Imino-C-nucleoside Synthesis: Heteroaryl Lithium Carbanion Additions to A Carbohydrate Cyclic Imine and Nitrone

Article abstract of DOI:10.1021/jo035744k

Promotion by Lewis acid of the addition of some aryllithiums to a carbohydrate-based imine, which has allowed a more facile synthesis of some imino-C-nucleoside analogues, is described. Use of the corresponding nitrone does not assist in some cases, but l

Full text of DOI:10.1021/jo035744k

SCHEME 1a
Im in o-C-n u cleosid e Syn th esis: Heter oa r yl
Lith iu m Ca r ba n ion Ad d ition s to a
Ca r boh yd r a te Cyclic Im in e a n d Nitr on e
Gary B. Evans,† Richard H. Furneaux,†
Herwig Hausler,‡ J anus S. Larsen,§ and
Peter C. Tyler*,†
Carbohydrate Chemistry, Industrial Research Limited,
P.O. Box 31310, Lower Hutt, New Zealand, Glycogroup at
Institute for Organic Chemistry, Technical University Graz,
Austria, and Chemistry Department, University of Southern
Denmark, Odense, Denmark
p.tyler@irl.cri.nz
Received November 27, 2003
Abstr a ct: Promotion by Lewis acid of the addition of some
aryllithiums to a carbohydrate-based imine, which has
allowed a more facile synthesis of some imino-C-nucleoside
analogues, is described. Use of the corresponding nitrone
does not assist in some cases, but lithiated acetonitrile adds
to it efficiently to give a product from which further
C-nucleoside analogues can be derived.
a
Conditions: (a) ether-anisole, -70 to 0 °C.
imine or gave disappointingly poor yields of adducts. The
syntheses of other immucillin analogues that were sought,
such as 10-12, which are obtainable in principle from
lithiated species 5-7, respectively, would be greatly
simplified if such additions could be carried out satisfac-
torily. We report here two adaptations of the reaction
exemplified in Scheme 1 which have proved helpful.
The addition of organometallic reagents to imines is a
well-known and synthetically useful procedure, but it is
equally well-known that, especially in the case of imines
having hydrogen atoms at the R-carbon positions, it can
be problematical.6 For example, while the reaction de-
picted in Scheme 1 affords a high yield, it proceeds only
above -20 °C, and in practice the solution was allowed
to warm to 0 °C.1 However, the heterocyclic aryllithiums
5-7 appear not to survive these temperatures and are
probably quenched by proton abstraction from solvent
and/or substrate. The alkynyllithium 8 decomposes at the
same temperature as it adds to the imine 3 (10 °C),
limiting the yield of target 10 which is available from
the adduct.7 Furthermore, targets 11 and 12 are acces-
sible in an alternative manner from compound 18 (il-
lustrated in Scheme 3), obtained by addition of lithiated
acetonitrile 9 to 3 at -70 °C,8 but this reaction is
capricious and difficult to scale-up because the 1:1 adduct
reacts further with the imine to give the 2:1 adduct. A
significant objective, therefore, became the discovery of
improved means of adding lithio derivatives such as 5-9
to 3.
In connection with the design and synthesis of transi-
tion state analogue inhibitors of human purine nucleoside
phosphorylase, as agents capable of preventing T cell
proliferation, we recently reported1 a convergent synthe-
sis of immucillin-H 1. This material is under clinical
study to assess its utility for the control of T-cell
proliferative disorders.2-5 A critical step in the synthesis
was the addition of the 9-lithio-9-deazapurine derivative
2 to the carbohydrate-based imine 3 that affords an
excellent yield of the protected immucillin 4 (Scheme 1).
However, a number of other alkyl and aryllithium
derivatives, for example 5-9, either failed to add to this
* Corresponding author. Phone: +64 4 931 3062. Fax: +64 4 931
3055.
† Industrial Research Limited.
‡ Technical University Graz.
§ University of Southern Denmark.
