Synthesis of N,N′-Orthogonally Protected (S)-Piperazine-2-carboxylic Acid

Full text of DOI:10.1021/jo970823f

J . Org. Chem. 1997, 62, 6439-6440
6439
Sch em e 1
Syn th esis of N,N′-Or th ogon a lly P r otected
(S)-P ip er a zin e-2-ca r boxylic Acid
Alan M. Warshawsky,* Meena V. Patel, and
Teng-Man Chen
Hoechst Marion Roussel, 2110 East Galbraith Road,
Cincinnati, Ohio 45215
Received May 7, 1997
Piperazine-2-carboxylic acid (1) is a conformationally
restricted nonproteinogenic amino acid which has been
incorporated into a number of medicinally useful com-
pounds. N-methyl-D-aspartate (NMDA) antagonist 21
and HIV protease inhibitor 32 provide examples. Pip-
erazine-2-carboxylic acid is commercially available only
in racemic form. Homochiral material has been obtained
from racemic preparations by separating enantiomers
through the corresponding chiral amine salts3 or menthol
esters.4 An enzymatic resolution of the Nâ-tert-Boc
carboxamide derivative has also provided optically en-
riched material.5 Aebischer et al.4 reported a synthesis
of (R)-piperazine-2-carboxylic acid from D-asparagine to
correlate the absolute configurations of compounds de-
rived from a separation of enantiomers; however, this
sequence proceeded in less than 5% overall yield. Herein
we describe an efficient asymmetric synthesis of N,N′-
diprotected (S)-piperazine-2-carboxylic acid utilizing an
extension of Vederas’ serine lactone ring opening meth-
odology and a chemoselective reduction of an aminal
intermediate.6
In 1985, Vederas described the conversion of N-tert-
Boc- and N-Cbz-L-serine to the corresponding â-lactones
and subsequent nucleophilic ring opening reactions.7
Depending upon the choice of nucleophile and reaction
conditions, selective ring opening at either the lactone
methylene or carbonyl carbon could be achieved.7,8 For
the synthesis of N,N′-diprotected (S)-piperazine-2-car-
boxylic acid, allylamine was chosen as the nucleophile,
being an inexpensive and volatile R-amino aldehyde
surrogate.
Our synthesis began with the conversion of com-
mercially available N-tert-Boc-L-serine (4) to lactone 5 by
the literature protocol7c (Scheme 1). We found that the
addition of allylamine to a solution of lactone 5 in CH3CN
or THF yielded serine amide 7 predominantly. However,
inverse addition of lactone 5 to allylamine in CH3CN
afforded the desired amino acid 6 in 52% yield along with
amide 7 in 41% yield. The reaction workup was quite
simple. The solution was concentrated, and the residue
was slurried with acetonitrile to give essentially pure
amino acid 6 by filtration and amide 7 by concentration
of the filtrate.
Amino acid 6 was protected as Cbz derivative 8 using
standard Schotten-Baumann conditions in 97% yield.
Cleavage of the olefin by ozonolysis gave the 6-membered
ring aminal 9.9 This assignment was consistent with the
following spectral data. The mass spectrum (CI/CH4)
showed the molecular ion of m/ z 363 corresponding to
[M + H - H2O]+, and no aldehyde resonance was
(1) Lehmann, J .; Schneider, J .; McPherson, S.; Murphy, D. E.;
Bernard, P.; Tsai, C.; Bennett, D. A.; Pastor, G.; Steel, D. J .; Boehm,
C.; Cheney, D. L.; Liebman, J . M.; Williams, M.; Wood, P. L. J .
Pharmacol. Exp. Ther. 1987, 240, 737-746.
(2) Dorsey, B. D.; Levin, R. B.; McDaniel, S. L.; Vacca, J . P.; Guare,
J . P; Darke, P.L.; Zugay, J . A.; Emini, E. A.; Schleif, W. A.; Quintero,
J . C.; Lin, J . H.; Chen, I.-W.; Holloway, M. K.; Fitzgerald, P. M. D.;
Axel, M. G.; Ostovic, D.; Anderson, P. S.; Huff, J . R. J . Med. Chem.
1994, 37, 3443-51.
(3) (a) Felder, E.; Maffei, S.; Pietra, S.; Pitre, D. Helv. Chim. Acta
1960, 43, 888-896L; (b) Stingl, K.; Kottenhahn, M.; Drauz, K.
