Making Enolates Diastereoselective Aldol Reactions for Everyone E Enolate Stereocenter E enolate,

Eugene Kwan anti aldol

O OLi OLi
Me + Me Zimmerman–Traxler H OM O OH
MeO MeO MeO R OH O O
OM RL + RL
Me O R
- ignore IUPAC C Me R R H R
"Z" enolate "E" enolate R O Me Me Me Me
- "hard enolization" M Me
Me H
- trap with TMSCl for LDA , THF add DMPU anti aldol H 1,3-syn
silyl enol ether LiTMP, THF add LiBr E enolate R R
Me O
Soft Enolization counterion effect: R OH O Me - for alpha
OM O L
- L 2BOTf favors O M stereocenters
Z enolate Me C H A(1,3) H only, beta has
- add amine base and Lewis acid
R O R R
- Bu 2BOTf, i-Pr2NEt (Z enolate) M min. L no effect
- L 2BCl favors H Me H Me
- Cy2BCl, Et 3N (E enolate)
E enolate Z enolate R syn aldol RL

Chelate Control Felkin Control Z Enolate Stereocenter Z enolate,

Nu front RL
OH syn aldol
O H face OH O
Cram RL R L
R R R H C O Nu OM O OH
H O Nuc H O
H Me Me RL Me + RL
OP M OP OP Me R
H R
1,2-syn polar Felkin: R L = X Nu 1,2-syn Me Me Me
back M - use monodentate Me 1,3-syn
Evans OH OP Polar Control Nu R
face O OP Lewis acid (BF 3)
O
Nuc R H H OH OP H
Nu H R O OP L O
H C O M
1,3-anti ML n Nuc R H
Nu H R
- bidentate Lewis acid needed (Ti, Mg, Al, Sn) L
dipole-dipole
C H Me
- small protecting groups are best 1,3-anti A(1,2)
- 1,3 behavior can be interpreted as half-chair or boat minimization PO H
min. RL
R
1,2-syn
Aldehyde Alpha Stereocenter Aldehyde Beta Stereocenter Chiral Auxiliaries "Evans syn"
Me O OH
OM RL OP H
H R
O OP H O O O O OH
Me Me H PO Bu 2BOTf,
R
RL H RL Me
H RL H H i-Pr 2NEt; RCHO O R
O H R O O N N
Me Me C Nu O Nu H
O H Me
O ML n OTMS CH 2Cl 2
E enolate, H + favored disfavored iPr iPr
RL strong Felkin R O - via Z enolate
H H R - Felkin: Nu opposite large group
iPr
Me Z enolate, Me OP O - use Crimmins
weak anti-Felkin O OH OP N H Bu thiazolidine to
R Me H
O L RL
R dipole H get either Evans
OM C H H SiR 3 R R B or non-Evans syn
- Felkin fights O O min. O Bu
Me L nM 1,2-anti
H O H
syn-pentane R H 1,3-anti O - removal: alcohol (LiBH 4),
O OH
R R RL - with added alpha methyl (not shown), R acid (LiOOH), thioester (RSLi),
anti array is Felkin reinforcing Me amide (Weinreb salt, AlMe3)
Me Me