Addition of lithiated 9-deazapurine derivatives to a carbohydrate cyclic imine: Convergent synthesis of the aza-C-nucleoside immucillins

Article abstract of DOI:10.1021/jo0155613

Means have been developed for the synthesis and addition of 9-deaza-9-lithiopurine derivatives to the carbohydrate-derived cyclic imine 6 in facile convergent syntheses of biologically active aza-C-nucleosides.

Full text of DOI:10.1021/jo0155613

J . Org. Chem. 2001, 66, 5723-5730
5723
Ad d ition of Lith ia ted 9-Dea za p u r in e Der iva tives to a
Ca r boh yd r a te Cyclic Im in e: Con ver gen t Syn th esis of th e
Aza -C-n u cleosid e Im m u cillin s
Gary B. Evans,† Richard H. Furneaux,† Tracy L. Hutchison,§ Hollis S. Kezar,§
Philip E. Morris, J r.,§ Vern L. Schramm,‡ and Peter C. Tyler*,†
Carbohydrate Chemistry, Industrial Research Limited, P.O. Box 31310, Lower Hutt, New Zealand,
Department of Biochemistry, Albert Einstein College of Medicine, Bronx, New York 10461, and Biocryst
Pharmaceuticals Inc., 2190 Parkway Lake Drive, Birmingham, Alabama 35244
p.tyler@irl.cri.nz
Received February 7, 2001
Means have been developed for the synthesis and addition of 9-deaza-9-lithiopurine derivatives to
the carbohydrate-derived cyclic imine 6 in facile convergent syntheses of biologically active aza-
C-nucleosides.
Sch em e 1
In tr od u ction
Combined work by some of us has led to the recent
synthesis of aza-C-nucleosides 1 and 2 (“immucillins”).
These compounds, and their 5′-monophosphate esters,
are extremely powerful inhibitors of human purine
nucleoside phosphorylase (PNP), protozoan nucleoside
hydrolases, and purine phosphoribosyltransferases.1 In-
hibitors of PNP have become targets for drug design,
because they are expected to selectively control the
proliferation of T-cells. Such inhibitors offer the prospect
of controlling disorders of T-cell function, such as T-cell
lymphoma, organ transplant rejection, rheumatoid ar-
thritis, psoriasis, and other autoimmune diseases.2 The
potential utility of these compounds has focused our
attention on improved methods for their synthesis.
In our initial synthesis of the immucillins, we employed
a linear approach with >20 steps (Scheme 1).3 Protected
1,4-dideoxy-1,4-imino-D-ribitol (3), synthesized from D-
gulonolactone by known procedures,4,5 was treated with
N-chlorosuccinimide and then with a hindered base to
give an intermediate imine which, without isolation, was
condensed with lithiated acetonitrile to afford adduct 4.
By the use of previously described chemistry applied to
the synthesis of 9-deazanucleosides, 4 was converted into
pyrrole 5, from which both 1 and 2 were readily obtained.
Unfortunately, this synthesis is impractical for the
production of more than milligram to gram quantities of
immucillins, particularly because the conversion of 3 to
4 was unreliable on scale-up.
While we have investigated several possible alternative
routes to the immucillins based on literature precedents,
these were either unsuccessful or proved impractical for
large scale synthesis.6 An apparently useful synthesis of
C-linked (1,4-dideoxy-1,4-imino-â-D-ribofuranosyl)hetero-
cycles by reductive amination of 1-C-substituted D-erythro-
* To whom correspondence should be addressed. Fax: +64-4-
5690055. E-mail: p.tyler@irl.cri.nz.
† Industrial Research Limited.
‡ Albert Einstein College of Medicine.
§ Biocryst Pharmaceuticals.
(1) Miles, R. W.; Tyler, P. C.; Furneaux, R. H.; Bagdassarian, C. K.;
Schramm, V. L. Biochemistry 1998, 37, 8615. Miles, R. W.; Tyler, P.
C.; Evans, G. B.; Furneaux, R. H.; Parkin, D. W.; Schramm, V. L.
Biochemistry 1999, 38, 13147. Shi, W.; Li, C. M.; Tyler, P. C.; Furneaux,
R. H.; Cahill, S. M.; Girvin, M. E.; Grubmeyer, C.; Schramm, V. L.;
Almo, S. C. Biochemistry 1999, 38, 9872. Li, C. M.; Tyler, P. C.;
Furneaux, R. H.; Kicska, G.; Xu, Y.; Grubmeyer, C.; Girvin, M.;
Schramm, V. L. Nat. Struct. Biol. 1999, 6, 582.
(3) Evans, G. B.; Furneaux, R. H.; Gainsford, G. J .; Schramm, V.
L.; Tyler, P. C. Tetrahedron 2000, 56, 3053.
(4) Horenstein, B. A.; Zabinski, R. F.; Schramm, V. L. Tetrahedron
Lett. 1993, 34, 7213.
(2) Montgomery, J . A. Med. Res. Rev. 1993, 13, 209. Sircar, J . C.;
Gilbertsen, R. B. Drugs Future 1988, 13, 653. Morris, P. E., J r.;
Montgomery, J . A. Expert Opin. Ther. Pat. 1998, 8, 283.
(5) Fleet, G. W. J .; Son, J . C. Tetrahedron 1988, 44, 2637.
(6) Synthetic approaches to aza-C-nucleosides have been reviewed:
Yokoyama, M.; Momotake, A. Synthesis 1999, 1541.
10.1021/jo0155613 CCC: $20.00 © 2001 American Chemical Society
Published on Web 08/01/2001

5724 J . Org. Chem., Vol. 66, No. 17, 2001
Evans et al.
Sch em e 2
Sch em e 3a
a
Reagents: i, POCl3; ii, NaOMe; iii, NaOBn; iv, tButoxybis-
(dimethylamino)methane; v, DMF(OMe)2; vi, Raney nickel; vii, Zn/
HOAc.
9-bromo-9-deaza compounds that are protected at N-7
and O-6 (rather than N-1) are needed to survive bromine/
lithium exchange. At the initiation of this work, there
were no facile syntheses of 8 or 9, nor any reports of their
derivatives appropriately functionalized for lithiation. We
therefore chose initially to work with some readily
available 9-deazaxanthine derivatives.
pentose-4-uloses7 cannot be applied, because it has
subsequently been shown to afford only products with
the â-L-lyxo-configuration,8 that is, the 1′,4′ epimers of
the required products. Consequently, we decided to
refocus on the iminoribitol 3 as a key compound; it has
the advantages of being relatively readily available and
having all but one of the chiral centers in place. The
synthetic challenge, therefore, was to shorten the route
from 3 to 1 and 2. An efficient convergent synthesis
involving the addition of a lithiated 9-deazapurine de-
rivative 7 to imine 6 (Scheme 2) would represent a major
improvement. A recent report9 on the addition of aryl-
lithiums to cyclic nitrones derived from D-ribose repre-
sents a similar approach, but we have not investigated
whether this can be utilized for our purposes.
We have recently reported new facile syntheses of
9-deazahypoxanthine (8) and 9-deazaguanine (9),10 from
which suitably protected 9-bromo-9-deazapurine deriva-
tives may be available for lithiation studies. Here, we
describe our results on the synthesis of appropriately
protected 9-bromo-9-deazapurine derivatives, their sub-
sequent lithiation, and the conditions required for addi-
tion of the heterocycles to imine 6.
A reported synthesis of 2,4-dimethoxypyrrolo[3,2-d]-
pyrimidine (9-deaza-2,6-di-O-methylxanthine) (16)12
(Scheme 3) offered useful methodology, and 6-methyl-5-
nitrouracil (10) was converted into the bis-O-protected
9-deazaxanthine derivative 16 in this manner. However,
because of the reported13 difficulties in deprotecting a
9-ribosylated derivative of 16 (the di-O-methyl moieties
were resistant to acid hydrolysis), we decided to prepare
2,6-di-O-benzyl-9-deazaxanthine (17), which should be
readily deprotected by hydrogenolysis. Dichloropyrimi-
dine 11, on exposure to sodium benzyloxide, afforded di-
O-benzyl derivative 13, and this, treated with the formy-
lating reagent DMF dimethylacetal, gave the enamine
15. Reduction of the nitro group with zinc in acetic acid
engendered cyclization and loss of dimethylamine to give
17. The pyrrole nitrogen atom in 17 was readily benz-
ylated or silylated (Scheme 4), and the products when
treated with N-bromosuccinimide gave the desired fully
protected 9-bromo-9-deazapurines 18 and 19.
