Total synthesis of Q base (Queuine)

Article abstract of DOI:10.1016/S0040-4020(00)00895-4

The total synthesis of Q Base (Queuine) has been accomplished in eleven steps from ribose. Mitsunobu reaction of nosyl protected amine 12 with known cyclopentenol 7, derived from ribose, gave 13, the first key intermediate in the synthesis. The pyrrolo[2,3-d]pyrimidine ring system of Q Base was built via a cyclocondensation reaction between a β-aminobromoaldehyde 16, derived from the Mitsunobu product 13, and 2,4-diamino-6-hydroxypyrimidine. Deprotection of the product from the cycloccondensation reaction (17) gave Q Base. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4020(00)00895-4

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 9221±9225
Total Synthesis of Q Base (Queuine)
,²
*
Charles J. Barnett and Lana M. Grubb
Chemical Process Research and Development, Lilly Research Laboratories, a division of Eli Lilly & Company,
Indianapolis, IN 46285-4813, USA
Received 23 August 2000; revised 24 September 2000; accepted 26 September 2000
AbstractÐThe total synthesis of Q Base (Queuine) has been accomplished in eleven steps from ribose. Mitsunobu reaction of nosyl
protected amine 12 with known cyclopentenol 7, derived from ribose, gave 13, the ®rst key intermediate in the synthesis. The
pyrrolo[2,3-d]pyrimidine ring system of Q Base was built via a cyclocondensation reaction between a b-aminobromoaldehyde 16, derived
from the Mitsunobu product 13, and 2,4-diamino-6-hydroxypyrimidine. Deprotection of the product from the cycloccondensation reaction
(17) gave Q Base. q 2000 Elsevier Science Ltd. All rights reserved.
Introduction
gave Q Base (1) in a total of 19 steps. Route B was reported
by Akimoto, et al. in 1988.6 The strategy of their synthesis
was to use an amine exchange between pyrrolopyrimidine 4
and amine 3 to obtain the desired product. This route suffers
from the requirement of ®ve equivalents of 3, also obtained
from a multistep synthesis,5 to drive the reaction to comple-
tion. We would like to report here the total synthesis of Q
Base (1) via a new route utilizing a different disconnection.
Q Base (1), also known as queuine, is found in the tRNA of
both plants and animals. Isolated and identi®ed in the
1970's, much work has been undertaken to understand the
biological function of 1.1 Of particular interest is the fact
that the tRNA isolated from various tumors was found to be
de®cient in Q Base. Administration of Q Base in one tumor
cell line in mice was found to inhibit tumor growth.2 There
continues to be an interest in the biological role of Q Base,
as much is still not understood.3
Results and Discussion
Two syntheses of Q Base (1) have been reported to date. The
two approaches are outlined in Scheme 1. Route A was
reported by Kondo, et al. in 1983.4 The key step in this
synthesis was the formation of the Schiff base of aldehyde
2 and cyclopentylamine 35 and reduction of this species to
give a protected version of 1. Deprotection of this product
Scheme 2 outlines our retrosynthetic approach to the synth-
esis of Q Base (1). Based on work we recently reported,7 we
envisioned that the pyrrolopyrimidine ring system could be
constructed from the cyclocondensation of 2,4-diamino-6-
hydroxypyrimidine (5) and a bromoaldehyde such as 6.8 We
then hypothesized that bromoaldehyde 6 might be derived
Scheme 1. Previous approaches to the synthesis of Q Base (1).
Keywords: Q Base; cyclocondensation; pyrrolopyrimidine.
* Corresponding author. Tel.: 1518-464-0279, fax: 1518-464-0289; e-mail: lanag@albmolecular.com
²
Lilly Postdoctoral Fellow, 1999-2000. Current address: Albany Molecular Research, Inc., 21 Corporate Circle, P. O. Box 15098, Albany, NY 12212-5098
0040±4020/00/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00895-4

9222
C. J. Barnett, L. M. Grubb / Tetrahedron 56 (2000) 9221±9225
was carried out with alcohol 7 using diisopropyl azodi-
carboxylate (DIAD) and PPh3 in THF at re¯ux for 24 h.
