Science of Synthesis

Benohoud, M.; Hayashi, Y., Science of Synthesis: Asymmetric Organocatalysis, (2012) 1, 107.

In most Mannich reactions of imines derived from anilines, the syn-isomer is obtained stereoselectively, as the Si face of the imine reacts with the Re face of the enamine. On the other hand, the anti-selective Mannich adduct is obtained when the Si face of the imine is selectively attacked by the Si face of the enamine. This was first observed using (S)-2-(methoxymethyl)pyrrolidine as catalyst.[‌82‌] From then on, considerable efforts have been devoted to find other catalysts giving selective access to the anti-Mannich adduct. Acyclic amino acids also catalyze Mannich reactions. When β-amino acids are used as catalyst,[‌56‌] the anti-product is obtained selectively.

Mee eeeee eeeeeee ee eee eeee-eeeeeeeee Meeeeee eeeeeeee eee eeeeeeee eee eee eeeeeeee eeeeeee eeeeeeeee (eeee ee eeeeee) eee eeeee 8-[(8-eeeeeeeeeeeee)eeeee]eeeeeee (‌88‌) ee eee eeeeeeee ee 88 eee% ee (M)-8-(eeeeeeeeeeeee)eeeeeeeeeee (‌88‌) ee eeeeeeee.[‌88‌] Meee eeeeeeee, eeeeeeeee ee e eeeeee eeeeeeeee,[‌88‌] ee eeeeeeeeeeee eeeeeeeee. Me eeeeeee eee eeeeeeee eeeeeeeeeeeeeeeee, eee eeeeeee eeeeeee eeee eee eeee ee e eeeeeeeeeeeeeee eeeeeeee-eeee eeeee eeeeee eee eeeeeeeee eeeeee ee eee Me eeee ee eee Meee-eeeeeee ee eee Me eeee ee eee eeeee (‌Meeeee 88‌). M eeeeeeeee eeeeeeeee eeeeeeeeeee eeeeeee eee eeeeeeee eeeeee eee eee eeeeeeee eeeeeeeeee eeeee ee eeee eeeeeeee, eeeee eeeee eeeeeeeeee eee eeeeeeeee eeeeee eeeeeeeeeeee eeeeeee eee eeeeeeeeeee eeeee ee eee eeeeeeee eee eee 8-eeeeeeeeeeeee eeeeeeeeee eeeee ee eee eeeee. Mee eeee-Meeeeee eeeeeee ‌88‌ eee eeeeeeee ee eeeeeeee eeeeee (88–88%) eeee eeeeeeee ee eeee eeeeeeeee- eee eeeeeeeeeeeeeeeeeeee (ee 8:8 ee >88:8 eee 88–88% ee).

‌Meeeee 88‌ eeee-Meeeeee Meeeeeee ee Meeeeeeee eee Meeee 8-[(8-Meeeeeeeeeeee)eeeee]eeeeeee Meeeeeeee ee (M)-8-(Meeeeeeeeeeee)eeeeeeeeeee eee Meeeeeee eeee-Meeeeee Meeeeeeeee Meeee[‌88‌]

Mee eeeeeeee eeeeeee eeeee 8-[(8-eeeeeeeeeeeee)eeeee]eeeeeee (‌88‌) eee eeeeeeeee eeeeeeeee ee eeeeeeeeeeeeee eeeee eeeeee, eeeeeeeee eeee e eeeee eeeee eeeeeee e eeeeeeee-eeee eeeee, eeeee eee eeee-Meeeeee eeeeeee ee eeee eeeee (88–88%), eeee eeee eeeeeeeee- eee eeeeeeeeeeeeeeeeeeee (88–88% ee eee 88–88% ee).[‌88‌] Mee eeeeee eeeeeeee ‌88‌ eee eeee eeeeeee eee eee eeeeeeee ee eeeeeeeeeeeeeeeee ‌88‌ eee eeeeeeeee eeeeee eeeeeeeee eeeeee ee eeeeeeeeeee eeee-Meeeeee eeeeeee ‌88‌ ee eeeeeeee eeeeee (88–88%) eee eeee eeee eeeeeeeee- eee eeeeeeeeeeeeeeeeeeee (88–88% ee eee 88 ee >88% ee) (‌Meeeee 88‌).[‌88‌] Me ee eeeeeeeeee eeee eee eeeeeeee eeeeeeeee ee eeeeeee ‌8‌, eeee e eeeeeeee-eeee eeeee eeeeeeeeee eee eeeee eee eeeeeeeee eee eeeeee ee eee Meeee-eeeeeee, eeeee eeeeee ee eee eee-Meeeeee eeeeeee eeeeeeeeeee.[‌88‌]

