A new method for the preparation of unsymmetrical 1,4-substituted piperazine derivatives

Article abstract of DOI:10.1016/S0957-4166(99)00049-X

Symmetrical and unsymmetrical N,N'-piperazine derivatives of (-)- norephedrine and o-aminophenol were synthesized stereoselectively in yields >70% by reduction of the corresponding N,N'-ethylenebisoxazolidine heterocycles. The stereochemistry at the ring fusion carbons was established by NMR spectroscopy and X-ray crystallography.

Full text of DOI:10.1016/S0957-4166(99)00049-X

Pergamon
Tetrahedron: Asymmetry 10 (1999) 799–811
A new method for the preparation of unsymmetrical
1,4-substituted piperazine derivatives
Aurelio Ortiz,a Norberto Farfán,a,∗ Herbert Höpfl,b Rosa Santillan,a María E. Ochoa a and
Atilano Gutiérrez c
aDepartamento de Química, Centro de Investigación y de Estudios Avanzados del IPN, Apdo. Postal 14-740,
07000 Mexico D.F., Mexico
bUniversidad Autónoma del Estado de Morelos, Centro de Investigaciones Químicas, Av. Universidad 1001, Col. Chamilpa
C. P. 62210, Cuernavaca, Morelos, Mexico
cLab. de RMN, Universidad Autónoma Metropolitana, Av. Michoacan y la Purisima s/n, Col. Vicentina, 09340 Ixtapalapa,
Mexico D.F., Mexico
Received 1 February 1999; accepted 2 February 1999
Abstract
Symmetrical and unsymmetrical N,N0-piperazine derivatives of (−)-norephedrine and o-aminophenol were
synthesized stereoselectively in yields >70% by reduction of the corresponding N,N0-ethylenebisoxazolidine
heterocycles. The stereochemistry at the ring fusion carbons was established by NMR spectroscopy and X-ray
crystallography. © 1999 Elsevier Science Ltd. All rights reserved.
1. Introduction
Previously we have described a variety of interesting heterocyclic products obtained by condensation
of aminoalcohols with α-diketones.1–3 Our interest in the synthesis of new bisoxazolidine heterocy-
cles led us to the preparation of five new piperazine derivatives (14–18) obtained by reaction of β-
aminoalcohols with α-dicarbonyls. The piperazine structure is particularly attractive since it is present in
a large number of biologically active compounds.4–15 Common routes described so far include cyclization
of different acyclic compounds such as diethylenetriamine, ethylenediamine,16 diethanolamine,17 β,β0-
dihaloethylamines,18 as well as β-aminoalcohol N-oxides.19 However, few provide pure optically active
compounds.20 Herein we report a new route to these heterocycles which allowed the preparation of
piperazines 14–18 (Schemes 1–3).
∗
Corresponding author. E-mail: jfarfan@mail.cinvestav.mx
0957-4166/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(99)00049-X

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2. Results and discussion
Treatment of (1R,2S)-(−)-norephedrine 1 with diethyl oxalate in a 2:1 molar ratio yielded oxamide
2, which was reduced with BH3·THF to give diamine 3 (Scheme 1). Subsequent condensation with
glyoxal or butanedione gave the symmetrical derivatives 4 and 5, while the reaction with 1-phenyl-
1,2-propanedione led to the unsymmetrical ethylenebisoxazolidine 6. The piperazine compounds 14–16
were obtained selectively in yields >70% by reaction with two equivalents of BH3·THF. Evidence for
the formation of these compounds was obtained from their 13C NMR spectra which showed signals
at δ 93.77 (4), 95.57 (5), 101.71 and 94.11 ppm (6) for the carbons at the fusion of the heterocycles.
1
1
Unequivocal H and 13C NMR assignments for compounds 4, 5 and 6 were achieved by 2D H–13C
correlated experiments. COSY and NOESY spectra allowed the complete assignment of compound 6.
Scheme 1. Reagents: (I) diethyl oxalate, (II) BH3·THF, (III) glyoxal, (IV) butanedione, (V) 1-phenyl-1,2-propanedione, (VI)
BH3·THF
The synthesis of the unsymmetrical N,N0-piperazine derivative 17 was achieved by the reaction of
ethyl oxalyl chloride with o-aminophenol to yield 7, which was further reacted with (−)-norephedrine
to provide the unsymmetrical diamide 8 (Scheme 2). The latter was reduced with BH3·THF to obtain
ethylenediamine 9.
Subsequent condensation of 9 with glyoxal or 1-phenyl-1,2-propanedione allowed the preparation
of unsymmetrical N,N0-ethylenebisoxazolidines 10 and 11, respectively. The ethylenebisoxazolidine
formation was evidenced by 13C NMR with the signals at δ 96.10, 90.83 (10) and 103.06, 95.26 ppm
(11) for the carbon atoms at the ring fusion of the heterocycles. Compound 10 was treated with two
equivalents of BH3·THF to give the piperazine derivative 17.
The piperazine derivative 18 was prepared in 70% yield by the reaction of N,N0-ethylenebisoxazolidine
13 with two equivalents of BH3·THF, whereby 13 was obtained by condensation of N,N0-bis-(o-