Conditions were optimized using those from Mitsunobu
reactions of nosyl amines10 and reactions reported using
alcohol 7.13 It was determined that a slight excess of alcohol
7 (about 1.2 equiv) was needed to ensure complete reaction
and allow for puri®cation of the product. If unreacted amide
12 remained, it was dif®cult to separate it from the desired
product (13). The stereochemical outcome of the Mitsunobu
reaction was expected to be complete inversion at the center
where displacement takes place. This is predicted by the
outcome of reactions of 713 reported previously, but was
also con®rmed independently in our labs. Synthesis of alco-
hol 14, derived from known amine 3,5 was carried out as
outlined in our earlier work and optical rotations of alcohol
14 obtained from the different routes were compared.14
Values were in good agreement and no diastereomers
were observed by NMR, con®rming that the Mitsunobu
reaction had proceeded cleanly with inversion. No products
from other possible competing mechanisms (SN1 or SN2')
were detected.
Scheme 2. Retrosynthetic analysis of Q Base (1).
from a Mitsunobu reaction between known cyclopentenol 7,
available in four steps from ribose,9 and a suitably protected
nitrogen intermediate 8. This approach would allow
construction of Q Base (1) in a sequence of eleven linear
steps from ribose. The choice of nitrogen protecting group
for 8 would affect two synthetic steps: Mitsunobu reaction
of 8 with 7 and bromination of the aldehyde needed to
obtain 6. In our previous work we determined that the
o-nitrophenylsulfonyl (o-Ns) group provided suf®cient
stabilization of bromoaldehyde products similar to 6 to
allow for their isolation and cyclocondensation to form
pyrrolopyrimidines.7 Additionally, recent work in the area
of Mitsunobu reactions has shown that o-Ns amides work
well in reactions with alcohols in a manner similar to that
needed in our construction.10 Thus the o-Ns group was
chosen for our synthesis.
Completion of the synthesis of Q Base (1) from Mitsunobu
product 13 is shown in Scheme 4. Desilyation of the oxygen
using TBAF in THF gave alcohol 14 in 87% yield. 2,2,6,6-
tetramethyl-1-piperidinyloxy free radical (TEMPO) oxi-
dation15 of 14 provided aldehyde 15 in 88% yield. Bromi-
nation of 15 using TMSBr and DMSO (1 equiv. each) in
acetonitrile16 was followed by immediate condensation with
2,3-diamino-6-hyrdoxypyrimidine17 to give cyclized
product 17 in 45% yield for the two steps. Bromoaldehyde
16 proved to be unstable and the duration of the bromination
1
reaction was critical for its success. H NMR analysis was
used to determine the exact time needed for the bromination
reaction to reach completion. Longer reaction times led to
decomposition. Concentration was also very important in
this reaction. If the reaction mixtures were too dilute, bromi-
nation proceeded very slowly and was accompanied by
appreciable decomposition of the product. It should also
be noted that the method of bromination used in our synth-
esis of 1 differs from that employed in our methodolgy
studies.7 This change is due to the increased sensitivity of
substrate 16 and product 17. By employing the TMSBr and
DMSO in MeCN conditions we were able to perform a one
pot bromination and cyclocondensation reaction without the
need to isolate unstable bromide 16.
Synthesis of the protected amine piece for the Mitsunobu
reaction was carried out as shown in Scheme 3. Bis-sily-
lation of 3-amino-1-propanol (9) was achieved by reaction
of 9 with 2.1 equiv. of TBDMSCl and DBU11 to give amine
10. Protection of the nitrogen of 10 as a sulfonamide using
o-nosyl chloride in CH2Cl2 gave fully protected amide 11 in
93% yield for the two steps. Selective removal of the silyl
group from nitrogen using NH4F in MeOH12 gave nosyl
amine 12 in 71% yield. Mitsunobu coupling of amine 12
Scheme 3. Synthesis of nosyl amine and Mitsunobu reaction.

C. J. Barnett, L. M. Grubb / Tetrahedron 56 (2000) 9221±9225
9223
Scheme 4. Completion of synthesis of Q Base (1).
