Stereoselective synthesis of 2'-amino-2',3'-dideoxynucleosides by nitrone 1,3-dipolar cycloaddition: A new efficient entry toward d4T and its 2-methyl analogue

Article abstract of DOI:10.1021/jo972264i

An efficient access to 2'-(dimethylamino)-2',3'-dideoxynucleosides is reported. The synthetic strategy relies on the 1,3-dipolar cycloaddition of C-alkoxycarbonyl nittones to allyl acetate, followed by reductive ring opening to substituted lactones, DIBALH reduction to the corresponding 3- (dimethylamino)tetrahydro-2-furanols, and coupling with silylated thymine. The removal of the dimethylamino group by Cope elimination affords a new formal synthesis of d4T and analogous unsaturated 2',3'-dideoxynucleosides.

Full text of DOI:10.1021/jo972264i

28
J . Org. Chem. 1999, 64, 28-36
Ster eoselective Syn th esis of 2′-Am in o-2′,3′-d id eoxyn u cleosid es by
Nitr on e 1,3-Dip ola r Cycloa d d ition : A New Efficien t En tr y Tow a r d
d 4T a n d Its 2-Meth yl An a logu e†
Ugo Chiacchio,*,‡ Antonio Rescifina,‡ Daniela Iannazzo,§ and Giovanni Romeo§
Dipartimento di Scienze Chimiche, Viale A. Doria 6, Universita` di Catania, Italy, and
Dipartimento Farmaco-Chimico, Viale SS. Annunziata, Universita` di Messina, Italy
Received December 15, 1997
An efficient access to 2′-(dimethylamino)-2′,3′-dideoxynucleosides is reported. The synthetic strategy
relies on the 1,3-dipolar cycloaddition of C-alkoxycarbonyl nitrones to allyl acetate, followed by
reductive ring opening to substituted lactones, DIBALH reduction to the corresponding 3-(di-
methylamino)tetrahydro-2-furanols, and coupling with silylated thymine. The removal of the
dimethylamino group by Cope elimination affords a new formal synthesis of d4T and analogous
unsaturated 2′,3′-dideoxynucleosides.
Sch em e 1
In tr od u ction
The development of new methodologies enabling the
synthesis of unnatural nucleosides plays a significant role
in the search for new antitumor and antiviral agents.
Following the discovery of AZT, DDC, DDI, and d4T as
potent antiviral agents1 acting as competitive inhibitors
of the viral reverse transcriptase (RT),2 the preparation
of modified nucleosides with structural alterations in the
heterocyclic ring, the sugar moiety, or both has become
a very active research area, and new synthetic methods
have been designed and developed.3
sugars with nucleoside bases, eventually followed by
formation of a double bond at the 2′,3′ position.
Saturated and unsaturated 2′,3′-dideoxynucleosides,
containing different functionalities and lacking the 3′-
hydroxyl group, are expected to terminate viral DNA
synthesis after their incorporation in the chains.4 In this
context, a number of recent synthetic efforts have been
focused on this type of nucleoside analogue.5 The syn-
theses are largely classified into two approaches. The first
is based on the structural modification of the sugar part
of intact nucleosides available from natural sources, and
the second consists of the coupling of suitably modified
In connection with our previous reports on the syn-
thesis of 2(5H)furanones,6 involving the 1,3-dipolar cy-
cloaddition of C-alkoxycarbonyl nitrones 1, followed by
reductive ring opening of the N,O-heterocyclic nucleus
to unsaturated γ-lactones 2, we have now extended this
utility to provide a new and direct entry to nucleoside
analogues 3, containing an amino function at the 2′
positions.7 Furthermore, the synthetic scheme employed
can be directed toward the synthesis of modified unsat-
urated 2′,3′-dideoxynucleoside 4 (Scheme 1).
† Second German-Italian Symposium, May 29-J une 1, 1997,
Goslar, Germany.
Resu lts a n d Discu ssion
‡ Universita` di Catania.
§ Universita` di Messina.
The synthetic design, reported in Scheme 2, involved
the formation of a key intermediate, the tetrahydrofuran
acetate 11, which could then be condensed with various
nucleoside bases. Our experiments were carried out as
follows. The initial 1,3-dipolar cycloaddition of nitrone 5
with allyl acetate at 75 °C for 48 h in a sealed tube
afforded an epimeric mixture of 5-substituted isoxazo-
lidines 6 (95% yield) as exclusive adducts. It is note-
(1) Huryn, D. M.; Okabe, M. Chem. Rev. 1992, 92, 1745.
(2) (a) De Clercq, E. J . Med. Chem. 1995, 38, 2491. (b) Schinazi, R.
F.; Mead, J . R.; Feorino, P. M. AIDS RES. Hum. Retroviruses 1992, 8,
963.
(3) (a) Weaver, R.; Gilbert, I. H. Tetrahedron 1997, 53, 5537. (b)
Talekar, R. R.; Wightman, R. H. Tetrahedron 1997, 53, 3831. (c) Gi,
H. J .; Xiang, Y.; Schinazi, R. F.; Zhao, K. J . Org. Chem. 1997, 62, 82.
(4) (a) Kilby, J . M.; Saag, M. S. Infect. Med. 1966, 13, 903. (b) J ones,
R. S.; Gelone, S. P. Hosp. Med. 1977, 33, 31.
(5) (a) Sujino, K.; Yoshida, T.; Sugimura, H. Tetrahedron Lett. 1996,
37, 6133. (b) Beach, J . W.; Kim, H. O.; J eong, L. S.; Nampalli, S.; Islam,
Q.; Ahn, S. K.; Babu, J . R.; Chu, C. K. J . Org. Chem. 1992, 57, 3887.
(c) McDonald, F. E.; Gleason, M. M. Angew. Chem., Int. Ed. Engl. 1995,
34, 350. (d) Chao, Q.; Nair, V. Tetrahedron 1997, 53, 1957. (e)
Haraguchi, K.; Tanaka, Y. I.; Yamaguchi, K.; Miyasaka, T. J . Org.
Chem. 1996, 61, 851. (f) Bonaffe`, D.; Dupraz, B.; Ughetto-Monfrin, J .;
Namane, A.; Henin, Y.; Dinh, T. H. J . Org. Chem. 1996, 61, 895. (g)
Bar, N. C.; Patra, R.; Achari, B.; Mandal, S. B. Tetrahedron 1997, 53,
4727. (h) Niihata, S.; Ebata, T.; Kawakami, H.; Matsushita, H. Bull.
Chem. Soc. J pn. 1995, 68, 1509. (i) Giri, I.; Bolon, P. J .; Chu, C. K.
Nucleosides Nucleotides 1996, 15, 183. (j) Chiacchio, U.; Gumina, G.;
Rescifina, A.; Romeo, R.; Uccella, N.; Casuscelli, F.; Piperno, A.; Romeo,
G. Tetrahedron 1996, 52, 8889.
(6) (a) Chiacchio, U.; Di Bella, M. R.; Rescifina, A.; Romeo, G.;
Uccella, N. Heterocycles 1993, 36, 2209. (b) Casuscelli, F.; Chiacchio,
U.; Di Bella, M. R.; Rescifina, A.; Romeo, G.; Romeo, R.; Uccella, N.
Tetrahedron 1995, 51, 8605. (c) Chiacchio, U.; Romeo, G.; Uccella, N.
Trends Hetrocycl. Chem. 1995, 4, 261. (d) Casuscelli, F.; Di Bella, M.
R.; Ficarra, R.; Melardi, S.; Romeo, G.; Chiacchio, U.; Rescifina, A.
Gazz. Chim. It. 1997, 127, 367.
(7) (a) McGee, D. P. C.; Vaughn-Settle, A.; Vargeese, C.; Zhai, Y. J .
Org. Chem. 1996, 61, 781. (b) Bera, S.; Pathak, T.; Langley, G. J .
Tetrahedron 1995, 51, 1459. (c) Wu, J -C.; Pathak, T.; Tong, W.; Vial,
J -M.; Remaud, G.; Chattopadhyaya, J . Tetrahedron 1988, 44, 6705.
10.1021/jo972264i CCC: $18.00 © 1999 American Chemical Society
Published on Web 12/19/1998

Synthesis of 2′-Amino-2′,3′-dideoxynucleosides
J . Org. Chem., Vol. 64, No. 1, 1999 29
Sch em e 2a
a
Reaction conditions: (a) allyl acetate, 75 °C, 48 h; (b) TfOMe, CCl4, 0 °C, 3 h; (c) H2, Pd/C, 70 °C, 36 h; (d) TBDPSCl, imidazole,
CH2Cl2, 0 °C, 3 h; (e) DIBALH, toluene, -78 °C, 3 h; (f) AcCl, pyridine, CH2Cl2, 0 °C, 4 h; (g) O,O′-bis(trimethylsilyl)thymine, SnCl4,
CH2Cl2, overnight; (h) TBAF, THF, 3 h.
worthy that the 1,3-dipolar cycloaddition proceeded with
a good stereoselectivity giving the trans isomer 6a as the
major product (3:1 ratio). Treatment of 6a with methyl
triflate, leading to 7, followed by catalytic hydrogenation
(H2/Pd in methanol), gave the cis 3-(dimethylamino)-5-
(hydroxymethyl)dihydro-2(3H)-furanone (8) in 88% yield.
Its formation is the result of the intramolecular lacton-
ization following the reductive ring opening and involving
the CO2Et group at position 3 in the N,O-ring. After
protection of the C5 hydroxyl group with TBDPSCl, direct
reduction of 9 with DIBALH (1.2 equiv) provided the
epimeric lactols 10; acetylation of 10 led to a readily
separable mixture of the acetates 11a and 11b in 46%
global yield starting from nitrone 5.
Compounds 11a and 11b were obtained in a 1:3
relative ratio; the respective configurations were deter-
mined by 1H NMR NOE experiments. Thus, whereas 11b
showed NOE correlation between H1 and H4, no NOE
effects between the same protons have been observed for
11a .
