LETTER
An Expedient Entry into the a-Mercaptodiketopiperazine Nucleus
2611
under basic conditions. To our delight however, reaction
of diketopiperazine 17 with 1.5 equivalents of boron tri-
bromide at –78 °C led to rapid cleavage of the para-meth-
oxybenzyl group from the sulfur atom and direct
production of the desired free thiol 18 in 62% yield
(5) Moody, C. J.; Slawin, A. M. Z.; Willows, D. Org. Biomol.
Chem. 2003, 1, 2716.
(
(
6) Fukuyama, T.; Kishi, Y. J. Am. Chem. Soc. 1976, 98, 6723.
7) Fukuyama, T.; Nakatsuka, S.; Kishi, Y. Tetrahedron 1981,
3
7, 2045.
8) Trown, P. W. Biochem. Biophys. Res. Commun. 1968, 33,
02.
(
(
(
Scheme 5).
4
9) Herscheid, J. D. M.; Nivard, R. J. F.; Tijhus, M. W.;
O
O
Ottenheijm, H. C. J. J. Org. Chem. 1980, 45, 1885.
(
10) Herscheid, J. D. M.; Nivard, R. J. F.; Tijhus, M. W.;
Scholten, H. P. H.; Ottenheijm, H. C. J. J. Org. Chem. 1980,
45, 1880.
11) Hino, T.; Sato, T. Tetrahedron Lett. 1971, 12, 3127.
12) Ottenheijm, H. C. J.; Kerkhoff, G. P. C.; Bijen, J. W. H. A.
J. Chem. Soc., Chem. Commun. 1975, 768.
13) Ottenheijm, H. C. J.; Herscheid, J. D. M.; Kerkhoff, G. P. C.;
Spande, T. F. J. Org. Chem. 1976, 41, 3433.
14) Ohler, E.; Tataruch, F.; Schmidt, U. Chem. Ber. 1973, 106,
RS
Bn
HS
Bn
Bn
1
) BBr3, CH2Cl2, –78 °C
N
N
N
N
2
) aq NH4Cl, –78 °C to r.t.
Bn
(
(
O
O
R = para-methoxybenzyl
1
7
18 62%
(
(
Scheme 5
3
96.
(15) Williams, R. M.; Rastetter, W. H. J. Org. Chem. 1980, 45,
625.
16) Miknis, G. F.; Williams, R. M. J. Am. Chem. Soc. 1993, 115,
36.
17) Wu, Z.; Williams, L. J.; Danishefsky, S. J. Angew. Chem.
Int. Ed. 2000, 39, 3866.
18) Yaouancq, L.; René, L.; Dau, M.; Badet, B. J. Org. Chem.
2002, 67, 5408.
A plausible explanation for the success of this reaction
may involve preferential complexation of the boron tri-
bromide with the amide carbonyl groups as implied in
Figure 2.
2
(
(
(
5
O
BBr2
Br
O
(19) Representative Procedure: Benzylamine (2.75 mL, 2.70 g,
5.22 mmol) was added to a solution of ethyl glyoxalate
5.00 mL of a 50% solution in toluene, 25.22 mmol) in
2
(
S
Bn
N
N
toluene (40 mL). This was followed 2 min afterwards by the
addition of p-methoxybenzylmercaptan (3.51 mL, 3.89 g,
Bn
O
25.22 mmol) and the resulting cloudy solution left to stir at
2
6
r.t. for 2 h. Organic solvent was removed by rotary
evaporation at a bath temperature of less than 55 °C to give
a yellow oil that was purified by flash column
Figure 2
chromatography to give the protected a-mercapto amino
+
acid ester as a colourless oil (8.01 g, 92%). MS (FAB ):
In summary, we have developed a mild and rapid route for
the assembly of the 3-mercaptopiperazine-2,5-dione unit
in 53% yield over four steps through selection of a useful
three-component reaction for the preparation of protected
a-mercaptoalkyl glycine derivatives. The successful
deprotection of the para-methoxybenzyl group from sul-
fur is also noteworthy. Further studies are currently under-
way to elaborate this general approach towards a variety
of precursors for the epidithiodiketopiperazine core
structure 1.
+
C H NO S requires [M + H]: 346.14819. Found: [M ]
1
9
24
3
3
1
46.14768. IR (film): nmax = 3347.2, 1732.0, 1511.1,
–1 1
301.9,1250.8, 1175.5, 1032.8 cm . H NMR (300 MHz,
CDCl ): d = 1.31 (3 H, t, J = 7.2 Hz, CO CH CH ), 3.72 (1
H, d, J = 13.1 Hz, SCH ), 3.75 (2 H, m, NHCH ), 3.79 (3 H,
3
2
2
3
2
2
s, OCH ), 3.87 (1 H, d, J = 13.1 Hz, SCH ), 4.22 (2 H, q, J =
3
2
7.2 Hz, CO
CH CH ), 4.35 (1 H, s, CH), 6.84 (2 H, d, J = 8.7
2
2 3
1
3
Hz, Ar-H), 7.23–7.29 (7 H, m, Ar-H). C NMR (75 MHz,
CDCl ): d = 14.15 (CO CH CH ), 33.23 (SCH ), 49.22
NHCH ), 55.28 (OCH ), 61.41 (CO CH CH ), 63.71 (CH),
14.00 (Ar-C-H), 127.19 (Ar-C-H), 128.41 (Ar-C-H),
28.48 (Ar-C-H), 130.07 (Ar-C-H), 130.07 (quaternary C),
38.79 (quaternary C), 158.76 (quaternary C), 169.97
3
2
2
3
2
(
2 3 2 2 3
1
1
1
Acknowledgment
(
CO CH CH ). MS: m/z (%) = 346 (49) [M + H], 214 (31),
2 2 3
We are grateful to the BBSRC (grant No. B16703) for the provision
of a postdoctoral fellowship (to S.T.H.) for this work.
192 (100), 165 (30).
(20) Zoller, U.; Ben-Ishai, D. Tetrahedron 1975, 31, 863.
(
(
(
21) Schouteeten, A.; Christidis, Y.; Mattioda, G. Bull. Soc.
Chim. Fr. 1978, 248.
22) Bock, M. G.; Dipardo, R. M.; Freidinger, R. M. J. Org.
Chem. 1986, 51, 3718.
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(
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Synlett 2004, No. 14, 2609–2611 © Thieme Stuttgart · New York