Completion of the synthesis of Q Base required only the
removal of the two protecting groups on 17. While ef®cient
methods were found to remove both the nosyl18 and the
acetonide groups,4 signi®cant challenges arose in the puri-
®cation of these products. Both compounds were quite
insoluble in most organic solvents, with MeOH and EtOH
being exceptions. No acceptable conditions were found that
would allow for crystallization, and ultimately, chromato-
graphy was utilized. Thus with polar eluents (mixtures of
EtOAc/EtOH/NH4OH, see Experimental) denosylated 17
and TBDMSCl (42.52 g, 282.1 mmol). After re¯uxing for
2 h, the solution was washed with water. The aqueous phase
was extracted with Et2O and the combined organic phases
dried over MgSO4, ®ltered and concentrated under reduced
pressure to give 41.1 g crude bis-TBS protected amino-
propanol 10 as a colorless oil. This material was character-
1
ized by H NMR and used without further puri®cation. A
small sample was puri®ed by vacuum (2±3 mm Hg) distil-
lation for characterization. 1H NMR: d 0.04 (s, 6H), 0.05 (s,
6H), 0.89 (s, 9H), 0.91 (s, 9H), 1.63±1.70 (m, 2H), 2.77±
2.84 (m, 2H), 3.63±3.71 (m, 2H). 13C: d 25.3, 23.4, 18.1,
18.3, 25.8, 26.0, 36.2, 39.4, 61.3.
1
and Q Base (1) were obtained in good purity. H and 13C
NMR data for 1 obtained by this synthesis agreed with that
reported for 1.19 Optical rotation data for Q Base obtained
from our synthesis were also in good agreement with the
published data,4 further con®rming that the stereochemical
outcome of the Mitsunobu reaction was as predicted.
N,O-Bis(tert-butyldimethylsilyl)-N-o-nitrobenzenesulfonyl-
3-amino-1-propanol (11). To a solution of bis-TBS
compound 10 (10.1 g, 33.3 mmol) in CH2Cl2 (100 mL)
were added Et3N (7.0 mL, 50.2 mmol), o-nitrobenzene-
sulfonyl chloride (8.05 g, 36.3 mmol), and DMAP (50±
100 mg, catalytic). The solution stirred for 3 h and then
washed sequentially with 1N HCl (50 mL), saturated
NaHCO3 (50 mL), and saturated NaCl (50 mL). The organic
phase was dried over MgSO4, ®ltered and concentrated
under reduced pressure to give 15.11 g (30.9 mmol, 93%
yield) of nosylate 11 as a yellow oil. This material was
used directly in the next reaction without further puri®ca-
tion. The 1H NMR spectrum indicated that partial N-desily-
Conclusion
We have achieved the synthesis of Q Base by a new route,
utilizing a Mitsunobu reaction and subsequent cycloconden-
sation reaction to build the core structures. The synthesis is
straightforward and ef®cient. A new entry into the construc-
tion of this class of molecules has been made which expands
the possible synthetic approaches available.
1
lation had occurred during the sulfonylation reaction. H
NMR: d 0.05 (s, 6H), 0.10 (s, 6H), 0.87 (s, 9H), 0.91
(s, 9H), 1.6±1.75 (m, 2H), 3.20±3.26 (m, 2H), 3.67
(m, 2H), 7.71±7.74 (m, 2H), 7.83±7.86 (m, 1H), 8.11±
8.14 (m, 1H).
Experimental
Materials and methods
N-o-Nitrobenzenesulfonyl-O-tert-butyldimethylsilyl-3-
amino-1-propanol (12). To a solution of nosylate 11
(30.8 g, 63.0 mmol) in MeOH (400 mL) was added NH4F
(2.57 g, 69.4 mmol). The solution was stirred for 30 min
before H2O (50 mL) was added and the solution concen-
trated under reduced pressure. The residue was taken up
in Et2O (300 mL) and washed sequentially with H2O
(2£75 mL) and saturated NaCl solution (50 mL). The
organic phase was dried over MgSO4, ®ltered and concen-
trated under reduced pressure to give 19.8 g (52.9 mmol,
84%) of crude 12 as a yellow oil. Puri®cation by column
chromatography (10±30% EtOAc/hexanes) gave 16.7 g
Reagents and solvents were used as received from the
supplier. Reactions were carried out under an atmosphere
of nitrogen with magnetic stirring. 1H and 13C NMR spectra
were collected at 300 MHz and 75 MHz respectively and
acquired in CDCl3 unless otherwise noted. TLC was carried
out on glass plates, precoated with silica gel 60. Column
chromatography was carried out using Silica gel 60, 230±
400 mesh.
N,O-Bis(tert-butyldimethylsilyl)-3-amino-1-propanol (10).
