

R RM

HO

R

RM

H

RL

HO

R Nu

RM

Nu

Nu(

O RL

favourable

R H

RL

nucleophile6approachs along6Burgi(Dunitz6angle passed6the6smallest6group RL R RM

O H

Nu(

unfavourable

RL OH

R RM

H Nu

RL

R

OH Nu

RM

unfavourable6approach passed6larger6group Chérest, M.; Felkin, H.; Prudent, N. Tetrahedron Lee. 1968, 18, 2199; Anh, N. T.; Eisenstein, O. Nouv. J. Chim. 1977, 1, 61; Bürgi, H. B.; Dunitz, J. D.; Sheser, E. J. Am. Chem. Soc. 1973, 95, 5065; Bürgi, H. B.; Dunitz, J. D.; Lehn, J. M.; Wipff, G. Tetrahedron 1974, 30, 1563

60


Acyclic Stereocontrol – aZack on aldehydes and ketones with α-‐stereocentres Examples

O Ph

LiAlH4

Me

OH Ph

OH

Me Me

Me

Ph

Me Me

Ph

O Ph

+ 3:1

Ph

LiAlH4 Me H

Me Me

O Me

Me

OH

H

Me

"H1"

Me Et

H NBn2

which0is0the0large0group?

OMe

Ph

Me

OH

Et

O OMe

NBn2

major7diastereomer

Me

+

Me Me

H

OLi

O

OH

OH

Et

O OMe

NBn2 24:1 92%0d.e.

appears0that0NBn20 funcCons0as0large0group

◾ Why is the stereocontrol so good when NBn2 and CH(Me)Et are similar in size?

61



Polar Felkin-‐Anh Model – use for aldehydes/ketones with α-‐electronega)ve groups. ◾ Conforma)ons where electronega)ve groups are perpendicular to the plane of the RC=O group are more reac)ve to nucleophilic axack. O

X X

Me

O

X%=%electroneag/ve%group e.g.%OR,%NR2,%SR,%Ph%etc.

C=O%π*

H overlap%to%give%new% lower%energy%LUMO

Me

π*%C=O

NBn2

NBn2 O CH(Me)Et

H H

H

Me

H

OH

H

CH(Me)Et

O

OH

Et

Nu

Nu/

new%lower energy%LUMO more%reac/ve

O OMe

NBn2 major5diastereomer

OH

LiBH(sBu)3 Ph

SMe

σ*C>X

C>O%σ*

Ph

+

SMe

OH Ph SMe

favoured:by:electronic model:(polar:FelkinEAnh model)

4:96

◾ Note: the reac)ve conforma)on of the substrate is not necessarily the ground state conforma)on. As all of the above reac)ons are kine)cally controlled it is the energies of the compe)ng transi)on states which are important. Anh, N. T.; Eisenstein, O. Nouv. J. Chim. 1977, 1, 61

62



◾ Cornforth-‐Evans Model -‐ polar Felkin-‐Anh model does not support all of the available experimental data (nevertheless it is a useful predic)ve tool). ◾ In the 1950s Cornforth proposed a model for addi)on to α-‐heteroatom subs)tuted carbonyls based on the minimisa)on of dipoles. Nu)

Features(and problems

RS X

O M

R

X

RL

Nu)

90-°-nucleophile trajectory

RS O M

R

net-dipoleminimised

Cornforth(model

ac>vated-carbonyl considered-to-belargest-group

RL

Nu X R

RS

RL

torsional-strain not-considered OH

◾ In 2003 the Cornfoth model was modified by Evans to take into account the Burgi-‐Dunitz angle and minimisa)on of torsional strain. ◾ The model predicts the same major diastereomer as the polar-‐Felkin-‐Anh model but assumes a more ionic transi)on state with dipole minimisa)on. Nu PO R

RM O M RL

D. A. Evans, S. J. Siska, V. J. Cee, Angew. Chem., Int. Ed., 2003, 42, 1761.

63



◾ Cram-‐Chelate model – use for aldehydes/ketones with α-‐electronega)ve groups when chela)on between the α-‐ electronega)ve group and the carbonyl group is possible.