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801
Scheme 2. Reagents: (I) ethyl oxalyl chloride, (II) (−)-norephedrine, (III) BH3·THF, (IV) glyoxal, (V) 1-phenyl-1,2-propane-
dione, (VI) BH3·THF
hydroxyphenylene)ethylenediamine 1221 with glyoxal (δ C-2, 92.9 ppm in the 13C NMR spectrum) as
can be seen from Scheme 3.
Scheme 3. Reagents: (I) glyoxal, (II) BH3·THF
It is worthwhile mentioning that the M+ was not observed for compounds 3 and 14–17, where instead
the M+−HOCHC6H5 ion was the base peak.
3
The JH–H coupling constants for the two hydrogen atoms at the ring fusion in 4, 10 and 13 were
1
extracted from the 13C satellites in the H NMR spectra.22 These data were used in combination with
the generalized Karplus type relationship23 to determine the dihedral angle between the two hydrogen
atoms giving values close to 150° for all three compounds (3J=6.6 Hz for 4, 7.3 Hz for 10 and 6.6
Hz for 13) and, therefore, a trans-stereochemistry at the ring fusion can be established. In order to
confirm the spectroscopic results, the structure of compound 4 was determined by X-ray crystallography

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A. Ortiz et al. / Tetrahedron: Asymmetry 10 (1999) 799–811
showing two five-membered rings fused to a six-membered ring in a chair-like conformation with a
trans-stereochemistry as established by the NMR experiments.
The molecular structures of compounds 4, 5, 6 and 11 were determined by X-ray crystallography
(Figs. 1 and 2). Compounds 4, 5 and 11 present a trans-fusion, in contrast to compound 6 which possesses
a cis-stereochemistry. The corresponding torsion angles are H2–C2–C20–H20, 170.9° for compound 4,
C8–C2–C20–C80, 167.8° for compound 5, C14–C2–C17–C28, 46.4° for 6 and C14–C2–C17–C25, 157.7° for
11. The bond lengths at the fused five-membered rings are significantly different: the C2–C20 bond length
is 1.484 (8) Å for 4, while C2–C17 is 1.570 (5) Å for 6. This notable difference between the bond lengths
may be attributed to a steric repulsion between the phenyl and methyl groups located at the ring fusion of
compound 6. The corresponding bond lengths in 5 and 11 are within the average values (C2–C20 1.527
(4) Å, C2–C17 1.556 (4) Å, respectively).
The molecular structures show that the substituents at the fusion of the rings are anti to the phenyl
group of the norephedrine moiety which is probably the substituent responsible for the asymmetric
induction in compounds 4, 5, 10 and 11. On the other hand, compound 6 appears to be an exception
since the phenyl group at the fusion is in an anti-relationship to the phenyl group of the norephedrine
fragment, while the methyl group at C-2 is in a syn-relationship to the phenyl substituents at C-17 and
C-5 (Figs. 1 and 2).
In general, the reaction of the diamines with glyoxal, butanedione and 1-phenyl-1,2-propanedione
occurs by attack of the nitrogen atoms to the Si face of each of the carbonyl groups providing a trans-
stereochemistry, as observed for bisoxazolidines 4, 5, 10, 11 and 13. However, steric interactions lead
to the formation of a cis-fusion product, as seen in bisoxazolidine 6, due to steric repulsion between the
phenyl groups.
The conformational analysis of N-methyl-piperidines has shown that the N-methyl group has a
preference for the equatorial over the axial orientation24 and also, the molecular structure of N,N0-
bis-(2-hydroxyethyl)piperazine 14 shows a preference for the hydroxyethyl groups in the equatorial
position.25 The 13C NMR spectrum of 14 at 209 K shows two diastereotopic carbons for the piperazine
ring, which coalesce at 263 K (∆G‡=12.30 kcal mol−1), a dynamic behaviour that may be attributed to
ring interconversion.26 In the case of piperazine 17 the 13C NMR spectrum at room temperature shows
two signals at δ 51.02 and 53.0 ppm for carbon atoms 3 and 2. These signals showed an interesting
dynamic behaviour, since the signal at δ 51.02 ppm splits into two with a difference of 174 Hz, when
the temperature is lowered to 209 K (∆G‡=12.23 kcal mol−1 at 263 K). Also, the signal at δ 53.0 ppm
consists of two signals with a difference of 8.8 Hz at 209 K, which gives rise to a single signal at 233 K
(∆G‡=12.16 kcal mol−1) the signals coalesce. This behaviour can be attributed to the fact that at room
temperature the piperazine ring is in continuous motion due to the nature of the substituents. Piperazines
15 and 16 are obtained diastereoselectively and it is important to note that this leads to the formation of
two piperazine rings with stereogenic centers.
3. Conclusions
In conclusion, the reaction of compounds 3, 9 and 12 with 1,2-dicarbonyls proceeds with high
diastereoselectivity to provide the ethylenebisoxazolidines with a trans-stereochemistry, except for
compound 6, due to steric interactions. As a consequence, the subsequent reduction yields only one
of the possible diastereomeric piperazine derivatives. The syntheses described herein constitutes a new
method for the preparation of symmetrical and unsymmetrical piperazines with chiral carbon atoms in
the ring.

A. Ortiz et al. / Tetrahedron: Asymmetry 10 (1999) 799–811
803
Figure 1. Perspective view of the molecular structures of 4 and 5. Numbering does not correspond to IUPAC nomenclature
4. Experimental
1H and 13C NMR spectra were recorded with JEOL FX90Q, JEOL GSX 270, and Bruker DMX-
500 spectrometers. Chemical shifts (ppm) are relative to (CH3)4Si. Coupling constants are quoted in
hertz. The HETCOR standard pulse sequence, which incorporates quadrature detection in both domains
was used. Infrared spectra were recorded on a Perkin–Elmer 16F spectrophotometer. Mass spectra
were obtained with a HP5989A equipment. Melting points were obtained on a Gallenkamp MFB-595

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A. Ortiz et al. / Tetrahedron: Asymmetry 10 (1999) 799–811
Figure 2. Perspective view of the molecular structures of 6 and 11