We next explored the coupling reaction with silylated
thymine according to the procedure of Niedballa and
Vorbru¨ggen.8 Nucleosidation, which occurred in high
yields (96-98%), was carried out in dichloromethane at
0 °C in the presence of SnCl4 as catalyst and proceeded
with a very high stereoselectivity to afford nearly exclu-
sively a single isomer, i.e., 12a (â-isomer) from 11a and
12b (R-isomer) from 11b. The 1H NMR of the crude
reaction mixture reveals only traces (∼1:40 relative ratio)
of the other stereoisomer.
equivocal configuration of the H4′ proton as reference.
Thus, â-nucleosides 12a and 13a show NOE correlations
between H1′-H4′, H2′-H3′b, and H3′b-H4′, whereas R-
nucleosides 12b and 13b showed NOE effects between
H2′-H3′a and H3′a-H4′.
The generality of the synthetic scheme has also been
tested by the preparation of the 2′-methyl analogue,
starting from C-methoxycarbonyl-C,N-dimethyl nitrone
(14) (Scheme 3). The reaction with allyl acetate gave rise
to a 1:1.2 mixture of adducts 15 (as observed by 1H NMR),
which was reacted with methyl triflate, subjected to
hydrogenolytic ring cleavage to afford lactones 17, and
then protected at the hydroxyl function by treatment with
TBDPSCl to afford 18a and 18b, which have been
separated by flash chromatography. The subsequent
DIBALH reduction proceeded with complete stereoselec-
tivity to give exclusively tetrahydro-2-furanols 19a (from
18a ) and 19b (from 18b).
The stereochemistry of 19a and 19b has been deter-
mined by NOE experiments. Irradiation of H4 in 19b gave
rise to a NOE effect for H1, the methyl group at C2, and
the downfield resonance of the methylene proton at C3,
thereby indicating a cis relationship of these protons.
Conversely, in compound 19a , no NOE on H1 was
observed by irradiation of H4, whereas positive NOE
enhancement is evidenced for the N-Me2 group and the
aromatic protons.
Compounds 19a and 19b were then acetylated and
coupled with silylated thymine to give, after deprotection
of the CH2OH group at C5′, the nucleosides 22a and 22b.
This method may be applied to other pyrimidine and
purine nucleosides to synthesize the corresponding 2-ami-
noribonucleoside analogues.
The reported methodology has been further investi-
gated to provide a new efficient entry toward unsaturated
2′,3′-dideoxynucleosides. Thus, d4T (24) and its methyl
analogue 26 were synthesized after elimination of the
Finally, deprotection of compounds 12 with TBAF gave
the modified 2′,3′-dideoxynucleosides 13 in a quantitative
yield.
The stereochemistry of thymine analogues 12 and 13
was determined by NOE experiments, using the un-
(8) Niedballa, U.; Vorbru¨ggen, H. Angew. Chem., Int. Ed. Engl. 1975,
34, 350.

30 J . Org. Chem., Vol. 64, No. 1, 1999
Chiacchio et al.
Sch em e 3a
a
Reaction conditions: (a) allyl acetate, 75 °C, 48 h; (b) TfOMe, CCl4, 0 °C, 3 h; (c) H2, Pd/C, 70 °C, 36 h; (d) TBDPSCl, imidazole,
CH2Cl2, 0 °C, 3 h; (e) DIBALH, toluene, -78 °C, 3 h; (f) AcCl, pyridine, CH2Cl2, 0 °C, 4 h; (g) O,O′-bis(trimethylsilyl)thymine, SnCl4,
CH2Cl2, overnight; (h) TBAF, THF, 3 h.
Sch em e 4a
Sch em e 5a
a
Reaction conditions: (a) m-CPBA, CH2Cl2, 0 f 25 °C, 3.5 h;
(b) DIBALH, toluene, -78 °C, 3 h; (c) AcCl, piridine, CH2Cl2, 0
°C, 4 h.
a
Reaction conditions: (a) m-CPBA, CH2Cl2, 0 f 50 °C, 3.5 h;
(b) TBAF, THF, 3 h.
stereoselective reduction of the cis lactone 9 (10a :10b
ratio ) 1:3). Nonetheless, we have overcome the problem
by performing the epimerization of 9 with DBU, followed
by DIBALH reduction, which afforded a mixture of the
tetrahydro-2-furanols (31; 3:1 ratio). After conversion into
the corresponding acetyl derivatives, 32a and 32b were
separated, and then 32a was transformed into d4T
through the 2′-dimethylamino nucleoside 33a , according
to the above-reported procedure. Moreover, 33a can be
also converted in 34a by reaction with TBAF (Scheme
6).
In conclusion, the novel [3 + 2] cycloaddition method-
ology outlined herein provides an efficient access to 2′-
dimethylaminonucleosides; furthermore, the reaction can
be directed toward the synthesis of unsaturated 2′,3′-
dideoxynucleosides. The designed scheme constitutes an
N-dimethylamino group in 12a and 21a , respectively,
performed according to a Cope elimination by treatment
with m-CPBA (60-65% yield) followed by TBAF treat-
ment (Scheme 4).5b,c,9
The alternative approach to synthesize 24 and 26, by
introduction of the unsaturated bond before the coupling
reaction with the silylated thymine, has been explored
with unsuccessful results. In fact, DIBALH reduction of
the butenolide 27, obtained via Cope elimination from
18a , afforded the compound 28 which on further acety-
lation furnished the tert-butyl[((4-methyl)-2-furyl)methoxy]-
diphenylsilane (29) (Scheme 5). Previous publications
describe 2,3-unsaturated pentafuranosides as sensitive
to both acidic and basic conditions, leading to furan
derivatives.10
This reported procedure for the synthesis of d4T is,
however, weakened by the consideration that the tet-
rahydro-2-furanyl acetate precursor 11a (Scheme 2) is
obtained only as a minor product during the DIBALH
(10) (a) Chu, C. K.; Babu, J . R.; Beach, J . W.; Ahn, S. K.; Huang,
H.; J eong, L. S.; Lee, S. J . J . Org. Chem. 1990, 55, 1418. (b) Abdel-
Megied, A. E. S.; Pedersen, E. B.; Nielsen, C. M. Synthesis 1991, 313.
(c) Hildesheim, J .; Cle´ophax, J .; Ge´ro, S. D. Tetrahedron Lett. 1967,
1685. (d) Koll, P.; Deyhim, S. Chem. Ber. 1978, 111, 2913. (e) Horwitz,
J . P.; Chua, J .; Da Rooge, M. A.; Noel, M.; Kundt, I. L. J . Org. Chem.
1996, 31, 205.
(9) (a) Matsuda, A.; Okajima, A.; Kakefuda, A.; Yoshimura, Y.; Ueda,
T. Nucleosides Nucleotides 1992, 11, 197. (b) Diaz, Y.; El-Laghdach,
A.; Matheu, M. I.; Castillo´n, S. J . Org. Chem. 1997, 62, 1501.

Synthesis of 2′-Amino-2′,3′-dideoxynucleosides
J . Org. Chem., Vol. 64, No. 1, 1999 31
Sch em e 6a
a
Reaction conditions: (a) DBU, benzene, 80 °C, 4 h; (b) DIBALH, toluene, -78 °C, 3 h; (c) AcCl, pyridine, CH2Cl2, 0 °C, 4 h; (d)
O,O′-bis(trimethylsilyl)thymine, SnCl4, CH2Cl2, overnight; (e) TBAF, THF, 3 h; (f) m-CPBA, CH2Cl2, 0 f 25 °C, 3.5 h.
excellent alternative to previously reported approaches
and shows its versatility in the potential construction of
other nucleosides with different purine and pyrimidine
bases. Additionally, hydrogenation of the 2′,3′-double
bond could represent an alternative synthetic pathway
to saturated dideoxynucleosides as DDC, DDI, and 3TC.11
Exploitations of the scope and potential of this synthetic
scheme, in the aim of the obtainment of optically active
dideoxynucleosides, are also in progress.
Further eluted product was 6b (0.943 g, 24%) as a
colorless oil: 1H NMR (CDCl3, 200 MHz) δ 1.26 (t, 3H, J
) 7.2 Hz), 2.09 (s, 3H), 2.26 (m, 1H, H4), 2.65 (m, 1H,
H4), 2.78 (s, 3H), 3.43 (m, 1H, H3), 4.13 (dd, 1H, J ) 6.3,
12.5 Hz), 4.20 (q, 2H, J ) 7.2 Hz), 4.22 (dd, 1H, J ) 4.1,
12.5 Hz), 4.36 (m, 1H, H5); 13C NMR (CDCl3, 50 MHz) δ
14.0, 20.4, 24.1, 41.1, 60.1, 62.4, 67.9, 75.2. Anal. Calcd
for C10H17NO5: C, 51.94; H, 7.41; N, 6.06. Found: C,
51.97; H, 7.45; N, 6.09.
(3RS,5RS)-5-({[1-(ter t-Bu tyl)-1,1-diph en ylsilyl]oxy}-
m e t h y l)-3-(d im e t h y la m in o )d ih y d r o -2(3H )-fu r a -
n on e (9). A solution of 6a (3.00 g, 13 mmol) and methyl
trifluoromethanesulfonate (1.75 mL, 15.6 mmol) in dry
CCl4 was stirred at 0 °C for 3 h. At the end of this time,
the reaction mixture was evaporated under reduced
pressure, and the residue, identified as (3RS,5RS)-5-
[(acetyloxy)methyl]-3-etoxycarbonyl-2,2-dimethylisoxazo-
lidinium trifluoromethanesulfonate (7) (100% yield, sticky
oil), was used in the next step without further purifica-
Exp er im en ta l Section
Gen er a l P r oced u r es. Melting points are uncorrected.
NMR spectra were recorded at 200 or 500 MHz (1H) and
at 50 or 125 MHz (13C) and are reported in ppm downfield
from TMS. Thin-layer chromatography was done on
Merck coated plate 60 F254. Silica gel chromatography
was done with Acros (0.035-0.07 mm). All reactions
involving air-sensitive agents were conducted under
nitrogen atmosphere. All reagents were purchased from
Aldrich or Acros Chimica and were used without further
purification. Solvents for chromatography were distilled
at atmospheric pressure prior to use and dried using
standard procedures. Nitrones 5 and 14 were prepared
according to literature method.12
1
tion. H NMR (CDCl3, 200 MHz) δ 1.36 (t, 3H, J ) 7.2
Hz), 2.15 (s, 3H), 3.03 (m, 1H, H4), 3.24 (m, 1H, H4), 3.67
(s, 6H), 4.02 (m, 2H), 4.39 (q, 2H, J ) 7.2 Hz), 4.85 (m,
1H, H3), 5.01 (m, 1H, H5); 13C NMR (CDCl3, 50 MHz) δ
13.7, 19.2, 30.5, 51.7, 56.5, 62.7, 64.4, 77.4, 83.3, 163.1,
163.5.
