Asymmetric synthesis of 4′-ethoxy-2′,3′-didehydro-2′, 3′-dideoxynucleosides by palladium-catalyzed kinetic discrimination between the corresponding diastereoisomeric lactol acetates

Article abstract of DOI:10.1021/jo011074b

4′-Substituted nucleoside analogues have been synthesized using palladium-catalyzed asymmetric allylic amination conditions. A kinetic discrimination between the diastereomeric lactol acetates (3) produced the desired aminated products (6a-d) and recovered acetate (α-3) in high yields and <97:3 diastereoselectivity. Epimerization of the recovered lactol acetate (α-3) produced a 60:40 α/β mixture of (3), which could be resubjected, in principle, to the palladium-catalyzed asymmetric allylic amination conditions.

Full text of DOI:10.1021/jo011074b

4076
J . Org. Chem. 2002, 67, 4076-4080
Asym m etr ic Syn th esis of
4′-Eth oxy-2′,3′-d id eh yd r o-2′,3′-d id eoxyn u cleosid es by
P a lla d iu m -Ca ta lyzed Kin etic Discr im in a tion betw een th e
Cor r esp on d in g Dia ster eoisom er ic La ctol Aceta tes
Louis S. Hegedus,* Katherine L. Hervert, and Satoshi Matsui
Department of Chemistry, Colorado State University, Fort Collins, Colorado 80523
hegedus@lamar.colostate.edu
Received November 14, 2001
4′-Substituted nucleoside analogues have been synthesized using palladium-catalyzed asymmetric
allylic amination conditions. A kinetic discrimination between the diastereomeric lactol acetates
(3) produced the desired aminated products (6a -d ) and recovered acetate (R-3) in high yields and
<97:3 diastereoselectivity. Epimerization of the recovered lactol acetate (R-3) produced a 60:40 R/â
mixture of (3), which could be resubjected, in principle, to the palladium-catalyzed asymmetric
allylic amination conditions.
In tr od u ction
lide bearing the incipient quaternary nucleoside 4′ posi-
tion, a feature of some significance in light of recent evi-
dence suggesting that unnatural L-enantiomers of nu-
cleoside analogues often maintain high levels of antiviral
activity but have reduced toxicity.8 The approach envi-
sioned (eq 1) involved conversion of the butenolide to a
lactol acetate and the use of π-allylpalladium chemistry
for introduction of the nucleoside bases.
Modified nucleoside analogues having substituents at
the 4′-position are of interest as antiviral agents because
some members of this class can act both as reverse
transcriptase inhibitors as well as DNA chain termina-
tors, with a mechanism of action different from AZT.1 In
addition, some 4′-substituted nucleoside analogues act
as selective agonists or antagonists at adenosine recep-
tors.2 Most syntheses of 4′-substituted nucleosides involve
4′ functionalizations of intact nucleosides,3 although de
novo syntheses4 offer more flexibility in regards to both
functionality and stereochemistry.
Research in these laboratories has centered on the
development of de novo synthetic approaches to nucleo-
side analogues5 from optically active butenolides,6 derived
from chromium carbene complex photochemistry.7 This
chemistry can provide either enantiomer of the buteno-
(1) For a review see: (a) Prisbe, E. J .; Maag, H.; Verheyden, J . P.
H.; Rydzewski, R. M. Structure-Activity Relationships Among HIV
Inhibitory 4′-Substituted Nucleosides. In Nucleosides and Nucleotides
as Antitumor and Antiviral Agents; Chu, C. K.; Baker, D. C.; Eds.,
Plenum Press: New York, 1993; pp 101-111. (b) Maag, H.; Rydzewski,
R. M.; McRoberts, M. J .; Crawford-Ruth, D.; Verheyden, J . P. H.;
Prisbe, E. J . J . Med. Chem. 1992, 35, 1440-1451. (c) O-Yang, C.; Wu,
H. Y.; Fraser-Smith, E. B.; Walker, K. A. M. Tetrahedron Lett. 1992,
33, 37-40. (d) O-Yang, C.; Kurz, W.; Eugui, E. M.; McRoberts, M. J .;
Verheyden, J . P. H.; Kurz, L. J .; Walker, K. A. M. Tetrahedron Lett.
1992, 33, 41-44. (e) Chen, M. S.; Suttmann, R. T.; Papp, E.; Cannon,
P. D.; McRoberts, M. J .; Bach, C.; Copeland, W. C.; Wang, T. S-F.
Biochemistry 1993, 32, 6002-6010. (f) Maag, H.; Nelson, J .T.; Rios
Steiner, J . L.; Prisbe, E. J . J . Med. Chem. 1994, 37, 431-438. (g) Waga,
T.; Ohrui, H.; Meguro, H. Nucleosides Nucleotides 1996, 15, 287-304.
(2) Siddiqi, S. M.; J acobson, K. A.; Esker, J . L.; Olah, M. E.; J i, X.-
D.; Melman, N.; Tiwari, K. N.; Secrist, J . A.; Schneller, S. W.; Cristalli,
G.; Stiles, G. L.; J ohnson, C. R.; Izzerman, A. P. J . Med. Chem. 1995,
38, 1174-1188.
(3) (a) Haraguchi, K.; Tanaka, H.; Itoh, Y.; Saito, S.; Miyasaka, T.
