An improved large scale synthesis of the Schoellkopf chiral auxiliaries: (2R)-and (2S)-2,5-Dihydro-3,6-dimethoxy-2-isopropylpyrazine

Article abstract of DOI:10.1021/op049777t

Syntheses of the Schoellkopf chiral auxiliaries have been carried out on large scale in high overall yields from D- and L-valine. This method avoids the use of highly toxic phosgene or triphosgene, low-temperature reactions, and unstable intermediates.

Full text of DOI:10.1021/op049777t

Organic Process Research & Development 2005, 9, 185−187
An Improved Large Scale Synthesis of the Scho¨llkopf Chiral Auxiliaries: (2R)-
and (2S)-2,5-Dihydro-3,6-dimethoxy-2-isopropylpyrazine
Jianxie Chen,* Scott P. Corbin, and Nicholas J. Holman
Albany Molecular Research, Inc., Syracuse Research Center, 7001 Performance DriVe,
North Syracuse, New York 13212, U.S.A.
Scheme 1
Abstract:
Syntheses of the Scho1llkopf chiral auxiliaries have been carried
out on large scale in high overall yields from D- and L-valine.
This method avoids the use of highly toxic phosgene or
triphosgene, low-temperature reactions, and unstable inter-
mediates.
Introduction
Preparation of nonproteinogenic R-amino acids has re-
ceived attention for decades1 due to their importance in the
medicinal and biotechnology fields.2 Since the optical purity
of R-amino acids is important for molecular recognition and
biological activity, highly enantioselective methodologies for
the preparation of R-amino acids have been sought. A variety
of methods has been reported for the asymmetric preparation
of nonproteinogenic R-amino acids.1 Several methods have
relied on diastereoselective alkylation of a masked glycine,3,4
controlled by an attached homochiral fragment. Scho¨llkopf
introduced his bis-lactim ether methodology in 1981,3 and
this protocol was demonstrated to be extremely successful
for the preparation of R-amino acids.5 Syntheses of the
Scho¨llkopf ethers have been reported in the literature.6
Although these synthetic procedures seem straightforward
transformations, they have drawbacks on the large scale
preparation: (1) the use of highly toxic phosgene or
triphosgene; (2) requirement of the low temperature (e-70
°C) reaction to minimize polymerization of the thermally
unstable methyl N-valyl glycinate; (3) extensive purification
of 3,6-piperazinedione; (4) requirement of freshly prepared
alkylating reagent for the last step. We now report an
improved synthesis for the large scale preparation of
Scho¨llkopf chiral auxiliary, which avoids many of these
problems.
Results and Discussion
Our synthetic strategy is outlined in Scheme 1. D-Valine
(1) was converted to Boc-D-valine (2)7 in quantitative yield
on kilogram scale. Intermediate 2 was treated with isobutyl
chloroformate and triethylamine at 0-5 °C for 0.5 h followed
by addition of a mixture of glycine methyl ester hydrochlo-
ride and triethylamine in dichloromethane, and the resulting
mixture was stirred at room temperature for 16 h to afford
the Boc-protected dipeptide 3, isolated in excellent yield as
a stable, crystalline solid at room temperature. Although
cyclization of the unprotected dipeptide proceeding in toluene
at reflux temperature has been reported by Davies and Cook,6
preparation of the unprotected dipeptide was carried out at
low temperature (e-70 °C) to minimize polymerization, and
purification of the cyclization product was tedious and its
quality is crucial for the methylation. Cledera et al.8 reported
quantitative yield for the gram scale preparation of 3,6-
piperazinedione 4 by heating dipeptide 3 neat at 200 °C.
Under these conditions the yield decreased dramatically at
a 40 g scale.9 As a result, we decided to investigate the
thermal cyclization of dipeptide 3 in the presence of an inert
solvent (Table 1).
(1) Williams, R. M. Synthesis of Optically ActiVe R-Amino Acids; Pergamon
Press: Oxford, 1989. Heimgartner, H. Angew. Chem., Int. Ed. Engl. 1991,
30, 238. Duthaler, R. O. Tetrahedron 1994, 50, 1539. Seebach, D.; Sting,
A. R.; Hoffmann, M. Angew. Chem., Int. Ed. Engl. 1996, 35, 2708. Wirth,
T. Angew. Chem., Int. Ed. Engl. 1997, 36, 225. Chinchilla, R.; Falvello, L.
R.; Galindo, N.; Na´jera, C. Angew. Chem., Int. Ed. Engl. 1997, 36, 995.
