Glucose-Derived 3′-(Carboxymethyl)-3′-deoxyribonucleosides and 2′,3′-Lactones as Synthetic Precursors for Amide-Linked Oligonucleotide Analogues

Article abstract of DOI:10.1021/jo991399g

Treatment of a 1,2-O-isopropylidene-3-ketopentofuranose derivative (obtained from D-glucose) with [(ethoxycarbonyl)methylene]triphenylphosphorane and catalytic hydrogenation of the resulting alkene gave stereodefined access to 3-(carboxymethyl)-3-deoxy-D-ribofuranose derivatives. Esters of 5-O-acetyl- or 5-azido-5-deoxy-3-(carboxymethyl)-D-ribofuranose were coupled with nucleobases to give branched-chain nucleoside derivatives. Ester saponification and protecting group manipulation provided 2′-O-(tert-butyldimethylsilyl) ethers of 5′-azido-5′-deoxy- or 5′-O-(dimethoxytrityl) derivatives of 3′-(carboxymethyl)-3′-deoxyribonucleosides that are effective precursors for synthesis of amide-linked oligoribonucleosides.

Full text of DOI:10.1021/jo991399g

J . Org. Chem. 2000, 65, 2939-2945
2939
Glu cose-Der ived 3′-(Ca r boxym eth yl)-3′-d eoxyr ibon u cleosid es a n d
2′,3′-La cton es a s Syn th etic P r ecu r sor s for Am id e-Lin k ed
Oligon u cleotid e An a logu es1
Morris J . Robins,* Bogdan Doboszewski,† Victor A. Timoshchuk,‡ and Matt A. Peterson*
Department of Chemistry and Biochemistry, Brigham Young University, Provo, Utah 84602-5700
Received September 3, 1999
Treatment of a 1,2-O-isopropylidene-3-ketopentofuranose derivative (obtained from D-glucose) with
[(ethoxycarbonyl)methylene]triphenylphosphorane and catalytic hydrogenation of the resulting
alkene gave stereodefined access to 3-(carboxymethyl)-3-deoxy-D-ribofuranose derivatives. Esters
of 5-O-acetyl- or 5-azido-5-deoxy-3-(carboxymethyl)-D-ribofuranose were coupled with nucleobases
to give branched-chain nucleoside derivatives. Ester saponification and protecting group manipula-
tion provided 2′-O-(tert-butyldimethylsilyl) ethers of 5′-azido-5′-deoxy- or 5′-O-(dimethoxytrityl)
derivatives of 3′-(carboxymethyl)-3′-deoxyribonucleosides that are effective precursors for synthesis
of amide-linked oligoribonucleosides.
In tr od u ction
gous couplings with 5′-O-protected 3′-O-[(aryloxy)thio-
carbonyl]ribonucleosides that have 2′-O-substituents gave
3′-branched derivatives with contaminating5d or predomin-
ant6a formation of the opposite (xylo) configuration,
presumably resulting from the more sterically demanding
effects of 2′-substituents on the R-face.
Interest in branched-chain nucleosides has been stimu-
lated by their potential as antitumor and antiviral
agents, and a number of (2′ or 3′)-branched-(2′ or 3′)-
deoxy, and 2′,3′-dideoxy nucleoside analogues have been
synthesized and evaluated in biological systems.2 Ad-
ditional impetus for the synthesis of 3′-branched-2′,3′-
dideoxynucleosides was provided by their utility as
building blocks for backbone-modified analogues of oli-
godeoxynucleotides for potential applications in antisense
therapeutics.3 Free radical-mediated coupling of [3′-O-
(aryloxy)thiocarbonyl or 3′-deoxy-3′-iodo)]-2′-deoxynucleo-
side precursors with (allyl4a or styryl4b)tributyltin/AIBN
has been employed to introduce substituents at C3′ that
were modified to generate internucleoside linkages for
ribonucleotide-dimer mimics.4b,5 Such radical couplings
are highly stereoselective and give 3′-branched deriva-
tives with the desired â-D-erythro configuration with 5′-
O-protected 2′-deoxynucleoside substrates. However, ana-
lo-
Very recently, the Novartis group6b and others7 have
reported adoption of our Wittig olefination/hydrogenation
methodology for stereodefined synthesis of ribonucleoside
amide precursors from 3′-ketonucleosides. We had de-
scribed efficient syntheses of 3′-deoxy-3′-(ethoxycarbonyl)-
methyl(adenosine or uridine) derivatives (80-90%) via
hydrogenation of the 2′,5′-bis-O-TBDMS-3′-deoxy-3′-
(ethoxycarbonyl)methylene(adenosine or uridine) Wittig
adducts.8a,b Diastereoselective reduction was observed,
and the 3′-(ethoxycarbonyl)methyl products had clean
NMR spectra and underwent quantitative conversion into
2′,3′-lactones with the ribo configuration. This approach
provides a valuable alternative to radical-coupling meth-
ods, which work well for 2′,3′-dideoxy analogues4,5 but
are not highly stereoselective for preparation of 3′-
substituted-3′-deoxyribonucleosides.5d,6 Saponification of
the 3′-esters gave 3′-(carboxymethyl) analogues, which
were condensed (DCC) with 5′-amino-5′-deoxynucleosides
to give amide-linked ribonucleoside dimers.8a,b
† Present address: Department of Fundamental Chemistry, Federal
University of Pernambuco, Recife, Brazil.
‡ Present address: TriLink Biotechnologies, San Diego, CA.
(1) Nucleic Acid Related Compounds. 111 (Amide-Linked Nucleo-
sides. 3). For paper 110 (Amide-Linked Nucleosides. 2), see ref 8b.
(2) (a) Garg, N.; Plavec, J .; Chattopadhyaya, J . Tetrahedron 1993,
49, 5189-5202. (b) Ichikawa, S.; Shuto, S.; Minakawa, N.; Matsuda,
A. J . Org. Chem. 1997, 62, 1368-1375. (c) Shuto, S.; Kanazaki, M.;
Ichikawa, S.; Minakawa, N.; Matsuda, A. J . Org. Chem. 1998, 63, 746-
754, and references therein.
(3) (a) Oligodeoxynucleotides. Antisense Inhibitors of Gene Expres-
sion; Cohen, J ., Ed.; CRC Press: Boca Raton, 1989. (b) Uhlmann, E.;
Peyman, A. Chem. Rev. 1990, 90, 543-584. (c) Cazenave, C.; He´le`ne,
C. In Antisense Nucleic Acids and Proteins; Mol, J . N. M., van der Krol,
A. R., Eds.; Marcel Dekker: New York, 1991; pp 47-93. (d) Antisense
Research and Applications; Crooke, S. T., Lebleu, B., Eds.; CRC
Press: Boca Raton, 1993.
(4) (a) Chu, C. K.; Doboszewski, B.; Schmidt, W.; Ullas, G. V.; Van
Roey, P. J . Org. Chem. 1989, 54, 2767-2769. (b) Sanghvi, Y. S.;
Bharadwaj, R.; Debart, F.; De Mesmaeker, A. Synthesis 1994, 1163-
1166.
(5) (a) Fiandor, J .; Tam, S. Y. Tetrahedron Lett. 1990, 31, 597-600.
(b) Caulfield, T. J .; Prasad, C. V. C.; Prouty, C. P.; Saha, A. K.; Sardaro,
M. P.; Schairer, W. C.; Yawman, A.; Upson, D. A.; Kruse, L. I. Bioorg.
Med. Chem. Lett. 1993, 3, 2771-2776. (c) Grunder-Klotz, E.; J ust, G.
Nucleosides Nucleotides 1994, 13, 1829-1841. (d) Bhat, B.; Swayze,
E. E.; Wheeler, P.; Dimock, S.; Perbost, M.; Sanghvi, Y. S. J . Org.
Chem. 1996, 61, 8186-8199. (e) Leitzel, J . C. Ph.D. Dissertation, The
University of Chicago, 1996. (f) Luo, P.; Leitzel, J . C.; Zhan, Z.-Y. J .;
Lynn, D. G. J . Am. Chem. Soc. 1998, 120, 3019-3031.
We now report general methodology for the synthesis
of 3′-(carboxymethyl)-3′-deoxyribonucleosides that in-
cludes efficient features of our work with adenosine and
uridine and adds additional flexibility with other bases.
Glucose is converted8c into derivatives of 3-deoxy-3-
(carboxymethyl)-D-ribofuranose and 5-azido-3-(carboxy-
methyl)-3,5-dideoxy-D-ribofuranose, which undergo cou-
pling with nucleobases to produce the protected 3′-
(6) (a) De Mesmaeker, A.; Lesueur, C.; Be´vie`rre, M.-O.; Waldner,
A.; Fritsch, V.; Wolf, R. M. Angew. Chem., Int. Ed. Engl. 1996, 35,
2790-2794. (b) von Matt, P.; Lochmann, T.; Kesselring, R.; Altmann,
K.-H. Tetrahedron Lett. 1999, 40, 1873-1876.
(7) Lu, D.-M.; Min, J .-M.; Zhang, L.-H. Carbohydr. Res. 1999, 317,
193-197.
(8) (a) Robins, M. J .; Sarker, S.; Xie, M.; Zhang, W.; Peterson, M. A.
Tetrahedron Lett. 1996, 37, 3921-3924. (b) Peterson, M. A.; Nilsson,
B. L.; Sarker, S.; Doboszewski, B.; Zhang, W.; Robins, M. J . J . Org.
Chem. 1999, 64, 8183-8192. (c) Xie, M.; Berges, D. A.; Robins, M. J .
J . Org. Chem. 1996, 61, 5178-5179.