Tetrahedron Lett. 1992, 33, 2841-2844. (b) Waga, T.; Nishizaki, T.;
Miyakawa, I.; Ohrui, H.; Meguro, H. Biosci. Biotech. Biochem. 1993,
57, 1433-1438. (c) Maag, H.; Schmidt, B.; Rose, S. J . Tetrahedron Lett.
1994, 35, 6449-6452. (e) Nomura, M.; Shuto, S.; Tanaka, M.; Sasaki,
T.; Mori, S.; Shigeta, S; Matsuda A. J . Med. Chem. 1999, 42, 2901-
2908. (f) J ung, M. E.; Toyota, A. J . Org. Chem. 2001, 66, 2624-2635.
(4) (a) For a review see: Wang, P.; Hong, J .-H.; Cooperwood, J . S.;
Chu, C. K. Anitviral Res. 1998, 40, 19-44. (b) Lipshutz, B. H.; Sharma,
S.; Dimock, S. H.; Behling, J . R. Synthesis 1992, 191-195. (c) Crich,
D.; Hao, X. J . Org. Chem. 1999, 64, 4016-4024. (d) Crich, D.; Hao, X.
J . Org. Chem. 1998, 63, 3, 3796-3797.
Palladium-catalyzed amination of allyl acetates has
been extensively developed as a synthetic tool.9 The
process is very general and is efficient for a broad range
of substrates and amines. The ability to induce asym-
metry into these reactions by use of chiral ligands10 has
greatly expanded the utility of this process. By far the
bulk of this work has been directed toward the desym-
metrization of meso substrates,11 or of meso-π-allyl
(5) (a) Brown, B.; Hegedus, L. S. J . Org. Chem. 1998, 63, 8012-
8018. (b) Brown, B.; Hegedus, L. S. J . Org. Chem. 2000, 65, 1865-
1872. (c) Geisler, L.; Hegedus, L. S. J . Org. Chem. 2000, 65, 4200-
4203.
(6) Reed. A. D.; Hegedus, L. S. Organometallics 1997, 16, 2313-
2317.
(7) For a review see: Hegedus, L. S. Tetrahedron 1997, 53, 4105-
4127.
(8) (a) Mansour, T. S.; Storer, R. Can. Curr. Pharm. Res. 1997, 3,
227-264. (b) Reference 4a.
(9) For a review see: (a) J ohannsen, M.; J ørgensen, K. A. Chem.
Rev. 1998, 98, 1689-1708.
(10) For reviews detailing the parameters of asymmetric induction
in palladium-catalyzed allylic alkylations, see: (a) Trost, B. M. Acct.
Chem. Res. 1996, 29, 355-364. (b) Trost, B. M.; Van Vranken, D. L.
Chem. Rev. 1996, 96, 395-422.
10.1021/jo011074b CCC: $22.00 © 2002 American Chemical Society
Published on Web 05/17/2002

4′-Ethoxy-2′,3′-didehydro-2′,3′-dideoxynucleosides
J . Org. Chem., Vol. 67, No. 12, 2002 4077
complex intermediates.12 Kinetic13 and dynamic kinetic14
resolution of racemic allyl acetates and carbonates can
also be efficiently achieved using appropriate chiral
ligands.
Sch em e 1
Allylic geminal dicarboxylates15 (acylals) and 4-car-
boxybutenolides16 (5-acyloxy-2(5H)-furanones) are special
cases in that the reacting allylic terminus is in the
aldehyde oxidation state and bears two enantiotopic
leaving groups. These also are reactive toward palladium-
catalyzed nucleophilic attack, and high asymmetric
induction has recently been achieved with the former
class of compounds.17 Given this extensive background,
lactol acetate 3 seemed a promising candidate for pal-
ladium-catalyzed introduction of nucleoside bases with
some degree of stereocontrol. Below are described experi-
ments addressing this issue.
Resu lts a n d Discu ssion
Lactol acetate 3 was made by reduction of butenolide
26 using diisobutylaluminum hydride. Because of the
leaving group (OEt) at the 4-position of butenolide 2, the
lactol itself was unstable and underwent a facile ring
opening to the open-chain keto aldehyde. The procedure
of Rhychnovsky,18 which involves low-temperature trap-
ping of the incipient lactol, proved effective, giving 3 in
reproducible yields of 85-95%. The resident chiral
quaternary center had no influence on the stereochemical
outcome of this reduction, and an inseparable ≈1:1
mixture of R- and â- acetoxy diastereoisomers was
obtained (eq 2).
into solution and then released by treatment with TBAF
after addition to the substrate/catalyst mixture. The
effect of the resident chiral quaternary center on selectiv-
ity between the two diastereoisomeric R and â acetates
was probed by using the achiral ligand dppf. As antici-
pated, the inherent lack of conformational rigidity of five
membered rings coupled with the 1,3 disposition of the
chiral centers resulted in little if any diastereoselectivity
(eq 3). Because the diastereoisomers of both 3 and 6 are
To probe the general reactivity of 3 toward π-allylpal-
ladium chemistry, reaction with dimethyl malonate was
attempted (Scheme 1). Only ring-opened product 4, from
overall loss of ethanol was observed.19 Use of dimethyl
methylmalonate led to the expected alkylation product
5 (eq 3), as a 1:1 mixture of C-1 epimers.
Next, the viability of nucleoside bases as nucleophiles
was examined. Since solubility of these in organic sol-
vents is low, they were first silylated in situ to bring them
inseparable and our interest lies with the â-anomer of
for nucleoside analogue chemistry,20 diastereoselective
amination of 3 was next examined.
