Diastereoselective synthesis of 5-(alditol-1-C-yl)-hydantoins and their use as precursors of polyhydroxylated-α-amino acids

Article abstract of DOI:10.1016/j.tetlet.2003.11.077

The synthesis of 5-(alditol-1-C-yl)-hydantoin derivatives was performed via diastereoselective aldol-type addition of 1,3-dibenzyl-hydantoin to enantiopure aldehydo sugars. Starting from the D-ribo-configured 5-(alditol-1-C-yl)-hydantoin template, the synthesis of (2R,3S,4R)-3,4,5- trihydroxynorvaline was carried out.

Full text of DOI:10.1016/j.tetlet.2003.11.077

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 1047–1050
Diastereoselective synthesis of 5-(alditol-1-C-yl)-hydantoins and
their use as precursors of polyhydroxylated-a-amino acids
a
Fausta Ulgheri, Gianmauro Orru, Marco Crisma and Pietro Spanu
b
a,
ꢀ a
*
aIstituto di Chimica Biomolecolare del CNR, Sezione di Sassari, Traversa La Crucca 3, 07040 Li Punti-Sassari, Italy
bIstituto di Chimica Biomolecolare del CNR, Sezione di Padova, Via F. Marzolo 1, 35131 Padova, Italy
Received 24 September 2003; revised 10 November 2003; accepted 18 November 2003
Abstract—The synthesis of 5-(alditol-1-C-yl)-hydantoin derivatives was performed via diastereoselective aldol-type addition of 1,3-
dibenzyl-hydantoin to enantiopure aldehydo sugars. Starting from the
synthesis of (2R,3S,4R)-3,4,5-trihydroxynorvaline was carried out.
Ó 2003 Elsevier Ltd. All rights reserved.
D
-ribo-configured 5-(alditol-1-C-yl)-hydantoin template, the
The search for new synthetic methodologies for the
synthesis of enantiomerically pure bioactive molecules is
an area of great interest in modern synthetic organic
chemistry. A complex structure or the presence of mul-
tiple stereocentres makes the synthetic approach to these
molecules a stimulating task.
OH
O
O
O
R
O
R
O
*
*
N
*
N
N
OP
OP
*
+
H
OP
OP
OP
n
N
R
OP
N
R
n
R=H Dihydrouracil
OH
O
O
O
R
R
*
*
*
*
N
+
H
Among the different strategies used, the stereoselective
and versatile approach based, as a key operation, on
carbon–carbon bond formation between heterocycles
and enantiopure sugar-derived templates has been
N
N
OP
OP
n
n
O
O
R
R
R=H Hydantoin
Figure 1.
widely used. Five-membered heterocycles such as furan,
pyrrole, thiophene,1 thiazole2 and isoxazoline3 deriva-
tives or six-membered heterocycles such as substituted
2,5-diketopiperazines4 have shown their utility for the
synthesis of a wide set of molecules of biological interest.
For this purpose hydantoin is an important molecule
because hydantoin derivatives such as 5-C-glycosylated
hydantoins show pharmacological or phytopharma-
cological activity. Specifically, the spirohydantoin of
glucopyranose 1 is a potent inhibitor of glycogen
phosphorylase and has been examined for the treatment
of late-onset diabetes,7 while hydantocidin 2, a ribo-
furanosyl spirohydantoin, displays potent herbicidal
activity.6;8;9
In this field we have recently reported the use of di-
hydrouracil for the diastereoselective chain extension
of isopropylidene-protected glyceraldehyde.5
Proceeding with our programme aimed to develop new
stereoselective procedures for the synthesis of enantio-
pure bioactive molecules, we have directed our attention
towards hydantoin, a five-membered analogue of dihy-
drouracil, as a new homologating reagent for aldehydo
sugars (Fig. 1).6
Furthermore, since this heterocycle has been used as a
synthetic equivalent of glycine by chemical or enzymatic
ring opening,10 5-(alditol-1-C-yl)-hydantoin derivatives
are precursors for the synthesis of sugar amino- and
ureido-acid hybrids.
Keywords: Hydantoin; Imidazolidin-2,4-dione.
