Synlett 2002(5): 0755-0758
DOI: 10.1055/s-2002-25336
LETTER
© Georg Thieme Verlag Stuttgart · New York

Synthesis of Enantiopure 1-Benzyl-2,3-disubstituted Piperazines from Enantiopure p-Toluenesulfinimines

Alma Viso*a, Roberto Fernández de la Pradilla*a, María L. López-Rodríguezb, Ana Garcíaa, Mariola Tortosaa
a Instituto de Química Orgánica, CSIC, Juan de la Cierva 3, 28006 Madrid, Spain
b Departamento de Química Orgánica I, Facultad de Ciencias Químicas, Universidad Complutense, 28040 Madrid, Spain
Fax: +34(91)5644853; e-Mail: [email protected]; e-Mail: [email protected];
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Publikationsverlauf

Received 7 February 2002
Publikationsdatum:
07. Februar 2007 (online)

Abstract

The treatment of enantiopure N-sulfinyl-N′-benzyldiaminoalcohols with diethyl oxalate and sodium methoxide followed by reduction with BH3 affords enantiopure 1-benzyl-2,3-disubstituted piperazines. A related sequence produces substituted monoketopiperazines in good yields.

    References

  • 1 Dorsey BD. Levin RB. McDaniel SL. Vacca JP. Guare JP. Darke PL. Zugay JA. Emini EA. Schleif WA. Quintero JC. Lin JH. Chen I.-W. Holloway MK. Fitzgerald PMD. Axel MG. Ostovic D. Anderson PS. Huff JR. J. Med. Chem.  1994,  37:  3443 
  • Some references on ET-743 and related compounds:
  • 2a Rinehart KL. Holt TG. Fregeau NL. Keifer PA. Wilson GR. Perun TJ. Sakai R. Thompson AG. Stroh JG. Shield LS. Seigler DS. Li LH. Martin DG. Grimmelikhuijzen CJP. Gäde G. J. Nat. Prod.  1990,  53:  771 
  • 2b Myers AG. Plowright AT. J. Am. Chem. Soc.  2001,  123:  5114 
  • 2c Scott JD. Williams RM. Angew. Chem. Int. Ed.  2001,  40:  1463 
  • 3a López-Rodríguez ML. Ayala D. Benhamú B. Morcillo MJ. Viso A. Curr. Med. Chem.  2002,  9:  1867 
  • 3b Olivier B. Soudijn W. van Wijngaarden I. Prog. Drug Res.  1999,  52:  103 
  • 4a Kawasaki T. Enoki H. Matsumura K. Ohyama M. Inagawa M. Sakamoto M. Org. Lett.  2000,  2:  3027 
  • 4b Miyake FY. Yakushijin K. Horne DA. Org. Lett.  2000,  2:  3185 
  • 4c For other piperazines with significant biological actitvity, see: Bedürftig S. Weigl M. Wünsch B. Tetrahedron: Asymmetry  2001,  12:  1293 ; and references cited therein
  • 4d Beugelmans R. Bigot A. Bois-Choussy M. Zhu J. J. Org. Chem.  1996,  61:  771 ; and references cited therein
  • 5 Dinsmore CJ. Bogusky MJ. Culberson JC. Bergman JM. Homnick CF. Zartman CB. Mosser SD. Schaber MD. Robinson RG. Koblan KS. Huber HE. Graham SL. Hartman GD. Huff JR. Williams TM. J. Am. Chem. Soc.  2001,  123:  2107 
  • 6a Rübsam F. Mazitschek R. Giannis A. Tetrahedron  2000,  56:  8481 
  • 6b Nefzi A. Giulianotti MA. Houghten RA. Tetrahedron  2000,  56:  3319 
  • 6c Bailey PD. Boa AN. Baker SR. Clayson J. Murray EJ. Rosair GM. Tetrahedron Lett.  1999,  40:  7557 
  • For other biologically active ketopiperazines, see:
  • 7a Govek SP. Overman LE. J. Am. Chem. Soc.  2001,  123:  9468 
  • 7b Overman LE. Paone DV. J. Am. Chem. Soc.  2001,  123:  9465 
  • 7c Singh SB. Tomassini JE. J. Org. Chem.  2001,  66:  5504 
  • 8a Iyer MS. Gigstad KM. Namdev ND. Lipton M. J. Am. Chem. Soc.  1996,  118:  4910 