It was therefore expected that appropriately protected
9-bromo-9-deaza-hypoxanthine and -guanine derivatives
would be accessible from the now readily available 8 and
9.10 Indeed, following the known conversion of 8 into 20,14
this latter compound was sequentially N-protected and
treated with sodium methoxide and then N-bromosuc-
cinimide to give 21 (Scheme 5). However, the same
process applied to 9 was not successful, as treatment with
Although the addition of organometallic reagents to
imines is well-known, we were aware that in the case of
imines derived from enolizable carbonyl compounds the
reaction is not general and is often accompanied by
enolization and other side reactions. Aryllithiums, in
particular, generally afford poor yields on addition to
enolizable imines.11
Resu lts a n d Discu ssion
Syn th esis of P r otected 9-Br om o-9-d ea za p u r in es.
Suitably functionalized derivatives of 8 and 9 are re-
quired for the synthesis of immucillins 1 and 2, using
the methodology outlined in Scheme 2. In particular,
(11) Volkmann, R. A. In Comprehensive Organic Synthesis, Addi-
tions to C-X π Bonds, Part 1; Schreiber, S. L., Ed.; Pergamon Press:
Oxford, U.K., 1991; Vol. 1, Chapter 1.12. Katritzky, A. R.; Hong, Q.;
Yang, Z. J . Org. Chem. 1995, 60, 3405. Yamada, H.; Kawate, T.;
Nishida, A.; Nakagawa, M. J . Org. Chem. 1999, 64, 8828 and references
therein.
(12) Cupps, T. L.; Wise, D. S.; Townsend, L. B. J . Org. Chem. 1983,
48, 1060.
(13) Cupps, T. L.; Wise, D. S., J r.; Townsend, L. B. J . Org. Chem.
1986, 51, 1058.
(7) Yokoyama, M.; Akiba, T.; Ochiai, Y.; Momotake, A.; Togo, H. J .
Org. Chem. 1996, 61, 6079.
(8) Momotake, A.; Mito, J .; Yamaguchi, K.; Togo, H.; Yokoyama, M.
J . Org. Chem. 1998, 63, 7207.
(9) Holzapfel, C. W.; Crous, R. Heterocycles 1998, 48, 1337.
(10) Furneaux, R. H.; Tyler, P. C. J . Org. Chem. 1999, 64, 8411.
(14) Imai, K. Chem. Pharm. Bull. 1964, 12, 1030.

Synthesis of the Aza-C-nucleoside Immucillins
J . Org. Chem., Vol. 66, No. 17, 2001 5725
Sch em e 4a
ing reaction generated 9-deazaguanine (9) with the
2-amino group unsubstituted. The N-formyl group was
useful, however, allowing benzyloxymethylation of 29 at
N-7 and affording a product which, after subsequent
deformylation and bromination with N-bromosuccinim-
ide, gave 6-O-benzyl-7-N-benzyloxymethyl-9-bromo-9-
deazaguanine (30) in 59% overall yield. N-Bisbenzylation
then provided 31 suitably protected for lithiation studies.
Commercially available 2-chloro-4-methyl-3-nitropyridine
(26) was also taken through the same sequence via 27,
28, 32, and 33 to give the 3,9-dideazapurine derivative
34.
a
Reagents: i, NaH, THF or DMF, RBr (or RCl); ii, NBS.
Sch em e 5a
Ad d ition of Lith ia ted 9-Dea za p u r in es to Im in e 6.
Lithium/halogen exchange applied to 18 or 19 with
n-butyllithium in THF at -78 °C afforded lithiated
species which, when used immediately, reacted with
benzaldehyde to give products which were not character-
ized but which gave NMR spectra consistent with those
expected for phenylcarbinols. However, these aryllithi-
ums did not give detectable products when treated in
THF with imine 6 under conditions used in analogous
reactions during the synthesis of various aryl aza-C-
nucleosides.16 In this earlier work, the imine was used
without purification, but for the present requirements,
quick chromatography on silica gel using a basic eluant
gave clean imine 6 that was stable for several days at 0
°C, provided no trace of acid was present. Further
attempts to cause the aryllithiums derived from 18 and
19 to react with this purified imine 6 in THF at -70 °C
were again unsuccessful, apparently because these aryl-
lithiums were sufficiently basic to abstract protons from
the reagents and/or solvent. The relative longevities of
the lithiated deazapurines 18 and 19 in different solvents
were therefore assessed by determining the yields of
adducts formed on reaction with benzaldehyde. Ether
looked to be a promising candidate, but the protected
deazapurines are almost insoluble in this solvent, and
ether/anisole mixtures were chosen to allow, at -70 °C,
the generation of partial solutions of 18 and 19 which,
after lithium-bromine exchange, afforded homogeneous
solutions of the aryllithium species. When purified imine
6 was added, warming was required before addition
reactions took place (at approximately -15 °C) to give,
after chromatography, the protected aza-C-nucleosides
36 and 37 in 62% and 41%, respectively (Scheme 6).
When the same procedure was applied to 9-deazahypox-
anthine derivative 21, efficient addition occurred to give
condensation product 38, which was isolated either as
the alcohol 39 (69%) or, preferably, as the N-Boc deriva-
tive 40 (76%).
a
Reagents: i, POCl3; ii, NaH, BnOCH2Cl; iii, NaOMe; iv, NBS.
phosphoryl chloride led to an intractable product, prob-
ably as a result of N-phosphorylation. An alternative and
successful approach involved O-protection of an early
intermediate in the synthesis of 9, and thus, acetylation
of 2-amino-6-methyl-5-nitropyrimidin-4-one (22) in re-
fluxing acetic anhydride selectively afforded monoacetate
23.15 When this was treated with phosphoryl chloride and
then sodium benzyloxide, the desired O-protected pyri-
Both of the latter compounds were readily separated
chromatographically from excess deazapurine. This reac-
tion has been successfully performed on a 0.5 kg scale,
affording >75% yield of 40. On this scale, a small amount
(0.65%) of the n-butyl adduct 42 was also isolated,
resulting from reaction of the nitrogen anion of the
product with in situ n-butyl bromide derived from the
bromine-lithium exchange.
Similarly, the guanine analogue 31, after lithium-
bromine exchange, added to imine 6 to give compound
41, but only in 31% yield. Yields of the adducts therefore
decreased as the 2-substituent of the pyrrolopyrimidine
midine 24 was produced in 90% yield. This was then
converted to a pyrrolopyrimidine, as was the uracil
analogue 13. Thus, the formylating reagent DMF di-
methylacetal applied to 24 generated 4-benzyloxy-2-[(di-
N,N-methylamino)methylene]amino-6-[2-(di-N,N-meth-
ylamino)vinyl]-5-nitropyrimidine (25) (82%). Reduction
of the nitro group was achieved using sodium dithionite
in refluxing aqueous ethanol to give 6-O-benzyl-9-deaza-
2-N-formylguanine (29) (85%). Surprisingly, the 2-(di-
methylaminomethylene)amino moiety, after hydrolysis
under the reduction conditions, gave the N-formyl de-
rivative 29, whereas in the synthesis of 9 the correspond-
(16) Furneaux, R. H.; Limberg, G.; Tyler, P. C.; Schramm, V. L.
Tetrahedron 1997, 53, 2915. Furneaux, R. H.; Schramm, V. L.; Tyler,
P. C. Bioorg. Med. Chem. 1999, 7, 2599.
(15) Shirakawa, K. Yakukagu Zasshi 1953, 73, 643; Chem. Abstr.
1954, 48, 9364f.

5726 J . Org. Chem., Vol. 66, No. 17, 2001
Evans et al.
Sch em e 6a
N-benzyl moiety was resistant even under forcing condi-
tions. The silylated analogue 37, however, was readily
deprotected by hydrogenolysis followed by acid hydrolysis
to give (1S)-1-(9-deazaxanthin-9-yl)-1,4-dideoxy-1,4-imino-
D-ribitol hydrochloride (47‚HCl) in 57% yield, a 9-dea-
zaxanthosine analogue of the immucillins 1 and 2. The
deazahypoxanthine derivatives 39 and 40 could be
deprotected by treatment in boiling concentrated HCl to
give initially a mixture of 2‚HCl and the corresponding
compound with a hydroxymethyl group on N-7. This
group was surprisingly stable to acid, but when the
hydrolysis product mixture was subjected to chromatog-
raphy on silica gel with an eluting solvent containing
ammonia, the required product 2 was generated in good
yield. A more satisfactory protocol was to hydrogenolyze
compound 40 to remove the benzyl ether group and treat
the product with aq ammonia to cleave the N-CH2OH
group. This afforded a mixture of 43 and 44, as the
hydrogenolysis reaction solution became slightly acidic,
and this effected partial desilylation. Then, slightly
milder acid hydrolysis afforded an excellent yield (91%
overall) of the target 2‚HCl. Hydrogenolysis of the
deazaguanine derivative 41 successfully cleaved the
O-benzyl groups, but again, the N-benzyl moieties were
resistant even under forcing conditions, and when the
N-benzyl groups in 31 were replaced with the potentially
more labile p-methoxybenzyl moiety, only poor yields
were obtained from addition to imine 6. The n-butyl
derivative 42 was hydrogenolyzed to 45, and then acid
hydrolysis afforded 48, whereas the 3-deaza analogue 46
was subjected to prolonged acid hydrolysis to give the
immucillin analogue 49 in low yield.
a
Reagents: i, Bu4NF; ii, (Boc)2O; iii, H2, Pd/C, EtOH, then aq
NH3.
was changed from H to OBn to NBn2, perhaps because
the increased electron-donating ability of the O- and
N-substituents caused further destabilization of the
lithiated moieties.