Here we report the exploitation of two opportunities
based on the facts that Lewis acids can activate imines
(1) Evans, G. B.; Furneaux, R. H.; Hutchison, T. L.; Kezar, H. S.;
Morris, P. E., J r.; Schramm, V. L.; Tyler, P. C. J . Org. Chem. 2001,
66, 5723-5730.
(2) Miles, R. W.; Tyler, P. C.; Furneaux, R. H.; Bagdassarian, C. K.;
Schramm, V. L. Biochemistry 1998, 37, 8615-8621.
(3) Kicska, G. A.; Long, L.; Ho¨rig, H.; Fairchild, C.; Tyler, P. C.;
Furneaux, R. H.; Schramm, V. L.; Kaufman, H. L. Proc. Natl. Acad.
Sci. U.S.A. 2001, 98, 4593-4598.
(4) Bantia, S.; Miller, P. J .; Parker, C. D.; Ananth, S. L.; Horn, L.
L.; Kilpatrick, J . M.; Morris, P. E.; Hutchison, T. L.; Montgomery, J .
A.; Sandhu, J . S. Int. Immunopharmacol. 2001, 1, 1199-1210.
(5) Bantia, S.; Miller, P. J .; Parker, C. D.; Ananth, S. L.; Horn, L.
L.; Babu, Y. S.; Sandhu, J . S. Int. Immunopharmacol. 2002, 2, 913-
923.
(6) Volkmann, R. A. In Comprehensive Organic Synthesis, Additions
to C-Xπ Bonds, Part 1; Schreiber, S. L., Ed.; Pergamon Press: Oxford,
1991; Vol. 1, Chapter 1.12. Katritzky, A. R.; Hong, Q.; Yang, Z. J . Org.
Chem. 1995, 60, 3405-3408. Yamada, H.; Kawate, T.; Nishida, A.;
Nakagawa, M. J . Org. Chem. 1999, 64, 8821-8828 and references
therein.
(7) Evans, G. B.; Furneaux, R. H.; Gainsford, G. J .; Hanson, J . C.;
Kicska, G. A.; Sauve, A. A.; Schramm, V. L.; Tyler, P. C. J . Med. Chem.
2003, 46, 155-160.
(8) Evans, G. B.; Furneaux, R. H.; Gainsford, G. J .; Schramm, V.
L.; Tyler, P. C. Tetrahedron 2000, 56, 3053-3062.
10.1021/jo035744k CCC: $27.50 © 2004 American Chemical Society
Published on Web 02/24/2004
J . Org. Chem. 2004, 69, 2217-2220
2217

toward nucleophilic addition,9 and nitrones are more
electrophilic than the corresponding imines.6 In the latter
case, addition of organometallic reagents to nitrones gives
hydroxylamines which are readily reduced to the parent
amines. Consequently, the Lewis acid activation of imine
3 and the use of its nitrone analogue 17 were assessed
as means of increasing the range of carbon nucleophiles
that could be used in reactions such as that illustrated
in Scheme 1.
SCHEME 2a
Lew is Acid Activa tion . A number of Lewis acids
were surveyed as facilitators of the reaction between 2
and 3 with the temperature maintained at -70 °C
(Scheme 1). As indicated above, in the absence of Lewis
acid promoters, temperatures above -20 °C are required
for significant reaction to occur. When BF3‚OEt2, TiCl4,
SnCl4, InCl3, TmsOTf, Sc(OTf)3, Bu2BOTf and ZnCl2 were
separately added to the reaction mixture at -70 °C, only
the first three promoted the formation of product 4. The
reaction involving SnCl4 was clearly the most selective
and efficient (TLC evidence), but the isolated yield of 4
obtained with this catalyst (∼60%) was nevertheless less
than that obtained from the uncatalyzed process.1
a
Reagents and conditions: (a) SnCl4, ether-anisole, -70 °C;
i
(b) SnCl4, THF, -70 °C; (c) Pr2NEt, Cl3CCH2OCOCl.