Induction of asymmetry into palladium-catalyzed reac-
tions of allylic substrates is a highly active field, with
new chiral ligands being reported almost on a daily
basis.21 One of the most extensively studied and broadly
useful ligands for these processes is the trans-1,2-
cyclohexanediamine-based ligand 7 of Trost,10 which is
highly effective in very wide range of reaction types. In
(11) (a) For an example on the context of nucleoside synthesis, see:
Trost, B. M.; Shi, Z. J . Am. Chem. Soc. 1996, 118, 3037-3038. (b) For
use in carbacyclic nucleoside synthesis, see: Trost, B. M.; Kallander,
L. S. J . Org. Chem. 1999, 64, 5427-5435.
(12) (a) Trost, B. M.; Bunt, R. C. J . Am. Chem. Soc. 1994, 116, 4089-
4090. (b) Sprinz, J .; Helmchen, G. Tetrahedron Lett. 1993, 34, 1769-
1772. (c) Baldwin, I. C.; Williams, J . M. J .; Tetrahedron Asymmetry
1995, 6, 1515-1518. (d) Williams, J . M. J . Synlett 1996, 8, 705-710.
(13) For recent examples, see: (a) Gais, H.-J .; Spalthoff, M.; J agusch,
T.; Frank, M.; Raabe, G. Tetrahedron Lett. 2000, 41, 3809-3812.
(14) Longmire, J . M.; Wang, B.; Zhang, X. Tetrahedron Lett. 2000,
41, 5435-5439.
(15) (a) Lu, X.; Huang, Y. J . Organomet. Chem. 1984, 268, 185-
190. (b) Trost, B. M.; Vercauteren, J . Tetrahedron Lett. 1985, 26, 131-
134.
(16) (a) van der Deen, H.; van Oeveren, A.; Kellogg, R. M.; Feringa,
B. Tetrahedron Lett. 1999, 40, 1755-1758. (b) Trost, B. M.; Toste, F.
D. J . Am. Chem. Soc. 1999, 121, 3543-3544.
(20) It has been shown that both R and â anomers of nucleoside
analogues are of biological interest. Pe´licano, H.; Pierra, C.; Eriksson,
S.; Gosselin, G.; Imbach, J . L.; Maury, G.; J . Med. Chem. 1997, 40,
3969-3973. (b). Van Draanen, N. A.; Tisdale, M.; Parry, N. R.; J ansen,
R.; Dornsife, R. E.; Tuttle, J . V.; Averett, D. R.; Koszalka, G. W.
Antimicrob. Agents Chemother. 1994, 38, 868-871. (c) Migawa, M, T.;
Girardet, J .-L.; Walker, J . A., II; Koszalka, G. W.; Chamberlain, S. D.;
Drach, J . C.; Townsend, L. B. J . Med. Chem. 1998, 41, 1242-1251.
(21) For annual summaries of activity in this area, see: (a) Hegedus,
L. S. Coord. Chem. Rev. 2000, 204, 199-307. (b) Hegedus, L. S.
Coord. Chem. Rev. 1998, 175, 159-270. (c) Hegedus, L. S. Coord. Chem.
Rev. 1998, 168, 49-176. (d) Hegedus, L. S. Coord. Chem. Rev. 1997,
161, 129-255. (e) Hegedus, L. S. Coord. Chem. Rev. 1996, 147, 443-
545.
(17) For an in-depth study of these systems, see: (a) Trost, B. M.;
Lee, C. B. J . Am. Chem. Soc. 2001, 123, 3671-3686. (b) Trost, B. M.;
Lee, C. B. J . Am. Chem. Soc. 2001, 123, 3687-3696.
(18) Dahanukar, V. H.; Rychnovsky, S. D. J . Org. Chem. 1996, 61,
8317-8320.
(19) A similar elimination was observed in the reaction of dimethyl
malonate with the gem diacetate of cinnamaldehyde. See ref 15b.

4078 J . Org. Chem., Vol. 67, No. 12, 2002
Hegedus et al.
range of conditions22 resulting either in no reaction or in
decomposition. Finally, treatment of R-3 with zinc acetate
in acetic acid at 35 °C produced a 60:40 mixture of R/â
anomers, which could be, in principle, resubjected to the
amination procedure to produce more â-nucleoside, al-
lowing the complete conversion of a 1:1 mixture of R- and
â-3 to the exclusively â-nucleoside.
Ta ble 1. Kin etic Dia ster eod iffer en tia tion s of r/â-3 To
P r od u ce 4′-Eth oxy Nu cleosid e An a logs 6a -d (eq 4)
base
product
yield (%)a
3R yield (%)a
thymine
cytosine
uracilc
6a b
6b
6c
49
51
49
38
41
44
44
39
adenined
6d
a
Yields are for isolated product purified by silica gel column
b
chromatograph. Stereochemistry was confirmed by an X-ray
Con clu sion
crystal structure. See Supporting Information for details. c The
d
reaction was run at 0 °C. The R:â ratio of 3 was 45:55.
In summary, a synthesis of 4′-ethoxy-2′,3′-unsaturated
nucleoside analogues via diastereoselective, palladium-
catalyzed amination of the corresponding lactol acetate
has been developed. Equilibration of the undesired di-
astereoisomer of the lactol acetate allowed the conversion
of a 1:1 mixture of R- and â-anomeric lactol acetates to a
single â-anomer of the nucleoside analogue.
contrast to these enantioselective processes, what is
needed in the context of these studies is kinetic diaste-
reoselectivity for the â-acetate, coupled with equilibration
of the unreacted R-acetate (eq 4).