* Corresponding author. Tel.: +39-079-3961033; fax: +39-079-39610-
36; e-mail: p.spanu@iatcapa.ss.cnr.it
Herein is disclosed the simple and diastereoselective
synthesis of 5-(alditol-1-C-yl)-hydantoin derivatives via
0040-4039/$ - see front matter Ó 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.11.077

1048
F. Ulgheri et al. / Tetrahedron Letters 45 (2004) 1047–1050
the aldol-type addition of 1,3-dibenzyl-hydantoin
(DBH) 4 to enantiopure aldehydo sugars 5 and 10.
Extending the scope of this methodology, the synthesis
of the polyhydroxylated-a-amino acid 12 is also re-
ported. Trihydroxylated norvaline congeners are bio-
logically important molecules. For example, (2S,3S,4S)-
3,4,5-trihydroxynorvaline [(+)polyoxamic acid] is a
component of the polyoxins, an important family of
complex peptidyl nucleosides with potent antibiotic
activity.11
obtained in high yield and good diastereoselectivity with
a small amount of its C-5 epimer 7 (80/20 isomer ratio
6/7 determined by NMR analysis) (Scheme 1).13 Purifi-
cation of compound 6 was achieved at this stage by
crystallization of the crude reaction mixture from
CH2Cl2/hexane 1/3 or by flash chromatography (hex-
anes/EtOAc 6/4) of the protected mixture of 8 and 9
obtained by exposure of the crude material to TBSOTf
in CH2Cl2 in the presence of 2,6-lutidine.14 Epimeriza-
tion at C-5 was observed when compound 6 was allowed
to react from )80 to )30 °C with 2.0 equiv of LDA for
3 h. After aqueous workup, the two epimers 6 and 7
were obtained in a 73/27 isomeric ratio.
H
O
O
N
HO
HN
HO
O
O
The (5R,10S) configuration of the two new stereocentres
in 5-(alditol-1-C-yl)-hydantoin 6 was unambiguously
established by single crystal X-ray analysis on the basis
of the known (R) configuration at the 20 carbon atom
(Fig. 2).15;16 On the basis of the configurations of the
stereocentres of compound 6 the (5S,10S) configuration
of its C-5 epimer 7 can be inferred.
O
N
H
OH
NH
HO
O
HO
HO
OH
1
2
Formation of 5,10-anti-10,20-anti aldol 6 and 5,10-syn-
10,20-anti aldol 7 results from an unlike (Re enolate, Si
aldehyde) and like (Si enolate, Si aldehyde) approach,
respectively, of the reaction partners in the addition
step. In both cases the Si-face of aldehyde 5 reacts
selectively.17
Initially we prepared DBH 4 by N-protection of com-
mercially available hydantoin 3 under weakly basic
conditions in 85% yield (Scheme 1).12
Then we examined the addition reaction of the aldehyde
5 with the DBH lithium enolate, derived from the
reaction of 4 with 1.2 equiv of LiHMDS in anhydrous
THF at )80 °C. After quenching and aqueous workup,
To demonstrate the synthetic versatility of this procedure
for the diastereoselective preparation of 5-(alditol-1-C-
yl)-hydantoin derivatives containing multiple stereo-
genic centres and different lengths of the polyol chains,
the synthesis of hydantoin templates 11 was also
undertaken (Scheme 2).
D
-ribo-configured 5-(alditol-1-C-yl)-hydantoin 6 was
O
O
H
RN
O
+
The addition of 2,3:4,5-di-O-isopropylidene-D-xylose 10
NR
O
to DBH lithium enolate under the same reaction
conditions reported for the glyceraldehyde derivative
furnished preferentially D-glycero-L-talo configured 5-
(alditol-1-C-yl)-hydantoin 11 in 70% yield (a 72/28 iso-
meric ratio was detected by NMR analysis of the crude
material).18
O
5
3 R=H
BnBr, K2CO3,
DMF, 85%
4 R=Bn
LiHMDS, THF, -80 ˚C,
83%
OH
1'
S
OH
O
O
3'
2'
R
5
4
R
O
O
3
Bn
N
Bn
N
+
1
2
N
O
N
O
Bn
Bn
O
O
6
7
LDA 2 equiv, THF, -30 ˚C, 3 h
TBSOTf, CH2Cl2, 2,6-lutidine
92%
OTBS
OTBS
O
O
O
O
+
Bn
N
Bn
N
N
O
N
O
Bn
Bn
O
O
Figure 2. X-ray diffraction structure of compound 6. Thermal ellip-
soids are drawn at the 30% probability level. Stereocentres at positions
5, 10 and 20 are labelled as C3, C4 and C5, respectively.