(2) Kompella, U. B.; Lee, V. H. L. AdV. Drug DeliVery ReV. 1992, 8, 115.
McMartin, C. Handb. Exp. Pharmacol. 1994, 110, 371.
(3) Deng, C.; Groth, U.; Scho¨llkopf, U. Angew. Chem., Int. Ed. Engl. 1981,
21, 798. Scho¨llkopf, U. Tetrahedron 1983, 39, 2085.
(4) Williams, R. M.; Im, M.-N. J. Am. Chem. Soc. 1991, 113, 9276. Maruoka,
K.; Ooi, T. Chem. ReV. 2003, 103, 3013.
(5) Lange, M.; Undheim, K. Tetrahedron 1998, 54, 5337. Hammer, K.;
Rømming, C.; Undheim, K. Tetrahedron 1998, 54, 10837. Hinterding, K.;
Albert, R.; Cottens, S. Tetrahedron Lett. 2002, 43, 8095. Adamczyk, M.;
Akireddy, S. R.; Reddy, R. E. Tetrahedron 2002, 58, 6951.
(6) Bull, S. D.; Davies, S. G.; Moss, W. O. Tetrahedron: Asymmetry 1998, 9,
321 and references therein. Ma, C.; Liu, X.; Li, X.; Flippen-Anderson, J.;
Yu. S.; Cook, J. M. J. Org. Chem. 2001, 66, 4525.
As illustrated in Table 1, when the reaction was carried
out in toluene or xylene, the conversion of dipeptide 3 to
(7) Both Boc-D-valine and Boc-L-valine are commercially available.
(8) Cledera, P.; Avendan˜o, C.; Mene´ndea, J. C.Tetrahedron 1998, 54, 12349.
(9) Intermediate 4 was obtained in 45% yield when the reaction was carried
out on 40 g scale.
10.1021/op049777t CCC: $30.25 © 2005 American Chemical Society
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Table 1. Cyclization of dipeptide 3 to 4
simplified by switching from sodium bicarbonate to sodium
hydroxide to adjust the pH of the reaction mixture. The
process is easy to execute and scale-up. The synthesis was
also applied successfully to preparation of (2S)-2,5-dihydro-
3,6-dimethoxy-2-isopropylpyrazine.
solvent
temp, °C
time, h
yield, %
toluene
xylene
ethylene glycol
diphenyl ether
1,2-dichlorobenzene
110
138
200
210
180
16
20
2
2
20
37
37
48
32
69
Experimental Section
Reagents and solvents were used as received from
commercial suppliers. D-Valine was purchased from Alfa
Aesar (98%). Trimethyloxonium tetrafluoroborate was re-
ceived from Aldrich. Thin-layer chromatography (TLC) was
performed using Analtech silica gel plates 60 F254 and
3,6-piperazinedione 4 was low. While no starting material
remained after 2 h at 200 °C when the reaction was run in
ethylene glycol or diphenyl ether, the isolated yields of 3,6-
piperazinedione 4 were moderate. 1,2-Dichlorobenzene was
found to be the best solvent for the cyclization as the product
has low solubility in this solvent. It was essential to remove
methanol formed during the reaction in order to achieve a
high yield. When the reaction was complete, about two-thirds
of the solvent was removed by distillation; tert-butyl methyl
ether was carefully added at 50 °C to precipitate any 3,6-
piperazinedione 4 remaining in solution. Solvent free 4 was
easily obtained after filtration and drying under vacuum.