(3RS,5RS)- a n d (3RS,5SR)-5-[(Acetyloxy)m eth yl]-
3-et h oxyca r b on yl-2-m et h yl isoxa zolid in e (6a a n d
6b). A solution of C-ethoxycarbonyl-N-methyl nitrone (5)
(2.25 g, 17 mmol) in allyl acetate (40 mL) was heated at
75 °C, in a sealed tube, for 48 h. The reaction mixture
(6a :6b epimeric ratio ) 3:1) was evaporated, and the
residue was purified by column chromatography (cyclo-
hexane/ethyl acetate 7:3). First eluted fraction give 6a
(2.78 g, 71%) as a colorless oil: 1H NMR (CDCl3, 200
MHz) δ 1.30 (t, 3H, J ) 7.2 Hz), 2.10 (s, 3H), 2.28 (m,
1H, H4), 2.61 (m, 1H, H4), 2.81 (s, 3H), 3.35 (m, 1H, H3),
4.05 (dd, 1H, J ) 6.4, 12.6 Hz), 4.23 (q, 2H, J ) 7.2 Hz),
4.25 (dd, 1H, J ) 3.9, 12.6 Hz), 4.34 (m, 1H, H5); 13C NMR
(CDCl3, 50 MHz) δ 14.1, 19.2, 21.1, 34.6, 61.59, 63.9, 69.2,
78.2, 168.1, 170.0. Anal. Calcd for C10H17NO5: C, 51.94;
H, 7.41; N, 6.06. Found: C, 51.98; H, 7.39; N, 6.08.
A solution of 7 (3.93 g, 10 mmol) in 50 mL of methanol
was stirred under a hydrogen atmosphere with 10% Pd
on activated carbon for 36 h at 70 °C. After removal of
catalyst by Celite filtration, to the filtrate was added 10
mL of a 10% NaHCO3 aqueous solution. The solvent was
evaporated under reduced pressure, and the residue was
than purified by column chromatography (CHCl3/MeOH
97:3) to give (3RS,5RS)-3-(dimethylamino)-5-(hydroxy-
methyl)dihydro-2(3H)-furanone (8) (1.39 g, 88%) as a
light yellow oil: 1H NMR (CDCl3, 200 MHz) δ 2.26 (m,
2H, H4), 2.43 (s, 6H), 3.02 (bs, 1H), 3.63 (m, 1H, H3), 3.91
(m, 2H), 4.49 (m, 1H, H5); 13C NMR (CDCl3, 50 MHz) δ
25.0, 41.8, 63.2, 64.1, 77.5, 174.6. Anal. Calcd for C7H13
-
NO3: C, 52.82; H, 8.23; N, 8.80. Found: C, 52.96; H, 8.25;
N, 8.78.
A mixture of 8 (2.52 g, 15.8 mmol), tert-butyldiphenyl-
silyl chloride (TBDPSCl, 4.53 mL, 17.4 mmol), and
imidazole (2.37 g, 34.8 mmol) in dry CH2Cl2 (50 mL) was
stirred for 3 h at 0 °C. The solvent was evaporated, and
the residue was purified by silica gel column (cyclohex-
ane/ethyl acetate 1:1) to give 9 (5.48 g, 87%) as a clear
oil: 1H NMR (CDCl3, 500 MHz) δ 1.07 (s, 9H), 2.19 (ddd,
(11) (a) Manchand, P. S.; Belica, P. S.; Holman; M. J .; Huang, T.
N.; Maehr, H.; Tam, S. Y. K.; Yang, R. T. J . Org. Chem. 1992, 57, 3473.
(b) Mansuri, M. M.; Starrett, J . E., J r.; Wos, J . A.; Tortolani, D. R.;
Brodfuehrer, P. R.; Howell, H. G.; Martin, J . C. J . Org. Chem. 1989,
54, 4780.
(12) Inouye, Y.; Takaya, K.; Kakisawa, H. Bull. Chem. Soc. J pn.
1983, 56, 3541.

32 J . Org. Chem., Vol. 64, No. 1, 1999
Chiacchio et al.
1H, J ) 6.0, 8.5, 12.5 Hz, H4a), 2.33 (ddd, 1H, J ) 11.0,
12.5, 12.5 Hz, H4b), 2.43 (s, 6H), 3.72 (dd, 1H, J ) 8.5,
12.5, Hz, H3), 3.75 (dd, 1H, J ) 3.6, 11.6 Hz), 3.93 (dd,
1H, J ) 3.1, 11.6 Hz), 4.41 (dddd, 1H, J ) 3.1, 3.6, 6.0,
11.0 Hz, H5), 7.39-7.69 (m, 10H); 13C NMR (CDCl3, 125
MHz) δ 19.2, 24.3, 26.7, 41.6, 64.2, 64.3, 76.7, 127.8,
129.9, 132.6, 133.0, 135.5, 135.6, 174.6. Anal. Calcd for
C23H31NO3Si: C, 69.48; H, 7.86; N, 3.52. Found: C, 69.33;
H, 7.84; N, 3.50.
21.6, 26.7, 30.6, 44.9, 67.0, 69.2, 80.5, 95.2, 127.6, 129.6,
133.2, 133.3, 135.48, 135.53, 170.7; MS (FAB) m/z 442
(MH+).
1-[(2SR,3RS,5RS)-3-(Dim eth yla m in o)-5-(h yd r oxy-
m eth yl)tetr a h yd r o-2-fu r a n yl]-th ym in e (13a ). Under
a nitrogen atmosphere, O,O′-bis(trimethylsilyl)thymine
(0.820 g, 3.0 mmol) and 11a (0.265 g, 0.6 mmol) were
dissolved in anhydrous CH2Cl2 (5 mL). This solution was
cooled to 0 °C, and SnCl4 (1.0 mmol) was added. The
mixture was then warmed to room temperature, left to
stir overnight, and finally, poured slowly into a mixture
of cold saturated aqueous NaHCO3 (5 mL) and CHCl3 (10
mL). The resulting emulsion was separated by filtration
through Celite, the aqueous layer was extracted further
with ethyl acetate (3 × 10 mL), and the combined organic
layers were dried over Na2SO4 and evaporated under
reduced pressure. The residue was purified by silica gel
column chromatography (CHCl3/MeOH 9:1) to afford
1-[(2SR,3RS,5RS)-5-({[1-(tert-butyl)-1,1-diphenylsilyl]-
oxy}methyl)-3-(dimethylamino)tetrahydro-2-furanyl]th-
ymine (12a ) (0.292 g, 96%) as a white foam: 1H NMR
(CDCl3, 500 MHz) δ 1.07 (s, 9H), 1.90 (s, 3H), 2.09 (ddd,
1H, J ) 6.2, 7.6, 12.1 Hz, H3′a), 2.15 (ddd, 1H, J ) 9.1,
10.2, 12.1 Hz, H3′b), 2.34 (s, 6H), 3.38 (ddd, 1H, J )
7.3,7.6, 10.2 Hz, H2′), 3.70 (dd, 1H, J ) 4.0, 11.0 Hz, H5′),
3.77 (dd, 1H, J ) 4.0, 11.0 Hz, H5′), 4.40 (dddd, 1H, J )
4.0, 4.0, 6.2, 9.1 Hz, H4′), 6.04 (d, 1H, J ) 7.3 Hz, H1′),
7.05 (s, 1H, H6), 7.36-7.68 (m, 10H), 9.73 (bs, 1H); 13C
NMR (CDCl3, 125 MHz) δ 12.5, 19.2, 26.8, 42.3, 65.7,
69.5, 79.4, 87.1, 110.9, 127.7, 129.7, 133.2, 133.3, 135.57,
135.62, 136.2, 150.3, 163.9. Anal. Calcd for C28H37N3O4-
Si: C, 66.24; H, 7.35; N, 8.28. Found: C, 66.30; H, 7.36;
N, 8.29.