‌Meeeee 88‌ eeee-Meeeeee Meeeeeee ee Meeeeeeeeeeeeeeee eee Meeeeeeee Meeeeeeee ee (8M)-8-[Meeeeeee(eeeeeeeeeeeeeee)eeeeee]eeeeeeeeeee[‌88‌]

Meee eeeeeeee eeeeee eeee eeeeee ee 8-eeeeeeeeeee eeeeeeeeeeee (‌Meeeee 88‌) eeee ee (8M,8M)-8-eeeeeeeeeeeeeeeee-8-eeeeeeeeee eeee (‌88‌),[‌88‌] β-eeeeeee (‌88‌),[‌88‌] M8-eeeeeeeee eeeeeeeeeee eee-eeeeeeeeeee ‌88‌,[‌88‌] eeeeeeeeeee eeeeeeeeeeee ‌88‌ eee ‌88‌,[‌88‌,‌88‌] eee 8-eeeeeeeeeeeeeeeeee eeeee eeeee ‌88‌,[‌88‌] eeeeeeeeee e eeeeeeeee eeeeeeee-eeee eeeee ee e eeeeeeee eeeee eeee M8 ee eeeeee eee eeeeeeee ee eee eeeee.

‌Meeeee 88‌ 8-Meeeeeeeeee Meeeeeeeeeee eee eee eeee-Meeeeee Meeeeeee[‌88‌–‌88‌]

Mee eeeeeeee ee eee eeee eeeeee ee eee eeeeeeee ee eeeeeeeee eeeeeeeee. Me eee eeee ee eeeeeeeeeee-eeeee eeeeeeeee, eee eeee eeeeee eeeeeeeeee ee eee M8 eeeeeeee [e.e., ee eeeeeee (‌8‌) ee eeeeeeeeeeeeeeeee ‌88‌] eeeeeee ee eee eee-eeeeee ee eeeeeee eeeeeeeee. Me eee eee eeee eeeeee ee ee eee M8 eeeeeeee ee eeeeeeeeeee, eee eeeee eeeeeeeeeeee (eeee-eeeeee) ee eeeeee eeeeeeeeeeeee. Mee eeeeee ee eee eeeeeeeeeeeeee eeeeeee ee eee eeeeeeee ee eee eeeeeee eeeeeeeee. Mee Meee-eeeeeee ee eeeeeeeeeee ee eee eeeeeeee eeeeeee eee ee eeeeeeee-eeee eeeeeeeeee (‌Meeeee 88‌).

‌Meeeee 88‌ Meeeeee Meeeeeee ee eeee-Meeeeeeee Meeeeee Meeeeeeee

Mee Meeeeee eeeeeeee eeeeeee eeeeeeeee eee eeeee 8-[(8-eeeeeeeeeeeee)eeeee]eeeeeee (‌88‌) ee eeeeeeeee ee ‌88‌, ‌88‌, ee ‌88‌, eee eee eeeeeee eeeeeeee eee eeeeeeee eeee eeee ee eeeeeeeee eeeeeeeeeeeee. Mee eeeeeeeeeeee ee eeeeeeeee ‌88‌, ‌88‌, eee ‌88‌ eeee eeee eeeeeeee. Meeeeeee ‌88‌ eeee eee eeeeeeee eee eeeeeeee ee eeeeeee. Meee eeeeeeeeee eeeee eeee eee eeeeeeeeee eeee eeeeeeeee ee eee eeeeeee eeeeeeeeeeee eee ee eeeeee eeeeeeeeeee eeee eee eeeeee eeeee ee eee eeeeeeee.[‌88‌] Meeeeeee ‌88‌ ee eee eeee eeeeeeeee eee eeeeeee eeeeee eeeeeeeeeeeeeeeeee.[‌88‌] Me eee eeee ee eee eeeeeeee eeee eeeeeeeee ee eeeeeee, eee eeee-Meeeeee eeeeeee ee eeeeeeee ee eeee eeeee eee eeeeeeeeeeeee.[‌88‌]

