Amide-Linked Ribonucleoside Dimers Derived from S′-Amino-5′-deoxy- and 3′-(Carboxymethyl)-3′-deoxynucleoside Precursors

Article abstract of DOI:10.1021/jo9908647

Treatment of tert-butyldimethylsilyl (TBDMS) derivatives of 3′-keto(adenosine or uridine) with [(ethoxycarbonyl)methylene]triphenylphosphorane gave exocyclic alkenes that underwent stereo-selective hydrogenation to give 3′-deoxy-3′-[(ethoxycarbonyl)methyl](Ado or Urd) analogues. Saponification provided the 3′-(carboxymethyl)-3′-deoxy(Ado and Urd) derivatives 37 and 38. Treatment of 37 or 38 with DCC and 5′-amino-2′,3′-bis-O-TBDMS-5′-deoxynucleosides gave the amide-linked dimers (74-82%). Activation of 37 or 38 with 4-nitrophenol/DCC, and direct coupling of the 4-nitrophenyl esters with 5′-amino-5′-deoxy(Ado or Urd) in pyridine also produced amide dimers efficiently (65-70%). Analogous activation of a 5′-O-DMT-protected carboxylate, and its coupling with 5′-amino-5′-deoxy-2′-O-methyladenosine gave the amide dimer in good yield (74%). Coupling (DCC) of a 5′-azido-2′-O-TBDMS-3′-(carboxymethyl)-3′,5′- dideoxyuridine intermediate with 5′-amino-5′-deoxynucleosides gave amide-linked dimers (72-78%) that can serve as masked (azide reduction) 5′-amino dimers for analogous synthesis of extended amide-linked oligomers.

Full text of DOI:10.1021/jo9908647

J . Org. Chem. 1999, 64, 8183-8192
8183
Am id e-Lin k ed Ribon u cleosid e Dim er s Der ived fr om
5′-Am in o-5′-d eoxy- a n d 3′-(Ca r boxym eth yl)-3′-d eoxyn u cleosid e
P r ecu r sor s1
Matt A. Peterson,* Bradley L. Nilsson, Sanchita Sarker, Bogdan Doboszewski,†
Weijian Zhang,‡ and Morris J . Robins*
Department of Chemistry and Biochemistry, Brigham Young University, Provo, Utah 84602-5700
Received May 27, 1999
Treatment of tert-butyldimethylsilyl (TBDMS) derivatives of 3′-keto(adenosine or uridine) with
[(ethoxycarbonyl)methylene]triphenylphosphorane gave exocyclic alkenes that underwent stereo-
selective hydrogenation to give 3′-deoxy-3′-[(ethoxycarbonyl)methyl](Ado or Urd) analogues.
Saponification provided the 3′-(carboxymethyl)-3′-deoxy(Ado and Urd) derivatives 37 and 38.
Treatment of 37 or 38 with DCC and 5′-amino-2′,3′-bis-O-TBDMS-5′-deoxynucleosides gave the
amide-linked dimers (74-82%). Activation of 37 or 38 with 4-nitrophenol/DCC, and direct coupling
of the 4-nitrophenyl esters with 5′-amino-5′-deoxy(Ado or Urd) in pyridine also produced amide
dimers efficiently (65-70%). Analogous activation of a 5′-O-DMT-protected carboxylate, and its
coupling with 5′-amino-5′-deoxy-2′-O-methyladenosine gave the amide dimer in good yield (74%).
Coupling (DCC) of a 5′-azido-2′-O-TBDMS-3′-(carboxymethyl)-3′,5′-dideoxyuridine intermediate with
5′-amino-5′-deoxynucleosides gave amide-linked dimers (72-78%) that can serve as masked (azide
reduction) 5′-amino dimers for analogous synthesis of extended amide-linked oligomers.
In tr od u ction
bioavailability and/or sequence-nonspecific side effects
stimulate continued research in this area.5
Major research efforts have been focused on synthesis
of modified oligomers for antisense applications.2 Oligo-
nucleotide analogues have been designed to have desir-
able properties, including (1) increased cellular perme-
ability, (2) resistance to nucleolytic degradation, and (3)
increased affinity for target nucleic acids. Sugar and base
modifications have been examined,3 but the primary
target has been modification of the phosphodiester
backbone. Serious limitations of phosphodiesters as an-
tisense therapeutics are their low membrane perme-
ability (negative charge density) and their high suscep-
tibility to nucleolytic degradation. A number of phospho-
diester replacements have been examined,2,4 and ana-
logues containing modified linkages have exhibited prom-
ising properties in vitro and in vivo. Problems with
We6 and others7,8 became interested in amide-linked
oligonucleotide analogues for potential antisense applica-
tions. The Novartis group7 have shown that oligomers
containing amide-linked 2′-deoxynucleoside analogues
exhibited increased duplex stability (0.4-0.9 °C/dimer)
and resistance to degradation by (endo and exo)nucleases.
Additional enhancements of duplex stability observed
with oligomers containing amide-linked dimers with 2′-
O-methyl substituents on both sugar rings were at-
tributed to increased population of the 3′-endo (ribo-like)
furanose conformation range.7e NMR and molecular
modeling studies were consistent with similar trends
observed with oligonucleotides with analogous 2′-sub-
stituents.9
(5) (a) Stein, C. A.; Cheng, Y.-C. Science, 1993, 261, 1004-1012. (b)
Gura, T. Science, 1995, 270, 575-577. (c) Brach, A. D. TIBS 1998, 23,
45-50. (d) Damha, M. J .; Wilds, C. J .; Noronha, A.; Brukner, I.;
Borkow, G.; Arion, D.; Parniak, M. A. J . Am. Chem. Soc. 1998, 120,
12976-12977.
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De Mesmaeker, A.; Lebreton, J .; Waldner, A.; Fritsch, V.; Wolf, R. M.;
Freier, S. M. Synlett 1993, 733-736. (c) Lebreton, J .; Waldner, A.;
Lesueur, C.; De Mesmaeker, A. Synlett 1994, 137-140. (d) De
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229. (e) De Mesmaeker, A.; Lesueur, C.; Be´vie`rre, M.-O.; Waldner, A.;
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2794. (f) von Matt, P.; Lochmann, T.; Kesselring, R.; Altmann, K.-H.
Tetrahedron Lett. 1999, 40, 1873-1876.
* To whom correspondence should be addressed. Fax: (801) 378-
5474.
† Present address: Department of Fundamental Chemistry, Federal
University of Pernambuco, Recife, Brazil.
‡ Present address: ICN Pharmaceuticals, Costa Mesa, CA.
(1) Nucleic Acid Related Compounds. 110. (Amide-Linked Nucleo-
sides. 2.). Part 109: Robins, M. J .; Ewing, G. J . J . Am. Chem. Soc.
1999, 121, 5823-5824. (Amide-Linked Nucleosides. 1: Reference 10
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(2) (a) Oligodeoxynucleotides. Antisense Inhibitors of Gene Expres-
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Peyman, A. Chem. Rev. 1990, 90, 544-584. (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
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374. (d) Crooke, S. T. Therapeutic Applications of Oligonucleotides; R.
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10.1021/jo9908647 CCC: $18.00 © 1999 American Chemical Society
Published on Web 10/08/1999

8184 J . Org. Chem., Vol. 64, No. 22, 1999
Peterson et al.
Sch em e 1a
Monomers prepared by free-radical methods are obtained
with high R-facial diastereoselectivity at C3′ from 5′-O-
protected 2′-deoxynucleosides. However, analogous treat-
ment of 2′,5′-di-O-protected ribonucleosides resulted in
coupling at the opposite (â) face to give contaminating15f
or predominant7e formation of xylofuranosyl products.
The sequence we have employed provides efficient access
to 3′-(carboxymethyl)-3′-deoxy compounds with the de-
sired ribo configuration. The Novartis group7f has re-
cently reported adoption of our approach10 for the stereo-
selective preparation of the ribo monomers.
Treatment of 1 or 3 with TFA/H2O (9:1, 0 °C)16 effected
clean O5′ desilylation to give 2 (90%) or 4 (84%),
respectively. Hydrogenation of 2 or 4 gave 7 or 8 (80-
98%). Hydrogenation of the adenine analogues 1 and 2
required more forcing conditions [150% (w/w) catalyst,
30-35 psi, 4 days) than the uracil derivatives 3 and 4
[5-40% (w/w) catalyst, 5-10 psi, 1-2 days]. Partial
saturation of the 5,6-double bond of uracil sometimes
occurred with 3 and 4 (e10%, dependent on the catalyst
batch), but this could be avoided by adjustments of H2
pressure, catalyst ratio, and reaction time. Desilylation
(TBAF/THF) of 5 or 7 gave 9 (72 or 83%, respectively),
and parallel treatment of 6 or 8 gave 10 (85 and 93%,
respectively). Treatment of 9 or 10 with 5′-amino-5′-
deoxy(Ado or Urd) under various conditions failed to give
amide-linked dimers. However, 9 or 10 reacted with 5′-
amino-5′-deoxyAdo (5 equiv) in the presence of 2-pyridone
(2 equiv) in DMF (70 °C, 24-30 h) to give 11 (65%) or 12
(83%), respectively. Low reactivity of nucleoside fused-
lactones with isobutylamine has been noted previously.17
We next examined coupling reactions of 4-nitrophenyl
esters, and condensation of carboxylates (DCC), with
aminonucleosides. Protection of 5′-azido-5′-deoxy[Ado (13)
or Urd (14)] (TBDMSCl/imidazole/pyridine) and azide
reduction (1,3-propanedithiol) gave the 5′-amino-5′-deoxy
derivatives 17 (51%) or 18 (62%) (Scheme 2). Silylation
of 2′-O-methyl[Ado (19) or 5-methylUrd (20)] gave 21 or
22, which were selectively deprotected (O5′), converted
to the 5′-chloro-5′-deoxy derivatives 23 or 24, and treated
with lithium or sodium azide to give 25 or 26. Deprotec-
tion of 25 or 26 (TBAF/THF) gave 27 or 28, which were
hydrogenolyzed (10% Pd-C/EtOH) to give 29 or 30.
Benzoylation of 31 gave 32 (96%), and selective depro-
tection (O5′) gave 33 (81%). The limited solubility of 32
in TFA/H2O required the use of a cosolvent (CH2Cl2). The
5′-O-TBDMS linkage is more stable in CH2Cl2/TFA/H2O
(20:9:1) than in TFA/H2O (9:1), and longer reaction times
at ambient temperature (extremely slow at 0 °C) were
required to effect complete cleavage. Treatment of 33
with SOCl2/pyridine overnight at ambient temperature
gave 34 (70%), which was stirred with LiN3/DMF/110 °C
to give 35. SnCl2/MeOH effected clean (TLC) reduction
a
Key: (a) TFA/H2O (9:1)/0 °C; (b) H2/Pd-C; (c) TBAF/THF; (d)
2-Pyridone/DMF/70 °C.
We have communicated10 synthesis of the γ-butyrolac-
tone-fused (3.3.0) nucleosides 9 and 10 and their applica-
tion for the preparation of amide-linked ribonucleoside
dimers (Scheme 1) that were expected to have a favorable
3′-endo conformational bias,7e,9 resistance to nucleases,
and enhanced membrane permeability (no backbone
charge).11 We had hoped that the lactones would be
readily susceptible to ring opening with 5′-amino-5′-
deoxynucleosides by analogy with model reactions.6,12
However, 9 and 10 proved to be unreactive with 5′-amino-
5′-deoxyadenosine at ambient temperature under a num-
ber of reaction conditions, including addition of several
acylation promoters. Effective lactone opening (65-83%)
was achieved only at elevated temperatures (70 °C/DMF/
24 h) with excess aminonucleoside (5 equiv) and 2-pyri-
done (2 equiv) as a promoter. We now report an alter-
native approach that employs ester saponification,
carboxylate activation, and stoichiometric coupling with
aminonucleosides to provide efficient conversions of 5,
6, and 8 to a number of amide-linked ribonucleoside
dimers and intermediates suitable for further elongation.
Resu lts a n d Discu ssion
Treatment of 2′,5′-bis-O-TBDMS-3′-keto(uridine or ad-
enosine)13 with [(ethoxycarbonyl)methylene]triphenyl-
phosphorane in refluxing CH2Cl2 gave adducts 114 or 36
(80-96%). Stereoselective reduction10,14 of 3 (10% Pd-
C/MeOH) gave 6, whose ribo configuration was indicated
by difference NOE (6% enhancement of the H3′ resonance
upon irradiation of H2′) and corroborated by conversion
to lactone 10. This two-step sequence (Wittig olefination
and stereoselective hydrogenation) provides a valuable
alternative to free-radical coupling methods15 used for the
preparation of 3′-substituted 2′,3′-dideoxynucleosides.7,8
(15) (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. (c) Leitzel, J . C. Ph.D. Dissertation, The University of Chicago,
1996. (d) Grunder-Klotz, E.; J ust, G. Nucleosides Nucleotides 1994,
13, 1829-1841. (e) Caulfield, T. J .; Prasad, C. P.; Prouty, C. P.; Saha,
A. K.; Sardaro, M. P. Bioorg. Med. Chem. Lett. 1993, 3, 2771-2776.
(f) Bhat, B.; Swayze, E. E.; Wheeler, P.; Dimock, S.; Perbost, M.;
Sanghvi, Y. S. J . Org. Chem. 1996, 61, 8186-8199. (g) Fiandor, J .;
Tam, S. Y. Tetrahedron Lett. 1990, 31, 597-600.
(16) Robins, M. J .; Samano, V.; J ohnson, M. D. J . Org. Chem. 1990,
55, 410-412.
(17) (a) Vela´zquez, S.; Huss, S.; Camarasa, M.-J . J . Chem. Soc.,
Chem. Commun. 1991, 1263-1265. (b) Vela´zquez, S.; J imeno, M. L.;
Huss, S.; Balzarini, J .; Camarasa, M.-J . J . Org. Chem. 1994, 59, 7661-
7670.
(10) Robins, M. J .; Sarker, S.; Xie, M.; Zhang, W.; Peterson, M. A.
Tetrahedron Lett. 1996, 37, 3921-3924.
(11) J aroszewski, J . W.; Cohen, J . S. Adv. Drug Delivery Rev. 1991,
6, 235-250.
(12) (a) Rosenthal, A.; Baker, D. A. J . Org. Chem. 1973, 38, 198-
201. (b) Lawrence, A. J .; Pavey, J . B. J .; O’Neil, I. A.; Cosstick, R.
Tetrahedron Lett. 1995, 36, 6341-6344.
(13) Hansske, F.; Madej, D.; Robins, M. J . Tetrahedron 1984, 40,
125-135.
(14) Lee, K.; Wiemer, D. F. J . Org. Chem. 1993, 58, 7808-7812.

Amide-Linked Ribonucleoside Dimers
J . Org. Chem., Vol. 64, No. 22, 1999 8185
Sch em e 2a
Sch em e 3a
a
Key: (a) TBDMSCl/imidazole/pyridine; (b) HS(CH2)3SH/Et3N;
(c) TFA/H2O (9:1)/0 °C; (d) (SOCl2 or MsCl)/pyridine; (e) (NaN3 or
LiN3)/DMF/110 °C; (f) Bu4NF/THF; (g) H2/Pd-C; (h) BzCl/pyridine;
(i) SnCl2‚2H2O/MeOH.
a
Key: (a) (i) NaOH/H2O, (ii) HCl/H2O; (b) 4-nitrophenol/DCC;
(c) (17 or 18)/DCC/CH2Cl2; (d) 5′-amino-5′-deoxy(Ado or Urd)/
EtOH; (e) (i) MsCl/pyridine/CH2Cl2, (ii) NaN3/DMF/110 °C; (f)
DMTCl/Et3N/pyridine; (g) HS(CH2)3SH/Et3N; (h) H2/Pd-C; (i) 36/
DCC/CH2Cl2; (j) 29/EtOH; (k) 42/DCC/CH2Cl2.
of 35 to 36 (52%), whereas certain other methods for
conversion of azides to amines (H2/Pd-C, 1,3-propanedithi-
ol, Ph3P/NH3/H2O/dioxane) gave mixtures.