RL

O

NuM

RL

R'

M+

OR

O O R

RL

favourable

R' H

nucleophile6approachs along6Burgi(Dunitz6angle passed6the6smallest6group in6chelated6transi?on6state MeO

Me2Mg Ph

Me

HO Me MeO

Ph

R'

RO

H Nu

Nu(

O

HO

RL

HO

R' Nu

OR epimer6to6that6predicted by6polar6Felkin(Anh6model

Me OH +

Me

MeO

Ph Me

1:99

◾ Two things are required for chela)on control: i) a heteroatom available for coordina)on to a metal ion; ii) a metal ion that favours coordina)on to both C=O and the heteroatom. ◾ Mg2+ , Zn2+ , Al3+ , Ce3+ , Ti4+ generally excellent at chela)on (highly charged ca)ons generally good). ◾ Li+ some)mes can chelate. ◾ Na+ and K+ generally poor at chela)ng. Cram, D. J.; Elhafez, F. A. A., J. Am. Chem. Soc., 1952, 74, 5828 Cram, D. J.; Kopecky, K. R. J. Am. Chem. Soc. 1959, 81, 2748

64


Acyclic Stereocontrol – aZack on aldehydes and ketones with α-‐stereocentres Summary

O R

YES

Is there a heteroatom at the α-‐stereogenic centre?

X Y Z

NO Use Felkin-‐Anh model: consider reac)ons on conforma)ons with largest group perpendicular to RC=O plane.

RL O RM

R H Nu(

Is there a metal ion capable of chela)on with the heteroatom?

NO

YES

Use polar Felkin-‐Anh model: consider reac)ons on conforma)ons with the most electronega)ve atom perpendicular to RC=O plane. Or use Evans-‐Cornforth model – minimise dipoles.

X O R

R R' H Nu(

M O H

Use Cram-‐chelate model: consider reac)ons on conforma)ons with C=O and heteroatom chelated by metal ion.

RL M+

R' X Nu

O O R

R' H Nu(

65


Problem: Ra)onalise the stereochemical course of the following reac)ons. L. E. Overman, R. J. McCready, Tetrahedron Lee., 1982, 23, 2355.

O Me

Me Me

OH

LiAlH4,,THF

OH Me

Me Me

OR R,=,CH2OBn R,=,SiPh2tBu

+

Me

Me Me

OR

70 5

OR

30 95

Problem: Predict the stereochemical outcome of the following reac)on.

T. B. Durham, N. Blanchard, B. M. Savall, N. A. Powell, W. R. Roush, J. Am .Chem. Soc., 2004, 126, 9307. TBSO

TMSO

OTBS OBz

TMS

O

Me

OTBS OH

H

O

OTBS OBz

Me

Me

Me

OMe

BF3•OEt2

Me Me

Me

Me

OMe

TMS

66


Acyclic Stereocontrol – aZack on alkenes with α-‐stereocentres

◾ The low energy conforma)ons of alkenes carrying allylic subs)tuents have one subs)tuent eclipsing the alkene. ◾ The lowest energy conforma)on of but-‐1-‐ene has the hydrogen atom (smallest group) eclipsing the alkene. ◾ Another low energy conforma)on has the methyl group eclipsing the alkene. ◾ Eclipsing the smallest group with the alkene minimises allylic 1,3-‐strain (A1,3 strain). H Me H H H

H6outside3 conforma,on

C

H

H H

C

C

C

H Me

H

H 5

H6inside3conforma,on minimises3A1,33strain

4

H

rela,ve energy 3 kJ3mol61

H C H Me

2

C

H

5.56

H H H

2.05

0

60

C H 120

C

1

2

H

Me

H H 180

◾ The H-‐outside conforma)on suffers from destabilising overlap of filled orbitals which is absent in the H-‐inside conforma)on. ◾ With (Z)-‐alkenes the difference in energy between Me-‐inside and H-‐inside is greatly increased. Wiberg, K. B.; Mar)n, E., J. Am. Chem. Soc. 1985, 107, 5035. Dorigo, A. E., Prax, D. W., Houk, K. N., J. Am. Chem. Soc. 1987, 109, 6591. For a review see: R. W. Hoffmann, Chem. Rev., 1989, 89, 1841.

H

3

Me

1

0

H

5.52

φ

H

destabilising,interac/on between,filled,orbitals (σC5H!πC5C) HH

H H5outside

H

H

H H H5inside

67



Strategy ◾ Draw lowest energy conforma)on of alkene. ◾ Is the approach of the reagent to both sides of the alkene equally favourable? ◾ Watch out for groups capable of delivering the reagent to one face of the alkene.