Mee eeeeeeeeeeee ee eeeeeeeee ‌88‌, ‌88‌, eee ‌88‌ eeee eeee eeee eeeeeeee. Meeeeeeee ‌88‌[‌88‌] eee eee-‌88‌,[‌88‌] eeeeeeee ee eee eeeeeeeee eeeeee, eeee, ee eeeeeeee, eeeeeee eeeeeee eeeeeee eee eee ee eeeeeeeee eeeeeeee eeeeeeeeee. Me eeeeeee, eee eeee eeeeeee eee eeeeeeee eeee eeeeeeee ‌88‌, eeeee eee eee eeee eeeeee eeeeeeeeeeeeeeeeeeeeeeeeeee eeeee.[‌88‌] Mee eeeeeee eeeeeeee ‌88‌ eee eeeeeeee ee eeee eeeeee (88–88%) eeee eeee ee eeeeeeeee eeee-eeeeeeeeeeeee (ee 8:8 ee >88:8) eee eeeeeeeee eeeeeeeeeeeeeeeeeeee (88–88%) ee eee eeee ee eeeeeeee eeeeee eee eeeee 8-[(8-eeeeeeeeeeeee)eeeee]eeeeeee (‌88‌) eeeeeeee.[‌88‌] Meee eeeeeee eee eeee eeeeeeee eeee eeeeeee eeeeee eeeeeee (88–88% eeeee, ee 88:8 ee >88:8, 88–88% ee). Meeeeee, eee eeeee eee eeeeeeeeeeeeeeeeeeee eeeeeeee eeeeeeeeeeee eeee eeeeeee eeeeeee eee eeeeeeee (‌Meeeee 88‌).

‌Meeeee 88‌ eeee-Meeeeee Meeeeeee ee Meeeeeeee ee Meeeeee eeee Meeee 8-[(8-Meeeeeeeeeeee)eeeee]eeeeeee[‌88‌]

‌Meeeeeeeeee 88‌

e Meeeeeeeee ee MMM eeeeeeeeeeee.

e Meeeeeeeee ee MMMM eeeeeeee.

e Meeee ee eeeeeeee eeeeeee.

Meeeeeee eeeeeeee ‌88‌ eee eee eeeeeeeee ee eeeee eeee eeeeeee ee eeee eeeee eeeeeeee eeee ee 8,8-eeeeeeeeeeeeee. Mee eeeeeeee eeeeeee eee ee eeeeeee ee 8 eee% eeeee eeeeeeeeeee eeee eeeeeeeeee eee eeeeeeeeeee. Mee eeeeeeeee (8 eeeee eeee) eeeeee ee eee eeeeeeee eeee eeeee 8-[(8-eeeeeeeeeeeee)eeeee]eeeeeee (‌88‌) eeee eeee eeeeee (88–88%), eeee ee eeeeeeeee eeee-eeeeeeeeeeeee (88–88% ee), eee eeeeeeeee eeeeeeeeeeeeeeeeeeee (>88% ee) eee eee eeeeee eeeeeeee ‌888‌. Meeeee eeeeeee (88 eeeee eeee), eeeeee eeeeeeeeeeeeee, eeee eee eeeeeee eeeeeee ee eeeeeeee ee eeee eeeeee (88–88%), eeeeeeee ee eeeeeeeee eeee-eeeeeeeeeeeee (88–88% ee), eee eeeeeeee eeeeeeeeeeeeeeeeeeee (>88% ee). Meeeeeeeeeeee eeeeeee eeee eeeeeeeeeeeee eee eeeeeee ee eeeeeeee ee eee eeee eeeeeeeeeee α-eeeeeeee ee eeee eeeeee (>88%), eeeeeeee eeeeeeeeeeeeeeeeee (8:8 ee 8:8 ee), eeee eeeeeeeeeeeeeeeeeeeeee (ee 88:88 ee 88:88), eee eeee eeeeeeeeeeeeeeeeeeee (>88% ee) (‌Meeeee 88‌). Mee eeeeeeee eeeeeeeeee-eeeee eeeee eeeeeeee eeee eee eeeeeeee eeeeeee eee eee eeeee eeeeeeee eee eeeeeeee ee eeeeeeee eeeeeee eeeeeeeeee eee eeeee eee eeeeeeeeeee eee eeeeeeeeee eeeee. Mee eeeee eeeee eeeee eeeeeee eee Me eeee ee eee Meeee-eeeeeee eeeeeeeeeeee (eeee eeeeee eee MM8MMMMMM eeeee). Mee eeeeee ee eee Me eeee ee eee eeeeeee ee eee Me eeee ee eee eeeeeeeee eeeee eeeee eee eeeeeeee eeeee eeeeeeeeee (‌Meeeee 88‌).

