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DOI: 10.1055/s-2003-41423
One-Pot Organocatalytic Direct Asymmetric Synthesis of γ-Amino Alcohol Derivatives
Publication History
Publication Date:
22 September 2003 (online)
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Abstract
This report describes the unprecedented use of unmodified aldehydes as donors in catalytic three component one-pot asymmetric Mannich reactions. The Mannich-type reactions were also readily performed for the first time with both in situ generated and preformed N-PMP protected aromatic aldimines. The proline-catalyzed reactions provided an efficient and very mild entry to either enantiomer of γ-amino alcohol derivatives in high yield and stereoselectivity.
Key words
asymmetric synthesis - asymmetric catalysis - Mannich reactions - aldehydes - imines
-
2a
Enantioselective Synthesis of β-Amino Acids
Juaristi E. Wiley-VCH; Weinheim: 1997. -
2b
Kleinmann EF. In Comprehensive Organic Synthesis Vol. 2:Trost BM.Flemming I. Pergamon Press; New York: 1991. Chap. 4.1. -
2c
Seebach D.Matthews JL. Chem. Commun. 1997, 2015 -
2d
Knapp S. Chem. Rev. 1995, 95: 1859 -
2e
Wang Y.-F.Izawa T.Kobayashi S.Ohno M. J. Am. Chem. Soc. 1982, 104: 6465 - For examples of alternative asymmetric synthesis of 1,3-amino alcohols, see:
-
3a
Kochi T.Tang TP.Ellman JA. J. Am. Chem. Soc. 2002, 124: 6518 -
3b
Yamamoto Y.Kornatsu T.Maryama K. J. Chem. Soc., Chem. Commun. 1985, 814 -
3c
Toujas J.-L.Toupet L.Vaultier M. Tetrahedron 2000, 56: 2665 -
3d
Barluenga J.Fernandez-Marí F.Viado AL.Aguilar E.Olano B. J. Org. Chem. 1996, 61: 5659 - For examples of alternative catalytic asymmetric synthesis of β-amino acid derivatives, see:
-
4a
Sibi MP.Shay JJ.Liu M.Jasperese CP. J. Am. Chem. Soc. 1998, 120: 6615 -
4b
Myers JK.Jacobsen EN. J. Am. Chem. Soc. 1999, 121: 8959 -
4c
Nelson S.Spencer KL. Angew. Chem. Int. Ed. 2000, 39: 1323 -
4d
Davies HML.Venkataramani C. Angew. Chem. Int. Ed. 2002, 41: 2197 -
4e
Hodous BL.Fu GC. J. Am. Chem. Soc. 2002, 124: 1578 - For review, see:
-
5a
Arend M.Westerman B.Risch N. Angew. Chem. Int. Ed. 1998, 37: 1044 -
5b
Kobayashi S.Ishitani H. Chem. Rev. 1999, 99: 1069 -
5c
Denmark S.Nicaise OJ.-C. In Comprehensive Asymmetric Catalysis Vol. 2:Jacobsen EN.Pfaltz A.Yamomoto H. Springer; Berlin: 1999. p.93 -
6a
Palomo C.Oiarbide M.Gonzales-Rego MC.Sharma AK.Garcia JM.Landa C.Linden A. Angew. Chem. Int. Ed. 2000, 39: 1063 -
6b
Corey EJ.Decicco CP.Newbold RC. Tetrahedron Lett. 1991, 39: 5287 -
6c
Seebach D.Betschart C.Schiess M. Helv. Chim. Acta 1984, 67: 1593 -
6d
Evans DA.Urpi F.Somers TC.Clark JS.Bilodeau MT. J. Am. Chem. Soc. 1990, 112: 8215 - For recent catalytic asymmetric examples, see:
-
7a
Ishitani H.Ueno M.Kobayashi S. J. Am. Chem. Soc. 2000, 122: 8180 -
7b
Kobayashi S.Matsubara R.Kitagawa H. Org. Lett. 2002, 4: 143 -
7c
Wenzel AG.Jacobsen EN. J. Am. Chem. Soc. 2002, 124: 12964 -