9
8
Scheme 1.

F. Ulgheri et al. / Tetrahedron Letters 45 (2004) 1047–1050
1049
Ms. Manuela Azara and Mrs. Barbara Sechi for GC and
HPLC Mass spectra.
O
O
O
BnN
H
O
+
NBn
O
O
O
10
References and notes
3
LiHMDS, THF, -80 ˚C,
70%
1. For a review, see: (a) Casiraghi, G.; Zanardi, F.; Rassu,
G.; Spanu, P. Chem. Rev. 1995, 95, 1677–1716; (b)
Casiraghi, G.; Rassu, G. Synthesis 1995, 607–629; (c)
Casiraghi, G.; Zanardi, F.; Appendino, G.; Rassu, G.
Chem. Rev. 2000, 100, 1929–1972; (d) Battistini, L.;
Casiraghi, G.; Rassu, G.; Zanardi, F. Chem. Soc. Rev.
2000, 29, 109–118; (e) For example, syntheses see: Casi-
raghi, G.; Colombo, L.; Rassu, G.; Spanu, P.; Gasparri
Fava, G.; Ferrari Belicchi, M. Tetrahedron 1990, 46, 5807–
5824; (f) Casiraghi, G.; Rassu, G.; Spanu, P.; Pinna, L. J.
Org. Chem. 1992, 57, 3760–3763; (g) Spanu, P.; Rassu, G.;
Pinna, L.; Battistini, L.; Casiraghi, G. Tetrahedron:
Asymmetry 1997, 8, 3237–3243; (h) Spanu, P.; Rassu, G.;
Ulgheri, F.; Zanardi, F.; Battistini, L.; Casiraghi, G.
Tetrahedron 1996, 52, 4829–4838; (i) Rassu, G.; Pinna, L.;
Spanu, P.; Zanardi, F.; Battistini, L.; Casiraghi, G. J. Org.
Chem. 1997, 62, 4513–4517.
O
OH
Bn
O
O
Bn
N
O
O
N
O
11
Scheme 2.
OH
OH
O
HOOC
O
57% HI , 110 ˚C
2. For a review on the synthetic application of thiazole see:
(a) Dondoni, A. Synthesis 1998, 1681–1706; (b) Applica-
tion in carbohydrate chemistry: Dondoni, A.; Marra, A.
In Preparative Carbohydrate Chemistry; Hanessian, S.,
Ed.; Marcel Dekker: New York, 1997; p 173; (c) Dondoni,
A.; Marra, A. Chem. Rev. 2000, 100, 4395–4422.
Bn
N
OH
N
O
NH2 OH
Bn
O
12
6
Scheme 3.
3. (a) Lopez-Sastre, J. A.; Martin-Ramos, J. D.; Rodriguez-
Amo, J. F.; Santos-Garcia, M.; Sanz-Tejedor, M. A.
Tetrahedron: Asymmetry 2000, 11, 4791–4803; (b) Santos,
M.; Sanz-Tejedor, M. A.; Rodriguez-Amo, J. F.; Arroyo,
Y.; Lopez-Sastre, J. A. Tetrahedron: Asymmetry 2001, 12,
3447–3456.
4. (a) Schollkopf, U. Tetrahedron 1983, 39, 2085–2091; (b)
Grauert, M.; Schollkopf, U. Liebigs Ann. Chem. 1985,
1817–1824; (c) Kobayashi, S.; Furuta, T.; Hayashi, T.;
Nishijima, M.; Hanada, K. J. Am. Chem. Soc. 1998, 120,
908–919; (d) Kobayashi, S.; Furuta, T. Tetrahedron 1998,
54, 10275–10294; (e) Ruiz, M.; Ojea, V.; Ruanova, T. M.;
Quintela, J. M. Tetrahedron: Asymmetry 2002, 13, 795–
799; (f) Ruiz, M.; Ojea, V.; Quintela, J. M. Synlett 1999,
204–206; (g) Ruiz, M.; Ruanova, T. M.; Quintela, J. M.
