RSS-Feed abonnieren
DOI: 10.1055/s-2004-835622
A Mannich-Cyclization Approach for the Asymmetric Synthesis of Saturated N-Heterocycles
Publikationsverlauf
Publikationsdatum:
22. Oktober 2004 (online)
![](https://www.thieme-connect.de/media/synlett/200415/lookinside/thumbnails/10.1055-s-2004-835622-1.jpg)
Abstract
A concise asymmetric synthesis of disubstituted N-heterocycles is reported. Our approach utilizes an optimized Mannich reaction of functionalized aldehydes, followed by a novel dehydrative cyclization mediated by the Staab reagent (1,1′-carbonyldiimidazole, CDI). The method was applied to the synthesis of azetidines, piperidines and pyrrolidines.
Key words
stereoselective synthesis - heterocycles - cyclizations - azetidines - organocatalysis
- 1
Hutchinson A.Nadin A. J. Chem. Soc., Perkin Trans. 1 2000, 2862 - 2
Breinbauer R.Vetter IR.Waldmann H. Angew. Chem. Int. Ed. 2002, 41: 2878 - Astrophylline:
-
3a
Lloyd HA. Tetrahedron Lett. 1965, 50: 4537 -
3b
Schaudt M.Blechert S. J. Org. Chem. 2003, 68: 2913 - 4 Trachelanthamidine:
Liddell JR. Nat. Prod. Rep. 2000, 17: 455 - 5 Ezetimibe:
Earl J.Kirkpatrick P. Nat. Rev. Drug Discov. 2003, 2: 97 - 6 For another interesting approach, see:
Banwell MG.Beck DAS.Smith JA. Org. Biomol. Chem. 2004, 2: 157 -
7a
Eder U.Sauer G.Wiechert R. Angew. Chem., Int. Ed. Engl. 1971, 10: 496 -
7b
Hajos ZG.Parrish DR. J. Org. Chem. 1974, 39: 1615 -
8a
List B.Lerner RA.Barbas CF. J. Am. Chem. Soc. 2000, 122: 2395 -
8b
Northrup AB.MacMillan DWC. J. Am. Chem. Soc. 2002, 124: 6798 -
9a
List B. J. Am. Chem. Soc. 2000, 122: 9336 -
9b
List B.Pojarliev P.Biller WT.Martin HJ. J. Am. Chem. Soc. 2002, 124: 827 - 10 For an account, see:
Cordova A. Acc. Chem. Res. 2004, 37: 102 - For other leading references, see:
-
11a
Wenzel AG.Jacobsen EN. J. Am. Chem. Soc. 2002, 124: 12964 -
11b
Trost BM.Terrell LR. J. Am. Chem. Soc. 2003, 125: 338 -
11c
Kobayashi S.Matsubara R.Nakamura Y.Kitagawa H.Sugiura M. J. Am. Chem. Soc. 2003, 125: 2507 -
11d
Matsunaga S.Kumagai N.Harada S.Shibasaki M. J. Am. Chem. Soc. 2003, 125: 4712 -
11e
Josephsohn NS.Snapper ML.Hoveyda AH. J. Am. Chem. Soc. 2004, 126: 3734 -
11f
Uraguchi D.Terada M. J. Am. Chem. Soc. 2004, 126: 5356 -
11g
Akiyama T.Itoh J.Yokota K.Fuchibe K. Angew. Chem. Int. Ed. 2004, 43: 1566 - 12
Notz W.Tanaka F.Watanabe S.-i.Chowdari NS.Turner JM.Thayumanavan R.Barbas CF. J. Org. Chem. 2003, 68: 9624 -
13a
Hayashi Y.Tsuboi W.Ashimine I.Urushima T.Shoji M.Sakai K. Angew. Chem. Int. Ed. 2003, 42: 3677 -
13b
Cordova A. Chem.-Eur. J. 2004, 10: 1987 - 14
Mann S.Carillon S.Breyne O.Marquet A. Chem.-Eur. J. 2002, 2: 439 - 16
Holmes AB.Smith AL.Williams SF.Hughes LR.Lidert Z.Swithenbank C. J. Org. Chem. 1991, 56: 1393 - 18
Pulz R.Al-Harrasi A.Reissig H.-U. Org. Lett. 2002, 4: 2353 -
19a
Appel R. Angew. Chem., Int. Ed. Engl. 1975, 14: 801 -
19b
Harris JM.Padwa A. J. Org. Chem. 2003, 68: 4371 -
19c
Pu X.Ma D. J. Org. Chem. 2003, 68: 4400 -
20a
Mitsunobu O. Synthesis 1981, 1 -
20b
Itoh T.Miyazaki M.Nagata K.Yokoya M.Nakamura S.Oshawa A. Heterocycles 2002, 58: 115 -
21a
Staab HA. Angew. Chem., Int. Ed. Engl. 1962, 1: 351 -
21b
Staab HA.Bauer H.Schneider KM. Azolides in Organic Synthesis and Biochemistry Wiley-VCH; Weinheim: 2002. -
22a
Mulvihill MJ.Cesario C.Smith V.Beck P.Nigro A. J. Org. Chem. 2004, 69: 5124 -
22b
Totleben MJ.Freeman JP.Szmuszkovicz J. J. Org. Chem. 1997, 62: 7319 - 23 For a review, see:
Couty F.Evano G.Prim D. Mini-Rev. Org. Chem. 2004, 1: 133 -
24a
Barluenga J.Sanz R.Fananas FJ. J. Org. Chem. 1997, 62: 5953 -
24b