A. Ortiz et al. / Tetrahedron: Asymmetry 10 (1999) 799–811
805
apparatus and are uncorrected. Elemental microanalyses were determined on an EA1108 elemental
analyzer Fissons instruments and some were performed by Oneida Research Services, Whitesboro, NY.
4.0.1. X-Ray analysis
A selected monocrystal was set upon an automatic diffractometer, and unit cell dimensions with
estimated standard deviations were obtained from least-squares refinements of the setting angles of 24
well centered reflections. Two standard reflections were monitored periodically; they showed no change
during data collection. Corrections were made for Lorentz and polarization effects. Empirical absorption
corrections (DIFABS)27 were applied. Computations were performed by using CRYSTALS28 adapted on
a Micro Vax II. Atomic form factors for neutral C, N, O and H were taken from the International Tables
for X-ray Crystallography.29
The structures were solved by direct methods using the SHELXS86 program.30 Hydrogen atoms were
calculated and refined with an overall isotropic temperature factor. Anisotropic temperature factors were
introduced for all non-hydrogen atoms, and least-squares refinements were carried out by minimizing
P
w(|Fo|−|Fc|)2, where Fo and Fc are the observed and calculated structure factors. Unit weight was
P
P
used for structures 4–6 and w=1/σ2 for 11. Models reached convergence with R= (kFo|−|Fck)/ |Fo|
P
P
and Rw=[ w(|Fo|−|Fck)2 /w (Fo)2]1/2. Criteria for a satisfactorily complete analysis were the ratios of
rms shift to standard deviation being less than 0.1 and no significant features in the final difference map.
There are two independent molecules in the unit cell of 11 and no correlation could be found between
the two molecules as expected for an enantiomerically pure compound.
4.0.2. Supplementary material available
Tables of atomic coordinates, thermal parameters, bond lengths and angles as well as observed and
calculated structure factors have been deposited at the Cambridge Crystallographic Data Centre.
4.1. (1S,2R)-N,N0-Bis-[(2-hydroxy-1-methyl-2-phenyl)ethyl]oxamide (2)
Diethyl oxalate (2.4 g, 16.5 mmol) was added to a solution of (−)-norephedrine (5.0 g, 33.0 mmol)
in THF (50 ml). The reaction mixture was stirred for 1 h and the oxamide 2 was removed by filtration
and obtained as a white solid (4.6 g, 85%), m.p. 233–235°C. [α]D25=+25.2 (c 0.11 in EtOH). 1H NMR
(DMSO-d6, 270 MHz) δ: 8.37 (1H, d, J=9.2 Hz, NH), 7.36–7.22 (5H, m, C6H5), 5.62 (1H, s, OH), 4.68
(1H, d, J=4.6 Hz, H-2), 3.97 (1H, m, H-1), 0.96 (3H, d, J=6.6 Hz, CH3-1). 13C NMR (DMSO-d6, 67.80
MHz) δ: 158.80 (C=O), 142.73 (Ci), 127.78 (Cm), 126.82 (Cp), 126.10 (Co), 73.66 (C-2), 50.84 (C-1),
14.20 (CH3-1). MS (EI, 15 eV) m/z: [M+−OH, 339 (2)], 250 (5), 231 (3), 187 (2), 160 (2), 118 (100),
44 (5). IR νmax (KBr) 3284, 1652, 1522, 1040 cm−1. Anal. calcd for C20H24N2O4: C, 67.41; H, 6.74; N,
7.86. Found: C, 66.76; H, 6.85; N, 7.67.
4.2. (1S,2R)-N,N0-Bis-[(2-hydroxy-1-methyl-2-phenyl)ethyl]ethylenediamine (3)
To a solution of 2 (2.0 g, 5.6 mmol) in anhydrous THF (100 ml) a 1.6 M solution of BH3·THF (20
ml) was added. The mixture was refluxed for 5 h and then cooled to room temperature; after addition of
water, the THF was removed and the organic phase extracted with ethyl acetate (3×30 ml). The extracts
were washed with NaOH solution, dried (MgSO4), and concentrated under vacuum to give diamine 3 as
a white solid (1.1 g, 60%), m.p. 115–116°C. [α]D25=−6.1 (c 0.41 in EtOH). 1H NMR (CDCl3, 270 MHz)
δ: 7.46–7.15 (5H, m, C6H5), 4.67 (1H, d, J=3.3 Hz, H-2), 2.83–2.61 (3H, m, H-1 and CH2-N), 0.83 (3H,
d, J=6.6 Hz, CH3-1). 13C NMR (CDCl3, 67.80 MHz) δ: 141.69 (Ci), 127.90 (Cm), 126.90 (Cp), 126.04