To a THF solution (5 mL) of 12a (0.173 g, 0.34 mmol)
was added TBAF (0.375 mL, 0.37 mmol; 1 M solution in
THF), and the mixture was stirred at room temperature
for 3 h. At the end of this time, the solvent was removed,
and the residue was subjected to silica gel column
chromatography (CHCl3/MeOH 9:1) give 13a (0.091 g,
99%) as a white solid: mp 129-133 °C; 1H NMR (CDCl3,
500 MHz) δ 1.94 (d, 3H, J ) 1.2 Hz), 2.13 (ddd, 1H, J )
6.1, 6.2, 10.4 Hz, H3′a), 2.17 (ddd, 1H, J ) 6.2, 6.2, 10.4
Hz, H3′b), 2.38 (s, 6H), 2.63 (bs, 1H), 3.13 (ddd, 1H, J )
3.9, 6.2, 6.2 Hz, H2′), 3.56 (dd, 1H, J ) 3.5, 12.3 Hz, H5′),
3.85 (dd, 1H, J ) 2.6, 12.3 Hz, H5′), 4.62 (dddd, 1H, J )
2.6, 3.5, 6.1, 6.2 Hz, H4′), 6.07 (d, 1H, J ) 3.9 Hz, H1′),
7.08 (d, 1H, J ) 1.2 Hz, H6), 9.07 (bs, 1H); 13C NMR
(CDCl3, 125 MHz) δ 12.7, 29.3, 29.7, 43.2, 64.2, 70.4, 81.3,
(2SR,3RS,5RS) a n d (2RS,3RS,5RS)-5-({[1-(ter t-Bu -
tyl)-1,1-d ip h en ylsilyl]oxy}m eth yl)-3-(d im eth yla m i-
n o)tetr a h yd r o-2-fu r a n yl a ceta te (11a a n d 11b). To
a stirred solution of 9 (1.99 g, 5 mmol) in anhydrous
toluene (10 mL) at -78 °C under nitrogen was added
DIBALH (10 mL, 1.0 M solution in toluene) dropwise
while the reaction temperature was mantained below
-70 °C. The reaction mixture was stirred for 3h and then
was quenched with ethyl acetate (1 mL). The mixture
was left to warm to room temperature, water (1 mL) was
added, and the mixture was stirred for 3 h. The solvent
was removed under reduced pressure, and the residue
was purified by silica gel column chromatography (CHCl3/
MeOH 95:5) to afford an anomeric mixure (1:3) of
(2RS,3RS,5RS) and (2SR,3RS,5RS)-5-({[1-(tert-butyl)-
1,1-diphenylsilyl]oxy}methyl)-3-(dimethylamino)tetrahy-
dro-2-furanol (10) (1.80 g, 90%). Minor isomer: 1H NMR
(CDCl3, 200 MHz) δ 1.05 (s, 9H), 1.67 (m, 1H, H3), 2.04
(m, 1H, H3), 2.24 (s, 6H), 2.82 (m, 1H, H2), 3.75 (m, 2H,
H5), 3.95 (bs, 1H), 4.35 (m, 1H, H4), 5.37 (d, 1H, J ) 3.0
Hz, H1), 7.36-7.71 (m, 10H); 13C NMR (CDCl3, 50 MHz)
δ 19.1, 26.8, 31.8, 43.4, 65.8, 73.4, 78.0, 100.9, 127.6,
129.6, 133.4, 135.6. Major isomer: 1H NMR (CDCl3, 200
MHz) δ 1.07 (s, 9H), 1.75 (m, 1H, H3), 2.07 (m, 1H, H3),
2.28 (s, 6H), 2.58 (m, 1H, H2), 3.73 (m, 2H, H5), 3.94 (bs,
1H), 4.22 (m, 1H, H4), 5.20 (d, 1H, J ) 4.0 Hz, H1), 7.33-
7.71 (m, 10H); 13C NMR (CDCl3, 50 MHz) δ 19.1, 26.8,
30. 8, 34.4, 67.3, 69.9, 79.2, 95.2, 127.6, 129.6, 133.3,
135.6.
To a solution of acetyl chloride (0.195 mL, 2.75 mmol)
and pyridine (0.21 mL, 2.63 mmol) in CH2Cl2 (10 mL) at
0 °C under nitrogen was added dropwise a dichlo-
romethane solution (10 mL) of lactols 10 (1.00 g, 2.5
mmol). The reaction mixture was stirred for 4 h; the
solvent was removed under reduced pressure, and the
residue was purified by silica gel chromatography (CHCl3/
MeOH 97:3). First eluted product was a colorless oil
which was identified as 11b (0.784 g, 71%): 1H NMR
(CDCl3, 500 MHz) δ 1.07 (s, 9H), 1.86 (ddd, 1H, J ) 7.8,
9.7, 13.5 Hz, H3), 2.07 (s, 3H), 2.15 (ddd, 1H, J ) 5.8,
7.8, 13.5 Hz, H3), 2.26 (s, 6H), 3.15 (ddd, 1H, J ) 2.4,
2.4, 7.8 Hz, H2), 3.76 (dd, 1H, J ) 5.2, 10.8 Hz, H5), 3.84
(dd, 1H, J ) 4.6, 10.8 Hz, H5), 4.29 (dddd, 1H, J ) 4.6,
5.2, 5.8, 9.7 Hz, H4), 6.24 (d, 1H, J ) 2.4 Hz, H1) 7.37-
7.70 (m, 10H); 13C NMR (CDCl3, 125 MHz) δ 19.2, 21.3,
26.8, 30.4, 42.8, 65.1, 71.5, 79.8, 99.7, 127.6, 129.6, 133.3,
135.56, 135.59, 170.1; MS (FAB) m/z 442 (MH+). Further
eluted product was 11a (0.265 g, 24%) as a colorless oil:
1H NMR (CDCl3, 500 MHz) δ 1.05 (s, 9H), 1.89 (ddd, 1H,
J ) 9.5, 11.5, 12.1 Hz, H3), 1.96 (s, 3H), 2.20 (ddd, 1H, J
) 6.3, 6.9, 11.5 Hz, H3), 2.29 (s, 6H), 2.72 (ddd, 1H, J )
4.1, 6.9, 12.1 Hz, H2), 3.66 (dd, 1H, J ) 5.2, 10.6 Hz, H5),
3.74 (dd, 1H, J ) 5.4, 10.6 Hz, H5), 4.31 (dddd, 1H, J )
5.2, 5.4, 6.3, 9.5 Hz, H4), 6.25 (d, 1H, J ) 4.1 Hz, H1),
7.32-7.71 (m, 10H); 13C NMR (CDCl3, 125 MHz) δ 19.2,
89.1, 111.0, 135.6, 150.2, 163.8. Anal. Calcd for C12H19
-
N3O4: C, 53.52; H, 7.11; N, 15.60. Found: C, 54.03; H,
7.14; N, 15.62.
1-[(2RS,3RS,5RS)-3-(Dim eth yla m in o)-5-(h yd r oxy-
m eth yl)tetr a h yd r o-2-fu r a n yl]-th ym in e (13b). Under
a nitrogen atmosphere, O,O′-bis(trimethylsilyl)thymine
(0.820 g, 3.0 mmol) and 11b (0.265 g, 0.6 mmol) were
dissolved in anhydrous CH2Cl2 (5 mL). This solution was
cooled to 0 °C, and SnCl4 (1.0 mmol) was added. The
mixture was then warmed to room temperature, left to
stir overnight, and finally, poured slowly into a mixture
of cold saturated aqueous NaHCO3 (5 mL) and CHCl3 (10
mL). The resulting emulsion was separated by filtration
through Celite, the aqueous layer was extracted further
with ethyl acetate (3 × 10 mL), and the combined organic
layers were dried over Na2SO4 and evaporated under
reduced pressure. The residue was purified by silica gel
column chromatography (CHCl3/MeOH 9:1) to afford

Synthesis of 2′-Amino-2′,3′-dideoxynucleosides
J . Org. Chem., Vol. 64, No. 1, 1999 33
1-[(2RS,3RS,5RS)-5-({[1-(tert-butyl)-1,1-diphenylsilyl]-
oxy}methyl)-3-(dimethylamino)tetrahydro-2-furanyl]th-
ymine (12b) (0.298 g, 98%) as a white foam: 1H NMR
(CDCl3, 200 MHz) δ 1.07 (s, 9H), 1.91 (d, 3H, J ) 0.9
Hz), 2.15-2.28 (m, 2H, H3′), 2.44 (s, 6H), 3.66-3.84 (m,
3H, H2′ and H5′), 4.47 (m, 1H, H4′), 6.03 (d, 1H, J ) 6.3
Hz, H1′), 7.13 (q, 1H, J ) 0.9 Hz, H6), 7.34-7.69 (m, 10H),
9.99 (bs, 1H); 13C NMR (CDCl3, 50 MHz) δ 12.4, 19.2,
26.8, 29.6, 41.7, 65.2, 69.3, 80.1, 87.9, 111.0, 127.7, 129.8,
A solution of 16 (3.93 g, 10 mmol) in 50 mL of methanol
was stirred under hydrogen atmosphere with 10% Pd on
activated carbon for 36 h at 70 °C. After removal of
catalyst by Celite filtration, to the filtrate was added 10
mL of a 10% NaHCO3 aqueous solution. The solvent was
evaporated under reduced pressure, and the residue was
than purified by column chromatography (CHCl3/MeOH
97:3) to give an epimeric mixture of 3-(dimethylamino)-
5-(hydroxymethyl)-3-methyldihydro-2(3H)-furanones (17)
(1.66 g, 96%) as a light yellow oil. Major isomer: 1H NMR
(CDCl3, 500 MHz) δ 1.37 (s, 3H), 1.96 (dd, 1H, J ) 8.5,
14.0 Hz, H4), 2.32 (s, 6H), 2.43 (dd, 1H, J ) 7.8, 14.0 Hz,
H4), 3.59 (dd, 1H, J ) 4.0, 12.5 Hz), 3.90 (dd, 1H, J )
2.5, 12.5 Hz), 4.60 (dddd, 1H, J ) 2.5, 4.0, 7.8, 8.5 Hz,
H5), 4.73 (bs, 1H); 13C NMR (CDCl3, 125 MHz) δ 19.9,
33.1, 39.3, 63.5, 64.5, 77.8, 177.6. Minor isomer: 1H NMR
(CDCl3, 500 MHz) δ 1.39 (s, 3H), 2.01 (dd, 1H, J ) 7.5,
13.5 Hz, H4), 2.35 (s, 6H), 2.48 (dd, 1H, J ) 6.7, 13.5 Hz,
H4), 3.64 (dd, 1H, J ) 3.5, 12.5 Hz), 3.95 (dd, 1H, J )
3.5, 12.5 Hz), 4.55 (dddd, 1H, J ) 3.5, 3.5, 6.7, 7.5 Hz,
H5), 4.71 (bs, 1H); 13C NMR (CDCl3, 125 MHz) δ 18.6,
32.0, 39.0, 63.2, 64.4, 77.1, 177.3.