The lithiated compound derived from the pyrrolo[2,3-
c]pyridine 34 also added successfully to 6 under the same
conditions to give the adduct 46 in 69% yield. However,
the pyrazolopyrimidine 35,17 on lithiation in THF or
ether/anisole, failed to give any adduct with imine 6,
whereas it does add to benzaldehyde. The lithiated 35
does not survive warming to the temperature required
for addition to 6.
The choice of solvent was crucial to the success of these
additions, with ether being essential and ether/anisole
mixtures generally required to achieve sufficient solubil-
ity of the brominated heterocycles.
Only a single stereoisomer was observed from all
successful additions to the imine 6, and the conversion
of 40 into the previously characterized3 2 (vide infra)
established that the nucleophile had approached 6 from
the exo face of the molecule as expected and as has been
the case with other additions to this imine.3,16 The other
addition products reported here are assumed to have the
same stereochemistry, because the reaction conditions
are essentially identical.
Con clu sion s
Suitably protected 9-bromo-9-deazapurine derivatives
have been synthesized, and means have been found for
the condensation of their products of bromine-lithium
exchange with the carbohydrate cyclic imine 6 to allow
facile access to aza-C-nucleosides. This convergent ap-
proach to immucillin 2 has made possible its large scale
production for use in clinical trials.
Exp er im en ta l Section
Gen er a l Meth od s. Microanalyses were performed by the
Campbell Laboratory, Otago University, New Zealand, or
Atlantic Microlabs, Norcross, GA. High-resolution mass spec-
tra were recorded by Hort Research Limited, Palmerston
North, New Zealand, or the Southern Research Institute,
Birmingham, AL. Aluminum-backed silica gel sheets (Merck
or Riedel de Haen) were used for TLC. Column chromatogra-
phy was performed on silica gel (230-400 mesh, Merck).
Chromatography solvents were distilled prior to use. Anhy-
drous solvents were obtained from Aldrich or Acros. NMR
spectra were recorded at 300 MHz (1H) and 75 MHz (13C) in
Dep r otection of Aza -C-n u cleosid e Ad d u cts. Hy-
drogenolysis of 36 removed the O-benzyl groups, but the
(17) Stone, T. E.; Eustace, E. J .; Pickering, M. V.; Doyle Daves, G.,
J r. J . Org. Chem. 1979, 44, 505.

Synthesis of the Aza-C-nucleoside Immucillins
J . Org. Chem., Vol. 66, No. 17, 2001 5727
CDCl3 with tetramethylsilane as the internal standard unless
otherwise indicated.
δ 159.8, 157.2, 153.0, 137.2 (C), 135.8 (CH), 135.2 (C), 129.8,
128.7, 128.6, 128.5, 128.3, 127.8 (CH), 116.0, 92.6 (C), 69.1,
69.0 (CH2), 26.2 (CH3), 18.8 (C), -2.7 (CH3). Anal. Calcd for
2,4-Diben zyloxy-6-[2-(N,N-d im eth yla m in o)vin yl]-5-n i-
tr op yr im id in e (15). A solution of sodium benzyloxide in
benzyl alcohol (1.1 M, 100 mL) was added slowly with stirring
to a solution of 2,4-dichloro-6-methyl-5-nitropyrimidine12 (11)
(17 g, 82 mmol) in benzyl alcohol (80 mL). The resulting hot
solution was stirred for an additional 1 h, then ether (500 mL)
was added, and the solution was washed with water. The
organic phase was dried and concentrated to dryness under
high vacuum (bath temperature to 150 °C). A solution of the
crude residue of 13 in dry N,N-dimethylformamide (100 mL)
and N,N-dimethylformamide dimethylacetal (25 mL) was
heated at 100 °C for 3 h, and then the solution was concen-
trated to dryness. Trituration of the residue with ethanol
afforded crystalline 15 (24.5 g, 60 mmol, 73%). Recrystallized
C
26H30BrN3O2Si: C, 59.54; H, 5.76; Br, 15.23; N, 8.01. Found:
C, 59.75; H, 5.95; Br, 15.30; N, 8.11.
7-N-Ben zyloxym eth yl-9-br om o-9-d ea za -6-O-m eth ylh y-
p oxa n th in e (21). Sodium hydride (1.88 g, 60% dispersion, 47
mmol) was added to a stirred suspension of 6-chloro-9-
deazapurine10,14 (20) (5.19 g, 33.8 mmol) in THF (80 mL), and
the resulting mixture was stirred in an ice bath, while benzyl
chloromethyl ether (6 mL, 43 mmol) was added slowly. The
mixture was then stirred at room temperature for 1 h.
Methanol (20 mL) and then sodium hydride (1.6 g, 60%, 40
mmol) were added carefully, and after 1 h, N-bromosuccinim-
ide was added portionwise, until TLC analysis indicated the
initial material was replaced by a less polar product. The
solution was washed with water (×2) and processed normally.
Chromatography afforded 21 (6.83 g, 19.6 mmol, 52%) as a
white solid. Recrystallized from ethanol, it had mp 98-99 °C;
1H NMR δ 8.60 (s, 1H), 7.44 (s, 1H), 7.35-7.21 (m, 5H), 5.71
(s, 2H), 4.48 (s, 2H), 4.11 (s, 3H); 13C NMR δ 156.8 (C), 151.4
(CH), 148.8, 136.9 (C), 131.9, 128.9, 128.5, 128.0 (CH), 116.0,
1
from ethanol, it had mp 129-131 °C; H NMR δ 8.00 (d, J )
12.2 Hz, 1H), 7.56-7.26 (m, 10H), 5.45 (s, 2H), 5.39 (s, 2H),
5.35 (d, J ) 12.2 Hz, 1H), 3.01 (br s, 6H); 13C NMR δ 163.8,
161.9, 161.0 (C), 152.1 (CH), 137.0, 136.2 (C), 128.9, 128.4,
128.3, 127.9 (CH), 123.5 (C), 88.3 (CH), 69.8, 69.2 (CH2). Anal.
Calcd for C22H22N4O4: C, 65.01; H, 5.46; N, 13.78. Found: C,
64.86; H, 5.37; N, 14.03.
92.8 (C), 77.6, 70.8 (CH2), 54.2 (CH3). Anal. Calcd for C15H14
-
2,6-Di-O-ben zyl-9-d ea za xa n th in e (17). Zinc dust (30 g)
was added to a solution of 15 (20 g, 49 mmol) in acetic acid
(300 mL) with cooling to keep the temperature < 50 °C. The
resulting mixture was then stirred for 2 h and filtered, and
the filtrate was concentrated to dryness. The residue was
partitioned between chloroform and aq sodium bicarbonate;
the organic layer was dried and then concentrated to dryness
to give a solid residue of 17 (15.2 g, 46 mmol, 78%). Recrystal-
lized from ethanol, it had mp 172-174 °C; 1H NMR δ 8.66 (br
s, 1H), 7.52-7.26 (m, 11H), 6.49 (dd, J ) 2.1, 3.0 Hz, 1H), 5.53
(s, 2H), 5.47 (s, 2H); 13C NMR δ 160.0, 157.1, 152.2, 137.7,
136.5 (C), 129.3, 129.0, 128.9, 128.7, 128.5, 128.1 (CH), 112.2
(C), 102.8 (CH), 69.3, 68.6 (CH2). Anal. Calcd for C20H17N3O2:
C, 72.49; H, 5.17; N, 12.68. Found: C, 72.36; H, 5.12; N, 12.46.
