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HETEROCYCLES, Vol. 75, No.

6, 2008

1493

HETEROCYCLES, Vol. 75, No. 6, 2008, pp. 1493 - 1501. © The Japan Institute of Heterocyclic Chemistry
Received, 7th January, 2008, Accepted, 18th February, 2008, Published online, 22nd February, 2008. COM-08-11328

STEREOSELECTIVE SYNTHESIS OF A NOVEL CHIRAL PIPERAZINE

Satoshi Kojima,1,2* Takashi Chabayashi, 1 Yasuhiro Umeda, 1 Akihisa
Iwamoto, 1 Kazuhisa Tanabe, 1 and Katsuo Ohkata1

1

Department of Chemistry, Graduate School of Science, Hiroshima University,

1-3-1 Kagamiyama, Higashi-Hiroshima 739-8526, Japan. 2Center for Quantum
Life Sciences, Hiroshima University, 1-3-1 Kagamiyama, Higashi-Hiroshima
739-8526, Japan. E-mail: skojima@sci.hiroshima-u.ac.jp

Abstract – (2S,6S)-2,4,6-Tris(phenylmethyl)piperazine was prepared in 11 steps
and 53% overall yield from S-phenylalanine. Key steps in the synthesis involved
reductive amination to introduce an ethoxycarbonylmethyl group on to the
secondary nitrogen of the product and selective alkylation to introduce a benzyl
group with complete diastereoselectivity.

INTRODUCTION
Chiral amines have enjoyed wide application as chiral auxiliaries and chiral ligands in organic synthesis.1
While cinchona alkaloids have successfully been applied to certain asymmetric reactions as catalysts
themselves since the early ’80s,2 it was not until the seminal widespread application of proline to the aldol
reaction3 and phenylalanine derived chiral 4-imidazolidinone catalysts to the Diels-Alder reaction4 in
2000, that chiral amines had come to be recognized as catalysts of general applicability. Since then, many
novel chiral amines have been designed and prepared as catalysts, thus establishing organocatalysis as
one of the mainstream fields in asymmetric synthesis.5 In connection with projects on total synthesis of
natural products, we also have been interested in organocatalysis.6 In order to develop a group of catalysts
of our own, we devised the synthesis of piperazines bearing benzyl groups in the 2 and 6 positions with
trans relative stereochemistry. Such substitution should be favorable for reducing possible reaction
pathways and the installation of the second nitrogen was to enable facile chemical modification at this
sight for further functionalization. Not to mention that the compound also has the potential to function as
a diamine, a bifunctional compound. The inclusion of benzyl groups was based upon the precedence