Tetrahedron Lett. 1999, 40, 2021–2024.
Starting from the
D
-ribo-configured enantiopure pre-
cursor a simple procedure for the synthesis of the bio-
logically important polyhydroxylated-a-amino acid 12
was carried out. When compound 6 was refluxed with
57% HI, the acetonide and benzyl protecting groups
were removed with concomitant hydrolytic cleavage of
the heterocyclic ring (Scheme 3). After ion-exchange
chromatography with Amberlyst H 15 (Hþ form), 2-
amino-2-deoxy-D-ribonic acid 12 was obtained in 48%
yield. The optical rotation for 12 [)3.0 (c 0.37, H2O)]
and its NMR spectra matched well with the reported
data of an authentic sample of 12.11b;c
5. Ulgheri, F.; Bacsa, J.; Nassimbeni, L.; Spanu, P. Tetra-
hedron Lett. 2003, 44, 671–675.
In conclusion, we have shown the use of 1,3-dibenzyl-
hydantoin as homologating reagent for the diastereo-
selective chain extension of aldehydo sugars. Enantio-
merically pure 5-(alditol-1-C-yl)-hydantoin derivatives
with variable polyol chains have been synthesized in
good diastereoselectivity and yield. Starting from the
6. An example of an aldol condensation of hydantoin
derivatives with a C-4 aldehydo sugar has been reported:
(a) Mio, S.; Ichinose, R.; Goto, K.; Sugai, S.; Sato, S.
Tetrahedron 1991, 47, 2111–2120; (b) Mio, S.; Shiraishi,
M.; Sugai, S.; Haruyama, H.; Sato, S. Tetrahedron 1991,
47, 2121–2132.
7. (a) Bichard, C. J. F.; Mitchell, E. P.; Wormald, M. R.;
Watson, K. A.; Johnson, L. N.; Zographos, S. E.; Koutra,
D. D.; Oikonomakos, N. G.; Fleet, G. W. J. Tetrahedron
Lett. 1995, 36, 2145–2148; (b) Somsak, L.; Kovacs, L.;
Toth, M.; Osz, E.; Szilagyi, L.; Gyorgydeak, Z.; Dinya, Z.;
Docsa, T.; Toth, B.; Gergely, P. J. Med. Chem. 2001, 44,
2843–2848; (c) de la Fuente, C.; Krulle, T. M.; Watson, K.
A.; Gregoriou, M.; Johnson, L. N.; Tsitsanou, K. E.;
Zographos, S. E.; Oikonomakos, N. G.; Fleet, G. W. J.
Synlett 1997, 485–487.
D
-ribo-configured enantiopure precursor, a simple pro-
cedure for the synthesis of the biologically important
trihydroxylated norvaline 12 was realized. Application
of this procedure to the synthesis of sugar amino and
ureido acid hybrids is in progress.
Acknowledgements
8. (a) Nakajima, N.; Itoi, K.; Takamatsu, Y.; Okazaki, H.;
Kinoshita, T.; Shindo, M.; Kawakubo, K.; Honma, T.;
Toujigamori, M.; Haneishi, T. J. Antibiot. 1991, 44, 293–
300; (b) Nakajima, N.; Matsumoto, M.; Kirihara, M.;
The authors thank the Regione Autonoma della
Sardegna for generous financial support, and

1050
F. Ulgheri et al. / Tetrahedron Letters 45 (2004) 1047–1050
Hashimoto, M.; Katoh, T.; Terashima, S. Tetrahedron
1996, 52, 1177–1194, and references cited therein.
1H), 4.08 (d, J ¼ 9:0, 1H), 3.99 (dd, J ¼ 8:4, 6.0, 1H), 3.85
(m, 1H), 3.71 (dd, J ¼ 8:1, 5.4, 1H), 1.33 (s, 3H), 1.22 (s,
3H), 0.81 (s, 9H), 0.22 (s, 3H), 0.14 (s, 3H). 13C NMR
(75.4 MHz, CDCl3) d 171.8, 157.8, 136.4, 135.9, 129.2,
128.9, 128.1, 127.9, 127.4, 127.1, 109.5, 75.7, 72.9, 68.5,
9. 5-(Alditol-1-C-yl)-hydantoin derivatives have been syn-
thesized as intermediates for the synthesis of spirohydan-
toins or for their potential biological activity. See Refs. 7c,
8b and (a) Dziedzic, B.; Korohoda, M. J.; Rydzik, E. Pol.