Saponification of 5 or 6 (NaOH/H2O/MeOH) gave the
3′-(carboxymethyl) derivatives 37 (73%) or 38 (88%),
respectively (Scheme 3). Analogous treatment of 8 or 40
gave 43 (66%) or 41 (77%), respectively. Stoichiometric
DCC-mediated condensation of 37 or 38 with 17 or 18
generated the amide-linked dimers 46-48 (74-82%), and
analogous coupling of 41 with 18 (0.9 equiv) or 42 (1.1
equiv) gave dimers 53 (78%) or 55 (72%).
Block incorporation of amide dimers into oligonucleo-
tides via automated synthesizer technology requires
appropriate protection, and the DMT group at O5′ is used
extensively. Treatment of 43 with DMTCl/pyridine gave
44 (62%), which was subjected to DCC-mediated conden-
sation with 36 to give 51 (71%). Active ester 45 [prepared
(61%) from 44/4-nitrophenol/DCC] was treated with 29
(1.2 equiv)/THF/EtOH to give 52 (74%) and 39 [prepared
(72%) from 37/4-nitrophenol/DCC] was treated with 5′-
amino-5′-deoxy(Ado or Urd) to give dimers 49 (65%) or
50 (70%), respectively. Thus, standard protecting group
manipulation is compatible with the present amide-
dimer chemistry. Dimers 53-57 were prepared to explore
the potential of this approach for synthesis of amide
oligomers. Key intermediate 55 underwent saponification
to give 57 (64%). Treatment of 55 with 1,3-propanedithiol/
EtOH gave 56 (71%), and hydrogenation of 53 (H2/10%
Pd-C/THF) proceeded without incident to give 54 (63%).
to 3′-deoxy-3′-(carboxymethyl)ribonucleoside derivatives.
The 3′-deoxy-3′-[(ethoxycarbonyl)methyl](Ado and Urd)
compounds 5-8 have been employed for synthesis of
amide-linked ribonucleoside dimers. Derivatives 5-8
were saponified to give 3′-(carboxymethyl)-3′-deoxy(Ado
or Urd) intermediates, which were condensed (DCC) with
protected 5′-amino-5′-deoxynucleosides to give amide
dimers in good yields. Conversion of the carboxymethyl
intermediates into active esters (4-nitrophenol/DCC)
allowed their coupling with unprotected 5′-amino-5′-
deoxynucleosides to give amide dimers with free hydroxyl
groups. No problems were encountered with chemistry
involved with the use of dimethoxytrityl (DMT) and other
standard protecting groups.
Exp er im en ta l Section
Uncorrected melting points were determined with a capil-
1
lary apparatus. H (200 or 500 MHz) and 13C (50 MHz) NMR
spectra were determined with solutions in (Me4Si)/CDCl3
unless otherwise noted. Observed (“apparent”) multiplicities
1
are noted with quotation marks for H NMR peaks that should
exhibit more complex splitting patterns. Mass spectra (MS and
HRMS) were obtained with electron impact (EI, 20 eV),
chemical ionization (CI, isobutane), or fast-atom bombardment
(FAB, NaOAc/thioglycerol or thioglycerol matrix) techniques.
Reagent chemicals were used, and solvents were dried by
reflux and distillation from standard drying agents under N2.
TLC was performed on Merck kieselgel 60-F254 sheets, and
Merck kieselgel 60 (230-400 mesh) was used for flash chro-
matography.18 “Solvent system A (SSA)” for chromatography
is the separated organic phase of EtOAc/i-PrOH/H2O (4:1:2).
Elemental analyses were determined by M-H-W Laborato-
Con clu sion s
Free radical-mediated coupling procedures with 2′,5′-
di-O-protected nucleosides have resulted in contamina-
ting15f or preferential7e attack at the â face to give
xylofuranosyl products, whereas the present Wittig ole-
fination of 3′-keto-2′,5′-bis-O-TBDMS nucleosides and
stereoselective10,14 hydrogenation provides efficient access
(18) Still, W. C.; Kahn, M.; Mitra, A. J . Org. Chem. 1978, 43, 2923-
2925.

8186 J . Org. Chem., Vol. 64, No. 22, 1999
Peterson et al.
ries, Phoenix, AZ. Compounds 1,19 5,14 13,20 14,21 19,22 20,22
and 3123 were prepared as described.
Et (550 mg, 1.58 mmol) in CH2Cl2 (25 mL) was refluxed for
16 h. Volatiles were evaporated, and the residue was chro-
matographed (CH2Cl2) to give 3 (689 mg, 96%) as a solid
foam: 1H NMR δ 9.39 (br s, 1H), 8.01 (d, J ) 8.0 Hz, 1H),
5.98 (d, J ) 7.7 Hz, 1H), 5.88 (“t”, J ) 2.2 Hz, 1H), 5.76 (dd,
J ) 8.1, 1.6 Hz, 1H), 5.36-5.32 (m, 1H), 4.68 (dt, J ) 7.6, 2.0
Hz, 1H), 4.28-4.13 (m, 3H), 3.92 (dd, J ) 11.1, 2.0 Hz, 1H),
1.29 (t, J ) 7.1 Hz, 3H), 0.88 (br s, 18H), 0.05, 0.03, 0.02, -0.08
(4 × s, 4 × 3H); 13C NMR δ 165.1, 162.9, 159.2, 150.5, 139.8,
113.9, 103.2, 85.6, 80.0, 76.9, 64.5, 60.6, 25.8, 25.5, 18.3, 17.8,
14.2, -4.9, -5.1, -5.6; MS (FAB) m/z 541.2773 (MH+
[C25H45N2O7Si2] ) 541.2765). Anal. Calcd for C25H44N2O7Si2:
C, 55.52; H, 8.20; N, 5.18. Found: C, 55.69; H, 8.00; N, 5.09.
2′-O-(ter t-Bu tyld im eth ylsilyl)-3′-d eoxy-3′-[(eth oxyca r -
bon yl)m eth ylen e]u r id in e (4). Procedure A [3 (3.00 g, 5.55
mmol), TFA/H2O (9:1, 60 mL), partitioned (EtOAc//NaCl/H2O),
aqueous layer extracted (EtOAc, 2×), chromatography (30 f
70% EtOAc/hexanes)] gave 4 (1.99 g, 84%) as a solid foam:
1H NMR δ 9.81 (br s, 1H), 7.60 (d, J ) 8.3 Hz, 1H), 5.89 (“t”,
J ) 2.2 Hz, 1H), 5.82 (d, J ) 8.1 Hz, 1H), 5.49 (d, J ) 7.9 Hz,
1H), 5.36 (br s, 1H), 5.12 (“d”, J ) 7.8 Hz, 1H), 4.15 (q, J ) 7.1
Hz, 2H), 4.11-4.04 (m, 1H), 3.90 (dd, J ) 11.7, 1.8 Hz, 1H),
3.25 (br s, 1H), 1.28 (t, J ) 7.1 Hz, 3H), 0.86 (s, 9H), 0.06 (s,
3H), -0.08 (s, 3H); 13C NMR δ 165.1, 163.4, 158.7, 150.6, 142.3,
114.5, 103.2, 90.4, 80.3, 74.3, 63.4, 60.6, 25.5, 17.7, 14.1, -4.9,
-5.1; MS (FAB) m/z 427.1916 (MH+ [C19H31N2O7Si] ) 427.1901).
Anal. Calcd for C19H30N2O7Si: C, 53.50; H, 7.09; N, 6.57.
Found: C, 53.36; H, 7.23; N, 6.42.
2′,5′-Bis-O-(ter t-bu tyldim eth ylsilyl)-3′-deoxy-3′-[(eth oxy-
ca r bon yl)m eth yl]u r id in e (6). Procedure B [3 (100 mg, 0.185
mmol), 10% Pd-C (39 mg), H2 (5-10 psi), dried MeOH (15
mL), 38 h] gave 6 (94 mg, 94%) as a solid foam: 1H NMR δ
8.55 (br s, 1H), 8.20 (d, J ) 8.2 Hz, 1H), 5.71 (s, 1H), 5.61 (dd,
J ) 8.3, 1.5 Hz, 1H), 4.43 (d, J ) 3.7 Hz, 1H), 4.19-3.99 (m,
4H), 3.70 (dd, J ) 12.0, 1.6 Hz, 1H), 2.69-2.50 (m, 2H), 2.22
(“d”, J ) 12.8 Hz, 1H), 1.25 (t, J ) 7.2 Hz, 3H), 0.92 (s, 9H),
0.90 (s, 9H), 0.23 (s, 3H), 0.11 (br s, 6H), 0.07 (s, 3H); 13C NMR
δ 171.6, 163.3, 150.1, 140.4, 101.2, 91.3, 84.4, 69.1, 61.3, 60.7,
37.0, 29.1, 25.9, 25.8, 18.4, 18.1, 14.2, -4.5, -5.5, -5.6, -5.7;
MS (FAB) m/z 543.2927 (MH+ [C25H47N2O7Si2] ) 543.2922).
Anal. Calcd for C25H46N2O7Si2: C, 55.32; H, 8.54; N, 5.16.
Found: C, 55.10; H, 8.23; N, 5.07.
General procedures A-F were performed with quantities
and other conditions specified for the individual compounds.
P r oced u r e A (Desilyla tion of O5′). TFA/H2O was added to
a cold flask (ice/H2O bath) containing the silyl ether, and the
solution was stirred at ∼0 °C until the desilylation was
complete (TLC). Volatiles were evaporated quickly at e17 °C
(to minimize further solvolysis reactions). The residue was
partitioned, and the aqueous layer was extracted. The com-
bined organic phase was washed (H2O, brine) and dried
(MgSO4). Filtration, evaporation of volatiles, and chromatog-
raphy of the residue gave the product. P r oced u r e B (Hy-
d r ogen a tion of Alk en es). A mixture of the compound, 10%
Pd-C, and H2 in a solvent was shaken (Parr apparatus) at
ambient temperature. The mixture was filtered (with Celite),
and the filter cake was washed with solvent. Volatiles were
evaporated from the combined filtrate to give the product.
P r oced u r e C (Ch em ica l Red u ction of Azid es). Et3N and
1,3-propanedithiol were added to a stirred, deoxygenated (N2)
solution of the azide in a solvent. Stirring was continued at
ambient temperature (under N2) until reduction was complete
(TLC). Volatiles were evaporated, and the residue was chro-
matographed to give the product. P r oced u r e D (Sa p on ifica -
tion of Ester s). Solid NaOH was added to a stirred solution
of the compound in an aqueous solvent mixture, and stirring
was continued at ambient temperature until saponification
was complete (TLC). The solution was concentrated under
reduced pressure, and the resulting aqueous solution was
cooled (∼0 °C) and carefully acidified to pH ∼2-4 (HCl/H2O).
The suspension was immediately partitioned (EtOAc/brine),
and the organic layer was dried (MgSO4) and filtered. Volatiles
were evaporated, and the residue was chromatographed to give
the product. P r oced u r e E [DCC-Med ia ted Con d en sa tion
of 3′-(Ca r boxym eth yl)-3′-d eoxy- a n d 5′-Am in o-5′-d eoxy-
n u cleosid e Com p on en ts]. A solution of the protected 3′-
(carboxymethyl)-3′-deoxy- and 5′-amino-5′-deoxynucleoside com-
ponents and DCC in dried CH2Cl2 was stirred overnight at
ambient temperature (under N2). When coupling was complete
(TLC), the suspension was filtered (with Celite), the filter cake
was washed (CH2Cl2), and the combined filtrate was evapo-
rated. The residue was chromatographed to give the amide
product. P r oced u r e F (Con d en sa tion of 3′-[[(4-Nitr op h e-
n oxy)ca r bon yl]m eth yl]-3′-d eoxy- a n d 5′-Am in o-5′-d eoxy-
n u cleosid e Com p on en ts). A solution of the protected 3′-
(carboxymethyl)-3′-deoxynucleoside 4-nitrophenyl ester and 5′-
amino-5′-deoxynucleoside components in a solvent was stirred
at ambient temperature (coupling progress was monitored by
TLC). Volatiles were evaporated, and the residue was chro-
matographed to give the amide product.
2′-O-(ter t-Bu tyld im eth ylsilyl)-3′-d eoxy-3′-[(eth oxyca r -
bon yl)m eth yl]a d en osin e (7). Procedure B [2 (100 mg, 0.222
mmol), 10% Pd-C (0.150 g), H2 (30-35 psi), dried MeOH, 4
days] gave 7 (80 mg, 80%) as a solid foam: 1H NMR δ 8.31 (s,
1H), 8.26 (s, 1H), 6.80 (br s, 2H), 5.81 (d, J ) 3.7 Hz, 1H), 4.91
(dd, J ) 5.6, 4.7 Hz, 1H), 4.06-4.22 (m, 4H), 3.75 (dd, J )
12.2, 1.6 Hz, 1H), 3.10-2.96 (m, 1H), 2.74 (dd, J ) 17.3, 6.4
Hz, 1H), 2.25 (dd, J ) 17.5, 8.1 Hz, 1H), 1.27 (t, J ) 7.2 Hz,
3H), 0.85 (s, 9H), -0.05 (s, 3H), -0.12 (s, 3H); 13C NMR δ
172.3, 153.9, 149.6, 148.2, 141.1, 120.0, 91.8, 85.8, 76.2, 62.3,
60.9, 38.0, 31.0, 25.6, 17.9, 14.2, -5.1, -5.4; MS (FAB) m/z
452.2330 (MH+ [C20H34N5O5Si] ) 452.2329). Anal. Calcd for
2′-O-(ter t-Bu tyld im eth ylsilyl)-3′-d eoxy-3′-[(eth oxyca r -
bon yl)m eth ylen e]a d en osin e (2). Procedure A [1 (5.00 g,
8.87 mmol), TFA/H2O (9:1, 80 mL), ∼20 min, partitioned
(EtOAc//NaCl/H2O), aqueous layer extracted (EtOAc, 2×),
chromatography (EtOAc/hexanes, 7:3)] gave 2 (3.58 g, 90%)
as a solid foam: 1H NMR δ 8.35 (s, 1H), 7.85 (s, 1H), 6.45 (br
s, 2H), 5.92 (“t”, J ) 2.1 Hz, 1H), 5.60-5.50 (m, 3H), 4.21 (q,
J ) 7.1 Hz, 2H), 4.10 (dd, J ) 11.8, 1.6 Hz, 1H), 3.99 (dd, J )
12.0, 1.6 Hz, 1H), 1.30 (t, J ) 7.1 Hz, 3H), 0.80 (s, 9H), -0.09
(s, 3H), -0.58 (s, 3H); 13C NMR (CDCl3) δ 165.1, 158.6, 155.9,
152.2, 148.6, 140.7, 121.0, 114.2, 90.1, 81.9, 75.0, 63.8, 60.6,
25.5, 17.7, 14.2, -4.9, -5.9; MS (FAB) m/z 450.2180 (MH+
[C20H32N5O5Si] ) 450.2173).
C
20H33N5O5Si: C, 53.19; H, 7.37; N, 15.51. Found: C, 53.08;
H, 7.15; N, 14.95.
