5200
A.-C. Carlsson et al. / Tetrahedron Letters 47 (2006) 5199–5201
4
chloroformate. Aqueous workup, evaporation of the
solvent and drying under reduced pressure afforded 2
as a white powder which was used in the next step with-
out any further purification.
In conclusion, we have developed an efficient and
straightforward protocol for the preparation of bis-
lactim ether 4 from D-valine. The key step is the
preparation of 2,5-diketopiperazine 3 in water by micro-
wave-assisted heating. The protocol involves only one
chromatographic purification step.
Dipeptide 2 was then converted to 2,5-diketopiperazine
3
. This is normally done in two steps: (1) removal of the
Boc-group from dipeptide 2 under acidic conditions, fol-
lowed by (2) cyclisation to form 2,5-diketopiperazine 3
by heating. Cledera et al. reported a quantitative yield
Acknowledgements
3
5
Financial support was obtained from the Knut and
Alice Wallenberg Foundation.
for the preparation of 3 by heating neat dipeptide 2 at
2
00 ꢁC. However, this procedure only gave a moderate
4
yield on a multigram scale. We reasoned that by using
microwave-assisted heating, both removal of the Boc
group and cyclisation of the dipeptide could be achieved
in one step, avoiding the reduction in yield by prolonged
thermal heating at 200 ꢁC. Furthermore, we have
recently demonstrated the advantages of using micro-
wave-assisted heating combined with water as solvent
for the solution phase synthesis of 2,5-diketopipera-
References and notes
1
. For representative reviews on the preparation of optically
active amino acids: (a) Williams, R. M. In Synthesis of
Optically Active a-Amino Acids; Baldwin, J. E., Ed.;
Organic Chemistry Series; Pergamon Press: Oxford, 1989;
(
8
b) Williams, R. M.; Hendrix, J. A. Chem. Rev. 1992, 92,
89; (c) Duthaler, R. O. Tetrahedron 1994, 50, 1539; (d)
6
zines. A suspension of dipeptide 2 (6.67 mmol) in water
was heated at 150 ꢁC using microwave irradiation for
Seebach, D.; Sting, A. R.; Hoffmann, M. Angew. Chem.,
Int. Ed. 1996, 35, 2708; (e) Cativiela, C.; Diaz-de-Villegas,
M. D. Tetrahedron: Asymmetry 1998, 9, 3517.
. Abellan, T.; Chinchilla, R.; Galindo, N.; Guillena, G.;
Najera, C.; Sansano, J. M. Eur. J. Org. Chem. 2000, 2698,
and references therein.
. (a) Bull, S. D.; Davies, S. G.; Moss, W. O. Tetrahedron:
Asymmetry 1998, 9, 321–327; (b) Liu, X.; Li, X.; Flippen-
Anderson, J.; Yu, S.; Cook, J. M. J. Org. Chem. 2001, 66,
1
5 min in a sealed vial. TLC showed complete conver-
sion. The pressure in the reaction vial almost exceeded
the upper pressure range for the instrument (20 bars),
2
3
due to the generation of CO gas during the thermal
2
breakdown of the Boc protecting group. In order to
scale up the reaction further, a large scale instrument
for microwave-assisted synthesis was employed. Several
experiments were conducted by increasing the amount
of 2 suspended in water and heating at 200 ꢁC for
4
525.
4
. Chen, J.; Corbin, S. P.; Holman, N. J. Org. Process Res.
Dev. 2005, 9, 185.
1
5 min in a sealed container. It was found that 12 g
batches of 2 could efficiently be converted to 2,5-diketo-
piperazine 3 without exceeding the 20 bar pressure lim-
it. Seven batches (7 · 41.6 mmol) were pooled, the
solvent was evaporated and the residue dried under vac-
uum. The crude product was recrystallised from etha-
nol:chloroform (3:1 v/v) to afford a white powder in
5. Cledera, P.; Avendano, C.; Menendea, J. C. Tetrahedron
1998, 54, 12349.