A mixture of 17 (2.73 g, 15.8 mmol), tert-butyldiphe-
nylsilyl chloride (TBDPSCl, 4.53 mL, 17.4 mmol), and
imidazole (2.37 g, 34.8 mmol) in dry CH2Cl2 (50 mL) was
stirred for 3 h at 0 °C. The solvent was evaporated, and
the residue was purified by silica gel column (cyclohex-
ane/ethyl acetate 1:1). First eluted fraction was 18a (3.05
g, 47%) as a clear oil: 1H NMR (CDCl3, 500 MHz) δ 1.06
(s, 9H), 1.37 (s, 3H), 2.06 (dd, 1H, J ) 8.0, 13.5 Hz, H4a),
2.32 (s, 6H), 2.40 (dd, 1H, J ) 7.7, 13.5 Hz, H4b), 3.66
(dd, 1H, J ) 3.8, 11.8, Hz), 3.86 (dd, 1H, J ) 3.5, 11.8
Hz), 4.54 (dddd, 1H, J ) 3.5, 3.8, 7.7, 8.0 Hz, H5), 7.38-
7.68 (m, 10H); 13C NMR (CDCl3, 125 MHz) δ 19.2, 20.2,
26.7, 33.6, 39.4, 64.3, 64.6, 77.1, 127.8, 129.8, 132.7,
133.0, 135.5, 135.6, 177.2. Anal. Calcd for C24H33NO3Si:
C, 70.03; H, 8.08; N, 3.40. Found: C, 70.31; H, 8.07; N,
3.40. Further elution gave 18b (2.79 g, 43%) as a clear
oil: 1H NMR (CDCl3, 500 MHz) δ 1.06 (s, 9H), 1.45 (s,
3H), 1.77 (dd, 1H, J ) 6.9, 12.7 Hz, H4a), 2.34 (s, 6H),
2.52 (dd, 1H, J ) 10.1, 12.7 Hz, H4b), 3.73 (dd, 1H, J )
4.3, 11.5, Hz), 3.91 (dd, 1H, J ) 3.5, 11.5 Hz), 4.43 (dddd,
1H, J ) 3.5, 4.3, 6.9, 10.1 Hz, H5), 7.40-7.69 (m, 10H);
13C NMR (CDCl3, 125 MHz) δ 19.2, 22.2, 26.7, 29.5, 39.4,
64.3, 65.3, 76.3, 127.8, 129.9, 132.7, 132.9, 135.56, 135.64,
177.9. Anal. Calcd for C24H33NO3Si: C, 70.03; H, 8.08;
N, 3.40. Found: C, 70.09; H, 8.06; N, 3.40.
133.0, 135.5, 137.1, 150.6, 164.1. Anal. Calcd for C28H37
-
N3O4Si: C, 66.24; H, 7.35; N, 8.28. Found: C, 66.42; H,
7.33; N, 8.24.
To a THF solution (5 mL) of 12b (0.290 g, 0.34 mmol)
was added TBAF (0.375 mL, 0.37 mmol; 1 M solution in
THF), and the mixture was stirred at room temperature
for 3 h. At the end of this time, the solvent was removed,
and the residue was subjected to silica gel column
chromatography (CHCl3/MeOH 9:1) give 13b (0.092 g,
1
99%) as a white solid: mp 177-178 °C; H NMR (CD3-
OD, 500 MHz) δ 1.90 (d, 3H, J ) 1.2 Hz), 2.05 (ddd, 1H,
J ) 9.0, 9.4, 12.7 Hz, H3′a), 2.33 (ddd, 1H, J ) 5.8, 7.4,
12.7 Hz, H3′b), 2.46 (s, 6H), 3.54 (ddd, 1H, J ) 5.8, 5.9,
9.0 Hz, H2′), 3.55 (dd, 1H, J ) 4.5, 12.2 Hz, H5′), 3.72
(dd, 1H, J ) 3.4, 12.2 Hz, H5′), 4.54 (dddd, 1H, J ) 3.4,
4.5, 7.4, 9.4 Hz, H4′), 6.09 (d, 1H, J ) 5.9 Hz, H1′), 7.53
(q, 1H, J ) 1.2 Hz, H6); 13C NMR (CD3OD, 125 MHz) δ
12.4, 30.9, 43.4, 64.6, 71.3, 81.8, 89.0, 112.3, 138.37,
152.5, 163.7. Anal. Calcd for C12H19N3O4: C, 53.52; H,
7.11; N, 15.60. Found: C, 53.68; H, 7.13; N, 15.55.
5-Acetyloxym eth yl-2,3-d im eth yl-3-m eth oxyca r bo-
n yl isoxa zolid in es (15). A solution of C-methoxycarbo-
nyl-C,N-dimethyl nitrone (14) (2.25 g, 17 mmol) in allyl
acetate (40 mL) was heated at 75 °C, in a sealed tube,
for 48 h. The reaction mixture was evaporated, and the
residue was purified by column chromatography (cyclo-
hexane/ethyl acetate 7:3) to give 15 in a 1.2:1 epimeric
ratio (3.81 g, 97%) as a colorless oil. Major isomer: 1H
NMR (CDCl3, 200 MHz) δ 1.39 (s, 3H), 2.10 (s, 3H), 2.22
(dd, 1H, J ) 3.6, 12.8 Hz, H4), 2.65 (s, 3H), 2.91 (dd, 1H,
J ) 8.3, 12.8 Hz, H4), 3.76 (s, 3H) 4.15 (m, 2H), 4.31 (m,
1H, H5); 13C NMR (CDCl3, 50 MHz) δ 20.8, 38.6, 41.9,
52.0, 65.1, 69.6, 73.9, 170.8, 173.1. Minor isomer: 1H
NMR (CDCl3, 200 MHz) δ 1.41 (s, 3H), 1.82 (dd, 1H, J )
7.0, 12.6 Hz, H4), 2.09 (s, 3H), 2.63 (s, 3H), 2.64 (m, 1H,
H4), 3.75 (s, 3H), 4.13 (m, 2H), 4.28 (m, 1H, H5); 13C NMR
(CDCl3, 50 MHz) δ 19.3, 30.6, 38.8, 40.9, 52.3, 65.7, 70.4,
74.2, 170.8, 172.3; MS (FAB) m/z 232 (MH+).
1-[(2RS,3RS,5SR)-3-(Dim eth yla m in o)-5-(h yd r oxy-
m ethyl)-3-m eth yltetr ah ydr o-2-fur anyl]-thym in e (22a).
To a stirred solution of 18a (2.06 g, 5 mmol) in anhydrous
toluene (10 mL) at -78 °C under nitrogen was added
DIBALH (10 mL, 1.0 M solution in toluene) dropwise
while the reaction temperature was maintained below
-70 °C. The reaction mixture was stirred for 3h and then
was quenched with ethyl acetate (1 mL). The mixture
was left to warm to room temperature, water (1 mL) was
added, and the mixture was stirred for 3 h. The solvent
was removed under reduced pressure, and the residue
was purified by silica gel column chromatography (CHCl3/
MeOH 9:1) to afford (2SR,3RS,5SR)-5-({[1-(tert-butyl)-
1,1-diphenylsilyl]oxy}methyl)-3-(dimethylamino)-3-me-
thyltetrahydro-2-furanol (19a ) (1.78 g, 86%) as a colorless
oil: 1H NMR (CDCl3, 200 MHz) δ 1.03 (s, 3H), 1.06 (s,
9H), 1.66 (dd, 1H, J ) 4.3, 12.3 Hz, H3a) 2.07 (dd, 1H, J
) 10.0, 12.3 Hz, H3b), 2.24 (s, 6H), 3.66 (dd, 1H, J ) 5.4,
10.6 Hz, H5), 3.72 (dd, 1H, J ) 4.7, 10.6 Hz, H5), 4.42
(3RS,5SR)- a n d (3SR,5SR)-5-({[1-(ter t-Bu tyl)-1,1-
d ip h en ylsilyl]oxy}m eth yl)-3-(d im eth yla m in o)-3-m e-
th yld ih yd r o-2(3H)-fu r a n on e (18a a n d 18b). A solu-
tion of 15 (3.00 g, 13 mmol) and methyl trifluoromethane-
sulfonate (1.75 mL, 15.6 mmol) in dry CCl4 was stirred
at 0 °C for 3 h. At the end of this time, the reaction
mixture was evaporated under reduced pressure, and the
residue, identified as an epimeric mixture of 5-[(acetyl-
oxy)methyl]-3-metoxycarbonyl-2,2,3-trimethylisoxazolidinium
trifluoromethanesulfonates (16) (100% yield, sticky oil),
was used in the next step without further purification.
1H NMR (CDCl3, 200 MHz) δ 1.93 (s, 3H), 1.97 (s, 3H),
2.08 (s, 3H), 2.11 (s, 3H), 2.41 (m, 1H), 2.63 (m, 1H), 2.94
(m, 1H), 3.28 (m, 1H), 3.61 (s, 6H), 3.63 (s, 6H), 3.93 (s,
3H) 3.96 (s, 3H), 4.22-4.37 (m, 4H), 5.14 (m, 2H); 13C
NMR (CDCl3, 50 MHz) δ 20.5, 20.8, 35.1, 36.2, 51.4, 51,7,
54, 7, 54.9, 55.2, 61.6, 62.1, 81.9, 83.5, 168.2, 169.0, 171.6,
172.1.

34 J . Org. Chem., Vol. 64, No. 1, 1999
Chiacchio et al.
(dddd, 1H, J ) 4.3, 4.7, 5.4, 10.0 Hz, H4), 4.90 (s, 1H,
H1), 5.08 (bs, 1H), 7.34-7.71 (m, 10H); 13C NMR (CDCl3,
50 MHz) δ 13.3, 19.2, 26.8, 37.8, 40.1, 65.9, 68.1, 77.8,
101.2, 127.6, 129.6, 133.3, 135.6.
79.4, 90.0, 110.0, 136.7, 150.7, 164.2. Anal. Calcd for
C13H21N3O4: C, 55.11; H, 7.47; N, 14.83. Found: C, 54.99;
H, 7.48; N, 14.80.
1-[(2SR,3SR,5SR)-3-(Dim eth yla m in o)-5-(h yd r oxy-
m ethyl)-3-m eth yltetr ah ydr o-2-fur anyl]-thym in e (22b).