2′-O-(ter t-Bu tyld im eth ylsilyl)-3′-d eoxy-3′-[(eth oxyca r -
bon yl)m eth yl]u r id in e (8). Procedure B [4 (65 mg, 0.15
mmol), 10% Pd-C (15 mg), H2 (5 psi), dried MeOH (10 mL), 2
days] gave 8 (63 mg, 98%) as a solid foam: 1H NMR δ 9.53 (br
s, 1H), 8.24 (d, J ) 8.2 Hz, 1H), 5.70 (dd, J ) 8.3, 2.2 Hz, 1H),
5.65 (s, 1H), 4.39 (d, J ) 3.6 Hz, 1H), 4.15 (q, J ) 7.2 Hz, 2H),
4.10-4.05 (m, 2H), 3.70 (“d”, J ) 13.6 Hz, 1H), 3.23 (br s, 1H),
2.64 (dd, J ) 16.1, 4.9 Hz, 1H), 2.57-2.43 (m, 1H), 2.37 (dd,
J ) 15.9, 6.5 Hz, 1H), 1.25 (t, J ) 7.1 Hz, 3H), 0.91 (s, 9H),
0.25 (s, 3H), 0.10 (s, 3H); 13C NMR δ 173.1, 164.3, 150.5, 140.9,
101.4, 91.8, 85.5, 78.8, 61.4, 60.8, 36.7, 30.1, 26.0, 18.2, 14.4,
-4.2, -5.3; MS (FAB) m/z 429.2067 (MH+ [C19H33N2O7Si] )
429.2057). Anal. Calcd for C19H32N2O7Si: C, 53.25; H, 7.53;
N, 6.54. Found: C, 53.13; H, 7.46; N, 6.43.
2′,5′-Bis-O-(ter t-bu tyldim eth ylsilyl)-3′-deoxy-3′-[(eth oxy-
ca r bon yl)m eth ylen e]u r id in e (3). A solution of 2′,5′-bis-O-
TBDMS-3′-ketouridine13 (619 mg, 1.32 mmol) and Ph3PCHCO2-
(19) Usui, H., Ueda, T. Chem. Pharm. Bull. 1986, 34, 15-23.
(20) Baker, D. C.; Horton, D. Carbohydr. Res. 1972, 21, 393-405.
(21) Horwitz, J . P.; Tomson, A. J .; Urbanski, J . A.; Chua, J . J . Org.
Chem. 1962, 27, 3045-3048.
3′-(Car boxym eth yl)-3′-deoxyaden osin e-2′,3′-lacton e (9).
TBAF/THF (1.0 M; 1.27 mL, 1.27 mmol) was added to a
solution of 7 (452 mg, 1.00 mmol) in THF (11 mL), and stirring
was continued for 16 h at ambient temperature. Silica gel (3
g) was added, volatiles were evaporated, and the loaded
(22) Sproat, B. S.; Lamond, A. I. In Oligonucleotides and Ana-
logues: A Practical Approach; Eckstein, F., Ed.; IRL: Oxford, 1991;
pp 49-86.
(23) Samano, V.; Robins, M. J . Synthesis 1991, 283-288.

Amide-Linked Ribonucleoside Dimers
J . Org. Chem., Vol. 64, No. 22, 1999 8187
adsorbent was added to a flash column. Chromatography
(3 f 5% MeOH/CH2Cl2) gave a solid that was triturated with
MeOH to give 9 (243 mg, 83%) with mp 233-236 °C dec: 1H
NMR (DMSO-d6) δ 8.35 (s, 1H), 8.16 (s, 1H), 7.36 (s, 2H), 6.27
(d, J ) 1.5 Hz, 1H), 5.48 (dd, J ) 7.0, 1.4 Hz, 1H), 5.06 (t, J )
5.7 Hz, 1H), 4.01-3.95 (m, 1H), 3.63-3.56 (m, 1H), 3.20-3.00
(m, 1H), 2.95 (dd, J ) 18.0, 8.5 Hz, 1H), 2.54 (dd, J ) 18.1,
1.3 Hz, 1H; solvent-peak overlap); 13C NMR (DMSO-d6) δ
176.0, 156.4, 153.1, 149.0, 139.8, 119.3, 88.2, 87.3, 86.6, 84.6,
61.9, 32.3; MS (FAB) m/z 292.1040 (MH+ [C12H14N5O4] )
292.1046).
3′-(Ca r boxym eth yl)-3′-d eoxyu r id in e-2′,3′-la cton e (10).
TBAF/THF (1.0 M; 0.39 mL, 0.39 mmol) was added to a
solution of 8 (150 mg, 0.350 mmol) in THF (4 mL), and stirring
was continued for 24 h at ambient temperature. Evaporation
of volatiles gave a residue that was washed (EtOAc, 4×) and
chromatographed (3 f 5% MeOH/CH2Cl2) to give 10 (87 mg,
93%) as a solid foam: 1H NMR (DMSO-d6) δ 11.42 (br s, 1H),
7.81 (d, J ) 8.1 Hz, 1H), 5.91 (d, J ) 1.3 Hz, 1H), 5.66 (d, J )
8.0 Hz, 1H), 5.15 (dd, J ) 7.1, 1.4 Hz, 1H), 5.07 (“d”, J ) 5.3
Hz, 1H), 3.90-3.82 (m, 1H), 3.70-3.54 (m, 2H), 3.11 (“q”, J )
8.0 Hz, 1H), 2.84 (dd, J ) 18.0, 8.6 Hz, 1H), 2.45 (“d”, J )
18.5 Hz, 1H; solvent-peak overlap); 13C NMR (DMSO-d6) δ
175.6, 163.2, 150.2, 141.6, 101.8, 89.93, 89.87, 87.2, 85.8, 60.8,
31.7; MS (CI) m/z 268.0682 (M+ [C11H12N2O6] ) 268.0695).
Anal. Calcd for C11H12N2O6: C, 49.26; H, 4.51; N, 10.44.
Found: C, 49.24; H, 4.77; N, 10.54.
3′-Deoxy-3′-[[N-(5′-d eoxya d en osin -5′-yl)ca r boxa m id o]-
m eth yl]a d en osin e (11). A stirred solution of 9 (25 mg, 0.086
mmol), 5′-amino-5′-deoxyAdo (114 mg, 0.428 mmol), and
2-pyridone (16 mg, 0.17 mmol) in DMF (2 mL) was heated for
24 h at 70 °C. TLC indicated conversion to a less polar product
(Rf ∼0.5; SSA). Volatiles were evaporated, the residue was
suspended in MeOH, silica gel (∼1 g) was added, and the
mixture was added to a flash column. Chromatography (SSA)
gave 11 (31 mg, 65%): 1H NMR (DMSO-d6, 500 MHz) δ 8.41
(s, 1H), 8.34 (t, J ) 5.8 Hz, 1H), 8.31 (s, 1H), 8.17 (s, 1H), 8.13
(s, 1H), 7.31 (br s, 2H), 7.26 (br s, 2H), 5.89 (d, J ) 1.5 Hz,
1H), 5.83 (d, J ) 6.5 Hz, 1H), 5.81 (d, J ) 4.5 Hz, 1H), 5.39 (d,
J ) 6.5 Hz, 1H), 5.20 (d, J ) 4.5 Hz, 1H), 5.14 (t, J ) 5.8 Hz,
1H), 4.67 (“q”, J ) 6.0 Hz, 1H), 4.45 (dt, J ) 5.0, 1.8 Hz, 1H),
4.03 (dd, J ) 8.0, 5.0 Hz, 1H), 3.95-3.93 (m, 2H), 3.73 (ddd,
J ) 12.5, 5.5, 2.5 Hz, 1H), 3.53 (ddd, J ) 12.3, 6.0, 3.8 Hz,
1H), 3.44-3.34 (m, 2H), 2.74-2.67 (m, 1H), 2.53 (dd, J ) 16.0,
8.5 Hz, 1H), 2.28 (dd, J ) 15.5, 6.0 Hz, 1H); 13C NMR (DMSO-
d6, 125 MHz) δ 171.2, 156.1, 155.9, 152.4, 152.3, 149.1, 148.7,
140.2, 138.7, 119.4, 119.0, 90.1, 87.8, 84.5, 83.5, 75.5, 72.5, 71.1,
61.1, 30.9; MS (FAB) m/z 558.2184 (MH+ [C22H28N11O7] )
558.2173).
2H), 4.94 (t, J ) 4.3 Hz, 1H), 4.33 (t, J ) 4.3 Hz, 1H), 4.25-
4.15 (m, 1H), 3.72 (d, J ) 4.8 Hz, 2H), 0.93 (br s, 9H), 0.83 (br
s, 9H), 0.12, 0.11, -0.01, -0.18 (4 × s, 4 × 3H); 13C NMR δ
156.0, 152.9, 149.5, 140.0, 120.5, 89.8, 82.8, 74.2, 72.3, 51.5,
25.7, 25.6, 17.9, 17.7, -4.6, -4.9, -5.0, -5.1; MS (FAB) m/z
521.2826 (MH+ [C22H41N8O3Si2] ) 521.2840). Anal. Calcd for
C22H40N8O3Si2: C, 50.74; H, 7.74; N, 21.52. Found: C, 50.86;
H, 7.84; N, 21.70.
5′-Azid o-2′,3′-bis-O-(ter t-bu tyld im eth ylsilyl)-5′-d eoxy-
u r id in e (16). A solution of 14 (2.82 g, 10.5 mmol), TBDMSCl
(6.4 g, 43 mmol), and imidazole (3.4 g, 50 mmol) in dried
pyridine (30 mL) was stirred for 24 h at ambient temperature
(under N2). Volatiles were evaporated, and the residue was
partitioned (NaHCO3/H2O//CHCl3). The aqueous layer was
extracted (CHCl3, 2×), and the combined organic phase was
dried (Na2SO4) and filtered. Volatiles were evaporated to give
1
a solid foam (4.7 g, 90%; ∼95% H NMR purity): 1H NMR δ
8.83 (s, 1H), 7.70 (d, J ) 8.4 Hz, 1H), 5.77 (d, J ) 8.2 Hz, 1H),
5.67 (d, J ) 2.8 Hz, 1H), 4.21-4.13 (m, 2H), 3.99-3.93 (m,
1H), 3.87-3.81 (m, 1H), 3.61 (dd, J ) 13.6, 3.2 Hz, 1H), 0.91
(br s, 9H), 0.89 (br s, 9H), 0.12 (s, 3H), 0.09 (s, 9H); 13C NMR
δ 163.5, 150.2, 140.3, 102.2, 91.0, 81.2, 75.0, 71.1, 50.9, 25.71,
25.68, 17.94, 17.89, -4.4, -4.6, -5.0, -5.1; MS (FAB) m/z
498.2575 (MH+ [C21H40N5O5Si2] ) 498.2568).
5′-Am in o-2′,3′-bis-O-(ter t-bu tyld im eth ylsilyl)-5′-d eoxy-
aden osin e (17). Procedure C [Et3N (0.8 mL), 1,3-propanedithi-
ol (0.80 mL, 0.86 g, 8.0 mmol), 15 (294 mg, 0.564 mmol), THF/
EtOH (1:1, 2 mL), 36 h, chromatography (SSA)] gave 17 (249
mg, 84%) with mp 205-208 °C dec: 1H NMR (DMSO-d6) δ
8.41 (s, 1H), 8.12 (s, 1H), 7.30 (s, 2H), 5.86 (d, J ) 7.0 Hz,
1H), 4.97 (dd, J ) 7.0, 4.6 Hz, 1H), 4.34 (d, J ) 4.2 Hz, 1H),
4.00-3.92 (m, 1H), 3.47 (br s, 2H), 2.98-2.92 (m, 2H), 0.90
(br s, 9H), 0.67 (br s, 9H), 0.11, 0.09, -0.13, -0.50 (4 × s, 4 ×
3H); 13C NMR (DMSO-d6) δ 156.3, 152.6, 149.4, 140.8, 119.7,
87.4, 86.3, 73.5, 73.0, 42.8, 25.7, 25.4, 17.8, 17.4, -4.7, -4.8,
-5.8; MS (FAB) m/z 495.2921 (MH+ [C22H43N6O3Si2] )
495.2935). Anal. Calcd for C22H42N6O3Si2‚2H2O: C, 49.36; H,
8.76; N, 15.70. Found: C, 49.20; H, 8.11; N; 15.81.
5′-Am in o-2′,3′-bis-O-(ter t-bu tyld im eth ylsilyl)-5′-d eoxy-
u r id in e (18). Procedure C [Et3N (0.3 mL), 1,3-propanedithiol
(0.30 mL, 0.32 g, 3.0 mmol), 16 (250 mg, 0.502 mmol), EtOH
(2 mL), 18 h, chromatography (MeOH/CH2Cl2, 1:9)] gave 18
(164 mg, 69%) as a white solid: mp ∼198 °C dec; 1H NMR
(300 MHz) δ 7.85 (d, J ) 8.1 Hz, 1H), 5.73 (d, J ) 8.1 Hz, 1H),
5.69 (d, J ) 3.6 Hz, 1H), 4.25 (“t”, J ) 3.9 Hz, 1H), 4.07-4.02
(m, 1H), 3.96 (dd, J ) 5.6, 4.4 Hz, 1H), 3.10 (dd, J ) 14.0, 3.6
Hz, 1H), 2.90 (dd, J ) 13.4, 5.0 Hz, 1H), 0.92 (br s, 9H), 0.91
(br s, 9H), 0.11 (s, 3H), 0.09 (s, 6H), 0.086 (s, 3H); 13C NMR δ
163.5, 150.2, 141.2, 102.0, 91.3, 84.7, 75.2, 71.7, 42.4, 25.8, 25.7,
18.0, 17.9, -4.4, -4.7, -4.9; MS (FAB) m/z 472.2675 (MH+
[C21H42N3O5Si2] ) 472.2663). Anal. Calcd for C21H41N3O5Si2:
C, 53.47; H, 8.76; N, 8.91. Found: C, 53.79; H, 8.61; N, 9.02.
3′,5′-Bis-O-(ter t-b u t yld im et h ylsilyl)-2′-O-m et h yla d e-
n osin e (21). A solution of 19 (500 mg, 1.78 mmol), TBDMSCl
(590 mg, 3.91 mmol), and imidazole (400 mg, 5.88 mmol) in
dried pyridine (5 mL) was stirred for 8 h at 65 °C (under N2).
TBDMSCl (178 mg, 1.18 mmol) was added, and stirring was
continued until reaction was complete (TLC, 4 h). Volatiles
were evaporated, and the residue was partitioned (NaHCO3/
H2O//CHCl3). The aqueous layer was extracted (CHCl3, 2×),
and the combined organic phase was washed (brine), dried
(Na2SO4), and filtered. Volatiles were evaporated, and the
residue was chromatographed (EtOAc) to give 21 (846 mg,
93%) with mp 100-103 °C: 1H NMR δ 8.35 (s, 1H), 8.19 (s,
1H), 6.15 (d, J ) 3.6 Hz, 1H), 5.70 (br s, 2H), 4.54 (t, J ) 4.9
Hz, 1H), 4.19-4.08 (m, 2H), 4.01 (dd, J ) 11.4, 3.2 Hz, 1H),
3.78 (dd, J ) 11.2, 2.4 Hz, 1H), 3.49 (s, 3H), 0.93 (s, 9H), 0.92
(s, 9H), 0.11 (s, 12H); 13C NMR δ 156.0, 152.9, 149.3, 138.8,
119.9, 86.4, 84.5, 83.6, 69.4, 61.5, 58.2, 25.7, 25.5, 18.1, 17.8,
-4.9, -5.2, -5.7, -5.8; MS (FAB) m/z 510.2930 (MH+
[C23H44N5O4Si2] ) 510.2932). Anal. Calcd for C23H43N5O4Si2:
C, 54.19; H, 8.50; N, 13.74. Found: C, 54.37; H, 8.40; N, 13.90.