To a solution of 3-amino-1-propanol (9) (10.0 g, 133.1 mmol)
in toluene (200 mL) were added DBU (42.0 mL, 280.8 mmol)

9224
C. J. Barnett, L. M. Grubb / Tetrahedron 56 (2000) 9221±9225
(44.6 mmol, 71% yield) of sulfonamide 12 as a viscous
yellow oil. IR (cm21, ®lm) 3400, 2956, 2930, 2858, 1544,
1410, 1362, 1169, 1096, 838. 1H NMR: d 0.03 (s, 6H), 0.85
(s, 9H), 1.72 (quint, Jˆ6.2 Hz, 2H), 3.21 (q, Jˆ5.6 Hz, 2H),
3.67 (t, Jˆ5.6 Hz, 2H), 5.72 (t, Jˆ5.6 Hz, 1H), 7.69±7.73
(m, 2H), 7.81±7.84 (m, 1H), 8.08±8.11 (m, 1H). 13C NMR:
d 25.4, 18.3, 25.9, 31.8, 41.9, 61.1, 125.1, 130.9, 132.5,
133.4, 147.9. HRMS: calcd for C15H27N2O5SSi 375.1410,
found 375.1404.
procedure in Ref. [15]. Thus 1.63 g (4.1 mmol) of alcohol
14 was treated with 2,2,6,6-tetramethyl-1-piperidinyloxy
free radical (TEMPO) (15.7 mg, 0.10 mmol), KBr
(85.3 mg, 0.72 mmol) and NaOCl (5.25% solution,
6.7 mL, diluted with one volume water containing 463 mg
NaHCO3) to give 1.23 g (3.1 mmol, 88% yield) of aldehyde
15 as a yellow oil after workup. This material was used
1
directly as obtained without further puri®cation. H NMR:
d 1.28 (s, 3H), 1.39 (s, 3H), 2.77±2.87 (m 2H), 3.22 (ddd,
Jˆ6.7, 8.8, 14.4 Hz, 1H), 3.65 (ddd, Jˆ6.2, 8.7, 15.2 Hz,
1H), 4.43 (d, Jˆ5.9 Hz, 1H), 4.90 (d, Jˆ1.5 Hz, 1H), 5.22±
5.24 (m, 1H), 5.66±5.69 (m, 1H), 6.07 (ddd, Jˆ1.8, 2.0,
5.6 Hz, 1H), 7.62±7.77 (m, 3H), 8.08±8.11 (m, 1H), 9.72
(s, 1H). 13C NMR: d 25.2, 26.9, 39.2, 44.8, 70.5, 82.5, 83.9,
111.5, 123.9, 130.6, 131.3, 131.6, 132.2, 133.9, 137.0,
147.9, 199.4.
(1S,2R,3S)-N-(3-tert-Butyldimethylsilyloxypropyl)-N-(o-
nitrobenzenesulfonyl)-2,3-isopropylidinedioxycyclo-
pent-4-enylamine (13); Mitsunobu reaction of 7 and 12. To
a stirred solution of alcohol 79 (4.20g, 26.9 mmol) in THF
(50 mL) was added a solution of amine 12 (8.09 g,
21.6 mmol) in THF (50 mL). Triphenylphosphine
(10.56 g, 40.3 mmol) was added. To the mixture was
added a solution of DIAD (8.0 mL, 40.6 mmol) in THF
(10 mL) dropwise over 10±15 min. The solution was
re¯uxed for 24 h, cooled to room temperature, and ®ltered
through a plug of silica gel. The plug was eluted with Et2O
(200±300 mL) and the ®ltrate concentrated under reduced
pressure to give 31.60 g of a yellow oil. Careful chromato-
graphy (elution with 10±50% CH2Cl2/hexanes, followed by
CH2Cl2) gave 8.55 g (77%) of pure 13 as a yellow viscous
oil. IR (cm21, ®lm) 2956, 2931, 2858, 1546, 1373, 1258,
1166, 1097, 1051, 938, 837. 1H NMR: d 0.02 (s, 6H), 0.86
(s, 9H), 1.28 (s, 3H), 1.39 (s, 3H), 1.64±1.85 (m, 1H), 3.00±
3.10 (m, 1H), 3.33 (ddd, Jˆ5.3 Hz, 10.6 Hz, 15.2 Hz, 1H),
3.57 (t, Jˆ5.6 Hz, 2H), 4.50 (d, Jˆ5.9 Hz, 1H), 4.90 (d, Jˆ
1.8 Hz, 1H), 5.20±5.23 (m, 1H), 6.02 (ddd, Jˆ 1.8 Hz, a.8,
5.6 Hz, 1H), 7.65±7.73 (m, 3H), 8.06±8.12 (m, 1H). 13C
NMR: d 25.3, 14.2, 18.3, 21.7, 22.7, 25.6, 25.9, 27.3, 31.6,
33.9, 43.9, 70.4, 83.1, 84.2, 111.5, 123.9, 131.0, 133.2, 133.5,
136.6, 147.9. HRMS: calcd for C23H40N3O7SSi M1NH4
530.2356, found 530.2366. [a]2D3ˆ136.78 (cˆ1.09, MeOH).