Me

Me

mCPBA

Me

O

SiMe2Ph

Me

+ Me

SiMe2Ph

Me O

SiMe2Ph

61:39 major& Me conformer H gives&major product Me

Me

H SiMe Ph 2 H

Me

Me H

H OH

SiMe2Ph

Me

O

Me SiMe2Ph

Me

major&product

mCPBA,a.acks least,hindered,face


SiMe2Ph minor conformer gives&minor product

Me H

H Me

SiMe2Ph

Me H

O

H H

SiMe2Ph Me

Me

Me O

SiMe2Ph

minor&product

68



Me

Me Me

mCPBA

Me

O

Me

Me

SiMe2Ph

+ Me

SiMe2Ph

Me O Me SiMe2Ph

95:5

Me

Me Me

H SiMe Ph 2

Me Me

H

SiMe2Ph

Me H

Me


for,cis:alkenes only,one,heavily,populated conformer

H OH

SiMe2Ph Me

Me

O Me

Me SiMe2P h

Problem: Explain the stereochemical outcome of the following reac)on from Kishi’s synthesis of monensin. G. Schmid, T. Fukuyama, K. Akasaka, Y. Kishi, J. Am. Chem. Soc., 1979, 101, 259.

BH3•THF,*0*°C then*H2O2,*2OH OBn

O

OH OBn

O

Problem: Predict the stereochemistry of the major diastereomer formed in the following reac)on. W. Bernhard, I. Fleming, D. Waterson, Chem. Commun, 1984, 28. Me

OEt LDA.then.MeI

PhMe2Si

Me

O

PhMe2Si

Me

O

OEt


Diastereoselec-ve synthesis – Chiral Auxiliaries

◾ In order to achieve asymmetric synthesis, at least one component in the reac)on must be chiral and non-‐racemic. ◾ A general approach is the use of chiral auxiliaries. ◾ A prochiral substrate is axached to a chiral, non-‐racemic group – the chiral auxiliary. ◾ The reac)on is conducted which results in diastereomeric products which may be readily separated. ◾ Cleavage of the auxiliary from the purified reac)on mixture yields the chiral, non-‐racemic, products. ◾ The requirements of a good chiral auxiliary are as follows: i) enan)omerically pure and available as both enan)omers ii) cheap and available in quan)ty iii) easy to introduce into the substrate iv) gives high and predictable diastereocontrol v) easy to purify the major diastereomer vi) easy to remove from product without loss of diastereomeric and enan)omeric purity

69

70


Diastereoselec-ve Enolate Alkyla-on

O HO

install'chiral R auxiliary

O XC

R

i)'base ii)'R'X

O

remove'chiral R auxiliary

XC

O R

HO

R'

R'

◾ Reac)on proceeds by forma)on of the corresponding enolate which reacts with an electrophile to give the product. ◾ Reac)on requires a strong non-‐nucleophilic base to deprotonate the carbonyl compound. ◾ pKa (water) ketone ~ 20, ester ~ 25, amide ~ 26 ◾ Requires a base with a higher pKa (of the conjugate acid) for complete deprotona)on. ◾ Typically use, LDA, LiHMDS (and NaHMDS, KHMDS), and LiTMP

71


O P

Control of Enolate Geometry

O Me

N N NMe2 ◾ Control of enolate geometry is crucial in diastereoselec)ve enolate alkyla)on reac)ons. Me2N NMe 2 ◾ (Z)-‐Enolates are thermodynamically more stable than (E)-‐enolates. ◾ As the size of R increases the ra)o (Z):(E) increases. HMPA DMPU ◾ In the absence of addi)ves such as HMPA or DMPU, esters give predominantly (E)-‐enolates whereas ketones and amides give predominantly (Z)-‐enolates. ◾ In the presence of addi)ves such as HMPA and DMPU (Z)-‐enolates predominate for esters as well as amides and ketones. ◾ Take home message, Esters give E-‐enolates, other carbonyls (ketones and amides) give Z-‐enolates. OM H H H H OM base R Me (Z)'enolate O R O R H O R Me R H H H OM deprotona/on0has0C3H0bond0 perpendicular0to0the0plane of0the0carbonyl0group0for0maximum orbital0overlap0(σC3H0to0π*C=O)

(E)'enolate

R

Me

1,3+diaxial interac4on

◾ Ireland Model (Z):(E)-‐ra)o depends on a balance between the 1,3-‐diaxial interac)ons and the developing A1,3 strain.

R

R Me

O

H

H

Me

Li

Li N

O

H

(Z)+enolate1transi4on1state

N

H

(E)+enolate1transi4on1state

A1,31strain1 as1enolate1 begins1to1form

Me

72


Enolate Geometry

O

R

Me

OLi

LDA,*THF*.78*°C

OLi Me

R

+

ketones

R Me

R

(Z)

(E)

iPr

60

40

tBu

>98

99:1&dr imides*are*closer*to* esters*than*to*amides in*terms*of*acidity, enolate*nucleophilicity and*cleavage*chemistry

(Z)#enolate*formed with*very*high*selec7vity chelated*geometry*presumed in*ground*and*transi7on*state

