Application of germyldesulfonylation reactions to the synthesis of germanium-containing nucleoside analogues

Article abstract of DOI:10.1080/15257770903054340

Treatment of the protected (E)-5'-deoxy-5'-[(p-toluenesulfonyl)methylene] uridine and adenosine derivatives with tributyl- or triphenylgermane hydride (AIBN/toluene/) effected radical-mediated germyldesulfonylations to give 5'-(tributyl- or triphenylgermyl)methylene-5'-deoxyuridine and adenosine derivatives as single (E)-isomers. Analogous treatment of 2'-deoxy-2'- [(phenylsulfonyl)methylene]uridine with Ph3GeH afforded the corresponding vinyl triphenylgermane product. Stereoselective halodegermylation of the (E)-5'-(tributylgermyl)methylene-5'-deoxy nucleosides with N-iodosuccinimide or N-bromosuccinimide provided the Wittig-type (E)-5'-deoxy-5'-(halomethylene) nucleosides quantitatively, while no halodegermylations was observed with the 5'-deoxy-5'-(triphenylgermyl)methylene counterparts. Treatment of the vinyl trialkylgermanes with aqueous trifluoroacetic acid effected protiodegermylation, while vinyl triarylgermanes were stable under the acidic conditions.

Full text of DOI:10.1080/15257770903054340

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Application of Germyldesulfonylation
Reactions to the Synthesis of
Germanium-Containing Nucleoside
Analogues
Stanislaw F. Wnuk a , Pablo R. Sacasa a & Jorge Restrepo a
a Department of Chemistry & Biochemistry , Florida International
University , Miami , Florida , USA
Published online: 29 Jul 2009.
To cite this article: Stanislaw F. Wnuk , Pablo R. Sacasa & Jorge Restrepo (2009) Application of
Germyldesulfonylation Reactions to the Synthesis of Germanium-Containing Nucleoside Analogues,
Nucleosides, Nucleotides and Nucleic Acids, 28:5-7, 537-549, DOI: 10.1080/15257770903054340
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Nucleosides, Nucleotides and Nucleic Acids, 28:537–549, 2009
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1525-7770 print / 1532-2335 online
DOI: 10.1080/15257770903054340
APPLICATION OF GERMYLDESULFONYLATION REACTIONS TO
THE SYNTHESIS OF GERMANIUM-CONTAINING NUCLEOSIDE
ANALOGUES
Stanislaw F. Wnuk, Pablo R. Sacasa, and Jorge Restrepo
Department of Chemistry & Biochemistry, Florida International University,
Miami, Florida, USA
Treatment of the protected (E)-5ꢁ-deoxy-5ꢁ-[(p-toluenesulfonyl)methylene]uridine and adeno-
2
sine derivatives with tributyl- or triphenylgermane hydride (AIBN/toluene/ꢀ) effected radical-
mediated germyldesulfonylations to give 5ꢁ-(tributyl- or triphenylgermyl)methylene-5ꢁ-deoxyuridine
and adenosine derivatives as single (E)-isomers. Analogous treatment of 2ꢁ-deoxy-2ꢁ-
[(phenylsulfonyl)methylene]uridine with Ph3GeH afforded the corresponding vinyl triphenylger-
mane product. Stereoselective halodegermylation of the (E)-5ꢁ-(tributylgermyl)methylene-5ꢁ-deoxy
nucleosides with N-iodosuccinimide or N-bromosuccinimide provided the Wittig-type (E)-5ꢁ-deoxy-
5ꢁ-(halomethylene) nucleosides quantitatively, while no halodegermylations was observed with the
5ꢁ-deoxy-5ꢁ-(triphenylgermyl)methylene counterparts. Treatment of the vinyl trialkylgermanes with
aqueous trifluoroacetic acid effected protiodegermylation, while vinyl triarylgermanes were stable
under the acidic conditions.
Keywords Germyldesulfonylation; germanonucleosides; vinyl germanes, vinyl sulfones
INTRODUCTION
Radical-mediated substitution of the arylsulfonyl group with tributyl-
stannyl group at the vinylic carbon has been a critical step in the
synthesis of the various nucleoside and amino acids analogues bearing
a halo vinyl functionality. For example, McCarthy and coworkers em-
ployed a radical-mediated stannyldesulfonylation procedure (1a → 1b)
for the synthesis of (E)-fluorovinyl cytidine 1c (Tezacitabine; an inhibitor
Received 3 March 2009; accepted 19 May 2009.
In honor and celebration of Morris J. Robins’ 70th birthday.
This investigation was supported by NIGMS and NCI SC1CA138176 award. P.R.S and J.R. were
sponsored by MBRS RISE program (NIGMS; R25GM61347).
Address correspondence to Stanislaw F. Wnuk, Department of Chemistry & Biochemistry, Florida,
International University, Miami, FL, 33199, USA. E-mail: wnuk@fiu.edu
537