10.1021/jo991399g CCC: $19.00 © 2000 American Chemical Society
Published on Web 04/21/2000

2940 J . Org. Chem., Vol. 65, No. 10, 2000
Robins et al.
CBr4/LiN3)13 with 3a was much less efficient (5, 21%).
The use of hydrazoic acid was avoided with larger scale
preparations. Thus, alcohol 3a was converted into its
mesylate 6a (93%), which was treated with NaN3/DMF
to give 5 (88%). Attempted removal of the isopropylidene
group from 5 by various mildly acidic methods14,15
resulted in formation of products identified spectroscopi-
cally as lactones, A, which is consistent with results
involving similar compounds.10b,16
Sch em e 1a
Acetolysis of 5 (H2SO4/Ac2O/HOAc) gave the diacetate
8 in moderate yields (∼50%), and acetolysis of the 5-O-
mesyl compound 6a gave diacetate 9a in 70% yield. In
marked contrast, the 5-O-acetyl derivative 7 [obtained
smoothly (97%) by acetylation of 3a ] gave low yields of
triacetate 10a upon parallel acetolysis, and manipulation
of reaction conditions gave little improvement. Hydrolysis
of the isopropylidene group from 7 gave lactone A (R )
H, X ) OAc) plus small quantities of diol B. However,
nucleophilic displacement of mesylate from 9a by acetate
(CsOAc/DMF) proceeded without incident to give the
triacetate 10a (83%).
A large-scale preparation of 7 had been performed (in
anticipation of its conversion into 10a ). Deacetylation of
this 7 (NaOMe/MeOH) gave 3b (concomitant transes-
terification), which was mesylated to give 6b. Acetolysis
of 6b gave diacetate 9b (63%), which was converted into
triacetate 10b (71%) with CsOAc/DMF.
a
Key: (a) Bu4NF/THF; (b) H2/Pd-C/EtOH; (c) NaBH4/EtOH;
(d) Ph3P/DEAD/HN3; (e) Ph3P/CBr4/LiN3; (f) MsCl/DMAP/pyridine/
CH2Cl2; (g) Ac2O/DMAP/pyridine/CH2Cl2; (h) NaOMe/MeOH; (i)
NaN3/DMF/∆;. (j) H2SO4/Ac2O/HOAc; (k) CsOAc/DMF/∆.
(carboxymethyl)-3′-deoxyribonucleosides.Theazidofunction
serves as a convenient “masked amino group” that can
be reduced to provide 5′-amino-3′-(carboxymethyl)-3′,5′-
dideoxy residues for incorporation into amide-linked
oligonucleosides.
Resu lts a n d Discu ssion
Treatment of 5-O-TBDMS-1,2-O-isopropylidene-R-D-
erythro-pentofuranos-3-ulose9 with [(ethoxycarbonyl)-
methylene]triphenylphosphorane gave (E/ Z)-1 (∼7:1;
90%) (Scheme 1). Desilylation of 1 gave 2, and hydroge-
nation of 2 (25 psi H2/Pd-C) gave 3a plus trace amounts
of the over-reduced diol 4. Formation of 4 was minimized
at lower hydrogen pressure (5 psi). Reduction of 2 with
NaBH4/EtOH gave 3a and 4, but the proportion of 4 was
much greater. We then reexamined our prior preparation
of 3a from 1,2:5,6-di-O-isopropylidene-R-D-glucofuranose.
Whereas “clean” reduction of the double bond was
observed with the lot of NaBH4 used in our original
work,8c over-reduction of the ester function to give
contaminating diol was observed with the same excess
of freshly opened NaBH4. A 1,2-O-isopropylidene group
is known to direct incoming reagents to the â-face of
furanosyl carbohydrate derivatives with erythro or ribo
configurations,10 and ribo diastereomers 3a and 4 were
obtained with either catalytic hydrogenation or chemical
reduction.
Adenine (SnCl4),17 or trimethylsilylated derivatives of
6-N-benzoyladenine, thymine, or uracil (TMSOTf),18 un-
derwent coupling with the 5-azido diacetate 8, or triac-
etates 10a or 10b, to give the 3′-branched nucleoside
derivatives 11-18 (Scheme 2). Treatment of 12, 13, 16,
or 17 with NaOMe/MeOH effected deacetylation with
accompanying transesterification and lactonization [the
esters were more polar than the lactones (TLC)].
Saponification (NaOH/H2O/MeOH) of 11 or 13 gave the
3′-(carboxymethyl) sodium salts (TLC baseline). However,
neutralization, attempted purification, or other manipu-
lation of these salts resulted in partial lactonization. This
side reaction was minimized by drying and silylating the
crude mixtures directly. Thus, volatiles were evaporated
from the saponification solutions (without neutralization),
and then dried DMF/pyridine was added and evaporated
several times. The residues were dried in vacuo, and then
stirred with TBDMSCl/DMF/pyridine for several days at
ambient temperature to give mixtures (∼1:2) of lactones
Alcohol 3a was converted directly into the 5-azido
derivative 5 (91%) under Mitsunobu11 (Ph3P/DEAD/HN3)
conditions, whereas the modified Appel12 reaction (Ph3P/
(12) Appel, R. Angew. Chem., Int. Ed. Engl. 1975, 14, 801-811.
(13) Castro, B. R. Org. React. 1983, 29, 1-162.
(14) Green, T. W.; Wuts, P. G. M. Protective Groups in Organic
Synthesis, 3rd ed.; Wiley: New York, 1999.
(9) Yoshimura, Y.; Sano, T.; Matsuda, A.; Ueda, T. Chem. Pharm.
Bull. 1988, 36, 162-167.
(15) Kocienski, P. J . Protecting Groups; Georg Thieme Verlag: New
York, 1994.
(10) (a) Rosenthal, A.; Sprinzl, M. Can. J . Chem. 1969, 47, 4477-
4481. (b) Lourens, G. J .; Koekemoer, J . M. Tetrahedron Lett. 1975,
3715-3718. (c) Mazur, A.; Tropp, B. E.; Engel, R. Tetrahedron 1984,
40, 3949-3956. (d) Pudlo, J . S.; Townsend, L. B. Tetrahedron Lett.
1990, 31, 3101-3104. (e) Hanessian, S. Total Synthesis of Natural
Products: The “Chiron” Approach; Pergamon: New York, 1983.
(11) (a) Mitsunobu, O. Synthesis 1981, 1-28. (b) Hughes, D. L. Org.
React. 1992, 42, 335-656.
(16) (a) Ohrui, H.; Emoto, S. Tetrahedron Lett. 1975, 3657-3660.
(b) Lourens, G. J .; Koekemoer, J . M. Tetrahedron Lett. 1975, 3719-
3722. (c) Anderson R. C.; Fraser-Reid, B. J . Am. Chem. Soc. 1975, 97,
3870-3871. (d) Anderson, R. C.; Fraser-Reid, B. Tetrahedron Lett.
1977, 2865-2868.
(17) Saneyoshi, M.; Satoh, E. Chem. Pharm. Bull. 1979, 27, 2518-
2521.
(18) Vorbru¨ggen, H. Acc. Chem. Res. 1995, 28, 509-520.

Amide-Linked Oligonucleotide Analogues
J . Org. Chem., Vol. 65, No. 10, 2000 2941
Sch em e 2a
primary amine for condensation with activated 3′-(car-
boxymethyl)nucleosides for synthesis of amide-linked
oligomers. Catalytic hydrogenation of Wittig adduct 2
gave 3a much more readily than parallel reductions of
analogous unsaturated nucleosides. The present ap-
proach is more convenient and versatile than such
parallel syntheses.6b,7,8a,b
Exp er im en ta l Section
Uncorrected melting points were determined with a capil-
lary apparatus. NMR spectra were determined with solutions
in Me4Si/CDCl3 at 200 MHz (1H) or 50 MHz (13C) unless
otherwise noted. Protons labeled “ex” were exchanged with
D2O, but exchange was not performed with all NMR samples.
Observed (“apparent”) multiplicities are noted with quotation
marks for 1H NMR peaks that should exhibit more complex
splitting. High-resolution mass spectra (MS) were determined
under FAB conditions (NaOAc/thioglycerol matrix) unless
otherwise noted (CH4 was used for CI). Reagent chemicals
were used, and solvents were dried by distillation from
standard drying agents (under N2). TLC was performed with
Merck kieselgel 60-F254 sheets with visualization under 254-
nm light, or by spraying (5% H2SO4/EtOH) and then heating
the sheet.
a
Key: (a) adenine/SnCl4/MeCN or B(TMS)n/TMSOTf/DCE/∆;
(b) NaOH/H2O/MeOH; (c) DMTCl/Et3N/pyridine; (d) TBDMSCl/
DMF/pyridine or TBDMS-imidazolide/CH2Cl2/DMF.
5-O-(ter t-Bu tyld im eth ylsilyl)-3-d eoxy-3-[(eth oxyca r bo-
n yl)m eth ylen e]-1,2-O-isop r op ylid en e-r-D-er yth r o-p en to-
fu r a n ose (1). Oxidation9 of 5-O-TBDMS-1,2-O-isopropylidene-
R-D-xylofuranose (22.0 g, 72.3 mmol), treatment of the resulting
3-ulose with [(ethoxycarbonyl)methylene]triphenylphosphorane
[30.4 g (95%), 83.1 mmol] in CH2Cl2 (350 mL) overnight at
ambient temperature, evaporation of volatiles, filtration of a
solution of the residue in CH2Cl2 through silica gel (CH2Cl2
followed by MeOH/CH2Cl2, 0.1:20), and evaporation of volatiles
gave an E/ Z mixture (∼7:1) of 1 (24.3 g, 90%) as an oil: 1H
NMR (major isomer) δ 6.01 (t, J ) 1.7 Hz, 1H), 5.91 (d, J )
4.3 Hz, 1H), 5.68-5.62 (m, 1H), 4.85 (hept, J ) 1.9 Hz, 1H),
4.24 (q, J ) 7.2 Hz, 2H), 3.81 (dd, J ) 4.2, 10.0 Hz, 1H), 3.73
(dd, J ) 3.4, 10.0 Hz, 1H), 1.48, 1.43 (2 × s, 2 × 3H), 1.30 (t,
(18 or 20) and 2′-O-TBDMS-3′-(carboxymethyl) deriva-
tives (19 or 21), respectively.
