Rapid syntheses of either enantiomer of important carbocyclic nucleoside precursors

Article abstract of DOI:10.1016/S0040-4039(00)01668-3

The syntheses of both enantiomers of aminocyclopentanetriol 1, a versatile carbocyclic nucleoside precursor, is reported utilizing an amino acid-derived acylnitroso Diels-Alder cycloaddition. The sequence is practical and proceeds in an overall yield of 36% from the D-alanine-derived hydroxamic acid. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01668-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 9537–9540
Rapid syntheses of either enantiomer of important
†
carbocyclic nucleoside precursors
Brock T. Shireman and Marvin J. Miller*
Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46556, USA
Received 21 September 2000; accepted 26 September 2000
Abstract
The syntheses of both enantiomers of aminocyclopentanetriol 1, a versatile carbocyclic nucleoside
precursor, is reported utilizing an amino acid-derived acylnitroso Diels–Alder cycloaddition. The sequence
is practical and proceeds in an overall yield of 36% from the
Elsevier Science Ltd. All rights reserved.
D-alanine-derived hydroxamic acid. © 2000
The design and syntheses of carbocyclic nucleosides has led to the discovery of potent
medicinal agents that resist metabolism due to the replacement of an oxygen atom of the parent
1
furanose with a methylene unit. Amino alcohol 1 has been reported as a key intermediate in the
2
synthesis of the antiviral carbocyclic nucleoside 5%-noraristeromycin (2), albeit in racemic form.
2
,3
5
%-Noraristeromycin (2) was developed by Schneller as a non-toxic analog to the potent
4
,5
antiviral agent aristeromycin (3). The synthesis of racemic neplanocin A (4) by Jung also
utilized 1 as a key intermediate. Neplanocin A (4), is an antitumor compound isolated from
6
7
Ampullariella regularis.
NH2
N
NH2
N
N
N
N
N
HO
NH2
(
)n
N
N
HO
HO
O
O
HO
OH
HO
OH
2
3
, n=0 (-)-5'-noraristeromycin
, n=1 aristeromycin
1
4, neplanocin A
In both of the above cases, racemic 1 was generated utilizing the acylnitroso Diels–Alder
8
cycloaddition as a method to aminohydroxylate a 1,3-diene. Other nitroso Diels–Alder reac-
*
Corresponding author.
†
This paper is dedicated to Professor Harry H. Wasserman on the occasion of his 80th birthday.
0
040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01668-3

9538
9,10
tions have also been reported for the preparation of (±)-1.
A synthesis of enantiomerically
pure 1 was reported utilizing a camphor-derived hydroxamic acid as a chiral auxiliary in an
9
a
acylnitroso Diels–Alder cycloaddition. We report here the syntheses of 1 and ent-1 utilizing
common methodology derived from - or -amino acids as chiral auxiliaries in the amino
D
L
11
acid-derived acylnitroso Diels–Alder cycloaddition refined in our group. The synthesis
reported here complements earlier syntheses due to the ease of removal of the amino acid
chiral auxiliary and the ability to utilize either enantiomer of the amino acid delivering either
of the desired enantiomers, 1 or ent-1. In addition, a diastereospecific dihydroxylation pro-
vided the desired relative stereochemistry of the aminocyclopentanetriol.
The synthesis of 1 began with readily available hydroxamic acid 5, derived from
D
-Ala.
Trapping of the transient acylnitroso intermediate, generated from the oxidation of 5 under
1
2
Swern conditions, with cyclopentadiene generated cycloadduct 6 as a 5.9:1 mixture of readily
separable diastereomers in a 78% combined yield (50% yield of the single diastereomer shown).