Tetrahedron: Asymmetry 1997, 8, 979-982.
(4) Aebischer, B.; Frey, P.; Haerter, H.-P.; Herrling, P. L.; Mueller,
W.; Olverman, H. J .; Watkins, J . C. Helv. Chim. Acta 1989, 72, 1043-
1051.
(5) Bruce, M. A.; St. Laurent, D. R.; Poindexter, G. S.; Monkovic, I.;
Huang, S.; Balasubramanian, N. Synth. Commun. 1995, 25, 2673-
2684.
(6) A synthesis of optically active 5-alkylpiperazine-2-carboxylic
acids was reported recently: Falorni, M.; Giacomelli, G.; Satta, M.;
Cossu, S. Synthesis 1994, 4, 391-395.
(7) (a) Arnold, L. D.; Kalantar, T. H.; Vederas, J . C. J . Am. Chem.
Soc. 1985, 107, 7105-7109. (b) Arnold, L. D.; Drover, J . C. G.; Vederas,
J . C. J . Am. Chem. Soc. 1987, 109, 4649-4659. (c) Pansare, S. V.;
Huyer, G.; Arnold, L. D.; Vederas, J . C. Org. Synth. 1991, 70, 1-17.
(8) (a) Ratemi, E. S.; Vederas, J . C. Tetrahedron Lett. 1994, 35,
7605-7608. (b) Kucharczyk, N.; Badet, B.; Le Goffic, F. Synth.
Commun. 1989, 19, 1603-1609.
(9) (a) Zydowsky, T. M.; Dellaria, J . F.; Nellans, H. N. J . Org. Chem.
1988, 53, 5607-5616. (b) Holladay, M. W.; Nadzan, A. M. J . Org. Chem.
1991, 56, 3900-3905. (c) Stanley, M. S. J . Org. Chem. 1992, 57, 6421-
6430. (d) Parr, I. B.; Boehlein, S. K.; Dribben, A. B.; Schuster, S. M.;
Richards, N. G. J . J . Med. Chem. 1996, 39, 2367-2378.
S0022-3263(97)00823-2 CCC: $14.00 © 1997 American Chemical Society

6440 J . Org. Chem., Vol. 62, No. 18, 1997
Notes
(dd, 1H, J ) 1.4, 10 Hz), 5.19 (dd, 1H, J ) 1.4, 17 Hz), 5.62
(brd, 1H, J ) 7.0 Hz), 5.82 (ddt, 1H, J ) 5.4, 10, 17 Hz), 6.84
(brs, 1H); 13C NMR (100 MHz, DMSO-d6) δ 28.3, 41.7, 54.7, 62.8,
80.6, 116.3, 133.6, 156.3, 171.3. Anal. Calcd for C11H20N2O4:
C, 54.08; H, 8.25; N, 11.47. Found: C, 53.95, H, 8.44, N, 11.31.
(S)-N2-(ter t-Bu t oxyca r b on yl)-N3-(b en zyloxyca r b on yl)-
N3-(2-p r op en yl)-2,3-d ia m in op r op a n oic Acid (8). A solution
of amino acid 6 (1.08 g, 4.43 mmol) in saturated aqueous
NaHCO3 (14 mL) and water (2 mL) was treated dropwise at
ambient temperature with a solution of benzyl chloroformate
(0.71 mL, 5.0 mmol) in acetone (1 mL) over 10 min. The cloudy
reaction mixture was stirred for 2 h. The resulting solution was
partitioned between methyl tert-butyl ether (50 mL) and water
(25 mL). The aqueous layer was cooled in an ice bath, brought
to pH ∼2 using 5% aqueous HCl, saturated with NaCl, and
extracted with CH2Cl2 (2 × 50 mL). The combined organic layers
were dried (Na2SO4) and concentrated to give 8 as a viscous
colorless oil (1.62 g, 97%). This material was used in the next
Sch em e 2
detected in the 1H NMR spectrum using CDCl3 as
solvent. The crude ozonolysis reaction product was
carried on without purification. Chemoselective reduc-
tion of the aminal was effected using triethylsilane and
boron trifluoride diethyl etherate in CH2Cl2.10 Final
product 10 was obtained in 80% yield over the last two
steps after the only chromatographic purification of the
synthesis.