Esters 15 or 17 were saponified (NaOH/H2O/MeOH),
and the carboxylate salts were converted into their 5′-
O-(4,4′-dimethoxytrityl)-2′,3′-lactones 22 or 24, respec-
tively, with DMTCl/DMF/Et3N/pyridine. Base-promoted
hydrolysis of the lactones and treatment of the resulting
carboxylate salts with TBDMS-imidazolide/imidazole/
19
DMF/CH2Cl2 gave mixtures of lactones 22 or 24 and
the 3′-(carboxymethyl)-5′-O-DMT-2′-O-TBDMS deriva-
tives 23 or 25, respectively. The acids 19, 21, 23, or 25
were readily separated from the lactone byproducts 18,
20, 22, or 24, which were recycled (hydrolysis and
silylation).
J ) 7.2 Hz, 3H), 0.87 (s, 9H), 0.052, 0.045 (2 × s, 2 × 3H); 13
C
NMR δ 164.9, 156.8, 116.4, 112.7, 105.3, 81.0, 78.8, 65.3, 60.5,
27.4, 27.2, 25.7, 18.1, 14.1, -5.5, -5.6; MS m/z 395.1873 (MNa+
[C18H32O6NaSi] ) 395.1866).
Protection of the 2′-hydroxyl group to give 19, 21, 23,
and 25 was very slow, even with a large excess of
silylating agent. TBDMSCl/pyridine was adequate for 19
and 21, but TBDMS-imidazolide19 was required to give
reasonable yields of 23 and 25. The TBDMS-triazolide
analogue20 was no more effective than the imidazolide,
and TBDMS-OTf 21 caused cleavage of the acid-sensitive
5′-O-DMT group of 23 and 25.
3-Deoxy-3-[(eth oxyca r bon yl)m eth ylen e]-1,2-O-isop r o-
p ylid en e-r-D-er yth r o-p en tofu r a n ose (2). Bu4NF/THF (1 M,
22 mL, 22 mmol) was added to a cold solution of 1 (6.8 g, 18
mmol) in THF (150 mL), and stirring was continued at 4 °C
for 5 h and then ambient temperature for 2 h. Volatiles were
evaporated, and the residue was chromatographed (MeOH/
CH2Cl2, 0.4:20) to give 2 (4.47 g, 95%) as a syrup: 1H NMR
(Me2SO-d6) δ 6.04 (t, J ) 1.7 Hz, 1H), 5.90 (d, J ) 4.0 Hz,
1H), 5.58-5.52 (m, 1H), 4.95 (t, J ) 5.5 Hz, 1H, ex), 4.77
(heptet, J ) 1.8 Hz, 1H), 4.16 (q, J ) 7.0 Hz, 2H), 3.64 (dd, J
) 4.5, 11.0 Hz, 1H), 3.53 (dd, J ) 5.5, 12.0 Hz, 1H), 1.38, 1.35
(2 × s, 2 × 3H), 1.24 (t, J ) 7.0 Hz, 3H); 13C NMR (major
isomer) δ 164.8, 154.8, 116.7, 112.7, 104.8, 80.4, 78.3, 62.9,
60.6, 27.1, 26.9, 13.9; MS (CI) m/z 259.1190 (MH+ [C12H19O6]
) 259.1182).
3-Deoxy-3-[(eth oxyca r bon yl)m eth yl]-1,2-O-isop r op yl-
id en e-r-D-r ibofu r a n ose (3a ) a n d 3-Deoxy-3-(2-h yd r oxy-
eth yl)-1,2-O-isop r op ylid en e-r-D-r ibofu r a n ose (4). Meth od
A. Hydrogenation of 2 (4.1 g, 16 mmol) in EtOH (30 mL) [H2/
25 psi, 5% Pd-C (0.3 g), Parr apparatus] for 4 h gave 3a and
4. TLC (MeOH/CH2Cl2, 0.8:20) showed that 2 and 3a had
identical mobilities, but 3a was UV transparent. The catalyst
was filtered (with Celite), the filtrate was evaporated, and the
residue was chromatographed (MeOH/CH2Cl2, 0.2:10) to give
3a 8c (3.0 g, 73%). Further elution of the column (MeOH/CH2-
Cl2, 1:20) gave 4 (120 mg, 3.5%).
Su m m a r y
Conversion of 1,2:5,6-di-O-isopropylidene-R-D-gluco-
furanose into a 5-O-TBDMS-3-ketone, Wittig reaction
with [(ethoxycarbonyl)methylene]triphenylphosphorane,
removal of TBDMS protection, and catalytic hydrogena-
tion of the E/ Z adducts gave the 3-deoxy-3-[(ethoxycar-
bonyl)methyl] sugar 3a . Its 5-O-mesyl derivative 6a was
transformed into 1,2-di-O-acetyl-5-azido, 8, and 1,2,5-tri-
O-acetyl, 10a , intermediates that were coupled with
nucleobases. Base-promoted hydrolysis followed by silyl-
ation gave 2′-O-TBDMS-3′-(carboxymethyl)-3′-deoxyri-
bonucleosides. The 5′-azido group provides a “masked”
(19) Kerwin, S. M.; Paul, A. G.; Heathcock, C. H. J . Org. Chem. 1987,
52, 1686-1695.
Meth od B. Hydrogenation of 2 (30 mg, 0.12 mmol) in EtOH
(5 mL) [H2/5 psi, 10% Pd-C (3 mg), Parr apparatus] for 12 h
gave 3a (no 4 detected by TLC). The catalyst was filtered (with
Celite), the filtrate was evaporated, and the residue was
chromatographed (PTLC, EtOAc/hexanes, 1:1) to give 3a (26
mg, 86%).
(20) Fabrega, C.; Eritja, R.; Sinha, N. D.; Dosanjh, M. K.; Singer,
B. Bioorg. Med. Chem. 1995, 3, 101-108.
(21) (a) LaLonde, M.; Chan, T. H. Synthesis 1985, 817-845. (b)
J ones, D. M.; Nilsson, B.; Szelke, M.; J . Org. Chem. 1993, 58, 2286-
2290.

2942 J . Org. Chem., Vol. 65, No. 10, 2000
Robins et al.
Meth od C. Treatment of 2 (4.47 g, 17.3 mmol) with “freshly
opened” NaBH4 (0.96 g, 25 mmol) in dried EtOH (100 mL)
overnight also gave 3a (1.95 g, 43%), plus the alcohol 4 (1.29
g, 34%): 1H NMR (Me2SO-d6, 500 MHz) δ 5.68 (d, J ) 3.6 Hz,
1H), 4.77 (t, J ) 5.9 Hz, 1H, ex), 4.64 (t, J ) 5.1 Hz, 1H, ex),
4.61 (t, J ) 4.2 Hz, 1H), 3.68 (ddd, J ) 2.7, 4.6, 10.3 Hz, 1H),
3.61-3.57 (m, 1H; overlap with H2O peak), 3.52 (ddd, J ) 5.1,
7.6, 10.5 Hz, 1H), 3.46-3.41 (m, 1H), 3.38 (dd, J ) 4.9, 12.2
Hz, 1H), 1.91 (dddd, J ) 5.0, 5.0, 10.1, 10.1 Hz, 1H), 1.64-
1.57, 1.52-1.44 (2 × m, 2 × 1H), 1.35, 1.22 (2 × s, 2 × 3H);
13C NMR (Me2SO-d6) δ 110.5, 104.6, 82.6, 80.9, 61.1, 59.3, 41.0,
28.0, 26.8, 26.5; MS (CI) m/z 219.1238 (MH+ [C10H19O5] )
219.1232).
5-Azid o-3,5-d id eoxy-3-[(eth oxyca r bon yl)m eth yl]-1,2-O-
isop r op ylid en e-r-D-r ibofu r a n ose (5). Meth od A. Ph3P (2.0
g, 7.6 mmol), DEAD (1.2 mL, 1.3 g, 7.6 mmol), and HN3/toluene
[8 mL; stock solution prepared from NaN3 (3.0 g) and H2SO4
(1.1 mL) in 30 mL of toluene22] were added to a solution of 3a
(500 mg, 1.92 mmol) in dioxane (40 mL), and stirring was
continued (under Ar) for 30 min (TLC showed conversion of
3a into a less polar product). Volatiles were evaporated, and
the residue was chromatographed (CH2Cl2 f MeOH/CH2Cl2,
0.1:20, or EtOAc/hexanes, 1:9) to give 5 (500 mg, 91%) as an
oil.
3.07 (s, 3H), 2.72 (dd, J ) 10.4, 18.0 Hz, 1H), 2.50-2.31 (m,
2H), 1.58, 1.33 (2 × s, 2 × 3H), 1.28 (t, J ) 7.0 Hz, 3H); 13C
NMR δ 171.5, 112.1, 104.8, 81.1, 78.5, 68.4, 60.9, 40.8, 37.7,
29.7, 26.7, 26.3, 14.1; MS m/z 361.0916 (MNa+ [C13H22O8NaS]
) 361.0933). The extract of 6a (without chromatography) could
be used for the preparation of azide 5 or diacetate 9a .