Evans, D.A: Brixon. T.C; Dorow, R.L; Dellarfa, J.F., J. Am. Chem. Soc., 1986, 108, 6395; Evans, D.A; Brixon, T.C; Dorow, R.L; Dellarfa, J.F., Tetrahedron, 1988, 44, 5525.

iPr*group*blocks*one face*of*chelated*enolate

74


Diastereoselec-ve Enolate alkyla-on

◾ The oxazolidinone enolates react readily with a variety of reac)ve electrophiles, such as MeI, BnBr, allylBr, NBS, trisyl azide, oxaziridines, azodicarboxylates. ◾ Less reac)ve electrophiles e.g. β-‐branched alkyl halides do not react. ◾ Diastereocontrol in all of these reac)ons is predictable (from proposed chelated enolate) and high.

source,of,"HO+" O O

O

O

N

O

NaHMDS, THF,,-78,°C

OMe

Na

O

O

O

N

Me selecBve,enolisaBon here,probably,as,a,result of,chelaBon,of,imide,to,sodium ions

OMe

(±)Ph

O

Me

HO X alcohol

LiBH4

O

O

N Me

OMe OH 96:4,dr

O R

O

68%

most*reacon H

O B O

H H3C

O H

R

Hoffmann, R.; Zeiβ, H. –J. J. Org. Chem., 1981, 46, 1309

O B O

H

R0group0of aldehyde0in0pseudo equatorial0posi>on

O H3C

O B O

H O H

R

R

Ph CH3 iPr

94:6 93:7 96:4

R

syn:anti

CH3

R

H3C

OH

syn:anti

Ph CH3 R iPr

OH CH3

4:96 3:97 6:94

93


Enan-oselec-ve Allyla-on and Crotyla-on reac-ons

◾ H. C. Brown has developed B-‐allyldiospinocampheyl borane and the corresponding (E) and (Z)-‐crotyl deriva)ves. ◾ All of the reagents are readily prepared from inexpensive α-‐pinene which is available in quan)ty in both Me enan)omers. ◾ These reagents react rapidly with aldehydes at low temperature to give the products in excellent yield and enan)omeric excess. ◾ As with the aldol reac)on, the (Z)-‐crotyl borane gives the syn product and the (E)-‐crotyl borane gives the an99%2ee

(%)%Ipc2B

Nobel Prize with Georg Wivg, 1979 O Me

Me B CH3

H3C

O OH

H H3C

CH3 syn$selec(ve 90%$ee

Brown, H. C.; Jadhav, P. K. J. Am. Chem. Soc., 1983, 105, 2092. Racherla, U. S.; Brown, H. C. J. Org. Chem., 1991, 56, 401.

Me

Me B

CH3

H3C

OH

H H3C

CH3 an#$selec#ve 90%$ee

94



◾ The model to ra)onalise the stereoselec)vity involves minimising the interac)on of the allyl/crotyl unit with the Ipc –ligands.

O Me

Me

H3C

B

OH

H

CH3 >99%2ee

(%)%Ipc2B H"poin'ng"into Me ring"in"sterically" most"hindered"posi'on Me

H H

O H

R

Me H H Me B Me

Me

Me

H

H

Me

Me

H

H H Me

H (smaller)"oxygen"of RCHO"rather"than" CH2"of"allyl"unit sits"in"sterically"most encumbered"posi'on

Brown, H. C.; Jadhav, P. K. J. Am. Chem. Soc., 1983, 105, 2092. Racherla, U. S.; Brown, H. C. J. Org. Chem., 1991, 56, 401.

H

O H

R

H

H Me H H Me B Me H

Me H H Me B H Me

H Me

H

R

O H H

H

severe%steric clash%between%allyl unit%and%"Ipc"%unit

Me

95



◾ W. R. Roush has developed chiral allyl and crotyl boronate reagents based on tartrate esters and amides.

CO2iPr O R

H

O B

+

CO2iPr

O

RCHO

OH

toluene 0783°C,343A8 3sieves

yield3/3%

nC9H19CHO cC6H11CHO PhCHO

R

ee3/3%

86 77 78

79 78 71

CO2iPr O H

TBSO

O B

+

O

OH

toluene

CO2iPr

/782°C,242A7 2sieves

71%,285%ee 98:2,2an$:syn

TBSO Me

CO2iPr O H

TBSO

O B

+

a"rac%ve(electrosta%c interac%on(beteween(lone pair(and(carbonyl(carbon

O

H

O B O

H H

O H

R

CO2iPr

O

OH

toluene /782°C,242A7 2sieves

O

OiPr

O B O

H H

O H

R

Me

CO2iPr

OiPr OiPr

H CO2iPr

68%,272%ee 2:98,2an$:syn

TBSO

CO2iPr

OH

O

H

O O B

H H

O

R

R unfavourable+lone,pair lone,pair+repulsion

Roush, W. R.; Ando, K.; Powers, D. B.; Palkowitz, A. D.; Halterman, R. L. J. Am. Chem. Soc., 1990, 112, 6339. Gung, B. W.; Xue, X.; Roush, W. R. J. Am. Chem. Soc., 2002, 124, 10692-‐10697. For a discussion of the formyl hydrogen bond see: E. J. Corey, D. Barnes-‐Seeman, T. W. Lee, Tetrahedron Lee., 1997, 38, 4351.