step without further purification: [R]20 + 5.4 (c 0.98, CHCl3);
D
NMR data for major conformers, 1H NMR (400 MHz, DMSO-
d6) δ 1.37 (s, 9H), 3.23-3.33 (m, 1H), 3.65-3.72 (m, 1H), 3.75-
3.85 (m, 1H), 3.92-4.00 (m, 1H), 4.25 (dt, 1H, J ) 5.3, 8.4 Hz),
5.04-5.16 (m, 4H), 5.69-5.82 (m, 1H), 7.06 (d, 0.5H, J ) 8.3
Hz), 7.13 (d, 0.5H, J ) 8.3 Hz), 7.28-7.40 (m, 5H), 12.75 (brs,
1H); 13C NMR (100 MHz, DMSO-d6) δ 27.8, 28.1, 46.8, 47.8, 49.9,
52.2, 52.4, 66.2, 66.3, 78.2, 116.1, 116.6, 127.2, 127.7, 128.3,
133.6, 133.9, 136.8, 155.1, 155.4, 155.5, 172.2; HRMS calcd for
(C19H26N2O6 + H) 379.186912, found 379.186794.
The optical purity of 10 was determined using chiral
HPLC.11 For this analysis, a sample of racemic com-
pound was prepared according to the literature method.12
Racemic piperazine-2-carboxylic acid was treated sequen-
tially with N-[(benzyloxycarbonyl)oxy]succinimide and di-
tert-butyl dicarbonate (Scheme 2). The optical purity of
our final product was found to be >99.8%, exceeding the
detection limits of the chromatographic method used.
Thus, the optical purity of our starting material (4),
derived from naturally occuring L-serine, was retained
through the reaction sequence.
In summary, an asymmetric synthesis of N,N′-orthog-
onally protected (S)-piperazine-2-carboxylic acid has been
achieved in four steps and in 40% overall yield from
N-tert-Boc-L-serine â-lactone. The reaction sequence
required only a single chromatographic purification and
yielded optically pure material.
(S)-1,2,4-P ip er a zin etr ica r boxylic Acid , 1-ter t-Bu tyl-4-
ben zyl Ester (10). A solution of 8 (697 mg, 1.84 mmol) in
CH2Cl2 (25 mL) and MeOH (2.5 mL) was cooled in a dry ice/
acetone bath under argon. Ozone was passed through the
solution until a pale blue color persisted (6 psi O2, 1.5 SLPM,
75 V, 3 min). The excess ozone was purged by bubbling argon
through the solution for 15 min. Dimethyl sulfide (2.5 mL) was
added, and the solution was allowed to warm gradually to
ambient temperature overnight. After 20 h, the reaction mixture
was diluted with CH2Cl2 (50 mL) and washed with brine (20
mL). The organic layer was dried (Na2SO4) and concentrated
to a pale yellow foam (745 mg, 106%). The 1H NMR spectrum
(300 MHz, CDCl3) showed no aldehyde proton resonance; mass
spectral data gave the following molecular ions: (CI/CH4) m/ z
363 [M + H - H2O] and (CI/NH3) m/ z 380 [M + NH4 - H2O].
The crude material and triethylsilane (0.31 mL, 1.9 mmol) in
dry CH2Cl2 (45 mL) under argon were cooled in a dry ice/acetone
bath and treated dropwise with boron trifluoride diethyl etherate
(0.24 mL, 1.9 mmol). After 30 min, more triethylsilane (0.31
mL, 1.9 mmol) and boron trifluoride diethyl etherate (0.24 mL,
1.9 mmol) were added in similar fashion. The reaction mixture
was stirred for 2 h at -78 °C, brine (40 mL) was added, and the
cold mixture was extracted with CH2Cl2 (2 × 75 mL). The
combined organic extracts were dried (Na2SO4) and concentrated
in vacuo. The crude product was purified by flash chromatog-
raphy (3 × 20 cm silica column) using CH2Cl2:ethyl acetate:acetic
acid (2:1:0.03) to give 10 as an off-white solid (540 mg, 80%):
Exp er im en ta l Section
Gen er a l. Reagents and anhydrous solvents were obtained
from commercial sources and used without further purification.
Melting points are uncorrected.