3-Deoxy-1,2-O-isop r op ylid en e-5-O-m eth a n esu lfon yl-3-
[(m eth oxyca r bon yl)m eth yl]-r-D-r ibofu r a n ose (6b). Treat-
ment of 7 (5.5 g, 18 mmol) with NaOMe/MeOH [Na (chips) in
MeOH (300 mL)] overnight, neutralization (CO2), evaporation
of volatiles, and addition of toluene and evaporation gave a
light yellow oil. This oil was dissolved in CH2Cl2 (250 mL),
pyridine (15 mL), MsCl (7.30 mL, 10.8 g, 94.3 mmol), and
DMAP (trace) were added, and stirring was continued over-
night. H2O (3 mL) was added, and stirring was continued for
3 h. Extraction workup and chromatography (MeOH/CH2Cl2,
0.15:20) gave 6b (3.7 g, 63%), which crystallized spontane-
1
ously: mp 77-78 °C; H NMR (500 MHz) δ 5.83 (d, J ) 3.4
Hz, 1H), 4.81 (t, J ) 3.9 Hz, 1H), 4.43 (dd, J ) 2.4, 11.7 Hz,
1H), 4.26 (dd, J ) 4.4, 11.7 Hz, 1H), 4.05 (ddd, J ) 2.2, 4.9,
10.0 Hz, 1H), 3.72, 3.07 (2 × s, 2 × 3H), 2.73 (dd, J ) 10.3,
18.1 Hz, 1H), 2.44-2.39 (m, 2H), 1.50, 1.33 (2 × s, 2 × 3H);
13C NMR δ 171.9, 112.0, 104.8, 81.0, 78.3, 68.2, 52.0, 40.8, 37.6,
29.4, 26.7, 26.3; MS (thioglycerol) m/z 325.0942 (MH+ [C12H21
O8S] ) 325.0957).
-
Meth od B. Ph3P (1.3 g, 5.0 mmol), CBr4 (1.9 g, 5.7 mmol),
and LiN3 (0.56 g, 11 mmol) were added to a solution of 3a (1.0
g, 3.8 mmol) in dioxane (40 mL), and stirring (under Ar) was
continued for 96 h (the major amount of 3a remained unre-
acted). Volatiles were evaporated, and the residue was chro-
matographed to give 5 (230 mg, 21%).
5-O-Acetyl-3-d eoxy-3-[(eth oxyca r bon yl)m eth yl]-1,2-O-
isop r op ylid en e-r-D-r ibofu r a n ose (7). Acetylation (Ac2O/
pyridine) of 3a (8.10 g, 31.1 mmol) and extraction workup gave
7 (9.15 g, 97%): 1H NMR (Me2SO-d6) δ 5.79 (d, J ) 3.6 Hz,
1H), 4.72 (t, J ) 4.1 Hz, 1H), 4.22 (dd, J ) 1.8, 12.2 Hz, 1H),
4.12-3.85 (m, 4H), 2.51 (d, J ) 7.2 Hz, 2H; partial overlap
with solvent peaks), 2.28-2.05 (m, 1H), 2.03, 1.40, 1.24 (3 ×
s, 3 × 3H), 1.19 (t, J ) 7.0 Hz, 3H); 1H NMR δ 5.82 (d, J ) 3.2
Hz, 1H), 4.78 (t, J ) 4.1 Hz, 1H), 4.27 (dd, J ) 2.5, 12.1 Hz,
1H), 4.20-4.07 (m, 3H), 3.96 (ddd, J ) 2.7, 5.3, 10.1 Hz, 1H),
2.69 (dd, J ) 9.7, 16.9 Hz, 1H), 2.38 (dd, J ) 4.2, 16.6 Hz,
1H), 2.35-2.19 (m, 1H), 2.07, 1.48, 1.30 (3 × s, 3 × 3H), 1.26
(t, J ) 7.2 Hz, 3H); 13C δ 171.9, 170.9, 111.8, 104.9, 80.9, 78.5,
63.4, 60.7, 41.2, 29.5, 26.5, 26.2, 20.7, 14.0; MS (thioglycerol)
m/z 303.1461 (MH+ [C14H23O7] ) 303.1444.
5-O-Ace t yl-3-(ca r b oxym e t h yl)-3-d e oxy-D -r ib ofu r a -
n ose 2,3-la cton e (A; R ) H, X ) OAc) a n d 5-O-Acetyl-3-
d eoxy-3-[(eth oxyca r bon yl)m eth yl]-D-r ibofu r a n ose (B). A
solution of 7 (150 mg, 0.496 mmol) in AcOH/H2O (8:2, 14 mL)
was refluxed for 40 min [TLC showed lactone A (R ) H, X )
OAc) (major) plus diol B (minor)]. Volatiles were evaporated,
and the residue was chromatographed (MeOH/CH2Cl2, 1:20)
to give A (R ) H, X ) OAc) (70 mg, 65%): 1H NMR (Me2SO-
d6) δ 6.89 (d, J ) 4.6 Hz, 0.75H, ex), 6.79 (d, J ) 4.8 Hz, 0.25H,
ex), 5.40 (d, J ) 4.6 Hz, 0.25H), 5.33 (d, J ) 4.8 Hz, 0.75H),
4.84 (dd, J ) 4.0, 8.9 Hz, 0.25H), 4.77 (d, J ) 5.4 Hz, 0.75H),
4.16-4.03, 3.05-2.57 (2 × m, 2 × 3H), 2.03 (s, 3H); 13C NMR
(major anomer) δ 175.4, 171.2, 101.2, 87.6, 85.4, 66.7, 39.5,
33.9, 20.8; MS (CI) m/z 217.0728 (MH+ [C9H13O6] ) 217.0712).
Further elution gave B (6 mg, 5%): 1H NMR (Me2SO-d6) δ
6.24 (d, J ) 4.6 Hz, 1H, ex), 5.14 (d, J ) 4.8 Hz, 1H, ex), 4.98
(d, J ) 4.6 Hz, 1H), 4.19 (dd, J ) 2.2, 11.0 Hz, 1H), 4.06 (q, J
) 7.1 Hz, 2H), 3.96-3.78, 2.57-2.33 (2 × m, 2 × 3H), 2.01 (s,
3H), 1.18 (t, J ) 7.1 Hz, 3H); 13C NMR (Me2SO-d6) δ 172.2,
170.6, 102.5, 79.6, 75.7, 66.9, 60.1, 30.0, 20.8, 14.2; MS (CI)
m/z 263.1115 (MH+ [C11H19O7] ) 263.1131).
1,2-Di-O-a cetyl-5-a zid o-3,5-d id eoxy-3-[(eth oxyca r bon -
yl)m eth yl]-D-r ibofu r a n ose (8). A solution of 5 (500 mg, 1.75
mmol) in HOAc (10 mL)/Ac2O (1 mL)/H2SO4 (0.55 mL) was
stirred overnight (TLC, MeOH/CH2Cl2, 0.1:20, developed twice,
showed conversion of 5 to a slightly more polar product).
Extraction workup and chromatography (MeOH/CH2Cl2, 0.1:
20) gave an anomeric mixture (∼8:1) of 8 (290 mg, 50%) as a
syrup: 1H NMR (major anomer) δ 6.10 (s, 1H), 5.33 (d, J )
4.8 Hz, 1H), 4.16 (“q”, J ) 7.1 Hz, 3H), 3.65 (dd, J ) 3.2, 13.4
Hz, 1H), 3.24 (dd, J ) 4.1, 13.5 Hz, 1H), 3.05-2.87 (m, 1H),
2.55 (dd, J ) 8.5, 16.4 Hz, 1H), 2.39 (dd, J ) 6.4, 16.4 Hz,
1H), 2.12 (s, 6H), 1.27 (t, J ) 7.1 Hz, 3H); 13C NMR (major
anomer*) δ 170.9, 169.5, 169.1, 98.5*, 95.0, 83.4*, 83.2, 77.6*,
Meth od C. A solution of mesylate 6a (700 mg, 2.10 mmol)
and NaN3 (960 mg, 14.8 mmol) in DMF (30 mL) was stirred
at 90 °C for 4 h. The solution was cooled, CH2Cl2 and H2O
were added, and the aqueous layer was extracted (CH2Cl2).
The combined organic phase was evaporated, xylene was added
and evaporated several times, and the brown oil was dried in
vacuo. Filtration through a short bed of silica gel (CH2Cl2) gave
5 (520 mg, 88%): 1H NMR δ 5.85 (d, J ) 3.7 Hz, 1H), 4.80 (t,
J ) 3.9 Hz, 1H), 4.17 (q, J ) 7.1 Hz, 2H), 3.97 (dt, J ) 3.7, 9.9
Hz, 1H), 3.61 (dd, J ) 3.1, 13.5 Hz, 1H), 3.26 (dd, J ) 4.4,
13.5 Hz, 1H), 2.79-2.59 (m, 1H), 2.49-2.28 (m, 2H), 1.50, 1.33
(2 × s, 2 × 3H), 1.28 (t, J ) 7.1 Hz, 3H); 13C NMR (Me2SO-d6)
δ 171.1, 110.9, 104.4, 80.5, 79.2, 60.1, 50.9, 40.9, 29.0, 26.5,
26.3, 14.0; MS (CI) m/z 270.1102 (M - CH3 [C11H16N3O5] )
270.1090).