6-dimethyl groups. overnight. . (d) BH3-SMe2.10 Incidentally. (e) EtOCOCHO. 3 h. 2d.6-tris(phenylmethyl)piperazine. 2 h. THF. KHMDS. in regards with an axis positioned in the center of the 6-membered ring (2. reflux. For H2N Bn a BocHN CO2H Bn b BocHN CO2H 2 Bn2N 3 H N f O N Bn 8 Bn c O H2N Bn Bn2N O 4 Bn Boc N Bn g O N Bn 9 H2N d Bn O Boc N Bn N Bn 10 Bn O Bn Bn2N 6 i H N EtO2C e Bn2N 5 h Bn 7 H N Bn j Bn H N N Bn N Bn 11 1 Bn Scheme 1.6S)-2. CH2Cl2. 22 h. rt.5 h. Vol. followed by dibenzylamine to furnish known amide 412 in 89% yield over two steps. overnight.6S)-2. Removal of the protecting group with trifluoroacetic acid (TFA) yielded amide 5 also in practically quantitative yield. No. THF. 95%. Et3N. THF. rt. rt. 85%. rt.5 h. 50 °C. this was treated with (Boc)2O to give the known N-protected 3. 15. Using (S)-phenylalanine as the starting material. 95%. rt. 2. 3d. (i) TFA. NaBH4. CH2Cl2. EtOAc.6-tris(phenylmethyl)piperazine is shown in Scheme 1. 99%.11 Both of the reported syntheses involve the attachment of two chiral moieties of opposite stereochemistry. In contrast to these cases.5-disubstituted piperazines). reflux. EtOH. we describe the synthesis of (2S. (b) NMM.5 h. thus leaving the possibility for the stereoselective introduction of other groups at the second stereocenter. The reduction of 5 with the use of a large excess of BH3-SMe2 proceeded quantitatively to give diamine 6. we use diastereoselective alkylation to introduce the second stereocenter at a late stage of our synthesis. ClCO2Et. which was prepared in scalemic form by optical resolution of racemates. rt.5 equivs still gave rise to the desired product in a yield of 90%. reflux. CH2Cl2. 89% (2 steps). (j) BH3-SMe2. 3 h. has been reported in the Michael addition reaction.4.8 As for the synthesis of trans substituted piperazines with 2. -15 °C. 10. Reagents and conditions: (a) (Boc)2O. HCl. (g) (Boc)2O. 75. 99% or LiAlH4. with a comparable yield of 94%. RESULTS AND DISCUSSION The synthetic scheme for (2S. rt.1494 HETEROCYCLES. Lowering the amount of reagent to 2. -78 °C. 40 min. (h) BnBr. Bn2NH. 6. 99%. 2. 89% (2 steps). (f) 5% Pd/C. such as in the success particularly enjoyed with the MacMillan catalysts. the successful use of piperazines with C2-symmetry. p-TsOH. are also substructures of substances that have potential of clinical use. though not necessarily trans. 99% or LiAlH4. MeOH. 11. The crude product was treated with ethyl chloroformate in the presence of N-methylmorpholine. H2. 2008 where aryl groups have been found to be effective for stereodetermination via cation-π and π-π interactions.6-dimethylpiperazines.5 h.9. MeOH. When we initiated our project. there have been two previous reports. EtOH. 87%. 94%.7 Recently. A corresponding dibenzyl compound has been known in the pyrrolidine series. Herein.4. AcOH. (c) TFA. 50 °C. This reaction could also be performed with the less expensive LiAlH4. there were no reports to our knowledge on nitrogen containing 6-membered ring heterocycles having benzyl groups with trans substitution in regards with the nitrogen atom. THF.