3′,5′-Bis-O-(ter t-bu tyldim eth ylsilyl)-2′-O-m eth yl-5-m eth -
ylu r id in e (22). A solution of 20 (200 mg, 0.735 mmol),
TBDMSCl (277 mg, 1.84 mmol), and imidazole (165 mg, 2.42
3′-Deoxy-3′-[[N-(5′-d eoxya d en osin -5′-yl)ca r boxa m id o]-
m eth yl]u r id in e (12). A solution of 10 (14 mg, 0.052 mmol),
5′-amino-5′-deoxyAdo (69 mg, 0.26 mmol), and 2-pyridone (10
mg, 0.10 mmol) in DMF (1.5 mL) was stirred for 30 h at 70
°C. Workup and chromatography (as described for 9 f 11) gave
12 (23 mg, 83%): 1H NMR (DMSO-d6/D2O, 500 MHz) δ 8.33
(s, 1H), 8.22 (s, 1H), 8.07 (d, J ) 8.0 Hz, 1H), 5.87 (d, J ) 6.5
Hz, 1H), 5.67 (d, J ) 6.0 Hz, 1H), 5.64 (d, J ) 7.0 Hz, 1H),
4.67 (dd, J ) 6.4, 5.4 Hz, 1H), 4.17 (“d”, J ) 5.0 Hz, 1H), 4.08-
4.03 (m, 2H), 3.93-3.88 (m, 2H), 3.77 (dd, J ) 12.7, 2.0 Hz,
1H), 3.48 (dd, J ) 12.7, 3.4 Hz, 1H), 3.44 (dd, J ) 14.2, 5.4
Hz, 1H), 3.37 (dd, J ) 14.1, 4.5 Hz, 1H), 2.46-2.34 (m, 1H),
2.20 (dd, J ) 14.9, 5.2 Hz, 1H); 13C NMR (DMSO-d6, 125 MHz)
δ 172.4, 164.5, 156.4, 153.2, 151.0, 149.6, 141.3, 141.2, 119.8,
101.4, 91.5, 88.5, 85.0, 84.1, 76.3, 73.2, 71.6, 63.0, 60.7, 31.2,
25.7; MS (FAB) m/z 535.1904 (MH+ [C21H27N8O9] ) 535.1901).
5′-Azid o-2′,3′-bis-O-(ter t-bu tyld im eth ylsilyl)-5′-d eoxy-
a d en osin e (15). A solution of 13 (408 mg, 1.40 mmol),
TBDMSCl (742 mg, 4.92 mmol), and imidazole (344 mg, 5.05
mmol) in dried pyridine (6 mL) was heated for 8 h at 70 °C
(under N2). The mixture was poured into NaHCO3/H2O and
extracted (CHCl3, 3×). The combined organic phase was dried
(Na2SO4) and filtered. Volatiles were evaporated, and the
residue was chromatographed (EtOAc/hexanes, 7:3) to give 15
1
as a white solid (445 mg, 61%): mp 208-210 °C; H NMR δ
8.36 (s, 1H), 8.01 (s, 1H), 5.89 (d, J ) 4.2 Hz, 1H), 5.56 (br s,

8188 J . Org. Chem., Vol. 64, No. 22, 1999
Peterson et al.
mmol) in dried pyridine (2 mL) was stirred for 5.5 h at 70 °C
(under N2). Volatiles were evaporated, and the residue was
partitioned (NaHCO3/H2O//CH2Cl2). The organic phase was
dried (Na2SO4) and filtered, and volatiles were evaporated. The
residue was chromatographed (EtOAc/hexanes, 7:3) to give 22
(340 mg, 92%): 1H NMR δ 8.29 (br s, 1H), 7.48 (d, J ) 1.4 Hz,
1H), 6.01 (d, J ) 4.4 Hz, 1H), 4.25 (t, J ) 5.1 Hz, 1H), 4.02-
3.93 (m, 2H), 3.76 (dd, J ) 11.8, 2.2 Hz, 1H), 3.66 (“t”, J ) 4.7
Hz, 1H), 3.46 (s, 3H), 1.92 (d, J ) 1.0 Hz, 3H), 0.95 (s, 9H),
0.91, (s, 9H), 0.134, 0.127, 0.11, 0.09 (4 × s, 4 × 3H); 13C NMR
δ 164.4, 150.5, 135.3, 110.6, 87.0, 84.2, 83.5, 69.1, 61.5, 58.0,
25.8, 25.5, 18.3, 17.9, 12.3, -4.9, -5.1, -5.5, -5.7; MS (CI)
m/z 501.2805 (MH+ [C23H45N2O6Si2] ) 501.2816).
3′-O-(ter t-Bu t yld im et h ylsilyl)-5′-ch lor o-5′-d eoxy-2′-O-
m eth yla d en osin e (23). Procedure A [21 (831 mg, 1.63 mmol),
TFA/H2O (9:1, 4 mL), ∼45 min, partitioned (NaHCO3/H2O//
CH2Cl2), aqueous layer extracted (CH2Cl2, 2×), combined
organic dried (Na2SO4), chromatography (5 f 10% MeOH/CH2-
Cl2)] gave 3′-O-TBDMS-2′-O-methylAdo (383 mg, 60%): 1H
NMR (500 MHz) δ 8.35 (s, 1H), 7.89 (s, 1H), 6.81 (dd, J ) 11.8,
1.8 Hz, 1H), 5.87 (d, J ) 8.0 Hz, 1H), 5.79 (br s, 2H), 4.62 (dd,
J ) 7.5, 4.5 Hz, 1H), 4.58 (d, J ) 4.0 Hz, 1H), 4.21 (s, 1H),
3.95 (dt, J ) 13.0, 1.6 Hz, 1H), 3.72 (dd, J ) 12.8, 1.5 Hz, 1H),
3.26 (s, 3H), 0.94 (br s, 9H), 0.14 (s, 3H), 0.13 (s, 3H); 13C NMR
δ 156.4, 152.2, 148.3, 140.7, 121.0, 89.4, 89.3, 82.1, 71.3, 62.6,
58.1, 25.5, 17.9, -4.9, -5.1; MS (FAB) m/z 396.2082 (MH+
[C17H30N5O4Si] ) 396.2067). Anal. Calcd for C17H29N5O5Si: C,
51.62; H, 7.39; N, 17.71. Found: C, 51.85; H, 7.15; N, 17.84.
5′-Azid o-3′-O-(ter t-b u t yld im et h ylsilyl)-5′-d eoxy-2′-O-
m eth yla d en osin e (25). A solution of 23 (117 mg, 0.283 mmol)
and NaN3 (73 mg, 1.1 mmol) in dried DMF (2 mL) was stirred
for 5 h at 105 °C. Volatiles were evaporated, and the residue
was chromatographed (5 f 8% MeOH/CH2Cl2) to give 25 (117
mg, 98%): 1H NMR (500 MHz) δ 8.36 (s, 1H), 8.04 (s, 1H),
6.05 (d, J ) 3.5 Hz, 1H), 5.54 (s, 2H), 4.57 (t, J ) 5.5 Hz, 1H),
4.40 (t, J ) 4.5 Hz, 1H), 4.18 (dd, J ) 10.0, 4.5 Hz, 1H), 3.74
(dd, J ) 13.0, 4.0 Hz, 1H), 3.59 (dd, J ) 13.5, 4.5 Hz, 1H),
3.49 (s, 3H), 0.94 (br s, 9H), 0.15 (s, 3H), 0.14 (s, 3H); 13C NMR
δ 155.9, 153.1, 149.4, 139.5, 120.3, 87.6, 82.50, 82.46, 70.9, 58.6,
51.2, 25.6, 18.0, -4.8, -5.1; MS (FAB) m/z 421.2142 (MH+
[C17H29N8O3Si] ) 421.2132).
5′-Azid o-3′-O-(ter t-b u t yld im et h ylsilyl)-5′-d eoxy-2′-O-
m eth yl-5-m eth ylu r id in e (26). A solution of 24 (78 mg, 0.19
mmol) and LiN3 (40 mg, 0.82 mmol) in dried DMF (2.0 mL)
was stirred for 4 h at 110 °C (under N2). Volatiles were
evaporated, the residue was partitioned (EtOAc//NaHCO3/
H2O), and the aqueous layer was extracted (EtOAc, 2×). The
combined organic phase was dried (Na2SO4) and filtered, and
volatiles were evaporated. Chromatography of the residue
(EtOAc/hexanes, 1:1) gave 26 (75 mg, 96%): 1H NMR δ 8.71
(br s, 1H), 7.44 (d, J ) 1.2 Hz, 1H), 5.82 (d, J ) 2.2 Hz, 1H),
4.16 (dd, J ) 7.2, 5.2 Hz, 1H), 4.06 (dt, J ) 7.2, 3.0 Hz, 1H),
3.83 (dd, J ) 13.5, 3.0 Hz, 1H), 3.71 (dd, J ) 5.1, 2.5 Hz, 1H),
3.55 (dd, J ) 13.5, 3.0 Hz, 1H), 3.52 (s, 3H), 1.95 (d, J ) 1.4
Hz, 3H), 0.91 (br s, 9H), 0.11 (br s, 6H); 13C NMR δ 164.3,
150.3, 135.8, 111.0, 89.1, 83.1, 81.3, 70.0, 58.4, 50.7, 25.5, 18.0,
12.6, -4.8, -5.1; MS (CI) m/z 412.2003 (MH+ [C17H30N5O5-
Si] ) 412.2016).
5′-Azid o-5′-d eoxy-2′-O-m et h yla d en osin e (27). TBAF/
THF (1.0 M; 0.100 mL, 0.100 mmol) was added to a solution
of 25 (25 mg, 0.059 mmol) in THF (0.5 mL), and stirring was
continued for 2 h. Volatiles were evaporated, and the residue
was chromatographed (10% MeOH/CH2Cl2) to give 27 (16 mg,
88%): 1H NMR (DMSO-d6) δ 8.38 (s, 1H), 8.16 (s, 1H), 7.35 (br
s, 2H), 6.03 (d, J ) 5.4 Hz, 1H), 5.49 (br s, 1H), 4.53 (t, J ) 5.1
Hz, 1H), 4.38 (t, J ) 4.3 Hz, 1H), 4.05 (ddd, J ) 6.8, 3.7, 3.6
Hz, 1H), 3.70 (dd, J ) 13.1, 6.9 Hz, 1H), 3.53 (dd, J ) 13.0,
3.6 Hz, 1H), 3.32 (s, 3H); 13C NMR (DMSO-d6) δ 156.3, 152.9,
149.4, 140.0, 119.3, 85.7, 83.6, 81.6, 69.5, 57.7, 51.6; MS (FAB)
m/z 307.1264 (MH+ [C11H15N8O3] ) 307.1267).
5′-Azid o-5′-d eoxy-2′-O-m et h yl-5-m et h ylu r id in e (28).
TBAF/THF (1.0 M; 0.250 mL, 0.250 mmol) was added to a
solution of 26 (75 mg, 0.18 mmol) in THF (1.0 mL), and stirring
was continued for 3 h. MeOH (4 mL) and Dowex 1-X2 (-OH)
resin were added, and the suspension was stirred until the
supernatant was UV transparent. The mixture was filtered,
the resin was washed (MeOH, 4×, AcOH/MeOH), and the
combined filtrate was evaporated to give 28 (50 mg, 93%): 1H
NMR (DMSO-d6) δ 11.40 (s, 1H), 7.51 (d, J ) 1.0 Hz, 1H), 5.84
(d, J ) 5.0 Hz, 1H), 5.34 (d, J ) 6.0 Hz, 1H), 4.09 (dd, J )
10.8, 6.0 Hz, 1H), 3.94-3.86 (m, 2H), 3.58 (d, J ) 4.8 Hz, 2H),
3.31 (s, 3H), 1.77 (s, 3H); 13C NMR (DMSO-d6) δ 163.9, 150.7,
136.5, 110.1, 86.9, 82.5, 81.2, 69.2, 57.7, 51.6, 12.1; MS (FAB)
m/z 298.1168 (MH+ [C11H16N5O5] ) 298.1151).
This material (368 mg, 0.930 mmol) was dissolved in dried
pyridine, and volatiles were evaporated (∼5 mL, 2×). The
residue was dissolved in dried pyridine (4 mL) and cooled (0
°C) under N2. SOCl2/CH2Cl2 (2.0 M; 1.6 mL, 3.2 mmol) was
added, and stirring was continued at ambient temperature
until reaction was complete (TLC, ∼20 h). Volatiles were
evaporated, and the residue was partitioned (NaHCO3/H2O//
CH2Cl2). The combined organic phase was dried (Na2SO4) and
filtered, and volatiles were evaporated. Chromatography (5 f
8% MeOH/CH2Cl2) gave 23 (278 mg, 72%): 1H NMR δ 8.35 (s,
1H), 8.05 (s, 1H), 6.05 (d, J ) 4.2 Hz, 1H), 5.56 (s, 2H), 4.59 (t,
J ) 4.8 Hz, 1H), 4.52 (t, J ) 4.5 Hz, 1H), 4.32-4.05 (m, 1H),
4.01 (dd, J ) 11.8, 5.8 Hz, 1H), 3.72 (dd, J ) 12.0, 4.0 Hz,
1H), 3.47 (s, 3H), 0.94 (br s, 9H), 0.15 (s, 6H); 13C NMR δ 156.0,
153.0, 149.4, 139.7, 120.4, 87.7, 83.4, 82.0, 70.9, 58.5, 43.5, 25.6,
18.0, -4.9, -5.0; MS (FAB) m/z 414.1739 (MH+ [C17H29
-
35ClN5O3Si] ) 414.1728).
3′-O-(ter t-Bu t yld im et h ylsilyl)-5′-ch lor o-5′-d eoxy-2′-O-
m eth yl-5-m eth ylu r id in e (24). Procedure A [22 (270 mg,
0.540 mmol), TFA/H2O (9:1, 5 mL), ∼15 min, partitioned
(NaHCO3/H2O//CH2Cl2), aqueous layer extracted (CH2Cl2, 2×)
and combined organic dried (Na2SO4), chromatography (EtOAc/
hexanes, 7:3)] gave 3′-O-TBDMS-2′-O-methyl-5-methylUrd
(150 mg, 72%): 1H NMR δ 8.26 (br s, 1H), 7.36 (d, J ) 1.2 Hz,
1H), 5.54 (d, J ) 5.0 Hz, 1H), 4.39 (t, J ) 4.8 Hz, 1H), 4.13-
4.03 (m, 2H), 4.00-3.92 (m, 1H), 3.78-3.68 (m, 1H), 3.67 (s,
3H), 2.92 (dd, J ) 7.9, 3.1 Hz, 1H), 1.92 (d, J ) 1.4 Hz, 3H),
0.92 (br s, 9H), 0.12 (s, 3H), 0.10 (s, 3H); 13C NMR δ 164.2,
150.5, 138.5, 110.8, 91.8, 85.8, 81.9, 69.8, 61.3, 58.3, 25.6, 18.0,
12.3, -4.9, -5.0; MS (CI) m/z 387.1938 (MH+ [C17H31N2O6-
Si] ) 387.1951).