  • 8b Niwa S. Soai K. J. Chem. Soc., Perkin Trans. 1  1991,  2717 
  • 8c Falorni M. Satta M. Conti S. Giacomelli G. Tetrahedron: Asymmetry  1993,  4:  2389 
  • 8d Itsuno S. Matsumoto T. Sato D. Inoue T. J. Org. Chem.  2000,  65:  5879 
  • 8e Eriksson J. Arvidsson PI. Davidsson . Chem.-Eur. J.  1999,  5:  2356 
  • 9a Nefzi A. Giulianotti MA. Houghten RA. Tetrahedron Lett.  1999,  40:  8539 
  • 9b Santes V. Gómez E. Zárate V. Santillan R. Farfán N. Rojas-Lima S. Tetrahedron: Asymmetry  2001,  12:  241 
  • 9c Wang T. Zhang Z. Meanwell NA. J. Org. Chem.  2000,  65:  4740 
  • 9d Soukara S. Wünsch B. Synthesis  1999,  1739 
  • 9e Abdel-Jalil RJ. Al-Qawasmeh RA. Al-Abed Y. Voelter W. Tetrahedron Lett.  1998,  39:  7703 
  • 9f Mickelson JW. Belonga KL. Jacobsen EJ. J. Org. Chem.  1995,  60:  4177 
  • For an excellent review on vicinal diamines, see:
  • 10a Lucet D. Le Gall T. Mioskowski C. Angew. Chem. Int. Ed.  1998,  37:  2580 
  • 10b For recent references, see: Coldham I. Copley RCB. Haxell TFN. Howard S. Org. Lett.  2001,  3:  3799 
  • 10c See also: Seo R. Ishizuka T. Abdel-Aziz AA.-M. Kunieda T. Tetrahedron Lett.  2001,  42:  6353 
  • 10d Demay S. Kotschy A. Knochel P. Synthesis  2001,  863 
  • 10e Lee S. Lim CW. Lee JK. Jung O.-S. Lee Y. Tetrahedron: Asymmetry  2000,  11:  4709 
  • 11a López-Rodríguez ML. Viso A. Benhamú B. Rominguera JL. Murcia M. Bioorg. Med. Chem. Lett.  1999,  9:  2339 
  • 11b López-Rodríguez ML. Benhamú B. Ayala D. Rominguera JL. Murcia M. Ramos JA. Viso A. Tetrahedron  2000,  56:  3245 
  • 11c López-Rodríguez ML. Morcillo MJ. Fernández E. Porras E. Orensanz L. Beneytez ME. Manzanares J. Fuentes JA. J. Med. Chem.  2001,  44:  186 
  • 11d López-Rodríguez ML. Morcillo MJ. Fernández E. Rosado ML. Pardo L. Schaper K.-J. J. Med. Chem.  2001,  44:  198 
  • 12a Viso A. Fernández de la Pradilla R. Guerrero-Strachan C. Alonso M. Martínez-Ripoll M. André I. J. Org. Chem.  1997,  62:  2316 
  • 12b Viso A. Fernández de la Pradilla R. García A. Alonso M. Guerrero-Strachan C. Fonseca I. Synlett  1999,  1543 
  • 12c Viso A. Fernández de la Pradilla R. Recent Res. Devel. Organic Chem.  2000,  4:  327 
  • For a review on sulfinimines, see:
  • 13a Davis FA. Zhou P. Chen B.-C. Chem. Soc. Rev.  1998,  27:  13 
  • 13b For recent references on sulfinimines, see: Davis FA. Chao B. Rao A. Org. Lett.  2001,  3:  3169 
  • 13c See also: Lee A. Ellman JA. Org. Lett.  2001,  3:  3707 
  • 13d Kumareswaran R. Hassner A. Tetrahedron: Asymmetry  2001,  12:  2269 
  • 13e Wilhelm R. Widdowson DA. Org. Lett.  2001,  3:  3079 
  • 13f Surya Prakash GK. Mandal M. Olah GA. Org. Lett.  2001,  3:  2847 
  • 13g Asensio A. Bravo P. Crucianelli M. Farina A. Fustero S. García Soler J. Meille SV. Panzeri W. Viani F. Volonterio A. Zanda M. Eur. J. Org. Chem.  2001,  1449 
  • 15a The treatment of enantiopure N-sulfinyloxazolidinones with lithium alkoxides results in clean inversion at sulfur to produce enantiopure sulfinate esters. See: Evans DA. Faul MM. Colombo L. Bisaha JJ. Clardy J. Cherry D. J. Am. Chem. Soc.  1992,  114:  5977 
  • 15b