the use of LDA was detrimental and did not give rise to the desired product. The secondary nitrogen of piperazinone 8 was then protected with a BOC group to give 9. implying interconversion between the the axial and the equatorial benzyl groups on the NMR timescale. the subsequent reductive amination of the product was rather messy. since the use of this amine would potentially reduce the step involving the removal of a benzyl group in the overall synthesis. which showed sharp signals for the methylene protons of the benzyl group on 4-nitrogen.6S)-2.HETEROCYCLES. reduction did not proceed cleanly. otherwise (at rt) complex mixtures due to incomplete reaction resulted. The introduction of the second stereocenter was carried out using the Williams-Dellaria protocol with KHMDS followed by benzyl bromide to give the trans compound 10 as the exclusive stereoisomer. No. However. Although the route is rather lengthy. The use of the compound and its derivatives in catalytic . the reaction had to be carried out under reflux conditions. Vol. An alternative route involving benzylamine instead of dibenzylamine was also investigated.15. using recrystallization where necessary or carrying the product to the next step without purification at all. Although the route is rather lengthy. The trans substitution pattern of 1 was evident from its 1H NMR.4. in contrast with the amide bearing the dibenzylamine moiety and purification of the product was quite tedious. Removal of the BOC group with TFA furnished 11.14 Attempted alkylation with haloacetates resulted in mixtures and the isolated yield usually did not exceed 30%. it was possible to carry out the synthesis up to 9 without the use of chromatographic purification in the case of large scale synthesis.16 As stated in the reports by these authors. Furthermore. and BH3 economically prepared in situ from NaBH4 and BF3·Et2O did not effect reaction at all. 2008 1495 LiAlH4. 75. reflux). Red-Al in THF also gave complex mixtures. The introduction of an ethoxycarbonylmethyl group to the primary nitrogen atom to give 7 could be carried out by reductive amination in the presence NaBH(OAc)3 with ethyl glycoxylate. Only one benzyl group was cleaved off under these hydrogenation conditions. Conversion of 7 to heterocycle 8 could be realized by a two step procedure involving the monodebenzylation of the nitrogen atom by hydrogenolysis with Pd/C as catalyst in the presence of HCl followed by intramolecular amidation catalyzed by p-TsOH. 6. which has two benzyl groups in 11 steps and 53% overall yield. generated by periodate cleavage of ethyl tartrate. whereas NaBH(OAc)313 prepared in situ (CH2ClCH2Cl. the first 8 steps could be carried out without chromatographic purification.6-tris(phenylmethyl)piperazine. Reduction of the amide moiety to an amine moiety to give the desired end product 1 could be fulfilled by either BH3-SMe2 (87%) or LiAlH4 (94%) in satisfactory yield. CONCLUSION In conclusion we have prepared (2S. whereas the corresponding signals for the benzyl methylene groups attached to the stereogenic carbon centers showed broadened signals.