SCHEME 3a
a
Reagents and conditions: (a) SeO2, H2O2, Me2CO, -4 °C, 3-4
h; (b) 9, THF, -70 °C, 0.5 h; (c) Zn, HOAc, 6 h, 20-30 °C; (d)
(tBuOCO)2O, CHCl3 15 h.
alkyne adduct 15 may be converted into the 8-aza-
immucillin 10.7
Reaction of the organolithium reagents 5, 6 and 8 with
imine 3, when promoted by SnCl4 at -70 °C, gave the
required adducts (Scheme 2), but compound 7 did not.
The 8-aza-9-deazahypoxanthine C-nucleoside analogue
13 was obtained for the first time in 31% yield and the
9-deazaguanine 14 analogue in an improved 15% yield,
while the alkyne adduct 15 was generated consistently
in 76% yield. The yields from the corresponding unpro-
moted reactions are 0%, 5%, and ∼50% respectively. The
Ad d it ion s t o Nit r on e 17. Treatment of the imino-
ribitol derivative 16 with SeO2 and H2O2 converted it
directly into nitrone 17, a stable crystalline solid. Expo-
sure of this material separately to the organolithiums 8
and 9 in THF at -70 °C resulted in facile additions to
afford the corresponding N-hydroxy adducts. In the latter
case, reduction of the product with zinc in acetic acid
followed by N-protection with (Boc)2O afforded the ac-
etonitrile adduct 18 in up to 90% overall yield (Scheme
3). This compares extremely favorably with the unreliable
approach to this product involving reaction of 3 with 9.
On the other hand, reduction of the hydroxylamine
(9) Yamaguchi, M. In Comprehensive Organic Synthesis, Additions
to C-Xπ Bonds, Part 1; Schreiber, S. L., Ed.; Pergamon Press: Oxford,
1991; Vol. 1, Chapter 1.11.
2218 J . Org. Chem., Vol. 69, No. 6, 2004

0.84 (s, 9 H), 0.049, 0.031, 0.0 (s, 6H); 13C NMR δ 162.3 (C),
151.4 (CH), 139.6, 135.5, 135.3, 131.7, 114.9, 114.4 (C), 87.6, 87.1,
86.4, 85.9, 83.1, 82.8 (CH), 68.3, 68.0 (CH2), 66.9, 66.4 (CH), 63.0,
62.3(CH2), 61.7, 61.5 (CH), 54.3 (CH3), 30.0, 29.7 (CH2), 28.0,
26.2, 25.2 (CH3), 25.0 (CH2), 22.8, 22.6 (CH3), 18.6 (C), -4.9
(CH3); HRMS m/z (M+ + 1) calcd for C25H42N5O5Si 520.2955,
found 520.2943.
derived by reaction of alkyne 8 with nitrone 17 with zinc
in acetic acid was capricious and was generally ac-
companied by significant reduction of the acetylene
moiety to an alkene. Consequently this procedure was
inappropriate for the synthesis of 10.
When the aryllithium 2 was allowed to react with
nitrone 17 at -70 °C the highly basic aryllithium
appeared to promote degradation of the nitrone. Treat-
ment of the crude product with zinc in acetic acid
generated some 4, but in a poor yield relative to that
obtained on treatment of imine 3 with the lithiated 2.
The addition of SnCl4 to the reaction did not improve
matters in this case.
In conclusion, we have shown that SnCl4 promotes the
addition of some aryllithiums to imine 3 and allows the
formation of adduct 13 for the first time. Its use led to
the consistent production of 15 in an enhanced yield.
Importantly, for our purposes, the use of the nitrone 17
has enabled the reproducible synthesis of adduct 18, and
thus the immucillins 11 and 12, on a large scale.
Variations in the efficiencies of the reactions attempted
with compound 17, however, show that each target
compound should be made by the procedure best suited
to the specific purpose.