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(Co), 73.78 (C-2), 58.41 (C-1), 46.57 (C-N), 14.36 (CH3-1). MS (EI, 15 eV) m/z: [M+−HOCHC6H5, 221
(100)], 203 (4), 160 (2), 146 (3), 105 (1), 72.25 (1). IR νmax (KBr) 2816, 1456, 1344, 1080, 1050 and
1025 cm−1. Anal. calcd for C20H28N2O2: C, 73.17; H, 8.53; N, 8.53. Found: C, 72.57; H, 8.67; N, 8.49.
4.3. (4S,5R,2S,40S,50R,20S)-N,N0-Ethylene(4,40-dimethyl-5,50-diphenyl)-2,20-bisoxazolidine (4)
The procedure described below is representative for the synthesis of compounds 4–6, 10, 11, 13.
To a solution of 3 (1.0 g, 3.0 mmol) in benzene (30 ml), a 40 wt% solution of glyoxal in water (0.17 g,
3.04 mmol) was added dropwise. The reaction mixture was then brought to reflux for 3 h and cooled to
room temperature. Removal of the solvent under vacuum followed by crystallization from EtOH provided
N,N0-ethylenebisoxazolidine 4 as a white crystalline solid (0.8 g, 74%), m.p. 190–192°C. [α]D25=−54.88
(c 0.088 in CH2Cl2). 1H NMR (CDCl3, 270 MHz) δ: 7.34–7.20 (5H, m, C6H5), 5.10 (1H, d, J=8.0 Hz,
H-5), 3.96 (1H, s, H-2), 3.02 (1H, dq, J=8.0, 6.0 Hz, H-4), 2.98 and 2.41 (2H, AB, J=6.6 Hz, CH2-6),
0.66 (3H, d, J=6.0 Hz, CH3-4). 13C NMR (CDCl3, 67.80 MHz) δ: 139.60 (Ci), 127.82 (Cm), 127.63 (Co),
127.50 (Cp), 93.77 (C-2), 83.11 (C-5), 59.92 (C-4), 45.96 (C-6), 14.19 (CH3-4). MS (EI, 70 eV) m/z:
[M+, 350 (12)], 322 (28), 231 (31), 203 (32), 162 (16), 118 (100), 117 (71), 91 (55), 55 (26). IR νmax
(KBr) 2816, 1456, 1344, 1080, 1050, 1025 cm−1 Anal. calcd for C22H26N2O2: C, 75.42; H, 7.43; N, 8.00.
Found: C,75.36; H, 7.51; N, 8.00.
4.4. (5R,4S,2S,50S,40S,20S)-N,N0-Ethylene(5,50-diphenyl-4,40,2,20-tetramethyl)2,20-bisoxazolidine (5)
A solution of 3 (1.0 g, 3.0 mmol) in benzene (30 ml), was treated with 2,3-butanedione (0.26 g,
3.04 mmol) to yield N,N0-ethylenebisoxazolidine 5 as a white crystalline solid (0.92 g, 80%) m.p.
1
170–171°C (crystallized from EtOH). [α]D25=−103.59 (c 0.612 in CH2Cl2). H NMR (CDCl3, 270
MHz) δ: 7.37–7.24 (5H, m, C6H5), 5.16 (1H, d, J=8.6 Hz, H-5), 3.28 (1H, dq, J=8.6, 6.6 Hz, H-4),
2.80 and 2.60 (2H, AB, J=6.6 Hz, CH2-6), 1.54 (3H, s, CH3-2), 0.60 (3H, d, J=6.6 Hz, CH3-4). 13C
NMR (CDCl3, 67.80 MHz) δ: 139.98 (Ci), 127.81 (Cm), 127.66 (Co), 127.27 (Cp), 95.57 (C-2), 81.04
(C-5), 55.77 (C-4), 43.62 (CH2-6), 16.12 (CH3-4), 9.32 (CH3-2). MS (EI, 70 eV) m/z: [M+, 378 (9)], 319
(6), 287 (18), 245 (21), 203 (41), 176 (24), 134. (26), 118 (100), 117 (64), 116 (91), 69 (45), 43 (74). IR
νmax (KBr) 2964, 1456, 1368, 1316, 1180, 1132, 1082, 994,746 cm−1. Anal. calcd for C24H30N2O2: C,
76.19; H, 7.93; N, 7.40. Found: C,75.53; H, 7.93; N, 7.34.
4.5. (2R,4S,5R,17S,19S,20R)-N,N0-Ethylene(2,4,19-trimethyl-5,17,20-triphenyl)-2,17-bisoxazolidine
(6)
A solution of 3 (1.0 g, 3.04 mmol) in ethyl acetate (30 ml) was treated with 1-phenyl-1,2-propanedione
(0.46 g, 3.04 mmol) and refluxed for 5 h to provide N,N0-ethylenebisoxazolidine 6 as a white crystalline
solid, that was recrystallized from hexane/ethyl acetate, m.p. 190–193°C. [α]D25=−88.65 (c 0.097 in
CH2Cl2). 1H NMR (CDCl3, 500 MHz) δ: 7.75 (2H, d, J=6.6 Hz, H-29,33), 7.39–7.26 (13H, m, H-9-13,
H-23-27, H-30-32), 5.70 (1H, d, J=8.5 Hz, H-5), 4.60 (1H, dq J=8.5, 6.4 Hz, H-4), 4.53 (1H, d, J=9.2
Hz, H-20), 3.70 (1H, dq, J=9.2, 7.3 Hz, H-19), 3.45 (1H, ddd, J=14.7, 13.0, 3.0 Hz, H-7ax), 3.14 (1H,
dt, J=14.8, 2.5 Hz, H-7eq), 3.00 (1H, ddd, J=12.5, 12.4, 3.0 Hz, H-15ax), 2.44 (1H, dt, J=11.5, 2.5 Hz,
H-15eq), 1.27 (3H, s, CH3-14), 0.87 (3H, d, J=7.3 Hz, CH3-21), 0.73 (3H, d, J=6.4 Hz, CH3-6). 13C
NMR (CDCl3, 67.80 MHz) δ: 140.86, 140.62, 140.08 (C-8, 22, 28), 128.26, 127.87 (C-10, 12, 24, 26,
30, 32), 127.68, 127.40, 127.27 (C-11, 25, 31), 126.91, 126.22 (C-9, 13, 29, 33, 23, 27), 101.71 (C-17),
94.11 (C-2), 83.36 (C-5), 78.44 (C-20), 60.0 (C-19), 56.74 (C-4), 41.92 (C-7), 36.06 (C-15), 26.59 (CH3-

