224 J. CHEM. RESEARCH (S), 1997
J. Chem. Research (S),
1997, 224†
Comments on the Asymmetric Synthesis of Chrysogine†
Jan Bergman*
Institute of Biosciences at Novum, Department of Organic Chemistry, S-141 57 Huddinge,
Sweden and Department of Organic Chemistry, Royal Institute of Technology, S-100 44
Stockholm, Sweden
The absolute configuration of the mould metabolite chrysogine, (S)-(ꢀ)-2-(1-hydroxyethyl)quinazolin-4(3H)-one, was first
determined by asymmetric synthesis in 1990 and not in 1996 as recently claimed.
The mould metabolite chrysogine 1 was isolated in 1973 by
Hikino et al. from strains of Penicillium chrysogenum1 and
later by Chadwick from Alternaria citri.2 Related secondary
metabolites such as 2-acetylquinazolin-4(3H)-one 2 and
2-pyruvoylaminobenzamide 3 have also been isolated, the
former from Fusarium culmorum3 and Alternaria citri2 and the
latter from Penicillium chrysogenum4 and Colletotrichum
lagenarium.5
correctly arrived at the conclusion that chrysogine has the S
configuration using NMR methods.
In 1993 Tsantrizos et al. isolated the R form of chrysogine
(less than 20% ee) from Fusarium laterritium Nees. The
absolute configuration was proposed from studies using the
Mosher ester method.8 The Canadian workers were likewise
unaware of previous studies, as in fact the pure antipode of
(S)-chrysogine had already been prepared from 2-amino-
benzamide and (S)-2-chloropropanoyl chloride or, in a better
ee, by inversion of the S form by the Mitsunobu reaction.6
The unawareness of the relevant literature already
touched upon has recently led to a paper9 which claims to
report the first asymmetric synthesis of chrysogine. The
method is identical with ours described in 1990, with the
exception that the Indian workers used sodium hydroxide
rather than sodium carbonate in the final cyclization step.
This change is probably not the major cause for the relative
low rotation ([a]D ꢀ27°) reported, rather we consider it likely
that the (S)-2-acetoxypropanoyl chloride used by the Indian
workers was partially racemic. Anyhow, it is interesting to
note that both forms of chrysogine isolated from Nature are
partially racemic.
O
O
CONH2
O
NH
NH
OH
O
N
N
N
H
O
1
2
3
In 1990 we established, in connection with a comprehen-
sive study,6 the absolute configuration of chrysogine as
(S)-(ꢀ)-2-(1-hydroxyethyl)quinazolin-4(3H)-one by asym-
metric synthesis as outlined in Scheme 1. The sequence is
conveniently completed in one pot but the intermediate 4 can
be isolated in 76% yield. Ring closure of 4 and subsequent
saponification by aqueous sodium carbonate at room tem-
perature gives chrysogine 1 (75%) with an optical rotation of
Finally, Hikino et al. coined the name chrysogine which has
been used by all subsequent workers as well as in a recent
review on quinazoline alkaloids.10 The name ‘chrysogenine’
was probably used by the Indian workers inadvertently.
O
O
O
Received, 12th February 1997; Accepted, 21st February 1997
Paper E/7/01012E
NH2
NH2
NH2
NH
i
ii
OH
NH
N
References
OAc
O
1
1 H. Hikino, S. Nabetani and T. Takemoto, Yakugaku Zasshi, 1973,
93, 619.
4
2 D. J. Chadwick and I. W. Easton, Acta Crystallogr., Sect. C, 1983,
39, 454.
Scheme 1 Reagents: i, (S)-2-acetoxypropanoyl chloride; ii,
Na2CO3 (aq)
3 M. M. Blight and J. F. Grove, J. Chem. Soc., Perkin. Trans. 1,
1974, 1691.
4 P. J. Suter and W. B. Turner, J. Chem. Soc. C, 1967, 2240.
5 Y. Kimura, T. Inoue and S. Tamura, Agric. Biol. Chem., 1973, 37,
2213.
6 J. Bergman and A. Brynolf, Tetrahedron, 1990, 46, 1295.
7 D. Niederer, C. Tamm and W. Zu¨rcher, Tetrahedron Lett., 1992,
33, 3997.
8 Y. S. Tsantrizos, Xiao-Jin Xu, F. Sauriol and R. C. Hayes, Can. J.
Chem., 1993, 71, 1362.
9 D. K. Maiti, P. P. Ghoshdastidar and P. K. Bhattacharya, J.
Chem. Res. (S), 1996, 306.
10 S. Johne, in Rodd’s Chemistry of Carbon Compounds, vol. IV/J,
ed. M. F. Ansell, Elsevier, Amsterdam, 2nd edn., 1995, Supple-
ments, pp. 223–240.
[a]D ꢀ41°. This optical rotation is higher than that ([a]D
ꢀ26<4°) reported by Hikino et al.1
In 1992 Tamm and co-workers,7 unaware of our6 previous
work, incorrectly stated ‘The configuration of the chiral
centre of 1 has never been determined’.7 The Swiss workers
†This is a Short Paper as defined in the Instructions for Authors,
Section 5.0 [see J. Chem. Research (S), 1997, Issue 1]; there is there-
fore no corresponding material in J. Chem. Research (M).