Exp er im en ta l Section
Gen er a l Meth od s a n d Ma ter ia ls. THF was distilled from
sodium-benzophenone ketyl, and DMF was distilled from
MgSO4. Commercially available reagents were used as re-
ceived. 1H NMR (300 MHz) and 13C NMR (75 MHz) spectra
were recorded in CDCl3 unless otherwise noted and chemical
shifts are given in ppm relative to CDCl3 (7.27 ppm for 1H
NMR and 77.23 ppm for 13C NMR). Column chromatography
was performed with ICN 32-66 nm, 60 Å silica gel using flash
column techniques. All reactions were performed in flame-
dried glassware under an atmosphere of Ar unless otherwise
noted.
Aceta te 3. Butenolide (-)-2 (66 mg, 0.27 mmol) was placed
into a 100 mL round-bottom flask and dissolved in CH2Cl2 (20
mL). The mixture was cooled to -78 °C, and DIBALH (0.4 mL,
0.4 mmol) was added dropwise via syringe. The reaction was
stirred at -78 °C for 1.5 h or until the disappearance of
starting material was noted by TLC (silica gel, 3:1 hexanes/
ethyl acetate). Pyridine (0.06 mL, 0.8 mmol), DMAP (65 mg,
0.53 mmol) in a minimal amount of CH2Cl2, and acetic
anhydride (0.1 mL, 1.0 mmol) were added respectively, and
the solution was warmed to 0 °C for 4 h. The reaction mixture
was quenched with a saturated solution of Rochelle’s salt (50
mL), extracted with CH2Cl2, dried with MgSO4, and concen-
trated. The crude oil was purified by flash column chroma-
tography (10:1 hexanes/ethyl acetate) to yield acetate 3 (66
mg, 0.23 mmol, 85%) as a clear oil and as a 1:1 mixture of
diastereomers: Rf 0.46 (25% ethyl acetate in hexanes); IR
(neat) ν 1734 cm-1; 1H NMR δ 7.29 (m, 10H, both diast.), 6.84
(s, 1H), 6.66 (s, 1H), 6.11 (m, 4H, both diast.), 4.59 (s, 2H),
4.56 (s, 2H), 3.71 (m, 2H), 3.55 (m, 2H) 3.42 (m, 4H, both
diast.), 2.06 (s, 3H), 1.99 (s, 3H), 1.15 (t, J ) 6.9 Hz, 6H, both
diast.); 13C NMR δ 170.5, 170.1, 138.3, 138.1, 136.6, 134.4,
133.7, 130.2, 128.4, 128.4, 127.7, 127.6, 115.2, 114.1, 100.6,
99.0, 74.0, 73.9, 73.7, 73.5, 58.8, 58.4, 21.4, 15.6, 15.5.
Rin g-Op en ed P r od u ct 4. Dimethyl malonate (36 µL, 0.319
mmol) was added via syringe to a slurry of NaH (7.3 mg, 0.183
mmol, 60% in mineral oil) in THF (0.10 mL) in a 25 mL round-
bottom flask. The suspension bubbled for 2 min and then
subsided. Acetate 3 (30 mg, 0.103 mmol), allylpalladium
chloride (2.1 mg, 0.006 mmol, 5.5%), 1,2-bis(diphenylphosphi-
no)ethane (dppe) (6.4 mg, 0.016 mmol, 15.6%), and THF (0.1
mL) were placed into a second 25 mL flask and stirred for 5
min. The contents of the second flask were transferred to the
flask containing the NaH suspension via cannula needle, using
THF (0.2 mL) to rinse. The yellow/orange mixture turned a
dark orange after a few min. The reaction was monitored using
TLC (silica gel, 4:1 hexanes/ethyl acetate) and was finished
with the disappearance of starting material. After 3.5 h, the
reaction solution was diluted with CH2Cl2 (10 mL) and then
distilled H2O (10 mL). The aqueous layer was extracted with
(S,S) Ligand 7 proved highly effective in promoting
selective amination of â-3 by a range of purine and
pyrimidine bases, to produce â-4′-substituted nucleoside
analogues. Excellent yields of recovered R-3 were also
obtained (Table 1).
Both the products 6a -d and recovered starting mate-
rial R-3 were diastereoisomerically pure by H1 NMR
spectroscopy. Only guanine failed to react effectively.
Although â-3 was completely consumed and R-3 was
recovered in excellent yield, the base-containing products
were obtained as an inseparable mixture of several
components. Of the bases, uracil was by far the most
reactive, converting â-3 to 6c in less than 3h at 0 °C.
(When run at room temperature, some conversion of R-3
to R-6c was noted.)
Because R- and â-3 are diastereoismers rather than
enantiomers, the selectivity of R,R-7 need not mirror the
selectivity of S,S-7. Indeed in the reaction of 3 with
thymine, R,R-7 was much less selective for R-3 than S,S-7
was for â-3. Well before complete consumption of R-3, the
â-diastereoisomer began to convert, giving a mixture of
R- and â-6a .