A. Ortiz et al. / Tetrahedron: Asymmetry 10 (1999) 799–811
807
14), 16.96 (CH3-6), 13.43 (CH3-21). MS (EI, 70 eV) m/z: [M+, 440 (10)], 349 (16), 334 (12), 333 (19),
322 (20), 264 (13), 189 (20), 176 (29), 118 (100), 117 (58), 116 (78), 115 (21), 105 (74), 91 (27), 88
(36), 43 (38). IR νmax (KBr) 2964, 2836, 1456, 1316, 1180, 1132, 1082, 994, 702 cm−1. Anal. calcd for
C29H32N2O2: C, 79.09; H, 7.27; N, 6.36. Found: C, 77.47; H, 8.00; N, 6.30.
4.6. (2-Hydroxy)-ethyloxanilate (7)
To a solution of o-aminophenol (1.0 g, 9.2 mmol) in THF, 1.5 ml of triethylamine (1.1 g, 11 mmol) and
ethyl oxalyl chloride (1.5 g, 11.0 mmol) were added dropwise at 10°C. The reaction mixture was stirred
for 1 h at the same temperature, the product was separated by filtration, and washed with acetone to give
6 as a white solid (1.33 g, 70%), m.p. 179–181°C. 1H NMR (DMSO-d6, 270 MHz) δ: 10.20 (1H, s, OH),
9.60 (1H, s, NH), 7.90 (1H, d, J=8.0 Hz, H-6), 6.700–7.00 (3H, m, H-3,4,5), 4.25 (2H, q, J=7.2 Hz, CH2),
1.26 (3H, t, J=7.2 Hz, CH3). 13C NMR (DMSO-d6, 67.80 MHz) δ: 160.53 (C-7), 154.35 (C-8), 147.54
(C-2), 125.61 (C-5), 124.74 (C-1), 120.84 (C-4), 119.50 (C-3), 119.19 (C-6), 62.66 (CH2), 13.81 (CH3).
MS (EI, 15 eV) m/z: [M+, 209 (34)], 165 (10), 137 (9), 136 (100), 135 (22), 108 (15), 80 (10), 79 (6), 29
(11). IR νmax (KBr) 3362, 1654, 1596, 1464, 1350, 1292, 1106, 1026, 752, 744, 504 cm−1. Anal. calcd
for C10H11NO4: C, 57.47; H, 5.26; N, 6.69. Found: C, 57.05; H, 5.40; N, 6.43.
4.7. N-(20-Hydroxyphenyl)-N0-[9S,10R-(10-hydroxy-9-methyl-1-phenyl)ethyl]oxamide (8)
To a solution of 7 (1.0 g, 4.8 mmol) in anhydrous THF (30 ml), (−)-norephedrine (0.725 g, 4.8 mmol)
was added. The reaction mixture was then brought to reflux for 2 h. Removal of the solvent under vacuum
afforded a solid which was washed with CH2Cl2. Recrystallization from ethyl acetate provided 8 as a
1
white solid (0.9 g, 61%), m.p. 163–165°C. [α]D25=+30.6 (c 0.31 in EtOH). H NMR (DMSO-d6, 270
MHZ) δ: 10.33 (1H, s, HO-10), 9.68 (1H, s, HO-2), 8.70 (1H, d, J=8.6 Hz, NH-9), 8.1 (1H, d, J=8.0
Hz, H-3), 7.37–6.80 (8H, m, H-4-6, C6H5), 4.70 (1H, d, J=4.6 Hz, H-10), 4.01 (1H, dq, J=6.6, 4.6 Hz,
H-9), 1.09 (3H, d, J=6.6 Hz, CH3-9). 13C NMR (DMSO-d6, 67.80 MHz) δ: 158.87 (C-7), 157.16 (C-
8), 146.86 (C-2), 142.90 (Ci), 128.06 (Cm,), 127.23 (Cp) 126.47 (Co, C-5), 125.37 (C-1), 124.91 (C-4),
119.56 (C-3), 115.06 (C-6), 73.99 (C-10), 51.47 (C-9), 14.89 (CH3-9). MS (EI, 15 eV) m/z: [M+−OH,
296 (13)], 209 (12), 208 (100), 207 (18), 164 (2), 136 (25), 109 (16), 79 (2), 44 (63). IR νmax (KBr) 3383,
1670, 1560, 1522, 1458, 1380, 1044, 750 cm−1. Anal. calcd for C17H18N2O4: C, 64.93; H, 5.73; N, 8.91.
Found: C, 63.48; H, 5.81; N, 8.69.
4.8. N-(20-Hydroxyphenyl)-N0-[9S,10R-(10-hydroxy-9-methyl-10-phenyl)ethyl]ethylenediamine (9)
To a solution of 8 (1.0 g, 3.2 mmol) in anhydrous THF (50 ml), a 1.6 M solution of BH3·THF (8 ml)
was added. This mixture was refluxed for 5 h and then cooled to room temperature. After addition of
water, the THF was removed and the organic phase was extracted with ethyl acetate (3×30 mL). The
extracts were washed with brine, dried (MgSO4) and concentrated under vacuum to give the diamine 9
as a red oil (0.4 g, 50%). 1H NMR (CDCl3, 270 MHz) δ: 7.31–6.57 (9H, m, arom.), 4.80 (1H, d, J=3.3
Hz, H-10), 3.20 (2H, m, CH2-7), 2.90 (3H, m, H-9, CH2-8), 0.83 (3H, d, J=6.7 Hz, CH3-9). 13C NMR
(CDCl3, 67.80 MHz) δ: 145.57 (C-2), 141.20 (Ci), 137.04 (C-1), 128.08 (Cm), 127.11 (Cp), 126.01 (Co),
120.65 (C-5), 118.85 (C-4), 115.34 (C-3), 113.55 (C-6), 73.53 (C-10), 58.30 (C-9), 45.75 (CH2-7), 44.53
(CH2-8), 13.50 (CH3-9). IR νmax (KBr) 3240, 2985, 1636, 1110, 765 cm−1.