0.8 mL.1. 1 M HCl.8 mmol) at rt.4 Hz.6. the solution was allowed to gradually warm up to rt and then it was stirred overnight.18 g. Water was added and then the mixture was extracted with EtOAc. Et3N (12. 2. Rf = 0.1-Dimethylethoxy)carbonylamino]-3-phenylpropanoic acid 3 (20. 136. 155. J = 7.83 (SiO2. 128.5.5. .23 g. Silica gel column chromatography was carried out using Merck 7734 (63-200 mesh) or 9385 (230-400 mesh).2. and dibenzylamine (19. 85. 13. The organic layer was dried over anhyd. 126.96 (m. 2008 asymmetric reactions is currently underway and the results will be reported in due course. successively. ethyl chloroformate (9. Vol.9.5.40 (s. Rf = 0.4 mL.6. 78.8 Hz). Then the organic layer was dried over anhyd.0. 1.20 (m. CDCl3) 172. After stirring at 50 °C for 40 min. No.6. J = 6. 127.36-4. 48.95-4.03 (dd. (S)-[2-[Bis(phenylmethyl)amino]-2-oxo-1-(phenylmethyl)ethyl]carbamic acid 1. 136. 1H).86 (m. After stirring at 0 °C for 1 h.71 g) as a colorless oil. 1H). 126. the mixture was concentrated in vacuo. mp 108-110 ºC. 128. THF and ether were freshly distilled from sodium-benzophenone prior to use.6.01 g. Elemental analyses (CHN) were carried out on a Perkin–Elmer 2400CHN II elemental analyzer.0 mL. Na2SO4 and concentrated in vacuo to give (2S)-2-[(1. and extracted with EtOAc. Preparative thin layer chromatography was carried out with plates prepared with Merck 7730. 13. 9H). 89%) as a white solid.24 mmol. Optical rotations were recorded on a JASCO DIP-370. J = 14.7.2 mmol) slowly at −15 °C. 1H NMR (500 MHz. 1. 6. brine. 40. EXPERIMENTAL General Melting points were measured on a Yanaco micro melting point apparatus and are uncorrected.4. 1H). 13 C NMR (125 MHz.32 (d.1 mL. The organic layer was washed with sat. 136. 1H and 13 C NMR spectra were measured on a JEOL JNM–LA500 spectrometer with chemical shifts given from usual standards.18 (br s. 51. High resolution mass spectra were measured on a JEOL JMS-SX102A spectrometer under electron ionization conditions (70 eV) or fast atom bombardment conditions (glycerol as matrix). The crude mixture was purified by recrystallization (CH2Cl2/toluene) to give 4 (31.4 Hz. 127. 129.36-6. 98. 2H).95 (dd. 79. 5.1-dimethylethyl ester (4). 3. 98. CH2Cl2/MeOH = 15:1 v/v). J = 8.1496 HETEROCYCLES. 1H).9 Hz. 15H). aqueous NaHCO3. 4.4.3. CDCl3) 7. 49. 128. 98 mmol). brine. 1H).7.71 g) in EtOAc (180 mL) was added N-methylmorpholine (10. 128.2 mmol). The residue was diluted with EtOAc and quenched with 1 M HCl at 0 °C.69 (d. 4. To the solution of 3 (20.26 (CH2Cl2/MeOH = 15:1 v/v). IR spectra were measured on a HORIBA FT-720 infrared spectrometer. To the solution of (S)-phenylalanine 2 (13.9.0.78 mmol) in MeOH (100 mL) was added (Boc)2O (17.8.17 The crude product was used for the next reaction without further purification.77 mmol). Na2SO4 and concentrated in vacuo. 78. 75.8. 4. 70.