7-N -B e n zy l-2,6-d i-O -b e n zy l-9-b r o m o -9-d e a za x a n -
th in e (18). Sodium hydride (2.7 g, 60% dispersion, 67.5 mmol)
was added portionwise to a solution of 17 (15 g, 45 mmol) and
benzyl bromide (7.5 mL, 65 mmol) in dry DMF (120 mL). The
mixture was stirred at room temperature for 2 h and then
quenched with ethanol (10 mL). Then toluene (500 mL) was
added, and the reaction mixture was washed with water (×2),
dried, and concentrated to a solid residue. A solution of this
material in dichloromethane (160 mL) was stirred, while NBS
(7.2 g, 40 mmol) was added slowly portionwise, by which time
TLC analysis indicated complete conversion to a less polar
product. The solution was washed with water (×2), dried, and
concentrated to dryness. Trituration of the residue with ether
gave crystalline 18 (15.3 g, 30.6 mmol, 87%). Recrystallized
from ethanol, it had mp 122-123 °C; 1H NMR δ 7.56 (m, 2H),
7.37-7.15 (m, 12H), 6.96 (m, 2H), 5.49 (s, 2H), 5.48 (s, 2H),
5.36 (s, 2H); 13C NMR δ 160.2, 157.8, 149.9, 137.6, 137.5, 136.2
(C), 132.5, 129.2, 129.1, 128.9, 128.7, 128.3, 128.2, 127.2 (CH),
BrN3O2: C, 51.74; H, 4.05; Br, 22.95; N, 12.07. Found: C,
51.97; H, 3.91; Br, 23.19; N, 12.28.
4-Ben zyloxy-2-[(di-N,N-m eth ylam in o)m eth ylen e]am in o-
6-[2-(N,N-d im eth yla m in o)vin yl]-5-n itr op yr im id in e (25).
A suspension of 2-N-acetylamino-6-methyl-5-nitropyrimidin-
4-one15 (23) (10 g, 47 mmol) in phosphoryl chloride (100 mL)
and N,N-diethylaniline (10 mL) was heated under gentle reflux
for 5 min. The cooled solution was concentrated to dryness,
and chloroform (300 mL) was added; the solution was washed
with water and saturated aq NaHCO3, dried, and concentrated
to a dark red/brown solid (14.3 g). A solution of this material
in benzyl alcohol (30 mL) was added to sodium benzyloxide in
benzyl alcohol (1.9 M, 50 mL), and the resulting solution was
stirred for 1 h. Chloroform (500 mL) was added, and the
mixture was washed with water, dried, and then concentrated
under high vacuum (bath temperature 150 °C). A solution of
the residue in dichloromethane was filtered through a pad of
silica gel which was washed with ethyl acetate/dichloromethane/
petroleum ether (2/1/1 v/v/v) to elute all the product. Evapora-
tion of the eluant afforded 2-amino-4-benzyloxy-6-methyl-5-
nitropyrimidine (24) (11.0 g, 42.3 mmol, 90%) as an orange
solid. 1H NMR (DMSO-d6) δ 7.60 (br s, 2H), 7.47-7.13 (m, 5H),
5.44 (s, 2H), 2.36 (s, 3H); 13C NMR δ 164.2, 162.0, 161.7, 136.1
(C), 128.8, 128.5, 128.2 (CH), 125.4 (C), 68.3 (CH2), 22.0 (CH3).
A solution of this material (5.9 g, 22.7 mmol) in DMF (40 mL)
and DMF dimethyl acetal (15 mL) was heated at 80 °C for 24
h. Ether (200 mL) was added to the cooled mixture which was
then filtered and the bright orange solid washed with ether
to give 25 (6.9 g, 18.6 mmol, 82%). Recrystallized from ethanol,
1
it had mp 196-197 °C; H NMR δ 8.56 (s, 1H), 8.13 (d, J )
12.3 Hz, 1H), 7.43-7.25 (m, 5H), 5.48 (s, 2H), 5.39 (d, J )
12.3 Hz, 1H), 3.16 (s, 3H), 3.14 (s, 3H), 2.96 (br s, 6H); 13C
NMR δ 164.1, 162.4, 160.5 (C), 159.8, 151.6 (CH), 136.9 (C),
128.8, 128.2, 127.6 (CH), 123.6 (C), 88.5 (CH), 68.5 (CH2), 41.7,
35.7 (CH3). Anal. Calcd for C18H22N6O3: C, 58.37; H, 5.99; N,
22.69. Found: C, 58.02; H, 5.97; N, 22.83.
112.8, 89.7 (C), 69.6, 69.0, 53.3 (CH2). Anal. Calcd for C27H22
-
BrN3O2: C, 64.81; H, 4.43; Br, 15.97; N, 8.40. Found: C, 64.95;
H, 4.45; Br, 16.04; N, 8.52.
2,6-Di-O-ben zyl-9-br om o-7-N-ter t-bu tyld im eth ylsilyl-9-
d ea za xa n th in e (19). Sodium hydride (0.5 g, 60% dispersion,
12.5 mmol) was added to a solution of 17 (2.0 g, 6.0 mmol) in
THF (40 mL) followed by tert-butyldimethylsilyl chloride (1.37
g, 9.1 mmol), and the mixture was stirred for 1 h. The reaction
was carefully quenched with water, and the components were
partitioned between ether (100 mL) and water (150 mL). The
organic phase was dried and concentrated to dryness. A
solution of the residue in dichloromethane (40 mL) was stirred,
while N-bromosuccinimide was added slowly portionwise, until
TLC analysis indicated complete reaction to a less polar
product. The solution was washed with water and aq NaHCO3,
dried, and concentrated. Chromatography of the residue
afforded 19 as a white solid (1.8 g, 3.4 mmol, 57%). Recrystal-
lized from ethyl acetate/petroleum ether, it had mp 187-188
6-O-Ben zyl-9-d ea za -2-N-for m ylgu a n in e (29). A suspen-
sion of 25 (2.8 g, 7.57 mmol) and sodium dithionite (5.6 g, 32
mmol) in water (50 mL) and ethanol (25 mL) was heated under
reflux for 6 min. Water (50 mL) was added to the cooled
mixture which was filtered, and the solids were washed with
water and dried to give 29 (1.73 g, 6.46 mmol, 85%) as a white
1
solid. Recrystallized from ethanol, it had mp 177-179 °C; H
NMR (DMSO-d6) δ 10.52 (d, J ) 9.3 Hz, 1H), 9.41 (d, J ) 7.6
Hz, 1H), 7.57 (m, 3H), 7.44-7.32 (m, 3H), 6.39 (d, J ) 2.9 Hz,
1H), 5.60 (s, 2H); 13C NMR (DMSO-d6) δ 163.8 (CH), 155.7,
151.4, 150.3, 136.8 (C), 131.5, 128.8, 128.5 (CH), 112.2 (C),
101.2 (CH), 67.7 (CH2). Anal. Calcd for C14H12N4O2: C, 62.68;
H, 4.51; N, 20.88. Found: C, 62.62; H, 4.49; N, 20.93.
6-O-Ben zyl-7-N-ben zyloxym eth yl-9-br om o-9-d ea za gu a -
n in e (30). Sodium hydride (0.67 g, 60% dispersion) was added
to a stirred solution of 29 (1.5 g, 5.6 mmol) in THF (60 mL),
1
°C; H NMR δ 7.56 (d, J ) 6.9 Hz, 2H), 7.44-7.26 (m, 9H),
5.54 (s, 2H), 5.51 (s, 2H), 0.76 (s, 9H), 0.37 (s, 6H); 13C NMR

5728 J . Org. Chem., Vol. 66, No. 17, 2001
Evans et al.
1
followed by benzyl chloromethyl ether (0.8 mL, 5.8 mmol).
After 1 h, the reaction was quenched with water, and then
the mixture was concentrated to dryness. Methanol (60 mL),
and aq NaOH (1 M, 20 mL) were added, and the mixture was
heated under reflux for 0.5 h. The cooled solution was
partitioned between chloroform and water, and the organic
phase was processed normally. A solution of the crude residue
in dichloromethane (40 mL) was stirred in an ice bath, while
N-bromosuccinimide (1.0 g, 5.6 mmol) was added slowly with
stirring. Concentration of the solution and chromatography
of the residue afforded 30 (1.46 g, 3.3 mmol, 59%) as a white
33 (29.4 g, 109 mmol, 72%) as a straw-colored oil. H NMR δ
7.77 (d, J ) 5.6 Hz, 1H), 7.29-7.24 (m, 6H), 7.13 (d, J ) 5.6
Hz, 1H), 6.51 (d, J ) 3.1 Hz, 1H), 5.62 (s, 2H), 4.85 (s, 2H),
4.15 (s, 3H); 13C NMR δ 151.6, 137.4, 135.7, 135.6, 130.9, 128.4,
127.8, 127.7, 121.0, 110.5, 103.1, 76.7, 69.8, 52.9. Anal. Calcd
for C16H16N2O2: C, 71.62; H, 6.01; N, 10.44. Found: C, 71.36;
H, 6.15; N, 10.37.