Meth yl 5-Azid o-3-(ca r boxym eth yl)-3,5-d id eoxy-D-r ibo-
fu r a n osid e 2,3-la cton e (A; R ) CH3, X ) N3). A suspension
of 5 (147 mg, 0.515 mmol) and Dowex 50W-X8 (H+) resin (400
mg) in H2O/MeOH (1:10, 11 mL) was refluxed overnight (TLC,
MeOH/CH2Cl2, 0.2:20, showed conversion of 5 into a more polar
product). The resin was filtered, volatiles were evaporated, and
the residue was chromatographed (MeOH/CH2Cl2, 0.2:20) to
give an anomeric mixture (∼6:1) of the title compound (100
mg, 91%): 1H NMR (Me2SO-d6, major anomer) δ 5.11 (s, 1H),
4.91 (d, J ) 5.4 Hz, 1H), 4.19 (ddd, J ) 4.2, 4.3, 6.4 Hz, 1H),
3.39-3.32 (m, 5H), 2.99-2.83 (m, 2H), 2.68-2.58 (m, 1H); 13
C
NMR (Me2SO-d6, major anomer*) δ 175.8, 107.0*, 101.3, 86.3*,
85.6*, 81.5, 80.6, 55.0*, 54.5*, 54.3, 52.5, 38.3, 33.1*, 32.4; MS
(CI) m/z 214.0830 (MH+ [C8H12N3O4] ) 214.0828).
3-Deoxy-3-[(eth oxyca r bon yl)m eth yl]-1,2-O-isop r op yl-
id en e-5-O-m eth a n esu lfon yl-r-D-r ibofu r a n ose (6a ). A solu-
tion of 3a (8.06 g, 31.0 mmol), mesyl chloride (6.0 mL, 8.9 g,
78 mmol), pyridine (12.5 mL), and DMAP (trace) in CH2Cl2
(200 mL) was stirred overnight at ambient temperature (TLC,
MeOH/CH2Cl2, 0.4:20, showed conversion of 3a to a less polar
product). The solution was cooled in an ice bath, H2O was
added, and stirring was continued for 3 h. Extraction workup,
chromatography (EtOAc/hexanes 4:6), and recrystallization
(hexanes/EtOAc) gave 6a (9.75 g, 93%): mp 60-62 °C; 1H
NMR δ 5.81 (d, J ) 3.4 Hz, 1H), 4.82 (t, J ) 4.0 Hz, 1H), 4.45
(dd, J ) 2.2, 11.7 Hz, 1H), 4.25 (dd, J ) 4.2, 12.0 Hz, 1H),
4.17 (q, J ) 7.4 Hz, 2H), 4.06 (ddd, J ) 2.6, 4.4, 9.9 Hz, 1H),
(22) Wolff, H. Org. React. 1947, III, 307-336.

Amide-Linked Oligonucleotide Analogues
J . Org. Chem., Vol. 65, No. 10, 2000 2943
72.0, 61.0*, 60.9, 53.0, 52.6*, 37.8*, 36.2, 33.3, 30.3*, 21.0*,
20.5*, 14.1*; MS m/z 352.1104 (MNa+ [C13H19N3O7Na] )
352.1121].
exclusion of moisture) until a clear solution was formed.
Volatiles were evaporated, and xylene was added and coevapo-
rated several times. The residue was dried in vacuo, and a
solution of the carbohydrate derivative in 1,2-dichloroethane
(under Ar) was added. TMSOTf (trace) was added, and the
solution was stirred overnight (oil bath temperature 55-70
°C). Extraction workup and chromatography gave 12-14, 16-
18.
2′-O-Acetyl-5′-a zid o-3′,5′-d id eoxy-3′-[(eth oxyca r bon yl)-
m eth yl]a d en osin e (11). Procedure A [8 (580 mg, 1.76 mmol),
adenine (260 mg, 1.92 mmol), SnCl4 (0.4 mL, 890 mg, 3.42
mmol), MeCN (25 mL), chromatography (MeOH/CH2Cl2, 0.6:
20)] gave 11 (680 mg, 96%): 1H NMR δ 8.36, 8.01 (2 × s, 2 ×
1H), 6.04 (d, J ) 1.6 Hz, 1H), 5.86 (br s, 2H), 5.84 (dd, J )
1.6, 6.0 Hz, 1H), 4.15 (q, J ) 7.1 Hz, 2H), 4.21-4.10 (m, 1H),
3.71 (dd, J ) 3.3, 13.4 Hz, 1H), 3.60 (dd, J ) 4.9, 13.4 Hz,
1H), 3.50-3.40 (m, 1H), 2.64 (dd, J ) 8.2, 16.5 Hz, 1H), 2.47
(dd, J ) 6.6, 16.7 Hz, 1H), 2.15 (s, 3H), 1.26 (t, J ) 7.2 Hz,
3H); 13C NMR δ 170.9, 169.8, 155.6, 153.3, 149.5, 139.1, 120.1,
88.9, 82.9, 78.1, 61.1, 52.2, 38.8, 30.4, 20.5, 14.0; MS (thiogly-
cerol) m/z 405.1634 (MH+ [C16H21N8O5] ) 405.1635).
2′-O-Acetyl-5′-azido-6-N-ben zoyl-3′,5′-dideoxy-3′-[(eth oxy-
ca r bon yl)m eth yl]a d en osin e (12). Procedure B [8 (292 mg,
0.887 mmol), 6-N-benzoyladenine (480 mg, 2.01 mmol), TM-
SOTf (0.18 mL, 221 mg, 0.99 mmol), chromatography (MeOH/
CH2Cl2, 0.5:20)] gave 12 (350 mg, 77%): 1H NMR (Me2SO-d6,
500 MHz) δ 11.20 (br s, 1H, ex), 8.77, 8.62 (2 × s, 2 × 1H),
8.04 (d, J ) 7.0 Hz, 2H), 7.64 (t, J ) 8.0 Hz, 1H), 7.55 (t, J )
7.8 Hz, 2H), 6.24 (d, J ) 2.0 Hz, 1H), 5.85 (dd, J ) 2.0, 7.0 Hz,
1H), 4.19 (ddd, J ) 2.9, 5.9, 9.3 Hz, 1H), 4.07 (q, J ) 7.2 Hz,
2H), 3.75 (dd, J ) 2.8, 13.7 Hz, 1H), 3.56 (dd, J ) 6.0, 13.5
Hz, 1H), 3.38 (m, 1H), 2.68 (dd, J ) 5.8, 16.8 Hz, 1H), 2.60
(dd, J ) 9.0, 17.0 Hz, 1H), 2.09 (s, 3H), 1.18 (t, J ) 7.3 Hz,
3H); 13C NMR (Me2SO-d6) δ 171.0, 169.7, 165.9, 151.8, 150.5,
143.3, 133.6, 132.4, 128.4, 125.9, 88.3, 82.5, 76.8, 60.2, 51.4,
38.4, 29.8, 20.4, 14.0; MS m/z 531.1713 (MNa+ [C23H24N8O6-
Na] ) 531.1717).
2′-O-Acetyl-5′-a zid o-3′,5′-d id eoxy-3′-[(eth oxyca r bon yl)-
m eth yl]-5-m eth ylu r id in e (13). Procedure B [8 (320 mg,
0.972 mmol), thymine (250 mg, 2.00 mmol), TMSOTf (0.20 mL,
245 mg, 1.1 mmol), chromatography (MeOH/CH2Cl2, 0.4:20)]
gave 13 (320 mg, 81%): 1H NMR (Me2SO-d6, 500 MHz) δ 11.41
(s, 1H, ex), 7.55 (“q”, J ) 1.0 Hz, 1H), 5.68 (d, J ) 3.0 Hz, 1H),
5.39 (dd, J ) 2.9, 7.8 Hz, 1H), 4.05 (q, J ) 7.3 Hz, 2H), 3.99-
3.97 (m, 1H), 3.72 (dd, J ) 2.7, 13.4 Hz, 1H), 3.50 (dd, J )
5.9, 13.7 Hz, 1H), 2.95-2.85 (m, 1H), 2.57 (dd, J ) 5.6, 16.8
Hz, 1H), 2.48 (dd, J ) 9.3, 17.1 Hz, 1H), 2.03 (s, 3H), 1.79 (d,
J ) 1.0 Hz, 3H), 1.16 (t, J ) 7.3 Hz, 3H); 13C NMR (Me2SO-
d6) δ 171.1, 169.5, 163.7, 150.0, 137.3, 109.7, 90.3, 81.3, 76.0,
60.1, 51.4, 38.0, 30.0, 20.3, 14.0, 11.9; MS (thioglycerol) m/z
396.1517 (MH+ [C16H22N5O7] ) 396.1519).
1,2-Di-O-a cetyl-3-d eoxy-3-[(eth oxyca r bon yl)m eth yl]-5-
O-m eth a n esu lfon yl-D-r ibofu r a n ose (9a ). A solution of 6a
(930 mg, 2.75 mmol) in HOAc (20 mL)/Ac2O (2 mL)/H2SO4 (1.1
mL) was stirred overnight (TLC, MeOH/CH2Cl2, 0.25:20,
showed conversion of 6a to a more polar product). Extraction
workup and chromatography (MeOH/CH2Cl2, 0.25:20) gave 9a
(740 mg, 70%): 1H NMR δ 6.08 (s, 1H), 5.32 (d, J ) 4.8 Hz,
1H), 4.41 (dd, J ) 2.2, 10.6 Hz, 1H), 4.39-4.24 (m, 3H), 4.16
(q, J ) 7.2 Hz, 1H), 3.07 (s, 3H), 2.93-2.80 (m, 1H), 2.62 (dd,
J ) 6.8, 16.6 Hz, 1H), 2.48 (dd, J ) 7.0, 16.6 Hz, 1H), 2.12 (s,
6H), 1.27 (t, J ) 7.2 Hz, 3H); 13C NMR (major anomer*) δ
170.9, 169.5, 169.2, 98.5*, 94.9, 82.1*, 82.0, 77.2*, 71.8, 70.4*,
70.0, 61.1*, 37.6*, 37.5*, 35.9, 33.1, 21.0, 20.5, 14.0; MS m/z
405.0816 (MNa+ [C14H22O10NaS] ) 405.0831).
