Page 170 - Advanced Organic Chemistry Part B - Reactions & Synthesis

142 conjugate addition reactions carried out by in situ generation of , -unsaturated
carbonyl compounds from Mannich bases.
CHAPTER 2 186
-Methylenelactones are present in a number of natural products. The reaction
Reactions of Carbon of ester enolates with N,N-(dimethyl)methyleneammonium trifluoroacetate, 187 or
Nucleophiles with 188
Carbonyl Compounds Eschenmoser’s salt, has been used for introduction of the -methylene group in the
synthesis of vernolepin, a compound with antileukemic activity. 189 190

CH
CH CH 2
CH 2 1) LDA, THF, HMPA OH
OH + –
O 2) CH 2 N(CH ) I O H
3 2
H
3) H O + O CH
3
O H 2
H 4) CH I CH O
3
O 2
O
O 5) NaHCO 3 vernolepin
Mannich reactions, or a mechanistic analog, are important in the biosynthesis
of many nitrogen-containing natural products. As a result, the Mannich reaction has
played an important role in the synthesis of such compounds, especially in syntheses
patterned after the biosynthesis, i.e., biomimetic synthesis. The earliest example of
the use of the Mannich reaction in this way was Sir Robert Robinson’s successful
synthesis of tropinone, a derivative of the alkaloid tropine, in 1917.

CO 2 –
–
CH 2 CO 2
CH CH O
2
+H NCH + C O CH N O CH 3 N O
2
3
3
CH O
CH 2
CH 2 –
CO 2
CO 2 –
Ref. 191
As with aldol and Mukaiyama addition reactions, the Mannich reaction is subject
to enantioselective catalysis. 192 A catalyst consisting of Ag + and the chiral imino
aryl phosphine 22 achieves high levels of enantioselectivity with a range of N-(2-
methoxyphenyl)imines. 193 The 2-methoxyphenyl group is evidently involved in an
interaction with the catalyst and enhances enantioselectivity relative to other N-aryl
substituents. The isopropanol serves as a proton source and as the ultimate acceptor
of the trimethylsilyl group.

186
S. M. Kupchan, M. A. Eakin, and A. M. Thomas, J. Med. Chem., 14, 1147 (1971).
187 N. L. Holy and Y. F. Wang, J. Am. Chem. Soc., 99, 499 (1977).
188
J. L. Roberts, P. S. Borromes, and C. D. Poulter, Tetrahedron Lett., 1621 (1977).
189 S. Danishefsky, P. F. Schuda, T. Kitahara, and S. J. Etheredge, J. Am. Chem. Soc., 99, 6066 (1977).
190 For reviews of methods for the synthesis of -methylene lactones, see R. B. Gammill, C. A. Wilson,
and T. A. Bryson, Synth. Comm., 5, 245 (1975); J. C. Sarma and R. P. Sharma, Heterocycles, 24, 441
(1986); N. Petragnani, H. M. C. Ferraz, and G. V. J. Silva, Synthesis, 157 (1986).
191
R. Robinson, J. Chem. Soc., 762 (1917).
192 A. Cordova, Acc. Chem. Res., 37, 102 (2004).
193
N. S. Josephsohn, M. L. Snapper, and A. H. Hoveyda, J. Am. Chem. Soc., 126, 3734 (2004).