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A. Ortiz et al. / Tetrahedron: Asymmetry 10 (1999) 799–811
4.9. (5R,4S,2R,16R)-N,N0-Ethylene(4-methyl-5-phenyl-18,23-phenylene)-2,16-bisoxazolidine (10)
A solution of 9 (1.0 g, 3.5 mmol) in toluene (30 ml) was treated with 40% aq. glyoxal (0.2 g, 3.5
mmol). The solid was washed with MeOH and crystallized from a CHCl3:EtOH mixture (1:1) to provide
compound 10 as a white crystalline solid (0.7 g, 70%), m.p. 190–193°C. [α]D25=−155.56 (c 0.0655 in
CH2Cl2). 1H NMR (CDCl3, 270 MHz) δ: 7.32–7.25 (5H, m, C6H5), 6.77 (1H, t, J=7.3 Hz, H-20), 6.71
(1H, d, J=6.6 Hz, H-22), 6.60 (1H, t, J=7.3 Hz, H-21), 6.39 (1H, d, J=6.6 Hz, H-19), 5.63 (1H, d, J=7.3
Hz, H-16), 5.04 (1H, d, J=8.0 Hz, H-5), 3.84 (1H, d, J=7.3 Hz, H-2), 3.68 (1H, dd, J=16.5, 2.7 Hz, H-
14eq), 3.40 (1H, ddd, J=13.9, 11.9, 4.0 Hz, H-14ax), 2.87 (2H, m, H-7eq, H-4), 2.30 (1H, ddd, J=15.2,
11.9, 4.0 Hz, H-7ax), 0.68 (3H, d, J=6.6 Hz, CH3-6). 13C NMR (CDCl3, 67.80 MHz) δ: 139.00 (C-23),
138.60 (Ci), 127.87 (Cm), 127.83 (Co), 121.58 (C-20), 118.34 (C-21), 108.48 (C-22), 105.07 (C-19),
96.10 (C-16), 90.83 (C-2), 82.51 (C-5), 60.90 (C-4), 45.75 (C-7), 42.83 (C-14), 13.75 (CH3-6). MS (EI,
70 eV) m/z: [M+, 308 (75)], 280 (6), 189 (46), 146 (16), 116 (100), 91 (33), 55 (71), 28 (47). IR νmax
(KBr) 1772.0, 1740, 1492.0, 1456, 1306, 1176 cm−1. Anal. calcd for C19H20N2O2·H2O: C, 69.95; H,
6.74; N, 8.58. Found: C, 70.99; H, 6.85; N, 8.27.
4.10. (2S,4S,5R,17S)-N,N0-Ethylene(2,4-dimethyl-5,17-diphenyl-19,24-phenylene)-2,17-bisoxazoli-
dine (11)
A solution of 9 (1.0 g, 3.5 mmol) in benzene (30 ml) was treated with 1-phenyl-1,2-propanedione (0.5
g, 3.5 mmol) and refluxed for 2 h. The product was crystallized from a 2:1 CHCl3:hexane mixture to
yield 11 as a white crystalline solid (0.9 g, 65%), m.p. 184–186°C. 1H NMR (CDCl3, 270 MHz) δ: 7.78
(2H, d, J=2.0 Hz, H-26, 30), 7.34–7.23 (3H, m, H-27–H-29), 7.08 (1H, t, J=7.3 Hz, H-11), 6.97 (2H,
t, J=7.3 Hz, H-10, 12), 6.72 (1H, t, J=7.3 Hz, H-21), 6.68 (1H, d, J=7.3 Hz, H-23), 6.50 (1H, t, J=7.3
Hz, H-22), 6.35 (3H, d, J=7.3 Hz, H-20, 9, 13), 5.03 (1H, d, J=8.6 Hz, H-5), 4.00 (1H, ddd, J=13.9, 6.0,
12.5 Hz, H-15ax), 3.74 (1H, dd, 13.2, 4.0 Hz, H-15eq), 3.18 (1H, dq, J=8.6, 6.0 Hz, H-4), 2.98 (1H, dd,
J=6.0, H-7eq), 2.78 (1H, ddd, J=11.2, 11.2, 5.3 Hz, H-7ax), 1.42 (3H, s, CH3-14), 0.47 (3H, d, J=6.0 Hz,
CH3-6). 13C NMR (CDCl3, 67.80 MHz) δ: 149.69 (C-24), 140.72 (C-25), 138.85 (C-19), 138.59 (C-8),
128.82 (C-10, 12), 127.78 (C-27, 29), 127.66 (C-11), 127.40 (C-28), 127.21 (C-9, 13), 126.93 (C-26, 30),
120.98 (C-21), 117.33 (C-22), 107.03 (C-23), 104.04 (C-20), 103.06 (C-17), 95.26 (C-2), 80.75 (C-5),
56.76 (C-4), 44.27 (C-15), 42.94 (C-7), 15.44 (CH3-6), 11.59 (CH3-14). MS (EI, 70 eV) m/z: [M+, 398
(19)], 265 (10), 222 (15), 205 (18), 203 (100), 202 (16), 196 (17), 195 (22), 167 (13), 160 (22), 118 (24),
117 (33), 116 (95), 115 (15), 44 (31), 42 (18). IR νmax (KBr) 1772, 1654, 1636, 1492, 1458, 1068 cm−1.
4.11. N,N0-Ethylene-2,20-bisbenzoxazolidine (13)
A solution of N,N0-bis-(o-hydroxyphenyl)ethylenediamine21 12 (3.0 g, 12.3 mmol) in 350 mL THF
was treated with 40% aq. glyoxal (0.89 g, 15.36 mmol) and refluxed for 24 h at 45°C to yield 13 as a
white solid (43%). The product was recrystallized from acetone, m.p. 179–182°C. 1H NMR (DMSO-d6,
270 MHz) δ: 6.79 (1H, td, J=7.6, 1.3 Hz, H-8), 6.75 (1H, dd, J=7.3, 1.3 Hz, H-6), 6.65 (1H, dd, J=7.3,
1.3, H-9), 6.58 (1H, td, J=7.6,1.3 Hz, H-7), 5.48 (1H, s, H-2), 3.73 (1H, d, J=9.3 Hz, H-10a), 3.23 (1H,
d, J=9.3 Hz, 10b). 13C NMR (DMSO-d6, 67.80 MHz) δ: 149.2 (C-5), 137.5 (C-4), 121.9 (C-8), 118.6
(C-7), 107.9 (C-6), 106.2 (C-9), 92.9 (C-2), 41.4 (C-10). MS (EI, 70 eV) m/z [M+, 266 (38)], 147 (29),
120 (12), 119 (100), 91 (8), 65 (1). IR νmax (KBr) 3056, 2926, 1650, 1400, 1250 cm−1. Anal. calcd for
C16H14N2O2: C, 72.01; H, 5.35; N, 10.51. Found: C, 72.01; H, 5.28; N, 10.51.