(S)-N2-(ter t-Bu toxyca r bon yl)-N3-(2-p r op en yl)-2,3-d ia m i-
n op r op a n oic Acid (6). A solution of N-(tert-butoxycarbonyl)-
L-serine â-lactone (5)7c (1.50 g, 8.01 mmol) in dry CH3CN (150
mL) was added dropwise at ambient temperature over 2 h to a
stirred solution of allylamine (12.0 mL, 200 mmol) in dry CH3CN
(300 mL). After 2 h, the solution was concentrated using a
rotary evaporator. The solid residue was slurried with CH3CN
and filtered to afford 6 as a white solid (1.01 g, 52%). The filtrate
was concentrated to yield N-(tert-butoxycarbonyl)-L-serine allyl
amide (7) as a tan solid (0.803 g, 41%). Amino acid 6: mp 172-
173 °C (dec); [R]20D -3.6 (c 1.00, 0.01 M aqueous NaOH); 1H NMR
(300 MHz, DMSO-d6) δ 1.36 (s, 9H), 3.49-3.52 (m, 2H), 3.59-
3.75 (m, 2H), 3.90-3.97 (m, 1H), 4.80 (brs, 1H), 5.00 (dd, 1H, J
) 1.5, 10 Hz), 5.18 (dd, 1H, J ) 1.8, 17 Hz), 5.78 (ddt, 1H, J )
5.1, 10, 16 Hz), 6.58 (d, 1H, J ) 8.1 Hz), 7.92 (brt, 1H, J ) 4.5
Hz); 13C NMR (100 MHz, DMSO-d6) δ 28.1, 47.7, 49.0, 50.4, 78.1,
120.0, 131.9, 155.2, 171.7; HRMS calcd for (C11H20N2O4 + H)
245.150132, found 245.149973.
mp 50-53 °C; [R]20 -17.5 (c 1.02, CHCl3); 1H NMR (300 MHz,
D
DMSO-d6) δ 1.35 + 1.39 (2s, 9H), 2.77-3.27 (m, 3H), 3.70 (brd,
1H, J ) 12 Hz), 3.87 (brd, 1H, J ) 12 Hz), 4.30-4.57 (m, 2H),
5.05 (brs, 2H), 7.28-7.38 (m, 5H), 12.95 (brs, 1H); 13C NMR (75
MHz, DMSO-d6) δ 27.9, 28.1, 28.2, 41.2, 42.8, 43.98, 44.01, 44.4,
53.3, 54.6, 66.6, 79.8, 80.0, 127.6, 128.0, 128.2, 128.6, 136.9,
154.6, 154.8, 155.0, 171.6, 171.8; HRMS calcd for (C18H25N2O6
+ H) 365.170331, found 365.171262.
Amino amide 7: mp 125-126 °C; [R]20D -57.3 (c 0.99, CHCl3);
1H NMR (300 MHz, DMSO-d6) δ 1.45 (s, 9H), 3.26 (brs, 1H),
3.62-3.71 (m, 1H), 3.80-3.98 (m, 2H), 4.06-4.20 (m, 2H), 5.14
Ack n ow led gm en t. We thank Ms. Sarah E. Wein-
stein for technical assistance and Dr. Dirk Friedrich for
NMR spectra.
(10) Pedregal, C.; Ezquerra, J .; Escribano, A.; Carren˜o, M. C.; Ruano,
J . L. G. Tetrahedron Lett. 1994, 35, 2053-2056.
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectra for
compounds 6, 7, 8, and 10; chiral HPLC traces for (()-10 and
(-)-10 (5 pages). This material is contained in libraries on
microfiche, immediately follows this article in the microfilm
version of the journal, and can be ordered from the ACS; see
any current masthead page for ordering information.
(11) Chiral HPLC was performed using a 150 × 4.6 mm Ultron ES-
OVM column (Mac-Mod Analytical, Inc.; Chadds Ford, PA), a mobile
phase of water/ethanol (93/7) containing a 25 mM phosphate buffer
(pH 5.5), and a flow rate of 1.5 mL/min. UV detection was set at 210
nm. The retention times for the (R) and (S) isomers were 21.3 and
17.0 min, respectively.
(12) Kempf, D. J .; Norbeck, D. W.; Sham, H. L.; U.S. Patent
5,455,351, Oct 3, 1995.
J O970823F