Equilibration of R-3 back to a mixture of R- and â-
isomers would allow recycling of 3 with the eventual
conversion of both isomers to â-6. If this equilibration
could be carried out concurrent with the coupling, a one-
pot conversion of both diastereomeric acetates to the
â-nucleoside analogue would be possible. Unfortunately,
this could not be achieved. Subsequent epimerization of
the remaining R-acetate also proved difficult, with a wide
(22) See Table 6, Supporting Information, for details.

4′-Ethoxy-2′,3′-didehydro-2′,3′-dideoxynucleosides
J . Org. Chem., Vol. 67, No. 12, 2002 4079
CH2Cl2 (3 × 20 mL), and the organic layers were combined,
dried with Mg2SO4, and concentrated to give a brown oil.
Analysis of the crude 1H NMR spectrum showed no starting
material present and no indication of the desired product.
Alk yla t ion w it h Dim et h yl Met h ylm a lon a t e (5). Di-
methyl methylmalonate (23 µL, 0.172 mmol) was added via
syringe to a slurry of NaH (7.0 mg, 0.287 mmol, 60% in min-
eral oil) in THF (0.10 mL) in a 25 mL round-bottom flask.
After 5 min a mixture of the acetate 3 (25 mg, 0.086 mmol,
dr 55:45, R:â), allylpalladium chloride (3.12 mg, 0.009 mmol,
10%), and dppe (6.8 mg, 0.017 mmol, 20%) in THF (0.3 mL)
were transferred via cannula needle to the flask. The reac-
tion mixture turned orange, and then dark red after 5 min.
After being stirred at room temperature for 3 h, the reac-
tion mixture was diluted with CH2Cl2 and distilled H2O. The
layers were separated, and the aqueous layer was extracted
with CH2Cl2 (3 × 25 mL). The combined organic layers were
dried with MgSO4, filtered, and concentrated. Flash column
chromatography (10:1 hexanes/ethyl acetate) gave 5 as a
clear oil as a 55:45 (R:â) mixture of diastereomers (26 mg,
0.069 mmol, 82%.): Rf 0.42 (25% ethyl acetate in hexanes);
1.18 (t, J ) 6.9 Hz, 3H); 13C NMR δ 164.2, 151.3, 151.1, 137.7,
137.4, 136.5, 136.2, 135.4, 134.0, 131.3, 129.0, 128.7, 128.6,
128.2, 128.0, 127.9, 127.9, 114.2, 112.5, 111.4, 111.2, 88.7, 87.9,
73.7, 73.7, 72.9, 70.7, 58.9, 57.9, 15.5, 15.3, 12.6, 11.9. Anal.
Calcd for C19H22N2O5: C, 63.67; H, 6.18; N, 7.82. Found: C,
63.62; H, 6.07; N, 7.58.
Am in a tion w ith Th ym in e a n d S,S-7 (â-6a ). TBAF‚3H2O
(54 mg, 0.171 mmol) was weighed into a 5 mL round-bottom
flask and dried under vacuum for approximately 1 h. The
TBAF was dissolved in DMF (0.10 mL) and transferred via
syringe to a 10 mL round-bottom flask containing 4 Å MS and
was stirred for 45 min at room temperature. Thymine (27 mg,
0.214 mmol) and BSA (27 µL, 0.11 mmol) were placed in a 15
mL round-bottom flask and stirred for 10 min. Pd2(dba)3‚CHCl3
(8.9 mg, 0.0086 mmol, 5.0%) and 7 (12 mg, 0.017 mmol, 10%)
were weighed into a 15 mL Schlenk tube containing a stir bar.
First, the contents of the flask containing silylated base were
transferred via syringe to the reaction flask. The addition of
acetate 3 (50.8 mg, 0.171 mmol) via syringe to the reaction
tube followed. Last, the TBAF solution was transferred via
syringe to the reaction tube. The reaction mixture was light
yellow/orange in color and gradually darkened to a deep red
upon completion. The reaction’s progress was checked by the
analysis of the crude 1H NMR spectrum of isolated aliquots.
After 16 h the reaction was complete. The DMF was removed
under reduced pressure leaving a dark brown oil. The oil was
taken up in ethyl acetate and washed with brine. The brine
was extracted with ethyl acetate (3 × 50 mL). The organic
layers were combined and washed with brine, dried with
MgSO4, and concentrated. The crude oil was purified by flash
column chromatography (20:1 hexanes/ethyl acetate to 1:1
hexanes/ethyl acetate) producing 6a as a white solid (mp
133-135 °C), with a diastereomeric ratio of <97:3 (â:R) in 49%
(21 mg, 0.054 mmol) and recovering R-3 with a diastereomeric
ratio of <97:3 (R:â) in 41% (22 mg, 0.075 mmol): Spectral data
for â-6a : Rf 0.45 (5% CH3OH in CH2Cl2); [R]D +43 (c 0.9,
1
IR (neat) ν 1734 cm1; H NMR δ 7.34 (m, 10H, both diast.),
6.31 (dd, J ) 6.0, 1.2 Hz, 1H), 6.26 (dd, J ) 6.0, 1.2 Hz,
1H), 5.99 (dd, J ) 6.3, 2.4 Hz, 1H), 5.91 (dd, J ) 6.0, 2.4
Hz, 1H), 5.47 (dd, J ) 2.4, 1.5 Hz, 1H), 5.29 (t, J ) 2.1
Hz, 1H), 4.59 (m, 4H, both diast.), 3.78 (d, J ) 5.1 Hz,
1H), 3.76 (d, J ) 4.8 Hz, 1H), 3.72 (s, 12H, both diast.),
3.67 (d, J ) 6.0 Hz, 1H), 3.65 (d, J ) 4.2 Hz, 1H), 3.43 (m, 4H,
both diast.), 1.45 (s, 3H), 1.34 (s, 3H), 1.19 (t, J ) 6.9 Hz, 3H),
1.18 (t, J ) 6.9 Hz, 3H); 13C NMR δ 171.2, 170.1, 138.3, 134.4,
133.7, 130.2, 128.4, 128.4, 127.7, 127.6, 115.2, 114.1, 100.6,
99.0, 74.0, 73.9, 73.8, 73.5, 60.6, 58.8, 58.4, 21.4, 21.3, 15.6,
15.5, 14.4.