    Synthesis of (+)-(5R,6S)-1-benzyl-5-ethyl-6-hydroxymethylpiperazin-2,3-dione, 2a. From 1a (416 mg, 1.20 mmol) in anhyd CH2Cl2 (6 mL/mmol) at r.t., with diethyl oxalate (0.98 mL, 7.20 mmol, 6 equiv) and 0.5 equiv of a solution of NaOMe in MeOH (0.3 M, 2 mL, 0.60 mmol) a crude product was obtained after standard extractive isolation. Purification by washing thoroughly the crude product with 90% Et2O-hexane and chromatography (5% MeOH-CH2Cl2) of the mother liquor afforded 250 mg (0.95 mmol, 79%) of 2a as a white solid. Data of 2a: mp: 90-92 °C. Rf = 0.25 (12:1 CH2Cl2-MeOH). [α]20 D +166.5 (c 1.19, MeOH). 1H NMR (CD3OD, 400 MHz): δ = 0.75 (t, 3 H, J = 7.5 H), 1.33 (m, 1 H), 1.55 (m, 1 H), 3.52 (m, 1 H), 3.61 (ddd, 1 H, J = 7.6, 5.0, 1.1 Hz), 3.87 (dd, 1 H, J = 11.2, 7.6 Hz), 3.96 (dd, 1 H, J = 11.2, 5.0 Hz), 4.25 (d, 1 H, J = 14.2 Hz), 5.53 (d, 1 H, J = 14.2 Hz), 7.57 (m, 5 H). 13C NMR (DMSO-d6, 50 MHz): δ = 10.4, 28.2, 49.2, 50.6, 58.0, 61.0, 128.5, 129.3 (2 C), 129.6 (2 C), 137.5, 157.4, 157.8. IR(film): 3413, 2928, 1665, 1454, 1117, 1052, 757, 705 cm-1. MS (ES): 297 [M + Cl]+ (100%). Anal. Calcd for C14H18N2O3: C, 64.10; H, 6.92; N, 10.68. Found: C, 63.85; H, 7.04; N, 10.49.

  • 16 Initial attempts performed with LiAlH4 as reducing agent gave the expected piperazines in poor yields, see: Falorni M. Lardicci L. Giacomelli G. Marchetti M. Tetrahedron Lett.  1989,  30:  3551 
  • 18 Dinsmore CJ. Bergman JM. Bogusky MJ. Culberson JC. Hamilton KA. Graham SL. Org. Lett.  2001,  3:  865 
14

The preparation of 1a-c and 1f was carried out following the procedures described in ref. [12b] ; details will be published soon in a full account on this chemistry.

17

Synthesis of (-)-(2S,3R)-1-benzyl-3-ethyl-2-hydroxy-methylpiperazine, 4a. From 2a (188 mg, 0.713 mmol) in
anhyd THF (10 mL/mmol) with 9 equiv of BH3·SMe2 in THF (2 M, 3.21 mL, 6.417 mmol), after refluxing for 7 h, removal of the solvent and sequential treatment with 4 equiv of a 0.4 M HCl (30 min at 100 °C) and 6 equiv of a 0.4 M solution of NaOH (90 min at 0 ºC) a crude product was obtained after standard extractive isolation. Purification by chromatography (0-20% MeOH-Et2O) afforded 123 mg (0.525 mmol, 75%) of 4a as a colorless oil. Data of 4a: Rf = 0.10 (40% MeOH-Et2O). [α]20 D -14.1 (c 0.91, CHCl3). 1H NMR (CDCl3, 300 MHz): δ = 0.92 (t, 3 H, J = 7.3 Hz), 1.48 (sept, 1 H, J = 7.6 Hz), 1.72 (m, 1 H), 2.19 (m, 1 H), 2.29 (dt, 1 H, J = 9.9, 3.0 Hz), 2.70 (m, 1 H), 2.78-2.96 (m, 3 H), 3.29 (d, 1 H, J = 13.3 Hz), 3.65 (dd, 1 H, J = 11.7, 1.6 Hz), 4.02 (d, 1 H, J = 13.3 Hz), 4.05 (dd, 1 H, J = 11.8, 3.2 Hz), 7.26 (m, 5 H). 13C NMR (CDCl3, 50 MHz): δ = 10.3, 25.1, 43.1, 50.5, 58.3, 59.1, 63.3, 127.0, 128.3 (2 C), 128.7 (2 C), 138.4. IR(film): 3306, 3057, 3021, 2958, 1490, 1452, 1027, 739, 699 cm-1. MS (ES): 235 [M + 1]+ (100%).