538
S. F. Wnuk et al.
FIGURE 1 Nucleoside analogues whose synthesis were accomplished by tin radical-mediated extrusion
of sulfer atoms.
of ribonucleoside reductases with potent anticancer activity), from the
protected (α-fluoro)vinyl sulfone 1a (Figure 1).[1,2] Stannyldesulfonyla-
tion of the vinyl sulfone 2a followed by halodestannylation of the re-
sulting vinyl stannanes 2b was a key step in the synthesis of 5ꢁ-deoxy-
5ꢁ-(halomethylene)adenosines 2c, which were found to be potent in-
hibitors of S-adenosyl-L-homocysteine (AdoHcy) hydrolase and valuable
probes to study hydrolytic activity of the enzyme.[3–5] Stannyldesul-
fonylation/protiodestannylation of the (α-fluoro)vinyl sulfones and stan-
nyldesulfonylation/halodestannylation of the vinyl sulfones procedures al-
lowed synthesis of the various 5ꢁ-deoxy-5ꢁ-(halomethylene)nucleoside ana-
logues derived from uridine,[6] L-adenosine,[7] 3ꢁ-deoxyadenosine,[8] and
6-N-cyclopropyladenosine[9] as well as 5ꢁ-deoxy-5ꢁ-(halomethylene)ribose
derivatives,[10] among others.[11] The vinyl sulfone precursors have been
conveniently prepared by treatment of the nucleoside 2ꢁ-keto or 5ꢁ-aldehyde
derivatives with the sulfonyl-stabilized Wittig reagents.[1,12,13] The chemistry
of the vinyl-sulfone modified carbohydrates and nucleosides has been
reviewed.[14] Sulfur extrusion from nucleosidic vinyl sulfide 3a with trib-
utyltin hydride has been elaborated for the synthesis of the known AdoHcy
hydrolase inhibitors 3c via halodestannylation of the intermediary vinyl stan-
nane 3b.[15] The sequence involving introduction of the alkenes substituted
with F/SO2Ph, F/SnBu3, F/I, F/C, or F/H into the synthesis of fluorovinyl
analogues of amino acids has been developed by Berkowitz.[16,17]
In order to eliminate toxicity factors associated with the necessity of
using tributyltin hydride reagent in a stannyldesulfonylation reaction, we
developed a stereoselective radical-mediated silyl- and germyldesulfony-
lations of vinyl and (α-fluoro)vinyl sulfones with tris(trimethylsilyl)silane
(TTMSS) and germanium hydrides.[18] The germyldesulfonylation protocol
tolerates some functional groups vulnerable to the radical hydrogenolysis
with tributyltin hydride and TTMSS. For example, a chloro substituent was
not affected by the mild conditions required for germyldesulfonylation with
Ph3GeH.[18]

Germane-Containing Nucleosides
539
Chemistry[19] and biological activity of the organogermanium com-
pounds has been reviewed.[20,21] Germanium containing α-aminoacids and
peptides have been incorporated into biologically active decapeptides.[22,23]
The 6-trialkylgermyl-5-fluorouridine derivatives are one of the few known
examples of germanium-containing nucleoside analogues[24] and 5-
trimethylgermyl-2ꢁ-deoxyuridine was showed to inhibit HSV-1 replication in
vitro and blocked incorporation of thymidine into DNA of cancer ovarian
cells.[25] Herein, we report the application of germyldesulfonylation reac-
tions to the synthesis of novel pyrimidine and purine nucleoside analogues
modified in the sugar moieties with vinyl germane functionalities and their
further application towards the synthesis of vinyl halides.
RESULTS AND DISCUSSION
Moffatt oxidation of 2ꢁ,3ꢁ-O-isopropylideneuridine 4a or adeno-
sine 4b and Wittig treatment of the crude 5ꢁ-aldehydes with (p-
toluenesulfony1methylene)triphenylphosphorane gave (E)-vinyl sulfones
5[13] and 6,[12] respectively (Scheme 1). Treatment of the uridine-
derived sulfone 5 with tributylgermane hydrides (AIBN/toluene/ꢀ) ef-
fected stereoselective radical-mediated germyldesulfonylation to give the
5ꢁ-(tributylgermyl)methylene-5ꢁ-deoxyuridine 7a as a single (E)-isomer
ꢁ
ꢁ
(J 5 -6 (trans) = 18.5 Hz) in 57% yield. Adenosine-derived sulfone 6 also under-
went germyldesulfonylation reaction with Bu3GeH to afford the vinyl ger-
mane (E)-8a (46%). The analogous stannyldesulfonylation of 5 and 6 with
Bu3SnH afforded the corresponding (E/Z)-5ꢁ-(tributylstannyl)methylene-
5ꢁ-deoxyuridine[6] and adenosine[3] derivatives in 87% and 61% yields,
respectively. Treatment of 5 and 6 with triphenylgermane hydride gave
(E)-5ꢁ-deoxy-5ꢁ-(triphenylgermyl)methylene nucleosides 7b (72%) and 8b
(42%), respectively. Thus, both purine and pyrimidine nucleosides under-
went desulfonylation with either trialkyl- or triarylgermanes. The yields
were higher for the uridine substrates as was also observed in the case of
the stannyldesulfonylation reactions.[3,6] It is noteworthy that contrary to
the stannyldesulfonylation reactions,[3,6] the germyldesulfonylations of the
vinyl sulfones derived from the sugar modified nucleosides are stereoselec-
tive since the corresponding (Z)-isomers of vinyl germanes 7 or 8 were not
isolated from the crude reaction mixtures. Germyldesulfonylation reactions
presumably occurred via the radical addition-elimination mechanism in
analogy to the silyl- and stannyldesulfonylation processes.[11826]
Stereoselective iododegermylation[27,28] of tributylgermane 7a with
N -iodosuccinimide (NIS) provided the Wittig-type 5ꢁ-deoxy-5ꢁ-
(iodomethylene)uridine (E)-12 (92%). Analogous treatment of
tributylgermane 8a with N -bromosuccinimide (NBS) gave 5ꢁ-deoxy-5ꢁ-
(bromomethylene)adenosine (E)-13 (81%) with retention of the