P a lla d iu m -Ca ta lyzed Am in a tion of 3. Am in a tion w ith
Th ym in e a n d d p p f (r,â-6a ). Tetra-n-butylammonium fluo-
ride hydrate (TBAF‚3H2O) (21 mg, 0.068 mmol) was weighed
into a 10 mL round-bottom flask and dried under vacuum for
approximately 1 h. It was then dissolved in dry DMF (0.10
mL) and transferred via syringe to a 15 mL round-bottom flask
containing 4 Å MS and stirred for 45 min at room temperature.
A second 15 mL round-bottom flask was charged with the
thymine base (11 mg, 0.085 mmol) and N,O-bis(trimethylsilyl)-
methane (BSA) (11 µL, 0.044 mmol) in DMF (0.10 mL) and
stirred for 10 min. A 25 mL Schlenk tube was equipped with
1
CHCl3); IR (neat) ν 1694 cm-1; H NMR δ 8.19 (bs, 1H), 7.54
(s, 1H), 7.32 (m, 5H), 7.11 (s, 1H), 6.13 (s, 2H), 4.58 (s, 2 H),
3.75 (s, 2H), 3.49 (m, 1H), 3.39 (m, 1H), 1.48 (s, 3H), 1.18 (t, J
) 7.2 Hz, 3H); 13C NMR δ 163.8, 151.0, 137.5, 136.6, 134.2,
131.2, 128.8, 128.3, 128.0, 114.3, 111.2, 88.8, 73.8, 73.0, 58.0,
15.4, 12.0. Anal. Calcd for C19H22N2O5: C, 63.67; H, 6.18; N,
7.82. Found: C, 63.48; H, 6.29; N, 7.76.
Am in a tion w ith Cytosin e a n d S,S-7 (â-6b). TBAF‚3H2O
(55 mg, 0.174 mmol) was weighed into a 5 mL round-bottom
flask and dried under vacuum for approximately 1 h. The
TBAF was dissolved in DMF (0.10 mL) and transferred via
syringe to a 10 mL round-bottom flask containing 4 Å MS
which was stirred for 45 min at room temperature. Cytosine
(24 mg, 0.218 mmol) and BSA (28 µL, 0.113 mmol) were placed
in a 15 mL round-bottom flask and stirred for 40 min.
Pd2(dba)3‚CHCl3 (12 mg, 0.017 mmol, 5.0%) and 7 (9 mg,
0.0087 mmol, 10%) were weighed into a 15 mL Schlenk tube
containing a stir bar. First, acetate 3 (51 mg, 0.174 mmol) was
added to the reaction tube via syringe followed by the contents
of the flask containing the silylated base. Last, the TBAF
solution was transferred via syringe to the reaction tube. The
reaction mixture was light yellow/orange in color and gradually
darkened to a deep red upon completion. The reaction’s pro-
a
stir bar and charged with tris(dibenzylideneacetone)-
dipalladium(0)-chloroform adduct (Pd2(dba)3‚CHCl3) (3.5 mg,
0.0034 mmol, 5.0%) and 1,1-bis(diphenylphosphino)ferrocene
(dppf) (3.8 mg, 0.0068 mmol, 10%). First, acetate 3 (15.4 mg,
0.068 mmol) in DMF (0.10 mL) was added to the Schlenk tube
via syringe. Next, the silylated base was transferred via
syringe to the reaction tube. Last, the TBAF in DMF was
transferred via syringe to the reaction flask. The reaction
mixture was light yellow in color and gradually darkened to a
deep red upon completion. The reaction’s progress was moni-
tored by the consumption of the starting material by TLC
(silica gel, 3:1 hexanes/ethyl acetate) and of aliquots taken
from the reaction mixture. After the reaction was completed,
the DMF was removed under reduced pressure leaving a dark
brown oil. The oil was taken up in ethyl acetate and washed
with brine. The brine was extracted with ethyl acetate (3 ×
50 mL). The organic layers were combined and washed with
brine, dried with MgSO4, and concentrated. The crude oil was
purified by flash column chromatography (10:1 hexanes/ethyl
acetate; 4:1 hexanes/ethyl acetate; 1:1 hexanes/ethyl acetate)
to yield the allylated thymine product 6a as a 55:45 (R:â)
mixture of diastereomers (7.0 mg, 38%) and as a white solid
(mp 107-109 °C). 3 was recovered as a 65:35 (â:R) mixture of
diastereomers in 53% yield (8.2 mg, 0.028 mmol): Spectral
data for 6a : Rf 0.45 (5% CH3OH in CH2Cl2); IR (neat) ν 1695
1
gress was checked by the analysis of the crude H NMR spec-
trum of isolated aliquots. After 16 h the reaction was complete.