Davies6 found that a high yield in the methylation of 4
could only be achieved by using freshly prepared trimeth-
yloxonium tetrafluoroborate and completely solvent-free 3,6-
piperazinedione 4. When the methylation was carried out
using 4 that was prepared as described above and commercial
trimethyloxonium tetrafluoroborate in dichloromethane at
ambient temperature, (2R)-2,5-dihydro-3,6-dimethoxy-2-iso-
propylpyrazine (5) was isolated in 85% yield after vacuum
distillation. The workup of this reaction was improved by
the use of aqueous sodium hydroxide to adjust the pH to
8-9 rather than using sodium bicarbonate as in the original
procedure; the latter requires such an excess of sodium
bicarbonate that unstirrable mixtures resulted upon scale-
up. The product by GC-MS analysis was typically >96%
pure; the only impurities detected were the ethyl analogues,
(2R)-2,5-dihydro-3-ethoxy-6-methoxy-2-isopropy-
piperazine and (2R)-2,5-dihydro-6-ethoxy-3-methoxy-2-iso-
propypiperazine, resulting from an impurity of triethyloxo-
nium tetrafluoroborate present in the commercial trimethy-
loxonium tetrafluoroborate. However, the presence of these
impurities has no detrimental effect on the use of 5 for the
synthesis of chiral amino acids.
1
visualized by UV light at 254 nm or Hanessian stain. H
NMR and 13C NMR spectra were obtained on a Bruker
Avance-300 spectrometer at 300 and 75 MHz, respectively.
GC and GC/MS analyses were performed using a Hewlett-
Packard G1800A-GCD gas chromatograph using HP-5MS
column, 30 m × 0.25 mm × 0.25 µm. Carrier gas, He, 1
mL/min; injection temperature, 150 °C; column temperature,
100 °C (2 min) f 20 °C/min f 300 °C (5 min); detection,
EID at 280 °C. Optical rotations were recorded on a Perkin-
Elmer 343 polarimeter. Enantiomeric excess was determined
by Agilent 100 series HPLC on a Chiralcel OD-H column,
250 mm × 4.6 mm. Solvents, 2:98 2-propanol/heptane; flow
rate, 0.5 mL/min; wavelength, 210 nm; tR 7.3 min for (S)-
isomer and 7.9 min for (R)-isomer. GC and HPLC analyses
are reported in area %.
Preparation of N-(tert-Butoxycarbonyl)-D-valine (2).
NaHCO3 (717 g, 8.53 mol) was added to a solution of
D-valine (1) (500 g, 4.27 mol) in water (6.4 L) followed by
a solution of di-tert-butyl dicarbonate (932 g) in THF (6.4
L). The mixture was stirred and heated under reflux for 16
h and then concentrated under vacuum to remove THF.
EtOAc (4.5 L) was added, and the mixture was cooled to
10 °C and then adjusted to pH 3 with saturated aqueous
NaHSO4 (3.3 L). The layers were separated, and the aqueous
layer was extracted with EtOAc (4 L). The combined EtOAc
layers were washed with water (2 L) and brine (2 L), dried
over MgSO4, and concentrated under vacuum to give 2 (924
1
g, 99%). H NMR (CDCl3): δ 0.89 (d, 3H, J ) 6.8 Hz),
0.94 (d, 3H, J ) 6.8 Hz), 1.41 (s, 9H), 2.18 (m, 1H), 5.04
(m, 1H), 6.28 (d, 1H, J ) 7.4 Hz), 11.53 (br s, 1H).
Preparation of Methyl N-(tert-Butoxycarbonyl)-D-valyl
Glycinate (3). Isobutyl chloroformate (580 g, 4.25 mol) was
added over 30 min to a stirred mixture of 2 (924 g, 4.25
mol) and Et3N (430 g, 4.25 mol) in CH2Cl2 (12.3 L) at 5
°C. When the addition was complete, the mixture was stirred
at 0-5 °C for 30 min. In a separate flask, a mixture of
glycine methyl ester hydrochloride (534 g, 4.25 mol), Et3N
(430 g, 4.25 mol), and CH2Cl2 (12.3 L) was stirred for 30
min and this mixture was then added to the flask containing
2 over 2 h. After the addition was complete, the mixture
was stirred at room temperature for 16 h and then washed
with water (3 × 15 L) and brine (5 L), dried, and
The suitability of this process to the synthesis of the
Scho¨llkopf ether was confirmed by a similar synthesis of
the enantiomer (2S)-2,5-dihydro-3,6-dimethoxy-2-isoprop-
ylpyrazine in 46% overall yield from 200 g of L-valine.