1-N-Ben zyloxym eth yl-3-br om o-7-m eth oxyp yr r olo[2,3-
c]p yr id in e (34). A solution of bromine (6.0 mL, 117 mmol) in
chloroform (50 mL) was added dropwise to a stirred solution
of 33 (28.4 g, 106 mmol) in chloroform (200 mL), while the
reaction temperature was maintained at <10 °C. The solution
was washed with aq NaHCO3, dried, and concentrated. Chro-
matography of the residue afforded 34 (27.1 g, 78 mmol, 74%),
as a white solid. Recrystallized from hexanes, it had mp 69-
72 °C; 1H NMR δ 7.83 (d, J ) 5.6 Hz, 1H), 7.32-7.23 (m, 6H),
7.08 (d, J ) 5.6 Hz, 1H), 5.79 (s, 2H), 4.48 (s, 2H), 4.05 (s,
3H); 13C NMR δ 151.4, 137.0, 136.7, 134.7, 129.7, 128.4, 127.9,
127.7, 120.7, 108.6, 91.8, 76.8, 70.1, 53.2. Anal. Calcd for
1
solid. Recrystallized from ethanol, it had mp 158-159 °C; H
NMR δ 7.44-7.09 (m, 11H), 5.56 (s, 2H), 5.51 (s, 2H), 5.03 (br
s, 2H), 4.36 (s, 2H); 13C NMR δ 158.8, 157.2, 150.9, 137.2, 136.6
(C), 131.8, 129.0, 128.8, 128.6, 128.5, 128.3, 127.9 (CH), 111.3,
90.3 (C), 77.8, 70.7, 68.4 (CH2). Anal. Calcd for C21H19BrN4O2:
C, 57.41; H, 4.36; Br, 18.19; N, 12.75. Found: C, 57.44; H, 4.23;
Br, 18.18; N, 12.68.
2-Di-N,N-b en zyl-6-O-b en zyl-7-N-b en zyloxym et h yl-9-
br om o-9-d ea za gu a n in e (31). A solution of 30 (1.8 g, 4.1
mmol) in DMF (30 mL) was treated with sodium hydride (60%
dispersion, 0.49 g, 12.3 mmol) and benzyl bromide (1.22 mL,
10.2 mmol), and the mixture was stirred for 18 h at room
temperature. After quenching with water, chloroform (100 mL)
was added, and the solution was washed with water (×4) and
processed normally. Chromatography of the crude product gave
C
16H15N2O2Br: C, 55.35; H, 4.35; N, 8.07; Br, 23.01. Found:
C, 55.13; H, 4.41; N, 8.07; Br, 22.98.
5-O-ter t-Bu tyld im eth ylsilyl-1,N-d eh yd r o-1,4-d id eoxy-
1,4-im in o-2,3-O-isop r op ylid en e-D-r ibitol (6). The iminor-
ibitol derivative 3 was treated with N-chlorosuccinimide and
then lithium tetramethylpiperidide as described previously.3,4
The cold reaction mixture was partitioned between petroleum
ether and water and processed in the normal way. Chroma-
tography of the residue (EtOAc/light petroleum/triethylamine,
100/300/1 v/v/v) afforded imine 6 in ∼80-85% yield which was
used directly. 1H NMR δ 7.61 (s, 1H), 5.03 (d, J ) 5.1 Hz, 1H),
4.58 (d, J ) 5.4 Hz, 1H), 4.35 (br s, 1H), 3.94 (dd, J ) 10.3, 2.9
Hz, 1H), 3.81 (dd, J ) 10.3, 2.6 Hz, 1H), 1.39 (s, 3H), 1.37 (s,
3H), 0.86 (s, 9H), 0.04 (s, 3H), 0.01 (s, 3H); 13C NMR δ 166.4,
111.1, 86.9, 79.4, 79.3, 62.5, 27.1, 25.8, 25.7, 18.1, -5.4, -5.6.
(1-S)-1-(7-N-Ben zyl-2,6-d i-O-ben zyl-9-d ea za xa n th in -9-
yl)-5-O-ter t-bu tyld im eth ylsilyl-1,4-d id eoxy-1,4-im in o-2,3-
O-isop r op ylid en e-D-r ibitol (36). A solution of bromide 18
(0.75 g, 1.5 mmol) in dry anisole (5 mL) and ether (20 mL)
was cooled to -70 °C, and n-butyllithium (1.4 M in hexanes)
was added slowly until the starting material was metalated
(TLC analysis). (Some of the starting material precipitated
from the solution on cooling, but a homogeneous solution was
obtained after addition of the n-butyllithium). A solution of
imine 6 (0.15 g, 0.53 mmol) in dry ether (2 mL) was added,
and the resulting solution was allowed to warm to 0 °C and
washed with water. Normal processing followed by chroma-
tography gave 36 (0.23 g, 0.33 mmol, 62%) as a colorless syrup.
1H NMR δ 7.46 (d, J ) 7.1 Hz, 2H), 7.32-7.12 (m, 12H), 6.93
(m, 2H), 5.49-5.30 (m, 6H), 4.95 (dd, J ) 7.0, 5.3 Hz, 1H),
4.60 (dd, J ) 7.0, 5.1 Hz, 1H), 4.28 (d, J ) 5.3 Hz, 1H), 3.80
(dd, J ) 10.3, 4.3 Hz, 1H), 3.73 (dd, J ) 10.3, 4.9 Hz, 1H),
3.24 (dd, J ) 9.5, 4.7 Hz, 1H), 1.52 (s, 3H), 1.29 (s, 3H), 0.83
(s, 9H), 0.05 (s, 6H); 13C NMR δ 159.2, 157.6, 150.6, 138.0,
136.5 (C), 131.8, 129.1, 128.9, 128.7, 128.6, 128.5, 128.0, 127.3
(CH), 114.7, 114.6, 113.3 (C), 86.0, 82.7 (CH), 69.2, 68.6 (CH2),
66.5 (CH), 63.8 (CH2), 61.4 (CH), 52.9 (CH2), 28.0, 26.4, 25.9
(CH3), 18.8 (C), -4.9 (CH3). HRMS (MH+) Calcd for C41H51N4O5-
Si: 707.3629. Found: 707.3600.
1
31 (1.79 g, 2.89 mmol, 70%) as a pale yellow syrup; H NMR
δ 7.30-7.15 (m, 21H), 5.56 (s, 2H), 5.38 (s, 2H), 4.92 (s, 4H),
5.56 (s, 2H); 13C NMR δ 158.5, 156.6, 151.5, 139.7, 137.4, 136.9
(C), 131.6, 128.9, 128.8, 128.7, 128.4, 128.3, 128.0, 127.2 (CH),
110.6, 91.1 (C), 77.8, 70.6, 68.0, 50.3 (CH2). HRMS (MH+) Calcd
for C35H3279BrN4O2: 619.1709. Found: 619.1713.
2-Meth oxy-4-m eth yl-3-n itr op yr id in e (27). A solution of
2-chloro-4-methyl-3-nitropyridine (26) (20 g, 115.9 mmol) in
methanol (100 mL) containing sodium methoxide (25% solution
in MeOH, 50 mL, 219 mmol) was heated under reflux for 2 h,
and then the solution was concentrated to ∼75 mL. Water (100
mL) was added and the resulting solid filtered to give 27 as
an off-white solid (19.2 g, 114 mmol, 98%) that was pure by
NMR. Recrystallized from aq methanol, it had mp 38-40 °C;
1H NMR δ 8.11 (d, J ) 5.2 Hz, 1H), 6.83 (d, J ) 5.8 Hz, 1H),
4.02 (s, 3H), 2.33 (s, 3H); 13C NMR δ 155.5, 147.9, 141.8, 119.2,
83.9, 54.7, 17.0. Anal. Calcd for C7H8N2O3: C, 50.00; H, 4.80;
N, 16.66. Found: C, 50.12; H, 4.76; N, 16.72.
4-[(2-Di-N,N-m et h yla m in o)vin yl]-2-m et h oxy-3-n it r o-
p yr id in e (28). A solution of 27 (19.1 g, 114 mmol) in DMF
(20 mL) and DMF dimethylacetal (50 mL) was heated at 130
°C for 18 h, cooled, and poured onto crushed ice to give 28 as
a reddish-orange solid (25.1 g, 112 mmol, 99%) that was pure
by NMR. Recrystallized from aq methanol, it had mp 138-
1
142 °C; H NMR δ 7.83 (d, J ) 5.8 Hz, 1H), 7.19 (d, J ) 13.2
Hz, 1H), 6.81 (d, J ) 5.8 Hz, 1H), 4.85 (d, J ) 13.2 Hz, 1H),
3.96 (s, 3H), 2.92 (s, 6H); 13C NMR δ 155.9, 146.4, 145.9, 142.3,
131.5, 110.0, 86.1, 77.3, 54.0. Anal. Calcd for C10H13N3O3: C,
53.80; H, 5.87; N, 18.82. Found: C, 53.98; H, 5.76; N, 18.80.
7-Meth oxyp yr r olo[2,3-c]p yr id in e (32). A solution of 28
(25.6 g, 114.7 mmol) in ethanol (1.5 L) containing 10% Pd/C
(8.4 g) was shaken under hydrogen at 15 psig for 15 min.