7
6
. Tullberg, M.; Grøtli, M.; Luthman, K. Tetrahedron 2006,
2, in press.
6
7
. (3R)-Isopropylpiperazine-2,5-dione (3). A suspension of
methyl N-(tert-butoxycarbonyl)-D-valyl-glycinate (2.0 g,
6
.9 mmol) in water (20 ml) was heated at 150 ꢁC by
7
3% yield.
microwave irradiation (in a Biotage Initiater Microwave
Synthesiser producing controlled radiation at 2450 MHz
and using fixed hold-time) for 15 min in a sealed vial. The
solvent was removed under reduced pressure and the
residue dried under vacuum overnight. The crude product
was recrystallised from ethanol:chloroform (3:1 v/v). The
target compound was obtained as a white powder in 75%
yield. In a typical large-scale experiment, a suspension of
methyl N-(tert-butoxycarbonyl)-D-valyl-glycinate (12.0 g,
In the final step of the synthesis, bis-O-alkylation of 2,5-
diketopiperazine 3 was carried out to afford the bis-lac-
tim ether 4. Bis-O-methylation is normally achieved with
Me OÆBF ; however, the quality of Me OÆBF is of great
3
4
3
4
importance and this reaction works best with freshly
3
a
prepared reagent.
The preparation of Me OÆBF
3 4
involves the use of gaseous Me O and although a proto-
2
4
1.6 mmol) in water (150 ml) was heated at 200 ꢁC by
col for kilogram-scale preparation of this oxophilic
microwave irradiation (in a Biotage Advancer Microwave
Synthesiser producing controlled radiation at 2450 MHz
and using fixed hold-time) for 15 min in a sealed container.
Work up and purification were carried out as described
3
a
alkylating agent is available, we decided to test the
commercially available Et OÆBF to generate 4. One
3
4
advantage of using Et OÆBF is that the reaction mixture
3
4
becomes homogeneous, and not a two-phase mixture of
thick floating oil and solvent, as is the case with
Me OÆBF . 2,5-Diketopiperazine 3 (28.8 mmol) and
above. The resulting white powder was obtained in 73%
1
yield. H NMR (400 MHz, CD
3
OD): d 0.97 (d, J = 6.9 Hz,
), 1.04 (d, J = 6.9 Hz, 3H, CH(CH ), 2.17–
), 3.72 (m, 1H, HNCH), 3.79 (d,
), 4.01 (d, J = 19 Hz, 1H, NHCH ).
3H, CH(CH
.30 (m, 1H, CH(CH
J = 19 Hz, 1H, NHCH
)
)
3 2
3
4
3
2
2
3
)
2
Et OÆBF (97 mmol) were dissolved in dichloromethane
3
4
2
2
and stirred at room temperature. TLC showed complete
reaction after 5 days. The pH of the reaction mixture
was adjusted to pH 9 during the workup in order to
minimise acid-catalysed hydrolysis of the bis-lactim
ether. Purification by flash chromatography afforded 4
1
3
C NMR (100 MHz, CD OD): d 16.0 (CH(CH ) ), 17.9
3
3 2
(
CH(CH ) ), 33.2 (CH(CH3)2), 44.0 (NHCH2), 60.5
3 2
(
HNCH), 167.5 (CO), 172.8 (CO). NMR spectral data
4
were consistent with the literature data.
8
. (3R)-3,6-Dihydro-2,5-diethoxy-3-isopropyl-pyrazine (4). In
a typical experiment, a mixture of 3(R)-isopropylpiper-
azine-2,5-dione (4.5 g, 28.8 mmol) and Et OÆBF (18.5 g,
8
as an oil. The overall yield starting from D-valine was
1
13
7
1%. H and C NMR spectra were in full agreement
3
4
3
a
with the published data.
97 mmol) in dichloromethane (150 ml) was stirred at room