H

96


Cataly-c Asymmetric Aldol Reac-ons – Introduc-on to Organocatalysis ◾ The Hajos, Parrish, Wiechert reac)on – intramolecular proline-‐catalysed aldol reac)on. O O

O Me

O

N H

Me O

Me O

CO2H O

3)mol%)catalyst DMF

Me O

Me

Me

O

OH

O

OH 100%)yield 93.4%)ee

enamine/ forma-on

H2O

CO2H

N H

iminium/ion hydrolysis

H2O O

N N O H O

O

Me chair&like transi-on/state

O O

O

N

OH

O Me

N O H O O

CO2H O Me

O N H O

Me

O

O Me

intramoleuclar acid/catalysis

O

chair&like transi-on/state

Hajos, Z. G.; Parrish, D. R. ; J. Org. Chem., 1974, 39, 1615. Eder, U.; Sauer, G.; Wiechert, R. Angew. Chem. Int. Ed., 1971, 10, 496. Overview of mechanis)c studies: Alleman, C.; Gordillo, R.; Clemente, F. R.; Cheong, P. H.-‐Y.; Houk, K. M. Acc. Chem. Res., 2004, 37, 558.

97


Cataly-c Asymmetric Aldol Reac-ons – Introduc-on to Organocatalysis

◾ The Hajos, Parrish, Wiechert reac)on was developed into an intermolecular reac)on by Barbas and List

N H

O + Me

Me

CO2H 30+mol%

O

RCHO DMSO:acetone,+4:1

O

OH

Me

OH

O

Me

R

O

R H R"group"of aldehyde"is equatorial

H Me

O

R

O O chair4like transi7on" state"with" intramolecular acid"catalysis

H

N

O

O

H Me

NO2

H2O

Me

O

62%,%60%%ee

OH R H

OH

Me

97%,%96%%ee

O

94%,%69%%ee

OH

Me

O

O

Cl

Me

68%,%76%%ee N

OH

N H

CO2H HO C 2

N

allylic+strain

H

◾ Aldol reac)on uses non-‐enolisable aldehydes or α-‐branched aldehydes which do not readily form enamines (due to A1,3 strain). ◾ Mechanism involves enamine forma)on from acetone followed by reac)on with RCHO via Zimmerman-‐Traxler type transi)on state. List, B.; Lerner, R. A.; Barbas III, C. F.; J. Am. Chem. Soc.., 2000, 122, 2395.

98


Cataly-c Asymmetric Aldol Reac-ons – Introduc-on to Organocatalysis ◾ MacMillan developed an efficient cross aldol reac)on of aldehydes.

N H

O Me

H

O Me +

H

Me +

O

H

OH

H

O

O Et

Me +

H

Me 80%,%99%ee, 4:1,%an#:syn

N H

N H

H

N H

CO2H 10(mol%

DMF,(+(4(°C

O

OH

H Me 88%,$97%ee, 3:1,$an#:syn

CO2H 10(mol%

DMF,(+(4(°C

O

O H

10(mol%

DMF,(+(4(°C

O H

CO2H

CO2H

O H

Me 87%,%99%ee, 14:1,%an#:syn

10(mol%

DMF,(+(4(°C

OH

O

OH

H Me 99%,$81%ee, 3:1,$an#:syn

◾ Aldol reac)on uses non-‐enolisable aldehydes or α-‐branched aldehydes which do not readily form enamines. ◾ Mechanism involves stereoselec)ve enamine forma)on from CH3CH2CHO followed by reac)on with acceptor aldehyde. ◾ Donor aldehyde (CH3CH2CHO) added slowly over course of reac)on to prevent homo-‐aldol reac)on. Northrup, A. B.; MacMillan, D. W. C. J. Am. Chem. Soc., 2002, 124, 6798.

99


Cataly-c Asymmetric Aldol Reac-ons – Introduc-on to Organocatalysis ◾ MacMillan developed an efficient cross aldol reac)on of aldehydes.