11b,13
Dihydroxylation of 6 provided a single diastereomer
that was protected as the correspond-
ing acetonide in 95% yield for the two steps. Reductive removal of the amino acid auxiliary
occurred under mild conditions, mediated by NaBH in MeOH, to provide enantiomerically
4
pure 7 in 76% yield. It is instructive to point out that 7 was isolated from 6 without any
chromatographic separation of the intermediates. In addition, 7 could be purified by standard
extractive methods. Hydrogenation of 7 utilizing Pd/C in MeOH under an atmosphere of H2
provided the desired amino alcohol, 1, in quantitative yield. An analogous sequence of steps
was carried out utilizing the enantiomer of 5,
L
-Ala-NHOH, providing ent-1. The free amines
of 1 or ent-1 were then treated separately with Boc O in the presence of Na CO in THF/H O
2
2
3
2
to provide Boc-protected amine 8 or ent-8 in 83 and 84% yields, respectively. The enan-
tiomeric purity of 8 and ent-8 was confirmed by conversion to the corresponding Mosher’s
19
esters. Each were demonstrated to be of >98% ee by comparison of their respective F NMR
spectra.
1
) OsO , NMO,
4
OH (COCl)2, DMSO, Cp
NH CH2Cl2, then Pyr
O
N
THF, H O
2
BocHN
BocHN
2) (CH3)2C(OMe)2
p-TsOH
3) NaBH , MeOH
-78 °C to rt.
O
O
5
6
4
Boc O
Na2CO3
HO
NHBoc
O
O
HO
NH2
2
H , Pd/C
MeOH
2
O
THF, H O
2
O
O
O
O
N
H
7
1
8
In conclusion, we have demonstrated the ability to synthesize both enantiomeric precursors
1
and ent-1 to the carbocyclic nucleosides 5%-noraristeromycin (2) and neplanocin A (4). Each
enantiomer is considered a valuable intermediate for the syntheses of 5%-norcarbocyclic
nucleosides. The ability to synthesize 1 or ent-1 rests in the choice of the configuration of the
amino acid chiral auxiliary. The overall yield of 1 from
D
-Ala-NHOH (5) was 36%. The
methodology is not only efficient and practical, but utilized a limited amount of
chromatography.

9539
Acknowledgements
The authors thank the NIH (AI30988) for support of this research. We acknowledge Don
Schifferl and Dr. Jaroslav Zajicek for NMR assistance, Dr. Bill Boggess and Nonka Sevova for
Mass Spectrometry. B.T.S. also gratefully acknowledges financial support in the form of
Lubrizol and J. Peter Grace fellowships at the University of Notre Dame. Special thanks are
extended to Maureen Metcalf for her assistance with this manuscript.
References
1. (a) Marquez, V. E.; Lim, M.-I. Med. Res. Rev. 1986, 6, 1. (b) Borthwick, A. D.; Biggadike, K. Tetrahedron 1992,
4
8, 571. (c) Agrofoglio, L.; Suhas, E.; Farese, A.; Condom, R.; Chailand, S. R.; Earl, R. A.; Guedj, R.
Tetrahedron 1994, 50, 10611. (d) Crimmins, M. T. Tetrahedron 1998, 54, 9229.
2
3
. Patil, S. D.; Schneller, S. W.; Hosoya, M.; Snoeck, R.; Andrei, G.; Balzarini, J.; De Clercq, E. J. Med. Chem.
1
992, 35, 3372.
. (a) Siddiqi, S. M.; Chen, X.; Schneller, S. W. Nucleosides Nucleotides 1993, 12, 267. (b) Siddiqi, S. M.; Chen, X.;
Schneller, S. W.; Ikeda, S.; Snoeck, R.; Andrei, G.; Balzarini, J.; De Clercq, E. J. Med. Chem. 1994, 37, 1382.
(
c) Siddiqi, S. M.; Chen, X.; Schneller, S. W.; Ikeda, S.; Snoeck, R.; Andrei, G.; Balzarini, J.; De Clerq, E. J.
Med. Chem. 1994, 37, 551. (d) Seley, K. L.; Schneller, S. W.; Korba, B. Nucleosides Nucleotides 1997, 16, 2095.
e) Seley, K. L.; Schneller, S. W.; Korba, B. J. Med. Chem. 1998, 41, 2168.
(
4
5
. Shealy, Y. F.; Clayton, J. D. J. Am. Chem. Soc. 1966, 88, 3885.
. For alternative routes to 5%-noraristeromycin or neplanocin A see: (a) Trost, B. M.; Madsen, R.; Guile, S. D.;
Brown, B. J. Am. Chem. Soc. 2000, 122, 5947. (b) Trost, B. M.; Kuo, G.-H., Benneche, T. J. Am. Chem. Soc.