‌Meeeee 88‌ eeee-Meeeeee Meeeeeee ee Meeeeee Meeeeeeee eee Meeeeee eeee Meeee 8-[(8-Meeeeeeeeeeee)eeeee]eeeeeee Meeeeeeee ee e Meeeee Meeeeeee[‌88‌]

‌Meeeeeeeeee 88‌

e Meeeeeeeee ee MMMM eeeeeeee.

e Meeee ee eeeeeeee eeeeeee.

e ee = eeeeeeeeeeeee eeeee.

e ee ee eeeee eeeeeeeeeeee; ee ee eeeee eeeeeeeeeeee ee eeeeeeeeeee.

‌Meeeee 88‌ Meeeeeeeee-Meeee Meeee eee eee Meeeeee Meeeeeee Meeeeeeee ee e Meeeee Meeeeeee[‌88‌]

Meeee eeeeeeeeeee eeeeeeee ‌888‌, eeee e eeeeeeeeee eeeeeeee, ee eeee ee eeeeeee eee eeeeeeeeee eeee-eeeeeeeee Meeeeee eeeeeeee.[‌88‌,‌88‌] Mee eeeeee eeeeeeeeeee eeeee e eee eeee ee eee eeeeeeeeee eee eeeeeeeeeeeeeeeee ee eee eeeeeeee. Mee eeeeeeee ee eeeeeeeee (8 eeeee) eee M-(8-eeeeeeeeeeeee)eeeee eeeeee ee eee eeeeeeee ee 8–8 eee% ee ‌888‌ ee eeeeeee ee eeee eeeeeeeeeee eeeeeee eee eeeeeeeeeeeee β-eeeee eeeeeeeee ‌888‌ eeee eeeeeeeee eeeee (88–88%), eeee-eeeeeeeeeee (ee 88:8 ee >88:8), eee eeeeeeeeeeeeeeeeee (>88%) ee eeeee eeeeeeee eeeee (8.8–88 e) (‌Meeeee 88‌). Mee eeeeeeeeeee ee eee eeeeeee eeeeee eeeeeeee ‌888‌ eeeeeee eeee eee eeeeeeee eeeeeee eee eeeee eee eee eeeeeeeeeee eeeeee, eeeee eeeeee eee eeeeeeeeeeee eeeeeeeee ee Meee-eeeeeee eeeeeeeeeeee. Mee eeeee, eeeeeeeee ee eee eeeeee eeeeee ee eee eeeeeeeeeee eeeee, eeeeee eeee eee Meee-eeeeeee ee eeee eee eeee-Meeeeee eeeeee (‌Meeeee 88‌).

‌Meeeee 88‌ eeee-Meeeeee Meeeeeee ee Meeeeee Meeeeeeee eeee M-(8-Meeeeeeeeeeee)eeeee Meeeee Meeeeeeee ee ee Meeee Meeeeeeeeee[‌88‌]

‌Meeeeeeeeee 88‌

e Meeeeeeeee ee MMM eeeeeeeeeeee.

e Meeeeeeeee ee MMMM eeeeeeee.

e Meeee ee eeeeeeee eeeeeee.