To a stirred solution of 18b (2.06 g, 5 mmol) in anhydrous
toluene (10 mL) at -78 °C under nitrogen was added
DIBALH (10 mL, 1.0 M solution in toluene) dropwise
while the reaction temperature was maintained below
-70 °C. The reaction mixture was stirred for 3h and then
was quenched with ethyl acetate (1 mL). The mixture
was left to warm to room temperature, water (1 mL) was
added, and the mixture was stirred for 3 h. The solvent
was removed under reduced pressure, and the residue
was purified by silica gel column chromatography (CHCl3/
MeOH 95:5) to afford (2RS,3SR, 5SR)-5-({[1-(tert-butyl)-
1,1-diphenylsilyl]oxy}methyl)-3-(dimethylamino)-3-me-
thyltetrahydro-2-furanol (19b) (1.88 g, 91%) as a colorless
oil: 1H NMR (CDCl3, 500 MHz) δ 1.03 (s, 3H), 1.06 (s,
9H), 1.73 (dd, 1H, J ) 9.5, 11.5 Hz, H3a) 1.80 (dd, 1H, J
) 6.8, 11.5 Hz, H3b), 2.20 (s, 6H), 3.66 (dd, 1H, J ) 6.5,
10.5 Hz, H5), 3.85 (dd, 1H, J ) 5.5, 10.5 Hz, H5), 4.25
(dddd, 1H, J ) 5.5, 6.5, 6.8, 9.5 Hz, H4), 4.83 (s, 1H, H1),
4.85 (bs, 1H), 7.35-7.69 (m, 10H); 13C NMR (CDCl3, 125
MHz) δ 11.7, 19.2, 26.8, 39.5, 39.7, 68.1, 68.1, 79.5, 100.9,
127.5, 129.5, 133.5, 133.6, 135.54, 135.56.
To a solution of acetyl chloride (0.195 mL, 2.75 mmol)
and pyridine (0.21 mL, 2.63 mmol) in CH2Cl2 (10 mL) at
0 °C under nitrogen was added dropwise a dichlo-
romethane solution (10 mL) of lactol 19b (1.03 g, 2.5
mmol). The reaction mixture was stirred for 4 h; the
solvent was removed under reduced pressure, and the
residue was purified by silica gel chromatography (cy-
clohexane/ethyl acetate 3:7) to give a colorless oil which
was identified as (2SR,3SR,5SR)-5-({[1-(tert-butyl)-1,1-
diphenylsilyl]oxy}methyl)-3-(dimethylamino)-3-methyltet-
rahydro-2-furanyl acetate (20b) (0.968 g, 85%): 1H NMR
(CDCl3, 500 MHz) δ 1.05 (s, 9H), 1.10 (s, 3H), 1.86 (dd,
1H, J ) 10.5, 11.5 Hz, H3), 1.94 (s, 3H), 1.97 (dd, 1H, J
) 6.5, 11.5 Hz, H3), 2.20 (s, 6H), 3.62 (dd, 1H, J ) 5.5,
10.0 Hz, H5), 3.75 (dd, 1H, J ) 6.1, 10.0 Hz, H5), 4.34
(dddd, 1H, J ) 5.5, 6.1, 6.5, 10.0 Hz, H4), 5.94 (s, 1H,
H1), 7.35-7.68 (m, 10H); 13C NMR (CDCl3, 125 MHz) δ
12.2, 19.1, 21.6, 26.8, 39.2, 40.1, 67.3, 67.9, 80.6, 100.1,
127.6, 129.6, 133.3, 133.5, 135.47, 135.50, 170.6; MS
(FAB) m/z 456 (MH+). Under a nitrogen atmosphere,
O,O′-bis(trimethilsilyl)thymine (0.820 g, 3.0 mmol) and
20b (0.273 g, 0.6 mmol) were dissolved in anhydrous CH2-
Cl2 (5 mL). This solution was cooled to 0 °C, and SnCl4
(1.0 mmol) was added. The mixture was then warmed to
room temperature, left to stir overnight, and finally,
poured slowly into a mixture of cold saturated aqueous
NaHCO3 (5 mL) and CHCl3 (10 mL). The resulting
emulsion was separated by filtration through Celite, the
aqueous layer was extracted further with ethyl acetate
(3 × 10 mL), and the combined organic layers were dried
over Na2SO4 and evaporated under reduced pressure. The
residue was purified by silica gel column chromatography
(CHCl3/MeOH 95:5) to afford 1-[(2SR,3SR,5SR)-5-({[1-
(tert-butyl)-1,1-diphenylsilyl]oxy}methyl)-3-(dimethylami-
no)-3-methyltetrahydro-2-furanyl]-thymine (21b) (0.282
g, 90%) as a white solid: mp 165-167 °C; 1H NMR
(CDCl3, 500 MHz) δ 1.01 (s,3H), 1.07 (s, 9H), 1.77 (dd,
1H, J ) 7.5, 13.5 Hz, H3′a), 1.94 (s, 3H), 2.27 (s, 6H), 2.42
(dd, 1H, J ) 6.0, 13.5 Hz, H3′b), 3.76 (dd, 1H, J ) 5.0,
10.0 Hz, H5′), 3.82 (dd, 1H, J ) 5.0, 10.0 Hz, H5′), 4.41
To a solution of acetyl chloride (0.195 mL, 2.75 mmol)
and pyridine (0.21 mL, 2.63 mmol) in CH2Cl2 (10 mL) at
0 °C under nitrogen was added dropwise a dichlo-
romethane solution (10 mL) of lactol 19a (1.03 g, 2.5
mmol). The reaction mixture was stirred for 4 h; the
solvent was removed under reduced pressure, and the
residue was purified by silica gel chromatography (CHCl3/
MeOH 95:5) to give a colorless oil which was identified
as (2RS,3RS,5SR)-5-([1-(tert-butyl)-1,1-diphenylsilyl]oxy-
methyl)-3-(dimethylamino)-3-methyltetrahydro-2-furanyl
acetate (20a ) (1.00 g, 88%): 1H NMR (CDCl3, 200 MHz)
δ 1.06 (s, 9H), 1.34 (s, 3H), 1.97 (dd, 1H, J ) 4.6, 12.3
Hz, H3a), 2.30 (s, 3H), 2.55 (s, 6H), 2.59 (dd, 1H, J ) 9.3,
12.3 Hz, H3b), 3.67 (dd, 1H, J ) 4.0, 11.3 Hz, H5), 3.77
(dd, 1H, J ) 4.3, 11.3 Hz, H5), 4.53 (dddd, 1H, J ) 4.0,
4.3, 4.6, 9.3 Hz, H4), 6.05 (s, 1H, H1) 7.34-7.70 (m, 10H);
13C NMR (CDCl3, 50 MHz) δ 15.9, 19.1, 21.5, 26.7, 35.6,
40.1, 64.4, 69.7, 79.1, 98.1, 127.7, 129.78, 129.82, 132.7,
135.5, 170.6; MS (FAB) m/z 456 (MH+). Under a nitrogen
atmosphere, O,O′-bis(trimethilsilyl)thymine (0.820 g, 3.0
mmol) and 20a (0.273 g, 0.6 mmol) were dissolved in
anhydrous CH2Cl2 (5 mL). This solution was cooled to 0
°C, and SnCl4 (1.0 mmol) was added. The mixture was
then warmed to room temperature, left to stir overnight,
and finally, poured slowly into a mixture of cold saturated
aqueous NaHCO3 (5 mL) and CHCl3 (10 mL). The
resulting emulsion was separated by filtration through
Celite, the aqueous layer was extracted further with ethyl
acetate (3 × 10 mL), and the combined organic layers
were dried over Na2SO4 and evaporated under reduced
pressure. The residue was purified by silica gel column
chromatography (cyclohexane/ethyl acetate 2:8) to afford
1-[(2RS,3RS,5SR)-5-({[1-(tert-butyl)-1,1-diphenylsilyl]-
oxy}methyl)-3-(dimethylamino)-3-methyltetrahydro-2-
furanyl]-thymine (21a ) (0.288 g, 92%) as a white solid:
mp 68-70 °C; 1H NMR (CDCl3, 200 MHz) δ 0.94 (s, 3H),
1.11 (s, 9H), 1.48 (d, 3H, J ) 1.2 Hz), 1.78 (dd, 1H, J )
11.6, 13.7 Hz, H3′), 2.23 (dd, 1H, J ) 4.4, 13.7 Hz, H3′),
2.38 (s, 6H), 3.85 (dd, 1H, J ) 3.5, 11.6 Hz, H5′), 4.14
(dd, 1H, J ) 2.6, 11.6 Hz, H5′), 4.35 (dddd, 1H, J ) 2.6,
3.5, 4.4, 11.6 Hz, H4′), 6.13 (s, 1H, H1′), 7.33-7.45 (m,
6H), 7.54 (q, 1H, J ) 1.2 Hz, H6), 7.64-7.72 (m, 4H), 9.13
(bs, 1H); 13C NMR (CDCl3, 50 MHz) δ 11.9, 19.5, 27.1,
36.7, 39.1, 64.2, 70.3, 79.2, 90.4, 110.3, 127.86, 127.90,
129.92, 130.0, 132.8, 133.4, 135.3, 135.4, 135.7, 150.6,
164.0. Anal. Calcd for C29H39N3O4Si: C, 66.76; H, 7.53;
N, 8.05. Found: C, 66.58; H, 7.53; N, 8.06.
To a THF solution (5 mL) of 21a (0.177 g, 0.34 mmol)
was added TBAF (0.375 mL, 0.37 mmol; 1 M solution in
THF), and the mixture was stirred at room temperature
for 3 h. At the end of this time, the solvent was removed,
and the residue was subjected to silica gel column
chromatography (CHCl3/MeOH 9:1) give 22a (0.095 g,
99%) as a white solid: mp 135-138 °C; 1H NMR (CDCl3,
200 MHz) δ 0.94 (s, 3H), 1.86 (dd, 1H, J ) 11.8, 14.1 Hz,
H3′), 1.89 (d, 3H, J ) 0.8 Hz), 2.21 (dd, 1H, J ) 4.6, 14.1
Hz, H3′), 2.39 (s, 6H), 2.86 (bs, 1H), 3.77 (dd, 1H, J )
3.4, 12.3 Hz, H5′), 4.14 (dd, 1H, J ) 2.4, 12.3 Hz, H5′),
4.36 (dddd, 1H, J ) 2.4, 3.4, 4.6, 11.8 Hz, H4′), 6.14 (s,
1H, H1′), 8.06 (q, 1H, J ) 0.8 Hz, H6), 9.27 (bs, 1H); 13C
NMR (CDCl3, 50 MHz) δ 11.8, 12.6, 35.5, 39.0, 61.9, 70.9,

Synthesis of 2′-Amino-2′,3′-dideoxynucleosides
J . Org. Chem., Vol. 64, No. 1, 1999 35
(dddd, 1H, J ) 5.0, 5.0, 6.0, 7.5 Hz, H4′), 616 (s, 1H, H1′),
7.08 (s, 1H, H6), 7.36-7.67 (m, 10H), 9.33 (bs, 1H); 13C
NMR (CDCl3, 125 MHz) δ 12.7, 13.1, 19.2, 26.8, 37.1,
39.5, 65.9, 69.1, 79.4, 90.3, 110.1, 127.6, 129.7, 133.3,
135.5, 136.1, 150.5, 163.9. Anal. Calcd for C29H39N3O4Si:
C, 66.76; H, 7.53; N, 8.05. Found: C, 66.90; H, 7.56; N,
8.08.
