Page 110 - Advanced Organic Chemistry Part B - Reactions & Synthesis

82 2.1.4. The Mukaiyama Aldol Reaction

CHAPTER 2 The Mukaiyama aldol reaction refers to Lewis acid–catalyzed aldol addition
Reactions of Carbon reactions of silyl enol ethers, silyl ketene acetals, and similar enolate equivalents. 48
Nucleophiles with Silyl enol ethers are not sufficiently nucleophilic to react directly with aldehydes or
Carbonyl Compounds
ketones. However, Lewis acids cause reaction to occur by coordination at the carbonyl
oxygen, activating the carbonyl group to nucleophilic attack.

LA
O OH
+ O
TMSO H
+
C C C R 1 R
R 1 R 2 R H R 2

Lewis acids such as TiCl and SnCl induce addition of both silyl enol ethers and
4
4
ketene silyl acetals to aldehydes. 49
OSi(CH ) TiCl 4 O OH
3 3
or
+ O CHCH(CH 3 2
)
Ph CH 2 SnCl 4 Ph CH(CH )
3 2
If there is no other interaction, the reaction proceeds through an acyclic TS and steric
factors determine the amount of syn versus anti addition. This is the case with BF ,
3
where the tetracoordinate boron-aldehyde adduct does not offer any free coordination
sites for formation of a cyclic TS. Stereoselectivity increases with the steric bulk of
1 50
the silyl enol ether substituent R .
– F B – – BF F B –
BF 3
3 3 3
+ O + +O +
O O
H CH H CH 3 H CH 3 H CH
3 3
syn anti syn anti
Ph H H Ph Ph H H Ph
R 1 OTMS Z-enol ether R 1 OTMS TMSO R 1 E-enol ether TMSO R 1
Z-silyl enol ether E-silyl enol ether
R 1 syn:anti syn:anti
Et 60:40 57:43
i-Pr 56:44 35:65
t-Bu <5 95 –
Ph 47:53 30:70

Quite a number of other Lewis acids can catalyze the Mukaiyama aldol reaction,
including Bu Sn O SCF , 51 Bu SnClO , 52 Sn O SCF , 53 Zn O SCF , 54 and
2 3 3 2 3 4 3 3 2 3 3 2
48
R. Mahrwald, Chem. Rev., 99, 1095 (1999).
49 T. Mukaiyama, K. Banno, and K. Narasaka, J. Am. Chem. Soc., 96, 7503 (1974).
50
C. H. Heathcock, K. T. Hug, and L. A. Flippin, Tetrahedron Lett., 25, 5973 (1984).
51
T. Sato, J. Otera, and H. Nozaki, J. Am. Chem. Soc., 112, 901 (1990).
52 J. Otera and J. Chen, Synlett, 321 (1996).
53 T. Oriyama, K. Iwanami, Y. Miyauchi, and G. Koga, Bull. Chem. Soc. Jpn., 63, 3716 (1990).
54
M. Chini, P. Crotti, C. Gardelli, F. Minutolo, and M. Pineschi, Gazz. Chim. Ital., 123, 673 (1993).