6-O-Ben zyl-7-N-ben zyloxym eth yl-9-br om o-9-deaza-2-N,N-
bis(4-m eth oxyben zyl)gu a n in e (6a ). Sodium hydride (0.3 g,
60%, 7.5 mmol) was added to a stirred solution of 6-O-benzyl-
7-N-benzyloxymethyl-9-bromo-9-deazaguanine1 (1.2 g, 2.73 mmol)
in DMF (25 mL) followed by 4-methoxybenzyl chloride (1.1 mL,
8.1 mmol). The mixture was stirred for 16 h, toluene (100 mL)
was added, and the solution was washed with water (2×) and
processed in the normal manner. Chromatography of the crude
material afforded the title compound (1.7 g, 2.5 mmol, 91%) as
a white solid. Recrystallized from ethanol it had: mp 102-104
1
°C; H NMR δ 7.31-7.16 (m, 15 H), 6.82 (d, J ) 8.6 Hz, 4 H),
5.56 (s, 2 H), 5.42 (s, 2 H), 4.82 (s, 4 H), 4.39 (s, 2 H), 3.78 (s, 6
H); 13C NMR δ 159.0, 158.5, 156.5, 151.5, 137.4, 137.0 (C), 131.8
(CH), 131.6 (C), 129.7, 128.9, 128.8, 128.4, 128.3, 128.0, 114.3
(CH), 110.5, 91.1(C), 77.9, 70.6, 68.0 (CH2), 55.7 (CH3), 49.4
(CH2). Anal. Calcd for C37H35BrN4O4: C, 65.39; H, 5.19; Br,
11.76; N, 8.24. Found: C, 65.47; H, 5.17; Br, 11.55; N, 8.42.
1-â-(6-O-Ben zyl-7-N-ben zyloxym eth yl-9-d ea za -2-N,N-bis-
(4-m et h oxyb en zyl)gu a n in -9-yl)-5-O-ter t-b u t yld im et h ylsi-
lyl-1,4-dideoxy-1,4-im in o-2,3-O-isopr opylidin e-D-r ibitol (14).
n-Butyllithium (0.33 mL, 1.5 M, 0.5 mmol) was added to a stirred
solution of 6-O-benzyl-7-N-benzyloxymethyl-9-bromo-9-deaza-2-
N,N-bis(4-methoxybenzyl)guanine (0.312 g, 0.46 mmol) in ether
(6 mL) and anisole (3 mL) at -78 °C to give the lithiated 6, and
after 20 min, a solution of imine 3 (0.1 g, 0.35 mmol) was added
followed by SnCl4 (82 µL, 0.7 mmol). Stirring was maintained
for 2 h, after which time NaOH (5 mL, 4 M) and ether (10 mL)
were added. Normal processing and chromatography afforded
the title compound 14 (0.047 g, 0.053 mmol, 15%) as a syrup:
1H NMR δ 0.00 (2s, 6 H), 0.84 (s, 9 H), 1.22 (s, 3 H), 1.53 (s, 3
H), 3.21 (dd, J ) 5.0, 10.1 Hz, 1 H), 3.78 (m, 2 H), 3.80 (s, 9 H),
4.26 (d, J ) 4.80 Hz, 1 H), 4.40 (s, 2 H), 4.44 (m, 1 H), 4.57 (d,
J ) 26.3 Hz, 1 H), 5.02 (m, 2 H), 5.42 (s, 2 H), 5.60 (s, 2 H), 6.81
(s, 1 H), 6.83 (m, 4 H), 7.15-7.30 (m, 9 H); 13C NMR δ 158.9,
157.6, 156.3, 152.5, 137.8, 137.3, 132.0, 130.9, 129.2, 128.8, 128.7,
128.3, 128.1, 127.9, 114.8, 114.1, 111.2, 86.4, 82.4, 77.6, 70.4,
67.5, 66.5, 63.9, 61.5, 55.6, 49.5, 27.9, 26.3, 25.6, 18.8; HRMS
m/z (M+ + 1) calcd for C51H64N5O7Si 886.4575, found 886.4589.