7d
Xue S.Yu S.Deng Y.Wulff WD. Angew. Chem. Int. Ed. 2001, 40: 2271 -
8a
Córdova A.Notz W.Barbas CF. J. Org. Chem. 2002, 67: 301 -
8b
Córdova A.Notz W.Barbas CF. Chem. Commun. 2002, 3024 -
8c
Watanabe S.-i.Córdova A.Tanaka F.Barbas CF. Org. Lett. 2002, 4: 4519 -
8d
Córdova A.Barbas CF. Tetrahedron Lett. 2003, 44: 1923 - For other l-proline catalyzed aldehyde addition reactions, see:
-
9a
Bøgevig A.Juhl K.Kumaragurubaran N.Jørgensen KA. Chem. Commun. 2002, 620 -
9b
Bøgevig A.Kumaragurubaran N.Zhuang W.Jørgensen KA. Angew. Chem. Int. Ed. 2002, 41: 1790 -
9c
List B. J. Am. Chem. Soc. 2002, 124: 5656 -
9d
Northrup AB.MacMillan DWC. J. Am. Chem. Soc. 2002, 124: 6798 -
10a
Córdova A.Watanabe S.-i.Tanaka F.Notz W.Barbas CF. J. Am. Chem. Soc. 2002, 124: 1866 -
10b
Córdova A.Barbas CF. Tetrahedron Lett. 2002, 43: 7749 - There are reports of direct asymmetric Mannich reactions with unmodified ketones, see:
-
11a
Notz W.Sakthivel K.Bui T.Zhong G.Barbas CF. Tetrahedron Lett. 2001, 42: 199 -
11b
Juhl K.Gathergood N.Jørgensen KA. Angew Chem. Int. Ed. 2001, 40: 2995 -
11c
Yamasaki S.Iida T.Shibasaki M. Tetrahedron 1999, 55: 8857 -
11d
List B. J. Am. Chem. Soc. 2000, 122: 9336 -
11e
Córdova A.Notz W.Zhong G.Betancort JM.Barbas CF. J. Am. Chem. Soc. 2002, 124: 1842 -
11f
Trost BM.Terrell LR. J. Am. Chem. Soc. 2003, 125: 338 -
11g
Matsunaga S.Kumagai N.Harada S.Shibasaki M. J. Am. Chem. Soc. 2003, 125: 4712 -
17a NMR-data of the major diastereomer of PMP-deprotected 6 was identical to the previously reported syn-diastereomer, see:
Jaeger V.Buss V.Schwab W. Liebigs Ann. Chem. 1980, 122 -
17b
(2 S ,3 S )-3-Amino-2-methyl-3-phenylpropan-1-ol (9): 1H NMR (CD3OD): δ = 1.10 (d, 3 H, J = 4.4 Hz), 2.35 (m, 1 H), 3.44 (d, 1 H, J = 5.14 Hz), 3.48 (d, 1 H, J = 6.6 Hz), 4.35 (d, 1 H, J = 6.6 Hz), 7.54 (m, 5 H). 13C NMR: δ = 12.0, 40.9, 59.1, 66.2, 126.9, 127.1, 128.2, 143.9.
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17c
l-Proline derived 6 had the same retention time as (2S,3S)-6 that had been synthesized via known procedures, see:
Vicario JL.Badía D.Carrillo L. J. Org. Chem. 2001, 66: 9030 -
17d See also:
Vicario JL.Badía D.Carrillo L. Org. Lett. 2001, 3: 773; HPLC (Daicel Chiralpak AD, hexanes/i-PrOH = 99:1, flow rate 1.0 mL/min, λ = 254 nm): t R = 14.02 min
References
Current address: Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University, SE-10691 Stockholm, Sweden. Fax: +46(8)154908
12We observed that Mannich product 1 was unstable and racemized if stored at room temperature or subjected to silica gel column chromatography. In addition, 1 is prone to epimerization that decreases the diastereomeric ratio.
13The reaction proceeded in other solvents as well at 23 °C: Dioxane: 65% yield, dr>10:1, 99% ee; THF: 51% yield, dr>10:1, 99% ee; Et2O: 40% yield, dr>10:1, 99% ee; and at 4 °C: THF: 36% yield, dr>10:1, >99% ee; dioxane: 62% yield, dr>10:1, 99% ee.
