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Please login or sign up for a free trial to access the full content. Stetter Reaction To Give 1,4-Diketones

DOI: 10.1055/sos-SD-215-00046

Pohl, M.; Wechsler, C.; Müller, M.Science of Synthesis: Biocatalysis in Organic Synthesis, (20152123.

The Stetter reaction is the conjugate 1,4-addition of an “umpoled” aldehyde derivative to an α,β-unsaturated carbonyl compound (Scheme 28).[‌5‌,‌6‌,‌147‌] The synthetic value of this name reaction is enormous, as the resulting 1,4-diketones are valuable building blocks often used in total synthesis. Nevertheless, their catalytic synthesis is quite challenging, especially if asymmetric reactions are envisaged. Although organocatalytic transformations[‌7‌,‌165‌,‌166‌] have opened access to the catalytic asymmetric Stetter reaction, certain limitations concerning the substrate range, catalytic efficiency, and enantioselectivity remained. In particular, the intermolecular asymmetric Stetter reaction is still a great challenge.

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MeeM eeeeeeeee eee 8,8-eeeeeeee, eee eee eee 8,8-eeeeeeee, ee eeeeeeeee eeeeeeeeeeee (eeeeeeeeeeeeee eeeeeeee) eeee e eeeeeee ee eeeeeeee eee eeeeeeeee α,β-eeeeeeeeeee eeeeeeeee. Meeeeee, ee eeeeeeee eee eeeeeeee eeeeeeee (eeeee eeeeeee eeeeeee ee eeeeeeeee ee eeeeeeee eeeeeeeeee), eee eeeeeeeee 8,8-eeeeeeee eee eeeeeeeeeeee eeeeeeee (Meeeee 88).[‌888‌] Mee eeeeeeeee ee 8,8-eeeeeee eeee eeeeeee ee eeeeeeee eeeeeeeeee eee eee eeeeeeee eeee MeeM. Meee ee ee eeeeeeee ee MeeM, eeeeeee MeMM eeeeeeeee eeeeee (eee Meeeeee[‌888‌] Meeee, eee eeeeeeeeeeeeee eeeeeee ee α,β-eeeeeeeeeee eeeeeeeee eee ee eeeeeeeeee; ee eee eeee ee α,β-eeeeeeeeeee eeeeeee, MeeM eeeeeeeee eee 8,8-eeeeeeee eeee.

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Meeeee 88 MeeM Meeeeeeee 8,8-Meeeeeeeeeeee[‌888‌]

Meeeeeeeeee 88

M8 M8 ee (%) Meeee (%) Mee
(MM8)8Me Me  88 88 [‌888‌]
Me Me  88  8 [‌888‌]
Me Me >88  8 [‌888‌]
(MM8)8Me Me >88 88 [‌888‌]
8-MeM8M8 Me  88 88 [‌888‌]
8-MMM8M8 Me  88 88 [‌888‌]

Meeeee 88 8,8-Meeeeeeeeeeee Meeeeeee Meeeeeee Meeee Meeeeee Meeeeeeeeee[‌888‌]

Meeeeeeeeee 88

M8 M8 Meeeee Meeeeeeeeee (%) eee (%) Meeeee Mee
M Me MeeM   8 [‌888‌]
M Me MeMMM >88 [‌888‌]
M Me MeeM   8.8 [‌888‌]
(MM8)8Me Me MeeM  88 >88 M [‌888‌]
(MM8)8Me Me MeMMM  88 >88 M [‌888‌]
(MM8)8Me Me MeeM  88 >88 M [‌888‌]
Me Me MeeM  88 88–88 M [‌888‌]
Me Me MeMMM eeeeeee e.e. M [‌888‌]
Me Me MeeM   8.8 88 M [‌888‌]
8-MeM8M8 Me MeeM  88 88 M [‌888‌]
8-MeM8M8 Me MeMMM   8 88 M [‌888‌]
8-MeM8M8 Me MeeM  88 88 M [‌888‌]
8-eeeee Me MeeM  88 <88 [‌888‌]
8-eeeee Me MeMMM   8 <88 [‌888‌]
8-eeeee Me MeeM   8 <88 [‌888‌]
(MM8)8Me M(MM8)8MMMe MeeM  88 e.e. [‌888‌]
(MM8)8Me M(MM8)8MMMe MeMMM  88 e.e. [‌888‌]
(MM8)8Me M(MM8)8MMMe MeeM  88 e.e. [‌888‌]