2-Amino-5-[(1S,2R,3S)-N-(o-nitrobenzenesulfonyl)-2,3-
isopropylidinedioxycyclopent-4-enylaminomethyl]-
pyrrolo[2,3-d]pyrimin-4(3H)-one (17). A solution of alde-
hyde 15 (5.2956 g, 13.3 mmol) in acetonitrile (26 mL) was
cooled to 08C. To this solution were added TMSBr (1.8 mL,
13.6 mmol) and DMSO (0.95 mL, 13.4 mmol) via syringe.
The ice bath was removed and the solution stirred for 4 h at
rt. At that time a solution of 2,4-diamino-6-hydroxypyrimi-
dine (1.65 g, 13.1 mmol) and NaOAc (1.22 g, 14.9 mmol) in
water (26 mL), warmed slightly to dissolve all solids, was
added to the reaction mixture. After stirring overnight, the
reaction mixture was extracted with EtOAc (5£200 mL).
The combined organic extracts were washed with water
(50 mL), dried over MgSO4, ®ltered, and concentrated
under reduced pressure to give 5.15 g (10.2 mmol, 77%)
of crude pyrrolopyrimidine 17 as an orange solid. The
crude material was puri®ed by column chromatography,
loading as a solution in EtOAc and eluting with the
following solvent systems: 1:1 EtOAc/hexanes, followed
by 99:0.9:0.1 EtOAc/EtOH/NH4OH, then 95:4.5:0.5
EtOAc/EtOH/NH4OH, and ®nally 90:9:1 EtOAc/EtOH/
NH4OH to give 3.02 g (6.0 mmol, 45% yield) of 17 as a
yellow amorphous solid which resisted crystallization.
Further puri®cation proved dif®cult but the material
obtained was suitable to carry forward in the synthesis. IR
(cm21, KBr) 3400, 2800, 1699, 1632, 1543, 1164, 1127. 1H
NMR (DMSO-d6): d 1.51 (s, 3H), 1.24 (s, 3H), 4.32±4.54
(m, 3H), 4.84±4.89 (m, 2H), 5.54 (dd, Jˆ5.6, 5.9 Hz), 5.87±
5.9 (m, 1H), 6.05 (s, 2H), 6.39 (d, Jˆ2.1 Hz, 1H), 7.76±8.03
(m, 4H), 10.24 (s, 1H), 10.88 (d, Jˆ2.1 Hz, 1H). 13C NMR
(CD3OD): d 25.8, 27.6, 42.7, 71.5, 84.2, 85.6, 99.7, 101.2,
112.3, 116.1, 118.8, 125.2, 131.7, 131.9, 132.8, 134.5,
134.9, 137.4, 149.1, 152.1, 153.8, 161.6. HRMS: calcd for
C21H22N6O7S (M11) 503.1349, found 503.1339.
(1S,2R,3S)-N-(3-Hydroxypropyl)-N-(o-nitrobenzene-
sulfonyl)-2,3-isopropylidinedioxycyclopent-4-enylamine
(14). To a solution of silyl alcohol 13 (2.61 g, 5.1 mmol) in
THF (50 mL) was added TBAF (1.0 M solution in THF,
6.6 mL, 6.6 mmol). The solution was stirred until TLC indi-
cated complete consumption of starting material (2±3 h).