Removal of the solids and solvent followed by chromatography
(1S)-1-(2,6-Di-O-b en zyl-7-N-ter t-b u t yld im et h ylsilyl-9-
d ea za xa n th in -9-yl)-5-O-ter t-bu tyld im eth ylsilyl-1,4-d id e-
oxy-1,4-im in o-2,3-O-isop r op ylid en e-D-r ibitol (37). A solu-
tion of 19 (0.786 g, 1.5 mmol) in dry anisole (20 mL) and ether
(30 mL) was treated with n-butyllithium and then imine 6
(0.215 g, 0.75 mmol), as described above in the preparation of
afforded 32 as
a white solid (15.2 g, 103 mmol, 89%).
1
Recrystallized from aq methanol, it had mp 110-114 °C; H
NMR δ 8.68 (br s, 1H), 7.76 (d, J ) 5.7 Hz, 1H), 7.26 (d, J )
4.6 Hz, 1H), 7.16 (d, J ) 5.7 Hz, 1H), 6.52 (t, J ) 2.9 Hz, 1H),
4.10 (s, 3H); 13C NMR δ 151.3, 135.3, 134.0, 126.1, 120.1, 110.3,
102.7, 53.1. Anal. Calcd for C8H8N2O: C, 64.85; H, 5.44; N,
18.91. Found: C, 65.06; H, 5.45; N, 18.86.
1
36, to give 37 (0.225 g, 0.31 mmol, 41%) as a syrup. H NMR
δ 7.53-7.26 (m, 10 H), 5.48 (m, 3H), 5.35 (d, J ) 12.4 Hz, 1H),
4.98 (dd, J ) 7.1, 5.1 Hz, 1H), 4.62 (dd, J ) 7.1, 5.2 Hz, 1H),
4.29 (d, J ) 5.1 Hz, 1H), 3.80 (dd, J ) 10.4, 4.3 Hz, 1H), 3.75
(dd, J ) 10.4, 4.6 Hz, 1H), 3.22 (dd, J ) 9.5, 4.6 Hz, 1H), 1.53
(s, 3H), 1.29 (s, 3H), 0.88 (s, 9H), 0.76 (s, 9H), 0.35 (s, 3H),
0.34 (s, 3H), 0.06 (s, 3H), 0.05 (s, 3H); 13C NMR δ 159.2, 157.4,
154.5, 138.0, 136.0 (C), 135.6, 130.2, 128.9, 128.8, 128.7, 128.5,
128.0 (CH), 117.3, 117.0, 114.5 (C), 86.0, 82.8 (CH), 69.1, 69.0
(CH2), 66.6 (CH), 63.6 (CH2), 61.6 (CH), 28.0, 26.8, 26.4, 26.0
1-N-Ben zyloxym et h yl-7-m et h oxyp yr r olo[2,3-c]p yr i-
d in e (33). A stirred solution of 32 (22.5 g, 152 mmol) in THF
(250 mL) was cooled to 4 °C under a N2 atmosphere, and
sodium hydride (6.7 g, 60%, 167 mmol) was added slowly in
portions. Benzyl chloromethyl ether (25.7 mL, 90%, 167 mmol)
was added, and the mixture was stirred at ambient temper-
ature for 2 h. Then chloroform (100 mL) was added, and the
mixture was washed with water (×2). Conventional processing
gave a syrup which was purified by chromatography affording

Synthesis of the Aza-C-nucleoside Immucillins
J . Org. Chem., Vol. 66, No. 17, 2001 5729
(CH3), 19.2, 18.8 (C), -2.2, -4.9 (CH3). HRMS (MH+) Calcd
(1S)-1-(Di-N,N-ben zyl-6-O-ben zyl-7-N-ben zyloxym eth yl-
9-d ea za gu a n in -9-yl)-5-O-ter t-bu tyld im eth ylsilyl-1,4-d id e-
oxy-1,4-im in o-2,3-O-isopr opyliden e-D-r ibitol (41). The 9-bro-
mo-9-deazaguanine derivative 31 (1.56 g, 2.52 mmol) was
treated with n-butyllithium and then imine 6 (0.60 g, 2.1
mmol), as described for the preparation of 36, to give, after
chromatography, syrupy 41 (0.54 g, 0.65 mmol, 31%). 1H NMR
δ 7.31-7.18 (m, 21H), 5.57 (s, 2H), 5.41 (s, 2H), 5.14 (d, J )
15.7 Hz, 2H), 4.99 (dd, J ) 7.0, 5.0 Hz, 1H), 4.64 (d, J ) 15.7
Hz, 2H), 4.43 (m, 3H), 4.24 (d, J ) 4.8 Hz, 1H), 3.74 (dd, J )
10.3, 4.7 Hz, 1H), 3.67 (dd, J ) 10.3, 5.0 Hz, 1H), 3.18 (dd, J
) 10.0, 4.9 Hz, 1H), 1.55 (s, 3H), 1.26 (s, 3H), 0.88 (s, 9H),
0.04 (s, 6H); 13C NMR δ 157.6, 156.4, 152.5, 139.9, 137.8, 137.2
(C), 131.0, 128.8, 128.7, 128.33, 128.27, 128.1, 127.9, 127.1
(CH), 114.9, 114.4, 111.3 (C), 85.9, 82.9 (CH), 77.6, 70.4, 67.6
(CH2), 66.6 (CH), 63.9 (CH2), 61.6 (CH), 50.6 (CH2), 27.9, 26.4,
25.7 (CH3), 18.8 (C), -4.9, -5.0 (CH3). HRMS (M+) Calcd for
C49H59N5O5Si: 825.4285. Found: 825.4272.
for C40H59N4O5Si2: 731.4024. Found: 731.4031.
(1S)-1-(7-N-Ben zyloxym et h yl-9-d ea za -6-O-m et h ylh y-
p oxa n t h in -9-yl)-1,4-d id eoxy-1,4-im in o-2,3-O-isop r op yli-
d en e-D-r ibitol (39). A solution of 21 (5.85 g, 16.8 mmol) in
anisole (60 mL) and ether (100 mL) was treated with n-
butyllithium and then imine 6 (3.36 g, 11.8 mmol), as described
above in the preparation of 36. Tetrabutylammonium fluoride
(15 mL, 1 M in THF) was added to a solution of the crude
product in THF (20 mL), and after 1 h, toluene (100 mL) was
added, and the solution was washed with water (×2) and then
processed normally. Chromatography afforded syrupy 39 (3.59
g, 8.16 mmol, 69%). 1H NMR δ 8.51 (s, 1H), 7.38 (s, 1H), 7.35-
7.22 (m, 5H), 5.73 (d, J ) 10.6 Hz, 1H), 5.65 (d, J ) 10.6 Hz,
1H), 4.89 (t, J ) 5.7 Hz, 1H), 4.77 (dd, J ) 6.0, 2.1 Hz, 1H),
4.50 (d, J ) 5.5 Hz, 1H), 4.48 (s, 2H), 4.09 (s, 3H), 3.74 (s,
1H), 3.73 (s, 1H), 3.64 (dd, J ) 5.3, 2.9 Hz, 1H), 1.61 (s, 3H),
1.36 (s, 3H); 13C NMR δ 156.8 (C), 150.1 (CH), 149.2, 137.3
(C), 130.9, 128.8, 128.4, 128.0 (CH), 118.3, 117.1, 113.1 (C),
86.1, 83.9 (CH), 77.3, 70.6 (CH2), 64.7, 64.6 (CH and CH2),
62.5 (CH), 54.0, 28.2, 25.8 (CH3). HRMS (MH+) Calcd for
C23H29N4O5: 441.2138. Found: 441.2115.