1
1
988, 110, 621. (c) Merlo, V.; Reece, F. J.; Roberts, S. M.; Gregson, M.; Storer, R. J. Chem. Soc., Perkin Trans.
1993, 1717.
6
7
8
9
. Jung, M.; Offenbacher, G.; Retey, J. Helv. Chim. Acta 1983, 66, 1915.
. Yaginuma, S.; Muto, N.; Tsujino, M.; Sudate, Y.; Hayashi, M.; Otani, M. J. Antibiot. 1981, 34, 359.
. Kirby, G. W. Chem. Soc. Rev. 1977, 6, 1–24.
. (a) Lin, C.-C.; Wang, Y.-C.; Hsu, J.-L.; Chiang, C.-C.; Su, D.-W.; Yan, T.-H. J. Org. Chem. 1997, 62 3806. (b)
Cowart, M.; Bennett, M. J.; Kerwin, J. F. J. Org. Chem. 1999, 64, 2240. (c) Ranganathan, S.; George, K. S.
Tetrahedron 1997, 53, 3347.
10. For non-acylnitroso Diels–Alder approaches see: (a) Gallos, J. K.; Goga, E. G.; Koumbis, A. E. J. Chem. Soc.,
Perkin Trans. 1 1994, 613. (b) Marco-Contelles, J.; Rodriguez-Fernandez, M. Tetrahedron: Asymmetry 1997, 8,
2
249. (c) Farkas, F.; Sequin, U.; Bur, D.; Zehnder, M. Tetrahedron 1992, 48, 103. (d) Ref. 6a.
1. (a) Vogt, P. F.; Miller, M. J. Tetrahedron 1998, 54, 1317. (b) Ritter, A. R.; Miller, M. J. J. Org. Chem. 1994, 59,
602. (c) Ritter, A. R.; Miller, M. J. Tetrahedron Lett. 1994, 35, 9379. (d) Vogt, P. F.; Miller, M. J.; Mulvihill,
1
4
M. J.; Ramurthy, S.; Savela, G. C.; Ritter, A. R. Enantiomer 1997, 2, 367. (e) Vogt, P. F.; Hansel, J.-G.; Miller,
M. J. Tetrahedron Lett. 1997, 38, 2803. (f) Hansel, J.-G.; O’Hogan, S.; Lensky, S.; Ritter, A. R.; Miller, M. J.
Tetrahedron Lett. 1995, 36, 2913. (g) Ghosh, A.; Ritter, A. R.; Miller, M. J. J. Org. Chem. 1995, 60, 5808.
2. Martin, S. F.; Hartmann, M.; Josey, J. A. Tetrahedron Lett. 1992, 33, 3583.
1
1
11b
3. (1S,4R,5S,6R)-2,3-Oxazabicyclo[2.2.1]heptane-5,6-dioxy-isopropylidene (7). To 6 (0.647 g, 2.41 mmol) in THF/
H O (5:1, 30 mL) was added N-methyl-morpholine-N-oxide (0.594 g, 5.07 mmol) followed by OsO (0.3 mol%).
2
4
After 30 min, EtOAc and 5% Na S O (aq.) were added. The layers were separated and the aqueous layer was
2
2
5
saturated with NaCl then extracted with EtOAc. The combined organics were washed with saturated NaHCO3
and brine, then dried (Mg SO ), filtered and concentrated to give a yellow oil that was dissolved in 2,2-
2
4
dimethoxypropane (15.0 mL), and p-TsOH·H O (0.047 g, 0.156 mmol) was added. After 20 min, the reaction was
2
partitioned between Et O and saturated NaHCO . The layers were separated and the aqueous was extracted with
2
3
Et O. The combined organics were washed with brine, dried (MgSO ), filtered, and concentrated to afford 0.783
2
4
g (95%) of a white solid.
To the white solid (0.610 g, 1.78 mmol) from above in MeOH (10.0 mL) was added NaBH (0.269 g, 7.12 mmol).
