Page 194 - Advanced Organic Chemistry Part B - Reactions & Synthesis

166 This version of the Wadsworth-Emmons reaction has been used in the scaled-up
syntheses of drugs and drug-candidate molecules. For example, it is used to prepare
CHAPTER 2
a cinnamate ester that is a starting material for pilot plant synthesis of a potential
Reactions of Carbon integrin antagonist. 263
Nucleophiles with
Carbonyl Compounds
O
Cl CH O DBU, LiCl Cl CH CHCO 2 CC(CH )
+ (C H O) PCH CO C(CH ) 3 3
2 5 2 2 2 3 3 CN
Br OCH 2 OCH 3 CH 3 Br OCH OCH 3
2
Entries 10 and 11 of Scheme 2.18 also illustrate this procedure.
Scheme 2.18 gives some representative olefination reactions of phosphonate
anions. Entry 1 represents a typical preparative procedure. Entry 2 involves formation
of a 2,4-dienoate ester using an -unsaturated aldehyde. Diethyl benzylphosphonate
can be used in the Wadsworth-Emmons reaction, as illustrated by Entry 3. Entries 4 to
6 show other anion-stabilizing groups. Intramolecular reactions can be used to prepare
cycloalkenes. 264

O O O
CH 3
CH C(CH ) CCH P(OC H ) NaH
3
2
2 5 2
2 3
O
Ref. 265
Intramolecular condensation of phosphonate carbanions with carbonyl groups carried
out under conditions of high dilution have been utilized in macrocycle syntheses.
Entries 7 and 8 show macrocyclizations involving the Wadsworth-Emmons reaction.
Entries 9 to 11 illustrate the construction of new double bonds in the course of a
multistage synthesis. The LiCl/amine conditions are used in Entries 9 and 10.
The stereoselectivity of the reactions of stabilized phosphonate anions is usually
considered to be the result of reversible adduct formation, followed by rate/product-
controlling elimination that favors the E-isomer. This matter has been investigated by
computation. The Wadsworth-Emmons reaction between lithio methyl dimethylphos-
∗
phonoacetate and acetaldehyde has been modeled at the HF/6-31G level. Energies
∗
were also calculated at the B3LYP/6-31G level. 266 The energy profile for the interme-
diates and TSs are shown in Figure 2.5. In agreement with the prevailing experimental
interpretation, the highest barrier is for formation of the oxaphosphetane and the
addition step is reversible. The stereochemistry, then, is determined by the relative
ease of formation of the stereoisomeric oxaphosphetanes. The oxaphosphetane species
is of marginal stability and proceeds rapidly to product. At the B3LYP/6-31 + G ∗
level, TS2 trans is 2.2 kcal/mol more stable than TS2 The path to the cis product
cis
encounters two additional small barriers associated with slightly stable stereoisomeric

263
J. D. Clark, G. A. Weisenburger, D. K. Anderson, P.-J. Colson, A. D. Edney, D. J. Gallagher,
H. P. Kleine, C. M. Knable, M. K. Lantz, C. M. V. Moore, J. B. Murphy, T. E. Rogers, P. G. Ruminski,
A. S. Shah, N. Storer, and B. E. Wise, Org. Process Res. Devel., 8, 51 (2004).
264 K. B. Becker, Tetrahedron, 36, 1717 (1980).
265 P. A. Grieco and C. S. Pogonowski, Synthesis, 425 (1973).
266
K. Ando, J. Org. Chem., 64, 6815 (1999).