1,2-Di-O-a cetyl-3-d eoxy-5-O-m eth a n esu lfon yl-3-[(m eth -
oxyca r bon yl)m eth yl]-r-D-r ibofu r a n ose (9b). A solution of
6b (3.0 g, 9.3 mmol) in HOAc (40 mL)/Ac2O (4 mL)/H2SO4 (2.2
mL) was stirred for 7 h (TLC, MeOH/CH2Cl2, 0.25:20, devel-
oped twice, showed conversion of 6b to a slightly more polar
product). Extraction workup gave clean 9b (2.16 g, 63%): 1H
NMR δ 6.42 (d, J ) 4.0 Hz, 0.15H), 6.09 (s, 0.85H), 5.32 (d, J
) 5.0 Hz, 1H), 4.42-4.19 (m, 3H), 3.73, 3.07 (2 × s, 2 × 3H),
2.94-2.80 (m, 1H), 2.63 (dd, J ) 7.3, 16.7 Hz, 1H), 2.48 (dd, J
) 7.0, 16.7 Hz, 1H), 2.12, 2.11 (2 × s, 2 × 3H); 13C NMR δ
171.3, 169.6, 169.3, 98.5, 82.1, 70.4, 52.2, 37.8, 37.6, 30.4, 21.0,
20.6; MS m/z 391.0680 (MNa+ [C13H20O10NaS] ) 391.0675).
1,2,5-Tr i-O-a cetyl-3-d eoxy-3-[(eth oxyca r bon yl)m eth yl]-
D-r ibofu r a n ose (10a ). Meth od A. A solution of 7 (141 mg,
0.466 mmol) in HOAc (10 mL)/Ac2O (1 mL)/H2SO4 (0.5 mL)
was stirred for 3 h [TLC, EtOAc/hexanes, 1:3, showed conver-
sion of 7 to a more polar product (major) and a less polar
byproduct (trace)]. Extraction workup and chromatography
(EtOAc/hexanes 1:4) gave 10a (41 mg, 25%).
Meth od B. A suspension of CsOAc (6.03 g, 31.4 mmol) in
DMF (200 mL) was stirred at reflux for 3 h, and the oil bath
was cooled to 120 °C. A solution of 9a (4.00 g, 10.5 mmol) in
DMF (30 mL) was added, stirring was continued for 20 min
(TLC, EtOAc/hexanes, 1:2, showed conversion of 9a into a less
polar product), and volatiles were evaporated. Extraction
workup and chromatography (EtOAc/hexanes, 1:2) of the
brown residue gave 10a (2.99 g, 83%): 1H NMR δ 6.11 (s, 1H),
5.30 (d, J ) 4.8 Hz, 1H), 4.29-4.06 (m, 5H), 2.88-2.72 (m,
1H), 2.56 (dd, J ) 8.6, 16.6 Hz, 1H), 2.44 (dd, J ) 6.5, 16.7
Hz, 1H), 2.10 (s, 3H), 2.08 (s, 6H), 1.25 (t, J ) 7.2 Hz, 3H); 13
C
NMR δ 171.1, 170.7, 169.7, 169.2, 98.7, 82.1, 77.1, 65.2, 61.0,
37.9, 30.3, 21.0, 20.7, 20.5, 14.0; MS (CI) m/z 347.1339 (MH+
[C15H23O9] ) 347.1342).
1,2,5-Tr i-O-a cetyl-3-d eoxy-3-[(m eth oxyca r bon yl)m eth -
yl]-D-r ibofu r a n ose (10b). A suspension of CsOAc (3.16 g, 16.5
mmol) in DMF (40 mL) was stirred at reflux for 1 h, and the
oil bath was cooled to ∼120 °C. A solution of 9b (1.82 g, 4.94
mmol) in DMF (40 mL) was added, stirring was continued for
80 min (TLC, EtOAc/hexanes, 1:1, showed conversion of 9b to
a less polar product), and volatiles were evaporated. Extraction
workup, chromatography (EtOAc/hexanes 1:2), and recrystal-
lization (hexanes/EtOAc) gave 10b (1.17 g, 71%) with mp 85-
88 °C: 1H NMR δ 6.41 (d, J ) 4.2 Hz, 0.15H), 6.10 (s, 0.85H),
5.31 (d, J ) 4.4 Hz, 1H), 4.35-4.08 (m, 3H), 3.70 (s, 3H), 2.88-
2.74 (m, 1H), 2.59 (dd, J ) 8.6, 16.4 Hz, 1H), 2.47 (dd, J )
5.8, 16.4 Hz, 1H), 2.11 (s, 3H), 2.09 (s, 6H); 13C NMR (major
anomer*) δ 171.4, 170.6, 169.6, 169.1, 98.7*, 95.0, 82.1*, 82.0,
77.2*, 72.0, 65.2*, 65.1, 52.1*, 38.1*, 36.3, 33.0, 30.2*, 21.1,
20.8, 20.6; MS m/z 355.1020 (MNa+ [C14H20O9Na] ) 355.1005).
P r oced u r e A (Cou p lin g Ad en in e w ith 8 or 10a ). Ad-
enine was added to a solution of the carbohydrate derivative
in dried MeCN, and SnCl4 (2 equiv) in dried MeCN was added
to the suspension. Stirring was continued for 24 h, and the
mixture was neutralized with saturated NaHCO3/H2O. Extrac-
tion workup (CH2Cl2) and chromatography gave 11 or 15.
P r oced u r e B (Cou p lin g 6-N-Ben zoyla d en in e, Ur a cil,
or Th ym in e w ith 8, 10a , or 10b). A suspension of nucleobase
and (NH4)2SO4 (trace) in HMDS was stirred at reflux (with
2′-O-Acetyl-5′-a zid o-3′,5′-d id eoxy-3′-[(eth oxyca r bon yl)-
m eth yl]u r id in e (14). Procedure B [8 (330 mg, 1.00 mmol),
uracil (260 mg, 2.32 mmol), TMSOTf (0.20 mL, 245 mg, 1.1
mmol), chromatography (MeOH/CH2Cl2, 0.4:20)] gave 14 (295
mg, 77%): 1H NMR (Me2SO-d6, 500 MHz) δ 11.91 (s, 1H, ex),
7.67 (d, J ) 8.3 Hz, 1H), 5.66 (d, J ) 2.0 Hz, 1H), 5.65 (d, J )
7.8 Hz, 1H), 5.37 (dd, J ) 2.7, 7.1 Hz, 1H), 4.02 (q, J ) 7.0 Hz,
2H), 3.99-3.97 (m, 1H), 3.69 (dd, J ) 2.4, 13.7 Hz, 1H), 3.48
(dd, J ) 5.9, 13.7 Hz, 1H), 2.89-2.82 (m, 1H), 2.54 (dd, J )
5.4, 17.2 Hz, 1H), 2.45 (dd, J ) 9.3, 17.0 Hz, 1H), 2.00 (s, 3H),
1.18 (t, J ) 7.0 Hz, 3H); 13C NMR (Me2SO-d6) δ 171.1, 169.5,
163.0, 150.0, 142.0, 102.0, 90.8, 81.4, 76.2, 60.1, 51.3, 38.0, 29.9,
20.3, 14.0; MS (thioglycerol) m/z 382.1356 (MH+ [C15H20N5O7]
) 382.1363).
2′,5′-Di-O-a cetyl-3′-d eoxy-3′-[(eth oxyca r bon yl)m eth yl]-
a d en osin e (15). Procedure A [10a (1.09 g, 3.15 mmol),
adenine (470 mg, 3.45 mmol), SnCl4 (0.74 mL, 1.65 g, 6.33
mmol), MeCN (50 mL), chromatography (MeOH/CH2Cl2, 0.6:
20)] gave 15 (1.0 g, 75%): 1H NMR δ 8.36, 7.98 (2 × s, 2 ×
1H), 6.03 (d, J ) 1.2 Hz, 1H), 5.90 (br s, 2H), 5.84 (dd, J )
1.3, 5.7 Hz, 1H), 4.47-4.40 (m, 1H), 4.35-4.20 (m, 2H), 4.14
(q, J ) 7.1 Hz, 2H), 3.48-3.32 (m, 1H), 2.63 (dd, J ) 8.5, 16.6
Hz, 1H), 2.50 (dd, J ) 6.2, 16.7 Hz, 1H), 2.15, 2.06 (2 × s, 2 ×
3H), 1.25 (t, J ) 7.1 Hz, 3H); 13C NMR δ 170.9, 170.6, 169.8,

2944 J . Org. Chem., Vol. 65, No. 10, 2000
Robins et al.
155.6, 153.2, 149.4, 139.0, 120.1, 89.3, 82.1, 78.0, 63.4, 61.0,
38.1, 30.2, 20.6, 20.5, 14.0; MS (thioglycerol) m/z 422.1667
(MH+ [C18H24N5O7] ) 422.1676).
the residue was dried in vacuo (e40 °C, 24 h). TBDMSCl (180
mg, 1.19 mmol) and dried DMF/pyridine (1:1, 3 mL) were
added, and stirring was continued for 5 days at ambient
temperature (while protected from moisture). MeOH (1-2 mL)
was added, volatiles were evaporated (e40 °C), and the residue
was chromatographed (5 f 7% MeOH/CH2Cl2) to give 20 (16
mg, 40%) [1H NMR δ 9.48 (br s, 1H, ex), 7.09, 5.57 (2 × s, 2 ×
1H), 5.33 (d, J ) 6.8 Hz, 1H), 4.03-3.94 (m, 1H), 3.65 (dd, J
) 4.2, 13.2 Hz, 1H), 3.54 (dd, J ) 5.4, 13.0 Hz, 1H), 3.41 (“q”,
J ) 7.8 Hz, 1H), 2.84 (dd, J ) 8.6, 18.4 Hz, 1H), 2.42 (d, J )
18.2 Hz, 1H), 1.93 (s, 3H); MS m/z 352.0620 ([MNa2 - H]+
[C12H12N5O5Na2] ) 352.0634)] and 21 (30 mg, 52%).