The solution was diluted with Et2O, washed successively
with water and saturated NaCl solution, dried over
MgSO4, ®ltered and concentrated under reduced pressure
to give crude alcohol 14. Chromatography on silica gel
(20±50% EtOAc/hexanes, followed with EtOAc) gave
1.77 g (87%) of pure alcohol 14 as a yellow oil. IR (cm21
thin ®lm) 3050, 2950, 1546, 1373, 1163, 1050. 1H NMR: d
1.21 (s, 3H), 1.31 (s, 3H), 1.63±1.72 (m, 2H), 2.51 (br s,
1H), 3.07 (dt, Jˆ7.3, 15.0 Hz, 1H), 3.33±3.43 (m, 1H), 3.58
(t, Jˆ5.8 Hz, 2H), 4.44 (d, Jˆ5.8 Hz, 1H), 4.80 (d, Jˆ1.0 Hz,
1H), 5.17±5.19 (m, 1H), 5.59±5.62 (m, 1H), 5.97±5.99 (m,
1H), 7.57±7.72 (m, 3H), 87.97±8.03 (m, 1H). 13C NMR: d
14.1, 21.0, 25.4, 27.1, 33.1, 43.7, 59.0, 60.3, 70.4, 83.0, 111.3,
123.9, 130.5, 131.0, 131.6, 132.7, 133.7, 136.5, 147.6. HRMS:
calcd for C17H21N2O7S1Na 421.1045, found 421.1033.
[a]2D3ˆ135.28 (cˆ0.95, MeOH).
2-Amino-5-[(1S,2R,3S)-2,3-isopropylidinedioxycyclo-
pent-4-enylaminomethyl]pyrrolo[2,3-d]pyrimin-4(3H)-
one. To a solution of 17 (284 mg, 0.57 mmol) in DMF
(2.5 mL) were added DBU (180 mL, 1.20 mmol) and
b-mercaptoethanol (44 mL, 0.63 mmol).18 After stirring at rt
for 24 h the DMF was removed in vacuo. The residue was
taken up in ethanol, silica gel added, and solvent removed
under reduced pressure. The resulting dry powder was put
on top of a column of silica. Elution of the product was carried
out with EtOAc, followed by 95:4.5:0.5 EtOAc/EtOH/
NH4OH to 70:27:3 EtOAc/EtOH/NH4OH. Concentration
(1S,2R,3S)-N-(3-Oxopropyl)-N-(o-nitrobenzenesulfonyl)-
2,3-isopropylidinedioxycyclopent-4-enylamine (15). Oxi-
dation of alcohol 14 was carried out according to the

C. J. Barnett, L. M. Grubb / Tetrahedron 56 (2000) 9221±9225
9225
3. (a) Kersten, H. Biofactors 1988, 1, 27±29. (b) Kinzie, S. D.;
Thern, B.; Iwata-Reuyl, D. Org. Lett. 2000, 2, 1307±1310.
4. Kondo, T.; Ohgi, T.; Goto, T. Chem. Lett. 1983, 419±422.
5. (a) Tanaka, K.; Ogasawara, K. Synthesis 1996, 219±222.
(b) Fang, J.; Chering, Y. J. Chem. Res., Miniprint 1986, 1564±
1572. (c) Oghi, T.; Goto, T. Tetrahedron Lett. 1976, 17, 367±370.
6. Akimoto, H.; Imamiya, E.; Hitaka, T.; Nomura, H. J. Chem.
Soc., Perkin Trans. 1 1988, 1637±1644.
of product containing fractions gave 83.2 mg (0.26 mmol,
46% yield) of denosylated 17 as a yellow solid. The low
yield is probably due to loss on chromatography since the
1
reaction appeared to be nearly quantitative by TLC. H
NMR (CD3OD): d 1.31 (s, 3H), 1.33 (S, 3H), 3.78±3.82
(m, 2H), 3.93 (d, Jˆ13.2 Hz, 1H), 4.59 (d, Jˆ5.7 Hz, 1H),
5.23 (d, Jˆ5.0 Hz, 1H), 5.85 (ddd, Jˆ1.1, 2.3, 5.9 Hz, 1H),
5.93 (dd, Jˆ1.5, 5.6 Hz), 6.66 (s, 1H). 13C NMR (CD3OD):
d 25.8, 27.6, 44.3, 69.4, 84.0, 85.9, 100.1, 112.0, 116.6,
117.3, 134.5, 153.2, 153.9, 162.02. HRMS: calcd for
C15H19N5O3 (M 1 1) 318.1566, found 318.1563.