This material (90 mg, 0.23 mmol), dried pyridine (3 mL),
and MsCl (0.15 mL, 0.22 g, 1.9 mmol) were added to a dried
flask, and the solution was stirred for 6 h at 90 °C (under N2).
Volatiles were evaporated, the residue was partitioned (NaH-
CO3/H2O//CH2Cl2), and the aqueous layer was extracted (CH2-
Cl2, 2×). The combined organic phase was dried (Na2SO4) and
filtered. Volatiles were evaporated, and the residue was
chromatographed (40 f 50% EtOAc/hexanes) to give 24 (78
mg, 84%): 1H NMR δ 8.74 (br s, 1H), 7.55 (d, J ) 1.2 Hz, 1H),
5.84 (d, J ) 2.8 Hz, 1H), 4.23 (“d”, J ) 2.6 Hz, 2H), 4.00 (dd,
J ) 13.1, 1.9 Hz, 1H), 3.80-3.72 (m, 2H), 3.53 (s, 3H), 1.93 (d,
J ) 1.0 Hz, 3H), 0.92 (br s, 9H), 0.13 (s, 6H); 13C NMR δ 164.3,
150.3, 135.9, 110.8, 89.0, 83.0, 81.6, 70.1, 58.4, 43.7, 25.5, 17.9,
12.5, -4.8, -5.1; MS (CI) m/z 405.1598 (MH+ [C17H3035ClN2O5-
Si] ) 405.1613).
5′-Am in o-5′-d eoxy-2′-O-m eth yla d en osin e (29). Proce-
dure B [27 (380 mg, 1.24 mmol), 10% Pd-C (102 mg), H2 (30
psi), EtOH (20 mL), overnight, filter cake washed (EtOH,
dilute NH3/H2O), recrystallized (EtOH)] gave 29 (300 mg,
86%): mp 200-202 °C; 1H NMR (DMSO-d6) δ 8.43 (s, 1H),
8.16 (s, 1H), 7.36 (br s, 2H), 5.98 (d, J ) 6.2 Hz, 1H), 5.27 (br
s, 3H), 4.47 (dd, J ) 6.0, 5.2 Hz, 1H), 4.35 (dd, J ) 4.6, 3.4 Hz,
1H), 3.88 (“q”, J ) 3.9 Hz, 1H), 3.30 (s, 3H), 2.84 (dd, J ) 13.4,
4.6 Hz, 1H), 2.74 (dd, J ) 13.2, 5.0 Hz, 1H), 1.70 (br s, 2H);
13C NMR (DMSO-d6) δ 156.3, 152.9, 149.5, 140.2, 119.4, 86.9,
85.4, 82.0, 69.2, 57.5, 43.8; MS (FAB) m/z 303.1164 (MNa+
[C11H16N6O3Na] ) 303.1182. Anal. Calcd for C11H16N6O3: C,
47.14; H, 5.75; N, 29.98. Found: C, 47.32; H, 5.54; N, 30.21.
5′-Am in o-5′-deoxy-2′-O-m eth yl-5-m eth ylu r idin e (30). Pro-
cedure B [28 (174 mg, 0.585 mmol), 10% Pd-C (83 mg), H2
(30 psi), EtOH (25 mL), overnight, filter cake washed (EtOH,
dilute NH3/H2O), recrystallized (EtOH)] gave 30 (135 mg,
85%): mp 140-143 °C; 1H NMR (DMSO-d6) δ 7.76 (s, 1H),
5.82 (d, J ) 5.4 Hz, 1H), 5.26 (br s, 4H), 4.11 (“t”, J ) 4.5 Hz,

Amide-Linked Ribonucleoside Dimers
J . Org. Chem., Vol. 64, No. 22, 1999 8189
1H), 3.84 (“t”, J ) 5.2 Hz, 1H), 3.74 (“d”, J ) 4.2 Hz, 1H), 3.33
(s, 3H), 2.78 (br s, 2H), 1.78 (s, 3H); 13C NMR (DMSO-d6) δ
164.0, 150.9, 136.7, 109.9, 86.0, 82.0, 69.0, 57.6, 43.0, 12.2; MS
(FAB) m/z 316.0903 {(MNa2 - H)+ [C11H16N3O5Na2] )
316.0885}.
J ) 8.2 Hz, 1H), 7.64-7.56 (m, 1H), 7.49-7.42 (m, 2H), 5.90
(d, J ) 4.0 Hz, 1H), 5.78 (d, J ) 7.8 Hz, 1H), 5.29 (br s, 1H),
4.60 (br s, 1H), 4.34 (br s, 1H), 3.40-2.5 (br s, 4H), 0.77 (s,
9H), 0.04 (s, 3H), -0.05 (s, 3H); 13C NMR δ 165.9, 163.4, 150.4,
140.9, 133.5, 129.9, 129.3, 128.5, 102.7, 90.8, 73.8, 72.3, 29.6,
25.4, 17.7-5.2, -5.3; MS (FAB) m/z 462.2051 (MH+ [C22H32N3O6-
Si] ) 462.2060.
2′,5′-Bis-O-(ter t-bu tyldim eth ylsilyl)-3′-(car boxym eth yl)-
3′-d eoxya d en osin e (37). Procedure D [NaOH (500 mg, 12.5
mmol), 5 (200 mg, 0.353 mmol), MeOH/H2O (9:1, 10 mL), 3 h,
pH ∼2 (0.5 M HCl/H2O), (EtOAc/brine), chromatography (3%
MeOH/CHCl3)] gave 37 (139 mg, 73%) as a solid foam: 1H
NMR (DMSO-d6) δ 12.4 (br s, 1H), 8.35 (s, 1H), 8.14 (s, 1H),
7.33 (br s, 2H), 5.92 (s, 1H), 4.58 (d, J ) 4.6 Hz, 1H), 4.03-
3.96 (m, 2H), 3.78 (dd, J ) 11.3, 2.2 Hz, 1H), 2.75-2.60 (m,
1H), 2.50-2.36 (m, 2H), 0.88 (s, 18H), 0.13 (s, 3H), 0.08 (s,
6H), 0.02 (s, 3H); 13C NMR (DMSO-d6) δ 173.6, 156.2, 152.8,
148.9, 138.1, 119.2, 89.9, 83.8, 77.5, 62.3, 37.6, 29.4, 25.9, 25.7,
18.1, 17.7, -4.7, -5.5, -5.58, -5.63; MS (FAB) m/z 538.2870
(MH+ [C24H44N5O5Si2] ) 538.2881). Anal. Calcd for C24H43N5O5-
Si2: C, 53.60; H, 8.06; N, 13.02. Found: C, 53.39; H, 7.85; N,
12.78.
2′,5′-Bis-O-(ter t-bu tyldim eth ylsilyl)-3′-(car boxym eth yl)-
3′-d eoxyu r id in e (38). Procedure D [NaOH (529 mg, 13.2
mmol), 6 (306 mg, 0.564 mmol), MeOH/THF/H2O (4:2:1, 3.5
mL), 1 h, pH ∼2 (0.5 M HCl/H2O), (EtOAc/brine), chromatog-
raphy (EtOAc)] gave 38 (256 mg, 88%) as a solid foam: 1H
NMR (500 MHz) δ 8.91 (br s, 1H), 8.21 (d, J ) 8.0 Hz, 1H),
5.72 (s, 1H), 5.66 (d, J ) 9.0 Hz, 1H), 4.45 (d, J ) 4.5 Hz, 1H),
4.17-4.13 (m, 2H), 4.05 (d, J ) 10.5 Hz, 1H), 3.72 (d, J ) 11.0
Hz, 1H), 2.70 (dd, J ) 16.8, 10.3 Hz, 1H), 2.55-2.52 (m, 1H),
2.30 (dd, J ) 16.8, 4.3 Hz, 1H), 0.93 (s, 9H), 0.92 (s, 9H), 0.25
(s, 3H), 0.13 (s, 6H), 0.12 (s, 3H); 13C NMR δ 176.9, 164.9,
150.6, 141.0, 101.2, 91.4, 84.5, 61.1, 36.7, 28.9, 25.8, 25.7, 18.3,
17.9, -4.6, -5.7, -5.9; MS (FAB) m/z 515.2597 (MH+
[C23H43N2O7Si2] ) 515.2609).
2′,5′-Bis-O-(ter t-bu tyld im eth ylsilyl)-3′-d eoxy-3′-[[(4-n i-
tr op h en oxy)ca r bon yl]m eth yl]a d en osin e (39). A solution
of 37 (500 mg, 0.930 mmol), 4-nitrophenol (190 mg, 1.37 mmol),
DCC (280 mg, 1.36 mmol), and 1-hydroxybenzotriazole (63 mg,
0.47 mmol) in dried DMF (10 mL) was stirred for 36 h at
ambient temperature (under N2). Volatiles were evaporated,
and the residue was suspended (CH2Cl2) and filtered (Celite).
The filter cake was washed (CH2Cl2), and the combined filtrate
was evaporated. The residue was chromatographed (30 f 50%
EtOAc/hexanes) to give 39 (441 mg, 72%): 1H NMR δ 8.37 (s,
1H), 8.32 (s, 1H), 8.26 (d, J ) 9.2 Hz, 2H), 7.24 (d, J ) 9.3 Hz,
2H), 6.20 (br s, 2H), 6.06 (s, 1H), 4.77 (d, J ) 4.0 Hz, 1H),
4.21-4.10 (m, 2H), 3.84 (“dd”, J ) 9.4, 2.4 Hz, 1H), 3.09-2.84
(m, 2H), 2.70 (dd, J ) 15.9, 2.8 Hz, 1H), 0.95 (br s, 18H), 0.24,
0.15, 0.14, 0.08 (4 × s, 4 × 3H); 13C NMR δ 169.9, 155.4, 154.1,
149.4, 149.3, 145.9, 140.6, 131.8, 125.8, 122.6, 120.2, 91.4, 84.7,
69.6, 62.7, 38.4, 30.1, 26.5, 26.3, 19.0, 18.5, 1.5, -3.9, -4.8,
-5.0; MS (FAB) m/z 659.3046 (MH+ [C30H47N6O7Si2] )
659.3045).
1-[3-O-Ben zoyl-2,5-bis-O-(ter t-bu tyld im eth ylsilyl)-â-D-
r ibofu r a n osyl]-3-N-(ben zoyl)u r a cil (32). Benzoyl chloride
(1.0 mL, 1.2 g, 8.6 mmol) was added to a solution of 31 (1.03
g, 2.18 mmol) in dried pyridine (5 mL), and the solution was
stirred overnight at ambient temperature (under N2). EtOAc
and NaHCO3/H2O were added, and the aqueous layer was
extracted (EtOAc, 2×). The combined organic phase was dried
(Na2SO4) and filtered. Volatiles were evaporated, and the
residue was chromatographed (10 f 20% EtOAc/hexanes) to
give 32 (1.42 g, 96%): 1H NMR δ 8.10-7.95 (m, 5H), 7.66-
7.41 (m, 6H), 6.17 (d, J ) 5.9 Hz, 1H), 5.86 (d, J ) 8.0 Hz,
1H), 5.40 (dd, J ) 4.9, 3.1 Hz, 1H), 4.50 (t, J ) 5.3 Hz, 1H),
4.39 (d, J ) 2.6 Hz, 1H), 4.05 (dd, J ) 12.1, 2.0 Hz, 1H), 3.92
(d, J ) 11.8 Hz, 1H), 0.98 (s, 9H), 0.74 (s, 9H), 0.17 (s, 6H),
0.05 (s, 3H), -0.05 (s, 3H); 13C NMR δ 168.4, 165.6, 162.0,
149.3, 139.6, 135.0, 133.5, 131.4, 130.4, 129.7, 129.2, 129.0,
128.4, 128.3, 102.6, 88.3, 83.1, 74.8, 72.9, 62.9, 25.9, 25.3, 18.3,
17.7, -5.18, -5.23, -5.6; MS (FAB) m/z 681.3020 (MH+
[C35H49N2O8Si2] ) 681.3027).
1-[3-O-Ben zoyl-2-O-(ter t-bu tyld im eth ylsilyl)-â-D-r ibo-
fu r a n osyl]-3-N-(ben zoyl)u r a cil (33). Procedure A [32 (1.42
g, 2.09 mmol), CH2Cl2/TFA/H2O (20:9:1, 15 mL), ambient
temperature, 45 min, volatiles evaporated, chromatography
(40 f 60% EtOAc/hexanes)] gave 33 (949 mg, 81%): 1H NMR
δ 8.09-7.86 (m, 5H), 7.71-7.42 (m, 6H), 5.90 (d, J ) 8.2 Hz,
1H), 5.83 (d, J ) 5.5 Hz, 1H), 5.46 (dd, J ) 4.9, 3.8 Hz, 1H),
4.74 (t, J ) 5.3 Hz, 1H), 4.38 (m, 1H), 4.06-3.82 (m, 2H), 2.80
(“t”, J ) 4.9 Hz, 1H), 0.79 (s, 9H), 0.08 (s, 3H), 0.01 (s, 3H);
13C NMR δ 168.4, 165.8, 162.1, 149.4, 141.2, 135.2, 133.5,
131.2, 130.4, 129.7, 129.2, 129.1, 128.4, 102.5, 90.9, 83.1, 73.6,
72.7, 61.6, 25.4, 17.7, -5.16, -5.24; MS (FAB) m/z 567.2147
(MH+ [C29H35N2O8Si] ) 567.2163).
1-[3-O-Ben zoyl-2-O-(ter t-bu tyld im eth ylsilyl)-5-ch lor o-
5-deoxy-â-D-r ibofu r an osyl]-3-N-(ben zoyl)u r acil (34). SOCl2/
CH2Cl2 (2.0 M; 2.2 mL, 4.4 mmol) was added to a stirred
solution of 33 (700 mg, 1.24 mmol) in dried pyridine (14 mL)
at 0 °C (under N2), and stirring was continued overnight at
ambient temperature. Volatiles were evaporated, the residue
was partitioned (EtOAc//NaHCO3/H2O), and the organic layer
was washed (NaHCO3/H2O and brine), dried (Na2SO4), and
filtered. Volatiles were evaporated, and the residue was
chromatographed (40% EtOAc/hexanes) to give 34 (505 mg,
70%): 1H NMR δ 8.10 (d, J ) 7.2 Hz, 2H), 7.96 (d, J ) 7.4 Hz,
2H), 7.75 (d, J ) 8.4 Hz, 1H), 7.68-7.27 (m, 6H), 6.13 (d, J )
6.2 Hz, 1H), 5.97 (d, J ) 8.2 Hz, 1H), 5.37 (dd, J ) 5.4, 3.4 Hz,
1H), 4.60-4.51 (m, 2H), 3.97 (d, J ) 2.8 Hz, 2H), 0.77 (br s,
9H), 0.07 (s, 3H), -0.02 (s, 3H); 13C NMR δ 168.3, 165.7, 161.8,
149.4, 139.3, 135.2, 133.8, 131.4, 130.5, 129.88, 129.17, 129.0,
128.6, 103.3, 88.5, 81.0, 73.7, 72.7, 44.8, 25.3, 17.7, -5.3; MS
(FAB) m/z 585.1807 (MH+ [C29H3435ClN2O7Si] ) 585.1824).