dried over anhyd. . 1H). 1. J = 17. 7.1889.0 Hz. 139. HRMS (EI+) m/z calcd for C23H24N2O 344. CH2Cl2/MeOH = 30:1 v/v) gave 6 (2. 53. 1H).6 Hz.9 Hz. (2S).50 g. After refluxing overnight.17.38-7. H. νmax(neat)/cm-1 1704. 1H).37 (SiO2. 129.7. CHCl3).93. H.06. N. 3. Rf = 0.7. mp 99-101 ºC. CH2Cl2/MeOH = 15:1 v/v). 42. J = 14. 2. 1H). 126. Found: C.23 (d. 100%) as a yellow oil. filtered and concentrated. 128. 39 mL. filtered and concentrated. 1H).4. 0.3.0. 75.39-7.7.9 mg. 1639.4 Hz.20. The organic phase was washed with water and brine.3.59. Anal. 48. 3293.6. Anal.9. 3. 3. 136. 2H). 59. 42. 1H NMR (500 MHz. [α]D22 -10.6 Hz.7. 50.92 (t.31 (d.2245. 1H). 2H). HRMS (EI+) m/z calcd C25H28N2 356.3 (c 1.37 (m.02. 60.34 mmol) in THF (50 mL) was added dropwise BH3-SMe2 (2. 128. J = 7. 8. 1H). The mixture was turned basic with 50% NaOH. 83.47-2. The combined filtrate was washed with brine and dried over anhyd. Purification by chromatography (SiO2. Found: C.3. H.10 (m. 78 mmol) at 0 ºC. 3. 127.22. (2S)-2-Amino-3-phenylmethyl-1-[bis(phenylmethyl)amino]propane (6). The organic phase was washed with brine. J = 17. 137.37. 8.0.4. 2.4 Hz.1.50 g. Na2SO4. Recrystallization from CH2Cl2-hexane gave 5 (1. 13.2-Amino-N. 4. 7. 129. 126.2. νmax(neat)/cm-1 3637. 7. 136.0 mL) at 0 ºC. The mixture was stirred at rt for 2 d. J = 4. 126.4.2433. found: 444. 4. 1H). N.4 Hz.54 mmol) in THF (2. J = 14. 15H).4. The mixture was concentrated. dried over anhyd. the mixture was quenched with H2O slowly at 0 °C.5. 13C NMR (125 MHz.1891.48.6 mmol) in CH2Cl2 (8. Vol. CDCl3) δ 7.0.3 (c 1. J = 14. J = 14. CHCl3). 15H). 5. the mixture was extracted with EtOAc.09 (m. CDCl3) δ 7. H.14. 4. KOH (15 g) was then added. 8.5. 4.93 (d.3.31 (SiO2.6 Hz.16.17 mmol) at 0 °C.1.4 Hz. 8.N-bis(phenylmethyl)benzenepropanamide (5).2413. The mixture was stirred for 1 h at 0 ºC and 20 h at rt.40 g. 49.1.0 M in toluene. 8. CH2Cl2/MeOH = 15:1 v/v).49 (d. 1 M NaHCO3 was added and the mixture was extracted with CH2Cl2. (Reduction with BH3-SMe2) To a solution of 5 (2. J = 7.0 mL) was added 5 (59.2252.0. After cooling to 0 ºC the reaction mixture was quenched by the slow addition of 10% HCl (8.7 (c 1. 6. 13. N. N. 0. Calcd for C23H24N2O: C.35. 80.3.0 mL). found 344. 83.20-3. Calcd for C25H28N2: C. 80.4.68 (d. After cooling to rt. (Reduction with LiAlH4) To a solution of LiAlH4 (20.07.84 (dd.6 Hz. 1H). 2008 1497 28. 2H). 3374. 128. CHCl3).9.HETEROCYCLES. [α]D22 54.90 g. To a solution of 4 (2. 7. 2. 129. Na2SO4. νmax(neat)/cm-1 3363. found 356. 128.0. Rf = 0.17 (d.80 (br s. 128.73 (dd. 1.05 (dd. J = 7. HRMS (EI+) m/z calcd for C28H32N2O3 444.13.03 (m. (2S)-2-Amino-3-phenyl-1-[bis(phenylmethyl)amino]propane (6). 1619. The precipitate was filtered off and washed with Et2O. 13. CDCl3) δ 175. 126.9.07. 3H). 13C NMR (125 MHz. 129. 127. and the mixture was heated at reflux for 24 h.9.71 (br s.4 Hz. No. CDCl3) δ 139. 1H NMR (500 MHz.3. 3. 99 %) as white crystals.0 mL) was added TFA (8. 2H).6 mg.4. [α]D22 32.