Conclusions
The synthesis of (2R)-2,5-dihydro-3,6-dimethoxy-2-iso-
propylpyrazine, one of the Scho¨llkopf bis-lactim ether chiral
auxiliaries, was carried out successfully on 125 g scale in
53% yield over four steps. This method avoided using highly
toxic phosgene or triphosgene. No exceptional purification
was required for all intermediates and reagents. The cycliza-
tion product was easily isolated from 1,2-dichlorobenzene
as the reaction solvent on a large scale. The commercial
trimethyloxonium tetrafluoroborate was used in the alkylation
without further purification. The workup on the last step was
1
concentrated under vacuum to give 3 (1118 g, 91%). H
NMR (CDCl3): δ 0.94 (d, 3H, J ) 6.7 Hz), 0.99 (d, 3H,
J ) 6.7 Hz), 1.40 (s, 9H), 2.18 (m, 1H), 3.75 (s, 3H), 3.94-
4.07 (m, 3H), 5.09 (br s, 1H), 6.62 (br s, 1H).
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Preparation of (2R)-Isopropylpiperazine-3,6-dione (4).
A solution of 3 (999 g, 3.46 mol) in 1,2-dichlorobenzene (9
L) was heated at 175-180 °C for 18 h, allowing any MeOH
formed to be removed by distillation. After removal of 6 L
of the solvent by distillation at atmospheric pressure with
the aid of a stream of nitrogen, the mixture was cooled to
50 °C and MTBE (5 L) was added cautiously. The mixture
was cooled to room temperature and filtered. The resulting
solid was washed with MTBE (200 mL) and dried under
vacuum at 100 °C to give 4 (372 g, 69%). 1H NMR (DMSO-
d6): δ 0.84 (d, 3H, J ) 6.8 Hz), 0.91 (d, 3H, J ) 6.8 Hz),
2.10 (m, 1H), 3.51 (m, 1H), 3.61 and 3.81 (AB, 2H, J )
17.7 Hz), 8.01 (s, 1H), 8.20 (s, 1H).
Preparation of (2R)-2,5-Dihydro-3,6-dimethoxy-2-iso-
propylpyrazine (5). To a mixture of 4 (135 g, 0.86 mol)
and trimethyloxonium tetrafluoroborate (450 g, 3.07 mol)
was added CH2Cl2 (2 L) at room temperature. The mixture
was stirred at room temperature for 84 h. The resulting solid
was collected by filtration under nitrogen and washed with
CH2Cl2 (300 mL). The solid was added in portions to a
vigorously stirred mixture of saturated aqueous NaHCO3 (3
L) and CH2Cl2 (2 L) at 4 °C, while maintaining the pH
between 8 and 9 by the simultaneous addition of 3 M
aqueous NaOH as required. The mixture was separated, and
the aqueous phase was extracted with CH2Cl2 (2 × 500 mL).
The combined organic phases were washed with brine (500
mL), dried, and concentrated under vacuum. The pale yellow
residual oil (93% pure by GC-MS) was purified by vacuum
distillation (bp 72 °C/4.5 Torr) to give 5 (134.6 g, 85%, 96%
ee) as a colorless oil. [R]25 ) -106.6° (c ) 1.0, EtOH),
D
[lit.10 [R]23 ) -108 ( 5° (c ) 1.0, EtOH), lit.3 [R]23
)
D
D
1
+106.3° (c ) 1.0, EtOH) for its enantiomer]. H NMR
(CDCl3): δ 0.77 (d, 3H, J ) 6.8 Hz), 1.04 (d, 3H, J ) 6.8
Hz), 2.33 (m, 1H), 3.69 (s, 3H), 3.73 (s, 3H), 3.90 (m, 3H).
13C NMR (CDCl3): δ 17.25, 19.30, 32.70, 46.88, 52.66,
52.71, 61.34, 162.60, 165.09. MS: m/z 184 (M+). The purity
of the product was 98% by GC-MS, and the remaining 2%
was the mixture of (2R)-2,5-dihydro-3-ethoxy-6-methoxy-
2-isopropypiperazine and (2R)-2,5-dihydro-6-ethoxy-3-meth-
oxy-2-isopropypiperazine.
Acknowledgment
We thank Kate A. Slick for her assistance.
Received for review December 8, 2004.
OP049777T
(10) Laboratory Chemicals and Analytical Reagents; Fluka: 2001/2002; p 508.
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