(1S)-1-(1-N-Ben zyloxym eth yl-7-m eth oxyp yr r olo[2,3-c]-
p yr id in -3-yl)-5-O-ter t-bu tyld im eth ylsilyl-1,4-d id eoxy-1,4-
im in o-2,3-O-isop r op ylid en e-D-r ib it ol (46). The bromo-
pyrrolopyridine derivative 34 (10 g, 28.8 mmol) was treated
with n-butyllithium and then imine 6 (6.9 g, 24.1 mmol), as
described for the preparation of 36, to give, after chromatog-
raphy, syrupy 46 (11.1 g, 20 mmol, 69%). 1H NMR (DMSO-d6)
δ 7.68 (d, J ) 5.6 Hz, 1H), 7.51 (s, 1H), 7.40-7.10 (m, 6H),
5.75 (s, 2H), 4.60-4.40 (m, 4H), 4.24 (d, J ) 4.0 Hz, 1H), 3.97
(s, 3H), 3.80-3.50 (m, 2H), 2.93 (br s, 1H), 1.51 (s, 3H), 1.26
(s, 3H), 0.86 (s, 9H), 0.05, 0.00 (s, 3H each); 13C NMR (DMSO-
d6) δ 150.9, 137.7, 134.8, 133.7, 129.1, 128.1, 127.4, 127.3,
120.6, 117.2, 112.7, 109.6, 85.6, 82.2, 76.7, 69.3, 65.0, 64.4, 60.8,
52.7, 27.4, 25.7, 25.2, 17.9, -5.4, -5.4. Anal. Calcd for
(1S)-1-(7-N-Ben zyloxym et h yl-9-d ea za -6-O-m et h ylh y-
p oxa n th in -9-yl)-N-ter t-bu toxyca r bon yl-5-O-ter t-bu tyld i-
m eth ylsilyl-1,4-d id eoxy-1,4-im in o-2,3-O-isop r op ylid en e-
D-r ibitol (40) a n d Its N-Bu tyl An a logu e 42. A solution of
21 (16.0 g, 46 mmol) in anisole (120 mL) and ether (200 mL)
was treated with n-butyllithium and then imine 6 (10.7 g, 37.5
mmol), as described in the preparation of 36. A small portion
of the crude product was purified by chromatography to give
syrupy (1S)-1-(7-N-benzyloxymethyl-9-deaza-6-O-methylhy-
poxanthin-9-yl)-5-O-tert-butyldimethylsilyl-1,4-dideoxy-1,4-
imino-2,3-O-isopropylidene-D-ribitol (38). 1H NMR δ 8.48 (s,
1H), 7.42 (s, 1H), 7.34-7.22 (m, 5H), 5.71, 5.66 (d, J ) 10.6
Hz, 1H each), 4.92 (dd, J ) 7.2, 5.6 Hz, 1H), 4.75 (dd, J ) 7.1,
5.0 Hz, 1H), 4.47 (s, 2H), 4.35 (d, J ) 5.5 Hz, 1H), 4.08 (s,
3H), 3.91-3.82 (m, 2H), 3.30 (dd, J ) 8.6, 3.8 Hz, 1H), 1.58 (s,
3H), 1.35 (s, 3H), 0.93 (s, 9H), 0.09, 0.07 (s, 3H each); 13C NMR
δ 156.5, 150.2, 150.0, 137.3, 131.0, 128.8, 128.3, 128.1, 116.9,
116.6, 114.8, 86.8, 82.7, 77.3, 70.5, 66.5, 62.9, 62.0, 60.7, 53.8,
28.0, 26.2, 25.9, 18.7, -5.06, -5.03. Anal. Calcd for C29H42N4O5-
Si: C, 62.79; H, 7.63; N, 10.10. Found: C, 62.95; H, 7.59; N,
9.95. The crude product in methylene chloride (100 mL) was
treated with di-tert-butyl dicarbonate (8.0 g, 36 mmol), and
the solution was stirred for 1 h and then concentrated to
dryness. Chromatography of the residue afforded 40 (18.8 g,
C
30H43N3O5Si: C, 65.06; H, 7.83; N, 7.58. Found: C, 65.20; H,
7.86; N, 7.51.
(1S)-1-(9-Dea za xa n t h in -9-yl)-1,4-d id eoxy-1,4-im in o-D-
r ibitol Hyd r och lor id e (47‚HCl). A solution of 37 (0.10 g,
0.137 mmol) in ethanol (5 mL) was stirred under hydrogen in
the presence of 10% Pd/C (0.05 g) for 2 h. Removal of the solids
and solvent and chromatography of the residue afforded (1S)-
1-(7-N-tert-butyldimethylsilyl-9-deazaxanthin-9-yl)-5-O-tert-
butyldimethylsilyl-1,4-dideoxy-1,4-imino-2,3-O-isopropylidene-
D-ribitol (0.058 g). A solution of this material in methanol (5
mL) and concentrated HCl (1 mL) was allowed to stand at
room temperature for 16 h and then concentrated to dryness.
The solid residue was washed (×2) with ether and then
triturated with ethanol to give 47‚HCl (0.025 g, 0.078 mmol)
1
as a white solid, mp > 250 °C (dec); H NMR (D2O) δ 7.42 (s,
1
28.7 mmol, 76%) as a syrup. H NMR (C6D6 at 70 °C) δ 8.67
1H), 4.65 (d, J ) 9.1 Hz, 1H), 4.51 (dd, J ) 9.1, 4.8 Hz, 1H),
4.28 (dd, J ) 4.6, 3.3 Hz, 1H), 3.82 (d, J ) 4.4 Hz, 2H), 3.75
(m, 1H); 13C NMR (D2O) δ 159.8, 155.8, 137.1 (C), 131.4 (CH),
114.2, 104.2 (C), 76.2, 73.7, 68.5 (CH), 61.6 (CH2), 58.5 (CH).
Anal. Calcd for C11H15ClN4O5: C, 41.45; H, 4.74; Cl, 11.12; N,
17.58. Found: C, 41.37; H, 4.94; Cl, 11.06; N, 17.31.
(s, 1H), 7.48 (1H, br s, 1H), 7.09 (m, 5H), 5.78 (br s, 1H), 5.67
(s, 1H), 5.44 (br s, 1H), 5.25 (s, 2H), 4.54 (br s, 1H), 4.23 (s,
2H), 4.09 (t, J ) 9.7 Hz, 1H), 3.97 (br s, 1H), 3.77 (s, 3H), 1.57
(s, 3H), 1.42 (s, 9H), 1.33 (s, 3H), 0.97 (s, 9H), 0.11 (s, 6H); 13
C
NMR (C6D6 at 70 °C) δ 156.7, 154.8 (C), 150.4 (CH), 149.4,
137.9, 133.8, 116.4, 111.9 (C), 84.6, 84.0 (CH), 79.6 (C), 77.3,
70.4 (CH2), 67.7 (CH), 63.4 (CH2), 61.9 (CH), 53.0 (CH3), 28.7,
27.9, 26.3, 25.8 (CH3), 18.6 (C), -4.9, -5.0 (CH3). Some
aromatic signals were obscured by the solvent. HRMS (MH+)
Calcd for C34H51N4O7Si: 655.3527. Found: 655.3553. Anal.
Calcd for C34H50N4O7Si: C, 62.43; H, 7.65; N, 8.56. Found: C,
62.79; H, 7.89; N, 8.47. On a large scale, a small amount
(0.65%) of syrupy (1S)-1-(7-N-benzyloxymethyl-9-deaza-6-O-
methylhypoxanthin-9-yl)-N-butyl-5-O-tert-butyldimethylsilyl-
1,4-dideoxy-1,4-imino-2,3-O-isopropylidene-D-ribitol (42) was
isolated by chromatography at this stage. 1H NMR (DMSO-
d6) δ 8.42 (s, 1H), 7.79 (s, 1H), 7.32-7.18 (m, 5H), 5.73 (s, 2H),
4.76 (dd, J ) 11.4, 6.1 Hz, 1H), 4.46 (s, 2H), 4.46-4.42 (m,
1H), 4.11 (d, J ) 5.1 Hz, 1H), 4.04 (s, 3H), 3.72-3.62 (m, 2H),
2.96-2.91 (m, 1H), 2.68-2.40 (m, 2H), 1.47 (s, 3H), 1.22 (s,
3H), 1.38-0.92 (m, 4H), 0.88 (s, 9H), 0.65 (t, J ) 3.3 Hz, 3H),
0.07 (s, 3H), 0.06 (s, 3H); 13C NMR (CDCl3) δ 156.1, 150.1,
150.0, 137.0, 131.4, 128.5, 128.0, 127.7, 118.6, 116.2, 112.6,
85.1, 81.7, 70.1, 69.5, 64.7, 64.6, 53.4, 51.8, 28.0, 27.9, 26.0,
25.6, 20.5, 18.3, 14.0, -5.26, -5.29. Anal. Calcd for C33H50N4O5-
Si: C, 64.88; H, 8.25; N, 9.17. Found: C, 64.58; H, 8.23; N,
8.90.
(1S)-1-(9-Deazah ypoxan th in -9-yl)-1,4-dideoxy-1,4-im in o-
d -r ibitol Hyd r och lor id e (2‚HCl). Meth od A. A solution of
39 (1.57 g, 3.57 mmol) in concentrated HCl (30 mL) was heated
under reflux for 1 h and then concentrated to dryness. Silica
gel (5 g) was added to a solution of the residue in water, and
the mixture was concentrated to dryness. The residue was
applied to a column of silica gel, and elution with CH2Cl2/
MeOH/concentrated aq NH4OH (5/4/1) gave a white solid (0.94
g). A solution of this material in water (20 mL) was treated
with concentrated HCl (2 mL) and the solution concentrated
to dryness. Trituration with ethanol afforded 2‚HCl (0.92 g,
3.04 mmol, 84%) as a white solid (mp > 300 °C) with the same
1H and 13C NMR data as reported previously.3
Meth od B. A solution of 40 (7.5 g, 11.5 mmol) in ethanol
(100 mL) was stirred under hydrogen in the presence of 10%
Pd/C (5.0 g) for 18 h. After removal of the catalyst, concen-
trated aq NH4OH (5 mL) was added to the filtrate and the
solution set aside until the two initial products were fully
replaced by products slightly less polar on TLC plates (∼1 h).