Using a procedure similar to that used for 22b, 25
(0.050 g, 0.105 mmol) was converted to a white foam
which was identified as 26 (0.025 g, 99%).9a
ter t-Bu tyl[(4-m eth yl-2-fu r yl)m eth oxy]d ip h en ylsi-
la n e (29). To an ice-cooled solution containing 0.165 g
(0.4 mmol) of 18a in 2 mL of CH2Cl2 was added a solution
containing 0.100 g (0.58 mmol) of m-CPBA in 5 mL of
CH2Cl2. After the addition was complete, the mixture was
stirred for additional 3 h at 25 °C, extracted with 10%
NaHCO3 solution, and dried over anhydrous Na2SO4. The
solvent was removed under reduced pressure to leave
behind a oil which was subjected to silica gel chroma-
tography (cyclohexane/ethyl acetate 85:15), giving a
colorless oil identified as (5SR)-({[1-(tert-butyl)-1,1-
diphenylsilyl]oxy}methyl)-3-methyl-2(5H)-furanone (27)
(0.145 g, 99%): 1H NMR (CDCl3, 200 MHz) δ 1.04 (s, 9H),
1.92 (s, 3H), 3.86 (m, 2H), 4.92 (m, 4H), 6.95 (m, 1H),
7.36-7.66 (m, 10H); MS (FAB) m/z 367 (MH+). Anal.
Calcd for C22H26O3Si: C, 72.09; H, 7.15. Found: C, 71.97;
H, 7.13.
To a THF solution (5 mL) of 21b (0.177 g, 0.34 mmol)
was added TBAF (0.375 mL, 0.37 mmol; 1 M solution in
THF), and the mixture was stirred at room temperature
for 3 h. At the end of this time, the solvent was removed,
and the residue was subjected to silica gel column
chromatography (CHCl3/MeOH 95:5) give 22b (0.096 g,
100%) as a white solid: mp 185-188 °C; 1H NMR (CDCl3,
200 MHz) δ 1.03 (s, 3H), 1.95 (d, 3H, J ) 1.0 Hz), 1.96
(dd, 1H, J ) 9.6, 14.4 Hz, H3′a), 2.43 (s, 6H), 2.47 (dd,
1H, J ) 2.2, 14.4 Hz, H3′b), 3.56 (dd, 1H, J ) 2.0, 12.0
Hz, H5′), 3.88 (dd, 1H, J ) 2.8, 12.0 Hz, H5′), 4.73 (dddd,
1H, J ) 2.0, 2.2, 2.8, 9.6 Hz, H4′), 5.63 (bs, 1H), 6.43 (s,
1H, H1′), 7.02 (q, 1H, J ) 1.0 Hz, H6), 10.17 (bs, 1H); 13
C
NMR (CDCl3, 50 MHz) δ 10.6, 12.8, 37.9, 39.2, 64.3, 70.5,
81.3, 90.7, 110.8, 134.9, 150.6, 164.1. Anal. Calcd for
C13H21N3O4: C, 55.11; H, 7.47; N, 14.83. Found: C, 55.28;
H, 7.47; N, 14.86.
To a stirred solution of 27 (0.092 g, 0.25 mmol) in
anhydrous toluene (2 mL) at -78 °C under nitrogen was
added DIBALH (0.5 mL, 1.0 M solution in toluene)
dropwise while the reaction temperature was maintained
below -70 °C. The reaction mixture was stirred for 3h
and then was quenched with ethyl acetate (0.2 mL). The
mixture was left to warm to room temperature, water
(0.2 mL) was added, and the mixture was stirred for 3 h.
The solvent was removed under reduced pressure, and
the residue was purified by silica gel column chromatog-
raphy (cyclohexane/ethyl acetate 8:2) to afford an ano-
meric mixture (1.5:1) of 5-({[1-(tert-butyl)-1,1-diphenylsilyl]-
oxy}methyl)-3-methyl-2,5-dihydro-2-furanol (28) (0.080 g,
87%) as a white solid: mp 102-104 °C. Major isomer:
1H NMR (CDCl3, 200 MHz) δ 1.06 (s, 9H), 1.88 (s, 3H),
3.29 (d, 1H, J ) 11.4 Hz, OH) 3.52 (dd, 1H, J ) 2.1, 11.1
Hz, H5), 3.82 (dd, 1H, J ) 3.3, 11.1 Hz, H5), 4.73 (dd, 1H,
J ) 2.1, 3.3 Hz, H4), 5.46 (s, 1H, H3), 5.65 (d, 1H, J )
11.4 Hz, H1), 7.36-7.68 (m, 10H). Minor isomer: 1H NMR
(CDCl3, 200 MHz) δ 1.05 (s, 9H), 1.81 (s, 3H), 2.76 (d,
1H, J ) 8.7 Hz, OH) 3.68 (m, 2H, H5), 4.94 (m, 1H, H4),
5.67 (m, 1H, H3), 5.83 (dd, 1H, J ) 3.9, 8.7 Hz, H1), 7.36-
7.68 (m, 10H).
1-[(2SR,5RS)-5-(H yd r oxym et h yl)-2,5-d ih yd r o-2-
fu r a n yl]-th ym in e (24).5b,9b To an ice-cooled solution
containing 0.092 g (0.2 mmol) of 12a in 2 mL of CH2Cl2
was added a solution containing 0.050 g (0.29 mmol) of
m-CPBA in 5 mL of CH2Cl2. After the addition was
complete, the mixture was stirred for 3 h at 25 °C and
an additional 0.5 h at 50 °C, extracted with 10% Na2CO3
solution, and dried over anhydrous Na2SO4. The solvent
was removed under reduced pressure to leave behind a
white foam which was subjected to silica gel chromatog-
raphy (CH2Cl2/MeOH 95:5), giving a thick syrup identi-
fied as compound 1-[(2SR,5RS)-5-({[1-(tert-butyl)-1,1-
diph en ylsilyl]oxy}m et h yl)-2,5-dih ydr o-2-fu r a n yl]-
thymine (23) (0.054 g, 60%) according to literature data.
Using a procedure similar to that used for 22b, 23
(0.050 g, 0.11 mmol) was converted to a white solid (mp
155-157 °C) which was identified as 24 (0.023 g,
95%).5b,9b
1-[(2RS,5SR)-5-(Hyd r oxym eth yl)-3-m eth yl-2,5-d i-
h yd r o-2-fu r a n yl]-th ym in e (26). To an ice-cooled solu-
tion containing 0.104 g (0.2 mmol) of 21a in 2 mL of
CH2Cl2 was added a solution containing 0.050 g (0.29
mmol) of m-CPBA in 5 mL of CH2Cl2. After the addition
was complete, the mixture was stirred for 3 h at 25 °C
and an additional 0.5 h at 50 °C, extracted with 10%
NaHCO3 solution, and dried over anhydrous Na2SO4. The
solvent was removed under reduced pressure to leave
behind a thick syrup which was subjected to silica gel
chromatography (CH2Cl2/MeOH 97:3), giving a white
foam identified as 1-[(2RS,5SR)-5-({[1-(tert-butyl)-1,1-
diphenylsilyl]oxy}methyl)-3-methyl-2,5-dihydro-2-furanyl]-
thymine (25) (0.062 g, 65%) according to its spectral
data: 1H NMR (CDCl3, 200 MHz) δ 1.00 (s, 9H), 1.46 (d,
3H, J ) 1.3 Hz), 1.70 (m, 3H), 3.84 (dd, 1H, J ) 4.4, 11.3
Hz, H5′), 3.87 (dd, 1H, J ) 4.0, 11.3 Hz, H5′), 4.86 (m,
1H, H4′), 5.93 (m, 1H, H3′), 6.83 (m, 1H, H1′), 7.05 (q, 1H,
J ) 1.3 Hz, H6), 7.32-7.68 (m, 10H), 8.57 (bs, 1H); 13C
NMR (CDCl3, 50 MHz) δ 11.6, 11.9, 19.4, 27.0, 65.9, 86.0,
91.1, 111.6, 127.8, 128.3, 129.9, 130.0, 132.9, 133.4, 135.0,
135.36, 135.40, 150.6, 163.5. Anal. Calcd for C27H32N2O4-
Si: C, 68.04; H, 6.77; N, 5.88. Found: C, 67.99; H, 6.79;
N, 5.87.
To a solution of acetyl chloride (0.195 mL, 2.75 mmol)
and pyridine (0.21 mL, 2.63 mmol) in CH2Cl2 (10 mL) at
0 °C under nitrogen was added dropwise a dichlo-
romethane solution (10 mL) of 28 (0.916 g, 2.5 mmol).
The reaction mixture was stirred for 4 h; the solvent was
removed under reduced pressure, and the residue was
purified by silica gel chromatography (cyclohexane/ethyl
acetate 95:5) to give a white foam which was identified
as 29 (0.859 g, 98%): 1H NMR (CDCl3, 200 MHz) δ 1.05
(s, 9H), 2.01 (s, 3H), 4.59 (s, 2H), 2.30 (s, 3H), 6.04 (s,
1H), 7.17 (s, 1H), 7.38-7.71 (m, 10H); 13C NMR (CDCl3,
50 MHz) δ 10.5, 20.0, 27.5, 59.7, 110.7, 121.1, 128.4,
130.4, 134.1, 136.4, 139.4, 154.7; MS (FAB) m/z 351
(MH+). Anal. Calcd for C22H26O2Si: C, 75.38; H, 7.48.
Found: C, 75.31; H, 7.51.
(2SR,3SR,5RS)- a n d (2RS,3SR,5RS)-5-({[1-(ter t-
Bu t yl)-1,1-d ip h en ylsilyl]oxy}m et h yl)-3-(d im et h y-
la m in o)tetr a h yd r o-2-fu r a n yl a ceta te (32a a n d 32b).