5′-Azid o-3′-O-ben zoyl-2′-O-(ter t-bu tyld im eth ylsilyl)-5′-
d eoxyu r id in e (35). A stirred solution of 34 (342 mg, 0.584
mmol) and LiN3 (144 mg, 2.94 mmol) in dried DMF (3 mL)
was heated for 2 h at 110 °C. Volatiles were evaporated (∼60
°C), and the residue was chromatographed (30 f 40% EtOAc/
hexanes) to give 35 (231 mg, 81%): 1H NMR δ 8.08 (br s, 1H),
8.07 (d, J ) 7.6 Hz, 2H) 7.62-7.43 (m, 4H), 6.00 (d, J ) 5.4
Hz, 1H), 5.84 (d, J ) 7.2 Hz, 1H), 5.25 (t, J ) 4.9 Hz, 1H),
4.50-4.40 (m, 2H), 3.86 (dd, J ) 13.2, 2.6 Hz, 1H), 3.75 (dd,
J ) 13.2, 3.0 Hz, 1H), 0.76 (br s, 9H), 0.027 (s, 3H), -0.05 (s,
3H); 13C NMR δ 165.8, 163.1, 150.4, 139.7, 133.7, 129.9, 129.0,
128.6, 103.3, 89.5, 80.1, 73.5, 72.3, 51.9, 25.3, 17.7, -5.2, -5.4;
MS (FAB) m/z 488.1964 (MH+ [C22H30N5O6Si] ) 488.1965).
5′-Am in o-3′-O-ben zoyl-2′-O-(ter t-bu tyld im eth ylsilyl)-5′-
d eoxyu r id in e (36). SnCl2‚2H2O (190 mg, 0.842 mmol) was
added to a cold (∼0 °C) solution of 35 (98 mg, 0.20 mmol) in
MeOH (5 mL), and stirring was continued overnight at
ambient temperature. Volatiles were evaporated, and the
residue was chromatographed (10% MeOH/CH2Cl2) to give 36
(48 mg, 52%): 1H NMR δ 8.07 (d, J ) 7.6 Hz, 2H), 7.91 (d,
5′-Azid o-2′-O-(ter t-bu tyld im eth ylsilyl)-3′,5′-d id eoxy-3′-
[(eth oxyca r bon yl)m eth yl]u r id in e (40). Meth od A. MsCl
(0.10 mL, 148 mg, 1.29 mmol) was added to a cold (∼0 °C)
solution of 8 (295 mg, 0.688 mmol) in dried pyridine (2 mL)
and stirred for 3 h at ∼0 °C (under N2). Volatiles were
evaporated, and the residue was chromatographed (5% MeOH/
CH2Cl2) to give 2′-O-TBDMS-3′-deoxy-3′-[(ethoxycarbonyl)-
methyl]-5′-O-methanesulfonylUrd (289 mg, 83%) as a white
solid: mp 120-123 °C; 1H NMR δ 8.40 (br s, 1H), 7.67 (d, J )
8.3 Hz, 1H), 5.74 (dd, J ) 8.2, 2.3 Hz, 1H), 5.69 (s, 1H), 4.60
(dd, J ) 11.7, 1.9 Hz, 1H), 4.50 (d, J ) 4.0 Hz, 1H), 4.40 (dd,
J ) 11.9, 3.4 Hz, 1H), 4.27-4.22 (m, 1H), 4.14 (q, J ) 7.2 Hz,
2H), 3.10 (s, 3H), 2.68-2.60 (m, 1H), 2.50-2.35 (m, 2H), 1.26
(t, J ) 7.2 Hz, 3H), 0.90 (s, 9H), 0.21 (s, 3H), 0.08 (s, 3H); 13
C
NMR δ 171.4, 163.7, 150.3, 139.3, 101.7, 92.0, 81.3, 77.1, 67.4,
60.9, 38.3, 37.6, 29.2, 25.6, 17.9, 14.0, -4.5, -5.8; MS (FAB)
m/z 507.1824 (MH+ [C20H35N2O9SSi] ) 507.1833).
A solution of this material (260 mg, 0.513 mmol) and LiN3
(92 mg, 1.9 mmol) in dried DMF (2 mL) was stirred for 5.5 h
at 97 °C (under N2). Volatiles were evaporated, the residue

8190 J . Org. Chem., Vol. 64, No. 22, 1999
Peterson et al.
was partitioned (NaHCO3/H2O//CH2Cl2), and the aqueous layer
was extracted (CH2Cl2, 2×). The combined organic phase was
dried (Na2SO4), volatiles were evaporated, and the residue was
chromatographed (EtOAc/hexanes, 1:1) to give 40 (214 mg,
92%) as a solid foam: 1H NMR (300 MHz) δ 9.19 (br s, 1 H),
7.77 (d, J ) 8.1 Hz, 1 H), 5.76 (d, J ) 8.4 Hz, 1 H), 5.71 (s, 1
H), 4.45 (d, J ) 4.5 Hz, 1 H), 4.15 (q, J ) 7.2 Hz, 2 H), 4.11
(dd, J ) 6.6, 3.3 Hz, 1H), 3.87 (dd, J ) 13.7, 2.9 Hz, 1H), 3.59
(dd, J ) 13.7, 3.8 Hz, 1H), 2.64 (dd, J ) 16.7, 8.3 Hz, 1H),
2.47-2.38 (m, 1H), 2.31 (dd, J ) 16.8, 5.4 Hz, 1H), 1.27 (t,
J ) 7.2 Hz, 3H), 0.90 (s, 9H), 0.21 (s, 3H), 0.07 (s, 3H); 13C
NMR (75 MHz) δ 171.8, 163.5, 150.4, 139.7, 102.2, 91.9, 82.1,
77.7, 61.2, 51.8, 39.6, 29.8, 26.0, 18.2, 14.4, -4.3, -5.4; MS
(FAB) m/z 454.2123 (MH+ [C19H32N5O6Si] ) 454.2122).
Meth od B. A solution of 8 (108 mg, 0.252 mmol), I2 (83 mg,
0.33 mmol), and Ph3P (86 mg, 0.33 mmol) in dried pyridine (2
mL) was stirred for 12 h at ambient temperature. Volatiles
were evaporated, the residue was partitioned (NaHCO3/H2O//
CHCl3), and the organic phase was washed (Na2S2O3/H2O) and
dried (Na2SO4). Volatiles were evaporated, and the residue was
chromatographed (EtOAc/hexanes, 2:1) to give 2′-O-TBDMS-
3′,5′-dideoxy-3′-[(ethoxycarbonyl)methyl]-5′-iodoUrd (101 mg,
74%) as a glass: 1H NMR (300 MHz) δ 9.50 (br s, 1H), 7.70 (d,
J ) 8.4 Hz, 1H), 5.77 (d, J ) 8.1 Hz, 1H), 5.73 (d, J ) 1.5 Hz,
1H), 4.53 (dd, J ) 5.1, 1.5 Hz, 1H), 4.15 (q, J ) 7.2 Hz, 2H),
3.79 (ddd, J ) 8.8, 5.6, 3.2 Hz, 1H), 3.60 (dd, J ) 11.6, 3.2 Hz,
1H), 3.36 (dd, J ) 11.4, 5.4 Hz, 1H), 2.63 (dd, J ) 16.8, 8.4
Hz, 1H), 2.35 (dd, J ) 16.4, 5.6 Hz, 1H), 2.30-2.25 (m, 1H),
1.27 (t, J ) 7.1 Hz, 3H), 0.89 (s, 9H), 0.17 (s, 3H), 0.05 (s, 3H);
13C NMR (75 MHz) δ 171.8, 163.7, 150.4, 140.3, 102.4, 91.6,
81.7, 77.7, 61.2, 44.3, 29.9, 25.9, 18.1, 14.3, 7.2, -4.4, -5.6;
MS (FAB) m/z 539.1073 (MH+ [C19H32IN2O6Si] ) 539.1074).
A solution of this material (101 mg, 0.188 mmol) and NaN3
(37 mg, 0.57 mmol) in dried DMF (3.5 mL) was stirred for 24
h at 65 °C. Volatiles were evaporated (∼60 °C), the residue
was partitioned (EtOAc//NaHCO3/H2O), and the organic layer
was washed (NaHCO3/H2O) and dried (Na2SO4). Volatiles were
evaporated to give 40 (85 mg, 99%) as a solid foam (∼95%, 1H
NMR).
5′-Azido-2′-O-(ter t-bu tyldim eth ylsilyl)-3′-(car boxym eth -
yl)-3′,5′-d id eoxyu r id in e (41). Procedure D [NaOH (43 mg,
1.1 mmol), 40 (85 mg, 0.19 mmol), MeOH/H2O (4:1, 2.1 mL), 3
h, pH ∼4 (4% HCl/H2O)]. The precipitate was filtered, washed
(cold H2O), and dried (vacuum) to give 41 (62 mg, 77%): 1H
NMR (300 MHz) δ 9.86 (br s, 1H), 7.83 (d, J ) 8.1 Hz, 1H),
5.80 (d, J ) 8.1 Hz, 1H), 5.68 (s, 1 H), 4.48 (d, J ) 4.5 Hz,
1H), 4.14 (dt, J ) 9.9, 2.9 Hz, 1H), 3.89 (dd, J ) 13.4, 2.6 Hz,
1H), 3.61 (dd, J ) 14.0, 3.5 Hz, 1H), 2.68 (dd, J ) 16.4, 8.3
Hz, 1H), 2.49-2.43 (m, 1H), 2.36 (dd, J ) 16.5, 4.8 Hz, 1H),
0.91 (s, 9H), 0.20 (s, 3H), 0.08 (s, 3H); 13C NMR (75 MHz) δ
176.3, 164.4, 150.5, 140.4, 102.1, 92.4, 82.2, 77.6, 51.7, 39.6,
29.9, 26.0, 18.2, -4.3, -5.4; MS (FAB) m/z 448.1610 (MNa+
[C17H27N5O6SiNa] ) 448.1628).
5′-Am in o-2′-O-(ter t-bu tyld im eth ylsilyl)-3′,5′-d id eoxy-3′-
[(eth oxyca r bon yl)m eth yl]u r id in e (42). Procedure C [Et3N
(0.95 mL), 1,3-propanedithiol (0.94 mL, 1.0 g, 9.4 mmol), 40
(708 mg, 1.56 mmol), dried EtOH (28 mL), 12 h, chromatog-
raphy (MeOH/CH2Cl2, 1:9)] gave 42 (512 mg, 77%): 1H NMR
(300 MHz) δ 8.28 (d, J ) 8.1 Hz, 1H), 5.71 (s, 1H), 5.70 (d,
J ) 8.1 Hz, 1H), 4.41 (d, J ) 3.6 Hz, 1H), 4.15 (q, J ) 7.2 Hz,
2H), 4.03 (d, J ) 8.4 Hz, 1H), 3.14 (br s, 1H), 2.91 (br s, 1H),
2.64 (dd, J ) 16.5, 7.2 Hz, 1H), 2.43-2.35 (m, 1H), 2.31 (dd,
J ) 16.0, 5.4 Hz, 1H), 1.27 (t, J ) 7.2 Hz, 3H), 0.92 (s, 9H),
0.22 (s, 3H), 0.08 (s, 3H); 13C NMR (75 MHz) δ 172.3, 164.0,
150.5, 140.8, 101.7, 92.1, 85.1, 78.4, 61.1, 39.2, 29.9, 26.0, 18.2,
14.4, -4.2, -5.4; MS (FAB) m/z 428.2233 (MH+ [C19H34N3O6-
Si] ) 428.2217).
0.92 (br s, 9H), 0.25 (s, 3H), 0.11 (s, 3H); 13C NMR (Me2CO-
d6) δ 174.1, 164.3, 151.6, 150.6, 141.5, 101.4, 92.3, 85.8, 79.1,
60.8, 38.0, 26.3, 18.7, -4.1, -5.4; MS (FAB) m/z 401.1762 (MH+
[C17H29N2O7Si] ) 401.1744).
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)u r id in e Tr ieth yla m m o-
n iu m Sa lt (44). Dried pyridine (1.0 mL), dried Et3N (0.10 mL),
DMTCl (120 mg, 0.354 mmol), and 43 (70 mg, 0.18 mmol) were
added to a flame-dried flask, and the solution was stirred for
4 h at ambient temperature (under N2). Volatiles were
evaporated, the residue was chromatographed (Et3N/MeOH/
CH2Cl2, 1:5:95), and the product was partitioned (NaHCO3/
H2O//CH2Cl2). The aqueous layer was extracted (CH2Cl2, 3×),
and the combined organic phase was dried (Na2SO4). Volatiles
were evaporated to give 44 (90 mg, 62%): 1H NMR δ 8.33 (br
s, 1H), 8.13 (d, J ) 8.4 Hz, 1H), 7.44-7.21 (m, 9H), 6.83 (d,
J ) 8.6 Hz, 4H), 5.70 (s, 1H), 5.25 (d, J ) 8.2 Hz, 1H), 4.55 (d,
J ) 3.0 Hz, 1H), 4.10 (d, J ) 9.4 Hz, 1H), 3.78 (s, 6H), 3.60 (d,
J ) 11.0 Hz, 1H), 3.31 (dd, J ) 11.0, 3.3 Hz, 1H), 2.94 (q, J )
7.3 Hz, 6H), 2.57-2.37 (m, 2H), 2.08-2.00 (m, 1H), 1.20 (t,
J ) 7.3 Hz, 9H), 0.88 (br s, 9H), 0.22 (s, 3H), 0.09 (s, 3H); 13
C
NMR δ 176.2, 163.9, 158.6, 150.2, 144.5, 140.7, 135.4, 135.2,
130.1, 128.1, 127.9, 127.0, 113.2, 101.1, 92.0, 86.7, 83.5, 61.7,
55.1, 45.2, 38.5, 30.1, 25.7, 17.9, 8.4, -4.7, -5.7; MS (FAB)
m/z 702.2971 [(M - Et3N)+ [C38H46N2O9Si] ) 702.2973].
2′-O-(ter t-Bu tyldim eth ylsilyl)-3′-deoxy-5′-O-(4,4′-dim eth -
oxyt r it yl)-3′-[[(4-n it r op h e n oxy)ca r b on yl]m e t h yl]u r i-
d in e (45). A solution of 44 (50 mg, 0.062 mmol), 4-nitrophenol
(10 mg, 0.072 mmol), and DCC (15 mg, 0.073 mmol) in dried
CH2Cl2 (1.0 mL) was stirred overnight at ambient temperature
(under N2). The suspension was filtered (Celite), volatiles were
evaporated, and the residue was chromatographed (EtOAc/
CH2Cl2, 1:9) to give 45 (31 mg, 61%): 1H NMR δ 8.28 (d, J )
9.2 Hz, 2H), 8.24 (d, J ) 8.4 Hz, 1H), 7.91 (br s, 1H), 7.51-
7.18 (m, 12H), 6.84 (dd, J ) 8.9, 2.3 Hz, 4H), 5.77 (s, 1H), 5.31
(dd, J ) 8.1, 2.5 Hz, 1H), 4.47 (d, J ) 3.8 Hz, 1H), 4.14-4.08
(m, 1H), 3.90 (“d”, J ) 12.2 Hz, 1H), 3.79 (s, 3H), 3.78 (s, 3H),
3.35 (“d”, J ) 13.4 Hz, 1H), 2.84-2.62 (m, 1H), 2.13 (m, 1H),
0.90 (br s, 9H), 0.25 (s, 3H), 0.08 (s, 3H); 13C NMR δ 169.3,
163.5, 158.8, 155.0, 150.3, 145.4, 144.3, 140.2, 135.1, 134.9,
130.2, 128.1, 127.2, 125.3, 122.1, 113.3, 101.6, 91.5, 87.3, 83.2,
77.4, 60.8, 55.2, 37.6, 29.6, 27.3, 25.7, 17.9, -4.5, -5.8; MS
(FAB) m/z 824.3220 (MH+ [C44H50N3O11Si] ) 824.3215).