129. aqueous NaHCO3.10 (m.1. 89%) as a yellow oil. Rf = 0.0 mL) was added (Boc)2O (0.56 (d. excess H2 was removed. CH2Cl2/MeOH = 15:1 v/v) to give 8 (600.39 (d.38 mmol) in 1.80 (SiO2. 2H). 139. 1H).0. 1H). 2. 53. J = 17.61 (dd.0. 4. 30:1 v/v) to give 6 (51. To a solution of 7 (1.2. 3. 0. Vol.9. Then 6 (63 mg.0. Na2SO4 and concentrated in vacuo. J = 13.HRMS (EI+) m/z calcd for C18H20N2O 416.94 mmol) at rt. 1H). 60. filtered. 2.1 Hz. 95%) as a white solid.2 mmol) and Et3N (0. 127. and concentrated. 7.2 Hz.8. 1H NMR (500 MHz.9.1. To a solution of NaBH4 (20.6 Hz. No. 49. 126. 128. 39. 1. J = 7. CDCl3) 7.3.1498 HETEROCYCLES. 2. After stirring at 50 °C for 2 h. Rf = 0.2 Hz. 129. 13. 2.00 g. 128.2 mmol) at 0 ºC. Purification with preparative TLC (SiO2. 3. 94%) as a yellow oil. 128.29 (t. CH2Cl2/MeOH = 15:1 v/v).77 (dd. 1H NMR (500 MHz. 6.86 (m.8.12 (m.0. 10H). 49. To a solution of 8 (510.4. 1H). 56.5-Bis(phenylmethyl)-2-piperazinone (8). 127. the mixture was concentrated in vacuo and quenched with sat.3. 1H). 14. found 280.7 Hz. 1H).19 (m. 1651.39-7.45 (d. HRMS (EI+) m/z calcd for C18H20N2O 280.5.20 (q.4.68 (d.0 Hz.9 Hz. 13C NMR (125 MHz. 1H). 13H). The crude product was purified by chromatography (SiO2.2. J = 17. 1. 2H). Saturated aqueous NaHCO3 was added and the mixture was extracted with EtOAc.9. CH2Cl2/MeOH. 2008 Na2SO4.61-2.9 mg. (5S)-1. CH2Cl2/MeOH = 40:1 v/v) gave 7 (75 mg. CDCl3) δ 167.06 (m.6. 128. [α]D22 70. J = 5.17 (d. 138.4 mg. and extracted with CH2Cl2.1573.4 (c 0.40 mmol) in 99% EtOH (12 mL) was added conc. and concentrated in vacuo. (2S)-2-(Ethoxycarbonylmethylamino)-3-phenyl-1-[bis(phenylmethyl)amino]propane (7). 4. 1H). The mixture was stirred at rt for 30 min.0 mL) was added to the mixture at rt and the mixture was stirred for 3 h.41 mL.7. the mixture was quenched with sat. 2. The organic layer was dried over anhyd. 13.21-3.5 Hz. 1H).82 mmol) in MeOH (6. 2. 4. J = 17. 128.2-dichloroethane (3. Na2SO4.50 (m. 58. HCl (2.4-bis(phenylmethyl)-1-piperazinecarboxylic acid 1.8.0.0 mL) was added AcOH (0.26 (SiO2.72 (dd.39-7.1576.3 mL) and 5% Pd/C (330 mg) at rt.5 Hz.62 (d. 126. The crude product was purified by preparative TLC (SiO2. J = 14. J = 7.0.0. 2. 1.4 mg. 2H). 13.8.95-2. 13C NMR (125 MHz. 39. . After stirring at this temperature for 2.2. J = 5. CH2Cl2/MeOH = 20:1 v/v). 3.5 h under an atmosphere of hydrogen.05 (br s.19 mmol) in 1.1-dimethylethyl ester (9). 1H).1 Hz. 0. After refluxing for 10 h. The organic phase was dried over anhyd. 3. CHCl3).90 (br s. 0.4.7 Hz.561. 137. 3H).1.8 mg. 2H). 3H). 3.7. 1. found 416. 75. 12. filtered.9.9 mmol) at rt. CDCl3) δ 171.5. νmax(neat)/cm-1 3054.5.47 mL. J = 13. 2.6 Hz.5 Hz.2-dichloroethane (1. 1H).6. 1H). J = 14. 136. 48.2464. 128. (2S)-5-Oxo-2. CDCl3) δ 7. 2H). 59.1 mg. 51.0 Hz.42 (dd. 2.070 mL.16-7.51 (d.7. νmax(neat)/cm-1 3300. J = 17. 3.2464. 1643. 1H). J = 8. The reaction mixture was filtered through Celite and concentrated in vacuo.67 (d. To the residue was added 99% EtOH (25 mL) and p-TsOH (162. J = 4. 3. 3.