J. Chem. 1995, 69, 90–94; (b) Matsumoto, M.; Kirihara,
M.; Yoshino, T.; Katoh, T.; Terashima, S. Tetrahedron
Lett. 1993, 34, 6289–6292.
10. (a) Koos, M.; Steiner, B.; Langer, V.; Gyepesova, D.;
Durik, M. Carbohydr. Res. 2000, 328, 115–126; (b) Keil,
O.; Schneider, M. P.; Rasor, J. P. Tetrahedron: Asymmetry
1995, 6, 1257–1260; For the use of hydantoin chiral
derivatives as glycine anion equivalents for the synthesis of
a-alkyl and a,a-dialkyl a-amino acids see: Leon-Romo, J.
L.; Virues, C. I.; Avina, J.; Regla, I.; Juaristi, E. Chirality
2002, 14, 144–150.
11. (a) Isono, K. J. Antibiot. 1988, 41, 1711–1739; For
example, syntheses see: (b) Casiraghi, G.; Rassu, G.;
Spanu, P.; Pinna, L. Tetrahedron Lett. 1994, 35, 2423–
2426; (c) Rassu, G.; Zanardi, F.; Cornia, M.; Casiraghi, G.
J. Chem. Soc., Perkin Trans. 1 1994, 2431–2437; (d)
Dondoni, A.; Franco, S.; Merchan, F. L.; Merino, P.;
Tejero, T. Tetrahedron Lett. 1993, 34, 5479–5482; (e)
Veeresa, G.; Datta, A. Tetrahedron Lett. 1998, 39, 119–
122, and references cited therein.
12. Compound 4: 1H NMR (300 MHz, CDCl3) d 7.42–7.20
(m, 10H), 4.66 (s, 2H), 4.52 (s, 2H), 3.68 (s, 2H). 13C NMR
(75.4 MHz, CDCl3) d 169.3, 156.4, 135.9, 135.2, 128.8,
128.6, 128.5, 128.0, 127.8, 48.9, 46.6, 42.5. White solid, mp
46–48 °C.
62.0, 46.7, 42.8, 26.3, 25.8, 25.3, 24.8, 17.8, )4.0, )5.3.
20
Colourless oil ½aꢀ )35 (c 0.5, CHCl3).
D
15. Crystallographic data for 6: C23H26N2O5; crystal system:
monoclinic; space group: P21. Unit cell parameters: a ¼
ꢁ
14:157ð3Þ, b ¼ 5:469ð2Þ, c ¼ 14:598ð3Þ A, b ¼ 110:40ð4Þ°.
3
ꢁ
Z ¼ 2. V ¼ 1059:4ð5Þ A . R1 ¼ 0:0501 [on F P 4rðF Þ];
wR2 ¼ 0:1389 (on F 2, all data). Data/restraints/parame-
ters: 2119/13/247. Goodness-of-fit on F 2 ¼ 1:018.
16. Crystallographic data for this structure have been depos-
ited with the Cambridge Crystallographic Data Centre as
supplementary publication no. CCDC 220239. Copies of
the data can be obtained free of charge on application to
CCDC 12 Union Road, Cambridge CB2 1EZ (Fax: +44-
1223-336-036. E-mail: deposit@ccdc.cam.ac.uk).
17. The diastereoselectivity observed can be explained by the
preferential formation of the cyclic transition state TS1
over TS2.