The DMF was removed under reduced pressure leaving a dark
brown oil. The oil was taken up in ethyl acetate and washed
with brine. The brine was extracted with ethyl acetate (3 ×
50 mL). The organic layers were combined and washed with
brine, dried with MgSO4, and concentrated. The crude oil was
purified by flash column chromatography (20:1 hexanes/ethyl
acetate to 1:1 hexanes/ethyl acetate then 1% CH3OH/CH2Cl2)
and produced 6b as a white solid (mp 164-166 °C) with a
diastereomeric ratio of <97:3 (â:R) in 51% (30 mg, 0.087 mmol)-
and recovered R-3 as a diastereomeric ratio of <97:3 (R:â) in
44% (23.3 mg, 0.076 mmol): Spectral data for â-6b: Rf 0.27
(5% CH3OH in CH2Cl2); [R]D +38 (c 0.9, CHCl3); IR (neat) ν
1
cm-1; H NMR δ 8.01 (bs, 2H, both diast.), 7.53 (s, 1H), 7.32
(m, 11 H, both diast.), 7.11 (s, 1H), 6.91 (s, 1H), 6.39 (dd, J )
5.7, 1.5 Hz, 1H), 6.13 (s, 2H), 6.03 (dd, J ) 5.7, 1.5 Hz, 1H),
4.60 (d, J ) 2.4 Hz, 2H), 4.57 (s, 2H), 3.84 (d, J ) 10.2 Hz,
1H), 3.75 (s, 2H), 3.62 (m, 2H), 3.50 (d, J ) 10.2 Hz, 1 H), 3.41
(m, 2H), 1.92 (s, 3H), 1.27 (s, 3H) 1.20 (t, J ) 6.9 Hz, 3H),
1
2923, 2853, 1650 cm-1; H NMR δ 7.87 (d, J ) 7.2 Hz, 1H),
7.31 (m, 5H), 7.24 (s, 1H), 6.19 (d, J ) 5.7 Hz, 1H), 6.02 (dd,

4080 J . Org. Chem., Vol. 67, No. 12, 2002
Hegedus et al.
J ) 6.0, 1.8 Hz, 1H), 5.30 (bs 2H) 5.15 (d, J ) 7.5 Hz, 1H),
4.57 (d, J ) 11.1 Hz, 1H), 4.52 (d, J ) 11.1 Hz, 1H) 3.77 (s,
2H) 3.49 (m, 1H), 3.39 (m, 1H), 1.17 (t, J ) 7.2 Hz, 3H); 13C
NMR (100 MHz) δ 165.8, 156.4, 142.5, 137.7, 132.6, 132.5,
128.7, 128.2, 128.1, 114.3, 94.4, 90.0, 73.8, 73.1, 57.8, 15.4;
HRFABMS (M + H) calculated for C18H22N3O4: 344.1622;
found 344.1610.
stir bar. First, acetate 3 (55 mg, 0.190 mmol) was added to
the reaction tube via syringe, followed by the flask containing
the silylated base. Last, the addition of the TBAF solution via
syringe was added to the reaction flask. The reaction mixture
was light yellow/orange in color and gradually darkened to a
deep red upon completion. The reaction’s progress was checked
by the analysis of the crude 1H NMR spectrum of isolated
aliquots. After 16 h the reaction was complete. The DMF was
removed under reduced pressure leaving a dark brown oil. The
oil was taken up in ethyl acetate and washed with brine. The
brine was extracted with ethyl acetate (3 × 50 mL). The
organic layers were combined and washed with brine, dried
with MgSO4, and concentrated. The crude oil was purified by
flash column chromatography (20:1 hexanes/ethyl acetate to
1:1 hexanes/ethyl acetate then 1% CH3OH/CH2Cl2 to 3%) and
Am in a tion w ith Ur a cil a n d S,S-7 (â-6c). TBAF‚3H2O (55
mg, 0.171 mmol) was weighed into a 5 mL round-bottom flask
and dried under vacuum for approximately 1 h. The TBAF
was dissolved in DMF (0.10 mL) and transferred via syringe
to a 10 mL round-bottom flask containing 4 Å MS which stirred
for 45 min at room temperature. Uracil (24 mg, 0.218 mmol)
and BSA (28 µL, 0.113 mmol) were placed in a 15 mL round-
bottom flask and stirred for 10 min. Pd2(dba)3‚CHCl3 (12 mg,
0.017 mmol, 5.0%) and 7 (9 mg, 0.0087 mmol, 10%) were
weighed into a 15 mL Schlenk tube containing a stir bar. The
reaction tube was cooled to 0 °C before the addition of acetate
3 (51 mg, 0.174 mmol) via syringe. Next, the silylated base
was added to the reaction tube via syringe followed by the
addition of TBAF via syringe. The reaction mixture was light
yellow/orange in color and gradually darkened to a deep red
upon completion. The reaction’s progress was checked by the
analysis of the crude 1H NMR spectrum of isolated aliquots.