CO2H

N H

O Me

H

R

O

OH Et

H

DMF,(+(4(°C

CO2H

N

H

HO2C allylic%strain

R s%trans (E)#enamine conforma8on favoured preferred

N

O H

R"group"of aldehyde"is equatorial

CO2H

N R

H R

H

(Z)%enamine disfavoured by4allylic%strain

H

H R

N

H

H

R'

80%,%99%ee, 4:1,%an#:syn

Me

CO2H

N H

O

10(mol%

H

H

R

O O

R'

O

H

N H Me

O

H2O

O

OH

H O

R R'

chair4like transi7on"state intramoleuclar"acid"catalysis

◾ Aldol reac)on uses non-‐enolisable aldehydes or α-‐branched aldehydes which do not readily form enamines ◾ Mechanism involves stereoselec)ve enamine forma)on from CH3CH2CHO followed by reac)on with acceptor aldehyde ◾ Donor aldehyde (CH3CH2CHO) added slowly over course of reac)on to prevent homo-‐aldol reac)on Northrup, A. B.; MacMillan, D. W. C. J. Am. Chem. Soc., 2002, 124, 6798.

100


Cataly-c Asymmetric Mannich Reac-ons

OMe

O R1 excess

R2

+

RCHO +

N H

5)35+mol% R1

1

HN 2

3

R

R2 OMe

HN

O

Me

O

DMSO

H2N

OMe O

OMe

CO2H

OMe

HN

O Me

Me

HN

Me

Me

OMe O

OMe

HN

O

Me NO2

92%,%99%ee >20:1,%dr

OMe

HN

O Me

Me OH

80%,%93%ee

56%,%70%ee

35%,%96%%ee

OH

HN

Me

Me Me

Me

57%,%65%ee 17:1,%dr

90%,%93%ee

◾ Imine formed in situ between aldehyde and amine. ◾ Opposite absolute configura)on at C-‐3 compared with aldol reac)on. ◾ syn-‐Diastereomer predominates (an< predominates in aldol reac)on). List, B.; J. Am. Chem. Soc., 2000, 122, 9336.

101


Cataly-c Asymmetric Mannich Reac-on Mechanism

OMe

O R1 excess

R2

RCHO +

+

N H

OMe

CO2H 5)35+mol%

O R1

DMSO

H2N

RCHO +

O

N H

Me OH

H2N

geometry-of-imine forces-Ar-and-R-intopseudo3axial-posi7ons-topermit-intramolecular acid3catalysis Ar N HO N H H O Me R chair3like transi7on-state

N R

H trans3imine favoured-on steric-grounds

CO2H N

CO2H

Me

R R2

OMe OMe

HN

HO2C

N

O

Me

OH favourable enamine-geometry minimises-allylic-strain

OH O

H

NHAr

Me

R OH

H2O

HO H R

Ar N

H Me

N O O

List, B.; J. Am. Chem. Soc., 2000, 122, 9336. W. Notz, F. Tanaka, S. Watanabe, N. S. Chowdari, J. M. Turner, R. Thayumanavan, and C. F.Barbas III, J. Org. Chem. 2003, 68, 9624.

102


Cataly-c Asymmetric Mannich Reac-on – an- selec-ve – catalyst design

◾ As noted above, the syn-‐selec)ve Mannich reac)on proceeds via a chair like transi)on state from the thermodynamically most favourable enamine conforma)on. ◾ In order to have an an99%,'98%'ee

>99%,'87%'ee

OH

>99%,'99%ee

O

>99%,'99%ee

OH

S

F3C

OH

Ph

OH

S

S

95%,'99%'ee [with'(R,'R))catalyst]

S O O 95%,'98%'ee [with'(R,'R))catalyst] OH

OH O

N NHCH3

(S))MA)20565

OMe

F3C

96%,'91%'ee

Cl

N 68%,'92%'ee [with'(R,'R))catalyst]

For perspec)ve and leading references see: Noyori, R.; Yamakawa, M.; Hashiguchi, S. J. Org. Chem., 2001, 66, 7932.

CO2Me

156


Cataly-c Asymmetric Reduc-on of Ketones – transfer hydrogena-on O H

HO

Cl H

Ru NTs N H

Ph

Ph

H O

H H

H

HO

Ru NTs N H

a"rac%ve CH(π#interac+on (electrosta+c)

Ph

Ph

H Ru NTs N H

H Ph

H

Ru

NTs Ph

R O H N

Ph

H

Ph

◾ Aryl ketones and propargylic ketones are the best substrates. ◾ Low catalyst loading. ◾ Can be conducted in an open reac)on vessel at high substrate (up to 10 M) concentra)on. ◾ Mechanism related to classical Meerewein-‐ Pondorf-‐Verley reduc)on.