The solution was concentrated, and short column chromatog-
raphy afforded 5.9 g of a syrupy mixture of 43 and 44. A small
portion of this mixture was separated by chromatography to

5730 J . Org. Chem., Vol. 66, No. 17, 2001
Evans et al.
afford 43 and 44 as white solids. Characterization of 43: mp
148-149 °C; 1H NMR (DMSO-d6) δ 12.0 (s, 1H, D2O exchange-
able), 8.4 (s, 1H), 7.4 (s, 1H), 5.3-5.1 (m, 2H), 4.9 (d, 1H), 4.1
(s, 3H), 4.1-3.4 (m, 3H), 1.5-1.3 (br s, 9H), 1.5 (s, 3H), 1.3 (s,
3H), 0.92 (s, 9H), 0.0 (s, 6H); 13C NMR δ 155.7, 154.7, 149.5,
147.2, 128.2, 115.5, 111.7, 82.7, 80.0, 77.3, 66.4, 62.5, 61.6, 53.3,
28.5, 27.8, 27.5, 25.9, 25.6, 17.9, -5.26, -5.33. Anal. Calcd for
in methanol (10 mL) and concentrated HCl (10 mL) was heated
under reflux for 3 h and then concentrated to dryness. The
residue was dissolved in aq ethanol and concentrated to
dryness three times. The hygroscopic residue in water was
treated with 1 M aq NaOH (5 mL, 5 mmol), then adsorbed
onto silica gel (2 g), and dried. Chromatography then afforded
48 (0.387 g, 1.2 mmol, 55%) as an off-white solid, mp > 230
°C (dec); 1H NMR (DMSO-d6) δ 11.85 (br s, 1H, D2O exchange-
able), 7.77 (s, 1H), 7.28 (d, J ) 3.1 Hz, 1H), 4.93 (br s, 1H,
D2O exchangeable), 4.58 (d, J ) 6.4 Hz, 1H, D2O exchange-
able), 4.48 (d, J ) 3.3 Hz, 1H, D2O exchangeable), 4.15-4.09
(m, 2H), 3.87-3.84 (m, 2H), 3.38-3.34 (m, 2H, coincident with
HOD), 2.76-2.75 (m, 1H), 2.59-2.42 (m, 2H), 0.66 (t, J ) 7.2
Hz, 3H); 13C NMR (DMSO-d6) δ 154.5, 143.5, 141.7, 127.2,
119.4, 119.3, 77.1, 74.3, 71.3, 64.8, 63.9, 53.9, 30.3, 20.6, 14.6.
Anal. Calcd for C15H22N4O4: C, 55.89; H, 6.88; N, 17.38.
Found: C, 55.78; H, 6.96; N, 16.98.
C
26H42N4O6Si: C, 58.40; H, 7.92; N, 10.48. Found: C, 58.51;
H, 8.00; N, 10.31. Characterization of 44: mp 174-175 °C;
1H NMR (DMSO-d6) δ 9.83 (br s, 1H, D2O exchangeable), 8.30
(s, 1H), 7.26 (d, J ) 2.8 Hz, 1H), 4.88-4.85 (m, 3H), 4.33-
4.29 (m, 2H), 3.86-3.78 (m, 1H), 3.78 (s, 3H), 1.65 (s, 3H), 1.45
(s, 9H), 1.29 (s, 3H); 13C NMR δ 156.2, 155.5, 148.4, 145.1,
129.8, 116.3, 115.0, 112.1, 85.6, 82.2, 81.3, 66.7, 64.4, 63.7, 53.4,
28.9, 28.5, 26.1. Anal. Calcd for C20H28N4O6: C, 57.13; H, 6.71;
N, 13.32. Found: C, 56.95; H, 6.88; N, 13.03. To a solution of
this mixture in methanol (50 mL) was added concentrated HCl
(50 mL), and the solution was heated under reflux for 1.5 h
and then concentrated to dryness. Trituration of the solid
residue with ethanol afforded 2‚HCl3 (3.17 g, 10.5 mmol, 91%)
as a white solid.
N-Bu t yl-5-O-ter t-b u t yld im et h ylsilyl-1,4-d id eoxy-1,4-
im in o-2,3-O-isop r op ylid en e-(1S)-1-(7-m et h oxyp yr r olo-
[2,3-c]p yr id in -3-yl)-D-r ibitol (45). A solution of 42 (6.25 g,
10.2 mmol) in ethanol (75 mL) containing 20% Pd(OH)2/C (6.2
g) was shaken in a hydrogen atmosphere at 40 psi for 36 h.
The catalyst was replaced with fresh material (6.2 g), and
hydrogenation continued at 40 psi for another 18 h. The
mixture was filtered through Celite, and concentrated aq NH4-
OH (5 mL) was added to the filtrate. After 72 h at room
temperature, the solution was concentrated to dryness. Chro-
matography of the residue afforded 45 (1.59 g, 3.24 mmol, 32%)
as a pale yellow solid, mp 152-162 °C; 1H NMR (DMSO-d6) δ
11.91 (br s, 1H, D2O exchangeable), 8.39 (s, 1H), 7.57 (d, J )
2.9 Hz, 1H), 4.81 (t, J ) 6.0 Hz, 1H), 4.43 (dd, J ) 6.5, 3.7 Hz,
1H), 3.10 (d, J ) 5.3 Hz, 1H), 4.06 (s, 3H), 3.71-3.61 (m, 2H),
2.94-2.89 (m, 1H), 2.45-2.36 (m, 1H), 1.46 (s, 3H), 1.32-1.15
(m, 2H), 1.20 (s, 3H), 1.06-0.93 (m, 2H), 0.88 (s, 9H), 0.66 (t,
J ) 7.3 Hz, 3H), 0.07 (s, 3H), 0.06 (s, 3H); 13C NMR (DMSO-
d6) δ 155.3, 148.6, 128.8, 115.4, 114.6, 111.6, 83.9, 81.2, 68.9,
64.5, 63.9, 52.9, 50.3, 27.7, 27.0, 25.7, 25.4, 19.8, 17.9, 13.6,
-5.48, -5.50. Anal. Calcd for C25H42N4O4Si: C, 61.19; H, 8.63;
N, 11.42. Found: C, 61.55; H, 8.62; N, 11.11.
1,4-Did eoxy-1,4-im in o-(1S)-1-(7-oxop yr r olo[2,3-c]p yr i-
d in -3-yl)-D-r ibitol Hyd r och lor id e (49‚HCl). A solution of
46 (0.71 g, 1.3 mmol) in methanol (2 mL) and concentrated
HCl (2 mL) was heated under reflux for 48 h and then
concentrated to dryness. Chromatography [CHCl3/MeOH/aq
NH4OH (5/4/1)] of the residue afforded the free base of the
title compound (0.03 g, 0.11 mmol, 9%). After treatment with
aq HCl and lyophilization, title compound 49‚HCl was ob-
tained as an extremely hygroscopic white solid. 1H NMR
(DMSO-d6) δ 12.16 (br s, D2O exchangeable, 1H), 11.19 (d, J
) 4.7 Hz, D2O exchangeable, 1H), 10.43 (br s, D2O exchange-
able, 1H), 8.30 (br s, D2O exchangeable, 1H), 7.37 (s, 1H), 7.11
(d, J ) 5.5 Hz, 1H), 6.70 (s, 1H), 5.70-5.20 (m, D2O exchange-
able, 3H), 4.45 (s, 2H), 4.09 (s, 1H), 3.90-3.40 (m, 2H); 13C
NMR (-DMSO-d6)
δ 154.5, 129.8, 126.7, 123.1, 105.6,
102.0, 72.0, 70.8, 65.4, 59.6, 58.6. HRMS (MH+) Calcd for
C
12H16N3O4: 266.1141. Found: 266.1146.
Ack n ow led gm en t. The authors thank Dr. Herbert
Wong for an excellent NMR service and Professor Robin
Ferrier for assisting with the preparation of the manu-
script. This work was supported by research grants from
the National Institutes of Health, USA, and the Foun-
dation for Research Science and Technology, New
Zealand.
N-Bu tyl-(1S)-1-(9-d ea za h yp oxa n th in -9-yl)-1,4-d id eoxy-
1,4-im in o-D-r ibitol (48). A solution of 45 (1.07 g, 2.18 mmol)
J O0155613