5-O-ter t-Bu t yld im et h ylsilyl-1,4-d id eoxy-1-â-(3,3-d iet h -
oxyp r op -1-yn yl)-1,4-im in o-2,3-O-isop r op ylid en e-N-(2,2,2-
tr ich lor oeth oxycar bon yl)-D-r ibitol (15). n-Butyllithium (109.5
mL, 1.6 M, 175 mmol) was added to a solution of propiolaldehyde
diethyl acetal (27.2 mL, 189.5 mmol) in THF (400 mL) with the
reaction temperature kept below -60 °C, and the solution was
stirred at -70 °C for 20 min. A solution of the imine 3 (20 g,
70.2 mmol) in THF (40 mL) was added followed by stannic
chloride (8.2 mL, 70.2 mmol), and the resulting solution was
stirred at -70 °C for 30 min. Aqueous sodium hydroxide (150
mL, 2.5 M) and petroleum ether (400 mL) were added, and the
organic phase was processed normally to give a syrup (35.4 g).
A solution of this material in dichloromethane (150 mL) was
treated with N,N-diisopropylethylamine (30 mL, 310 mmol) and
then trichloroethyl chloroformate (9.7 mL, 70.4 mmol) with
cooling to control the initial exotherm. After 1 h at 20 °C, the
solution was processed normally and chromatography afforded
title compound 15 as a syrup (31.5 g, 53.5 mmol, 76%) with 1H
and 13C NMR spectra identical to those reported.8
Exp er im en ta l Section
Gen er a l Meth od s. 1H and 13C NMR spectra were recorded
at 300 and 75 MHz, respectively, in CDCl3 unless stated
otherwise. “Normal processing” means the organic phase was
washed with aqueous acid and/or base as appropriate, dried, and
concentrated to dryness. Chromatography was conducted on
silica gel.
Gen er a l P r oced u r e for th e Lew is Acid P r om oted Con -
d en sa tion of Ar yllith iu m 2 w ith Im in e 3. n-Butyllithium
(0.77 mL, 1.5 M, 1.15 mmol) was added to a solution of 7-N-
benzyloxymethyl-9-bromo-9-deaza-6-O-methylhypoxanthine1 (375
mg, 1.08 mmol) in ether (6 mL) and anisole (3 mL) at -45 °C,
and after 10 min, the reaction mixture was cooled to -78 °C. A
solution of the imine 31 (0.1 g, 0.35 mmol) in ether (2 mL) was
added, followed by the Lewis acid (0.7 mmol), and the temper-
ature was kept at -78 °C for 2 h. The reaction was quenched
by the addition of Na2CO3 (saturated, aqueous) or NaOH and
processed in the normal manner. Chromatography afforded
syrupy 4, in those cases in which product was formed, with 1H
and 13C NMR data identical to those reported for the compound.1
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-1-â-(7-m eth oxy-2-tetr a h yd r op yr a n -2-yl-1H-
p yr a zolo[4,3-d ]p yr im id in -3-yl)-D-r ibitol (13). A stirred so-
lution of 3-bromo-7-methoxy-2-(tetrahydropyran-2-yl)-pyrazolo[4,3-
d]pyrimidine10 (1.0 g, 3.19 mmol) in dry THF at -78 °C was
treated with n-butyllithium (2.2 mL, 1.5 M, 3.3 mmol) to give
the lithiate 5, and after 20 min a solution of the imine 3 (0.63 g,
2.21 mmol) in THF (1 mL) was added followed by SnCl4 (0.51
mL, 4.4 mmol). The mixture was stirred at -70 °C for 2 h and
then allowed to warm to 20 °C over 1 h, after which time the
reaction was quenched by addition of NaOH (10 mL, 4 M). Ether
(20 mL) was added, the organic phase was separated and dried,
and the solvent was evaporated. Chromatography afforded the
title compound 13 (0.355 g, 0.68 mmol, 31%) as a clear oil: 1H
NMR (the product was a ∼ 6:4 diastereomeric mixture due to
the tetrahydropyranyl protecting group) δ 8.38 (s, 1 H), 5.97 (dd,
J ) 9.2, 2.7 Hz, 0.4 H), 5.87 (dd, J ) 9.9, 2.2 Hz, 0.6 H), 5.31
(dd, J ) 6.8, 4.9, Hz 0.6 H), 4.99 (t, J ) 6.4 Hz, 0.4 H), 4.82-
4.69 (m, 2H), 4.15 (s, 3 H), 4.01 (m, 1H), 3.92-3.52 (m, 4H), 3.33
(q, J ) 4.1 Hz, 0.4 H), 3.27 (q, J ) 3.9 Hz, 0.6 H), 2.59 (m, 1 H),
2.08 (m, 2 H), 1.70 (m, 2 H), 1.59, 1.56, 1.34, 1.32 (s, 3 H), 0.88,
5-O-ter t-Bu t yld im et h 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 N-Oxid e (17). A
stirred solution of 168 (30 g, 104 mmol) and selenium dioxide
(0.6 g, 5.4 mmol) in acetone (100 mL) was cooled to 0 °C, and
hydrogen peroxide (30%) was added slowly, with the tempera-
ture kept below 4 °C, until the reaction was complete (TLC
evidence) (3-4 h). Chloroform (250 mL) was added, the mixture
was washed with water, and the organic phase was dried
(MgSO4) and concentrated. Chromatography of the crude product
afforded crystalline nitrone 17 (18.3 g, 60.8 mmol, 58%): mp
(10) Stone, T. E.; Eustace, E. J .; Pickering, M. V.; Doyle Daves, G.,
J r. J . Org. Chem. 1979, 44, 505-509.