e Meeeeeeeee eeeee 88 e.

e Meeeeeeeee ee MM ee MMMM ee e eeeeee eeeeeeeeee eeeee; e.e. = eee eeeeeeeeee.

e Meeeee ee eee 8,8-eeeeeeeeeeeee eeeeeee eeeeeeee ee MM/MM eee MMMM-MM/MM.

MeMeeM eeeeeeeee e Meeeeee-eeee eeeeeeee ee α-eeeeeeeeeeeee ee eeeeeeeeeeeee {(M)-8-[(8-eeeeeeeeeeee)eee]-8-eeeeeeeeeeeeeeee-8,8-eeeee-8-eeeeeeeeeee} ee e eeeeeeeeeeeee eeeeeeee; ee eee eeee ee eeeeeee ee e eeeeeeee ee eeeeeeeeee eeeeeeeeeeeeee Meeeeee eeeeeeeee. Meeeeee eee eeeee eeeeeeeee eeeee ee MeMeeM eee 8,8-eeeeeeeee ee eeeeee eeeeeeeeee, MeMeeM eeeeeee e eeeee eeeee ee Meeeeee eeeeeeee eeeeeeeeee ee eeee eeee eeeee 88 (Meeeee 88).[‌888‌]

Meeeee 88 MeMeeM Meeeeeeee 8,8-Meeeeeeee[‌888‌]

Meeeeeeeeee 88

M8 M8 Meeeeeeeee (%) Mee
Me MM8M  88 [‌888‌]
M MM8M >88 [‌888‌]
M MM  88 [‌888‌]
M MM8Me  88 [‌888‌]
M Me  88 [‌888‌]

Meeeeeeeeeee Meeeeeeee

8,8-Meeeeeeee 88; Meeeeee Meeeeeeee:[‌888‌]

Mee eeeeeeee eeeeeeeee (88 eM) eee eeeeee eeeeeeee (88 eM) eeee eeeeeeeee ee e-MeMMe (888 µM), eee eeeeeeeee M8M (88.8 eM) eee eeeee. Meeee eeeeeeee ee MeeM ee eeeeee-eeeee eeeeee eeeeeeeeee 88% ee MeeM eeeeeee, eee eeeeeeee eee eeeeeeeee ee 88 °M eee 888 eee. Mee eeeeeeeee eeee (M)-eee-8-ee-8-eee, (M)-eee-8-ee-8-eee, (M)-8-eeeeeeeee-8-ee-8-eee, (M)-8,8-eeeeeeeeeeee-8-ee-8-eee, ee (M)-8-(8-eeeeeee)eee-8-ee-8-eee ee eeeeeeee eeeeeeeeee eeee eeeeeee eeee 88% ee eee eeeee eeeeee ee MeeM (eee eeeee 88% eee eeeee eeeee 88 e). Meee, eee eeeeeeeee eeee eeeeeee eeeee 88 e. Mee eeeeeeeee eeee (M)-8-(8-eeeeeeeeeeee)eee-8-ee-8-eee, (M)-8-(8-eeeeeeeeeeeee)-8-eeeeeeeeee-8-ee-8-eee, ee (M)-8-(8-eeeee)eee-8-ee-8-eee eeee eeeeeee eeee eee eeeee eeeeee ee eeeeeee eee eee eeeeeeeee eeee eeeeeee eeeee 88 e. Mee eeeeeee eee eeeeeee ee eeeeeeeeee eeeeeee Meeeee eee eeeeee eeee MeMMe (88 eM). Mee eeeeeee eeeee eee eeeeee eeee M8M eee eeeee eee eeeee (Me8MM8). Mee eeeeeee eee eeeeeeeeee eee eee eeeee eeeeeee eee eeeeeeee ee eeeeee eeeeeeeeeeeeee (eeeeee eee, eeeeeeeeeee/MeMMe).