A. Ortiz et al. / Tetrahedron: Asymmetry 10 (1999) 799–811
809
4.12. 1,4-Bis-[(10S,20R)-(20-hydroxy-10-methyl-20-phenyl-)]ethylpiperazine (14)
The procedure described below is representative for the synthesis of compounds 14–16.
To a solution of 4 (0.5 g, 1.4 mmol) in anhydrous THF (100 ml) a 1.6 M solution of BH3·THF (3.6
ml) was added. This mixture was refluxed for 3 h, cooled to room temperature, and water then added,
the THF removed and the organic phase extracted with CH2Cl2 (3×30 ml). The extracts were washed
with NaOH, dried (MgSO4) and concentrated under vacuum to give piperazine 14 as a white solid (0.4 g,
79%), m.p. 169–171°C. [α]D25=+5 (c 0.08 in CH2Cl2). 1H NMR (CDCl3, 270 MHz) δ: 7.36–7.21 (5H,
m, C6H5), 4.91 (1H, d, J=3.3 Hz, H-20), 2.73–2.61 (5H, m, CH2-2,6 and H-10), 0.84 (3H, d, J=6.6 Hz,
CH3-10). 13C NMR (CDCl3, 67.80 MHz) δ: 142.00 (Ci), 127.98 (Cm), 126.85 (Cp), 125.93 (Co), 71.87
(C-20), 64.32 (C-10), 50.83 (C-2), 10.12 (CH3-10). MS (EI, 70 eV) m/z: [M+−HOCHC6H5, 247 (100)],
113 (10), 112 (12), 111 (12), 107 (4), 84 (22), 43 (17), 28 (17). IR νmax (KBr) 3428, 2984, 2362, 1684,
1430, 1380 cm−1. Anal. calcd for C22H30N2O2: C, 74.57; H, 8.47; N, 7.90. Found: C, 74.42; H, 8.67; N,
7.87.
4.13. 1,4-Bis-[(10S,20R)-(20-hydroxy-10-methyl-20-phenyl-)ethyl]-2,3-dimethylpiperazine (15)
A solution of 5 (0.5 g, 1.3 mmol) in anhydrous THF (100 ml) was treated with a 1.6 M solution of
BH3·THF (3.30 ml) to give piperazine 15 as a white solid (0.3 g, 70%), m.p. 114–116°C. [α]D25=−16.9
(c 0.39 in EtOH). 1H NMR (CDCl3, 270 MHz) δ: 7.34–7.22 (5H, m, C6H5), 4.68 (1H, d, J=4.6 Hz, H-20),
2.97–2.91 (2H, m, H-10, H-2), 2.68 (1H, d, J=8.0 Hz, H-5ax), 2.19 (1H, d, J=8.0 Hz, H-5eq), 1.26 (3H, d,
J=6.6 Hz, CH3-2), 0.87 (3H, d, J=7.3 Hz, CH3-10). 13C NMR (CDCl3, 67.80 MHz) δ: 141.72 (Ci), 127.92
(Cm), 126.93 (Cp), 126.12 (Co), 73.14 (C-20), 60.52 (C-2), 58.95 (C-10), 41.69 (C-5), 12.36 (CH3-10),
11.63 (CH3-2). MS (EI, 70 eV) m/z: [M+−HOCHC6H5, 275 (100)], 153 (17), 98 (11), 79 (16), 70 (16),
56 (13). IR νmax (KBr) 3419, 2950, 2390, 1650, 1430, 1378 cm−1. Anal. calcd for C24H34N2O2·2H2O:
C, 71.62; H, 9.45; N, 6.96. Found: C, 70.22; H, 9.20; N, 6.76.
4.14. 1,4-Bis[(20R,200R,10S,100S)-(20,200-dihydroxy-10,100-dimethyl-20,200-diphenyl)diethyl]-3-methyl-
2-phenylpiperazine (16)
A solution of 6 (0.5 g, 1.3 mmol) in anhydrous THF (100 ml) was treated with a 1.6 M solution of
BH3·THF (1.62 ml), to give piperazine 16 as a white solid (0.4 g, 75%), m.p. 182–184°C. [α]D25=+59.6
(c 0.17 in CH2Cl2). 1H NMR (CDCl3, 270 MHz) δ: 50°C: 7.41–7.03 (15H, m, arom.), 4.78 (1H, d, J=4.0
Hz, H-20), 4.71 (1H, d, J=8.0 Hz, H-2), 3.68 (1H, d, J=4.0 Hz, H-200), 3.21 (1H, dq, J=8.0, 6.6 Hz, H-3),
3.10 (1H, dq, J=4.0, 6.6 Hz, H-10), 2.92 (1H, dq, J=4.0, 6.6 Hz, H-100), 2.80–2.67 (3H, m, CH2-5, H-6),
2.23 (1H, m, H-6), 1.06 (3H, d, J=6.6 Hz, CH3-3), 0.75 (3H, d, J=6.6 Hz, CH3-10), 0.45 (3H, d, J=6.6
Hz, CH3-100). 13C NMR (CDCl3, 67.80 MHz) δ (50°C): 143.62, 142.84, 138.20, 130.90, 128.51, 127.86,
127.65, 127.53, 126.90, 126.79, 126.70, 125.97 (arom.), 76.12 (C-2), 72.15 (C-20), 68.81 (C-200), 59.78
(C-10), 58.32 (C-3), 56.81 (C-100), 46.00 (CH2-6), 43.17 (CH2-5), 15.09 (CH3-3), 11.27 (CH3-10), 8.00
(CH3-100). MS (EI, 70 eV) m/z: (%) [M+−HOCHC6H5, 337 (100)], 321 (2.25), 266 (1.56), 215 (1.12),
117 (0.6). IR νmax (KBr) 3566, 3086, 2970, 1472, 1430 cm−1. Anal. calcd for C29H36N2O2·2HCl: C,
67.32; H, 7.35; N, 5.41. Found: C, 68.96; H, 7.77; N, 5.53.