Ph
O
N
O
H
O
N
Ph
O
H
M
N
H
Ph
M
O
O
Ph
N
H
O
O
O
H
O
13. Only a marginal amount (<7%) of the other two dia-
stereomers were detected by NMR analysis. Compound 6:
1H NMR (300 MHz, CDCl3) d 7.40–7.22 (m, 10H), 5.02 (d,
J ¼ 15:3, 1H), 4.69 and 4.64 (AB system, JAB ¼ 14:7, 2H),
4.36 (ddd, J ¼ 8:7, 6.0, 4.0, 1H), 4.27 (d, J ¼ 15:3, 1H),
4.11 (d, J ¼ 2:1, 1H), 4.02 (dd, J ¼ 8:7, 6.0, 1H), 3.93 (dd,
J ¼ 9:0, 4.2, 1H), 3.93–3.87 (m, 1H), 2.33 (d, J ¼ 5:4, 1H,
OH), 1.22 (s, 3H), 1.21 (s, 3H). 13C NMR (75.4 MHz,
CDCl3) d 170.2, 157.3, 135.8, 129.2, 128.8, 128.5, 127.9,
TS1
TS2
Aldol reactions between a-chiral aldehydes and E(O)-
enolates preferentially give the Felkin-type adduct by
abiding both the Felkin–Anh rule and the Zimmerman–
Traxler model (a) Mengel, A.; Reiser, O. Chem. Rev. 1999,
99, 1191–1223; (b) Roush, W. R. J. Org. Chem. 1991, 56,
4151–4157; (c) Gennari, C.; Vieth, S.; Comotti, A.;
Vulpetti, A.; Goodman, J. M.; Paterson, I. Tetrahedron
1992, 48, 4439–4458.
109.2, 74.2, 71.1, 67.0, 61.4, 45.5, 42.8, 26.8, 25.0. White
20
solid, mp 182–184 °C, ½aꢀ +44 (c 0.6, CHCl3).
D
14. Compound 8: 1H NMR (300 MHz, CDCl3) d 7.42–7.20
(m, 10H), 5.21 (d, J ¼ 15:3, 1H), 4.68 and 4.62 (AB
system, JAB ¼ 14:1, 2H), 4.32–4.23 (m, 1H), 4.13 (d,
J ¼ 15:3, 1H), 4.06 (d, J ¼ 1:5, 1H), 4.04 (dd, J ¼ 8:7,
3.3, 1H), 4.04–4.00 (m, 1H), 3.83 (dd, J ¼ 8:7, 4.5, 1H),
1.16 (s, 3H), 1.15 (s, 3H), 0.79 (s, 9H), 0.10 (s, 3H), )0.10
(s, 3H). 13C NMR (75.4 MHz, CDCl3) d 169.9, 155.8,
136.0, 135.5, 129.3, 128.9, 128.4, 128.1, 127.6, 109.7, 75.0,
18. The
D-glycero-L-talo configuration of compound 11 was
1
proposed based upon H NMR spectral data and reason-
able assumptions based upon mechanistic analogy. Com-
pound 11: 1H NMR (300 MHz, CDCl3) d 7.42–7.22 (m,
10H), 5.05 (d, J ¼ 15:3, 1H), 4.65 (d, J ¼ 2:7, 2H), 4.41–
4.43 (m, 1H), 4.28 (d, J ¼ 15:3, 1H), 4.18–4.08 (m, 2H),
4.40–3.75 (m, 2H), 3.83 (dd, J ¼ 8:7, 6.6, 1H), 3.50 (d,
J ¼ 2:7, 1H), 1.39 (s, 3H), 1.35 (s, 3H), 1.20 (s, 3H), 1.13
(s, 3H). 13C NMR (75.4 MHz, CDCl3) d 170.2, 157.3,
136.0, 135.8, 128.9, 128.4, 128.0, 127.6, 110.6, 110.2, 80.2,
73.0, 67.0, 61.9, 44.6, 42.6, 26.5, 25.9, 25.4, 17.9, )1.5,
20
)2.5. Colourless oil ½aꢀ +34 (c 0.7, CHCl3).
D
1
Compound 9: H NMR (300 MHz, CDCl3) d 7.50–7.30
(m, 10H), 4.96 (d, J ¼ 15:9, 1H), 4.69 and 4.64 (AB
75.1, 74.3, 72.3, 65.3, 61.4, 45.5, 42.5, 26.8, 26.3, 25.8, 24.5.
Light yellow oil ½aꢀ )24 (c 0.5, CHCl3).
20
D
system, JAB ¼ 14:4, 2H), 4.41 (d, J ¼ 15:3, 1H), 4.22 (s,