14Anhydrous DMF (3 mL) was added to a vial containing the aldimine (0.5 mmol) and proline (30 mol%) and placed in a 4 °C cold room. The reaction was initiated by slow addition (0.2 mL/min) of a pree-cooled mixture of propionaldehyde (5.0 mmol) in anhyd DMF (2 mL) with syringe pump at 4 °C. After 15 h the reaction mixture was diluted with anhyd Et2O (2 mL) and the temperature decreased to at 0 °C followed by reduction with NaBH4 (400 mg) for 10 min. Next, the reaction mixture was poured into a vigorously stirred bi-phaseic solution of Et2O and 1 M aq HCl. The organic layer was separated and the aq phase was extracted thoroughly with EtOAc. The combined organic phases were dried (MgSO4), concentrated, and purified by flash column chromatography (silica gel, mixtures of hexanes/EtOAc) to afford 2. (2 S ,3 S )-2-Methyl-3-(4-methoxyphenylamino)-3-(4-nitrophenyl)-propan-1-ol (2): 1H NMR (CDCl3): δ = 0.91 (d, 3 H, J = 7.0 Hz), 2.21 (m, 1 H), 3.64 (m, 2 H), 3.67 (s, 3 H, OMe), 4.65 (d, 1 H, J = 4.0 Hz), 6.42 (d, 2 H, J = 8.8 Hz), 6.68 (d, 2 H, J = 8.8 Hz), 7.51 (d, 2 H, J = 8.8 Hz), 8.17 (d, 2 H, J = 8.8 Hz). 13C NMR: δ = 11.9, 41.6, 56.0, 60.8, 66.0; 115.0, 115.1, 123.9, 128.3, 141.0, 147.3, 150.6, 152.6. HPLC (Daicel Chiralpak AD, hexanes/i-PrOH = 99:1, flow rate 1.0 mL/min, λ = 254 nm): major isomer: t R = 36.10 min; minor isomer: t R = 21.49 min; [α]D = -65.2 (c 0.2, MeOH). HRMS: 317.1496; C17H20N2O4 [(M + H+): calcd 317.1496]; C17H20N2O4 (316.1423).
15(1 S ,2 S )-1-(4-Methoxyphenylamino)-1-(4-nitrophenyl)-2-hydroxymethylheptane: 1H NMR (CD3OD): δ = 0.83 (t, 3 H, J = 7.0 Hz), 1.22-1.55 (m, 8 H), 2.08 (m, 1 H), 3.54 (d, 1 H, J = 3.3 Hz), 3.68 (s, 3 H, OMe), 3.73 (d, J = 3.3 Hz), 4.71 (d, J = 3.3 Hz), 6.48 (d, 2 H, J = 8.8 Hz), 6.68 (d, 2 H, J = 8.8 Hz). 13C NMR: δ = 14.4, 22.9, 27.8, 29.7, 46.4, 56.1, 63.9, 96.6, 115.3, 124.1, 128.7, 147.5. HPLC (Daicel Chiralpak AD, hexanes/i-PrOH = 90:10, flow rate 1.0 mL/min, λ = 254 nm): major isomer: t R = 17.79 min; minor isomer: t R = 7.43 min; [α]D = -24.7 (c 0.2, MeOH). HRMS: 373.2120; C21H28N2O4 [(M + H+): calcd 373.2122); C21H28N2O4 (372.2048968).
16Anhydrous DMF (3 mL) was added to a vial containing p-nitrobenzaldehyde (0.5 mmol), p-anisidine (0.5 mmol) and proline (30 mol%) and placed in a 4 °C cold room. The reaction was initiated by slow addition (0.2 mL/min) of a pree-cooled mixture of propionaldehyde (5.0 mmol) in anhyd DMF (2 mL) with syringe pump at 4 °C. After 16 h of total reaction time the temperature was decreased to 0 °C followed by dilution with anhyd Et2O (2 mL) and reduction with NaBH4 (400 mg) for 10 min. Next, the reaction mixture was poured into a vigorously stirred bi-phaseic solution of Et2O and 1 M aq HCl. The organic layer was separated and the aqueous phase was extracted thoroughly with EtOAc. The combined organic phases were dried (MgSO4), concentrated, and purified by flash column chromatography (silica gel, mixtures of hexanes/EtOAc) to afford 2.
18(2 S ,3 S )-2-Methyl-3-(4-methoxyphenylamino)-3-phenylpropan-1-ol (6): 1H NMR (CD3OD): δ = 0.95 (d, 3 H, J = 7.0 Hz), 2.05 (m, 1 H), 3.38 (dd, 1 H), 3.56 (dd, 1 H), 3.62 (s, 3 H, OMe), 4.43 (d, 1 H, J = 4.0 Hz), 6.38 (d, 2 H, J = 8.8 Hz), 6.50 (d, 2 H, J = 8.8 Hz), 7.12 (m, 1 H), 7.24 (m, 2 H); 7.31 (d, 2 H, J = 7.7 Hz). 13C NMR: δ = 12.8, 43.7, 56.3, 61.4, 66.0, 115.7, 116.0, 127.7, 128.6, 129.3, 143.9, 144.6, 151.9, 153.1, 157.7. HPLC (Daicel Chiralpak AD, hexanes/i-PrOH = 99:1, flow rate 1.0 mL/min, λ = 254 nm): major isomer: t R = 14.02 min; minor isomer: t R = 12.18; [α]D = -6.2. (c 1, MeOH). HRMS: 272.1647; C17H21NO2 [(M + H+): calcd 272.1645); C17H21NO2 (271.172206).