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A. Ortiz et al. / Tetrahedron: Asymmetry 10 (1999) 799–811
4.15. 1-(20-Hydroxyphenyl)-4-[(200 R,100S)(200-hydroxy-100methyl-200-phenyl)ethyl]piperazine (17)
A solution of 10 (0.5 g, 1.6 mmol) in anhydrous THF (100 ml) was treated with a 1.6 M solution
1
of BH3·THF (3.0 ml), to give piperazine 17 as a white solid (0.3 g, 70%), m.p. 116–117°C. H NMR
(CDCl3, 270 MHz) δ: 7.40–7.23 (5H, m, C6H5), 7.17 (1H, d, J=8.0 Hz, H-60), 7.08 (1H, t, J=8.0 Hz, H-
40), 6.94 (1H, d, J=8.0 Hz, H-30), 6.87 (1H, t, J=8.0 Hz, H-50), 4.95 (1H, d, J=2.6 Hz, H-200), 2.90–2.80
(5H, m, H-2-H-3, H-100), 0.91 (3H, d, J=6.6 Hz, CH3-100). 13C NMR (CDCl3, 67.80 MHz) δ: 151.44
(C-20), 141.87 (Ci), 138.77 (C-10), 128.05 (Cm), 126.98 (Cp), 126.48 (C-50), 125.91 (Co), 121.34 (C-40),
120.06 (C-30), 114.05 (C-60), 72.21 (C-200), 64.53 (C-100), 53.00 (C-2), 51.01 (C-3), 10.07 (CH3-100).
MS (EI, 70 eV) m/z: [M+−HOCHC6H5, 205 (100), 176 (10), 148 (14), 120 (22), 84 (37), 79 (17), 77
(16), 65 (6), 56 (12), 42 (10) 28 (11). IR νmax (KBr) 3630, 3422, 2816, 2360, 1500, 1450, 1380, 1230
cm−1. Anal. calcd for C19H24N2O2: C, 73.05; H, 7.37; N, 8.96. Found: C, 72.62; H, 7.72; N, 8.96.
4.16. 1,4-Bis-(20-hydroxyphenyl)piperazine (18)
A solution of 5 (0.5 g, 1.8 mmol) in anhydrous THF (100 ml) was treated with a 1.6 M solution of
1
BH3·THF (4.69 ml) to give piperazine 18 as a white solid (0.3 g, 70%), m.p. 263–267°C. H NMR
(DMSO-d6, 270 MHz) δ: 8.95 (1H, s, OH), 6.93 (1H, d, J=7.3 Hz, H-60), 6.83–6.73 (3H, m, H-40, H-50,
H-60), 3.10 (4H, s, CH2-2). 13C NMR (DMSO-d6, 67.80 MHZ) δ: 150.04 (C-20), 139.90 (C-10), 122.70
(C-50), 119.33 (C-40), 118.56 (C-30), 115.45 (C-60), 50.27 (C-2). MS (EI, 70 eV) m/z: [M+, 270 (57)],
255 (32), 149 (2), 148 (50), 136 (26), 134 (38), 120 (100), 93 (17), 65 (20), 39 (11). IR νmax (KBr) 2986,
2846, 1596, 1450, 1378, 1264, 1154 cm−1. Anal. calcd for C16H18N2O2: C, 71.11; H, 6.66; N, 10.37.
Found: C, 70.19; H, 6.57; N, 10.30.
Acknowledgements
We are grateful to CONACYT for financial support and Ing. Guillermo Uribe for NMR spectra.
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