R OH

For perspec)ve and leading references see: Noyori, R.; Yamakawa, M.; Hashiguchi, S. J. Org. Chem., 2001, 66, 7932.

157


Asymmetric Reduc-on of Ketones – chiral boranes / borohydrides

◾ Treatment of ketones with chiral boranes can result in highly enan)oselec)ve asymmetric reduc)on. ◾ The most efficient reagents for this reduc)on are Alpine-‐borane™ and DIP-‐chloride Me

Me

B

)2B

Cl

DIP'Cl (diisopinocampheylboron8chloride)

Alpine'borane™

O

O D

Me

OH

OH

B slow 10%$ee

D fast

O

100%$ee fast Me OH

100%$ee

For a review see: Brown, H. C.; Ramachandran, P. V. J. Organomet. Chem., 1995, 500, 1.

Me

R R B O H R Large H Me R Small

small%group bu,resses%against axial%Me%group

158


Asymmetric Reduc-on of Ketones – chiral boranes / borohydrides ◾ More Lewis acidic than Alpine-‐borane™ due to electronega)ve chlorine atom. ◾ reduces wide variety of ketones with high enan)oselec)vity. ◾ Ar group is the “large” group. Me

)2B

Cl

Me Me

small%group bu,resses%against axial%Me%group

DIP$Cl (diisopinocampheylboron6chloride) O Me

)2B

+

OH

OH

OH

R

Ar

Cl

or R1 R2

O

N R

R3

R R B O H R Large H Me R Small

87%$ee

92%$ee

OH

OH Cl

95%$ee

For a review see: H. C.; Ramachandran, P. V. J. Organomet. Chem., 1995, 500, 1.

91%$ee

98%$ee

159


Cataly-c Asymmetric Reduc-on of Ketones Corey, Bakshi, Shibata (CBS)-‐reduc-on

◾ E. J. Corey has developed a highly effec)ve cataly)c asymmetric reduc)on of prochiral ketones using BH3 as the hindered'concave stoichiometric reductant. face

H

CO2H

H Ph Ph

6,steps

Ph H

N B Me 10-mol%-catalyst BH3•THF-(0.6-equivalents) THF,-R.T.

O R Large

O

O

NH

R Large OH

B

BH3

O Ph H

N

B

Me

BH3

chiral borohydride

R Small OH

Cl

Me

N

Me

OH

R Small OH

Ph

Ph

Br

MeO 98%$ee

95%ee OH

97%$ee

OH

97%$ee

91%$ee OH

95%$ee small$group

For a review see: Corey, E. J.; Helal, C. J.; Angew. Chem., Int. Ed. 1998, 37, 1986.

E. J. Corey, Nobel Prize, 1990 for or his development of the theory and methodology of organic synthesis

160


Cataly-c Asymmetric Reduc-on of Ketones -‐ Corey, Bakshi, Shibata (CBS)-‐reduc-on Mechanism

OBH2 R Large

O

Ph

R Small

O Ph H

N

B

R Large

Me

BH3

BH3 Ph

Ph O

Ph H

N

B

BH2

Me R Small

O H

R Large

Ph H

R Small

ketone&coordinates from&most&accessible& face&of&oxazaborolidine with&R Small&bu8ressing&the Me&group Me O B R Small N O H2B R Large H

For a review see: Corey, E. J.; Helal, C. J.; Angew. Chem., Int. Ed. 1998, 37, 1986. For a large scale CBS-‐reduc)on (>1.5 kg) see: Duquexe, J.; Zhang, M.; Zhu, L.; Reeves, R. S. Org. Process Res. Dev. 2003, 7, 285

161


Asymmetric Reduc-on of Ketones -‐ Applica-ons H

Ph

Ph

CF3

O N B Me 10-mol%

O Cl

OH

O N

Cl

0.6-equiv.-BH3•THF THF-0-°C

H H--Cl (R)BfluoxeEne (Prozac™)

100%-yield Corey, E. J.; Reichard, G. A. Tetrahedron Lee., 1989, 30, 5207. 94%-ee Me B )2

Me

CF3

Cl

O

OH

O

Cl

N

Cl

Me

H H++Cl (R)'fluoxe;ne (Prozac™)

70'85%+yield 97%+ee Srebnik, M.; Ramachandran, P. V.; Brown, H. C. J. Org. Chem., 1988, 53, 2916.