J . Org. Chem, Vol. 69, No. 6, 2004 2219

121-124 °C (from petroleum ether); 1H NMR δ 6.86 (s, 1 H),
5.11 (m, 1 H), 4.81 (d, J ) 6.2 Hz, 1 H), 4.22 (dd, J ) 2.0, 11.0
Hz, 1 H), 4.01 (d, J ) 0.7 Hz, 1 H), 3.82 (dd, J ) 2.1, 11.0 Hz,
1 H), 1.40 and 1.35 (2s, 3 H each), 0.83 (s, 9 H), 0.04 and 0.02
(2s, 3 H each); 13C NMR δ 133.5 (CH), 112.0 (C), 81.1, 79.5, 77.5
(CH), 60.2 (CH2), 27.7, 26.3, 26.1 (CH3), 18.5 (C). Anal. Calcd
for C14H27NO4Si: C, 55.78; H, 9.03; N, 4.65. Found: C, 55.81;
H, 8.88; N, 4.75.
N-ter t-Bu toxyca r bon yl-7-O-ter t-bu tyld im eth ylsilyl-2,3,6-
tr id eoxy-3,6-im in o-4,5-O-isop r op ylid en e-D-a llo-h ep ton on i-
tr ile (18). Acetonitrile (4.2 mL, 80.2 mmol) was added slowly
to a solution of n-butyllithium (32.5 mL, 74.8 mmol) in THF (300
mL) with the reaction temperature kept below -65 °C to give
the lithiated 9. The resulting mixture containing a white
precipitate was stirred at -70 °C for 0.5 h, and a solution of the
nitrone 17 (15.0 g, 49.8 mmol) in THF (30 mL) was added. After
0.5 h at -70 °C, the reaction was quenched with water and
partitioned between petroleum ether (500 mL) and water (500
mL). The organic layer was dried (MgSO4) and concentrated to
dryness. The residue was dissolved in acetic acid (100 mL), and
zinc dust (30 g) was added with stirring. The resulting mixture
was stirred for 6 h with occasional cooling to keep the reaction
temperature below 30 °C, the solids and solvent were removed,
and a solution of the residue in chloroform (200 mL) was washed
with NaHCO3 (aqueous, saturated), dried and concentrated to
dryness. The residue in chloroform (100 mL) was treated with
di-tert-butyl dicarbonate (11.5 g, 52.7 mmol) and allowed to stand
overnight. The solution was concentrated and chromatography
of the residue afforded title compound 18 (19.1 g, 44.8 mmol,
1
90%) as a colorless syrup with H and 13C NMR spectra identical
to those reported for the compound.8
Ack n ow led gm en t. Professor Robin Ferrier assisted
with the preparation of the manuscript. This work was
supported by a research grant from the New Zealand
Foundation for Research, Science and Technology.
J O035744K
2220 J . Org. Chem., Vol. 69, No. 6, 2004