Enders D.Gries J.Kim Z.-S. Eur. J. Org. Chem. 2004, 4471 - 26
Franz T.Hein M.Veith U.Jäger V.Peters E.-M.Peters K.von Schnering HG. Angew. Chem., Int. Ed. Engl. 1994, 33: 1298 - 28
Hughes G.Kimura M.Buchwald SL. J. Am. Chem. Soc. 2003, 125: 11253
References
To a cooled (-40 °C) solution of (l)-proline (17.3 mg, 0.15 mmol) and p-anisidine (61.6 mg, 0.5 mmol) in MeCN (5 mL) was added 4-OTBS-butanal (809 mg, 4 mmol). The reaction mixture was stirred for 4 h at this temperature and then put into a freezer (-30 °C) overnight. The mixture was diluted with Et2O (2 mL) and allowed to reach 0 °C. After the addition of NaBH4 (500 mg), the reaction was stirred for 15 min at this temperature and allowed to reach r.t. The mixture was poured into half sat. aq NH4Cl (50 mL). After 30 min, the aqueous layer was extracted with Et2O (3 × 50 mL) and the combined organic layers are dried with Na2SO4. Removal of the solvent on a rotatory evaporator afforded the crude amino alcohol as a colorless oil. The main impurity, 4-OTBS-butanol, was removed by distillation in a Kugelrohr. The residue was purified by flash chromatography (Et2O-pentane 1:1) on silica gel to afford 10a (218 mg, 0.426 mmol, 85%, 98% ee) as a colorless oil. R f = 0.42 (Et2O-pentane 1:1); HPLC [Chiracel OD (4.6 × 250 mm] n-heptane-i-PrOH 95:5, 1.0 mL/min, λ = 254 nm): major isomer: t R = 13.3 min; minor isomer: t R = 5.9 min. 1H NMR (300 MHz, CDCl3): δ = 6.78 (d, J = 8.9 Hz, 2 H), 6.62 (d, J = 8.9 Hz, 2 H), 3.80-3.55 (m, 9 H), 3.41 (m, 1 H), 2.01 (m, 1 H), 1.70-1.48 (m, 6 H), 0.91 (s, 9 H) 0.89 (s, 9 H), 0.08 (s, 6 H), 0.03 (s, 6 H). 13C NMR (75 MHz, CDCl3): δ = 152.4, 141.7, 115.5 (2 C), 114.9 (2 C), 64.4, 62.7, 61.7, 58.0, 55.7, 40.1, 30.5, 29.8, 27.7, 25.9 (6 C), 18.2 (2 C), -5.5 (2 C), -5.4 (2 C). IR (CHCl3): 3378 (m), 2932 (s), 2891 (s), 2858 (s), 1513 (s), 1468 (m), 1251 (s), 1098 (s), 1043 (m), 836 (s), 776 (s) cm-1. MS (EI): m/z (%) = 511 (32) [M+], 308 (100), 176 (74). HRMS (EI): m/z calcd for C27H53NO4Si2 [M+]: 511.3515. Found: 511.3513. Anal. Calcd for C27H53NO4Si2: C, 63.35; H, 10.44; N, 2.74. Found: C, 62.91; H, 10.26; N, 3.17. [α]D 25 = -17.2 (c 0.98, CHCl3).
175-tert-Butyldimethylsilyloxypentanal afforded the corresponding dimer in 94% ee as a 2:1 mixture in favor of the syn-diastereomer.
25The starting materials were prepared according to ref. 15 or as described by Barbas et al. (ref. 12).
27A solution of the corresponding amino alcohol (0.2 mmol) and 1,1′-carbonyldiimidazole (0.4 mmol) in MeCN (10 mL) was refluxed for 2 h. The solvent was evaporated in vacuo and the intermediate carbamates were heated (150 °C) in a Kugelrohr oven under high vacuum (0.05 mbar) for 2 h. The residue was purified by flash chromatography on silica gel to afford the azetidines. Products of lower molecular weight were collected in the receiving flask. Spectral data for 22d: colorless oil; R f = 0.29 (Et2O-pentane 1:10). 1H NMR (400 MHz, CDCl3): δ = 6.80 (d, J = 8.9 Hz, 2 H), 6.51 (d, J = 8.9 Hz, 2 H), 3.77 (m, 1 H), 3.75 (s, 3 H), 3.62 (dd, J = 8.0, 6.8 Hz, 1 H), 3.48 (dd, J = 6.8, 3.2 Hz, 1 H), 2.65 (m, 1 H), 1.83 (m, 2 H), 1.30 (d, J = 7.2 Hz, 3 H), 0.92 (t, J = 7.5 Hz, 3 H). 13C NMR (75 MHz, CDCl3): δ = 152.2, 147.4, 114.5 (2 C), 113.5 (2 C), 67.9, 58.1, 55.7, 27.5, 23.8, 14.7, 10.2. IR (capillary): 2961 (s), 2873 (m), 2834 (m), 1511 (s), 1465 (s), 1293 (m), 1240 (s), 1120 (m), 1041 (m), 819 (s) cm-1. MS (EI): m/z (%) = 205 (100) [M+], 176 (58), 163 (52), 135 (45), 134 (54). HRMS (EI): m/z calcd for C13H19NO [M+]: 205.1467. Found: 205.1467. [α]D 25 -146.5 (c 1.04, CHCl3).