An enantioselective synthesis of the cyclopentene fragment of nucleoside Q

Article abstract of DOI:10.1016/S0040-4039(03)00973-0

An enantioselective synthesis of (3S,4R,5S)-(+)-3-amino-4,5-dihydroxycyclopentene, a segment of nucleoside Q and Q base, is reported utilizing an amino acid-derived acylnitroso Diels-Alder cycloaddition.

Full text of DOI:10.1016/S0040-4039(03)00973-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 4571–4573
An enantioselective synthesis of the cyclopentene fragment of
nucleoside Q
Kyung-Hee Kim and Marvin J. Miller*
Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46556, USA
Received 28 February 2003; revised 15 April 2003; accepted 16 April 2003
Abstract—An enantioselective synthesis of (3S,4R,5S)-(+)-3-amino-4,5-dihydroxycyclopentene, a segment of nucleoside Q and Q
base, is reported utilizing an amino acid-derived acylnitroso Diels–Alder cycloaddition. © 2003 Elsevier Science Ltd. All rights
reserved.
Nucleoside Q, 1a, also known as queuosine, was found
to be located in the first position of the anticodon
region of Escherichia coli tRNA1 (Fig. 1). Further
studies showed that nucleoside Q is widely distributed
in tRNA’s of both plants and animals.2 Nucleoside Q
and its biosynthetic precursors have potential as biolog-
ically active compounds since deficiency of nucleoside
Q is related to tumor growth.2c However, relatively
little is known about their biological role and the
molecular mechanisms. Detailed structural analysis of
this compound carried out by the Goto group3 found
that nucleoside Q consists of 7-deazaguanosine, the
7-position of which is connected via a methylene bridge
to the amino group of (3S,4R,5S)-(+)-3-amino-4,5-
dihydroxycyclopentene. The aglycone of nucleoside Q
was named Q base, 1b, and is also known as queuine.
In biological systems Q base is known to exist in four
forms: free queuine base, free nucleoside, free nucleo-
tide and nucleoside incorporated into tRNA. Interest-
ingly, the tRNA isolated from various tumors was
found to be deficient in Q base.4,5 The biological role of
Q base is not fully understood and the study of its
function continues.6 (3S,4R,5S)-(+)-3-Amino-4,5-dihy-
droxycyclopentene is a common fragment of both
nucleoside Q and Q base. Since this fragment is known
to play an important role in the exhibition of physio-
logical activity by nucleoside Q,7 its enantioselective
synthesis was investigated.
One of the synthetic routes to nucleoside Q or Q base
is the highly efficient condensation8 to form the Schiff
base of the partially protected 7-deazaguanine deriva-
tive with (+)-cyclopentenylamine acetonide 2a, the
reduction of which gives the protected nucleoside Q or
Q base. However, the disadvantage of this approach is
the lack of an efficient route to a suitable dihydroxycy-
clopentenylamine building block. Reported routes from
( )-dicyclopentadiene are lengthy.9 In order to more
effectively study the biochemical properties of RNA
fragments containing Q base or nucleoside Q as well as
its derivatives, an efficient route to a dihydroxylcy-
clopentenylamine building block is desirable. This
report provides a convenient and stereoselective route
to this compound utilizing an amino acid-derived
acylnitroso Diels–Alder cycloaddition. Previously,
asymmetric acylnitroso Diels–Alder reactions involving
amino acids as chiral auxiliaries were developed in our
group and applied to efficient syntheses of novel carbo-
cyclic nucleosides.10
Figure 1.
Keywords: enantioselective synthesis; nucleoside Q; acylnitroso Diels–
Alder cycloaddition.
* Corresponding author. Tel.: 574-631-7571; fax: 574-631-6652;
e-mail: mmiller1@nd.edu
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)00973-0

4572
K.-H. Kim, M. J. Miller / Tetrahedron Letters 44 (2003) 4571–4573
Scheme 1.
of compound 9 with t-BuOK resulted in alcohol 8 as
the major product although a syn elimination product
has been previously reported for a similar compound
with this base.15 Treatment of 9 with LiN3 led to anti
elimination at C-5 to produce desired compound 10,
however, only 10% conversion was observed. The effect
of basicity on this elimination reaction was investigated
with bases of various pKa values. Nitrogen containing
bases mostly produced compound 10 although the reac-
tion rates were slow. There is no clear correlation
between basicity and reaction rate, however, the highest
conversion to the desired product 10 was obtained with
DBU (pKa 12). The yield is dependent on the concen-
The synthetic route to (3S,4R,5S)-(+)-3-amino-4,5-dihy-
droxycyclopentene 2b is described in Scheme 1. Hydrox-
amic acid 4, readily accessible from L-Ala, was oxidized
to the acylnitroso species, which was trapped in situ with
cyclopentadiene to produce cycloadduct 5. Oxidation
carried out using NaIO4 in MeOH/water at 0°C resulted
in a 3:1 mixture of readily separable diastereomers 5 in
75% combined yield. The same compound was obtained
under Swern oxidation conditions at −78°C as a 5:1
mixture of diastereomers in 70% combined yield. The
major diastereomer was isolated in 50% yield and its
structure is shown in Scheme 1. The stereospecific
exo–cis-hydroxylation of 5 was achieved using OsO4 and
protection of the resulting diol was accomplished by
stirring with a catalytic amount of p-TsOH in 2,2-
dimethoxypropane as solvent to give the corresponding
acetonide. Reductive removal of the amino acid auxiliary
occurred under mild conditions, using NaBH4 in MeOH
to provide 6 in an enantiomerically pure form. Hydroly-
sis of simple primary and secondary amides usually
requires acidic or basic conditions. This Weinreb-type
amide 5 was easily reduced under mild conditions by
NaBH4 in methanol to give amine 6.11 The nitro-
genꢀoxygen bond in 6 was easily cleaved by hydrogena-
tion utilizing Pd/C in MeOH under an atmosphere of H2
to provide the amino alcohol 7. This amino alcohol has
been reported as a key intermediate in the synthesis of
carbocyclic nucleosides.12 The spectral data for 7 were in
good agreement with those reported earlier.10 This free
amine was treated with Boc2O in the presence of Na2CO3
in THF/H2O to provide Boc-protected amine 8. The
conversion from 5 to 8 was carried out in 64% yield
overall without any chromatographic separation of the
intermediates. Compound 8 was converted into the
corresponding mesylate 9 in 95% yield by treatment with
methanesulfonyl chloride and triethylamine in CH2Cl2.13
A direct base-induced elimination using DBU in toluene
produced the desired compound 10 in 76% yield.13,14
Table 1. Effect of base on elimination reaction of 9
Base
Conc. 9 (M)
Resulta (isolated yield)
t-BuOK(5 equiv.)b
LiN3 (2 equiv.)c
Pyridine (5 equiv.)
DMAP (2 equiv.)
4-Ethylmorpholine
(5 equiv.)
0.062
0.048
0.050
0.054
0.193
See text
10% conversion to 10
No reaction
33% conversion to 10
5% conversion to 10
Et3N (5 equiv.)
DBU (1.2 equiv.)
0.066
0.078
No reaction
50% conversion to 10
(40%)
DBU (1.2 equiv.)
DBU (1.2 equiv.)
0.27
1.35
75% conversion to 10
(66%)
89% conversion to 10
(76%)
a Reactions were heated at reflux for 2 days in toluene and conversion
ratios were determined by 1H NMR integration.
b Reaction done in THF at rt for 30 min.
The effects of base on the regiochemistry of elimination
were explored with various bases (Table 1). Treatment
c Reaction heated at reflux for 2 days in THF.