To a stirred solution of 9 (1.99 g, 5 mmol) in dry benzene
was added 1.07 g (7.0 mmol) of DBU under nitrogen
atmosphere, and the mixture was then heated at 80 °C
for 4 h. Evaporation of the solvent left a residue which,
purified by flash chromatography, gave a clear oil (1.79

36 J . Org. Chem., Vol. 64, No. 1, 1999
Chiacchio et al.
g, 90%) identified as (3SR,5RS)-5-({[1-(tert-butyl)-1,1-
diphenylsilyl]oxy}methyl)-3-(dimethylamino)dihydro-2(3H)-
furanone (30): 1H NMR (CDCl3, 500 MHz) δ 1.06 (s, 9H),
2.31 (m, 2H, H4), 2.41 (s, 6H), 3.65 (dd, 1H, J ) 2.7, 11.2
Hz), 3.88 (dd, 1H, J ) 2.7, 11.2 Hz), 3.92 (dd, 1H, J )
9.1, 9.1 Hz, H3), 4.55 (m, 1H, H5) 7.38-7.66 (m, 10H);
13C NMR (CDCl3, 125 MHz) δ 19.1, 25.6, 26.7, 41.5, 63.0,
65.7, 77.2, 127.8, 129.9, 132.2, 132.7, 135.4, 135.6, 175.3.
Anal. Calcd for C23H31NO3Si: C, 69.48; H, 7.86; N, 3.52.
Found: C, 69.43; H, 7.89; N, 3.51.
NMR (CDCl3, 500 MHz) δ 1.07 (s, 9H), 2.15 (s, 3H), 2.20
(m, 2H, H3), 2.34 (s, 6H), 2.98 (m, 1H, H2), 3.62 (dd, 1H,
J ) 3.0, 11.0 Hz, H5), 3.74 (dd, 1H, J ) 2.5, 11.0 Hz, H5),
4.43 (m, 1H, H4), 6.32 (d, 1H, J ) 4.0 Hz, H1) 7.37-7.67
(m, 10H); 13C NMR (CDCl3, 125 MHz) δ 19.2, 21.4, 26.8,
29.3, 44.8, 65.7, 68.5, 79.5, 95.5, 127.6, 127.7, 129.7,
133.0, 133.2, 135.5, 170.8; MS (FAB) m/z 442 (MH+).
1-[(2SR,3SR,5RS)-3-(Dim eth ylam in o)-5-(h ydr oxym -
eth yl)tetr a h yd r o-2-fu r a n yl]-th ym in e (34a ). Under a
nitrogen atmosphere, O,O′-bis(trimethilsilyl)thymine (0.820
g, 3.0 mmol) and 32a (0.265 g, 0.6 mmol) were dissolved
in anhydrous CH2Cl2 (5 mL). This solution was cooled to
0 °C, and SnCl4 (1.0 mmol) was added. The mixture was
then warmed to room temperature, left to stir overnight,
and finally, poured slowly into a mixture of cold saturated
aqueous NaHCO3 (5 mL) and CHCl3 (10 mL). The
resulting emulsion was separated by filtration through
Celite, the aqueous layer was extracted further with ethyl
acetate (3 × 10 mL), and the combined organic layers
were dried over Na2SO4 and evaporated under reduced
pressure. The residue was purified by silica gel column
chromatography (CHCl3/MeOH 95:5) to afford (1-
[(2SR,3SR,5RS)-5-({[1-(tert-butyl)-1,1-diphenylsilyl]oxy}-
methyl)-3-(dimethylamino)tetrahydro-2-furanyl]-thym-
ine (33a ) (0.265 g, 87%) as a white foam: 1H NMR
(CDCl3, 200 MHz) δ 1.12 (s, 9H), 1.60 (d, 3H, J ) 1.0
Hz), 2.22 (m, 2H, H3′), 2.38 (s, 6H), 3.29 (m, 1H, H2′), 3.68
(dd, 1H, J ) 2.8, 11.4 Hz, H5′), 3.99 (dd, 1H, J ) 2.5,
11.4 Hz, H5′), 4.26 (m, 1H, H4′), 6.13 (d, 1H, J ) 6.4 Hz,
H1′), 7.34-7.70 (m, 10H), 7.38 (q, 1H, J ) 1.0 Hz, H6),
9.35 (bs, 1H); 13C NMR (CDCl3, 50 MHz) δ 12.0, 19.4,
27.0, 27.5, 42.5, 65.7, 68.9, 78.0, 85.6, 111.3, 127.7, 127.9,
129.9, 130.0, 132.5, 133.1, 135.3, 135.5, 150.4, 163.8.
Anal. Calcd for C28H37N3O4Si: C, 66.24; H, 7.35; N, 8.28.
Found: C, 65.99; H, 7.33; N, 8.28.
To a stirred solution of 30 (1.99 g, 5 mmol) in
anhydrous toluene (10 mL) at -78 °C under nitrogen was
added DIBALH (10 mL, 1.0 M solution in toluene)
dropwise while the reaction temperature was mantained
below -70 °C. The reaction mixture was stirred for 3h
and then was quenched with ethyl acetate (1 mL). The
mixture was left to warm to room temperature, water (1
mL) was added, and the mixture was stirred for 3 h. The
solvent was removed under reduced pressure, and the
residue was purified by silica gel column chromatography
(CHCl3/MeOH 95:5) to afford an anomeric mixure (3:1)
of (2SR,3SR,5RS)- and (2RS,3SR,5RS)-5-({[1-(tert-butyl)-
1,1-diphenylsilyl]oxy}methyl)-3-(dimethylamino)tetrahy-
dro-2-furanol (31) (1.80 g, 90%). Minor isomer: 1H NMR
(CDCl3, 500 MHz) δ 1.08 (s, 9H), 2.11 (m, 2H, H3), 2.26
(s, 6H), 2.59 (ddd, 1H, J ) 4.0, 7.5, 11.5 Hz, H2), 3.70
(dd, 1H, J ) 5.5, 10.5 Hz, H5), 3.77 (dd, 1H, J ) 4.5, 10.5
Hz, H5), 4.19 (bs, 1H), 4.21 (m, 1H, H4), 5.21 (d, 1H, J )
4.0 Hz, H1), 7.39-7.69 (m, 10H); 13C NMR (CDCl3, 125
MHz) δ 18.8, 26.8, 43.4, 67.4, 70.0, 79.2, 96.1, 100.8,
127.7, 129.6, 133.3, 135.5. Major isomer: 1H NMR
(CDCl3, 500 MHz) δ 1.05 (s, 9H), 2.03 (m, 2H, H3), 2.29
(s, 6H), 2.74 (ddd, 1H, J ) 4.0, 8.5, 10.0 Hz, H2), 3.60
(dd, 1H, J ) 4.0, 11.0 Hz, H5), 3.66 (dd, 1H, J ) 4.5, 11.0
Hz, H5), 4.18 (bs, 1H), 4.39 (m, 1H, H4), 5.30 (d, 1H, J )
4.0 Hz, H1), 7.37-7.68 (m, 10H); 13C NMR (CDCl3, 125
MHz) δ 19.2, 26.8, 43.4, 65.8, 67.4, 78.1, 96.4, 100.5,
127.6, 129.9, 133.4, 135.6.
To a solution of acetyl chloride (0.195 mL, 2.75 mmol)
and pyridine (0.21 mL, 2.63 mmol) in CH2Cl2 (10 mL) at
0 °C under nitrogen was added dropwise a dichlo-
romethane solution (10 mL) of lactols 31 (1.00 g, 2.5
mmol). The reaction mixture was stirred for 4 h; the
solvent was removed under reduced pressure, and the
residue was purified by silica gel chromatography (CHCl3/
MeOH 97:3). First eluted product was a colorless oil
which was identified as 32b (0.243 g, 22%): 1H NMR
(CDCl3, 500 MHz) δ 1.05 (s, 9H), 2.00 (s, 3H), 2.18 (m,
2H, H3), 2.30 (s, 6H), 2.74 (m, 1H, H2), 3.66 (dd, 1H, J )
5.0, 10.5 Hz, H5), 3.74 (dd, 1H, J ) 4.5, 10.5 Hz, H5), 4.31
(m, 1H, H4), 6.25 (d, 1H, J ) 3.5 Hz, H1), 7.38-7.67 (m,
10H); 13C NMR (CDCl3, 125 MHz) δ 19.0, 21.2, 26.8, 30.4,
42.4, 67.1 69.2, 81.8, 95.1, 127.6, 127.7, 129.6, 133.4,
135.5, 170.5. MS (FAB) m/z 442 (MH+). Further eluted
product was 32a (0.729 g, 66%), as a colorless oil: 1H
To a THF solution (5 mL) of 33a (0.173 g, 0.34 mmol)
was added TBAF (0.375 mL, 0.37 mmol; 1 M solution in
THF), and the mixture was stirred at room temperature
for 3 h. At the end of this time, the solvent was removed,
and the residue was subjected to silica gel column
chromatography (CHCl3/MeOH 9:1) give 34a (0.091 g,
99%) as a white foam: 1H NMR (CDCl3, 200 MHz) δ 1.90
(d, 3H, J ) 1.0 Hz), 2.18 (m, 2H, H3′), 2.32 (s, 6H), 3.03
(bs, 1H), 3.31 (m, 1H, H2′), 3.66 (dd, 1H, J ) 3.2, 12.2
Hz, H5′), 3.91 (dd, 1H, J ) 2.6, 12.2 Hz, H5′), 4.28 (m,
1H, H4′), 5.93 (d, 1H, J ) 5.6 Hz, H1′), 7.45 (q, 1H, J )
1.0 Hz, H6), 9.63 (bs, 1H); 13C NMR (CDCl3, 50 MHz) δ
12.5, 27.8, 42.6, 63.9, 69.0, 79.3, 88.7, 111.0, 137.2, 150.5,
164.0. Anal. Calcd for C12H19N3O4: C, 53.52; H, 7.11; N,
15.60. Found: C, 53.31; H, 7.10; N, 15.59.
Ack n ow led gm en t. The authors are grateful to
M.U.R.S.T. for its financial support.
J O972264I