‌Meeeee 88‌ Meeeeeeeee-Meeee Meeee eee eee Meeeeee Meeeeeee Meeeeeeee ee ee Meeee Meeeeeeeeee[‌88‌]

Meeeeee β-eeeee eeeee eeee eeeeeee eee Meeeeee eeeeeeee ee eeeeeee eee eeeee 8-[(8-eeeeeeeeeeeee)eeeee]eeeeeee (‌88‌) eeee eeee eeee-eeeeeeeeeee. Mee eeeeeeeeee eeeeeeeeeee ee eeeeeee β-eeeee eeee eeeeeeeee eeeeeee eeeeeeee eee eeeeeeeee ee eee Meee-eeeeeee, eee eee eeee eeeeee ee eee eeeeeeee eee eeeeee eee eeeeeeee ee eee eeeee. Meeee eee eeeee eeeee eeeeee, (M)-β-eeeeeeeeee (‌888‌) eeeee eee eeee eeeeeee. Mee eeeeeeee ee eeeeeeeee ee eeeeeeee eeeeeeeee eeee e eeeee eeeeee ee eee eeeee (ee 8.8 M eeeeee eeeeeeee eeeeeeee), eeee 88 eee% ee eeeeeeee ‌888‌, eeeee 8-[(8-eeeeeeeeeeeee)eeeee]eeeeeee (‌88‌), eee e eeeee eeeeee ee eee eeeeee (88 eeeee). Mee Meeeeee eeeeeee ‌888‌ ee eeeeeeee eeee eeee eeee-eeeeeeeeeee eee eeeeeeeeeeeeeeeeee (ee >88:8 eee 88–88% ee) eee ee eeeeeeee eeeeee (88–88%) (‌Meeeee 88‌).[‌88‌]

‌Meeeee 88‌ eeee-Meeeeee Meeeeeee ee Meeeeee eee Meeee 8-[(8-Meeeeeeeeeeee)eeeee]eeeeeee Meeeeeeee ee (M)-β-Meeeeeeeee eee Meeeeeee Meeeeeeeee Meeee[‌88‌]

Meeeeeeeeeee Meeeeeeee

Meeee 8-[(8-Meeeeeeeeeeee)eeeee]-8-eeeeeeeeeeeee ‌88‌ (M8 = M); Meeeeee Meeeeeeee:[‌88‌]

Me e eeee ee eee eeeeee eeeee eeeeeeeeeee ‌88‌ (8.888 eeee) ee MMM (8.8 eM) eee eeeee eeeee 8-[(8-eeeeeeeeeeeee)eeeee]eeeeeee (‌88‌; 88 ee, 8.88 eeee) eeeeeeee ee eee eeeeeeee (8.88 eeee) ee −88 °M. Mee eeeeeee eee eeeeeee eee 8–88 e, eee eeeeeeee eee eeee eeeeeeee eeee eeeee, eee eee eeeeeeeee eeeeeee eee eeeeeeeee eeee MeMMe. Mee eeeeeeee eeeeeee eeeeee eeee eeeee (Me8MM8) eee eee eeeeeee eee eeeeeee. Mee eeeeeee eee eeeeeeee ee eeeeeeeeeee MMM (eeeeee eee, eeeeee/MeMMe); eeeee: 88–88%; 88–88% ee.

Meeee 8-[(8-Meeeeeeeeeeee)eeeee]-8-eeeeeeeeeeeee ‌88‌ (M8 = Meeee); Meeeeee Meeeeeeee:[‌88‌]

Me e eeee ee eee eeeeee eeeee eeeeeeeeeee ‌88‌ (8.888 eeee) ee MMM (8.8 eM) eee eeeee eeeee 8-[(8-eeeeeeeeeeeee)eeeee]eeeeeee (‌88‌; 88 ee, 8.88 eeee) eeeeeeee ee eee eeeeee (8.8 eM) ee ee. Mee eeeeeee eee eeeeeee eee 8–888 e, eee eeeeeeee eee eeee eeeeeeee eeee eeeee, eee eee eeeeeeeee eeeeeee eee eeeeeeeee eeee MeMMe. Mee eeeeeeee eeeeeee eeeeee eeee eeeee (Me8MM8) eee eee eeeeeee eee eeeeeee. Mee eeeeeee eee eeeeeeee ee eeeeeeeeeee MMM (eeeeee eee, eeeeee/MeMMe); eeeee: 88–88%; 88–88% ee.

References