K.-H. Kim, M. J. Miller / Tetrahedron Letters 44 (2003) 4571–4573
4573
tration of 9, while the relative amount of DBU did not
affect the rate or yield of this reaction. Higher concen-tra-
tions of 9 resulted in a higher yield of 10; the yield of 76%
was obtained when the concentration of 9 was 1.35 M.
Compound 2b was prepared from 10 by treating with
dilute aqueous HCl in ether.13 All the spectral data
including the specific optical rotation were in agreement
with those reported earlier for the same compound.9
12. (a) Patil, S. D.; Schneller, S. W.; Hosoya, M.; Snoeck, R.;
Andrei, G.; Balzarini, J.; De Clercq, E. J. Med. Chem. 1992,
35, 3372–3372; (b) Jung, M.; Offenbacher, G.; Retey, J. J.
Helv. Chim. Acta 1983, 66, 1915–1921; (c) Ranganathan,
S.; George, K. S. Tetrahedron 1997, 53, 3347–3362.
13. (1R,2R,3R,4S)-1-Methanesulfonyloxy-2,3-dioxyisopropyl-
idene - 4 - amino - (tert - butoxycarbonyl) - 1,2,3 - cyclopenta-
netriol (9): Alcohol 8 (0.84 g, 3.00 mmol) was dissolved in
CH2Cl2 (10 mL) and cooled to 0°C. Triethylamine (1.67
mL, 12.0 mmol) and methanesulfonyl chloride (0.46 mL,
6.00 mmol) were added to the solution. The reaction was
allowed to warm to room temperature while the mixture
was stirred for 1 h. The mixture was diluted with CH2Cl2
followed by washing with water, 1N HCl solution, and
brine. The solution was dried over MgSO4, filtered, and
concentrated under reduced pressure to give a colorless oil.
The crude residue was purified by flash chromatography
(20–50% EtOAc/hexanes) to give 1.01 g of white solid in
95% yield. Mp 113–114°C (recrystallized from EtOAc–hex-
anes); [h]2D0=−23.8° (c 3.129, CH2Cl2); 1H NMR (300 MHz,
CDCl3) l 1.26 (s, 3H), 1.41 (s, 3H), 1.44 (s, 9H), 1.98 (d,
J=15.3 Hz, 1H), 2.48 (ddd, J=5.8, 6.0, 15.1 Hz, 1H), 3.07
(s, 3H), 4.15 (m, 1H), 4.59 (d, J=5.3 Hz, 1H), 4.72 (dd,
J=1.4, 5.6 Hz, 1H), 4.83 (m, 1H), 4.96 (d, J=4.5 Hz, 1H);
13C NMR (75 MHz, CDCl3) l 24.2, 26.5, 28.6, 34.9, 38.7,
56.6, 84.5, 85.8, 86.7, 111.6, 155.2; IR (TF) 3453, 3399, 2981,
2938, 1713, 1504, 1365, 1177 cm−1; LRMS (FAB) m/z 142,
184, 238, 252, 296, 352 (M+H)+; HRMS (FAB) calcd for
C14H26O7NS (M+H)+ 352.1430, found 352.1446.
In conclusion, we present here an efficient route to
synthesize enantiomerically pure 2b, the side chain of
nucleoside Q. The overall yield of 2b from cycloadduct
5 was 43% and ease of scale up is superior to previously
reported syntheses. This improved route to 2b provides
a practical advantage for the preparation of nucleoside
Q and its derivatives.
Acknowledgements
We gratefully acknowledge Eli Lilly and Co. for support
of this research, the Lizzadro Magnetic Resonance
Research Center at Notre Dame for NMR facilities, and
Dr. W. Boggess and Ms. N. Sevova for mass spectrometry
facilities. Special thanks are extended to Maureen
Metcalf for her assistance with this manuscript and
Professor Scott Hill for useful comments.
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