4
After 30 min, the reaction mixture was partitioned between Et O and 1N HCl. The layers were separated and the
2

9540
organic layer was washed with 1N HCl. The combined acidic aqueous layers were extracted with Et O then
2
brought to pH 10 with saturated NaHCO followed by 2.5 M NaOH under a blanket of EtOAc. The basic
3
aqueous layer was saturated with NaCl and extracted with EtOAc (3×). The combined EtOAc extracts were
washed with brine, then dried (MgSO ), filtered and concentrated under reduced pressure to give a light yellow
4
solid that could be further purified with silica gel chromatography utilizing 70% EtOAc/hexanes to give 0.232 g
2
0
1
(
76%) of 7 as a white solid. R =0.40 (60% EtOAc/hexanes); [h] =+54.9 (c 1.03, CH Cl ); H NMR (300 MHz,
f D 2 2
CDCl ) l 4.42 (m, 1H), 4.28 (m, 1H), 4.19 (m, 1H), 3.77 (m, 1H), 2.28 (m, 1H), 1.64 (m, 1H), 1.45 (s, 3H), 1.30
3
13
+
(
s, 3H); C NMR (75 MHz, CDCl ) l 110.7, 78.9, 78.8, 75.3, 58.6, 33.6, 25.7, 24.2; MS m/z (MH ) calcd for
3
C H NO 172.0974, found 172.0979.
8
14
3
Representative procedure for the preparation of bicycle 8 or ent-8. (1S,2R,3S,4R)-2,3-Dioxy-isopropylidene-4-
amino-(tert-butyloxycarbonyl)-1,2,3-cyclopentane-triol (1). Bicycle 7 (0.102 g, 0.596 mmol) in MeOH (3.0 mL) was
reduced under an atmosphere of H in the presence 10% Pd/C for 30 min. Then the reaction was purged with Ar
2
and filtered through a short pad of Celite. After washing the Celite pad with MeOH until the washings were no
longer ninhydrin positive, the washes were concentrated to give amine 1 as a white solid. Mp=125.5–127°C
1
(
Et O); H NMR (500 MHz, CDCl ) l 4.70 (dd, J=5.5, 1.5 Hz, 1H), 4.41 (dd, J=5.0, 1.5 Hz, 1H), 4.10 (m, 1H),
2
3
3
.61 (dd, J=2.4, 1.0 Hz, 1H), 2.09 (ddd, J=13.5, 9.0, 4.5 Hz, 2H), 1.82 (bs, 3H), 1.65 (d, J=14.5 Hz, 2H), 1.41
13
(s, 3H), 1.30 (s, 3H); C NMR (75 MHz, CDCl ) l 109.7, 86.9, 85.7, 77.6, 57.6, 40.0, 26.1, 23.7.
3
The solid was partitioned between THF/H O (1:1, 3.0 mL) and treated sequentially with Na CO (0.070 g, 0.660
2
2
3
mmol) and Boc O (0.142 g, 0.651 mmol). After 2 h, the reaction was extracted with EtOAc (2×). The combined
2
organic layers were washed with brine, then dried (MgSO ), filtered and concentrated under reduced pressure to
4
give a solid that was purified on silica gel utilizing 50% EtOAc/hexanes to give 0.136 g (84%) of 8 as a white solid.
2
0
20
Mp=99.5–101°C (EtOAc/hexanes), [h] =+22.2 (c 0.78, CH Cl ), [h] =−20.2 (c 0.95, CH Cl ) for ent-8,
D
2
2
D
2
2
1
R =0.27 (50% EtOAc/hexanes); H NMR (500 MHz, CDCl ) l 5.99 (d, J=8.5 Hz, 1H), 5.35 (d, J=3.0 Hz, 1H),
f
3
4
9
2
.34 (m, 2H), 4.0 (m, 1H), 3.75 (m, 1H), 2.02 (ddd, J=5.0, 6.2, 13.3 Hz, 1H), 1.50 (d, J=14.0 Hz, 1H) 1.39 (s,
13
H), 1.31 (s, 3H), 1.18 (s, 3H); C NMR (125 MHz, DMSO-d ) l 155.1, 110.2, 86.2, 77.6, 56.8, 35.5, 28.4, 26.2,
6
+
3.8; MS m/z (MH ) calcd for C H NO 274.1654, found 274.1637.
13
24
5
.