1. 128.5 Hz. MgSO4 and concentrated in vacuo. 1H).45-3.41 (br s.0 (c 0.2H).26 mmol) in THF (1. 128.6. 136.64 (m. 11. 85%) as a white solid.2578. 2. 2. CH2Cl2/MeOH = 80:1 v/v) gave 11 (88 mg.8H).9. 3. hexane/EtOAc = 4:1 v/v). HRMS (EI+) m/z calcd for C23H28N2O3 470. 129. 1H).26 (m.73-6.64-2. 128.34 (m. 0. CDCl3) δ 7. To a solution of 9 (101 mg. 5H).5. 3. filtered.05-3. 1H NMR (500 MHz.4 Hz.2 (5 signals lack due to peak broadening).8.82-6.74 (m.76 (dd. mp = 113-115 ºC. 1H).6 Hz.1-dimethylethyl ester (10).5S). 153. . 1H).20 (c 0.4H).5 M in toluene.86-3. 137. 13.6H). 2. 1H NMR (500 MHz. 13 C NMR (125 MHz. 1 M NaHCO3 was added and the mixture was extracted with CH2Cl2. found 470.55 (m.0 mL) was added KHMDS (0.29 mmol) was added. 6.6S)-5-Oxo-2.04 mL. J = 4.6 Hz. J = 18. 1. J = 9. 13. 0. 2H). 8H).2. J = 4. The organic phase was dried over anhyd. 127.14 (m.82 (m.5. 128.11 (dd.4H). 4.95 (m.55 (m. 7.4 Hz. hexane/EtOAc = 4:1 v/v). found: 380.82-2.19-7. J = 14. νmax(neat)/cm-1 1697. The crude mixture was purified by recrystallization (EtOH/H2O) to give 9 (588. HRMS (EI+) m/z calcd for C23H28N2O3 380. 6. Then brine was added and the mixture was extracted with Et2O.3. 2. 1H). 0. 3.60 mL. 1. Vol.4 Hz.96 (m. mp 112-113 °C. J = 14.6 Hz. CDCl3) δ 7.7. 2. 13. 2.1. 0. νmax(neat)/cm-1 1689.439. 3. 0. J = 3.30 mmol) at –78 ºC. 2.0. 1H).1.22 (m.4). 1H). 0. No. 4. 3H).3. 0. CDCl3) δ 165.8.45 (SiO2. 1H). J = 14. Rf = 0.4 Hz.413. 1. 3. 128.77 (dd. The organic phase was dried over anhyd. 137.92 (d. 6.6-Tris(phenylmethyl)-1-piperazinecarboxylic acid 1. 0. 0.3 mg. 95%) as a white solid.57 (SiO2. CH2Cl2/MeOH = 30:1 v/v).20 (m. 6.0 mL) at rt. CDCl3) δ 7. and extracted with EtOAc.0 mL) was added TFA (1. 129.77 (m.80-3.46 (dd.4.4.8.9 Hz.4 Hz. 0.1. CDCl3): broadening too extensive for assignment. (2S.4 Hz.63-6. 3H). filtrated. 49.4. The mixture was stirred for 1. The mixture was stirred at –78 ºC for 3 h.53-4.46-3.72 (m.5. J = 1. 129.6 Hz. 3. Na2SO4.22 (dd.39-7. 4. 12.3.2569. 0. 1H). 1.5. 3.1. 1H). 2.1.HETEROCYCLES. 2H) 4. 1H). 2008 1499 aqueous NH4Cl and concentrated in vacuo. The organic layer was dried over anhyd. Purification by chromatography (SiO2. 128.74 (dd. 1H). J = 3.02 (m. 99%) as a white solid.35-3. 3.6H). To a solution of 10 (112 mg.6H). 4. 1H). 9H). 13 C NMR (125 MHz. [α]D22 −94.1. J = 6. 3. mp 138-139 ºC. and concentrated. J = 3. CHCl3).16 (SiO2. Purification by chromatography (SiO2. 15H). Rf = 0. 1H). 3. 13. After 30 min the reaction mixture was recooled to –78 ºC and BnBr (0. 6. 28.28 (m.94 (d.68-3. 1H).2084.40 (m.5 h at rt and then concentrated. 126.9.18 (dd.0.5. hexane/EtOAc = 6:1 v/v) gave 10 (118 mg.55-47 (m. 1H). 3.3 Hz. 1654.29 (m. 5H).76 (m. 137.24 mmol) in CH2Cl2 (1. 7. (3S. 1H).3. CDCl3) δ 169. 13. 4. 1654. 9H). 0. Na2SO4. [α]D22 −5. 13.0.0.78-65 (m.58 (s. J = 9.2100.99 (dd. 1H NMR (500 MHz. 13 C NMR (125 MHz.38-6. 2H).47-2.71 (d. J = 11. 3.15-7.5-Tris(phenylmethyl)-2-piperazinone (11).9. CHCl3).40-7. The reaction mixture was allowed to warm to 0 ºC. 136. 1H). Rf = 0. 75.16 (dd. 11. 1H).58 (d.75 (br s.88-2.80 (m.83 (dd.0 Hz. and concentrated.4. 2H). 11. 2.