8,8-Meeeeeeee 88; Meeeeee Meeeeeeee eeee MeMMM ee MeeM ee Meeeeeee:[‌888‌]

Mee eeeeeeeee eeeeeeeeeeeeeee (8.8 eM eeeeeeee eeeeee) eeee eeeeeeeee ee 88 eM eeeeeeeee eeeeeeeee eeeeee (eM 8.8), eeeeeeeeee MeMe8 (8.8 eM), MeMM (8.8 eM), eee MMMM [88% (e/e)], eeee eeeeeeee eeeeeeeee (88 eM) eee eeeeee eeeeeeee (88 eM). Meeeeeeeeeeeeee eeee MeeM eee MeMMM eeee eeeeeeeee ee 88 °M eeee eeeeeee eeeeeeeeeeeeee ee 8.88 ee/eM. Meeeeeeeeeeeeee eeee MeeM [8.8 ee/eM, eeeeee ee eee eeee eeeee M8 = (MM8)8Me; M8 = M(MM8)8MMMe (8.88 ee/eM)] eeee eeeeeeeee ee 88 °M. Meeeeeeeeeeeeee ee eee eeee eeeeeeeeee eeeeeeeee ee MeeM, MeMMM, eee MeeM eeee eeeeeeeee ee eeeeeeee. Meeee 88 e, 888 µM ee eeee eeeeeeeee eeeeeeeeeeeeee eee eeeeeeeee eeee MeMMe (888 µM) eee eeeeeeeeeeeee ee eee ee ee eee eeeeeee eee eee eeeeeeee eeeeeeeeee eeeee eeeeeee eeeeeeeeee eeeeeee. Mee eeeeeeeee eeeeeee eee eeeeeeeee eeee MMMe8 (8 × 888 µM) eee MMM eeeeeeee.

Meee Meeee 88; Meeeeee Meeeeeeee:[‌888‌,‌888‌]

MeMeeM (88 µe/eM eeeee) eee eeeeeeeee ee eeeeee (88 eM eeeeeeeee eeeeeeeee, MeMe8•8M8M (8 eM), MeMM (8.8 eM); eM 8; 88–88 eM]. Meeeeeeee ee eeeeeeeee eeeeeeeeee, MMMM [88% (e/e)] ee e-MeMMe [8% (e/e)] eeee eeeee eeee eeeeeeee eeeeeeeee (88–88 eM) eee eeeee eeeeeeeee α-eeeeeeeeeeeee (88–88 eM) ee 88 °M ee e eeeee eeeeeee, eeeeeeee eeee e eeeeeeee eeeeeee eee. Mee eeeeee eee eeeeee eeee e eeeeee eee eee eeeee M8. Meeee 88, 88, eee 88 e, 888 µM ee eee eeeeeee eee eeeeeeeee eeee MeMMe (888 µM) eeeeeeeeee eeeeee eeee [8% (e/e)] eee MM/MM eeeeeeee. Meeee 88 e, eee eeeeeee eee eeeeeeeee eeee MeMMe (8 × eeeee eeeeee). Mee eeeeeee eeeee eee eeeee (Me8MM8) eee eee eeeeeee eee eeeeeeeeee eeeee eeeeeee eeeeeeee. Meeeeeeeeeee ee eeeee eeeeeeeeeeeeee eee eeeeeeeee ee eeeeee.