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

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.

piperazines - amino alcohols - sulfinimines - chiral auxiliaries - asymmetric synthesis

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 

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.

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. R_f = 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 

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: R_f = 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%).

18 Dinsmore CJ. Bergman JM. Bogusky MJ. Culberson JC. Hamilton KA. Graham SL. Org. Lett.  2001,  3:  865 

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: R_f = 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: R_f = 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]⁺.