Problem: Predict the major enan)omer of the product in the following reac)on. E. J. Corey, C. J. Helal, Tetrahedron Lee., 1995, 36, 9153. Ph H

Ph

O N B Me 15+mol%

O

O

iPr3SiO

NO2

O

BH

toluene+378+°C

OH

iPr3SiO

NO2

162


Asymmetric Addi-on of Diethylzinc to aldehydes

RCHO

+

Et2Zn

H

NMe2 OH 2.mol%

OH

OH Et

toluene,.0.°C 97%$yield 98%$ee

OH Et

Et

96%$ee OH

nBu

90%$ee OH

Et

Et

Bu3Sn

60%$ee

85%ee

◾ Ac)ve catalyst formed from reac)on of Et2Zn with amino alcohol. ◾ Coordina)on of a second molecule of Et2Zn and of RCHO gives pre-‐transi)on state assembly. ◾ Et group delivered selec)vely to one the two prochiral faces of the aldehyde. ◾ Alipha)c aldehydes generally give products with moderate enan)omeric excess. Me2 Et N Zn O H Zn O Et Et

RCHO coordinates to+zinc+opposite gem?dimethyl+group

H+atom+bu8resses against+Et+group H

Me2 Et N Zn O H Zn O Et Et

For a review see: Noyori, R; Kitamura, M. Angew. Chem. Int. Ed., 1991, 30, 49.

unfavourable+interac/on of+alkyl/aryl+groups

H

163


Problem: Ra)onalise the stereochemical outcome of the following reac)on. J. Va´zquez, M. A. Pericas, F. Maseras, A. Lledos, J. Org. Chem., 2000, 65, 7303.

N O

Ph H

Ph Ph OH 6'mol%

Et2Zn,'toluene'0'°C

OH Me 99%#ee

164


Cataly-c Asymmetric Reduc-on with Organocatalysts Me

O

+

EtO2C

Me

Me

CO2Et N H

91%$yield,$93%$ee

O

Ph Me

O Me

Me

74%,%94%%ee

92%,%97%%ee

95%,%91%%ee

Me

O O Me 74%,%90%%ee

Me

O

Cl

Me

TIPSO

+

EtO2C

Cl

O

Ph

Me

N

•-TFA N 20-mol% H CHCl3,-830-°C

H H Ph

O

O

MeO Me 83%,%91%%ee

S. G. Ouellet, J. B. Tuxle, D. W. C. MacMillan, J. Am. Chem. Soc., 2005, 127, 32.

Me

O Me Me

95%,%97%%ee

CO2Et N

Me

165


Cataly-c Asymmetric Reduc-on with Organocatalysts O

Ph

Me

Me iminium%ion forma*on H2O Me

O N

O

O

Ph Me

N N •-TFA H

s4trans geometry minimises%allylic4strain

H2O Me

O N N

N

favoured iminium%ion geometry to%minimise allylic4strain

Me

Ph

hydride%delivered from%least%hindered face%of%iminium%ion

Me

Me H

Ph

Me

Me

EtO2C Me

CO2Et N H

N

N H

direct#a.ack on#imine hindered CO2Et

N H

Ph

O

H H EtO2C

tBu#group#blocks#a.ack of#nucleophiles#on#top#face

Me H CO2Et Me NH EtO2C Me hydride#a.ack from#most#accessible face#of#iminium#ion

Me

◾ α,β-‐Unsaturated iminium ion more electrophilic than α,β-‐unsaturated aldehyde (lower energy LUMO). ◾ Asymmetric iminium ion catalyst complementary to asymmetric enamine catalysis. ◾ LUMO lowering via asymmetric α,β-‐unsaturated iminium ion forma)on is a general and useful concept for asymmetric catalysis. S. G. Ouellet, J. B. Tuxle, D. W. C. MacMillan, J. Am. Chem. Soc., 2005, 127, 32.

166


Summary

O

Ph Me H "H("

O O Me

N

Bu H

B

O

H

O R Me

Bu

O

R H

RO O

N H Me

O O

RO2C OR O CO2R O Ti Ti O O

RO

◾ In order to ra)onalise the stereochemcial outcome of many of the reac)ons you have seen you need to consider: i)  steric and electronic factors ii)  steroelectronic effects iii)  associa)ve substrate-‐reagent interac)ons ◾ In order to do this it is impera)ve to draw clear conforma3onal diagrams.

O tBu

H O E

O

R1


Appendix

◾ Glossary of terms achiral – not chiral i.e. molecule/object has a superimposable mirror image. If a molecule can gain access to a conforma)on which has a plane of symmetry (or centre of inversion) it will be achiral, chiral – Molecules (and objects) which have a non-‐superimposable mirror image, chiral centre – see stereogenic centre, diastereomers – stereoisomers which are not related as enan