Lactone 20 was saponified and treated with TBDMSCl (60
mg, 0.40 mmol) and dried DMF/pyridine (1:1, 1.5 mL) as
described to give additional 21 (12 mg, 21%; combined yield,
73%): 1H NMR δ 9.53 (br s, 1H, ex), 7.63, 5.68 (2 × s, 2 ×
1H), 4.45 (d, J ) 4.2 Hz, 1H), 4.10 (d, J ) 10.0 Hz, 1H), 3.89
(dd, J ) 1.5, 13.7 Hz, 1H), 3.58 (dd, J ) 2.8, 13.6 Hz, 1H),
2.75-2.63 (m, 1H), 2.51-2.30 (m, 2H), 1.94 (s, 3H), 0.89 (br s,
9H), 0.18, 0.06 (2 × s, 2 × 3H); 13C NMR δ 164.5, 150.4, 136.0,
110.5, 92.0, 81.7, 77.3, 51.5, 39.2, 29.6, 25.7, 17.9, 12.6, -4.6,
-5.7; MS m/z 440.1971 (MH+ [C18H30N5O6Si] ) 440.1965).
2′-O-(ter t-Bu t yld im et h ylsilyl)-3′-(ca r b oxym et h yl)-3′-
d eoxy-5′-O-(4,4′-d im eth oxytr ityl)a d en osin e Tr ieth yla m -
m on iu m Sa lt (23). A solution of 15 (100 mg, 0.237 mmol) in
MeOH (0.45 mL) and NaOH/H2O (3.5 M, 0.45 mL) was stirred
overnight at ambient temperature and neutralized (dropwise
addition of 3% HCl/H2O), and volatiles were evaporated. Dried
DMF/pyridine (1:1) was added and evaporated several times,
and the residue was dried in vacuo (40 °C, 48 h). DMTCl (100
mg, 0.296 mmol) and dried Et3N/pyridine (1:1, 1.5 mL) were
added, and stirring was continued for 24 h at ambient
temperature. TLC (5% MeOH/CH2Cl2) showed conversion of
the “baseline” intermediate into a product (Rf 0.4) assumed to
be 3′-(carboxymethyl)-3′-deoxy-5′-O-(4,4′-dimethoxytrityl)ad-
enosine 2′,3′-lactone (22) (orange color developed with 5% H2-
SO4/EtOH).
2′,5′-Di-O-a cetyl-6-N-(ben zoyl)-3′-d eoxy-3′-[(eth oxyca r -
bon yl)m eth yl]a d en osin e (16). Procedure B [10a (1.50 g, 4.33
mmol), 6-N-benzoyladenine (2.07 g, 8.65 mmol), TMSOTf (0.87
mL, 1.1 g, 4.8 mmol), chromatography (MeOH/CH2Cl2, 0.65:
20)] gave 16 (1.51 g, 66%): 1H NMR δ 8.99 (s, 1H, ex), 8.83,
8.20 (2 × s, 2 × 1H), 8.03 (d, J ) 7.2 Hz, 2H), 7.66-7.50 (m,
3H), 6.10 (s, 1H), 5.87 (d, J ) 5.6 Hz, 1H), 4.50-4.29 (m, 3H),
4.16 (q, J ) 7.2 Hz, 2H), 3.50-3.31 (m, 1H), 2.66 (dd, J ) 8.4,
16.6 Hz, 1H), 2.54 (dd, J ) 6.0, 16.6 Hz, 1H), 2.18, 2.08 (2 ×
s, 2 × 3H), 1.26 (t, J ) 7.2 Hz, 3H); MS m/z 548.1760 (MNa+
[C25H27N5O8Na] ) 548.1757).
2′,5′-Di-O-a cetyl-3′-d eoxy-3′-[(eth oxyca r bon yl)m eth yl]-
5-m eth ylu r id in e (17a ). Procedure B [10a (1.45 g, 4.19 mmol),
thymine (1.10 g, 8.72 mmol), TMSOTf (0.88 mL, 1.1 g, 4.9
mmol), chromatography (MeOH/CH2Cl2, 0.6:20)] gave 17a
(1.73 g, quant.): 1H NMR (Me2SO-d6) δ 11.38 (s, 1H, ex), 7.51
(s, 1H), 5.67 (d, J ) 2.6 Hz, 1H), 5.34 (dd, J ) 2.7, 7.3 Hz,
1H), 4.30 (dd, J ) 2.5, 12.1 Hz, 1H), 4.16 (dd, J ) 5.6, 12.2
Hz, 1H), 4.02 (q, J ) 7.1 Hz, 2H), 4.08-3.97, 2.94-2.78 (2 ×
m, 2 × 1H), 2.57 (dd, J ) 5.8, 17.2 Hz, 1H), 2.46 (dd, J ) 9.0,
16.6 Hz, 1H), 2.02 (s, 6H), 1.78 (s, 3H), 1.14 (t, J ) 7.0 Hz,
3H); 13C NMR (Me2SO-d6) δ 171.4, 170.4, 169.7, 164.0, 150.3,
137.2, 109.9, 90.2, 80.5, 76.4, 63.7, 60.3, 37.6, 30.2, 20.6, 20.3,
14.0, 12.1; MS m/z 435.1370 (MNa+ [C18H24N2O9Na] )
435.1380).
2′,5′-Di-O-acetyl-3′-deoxy-3′-[(m eth oxycar bon yl)m eth yl]-
5-m eth ylu r id in e (17b). Procedure B [10b (166 mg, 0.500
mmol), thymine (126 mg, 1.00 mmol), TMSOTf (100 µL, 123
mg, 0.553 mmol), chromatography (MeOH/CH2Cl2, 0.6:20)]
gave 17b (155 mg, 78%): 1H NMR δ 8.63 (s, 1H, ex), 7.23 (s,
1H), 5.76 (d, J ) 1.8 Hz, 1H), 5.48 (dd, J ) 1.8, 6.6 Hz, 1H),
4.40 (dd, J ) 2.9, 12.9 Hz, 1H), 4.31 (dd, J ) 4.6, 13.2 Hz,
1H), 4.14 (dt, J ) 3.1, 9.5 Hz, 1H), 3.70 (s, 3H), 2.95-2.84 (m,
1H), 2.57 (dd, J ) 8.1, 16.0 Hz, 1H), 2.43 (dd, J ) 6.3, 16.0
Hz, 1H), 2.14, 2.12, 1.94 (3 × s, 3 × 3H); 13C NMR δ 171.3,
170.4, 169.5, 163.3, 149.8, 135.6, 111.2, 90.7, 81.4, 77.1, 63.2,
52.2, 38.1, 30.2, 20.8, 20.5, 12.6; MS m/z 421.1223 (MNa+
[C17H22N2O9Na] ) 421.1223).
5′-Azid o-2′-O-(ter t-bu tyld im eth ylsilyl)-3′-(ca r boxym e-
th yl)-3′,5′-d id eoxya d en osin e (19). A solution of 11 (65 mg,
0.16 mmol) in MeOH (0.3 mL) and NaOH/H2O (6 M, 0.17 mL)
was stirred overnight at ambient temperature. Volatiles were
evaporated, and dried DMF/pyridine (1:1) were added and
evaporated several times. The residue was dried in vacuo (40
°C, 24 h), TBDMSCl (300 mg, 2.0 mmol) and dried DMF/
pyridine (1:2, 1.5 mL) were added, and stirring was continued
for 5 days at ambient temperature (while protected from
moisture). MeOH (1-2 mL) was added, and volatiles were
evaporated (e40 °C). Chromatography of the residue (5 f 15%
MeOH/CH2Cl2) gave 18 (21 mg, 41%) [1H NMR δ 8.33, 7.91 (2
× s, 2 × 1H), 6.20 (s, 1H), 5.69 (s, 2H), 5.67 (d, J ) 6.2 Hz,
1H), 4.14-4.10, 3.88-3.76 (2 × m, 2 × 1H), 3.60-3.52 (m, 2H),
2.96 (dd, J ) 8.3, 18 Hz, 1H), 2.54 (d, J ) 18 Hz, 1H); MS m/z
317.1114 (MH+ [C12H13N8O3] ) 317.1111]] and 19 (34 mg,
47%).
Volatiles were evaporated, the residue was partitioned
(NaHCO3/H2O//CH2Cl2), and the combined organic phase was
evaporated. The residue was dissolved in MeOH (0.4 mL) and
NaOH/H2O (2.5 M, 0.4 mL), and conversion of this material
into TLC-baseline product was monitored. When saponification
was complete, the solution was neutralized carefully (pH ∼8,
dropwise addition of 5% AcOH/H2O at 0 °C). Volatiles were
evaporated, dried DMF was added and evaporated (2 × 30
mL), and the residue was dried in vacuo (overnight, 40 °C).
Dried DMF (11 mL), imidazole (720 mg, 10.6 mmol), and
TBDMS-imidazolide/CH2Cl2 (1 M, 5 mL, 5 mmol) were added,
and stirring was continued for 3 days at ambient temperature.