νmax(neat)/cm-1 3324. (f) C.6S)-2. CHCl3). To the mixture was added 10% HCl (2. 128. New York. ‘Organic Synthesis Highlights II. Y. 13 C NMR (125 MHz. 3. J = 12. The mixture was stirred for 3 d at rt. hexane/EtOAc = 2:1 v/v) to give 1 (252.58 (d. 3. CH2Cl2/MeOH. I.0 mL) was added 11 (278. (2S.39-2.0 mL) at 0 °C. ACKNOWLEDGEMENTS This work was supported in part by Grants-in-Aid for Scientific Research (No. filtered. Tetrahedron:Asymmetry.3.6S)-2. Toy.2.6. 58. .. 1H). (b) H. 128. 75.0 M in toluene. 4H). After refluxing for 11. (d) M. Na2SO4.1. Anaya de Parrodi and E.3.1500 HETEROCYCLES. 87%) as a yellowish solid. 16550098. 3. and concentrated in vacuo. 128.2040. The organic phase was dried over anhyd. The mixture was refluxed for 23 h and extracted with EtOAc.1.8 Hz. 59. 1H). 9843. Ager.0. 835. [α]D22 −58. 56. by H. (Reduction with BH3-SMe2) To a solution of 11 (449 mg.0 mL) and a mixture of NaOH and KOH (3. found 356. R.8 Hz. W. 2H). 39. No.2.3. 126. (2S.21-3. the mixture was slowly quenched with a small amount of H2O at 0 °C. 49-58.’ ed.1. 63.1 g). CDCl3) δ 139. Waldmann. and D.6 (br).2. Chem.27 (SiO2. pp. I. VCH. 1. D. (Reduction with LiAlH4) To a solution of LiAlH4 (143.9 (br). Prakash.19 (m.80-2.0 (br). 129. CDCl3) δ 7. 30:1 v/v). νmax(neat)/cm-1 3320.2450. 2. 2000. HRMS (EI+) m/z calcd for C25H26N2O 370. For example see: (a) J. REFERENCES 1.0 mL) was added BH3-SMe2 (2. Meyers. Purification with chromatography (SiO2. 50. Tetrahedron. 2H). (e) C. 14 mmol) at rt.2045.27 (m. 2H). H. CH2Cl2/MeOH = 50:1 v/v) gave 1 (374 mg. The precipitate was filtered off and washed with Et2O. 49. HRMS (EI+) m/z calcd for C25H28N2 365. 1643. 3.65-2. Seyden-Penne.0. 2004. and 19550042) from the Japan Society for the Promotion of Science.95 (m.8.2 (c 0. 2. Rev. 126. Juaristi.75 mmol) in THF (5. 15.8 mL. 126. 14540497. 52. 387. 37.1 mg. 0.6 (c 0. (c) D. 127.0 mg. mp 61-62 °C. Rf = 0. 52. 94%).9. Weinheim. CHCl3).77 mmol) in THF (3.2252.3 mg. J = 12. [α]D22 -37. The combined filtrate was washed with brine and dried over anhyd.4.690. 39. 1996.55 (m. 96.4. We also acknowledge the Natural Science Center for Basic Research and Development of Hiroshima University for machine time on analytical instruments. 15H).9.5. ‘Chiral Auxiliaries and Ligands in Asymmetric Synthesis’ Wiley. 1995. Synlett. Na2SO4.39 (d.6-Tris(phenylmethyl)piperazine (1). 138.5 h. and concentrated. 6. Vol.427. found 370.2 mmol) in THF (8. 1995. The crude product was purified by preparative TLC (SiO2. 2008 128. Schaad. 1H NMR (500 MHz. 126. Groaning and A. Chung and P.69 (m. Waldmann.6-Tris(phenylmethyl)piperazine (1).0.39-6.6. 6.1. 2.

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