One-Pot Organocatalytic Direct Asymmetric Synthesis of γ-Amino Alcohol Derivatives

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

References

• 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.

• 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

1

Current address: Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University, SE-10691 Stockholm, Sweden. Fax: [phone]

12

We 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.

13

The 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.

14

Anhydrous 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).

16

Anhydrous 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).