After 3 h the reaction was complete. The DMF was removed
under reduced pressure leaving a dark brown oil. The oil was
taken up in ethyl acetate and washed with brine. The brine
was extracted with ethyl acetate (3 × 50 mL). The organic
layers were combined and washed with brine, dried with
MgSO4, and concentrated. The crude oil was purified by flash
column chromatography (20:1 hexanes/ethyl acetate to 1:1
hexanes/ethyl acetate then 1% CH3OH/CH2Cl2) and produced
6c as a white solid (mp 146-148 °C) with a diastereomeric
ratio of <97:3 (â:R) in 49% (29.6 mg, 0.086 mmol) and
recovered R-3 as a diastereomeric ratio of <97:3 (R:â) in 44%
(22.5 mg, 0.077 mmol): Spectral data for â-6c: Rf 0.55 (5%
CH3OH in CH2Cl2); [R]D +17 (c 0.6, CHCl3); IR (neat) ν 1694,
produced â-6d as a tan solid (mp 112-115 °C) with
a
diastereomeric ratio of <97:3 (â:R) in 38% (21 mg, 0.057 mmol)
and recovered R-3 as a diastereomeric ratio of <97:3 (R:â) in
39% (21 mg, 0.072 mmol): Spectral data for â-6d : Rf : 0.36
(5% CH3OH in CH2Cl2); [R]D +27 (c 0.8, CHCl3); IR (neat) ν
1645, 1598 cm-1; 1H NMR δ 8.39 (s, 1H), 8.10 (s, 1H), 7.29 (m,
5H), 7.20 (s, 1H), 6.32 (d, J ) 6.0 Hz, 1H), 6.22 (dd, J ) 6.0,
1.8 Hz, 1H), 5.75 (bs, 2H), 4.58 (d, J ) 12.0 Hz, 1H), 4.50 (d,
J ) 12.0 Hz, 1H), 3.72 (d, J ) 10.2 Hz, 1H), 3.63 (d, J ) 10.2
Hz, 1H), 3.58 (m, 1H), 3.44 (m, 1H), 1.20 (t, J ) 6.9 Hz, 3H);
13C NMR (100 MHz) δ 155.6, 153.3, 139.5, 134.3, 130.3, 128.7,
128.2, 115.1, 94.6, 87.2, 73.7, 72.8, 58.1, 29.9, 15.4; Anal. Calcd
for C19H21N5O3: C, 62.11; H, 5.76; N, 19.06. Found: C, 61.99;
H, 5.64; N, 18.94.
Ep im er iza tion of r-3. A 10 mL round-bottom flask was
equipped with a stir bar and dried under argon. R-3 (21.1 mg,
0.072 mmol) was diluted with acetic acid (0.5 mL) and
transferred via syringe to the reaction flask. Zinc acetate (13.2
mg, 0.072 mmol) was then added to the reaction flask. The
reaction stirred at 35 oC for 12 h. The acetic acid was removed
under reduced pressure, and the resulting yellow oil was
dissolved with CH2Cl2. The crude mixture was washed with
brine, and then the brine was extracted with CH2Cl2 (2 × 25
mL). The organic layers were combined, dried with Mg2SO4,
and concentrated. The crude oil was purified by flash column
chromatography (10:1 hexanes/ethyl acetate) to give 3 with a
diastereomeric ratio of 60:40 (R:â) in 92% (19 mg, 0.065 mmol).
1
2359 cm-1; H NMR δ 8.38 (bs, 1H), 7.62 (d, J ) 8.4 Hz, 1H),
7.25 (m, 5H), 7.02 (s, 1H), 6.05 (dd, J ) 5.7, 1.8 Hz, 1H), 6.01
(d, J ) 5.7 Hz, 1H), 5.03 (d, J ) 8.1 Hz, 1H), 4.47 (d, J ) 11.1
Hz, 1H), 4.41 (d, J ) 10.8 Hz, 1H), 3.72 (d, J ) 9.9 Hz, 1H),
3.67 (d, J ) 10.2 Hz, 1H), 3.42 (m, 1H), 3.31 (m, 1H), 1.10 (t,
J ) 6.9 Hz, 3H); 13C NMR δ 163.1, 150.9, 141.2, 137.3, 134.4,
131.0, 128.8, 128.5, 128.4, 114.5, 102.4, 88.8, 74.0, 73.1, 58.0,
15.4. Anal. Calcd for C19H20N2O5: C, 62.78; H, 5.85; N, 8.13.
Found: C, 62.89; H, 5.65; N, 8.28.
Ack n ow led gm en t. Support for this research under
Grant No. GM26178 from the National Institutes of
General Medical Sciences (Public Health Service) is
gratefully acknowledged. Mass spectra were obtained
on instruments supported by the National Institutes of
Health shared instrumentation grant GM49631.
Am in a tion w ith Ad en in e a n d S,S-7 (â-6d ). TBAF‚3H2O
(60 mg, 0.190 mmol) was weighed into a 5 mL round-bottom
flask and dried under vacuum for approximately 1 h. The
TBAF was dissolved in DMF (0.10 mL) and transferred via
syringe to a 10 mL round-bottom flask containing 4 Å MS
which stirred for 45 min at room temperature. Adenine (32
mg, 0.238 mmol) and BSA (30 µL, 0.120 mmol) were placed in
a 15 mL round-bottom flask and stirred for 45 min. Pd2(dba)3‚
CHCl3 (9.8 mg, 0.0095 mmol, 5.0%) and 7 (13 mg, 0.019 mmol,
10%) were weighed into a 15 mL Schlenk tube containing a
Su p p or tin g In for m a tion Ava ila ble: Tables 1-6, 1H and
13C NMR spectra of 3, 5, 6, 6a , 6b, 6c, 6d , and full X-ray data
for 6a . This material is available free of charge via the Internet
at http://pubs.acs.org.
J O011074B