2′,5′-Bis-O-(ter t-bu tyldim eth ylsilyl)-3′-deoxy-3′-[[N-(2′,3′-
b is-O-(ter t-b u t yld im et h ylsilyl)-5′-d eoxya d en osin -5′-yl)-
ca r boxa m id o]m eth yl]a d en osin e (46). Procedure E [17 (100
mg, 0.202 mmol), 37 (110 mg, 0.204 mmol), DCC (50.0 mg,
0.241 mmol), dried CH2Cl2 (1.0 mL), chromatography (MeOH/
CH2Cl2, 1:9)] gave 46 (168 mg, 82%): 1H NMR (500 MHz) δ
8.56 (br s, 1H), 8.40, 8.37, 8.36, 7.85 (4 × s, 4 × 1H), 6.07 (d,
J ) 2.5 Hz, 1H), 5.75 (d, J ) 8.0 Hz, 1H), 5.74 (br s, 2H), 5.56
(br s, 2H), 4.90 (dd, J ) 7.8, 5.3 Hz, 1H), 4.83 (dd, J ) 5.0, 2.0
Hz, 1H), 4.28 (s, 1H), 4.21 (d, J ) 7.5 Hz, 1H), 4.10 (d, J ) 5.0
Hz, 2H), 4.08 (dd, J ) 11.5, 2.0 Hz, 1H), 3.80 (dd, J ) 11.8,
2.8 Hz, 1H), 3.27 (d, J ) 14.5 Hz, 1H), 2.97-2.89 (m, 1H), 2.72
(dd, J ) 15.5, 6.0 Hz, 1H), 2.44 (dd, J ) 15.0, 8.0 Hz, 1H),
0.94 (s, 18H), 0.87, 0.75, 0.14 (3 × s, 3 × 9H), 0.12, 0.11, 0.04,
-0.16, -0.57 (5 × s, 5 × 3H); 13C NMR δ 171.5, 156.5, 155.6,
152.9, 152.5, 149.6, 148.9, 141.2, 138.9, 121.3, 119.7, 90.2, 90.0,
86.3, 85.1, 78.4, 73.4, 73.1, 63.7, 40.8, 38.9, 32.5, 25.9, 25.7,
25.6, 25.4, 18.4, 17.8, 17.6, -4.7, -4.8, -5.0, -5.2, -5.5, -5.8;
MS (FAB) m/z 1014.5621 (MH+ [C46H84N11O7Si4] ) 1014.5632).
Anal. Calcd for C46H83N11O7Si4: C, 54.46; H, 8.25; N, 15.19.
Found: C, 54.37; H, 8.41; N, 15.05.
2′,5′-Bis-O-(ter t-bu tyldim eth ylsilyl)-3′-deoxy-3′-[[N-(2′,3′-
bis-O-(ter t-bu tyld im eth ylsilyl)-5′-d eoxyu r id in -5′-yl)ca r -
boxa m id o]m eth yl]a d en osin e (47). Procedure E [18 (46 mg,
0.098 mmol), 37 (53 mg, 0.099 mmol), DCC (25 mg, 0.12 mmol),
dried CH2Cl2 (0.5 mL), chromatography (EtOAc/hexanes, 7:3)]
gave 47 (73 mg, 75%): 1H NMR (500 MHz) δ 10.75, 8.54, 8.46
(3 × s, 3 × 1H), 7.15 (d, J ) 8.5 Hz, 1H), 7.12 (m, 1H), 6.19 (d,
J ) 2.0 Hz, 1H), 5.82 (br s, 2H), 5.73 (dd, J ) 7.8, 2.3 Hz, 1H),
5.10 (d, J ) 7.0 Hz, 1H), 4.83 (dd, J ) 7.5, 5.0 Hz, 1H), 4.46
(dd, J ) 4.3, 2.3 Hz, 1H), 4.14 (dt, J ) 8.0, 2.5 Hz, 1H), 4.11-
4.09 (m, 1H), 4.07 (dd, J ) 12.0, 2.5 Hz, 1H), 3.90 (dd, J )
2′-O-(ter t-Bu t yld im et h ylsilyl)-3′-(ca r b oxym et h yl)-3′-
d eoxyu r id in e (43). Procedure D [NaOH (640 mg, 16.0 mmol),
8 (774 mg, 1.81 mmol), MeOH/H2O (5:1, 60 mL), 5 h, pH ∼2
(0.5 M HCl/H2O), chromatography (MeOH/CH2Cl2, 1:9) gave
43 (480 mg, 66%): 1H NMR (Me2CO-d6) δ 10.04 (br s, 1H),
8.34 (d, J ) 8.0 Hz, 1H), 5.69 (s, 1H), 5.54 (d, J ) 8.2 Hz, 1H),
4.52 (br s, 1H), 4.06-4.00 (m, 2H), 3.82 (d, J ) 12.4 Hz, 1H),
3.50-3.31 (m, 1H), 3.00-2.81 (br s, 1H), 2.71-2.42 (m, 2H),

Amide-Linked Ribonucleoside Dimers
J . Org. Chem., Vol. 64, No. 22, 1999 8191
5.0, 1.5 Hz, 1H), 3.83-3.78 (m, 2H), 3.26 (dt, J ) 14.5, 3.1 Hz,
1H), 2.88 (ddd, J ) 15.5, 7.5, 5.0 Hz, 1H), 2.57 (dd, J ) 15.5,
8.0 Hz, 1H), 2.49 (dd, J ) 15.5, 8.0 Hz, 1H), 0.97, 0.91, 0.88,
0.87 (4 × s, 4 × 9H), 0.17, 0.16, 0.14 (3 × s, 3 × 3H), 0.09 (s,
6H), 0.04, 0.01, -0.01 (3 × s, 3 × 3H); 13C NMR (75 MHz) δ
171.2, 163.6, 163.6, 155.5, 153.0, 150.9, 149.5, 143.9, 139.4,
119.4, 102.7, 96.2, 89.4, 84.9, 84.3, 78.0, 73.3, 71.8, 63.3, 41.0,
38.3, 32.5, 29.7, 26.1, 25.8, 25.7, 18.6, 18.0, 17.9, -4.6, -4.7,
-4.8, -5.29, -5.33; MS (FAB) m/z 991.5354 (MH+ [C45H83N8O9-
Si4] ) 991.5360). Anal. Calcd for C45H82N8O9Si4: C, 54.51; H,
8.34; N, 11.30. Found: C, 54.46; H, 8.08; N, 10.96.
2′,5′-Bis-O-(ter t-bu tyldim eth ylsilyl)-3′-deoxy-3′-[[N-(2′,3′-
bis-O-(ter t-bu tyld im eth ylsilyl)-5′-d eoxyu r id in -5′-yl)ca r -
boxa m id o]m eth yl]u r id in e (48). Procedure E [38 (80 mg,
0.16 mmol), 18 (80 mg, 0.17 mmol), DCC (64 mg, 0.31 mmol),
dried CH2Cl2 (0.8 mL), chromatography (40 f 70% EtOAc/
hexanes)] gave 48 (115 mg, 74%): 1H NMR (500 MHz) δ 8.88
(br s, 1H), 8.66 (br s, 1H), 8.14 (d, J ) 8.3 Hz, 1H), 7.23 (d,
J ) 7.8 Hz, 1H), 6.91 (dd, J ) 6.7, 4.2 Hz, 1H), 5.80 (d, J )
2.5 Hz, 1H), 5.75 (d, J ) 7.5 Hz, 1H), 5.65 (d, J ) 8.5 Hz, 1H),
5.24 (d, J ) 6.0 Hz, 1H), 4.68 (dd, J ) 6.0, 5.0 Hz, 1H), 4.44
(dd, J ) 5.3, 2.3 Hz, 1H), 4.12-4.10 (m, 1H), 4.07-4.03 (m,
2H), 3.92 (dd, J ) 5.0, 3.0 Hz, 1H), 3.71 (dd, J ) 12.3, 1.8 Hz,
1H), 3.62 (quint, J ) 6.9 Hz, 1H), 3.40 (dt, J ) 14.3, 3.6 Hz,
1H), 2.65-2.62 (m, 1H), 2.53 (dd, J ) 15.4, 7.6 Hz, 1H), 2.26
(dd, J ) 15.4, 7.1 Hz, 1H), 0.93, 0.90, 0.89, 0.86 (4 × s, 4 ×
9H), 0.16 (s, 3H), 0.11 (s, 6H), 0.08 (s, 6H), 0.07, 0.04, -0.02
(3 × s, 3 × 3H); 13C NMR δ 171.3, 164.0, 163.5, 150.6, 150.5,
143.7, 140.7, 128.3, 102.5, 101.4, 95.6, 90.5, 84.5, 73.1, 72.2,
62.3, 41.1, 37.8, 31.4, 25.8, 25.70, 25.65, 25.6, 18.3, 17.91, 17.85,
17.8, -4.65, -4.72, -4.8, -4.9, -5.0, -5.5, -5.7, -5.8; MS
(FAB) m/z 968.5101 (MH+ [C44H82N5O11Si4] ) 968.5088). Anal.
Calcd for C44H81N5O11Si4: C, 54.57; H, 8.43; N, 7.23. Found:
C, 54.62; H, 8.18; N, 7.08.
chromatography (50 f 60% EtOAc/hexanes)] gave 51 (81 mg,
71%): 1H NMR δ 8.50 (s, 1H), 8.20-8.13 (m, 2H), 8.04 (“d”,
J ) 7.2 Hz, 2H), 7.58 (d, J ) 7.2 Hz, 1H), 7.49-7.17 (m, 12H),
6.85 (“d”, J ) 6.2 Hz, 4H), 6.73 (br s, 1H), 5.77 (s, 1H), 5.75 (d,
J ) 8.0 Hz, 1H), 5.36-5.21 (m, 3H), 4.90 (t, J ) 5.7 Hz, 1H),
4.60 (“d”, J ) 3.8 Hz, 1H), 4.39 (m, 1H), 4.08 (“d”, J ) 8.6 Hz,
1H), 3.80 (s, 6H), 3.69-3.63 (m, 1H), 3.39 (d, J ) 14.8 Hz,
1H), 3.22 (d, J ) 10.2 Hz, 1H), 2.79-2.61 (m, 1H), 2.53-2.41
(m, 1H), 2.10-2.00 (m, 2H), 0.88 (s, 9H), 0.72 (s, 9H), 0.23,
0.09, -0.04, -0.05 (4 × s, 4 × 3H); 13C NMR δ 171.2, 165.5,
163.7, 163.0, 158.7, 158.6, 150.4, 150.3, 144.4, 142.9, 140.6,
135.3, 135.0, 133.5, 130.3, 130.2, 129.8, 129.2, 128.5, 128.1,
128.0, 127.1, 113.3, 102.9, 101.4, 95.5, 91.3, 86.9, 83.3, 80.9,
73.1, 71.5, 61.7, 55.2, 41.1, 38.3, 30.6, 25.7, 25.3, 17.9, 17.6,
-4.7, -5.3, -5.3, -5.6; MS (FAB) m/z 1168.4785 (MNa+
[C60H75N5O14Si2Na] ) 1168.4747).
2′-O-(ter t-Bu tyldim eth ylsilyl)-3′-deoxy-5′-O-(4,4′-dim eth -
oxytr ityl)-3′-[[N-(2′-O-m eth yl-5′-d eoxya d en osin -5′-yl)ca r -
boxa m id o]m eth yl]u r id in e (52). Procedure F [45 (29 mg,
0.035 mmol)/THF/EtOH (1:1, 2.0 mL), 29 (12 mg, 0.043 mmol)/
EtOH (1.8 mL), 5 days, preparative TLC (Et3N/MeOH/CH2-
Cl2, 0.5:10:90)] gave 52 (25 mg, 74%): 1H NMR (500 MHz) δ
9.31 (br s, 1H), 8.21 (d, J ) 8.0 Hz, 1H), 8.13 (s, 1H), 7.92 (m,
1H), 7.91 (s, 1H), 7.41 (dd, J ) 7.0, 1.5 Hz, 2H), 7.32-7.22 (m,
7H), 6.82 (dd, J ) 6.8, 1.8 Hz, 2H), 6.80 (dd, J ) 7.5, 2.0 Hz,
2H), 6.06 (br s, 2H), 5.84 (d, J ) 6.5 Hz, 1H), 5.79 (s, 1H), 5.27
(d, J ) 8.0 Hz, 1H), 4.58-4.56 (m, 2H), 4.31 (m, 2H), 4.09 (d,
J ) 10.0 Hz, 1H), 3.97 (ddd, J ) 14.5, 8.3, 3.0 Hz, 1H), 3.77
(dd, J ) 12.0, 2.0 Hz, 1H), 3.73, 3.71, 3.32 (3 × s, 3 × 3H),
3.32-3.27 (m, 2H), 2.80-2.75 (m, 2H), 2.57 (dd, J ) 16.0, 8.5
Hz, 1H), 1.94 (dd, J ) 16.0, 4.5 Hz, 1H), 0.84 (br s, 9H), 0.22
(s, 3H), 0.06 (s, 3H); 13C NMR δ 171.1, 164.2, 158.7, 156.3,
152.8, 150.9, 149.0, 144.4, 141.0, 140.7, 135.3, 135.1, 130.4,
130.2, 128.2, 128.0, 127.1, 120.7, 113.3, 101.8, 91.3, 88.7, 87.1,
84.7, 83.5, 81.4, 78.0, 70.6, 61.5, 58.8, 55.1, 41.1, 38.0, 30.6,
25.7, 17.9, -4.8, -5.3; MS (FAB) m/z 987.4097 (MNa+
[C49H60N8O11SiNa] ) 987.4049).
5′-Azid o-2′-O-(ter t-bu tyld im eth ylsilyl)-3′-[[N-(2′,3′-bis-
O-(ter t-bu tyld im eth ylsilyl)-5′-d eoxyu r id in -5′-yl)ca r box-
a m id o]m eth yl]-3′,5′-d id eoxyu r id in e (53). Procedure E [41
(225 mg, 0.529 mmol), 18 (223 mg, 0.473 mmol), DCC (118
mg, 0.572 mmol), dried CH2Cl2 (2.2 mL), chromatography
(2.5 f 5% MeOH/CH2Cl2)] gave 53 (324 mg, 78%): 1H NMR
(300 MHz) δ 9.11 (br s, 1H), 8.93 (br s, 1H), 7.77 (d, J ) 8.4
Hz, 1H), 7.23 (d, J ) 8.1 Hz, 1H), 7.17 (dd, J ) 6.9, 3.6 Hz,
1H), 5.76 (s, 1H), 5.74 (t, J ) 2.0 Hz, 2H), 5.21 (d, J ) 6.6 Hz,
1H), 4.74 (dd, J ) 6.6, 5.1 Hz, 1H), 4.40 (dd, J ) 4.7, 1.7 Hz,
1H), 4.18-4.14 (m, 2H), 3.95 (dd, J ) 4.8, 2.1 Hz, 1H), 3.81
(dd, J ) 13.5, 2.7 Hz, 1H), 3.72-3.61 (m, 2H), 3.39 (dt, J )
13.8, 3.2 Hz, 1H), 2.59-2.49 (m, 2H), 2.34 (dd, J ) 17.0, 9.5
Hz, 1H), 0.92, 0.91, 0.86 (3 × s, 3 × 9H), 0.19, 0.10, 0.096,
0.09, 0.04, -0.02 (6 × s, 6 × 3H); 13C NMR (75 MHz) δ 171.4,
163.3, 162.9, 150.7, 150.5, 144.7, 139.9, 102.9, 102.4, 97.0, 91.2,
85.3, 82.6, 78.1, 73.5, 71.8, 52.7, 41.4, 40.1, 32.4, 26.04, 25.99,
25.9, 18.3, 18.1, -4.3, -4.4, -4.7, -5.1; MS (FAB) m/z
901.4114 (MNa+ [C38H66N8O10Si3Na] ) 901.4107).
