Organic Chemistry, Jonathan Clayden, Nick Greeves, Stuart Warren, Peter
Wothers. ◾ Stereochemistry of Organic Compounds, Ernest L. Eliel, Samuel H.
Wilen.
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
Introduction to Stereoselective Organic Synthesis
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
Introduction to Stereoselective Organic Synthesis
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
Introduction to Stereoselective Organic Synthesis
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
Introduction to Stereoselective Organic Synthesis
Acyclic Stereocontrol – aZack on aldehydes and ketones with α-‐stereocentres
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
Introduction to Stereoselective Organic Synthesis
Acyclic Stereocontrol – aZack on aldehydes and ketones with α-‐stereocentres
◾ 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
Introduction to Stereoselective Organic Synthesis
Acyclic Stereocontrol – aZack on aldehydes and ketones with α-‐stereocentres
◾ 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
Introduction to Stereoselective Organic Synthesis
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
Introduction to Stereoselective Organic Synthesis
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
Introduction to Stereoselective Organic Synthesis
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
Introduction to Stereoselective Organic Synthesis
Acyclic Stereocontrol – aZack on alkenes with α-‐stereocentres
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
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
Introduction to Stereoselective Organic Synthesis
Acyclic Stereocontrol – aZack on alkenes with α-‐stereocentres
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
mCPBA,a.acks least,hindered,face
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
Introduction to Stereoselective Organic Synthesis
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
Introduction to Stereoselective Organic Synthesis
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
Introduction to Stereoselective Organic Synthesis
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
Introduction to Stereoselective Organic Synthesis
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
Introduction to Stereoselective Organic Synthesis
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
Introduction to Stereoselective Organic Synthesis
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
Introduction to Stereoselective Organic Synthesis
Enan-oselec-ve Allyla-on and Crotyla-on reac-ons
◾ 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
Introduction to Stereoselective Organic Synthesis
Enan-oselec-ve Allyla-on and Crotyla-on reac-ons
◾ 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
Introduction to Stereoselective Organic Synthesis
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
Introduction to Stereoselective Organic Synthesis
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
Introduction to Stereoselective Organic Synthesis
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
Introduction to Stereoselective Organic Synthesis
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
Introduction to Stereoselective Organic Synthesis
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
Introduction to Stereoselective Organic Synthesis
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.
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Introduction to Stereoselective Organic Synthesis
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
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Introduction to Stereoselective Organic Synthesis
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
Introduction to Stereoselective Organic Synthesis
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%$ee
For a review see: Brown, H. C.; Ramachandran, P. V. J. Organomet. Chem., 1995, 500, 1.
Me
R R B O H R Large H Me R Small
small%group bu,resses%against axial%Me%group
158
Introduction to Stereoselective Organic Synthesis
Asymmetric Reduc-on of Ketones – chiral boranes / borohydrides ◾ More Lewis acidic than Alpine-‐borane™ due to electronega)ve chlorine atom. ◾ reduces wide variety of ketones with high enan)oselec)vity. ◾ Ar group is the “large” group. Me
)2B
Cl
Me Me
small%group bu,resses%against axial%Me%group
DIP$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%$ee
159
Introduction to Stereoselective Organic Synthesis
Cataly-c Asymmetric Reduc-on of Ketones Corey, Bakshi, Shibata (CBS)-‐reduc-on
◾ E. J. Corey has developed a highly effec)ve cataly)c asymmetric reduc)on of prochiral ketones using BH3 as the hindered'concave stoichiometric reductant. face
H
CO2H
H Ph Ph
6,steps
Ph H
N B Me 10-mol%-catalyst BH3•THF-(0.6-equivalents) THF,-R.T.
O R Large
O
O
NH
R Large OH
B
BH3
O Ph H
N
B
Me
BH3
chiral borohydride
R Small OH
Cl
Me
N
Me
OH
R Small OH
Ph
Ph
Br
MeO 98%$ee
95%ee OH
97%$ee
OH
97%$ee
91%$ee OH
95%$ee small$group
For a review see: Corey, E. J.; Helal, C. J.; Angew. Chem., Int. Ed. 1998, 37, 1986.
E. J. Corey, Nobel Prize, 1990 for or his development of the theory and methodology of organic synthesis
160
Introduction to Stereoselective Organic Synthesis
Cataly-c Asymmetric Reduc-on of Ketones -‐ Corey, Bakshi, Shibata (CBS)-‐reduc-on Mechanism
OBH2 R Large
O
Ph
R Small
O Ph H
N
B
R Large
Me
BH3
BH3 Ph
Ph O
Ph H
N
B
BH2
Me R Small
O H
R Large
Ph H
R Small
ketone&coordinates from&most&accessible& face&of&oxazaborolidine with&R Small&bu8ressing&the Me&group Me O B R Small N O H2B R Large H
For a review see: Corey, E. J.; Helal, C. J.; Angew. Chem., Int. Ed. 1998, 37, 1986. For a large scale CBS-‐reduc)on (>1.5 kg) see: Duquexe, J.; Zhang, M.; Zhu, L.; Reeves, R. S. Org. Process Res. Dev. 2003, 7, 285
161
Introduction to Stereoselective Organic Synthesis
Asymmetric Reduc-on of Ketones -‐ Applica-ons H
Ph
Ph
CF3
O N B Me 10-mol%
O Cl
OH
O N
Cl
0.6-equiv.-BH3•THF THF-0-°C
H H--Cl (R)BfluoxeEne (Prozac™)
100%-yield Corey, E. J.; Reichard, G. A. Tetrahedron Lee., 1989, 30, 5207. 94%-ee Me B )2
Me
CF3
Cl
O
OH
O
Cl
N
Cl
Me
H H++Cl (R)'fluoxe;ne (Prozac™)
70'85%+yield 97%+ee Srebnik, M.; Ramachandran, P. V.; Brown, H. C. J. Org. Chem., 1988, 53, 2916.
Problem: Predict the major enan)omer of the product in the following reac)on. E. J. Corey, C. J. Helal, Tetrahedron Lee., 1995, 36, 9153. Ph H
Ph
O N B Me 15+mol%
O
O
iPr3SiO
NO2
O
BH
toluene+378+°C
OH
iPr3SiO
NO2
162
Introduction to Stereoselective Organic Synthesis
Asymmetric Addi-on of Diethylzinc to aldehydes
RCHO
+
Et2Zn
H
NMe2 OH 2.mol%
OH
OH Et
toluene,.0.°C 97%$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
Introduction to Stereoselective Organic Synthesis
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
Introduction to Stereoselective Organic Synthesis
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
Introduction to Stereoselective Organic Synthesis
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
Introduction to Stereoselective Organic Synthesis
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
Introduction to Stereoselective Organic Synthesis
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