7. Barnett, C. J.; Grubb, L. M. Tetrahedron Lett., in press.
8. (a) Secrist, J. A.; Liu, P. S. J. Org. Chem. 1978, 43, 3937±3941.
(b) Noell, C. W.; Robins, R. K. J. Heterocycl. Chem. 1964, 1, 34±
41. (c) Migawa, M. T.; Hinkley, J. M.; Joops, G. C.; Townsend,
L. B. Synth. Commun. 1996, 26, 3317±3322.
2-Amino-5-[(1S,2R,3S)-2,3-dihyroxycyclopent-4-enyl-
aminomethyl]pyrrolo[2,3-d]pyrimin-4(3H)-one, Q base (1).
A solution of de-nosylated 17 (53.7 mg, 0.17 mmol) in 1N
HCl (4.5 mL) and MeOH (2.0 mL) was heated at 808C for
8 h.4 The solution was cooled and concentrated under
reduced pressure. A solution of 9:1 EtOH/NH4OH (5±
6 mL) was added and most solid dissolved. This solution
was loaded onto a short column of silica which was packed
using hexanes. The column was eluted with hexanes, 1:1
EtOAc/hexanes, 100% EtOAc, 90:9:1 EtOAc/EtOH/
NH4OH, 70:27: 3.0 EtOAc/EtOH/NH4OH, 50:45:5
NH4OH/EtOH/EtOAc and then with 9:1 EtOH/NH4OH.
Fractions containing the product were concentrated under
reduced pressure to give 39.4 mg of Q Base (1) (0.14 mmol,
84%) as a white solid. All spectra matched the published
data.19 1H NMR (CD3OD): d 4.17±4.18 (m, 1H), 4.25±4.29
(m, 1H), 4.34±4.38 (m, 1H), 4.44±4.48(m, 1H), 4.59±4.61
(m, 1H), 6.03±6.06 (m, 1H), 6.22±6.24 (m, 1H), 6.87
(s, 1H). 13C NMR (D2O, dioxane at 67.4): d 43.0, 67.3,
73.8, 74.5, 99.1, 108.5, 120.0, 129.8, 138.4, 152.1, 153.4,
161.9. HRMS: calcd for C12H15N5O3 (M11) 278.1254,
found 278.1253. Optical rotation data was obtained after
adding 2.5 equiv. HCl to form the salt, as the literature
value was obtained from the HCl salt. Observed
[a]D23ˆ11118 (cˆ0.30, H2O), lit. [a]2D6ˆ11138 (cˆ0.3,
H2O).4
9. (a) Ali, S. M.; Ramesh, K.; Borchardt, R. T. Tetrahedron Lett.
1990, 31, 1509±1512. (b) Borcherding, D. R.; Scholtz, S. A.;
Borchardt, R. T. J. Org. Chem. 1987, 52, 5457±5461. (c) Seley,
K. L.; Schneller, S. W.; Rattendi, D.; Lane, S.; Bacchi, C.J.
Antimicrob. Agents Chemother. 1997, 41, 1658±1661.
10. (a) Fukuyama, T.; Cheung, M.; Kan, T. Synlett 1999, 1301±
1303. (b) Fukuymam, T.; Cheung, M.; Jow, C-K.; Hidai, Y.; Kan,
T. Tetrahedron Lett. 1997, 38, 5831±5834. (c) Fukuyama, T.; Jow,
C-K.; Cheung, M. Tetrahedron Lett. 1995, 36, 6373±6374.
11. Hart, D. J.; Grillot, A. Heterocycles 1994, 39, 435±438.
12. Williams, D. M.; Brown, D. M. J. Chem. Soc., Perkin Trans. 1
1995, 1225±1231.
13. (a) Seley, K. L.; Schneller, S. W.; Korba, B. J. Med. Chem.
1998, 41, 2168±2170. (b) Seley, K. L.; Schneller, S. W.;
Rattendi, D.; Lane, S.; Bacchi, C. J. J. Med. Chem. 1997, 40,
625±629. See also Ref. [9c].
14. Synthesis was carried out similarly to that reported for cyclo-
pentylamine examples reported in Ref. [7]. The exact route is
outlined here:
15. Anelli, P. L.; Montanari, F.; Quici, S. Org. Synth. 1990, 69,
212±219.
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