Synlett 2017; 28(11): 1363-1367
DOI: 10.1055/s-0036-1558971
letter
© Georg Thieme Verlag Stuttgart · New York

Design of Novel Hydrogen-Bonding Donor Organocatalysts and Their Application to Asymmetric Direct Aldol Reaction

Hiroshi Akutsu
Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan   Email: [email protected]
,
Kosuke Nakashima
Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan   Email: [email protected]
,
Hikaru Yanai
Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan   Email: [email protected]
,
Akira Kotani
Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan   Email: [email protected]
,
Shin-ichi Hirashima
Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan   Email: [email protected]
,
Tomoyuki Yamamoto
Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan   Email: [email protected]
,
Ryuta Takahashi
Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan   Email: [email protected]
,
Akihiro Yoshida
Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan   Email: [email protected]
,
Yuji Koseki
Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan   Email: [email protected]
,
Hideki Hakamata
Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan   Email: [email protected]
,
Takashi Matsumoto
Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan   Email: [email protected]
,
Tsuyoshi Miura*
Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan   Email: [email protected]
› Author Affiliations
Further Information

Publication History

Received: 02 February 2017

Accepted after revision: 23 February 2017

Publication Date:
15 March 2017 (online)


Abstract

Asymmetric catalytic activities of various organocatalysts bearing double hydrogen-bonding donor units showing different pK a values were examined for direct aldol reactions of cyclohexanone with aromatic aldehydes. Organocatalyst with motif exhibiting the highest acidity resulted in the corresponding aldol products with the highest enantioselectivity. A good correlation has been observed between the asymmetric catalytic activity for direct aldol reactions and acidities of double hydrogen-bonding donating units.

Supporting Information

 
  • References and Notes


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  • 11 Organocatalyst 8 Colorless powder; mp 225–227 °C; [α]D 20 +79.2 (c 1.00, MeOH). 1H NMR (400 MHz, CD3OD): δ = 1.97 (m, 2 H), 2.13–2.15 (m, 2 H), 3.25–3.33 (m, 2 H), 3.5 (dd, J = 5.7, 14.8 Hz, 1 H), 3.78 (m, 1 H), 3.93 (m, 1 H), 7.55 (s, 1 H), 7.60 (s, 2 H). 13C NMR (100 MHz, CD3OD): δ = 25.6, 28.0, 45.0, 46.5, 62.4, 68.9, 116.7, 120.4, 125.0 (q, 1 J C–F = 271.7 Hz), 125.2, 132.5 (q, 2 J C–F = 32.7 Hz), 151.7, 154.2. Anal. Calcd for C17H15F12N3O4S2: C, 33.07; H, 2.45; N, 6.81. Found: C, 32.98; H, 2.59; N, 6.68. Organocatalyst 9 Colorless powder; mp 243–245 °C; [α]D 20 +85.7 (c 1.00, MeOH). 1H NMR (400 MHz, CD3OD): δ = 1.90–2.03 (m, 2 H), 2.11–2.19 (m, 2 H), 3.30–3.33 (m, 2 H), 3.55 (dd, J = 6.2, 15.0 Hz, 1 H), 3.84 (dd, J = 2.8, 15.0 Hz, 1 H), 3.87–3.97 (m, 1 H), 7.34 (S, 2 H), 7.51 (s, 1 H); 13C NMR (100 MHz, CD3OD): δ = 25.6, 28.1, 45.0, 46.6, 62.6, 68.8, 116.8, 125.0 (q, 1 J C-F = 272.0 Hz), 125.6, 132.7 (q, 2 J C–F = 33.0 Hz), 152.8, 154.4. Anal. Calcd for C18H15F12N3O4S2: C, 34.35; H, 2.40; N, 6.68. Found: C, 34.51; H, 2.68; N, 6.65.
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  • 14 Typical Procedure of the Aldol Reaction Using Organocatalyst 9 To a mixture of p-nitrobenzaldehyde (10a, 30.2 mg, 0.200 mmol) and cyclohexanone (209 μL, 2.00 mmol) was added organocatalyst 9 (12.6 mg, 0.0200 mmol) at r.t. After stirring at r.t. for 72 h, the reaction mixture was directly purified by flash column chromatography on silica gel with a 2:1 mixture of hexane and EtOAc to afford 12a (44.9 mg, 90%) as a white powder.