Page 124 - Advanced Organic Chemistry Part B - Reactions & Synthesis

96 Heteroatom substituents also introduce polar effects. In the case of -alkoxy
aldehydes the preferred TS appears to be F and G for the E- and Z-enolates, respec-
CHAPTER 2 tively. These differ from the normal Felkin TS for nucleophilic addition. The reactant
Reactions of Carbon conformation is believed to be determined by minimization of dipolar repulsion
Nucleophiles with 96
Carbonyl Compounds between the alkoxy substituent and the carbonyl group. This model predicts higher
3,4-anti ratios for Z-enolates, and this is observed.

RO R H R 1 OH O RO R R 2 BR 2 OH O
R 2 O BR 2 R H O R 1
O R 1 O R
H H R 2
H RO R 2 G RO
F R 2
2,3-anti-3,4-syn product Z-enolate
E-enolate 2,3-syn-3,4-anti product
Dipole-dipole interactions may also be important in determining the stereoselec-
tivity of Mukaiyama aldol reactions proceeding through an open TS. A BF -catalyzed
3
reaction was found to be 3,5-anti selective for several -substituted 5-phenylpentanals.
This result can be rationalized by a TS that avoids an unfavorable alignment of the
C=O and C–X dipoles. 97
TMSO X BF O OH X O OH X
CH + O CH 3 +
2
) CH Ph 3 5 Ph
) CH
(CH 3 2 3 5 Ph (CH 3 2
(CH ) CH
3 2
CH Ph 3,5-anti:syn
CH 2 X
CH CH Ph H 2
2
2
H H = OTMS H PMBO 81:19
CH 2
X OTBDMS 73:27
) H
H X CH(CH 3 2 CH CCH(CH ) OAc 43:57
HO 2 3 2
O H H Cl 83:17
O
BF 3
The same stereoselectivity was observed with a more complex pair of reactants in
which the -substituent is a cyclic siloxy oxygen. 98
CH 3
CH 3
CH 3 O 2 C
CH 3
(CH 3 ) 3 C CH 3 O 2 C
O
Si CH O O O
(CH 3 ) 3 C BF 3
O CH 3 O CH 3 O
CH 3 +
O CH 3
CH 3 (CH 3 ) 3 C
CH 3 O
Si CH 3
OTMS
(CH 3 ) 3 C O
O OH
OCH 3
CH 3
O
CH 3
OCH 3
Thus we see that steric effects, chelation, and the polar effects of - and
-substituents can influence the facial selectivity in aldol additions to aldehydes. These
relationships provide a starting point for prediction and analysis of stereoselectivity
96
D. A. Evans, S. J. Siska, and V. J. Cee, Angew. Chem. Int. Ed. Engl., 42, 1761 (2003).
97 D. A. Evans, M. J. Dart, J. L. Duffy, and M. G. Yang, J. Am. Chem. Soc., 118, 4322 (1996).
98
I. Paterson, R. A. Ward, J. D. Smith, J. G. Cumming, and K.-S. Yeung, Tetrahedron, 51, 9437 (1995).