19

Synthesis of (+)-(5R,6S,S S )-1-benzyl-6-[(t-butyldimethyl-silyloxy)methyl]-5-ethyl-4-(p-tolylsulfinyl)piperazin-2-one, 11. From 10 (315 mg, 0.59 mmol) in DMF (6 mL, 10 mL/mmol) at r.t., with 1.8 equiv of Cs2CO3 (340 mg, 1.04 mmol) at 65 °C (2 h) a crude product was obtained after standard extractive isolation. Purification by chromatography on silica gel (0-30% Et2O-CH2Cl2) afforded 269 mg (0.54 mmol, 92%) of 11 as a white foam. Data of 11: Rf = 0.27 (10% Et2O-CH2Cl2). [α]20 D +61.1 (c 1.10, CHCl3). 1H NMR (CDCl3, 500 MHz): δ = 0.07 (s, 3 H), 0.10 (s, 3 H), 0.54 (t, 3 H, J = 7.5 Hz), 0.90 (s, 9 H), 1.33-1.42 (m, 1 H), 1.75-1.83 (m, 1 H), 2.39 (s, 3 H), 3.08 (d, 1 H, J = 17.7 Hz), 3.26 (ddd, 1 H, J = 8.3, 5.3, 1.5 Hz), 3.66 (dd, 1 H, J = 9.8, 8.5 Hz), 3.71 (dd, 1 H, J = 9.7, 5.3 Hz), 3.75 (ddd, 1 H, J = 10.2, 4.7, 1.5 Hz), 3.80 (d, 1 H, J = 17.7 Hz), 3.84 (d, 1 H, J = 14.3 Hz), 5.33 (d, 1 H, J = 14.3 Hz), 7.24-7.33 (m, 7 H), 7.47 (d, 2 H, J = 8.1 Hz). 13C NMR (CDCl3, 50 MHz): δ = -5.3, -5.2, 10.3, 18.1, 21.3, 22.5, 25.8 (3 C), 39.7, 48.6, 57.8, 59.1, 62.4, 125.6 (2 C), 128.0, 128.8 (2 C), 128.9 (2 C), 129.8 (2 C), 136.6, 139.3, 141.8, 165.5. IR(film): 2963, 2855, 1732, 1646, 1435, 1260, 1090, 1018, 799 cm-1. MS (ES): 501 [M + 1]+ (100%), 502 [M + 2]+, 503 [M + 3]+, 523 [M + Na]+.
Synthesis of (+)-(5R,6S)-1-benzyl-6-(t-butyldimethylsilyl-oxymethyl)-5-ethyl-5,6-dihydro-1H-pyrazin-2-one, 12. From a cold (0 °C) suspension of 4 equiv of NaH in anhyd THF (5 mL/mmol of NaH), with a solution of 11 (72 mg, 0.144 mmol) in THF (5 mL/mmol) after stirring at r.t. (1 h) and at reflux (1 h), a crude product was obtained after standard extractive isolation. Purification by chromato-graphy on silica gel (30-80% Et2O-hexane) afforded 43 mg (0.119 mmol, 83%) of 12 as a colorless oil. Data of 12: Rf = 0.38 (80% Et2O-hexane). [α]20 D +188.3 (c 1.23, CHCl3). 1H NMR (CDCl3, 500 MHz): δ = 0.05 (s, 6 H), 0.54 (t, 3 H, J = 7.4 Hz), 0.86 (s, 9 H), 0.86-0.98 (m, 1 H), 1.40-1.49 (m, 1 H), 3.27 (ap t, 1 H, J = 6.5 Hz), 3.55 (dd, 1 H, J = 10.2, 6.9 Hz), 3.63 (dd, 1 H, J = 10.2, 5.8 Hz), 3.78 (dd, 1 H, J = 7.7, 5.5 Hz), 3.92 (d, 1 H, J = 14.3 Hz), 5.34 (d, 1 H, J = 14.3 Hz), 7.26-7.34 (m, 5 H), 7.70 (d, 1 H, J = 1.5 Hz). 13C NMR (CDCl3, 50 MHz): δ = -5.6, -5.5, 10.2, 18.1, 25.8 (4 C), 48.4, 55.2, 59.4, 63.0, 128.1, 128.8 (2 C), 129.1 (2 C), 136.1, 155.1 (2 C). IR(film): 3400, 3030, 2929, 2857, 1674, 1632, 1454, 1361, 1258, 1101, 908, 838, 804, 779, 704 cm-1. MS (ES): 361 [M + 1]+ (100%), 743 [2 M + Na]+.