Volatiles were evaporated, and the residue was partitioned
(NaHCO3/H2O//CH2Cl2). The combined organic phase was
dried (Na2SO4), evaporated, and chromatographed (5 f 10%
MeOH/CH2Cl2 containing 0.2% Et3N) to give 22 and 23 (102
mg, 52% from 15): 1H NMR (Me2SO-d6) δ 8.21, 8.13 (2 × s, 2
× 1H), 7.40-7.23 (m, 9H), 6.87-6.82 (m, 4H), 5.89 (d, J ) 1.0
Hz, 1H), 4.80 (d, J ) 4.8 Hz, 1H), 4.05-3.93 (m, 1H), 3.73 (s,
6H), 3.41-3.36 (m, 1H), 3.29 (dd, J ) 5.0, 11.2 Hz, 1H), 2.77
(q, J ) 7.2 Hz, ∼6H), 2.40 (dd, J ) 9.2, 16.8 Hz, 1H), 2.04 (dd,
J ) 4.3, 17.1 Hz, 1H), 1.06 (t, J ) 7.2 Hz, ∼9H), 0.84 (s, 9H),
0.51, 0.00 (2 × s, 2 × 3H); 13C NMR (Me2SO-d6) δ 173.6, 158.2,
156.2, 152.8, 149.0, 144.9, 138.4, 135.6, 129.8, 127.9, 127.8,
126.8, 119.3, 113.3, 90.0, 85.8, 82.5, 76.7, 63.6, 55.0, 45.4, 30.2,
Lactone 18 was subjected to the same saponification and
protection sequence [TBDMSCl (100 mg, 0.664 mmol) in dried
DMF/pyridine (1:2, 0.75 mL)] to give additional 19 (15 mg,
21%; combined yield, 68%): 1H NMR δ 8.30, 8.25 (2 × s, 2 ×
1H), 7.15 (br s, 2H), 6.02 (s, 1H), 4.77 (d, J ) 4.0 Hz, 1H), 4.25
(“d”, J ) 9.0 Hz, 1H), 3.87 (“d”, J ) 14.0 Hz, 1H), 3.62 (dd, J
) 3.9, 13.7 Hz, 1H), 2.81 (m, 1H), 2.71 (dd, J ) 8.2, 15.7 Hz,
1H), 2.40 (dd, J ) 4.5, 15.7 Hz, 1H), 0.93 (br s, 9H), 0.20, 0.09
(2 × s, 2 × 3H); 13C NMR δ 176.1, 155.6, 152.1, 149.1, 138.9,
119.1, 91.2, 82.6, 78.0, 52.0, 40.0, 29.7, 25.8, 18.0, -4.5, -5.4;
MS m/z 449.2074 (MH+ [C18H29N8O4Si] ) 449.2081).
5′-Azid o-2′-O-(ter t-bu tyld im eth ylsilyl)-3′-(ca r boxym e-
th yl)-3′,5′-d id eoxy-5-m eth ylu r id in e (21). NaOH/H2O (6 M,
0.1 mL) was added to a solution of 13 (50 mg, 0.13 mmol) in
MeOH (0.4 mL), and stirring was continued overnight at
ambient temperature. Volatiles were evaporated, dried DMF/
pyridine (1:1) was added and evaporated several times, and
1
25.6, 17.6, 9.8, -4.8, -5.6; H NMR δ 8.28, 8.07 (2 × s, 2 ×
1H), 7.49-7.12 (m, 9H), 6.80 (d, J ) 8.0 Hz, 4H), 6.04 (s, 1H),
5.82 (br s, 2H), 4.79 (d, J ) 3.8 Hz, 1H), 4.27-4.17 (m, 1H),
3.76 (s, 6H), 3.48-3.40 (m, 1H), 3.33 (dd, J ) 5.4, 10.8 Hz,
1H), 2.76 (q, J ) 7.2 Hz, ∼6H), 2.62-2.42, 2.16-2.04 (2 × m,
2 × 1H), 1.11 (t, J ) 7.3 Hz, ∼9H), 0.92 (s, 9H), 0.26, 0.10 (2
× s, 2 × 3H); 13C NMR δ 177.0, 158.5, 155.3, 152.6, 144.7,
138.8, 136.1, 135.8, 130.2, 130.1, 128.3, 127.9, 126.8, 113.2,
91.5, 86.4, 83.5, 77.8, 64.2, 55.1, 45.1, 40.3, 31.2, 25.8, 18.0,
9.5, -4.5, -5.5; MS m/z 748.3160 (MNa+ [C39H47N5O7SiNa] )
748.3142).
2′-O-(ter t-Bu t yld im et h ylsilyl)-3′-(ca r b oxym et h yl)-3′-
d eoxy-5′-O-(4,4′-d im eth oxytr ityl)-5-m eth ylu r id in e (25). A

Amide-Linked Oligonucleotide Analogues
J . Org. Chem., Vol. 65, No. 10, 2000 2945
solution of 17a (100 mg, 0.242 mmol) in MeOH (0.40 mL) and
NaOH/H2O (5 M, 0.40 mL) was stirred overnight at ambient
temperature and then neutralized by dropwise addition of HCl/
dioxane (4 M). Volatiles were evaporated, MeOH was added
and evaporated (3×), and the residue was dried in vacuo (40
°C, 48 h). DMTCl (164 mg, 0.48 mmol) and dried Et3N/pyridine
(1:1, 1.5 mL) were added, and stirring was continued for 24 h
at ambient temperature. TLC (5% MeOH/CH2Cl2) showed
conversion of the “baseline” intermediate into a single product
(Rf 0.5, orange color developed with 5% H2SO4/EtOH). Volatiles
were evaporated, the residue was partitioned (NaHCO3/H2O//
CH2Cl2), and the combined organic phase was dried (Na2SO4).
Volatiles were evaporated, and the residue was chromato-
graphed (5% MeOH/CH2Cl2 containing 0.2% Et3N) to give
amorphous 3′-(carboxymethyl)-3′-deoxy-5′-O-(4,4′-dimethoxy-
trityl)-5-methyluridine 2′,3′-lactone (24): 1H NMR δ 7.42-7.22
(m, 9H), 6.82 (dd, J ) 1.4, 9 Hz, 4H), 5.75 (s, 1H), 5.16 (dd, J
) 1.2, 6.8 Hz, 1H), 3.95-3.86 (m, 1H), 3.78 (s, 6H), 3.45 (“d”,
J ) 4.6 Hz, 2H), 3.32-3.19 (m, 1H), 2.74 (dd, J ) 8.2, 18.0
Hz, 1H), 2.33 (d, J ) 18.4 Hz, 1H), 1.76 (d, J ) 1.0 Hz, 3H);
MS m/z 584.2163 (M+ [C33H32N2O8] ) 584.2159).
silylation of the less polar compound]. Volatiles were evapo-
rated, the residue was partitioned (NaHCO3/H2O//CH2Cl2), and
the combined organic phase was dried (Na2SO4). Volatiles were
evaporated, and the residue was stirred in acetone (10 mL)/
H2O (10 drops)/Et3N (10 drops) for 3 days at ambient temper-
ature (TLC showed conversion of the less to more polar
product). Volatiles were evaporated, and the residue was
chromatographed (5 f 10% MeOH/CH2Cl2 containing 0.2%
Et3N) to give 25 (106 mg, 61% from 17): 1H NMR (500 MHz)
δ 9.58 (s, 1H), 7.83 (d, J ) 1.0 Hz, 1H), 7.42 (“d”, J ) 7.5 Hz,
2H), 7.31-7.26 (m, 7H), 6.85-6.82 (m, 4H), 5.71 (s, 1H), 4.53
(d, J ) 3.5 Hz, 1 H), 4.10 (dt, J ) 2.3, 9.5 Hz, 1H), 3.80-3.74
(m, 1H), 3.78 (s, 6H), 3.67 (dd, J ) 1.5, 11.5 Hz, 1H), 3.23 (dd,
J ) 3.3, 11.3 Hz, 1H), 2.69-2.56 (m, 2H), 2.10 (dd, J ) 3.0,
16.5 Hz, 1H), 1.40 (d, J ) 1.0 Hz, 3H), 0.88 (br s, 9H), 0.22,
0.07 (2 × s, 2 × 3H); 13C NMR (75 MHz) δ 176.3, 164.6, 158.7,
150.5, 144.1, 136.0, 135.2, 135.1, 130.1, 128.1, 128.0, 127.2,
126.2, 115.6, 113.3, 110.3, 92.0, 86.8, 83.1, 77.3, 61.8, 55.2, 38.4,
28.8, 25.8, 18.0, 12.0, -4.4, -5.7; MS m/z 761.2858 {(MNa2
-
H)+ [C39H47N2O9SiNa2] ) 761.2846}.
This material was dissolved in MeOH (0.4 mL) and NaOH/
H2O (2.5 M, 0.4 mL) and stirred at ambient temperature until
saponification was complete (TLC). The solution was neutral-
ized carefully (pH ∼8, 5% AcOH/H2O at 0 °C), and volatiles
were evaporated. Dried DMF was added and evaporated (2 ×
30 mL), and the residue was dried in vacuo (overnight, 40 °C).
DMF (11 mL), imidazole (720 mg, 10.6 mmol), and TBDMS-
imidazolide/CH2Cl2 (1 M, 5 mL, 5 mmol) were added, and
stirring was continued for 3 days at ambient temperature. TLC
showed formation of two major products [MS (FAB) m/z
853.3909 (MNa+ [C45H62N2O9Si2Na] ) 853.3892) indicated bis-
Ack n ow led gm en t. We thank Brigham Young Uni-
versity and Isis Pharmaceuticals for financial support
and Mrs. J eanny K. Gordon for assistance with the
manuscript.
1
Su p p or tin g In for m a tion Ava ila ble: Copies of H NMR
spectra for 1, 2, 4-19, 21, 23, and 25. This material is
available free of charge via the Internet at http://pubs.acs.org.
J O991399G