2′,5′-Bis-O-(ter t-bu tyld im eth ylsilyl)-3′-d eoxy-3′-[[N-(5′-
deoxyaden osin -5′-yl)car boxam ido]m eth yl]aden osin e (49).
Procedure F [39 (100 mg, 0.152 mmol), 5′-amino-5′-deoxyAdo
(40 mg, 0.15 mmol), pyridine (5 mL), 4 days, chromatography
1
(SSA)] gave 49 (77 mg, 65%): H NMR (DMSO-d6, 500 MHz)
δ 8.39 (s, 1H), 8.37 (s, 1H), 8.31 (t, J ) 4 Hz, 1H), 8.21 (s, 1H),
8.20 (s, 1H), 7.36 (br s, 4H), 5.95 (d, J ) 2.0 Hz, 1H), 5.89 (d,
J ) 6.5 Hz, 1H), 5.48 (d, J ) 5.5 Hz, 1H), 5.29 (d, J ) 4.0 Hz,
1H), 4.73 (d, J ) 5.5 Hz, 1H), 4.65 (dd, J ) 5.0, 1.5 Hz, 1H),
4.39 (d, J ) 4.0 Hz, 1H), 4.11-3.98 (m, 4H), 3.81-3.79, 3.53-
3.42, 2.82-2.74 (3 × m, 3 × 1H), 2.49 (dd, J ) 16.8, 7.2 Hz,
1H; overlap with solvent peaks), 2.30 (dd, J ) 16.8, 6.3 Hz,
1H), 0.93 (s, 9H), 0.86 (s, 9H), 0.12 (s, 3H), 0.11 (s, 6H), 0.10
(s, 3H); 13C NMR (DMSO-d6, 125 MHz) δ 170.5, 156.1, 156.0,
152.6, 152.4, 149.2, 148.8, 140.2, 137.9, 119.4, 118.9, 89.3, 87.9,
84.0, 83.2, 77.6, 72.6, 71.3, 62.8, 37.8, 30.5, 25.8, 25.6, 18.1,
17.6, -4.9, -5.5; MS (FAB) m/z 786.3919 (MH+ [C34H56N11O7-
Si2] ) 786.3903).
2′,5′-Bis-O-(ter t-bu tyld im eth ylsilyl)-3′-d eoxy-3′-[[N-(5′-
d eoxyu r id in -5′-yl)ca r boxa m id o]m eth yl]a d en osin e (50).
Procedure F [39 (10 mg, 0.015 mmol), 5′-amino-5′-deoxyUrd
(4 mg, 0.02 mmol), pyridine (0.5 mL), 3 days, chromatography
(SSA)] gave 50 (8 mg, 70%): 1H NMR (DMSO-d6, 500 MHz) δ
11.39, 8.38, 8.20 (3 × s, 3 × 1H), 8.15 (t, J ) 5.8 Hz, 1H), 7.70
(d, J ) 7.5 Hz, 1H), 7.35 (s, 2H), 5.95 (d, J ) 2.0 Hz, 1H), 5.77
(d, J ) 5.5 Hz, 1H), 5.66 (d, J ) 8.5 Hz, 1H), 5.42 (d, J ) 5.5
Hz, 1H), 5.17 (d, J ) 5.5 Hz, 1H), 4.66 (dd, J ) 5.0, 1.5 Hz,
1H), 4.11 (dd, J ) 10.8, 5.3 Hz, 1H), 4.05-4.02 (m, 2H), 3.87
(dd, J ) 10.0, 5.0 Hz, 1H), 3.84-3.78 (m, 2H), 3.52-3.49, 3.23-
3.19, 2.80-2.77 (3 × m, 3 × 1H), 2.48 (dd, J ) 16.0, 8.0 Hz,
1H), 2.30 (dd, J ) 15.8, 6.3 Hz, 1H), 0.94 (s, 9H), 0.89 (s, 9H),
0.13 (s, 3H), 0.12 (s, 6H), 0.11 (s, 3H); 13C NMR (DMSO-d6,
125 MHz) δ 170.5, 162.9, 156.0, 152.5, 150.6, 148.8, 141.3,
137.9, 118.9, 101.9, 89.3, 88.4, 83.9, 82.2, 77.6, 72.4, 70.9, 62.8,
41.2, 37.8, 30.5, 25.8, 25.6, 18.1, 17.6, -4.9, -5.5; MS (FAB)
m/z 763.3649 (MH+ [C33H55N8O9Si2] ) 763.3631).
5′-Am in o-2′-O-(ter t-bu tyld im eth ylsilyl)-3′-[[N-(2′,3′-bis-
O-(ter t-bu tyld im eth ylsilyl)-5′-d eoxyu r id in -5′-yl)ca r box-
a m id o]m eth yl]-3′,5′-d id eoxyu r id in e (54). Procedure B [53
(25 mg, 0.028 mmol), 10% Pd-C (5 mg), H2 (5 psi), dried THF
(5 mL), 8 h, chromatography (SSA)] gave 54 (15 mg, 63%): 1H
NMR (500 MHz) δ 8.30, 7.30, 7.24 (3 × br s, 3 × 1H), 5.76 (d,
J ) 7.0 Hz, 1H), 5.69 (d, J ) 6.5 Hz, 1H), 5.63 (s, 1H), 5.21 (s,
1H), 4.71 (br s, 1H), 4.41 (br s, 1H), 4.12 (br s, 2H), 3.95 (br s,
1H), 3.72 (m, 1H), 3.34 (d, J ) 12.5 Hz, 1H), 3.18 (m, 1H),
2.97 (br s, 1H), 2.55 (br s, 1H), 2.53 (d, J ) 15.5 Hz, 1H), 2.33
(m, 1H), 0.92, 0.91, 0.85 (3 × br s, 3 × 9H), 0.19 (s, 3H), 0.10
(s, 3H), 0.08 (s, 6H), 0.03 (s, 3H), -0.04 (s, 3H); 13C NMR (75
MHz) δ 172.0, 164.3, 163.8, 150.9, 150.7, 144.3, 141.7, 102.8,
101.8, 95.8, 92.4, 85.0, 84.3, 78.5, 73.3, 72.3, 42.6, 41.4, 39.9,
32.1, 30.4, 29.9, 26.04, 25.97, 25.9, 18.2, 18.2, 18.1, -4.30,
-4.32, -4.4, -4.5, -4.7, -5.1; MS (FAB) m/z 853.4390 (MH+
[C38H69N6O10Si3] ) 853.4386).
3′-[[N-(3′-O-Ben zoyl-2′-O-(ter t-b u t yld im et h ylsilyl)-5′-
d eoxyu r id in -5′-yl)ca r boxa m id o]m eth yl]-2′-O-(ter t-bu tyl-
d im et h ylsilyl)-5′-O-(4,4′-d im et h oxyt r it yl)-3′-d eoxyu r i-
d in e (51). Procedure E [44 (88 mg, 0.11 mmol), 36 (48 mg,
0.10 mmol), DCC (40 mg, 0.19 mmol), dried CH2Cl2 (0.9 mL),
5′-Azid o-2′-O-(ter t-bu tyld im eth ylsilyl)-3′-[[N-(2′-O-(ter t-
b u t yld im et h ylsilyl)-3′,5′-d id eoxy-3′-[(et h oxyca r b on yl)-

8192 J . Org. Chem., Vol. 64, No. 22, 1999
Peterson et al.
m eth yl]u r id in -5′-yl)ca r boxa m id o]m eth yl]-3′,5′-d id eoxy-
u r id in e (55). Procedure E [41 (447 mg, 1.05 mmol), 42 (494
mg, 1.16 mmol), DCC (237 mg, 1.15 mmol), dried CH2Cl2 (4.5
mL), chromatography (EtOAc/hexanes, 7:3)] gave 55 (630 mg,
72%): 1H NMR (500 MHz) δ 8.84 (br s, 1H), 8.81 (br s, 1H),
7.74 (d, J ) 8.5 Hz, 1H), 7.34 (d, J ) 7.5 Hz, 1H), 6.54 (t, J )
5.8 Hz, 1H), 5.76 (dd, J ) 8.3, 1.8 Hz, 1H), 5.73 (dd, J ) 7.5,
2.0 Hz, 1H), 5.71 (d, J ) 1.5 Hz, 1H), 5.49 (d, J ) 1.0 Hz, 1H),
4.58 (d, J ) 4.0 Hz, 1H), 4.46 (d, J ) 2.5 Hz, 1H), 4.16-4.13
(m, 1H), 4.14 (q, J ) 7.0 Hz, 2H), 4.08-4.04 (m, 1H), 3.83 (dd,
J ) 13.3, 2.8 Hz, 1H), 3.76 (ddd, J ) 14.5, 6.0, 2.5 Hz, 1H),
3.63 (dd, J ) 13.5, 4.0 Hz, 1H), 3.37-3.32 (m, 1H), 2.65 (dd,
J ) 16.3, 7.8 Hz, 1H), 2.58-2.50 (m, 2H), 2.44-2.36 (m, 2H),
2.27 (dd, J ) 14.3, 5.8 Hz, 1H), 1.27 (t, J ) 7.0 Hz, 3H), 0.91
78.6, 62.0, 44.5, 42.5, 42.1, 32.2, 30.6, 26.6, 26.5, 19.08, 19.05,
14.7, -4.0, -4.1, -4.9, -5.3; MS (FAB) m/z 809.3954 (MH+
[C36H61N6O11Si2] ) 809.3937).
5′-Azid o-2′-O-(ter t-bu tyld im eth ylsilyl)-3′-[[N-(2′-O-(ter t-
bu tyld im eth ylsilyl)-3′,5′-d id eoxy-3′-(ca r boxym eth yl)u r i-
d in -5′-yl)ca r boxa m id o]m eth yl]-3′,5′-d id eoxyu r id in e (57).
Procedure D [NaOH (109 mg, 2.73 mmol), 55 (380 mg, 0.455
mmol), MeOH/H2O (9:1, 11 mL), 8 h, pH ∼4 (4% HCl/H2O),
volatiles evaporated, MeOH added, NaCl filtered, filtrate
evaporated, residue chromatographed (MeOH/CH2Cl2, 1:9)]
gave 57 (235 mg, 64%): 1H NMR (MeOH-d4, 500 MHz) δ 7.87
(d, J ) 8.5 Hz, 1H), 7.78 (d, J ) 8.5 Hz, 1H), 5.72 (d, J ) 8.5
Hz, 1H), 5.71 (s, 1H), 5.70 (d, J ) 7.5 Hz, 1H), 5.62 (s, 1H),
4.56 (d, J ) 5.0 Hz, 1H), 4.50 (dd, J ) 5.3, 1.3 Hz, 1H), 4.12-
4.07 (m, 1H), 4.02 (ddd, J ) 10.5, 7.8, 2.8 Hz, 1H), 3.76 (dd,
J ) 13.5, 3.0 Hz, 1H), 3.63 (dd, J ) 13.8, 4.8 Hz, 1H), 3.56
(dd, J ) 14.5, 2.5 Hz, 1H), 3.46 (dd, J ) 14.3, 7.8 Hz, 1H),
2.59 (dd, J ) 17.0, 9.5 Hz, 1H), 2.56 (dd, J ) 15.8, 8.0 Hz,
1H), 2.50-2.44 (m, 2H), 2.33 (dd, J ) 15.5, 6.0 Hz, 1H), 2.20
(ddd, J ) 14.6, 9.9, 4.9 Hz, 1H), 0.91 (s, 18H), 0.17 (s, 3H),
0.16 (s, 3H), 0.08 (s, 6H); 13C NMR (MeOH-d4, 75 MHz) δ 173.9,
166.5, 166.4, 152.2, 142.4, 142.1, 102.5, 102.3, 93.9, 93.1, 84.7,
83.9, 79.1, 53.2, 43.3, 43.0, 41.3, 33.2, 32.2, 26.6, 19.1, -4.1,
(s, 9H), 0.90 (s, 9H), 0.19, 0.12, 0.08, 0.05 (4 × s, 4 × 3H); 13
C
NMR (75 MHz) δ 172.2, 171.3, 163.2, 163.0, 150.5, 150.2, 141.2,
139.9, 102.5, 102.4, 100.2, 95.3, 91.6, 82.6, 82.5, 77.9, 77.0, 61.2,
52.4, 41.5, 40.8, 40.2, 34.2, 32.1, 30.0, 26.0, 25.9, 18.3, 18.2,
14.4, -4.3, -5.2, -5.3; MS (FAB) m/z 857.3678 (MNa+
[C36H58N8O11Si2Na] ) 857.3662).
5′-Am in o-2′-O-(t er t -b u t yld im e t h ylsilyl)-3′-[[N -(2′-O-
(ter t-bu tyld im eth ylsilyl)-3′,5′-d id eoxy-3′-[(eth oxyca r bon -
yl)m eth yl]u r idin -5′-yl)car boxam ido]m eth yl]-3′,5′-dideoxy-
u r id in e (56). Procedure C [Et3N (0.3 mL), 1,3-propanedithiol
(0.276 mL, 297 mg, 2.75 mmol), 55 (380 mg, 0.455 mmol), dried
EtOH (8.6 mL), 12 h, chromatography (SSA)] gave 56 (260 mg,
71%): 1H NMR (MeOH-d4, 500 MHz) δ 7.79 (d, J ) 1.5 Hz,
1H), 7.77 (d, J ) 1.5 Hz, 1H), 5.70 (d, J ) 2.5 Hz, 1H), 5.69 (d,
J ) 3.0 Hz, 1H), 5.68 (s, 1H), 5.61 (d, J ) 1.0 Hz, 1H), 4.56-
4.54 (m, 2H), 4.11 (q, J ) 7.0 Hz, 2H), 4.05-3.98 (m, 2H), 3.52
(dd, J ) 15.0, 3.5 Hz, 1H), 3.47 (dd, J ) 14.8, 6.8 Hz, 1H),
3.05 (dd, J ) 13.8, 2.8 Hz, 1H), 2.94 (dd, J ) 13.8, 7.8 Hz,
1H), 2.62 (dd, J ) 17.0, 10.0 Hz, 1H), 2.59 (dd, J ) 15.0, 6.5
Hz, 1H), 2.51 (dd, J ) 17.8, 4.3 Hz, 1H), 2.39-2.30 (m, 2H),
2.23 (ddd, J ) 14.8, 10.0, 4.8 Hz, 1H), 1.24 (t, J ) 7.5 Hz, 3H),
0.91 (s, 9H), 0.90 (s, 9H), 0.16, 0.15, 0.08, 0.05 (4 × s, 4 × 3H);
13C NMR (MeOH-d4, 75 MHz) δ 174.1, 173.7, 166.4, 152.22,
152.17, 142.6, 142.4, 102.5, 102.4, 94.2, 93.9, 85.1, 84.1, 79.1,
-4.86, -4.92; MS (FAB) m/z 829.3344 (MNa+ [C34H54N8O11
Si2Na] ) 829.3349).
-
Ack n ow led gm en t. We thank Brigham Young Uni-
versity and the American Cancer Society (DPH-34) for
financial support and Mrs. J eanny K. Gordon for as-
sistance with the manuscript.
1
Su p p or tin g In for m a tion Ava ila ble: Copies of H NMR
spectra for 2, 9, 11, 12, 16, 22-28, 30, 32, 33-36, 38-45, and
49-57. This material is available free of charge via the
Internet at http://pubs.acs.org.
J O9908647