540
S. F. Wnuk et al.
SCHEME 1 Reagents and conditions: (a) (i) DCC/DMSO/Cl2CHCO2H, (ii) pH3P=CHTs;
(b) Bu3GeH or Ph3GeH/AIBN/PhCH3/heat; (c) NIS or NBS; (d) TFA/H2O; (e)
Bu3GeH/ACCN/HOCH2CH2SH/PhCH3/heat; (f) DMAP/Ac2O; (g) NH3/MeOH.
double-bond geometry.[27,28] It is noteworthy that substitution of the
trialkylgermyl group on a sp2 carbon with a halogen proceeded easier
than the substitution of the corresponding trialkylsilyl group with the
improved stereochemical outcome.[27] Interestingly, treatment of the
triphenylgermanes 7b and 8b with NBS or NIS failed to afford the
corresponding halomethylene nucleosides 12 or 13 resulting instead in
the recovery of the vinyl triphenylgermanes. Also treatment of 7b with
iodine (CH2Cl2/-78◦C to room temperature/14 hours) did not effect
iododegermylations, although iododestannylation of the vinyl triaryltin
2
derivatives is known.[29] Apparently, the strength of the Ge-Csp bond
depends on the nature of the substituents at the germanium atom[19,30]
and the stability of the Csp2-Ge(alkyl)3 bonds is different than that of the
Csp2-Ge(aryl)3 bonds.
Different patterns of reactivity between vinyl triaryl- and trialkylger-
manes were also observed for the protiodegermylation reactions. Thus,
treatment of the tributylgermanes 8a with aqueous trifluoroacetic acid
(TFA) effected simultaneous protiodegermylation and deacetonization
to afford 5ꢁ-deoxy-5ꢁ-methyleneadenosine 14. On the other hand, treat-
ment of the triphenylgermanes 7b with TFA effected only removal of
the isopropylidene protection group yielding germanonucleoside 10b.

Germane-Containing Nucleosides
541
Deprotected trialkylgermane 11b was synthesized using base-labile pro-
tection strategy. Thus, treatment of 2ꢁ,3ꢁ-O-diacetyl sulfone 9b with
Bu3GeH/AIBN provided 11a (49%), while germyldesulfonylation in the
presence of a 2-mercaptoethanol, as a radical carrier,[31,32] and 1,1ꢁ-
azobis(cyclohexanecarbonitrile; ACCN) afforded 11a in 58% yield. Sub-
sequent treatment of 11a with methanolic ammonia effected deacylation
yielding vinyl tributylgermane 11b (72%). The vinyl triphenylgermane 10b
could be also prepared from the sulfone 9b via 10a (65% overall yield)
utilizing the acetyl protection strategy.
Germyldesulfonylation reaction can also be applied for the removal
of the sulfonyl group from the multi-substituted alkenes at C2ꢁ posi-
tion of the nucleosides. Horner-Wittig treatment of the protected 2ꢁ-
ketouridine[33] 15 with sulfonyl-stabilized enolate derived from diethyl
(phenylsulfonyl)methylphosphonate[18] gave vinyl 2ꢁ-phenylsulfone 16 as
a single (Z)-isomer (Scheme 2). The Z stereochemistry was established
using NOESY experiments and was also in agreement with McCarthy’s
work utilizing the fluoro(phenylsulfonyl)methylphosphonate reagent.1 It
is noteworthy that reaction between ketone 15 and sulfonyl-stabilized
ylide, (p-toluenesulfonylmethylene)triphenylphosphorane,[12] failed to give
the analogous p-tolylsulfone. Germyldesulfonylation of 16 with Ph3GeH
afforded 2ꢁ-deoxy-2ꢁ-[(triphenylgermyl)methylene]uridine 17 (51%) as a
single (Z)-isomer. Desilylation of 17 with TBAF gave vinyl germane 18
(73%). Thus, germyldesulfonylation reaction has a general character and
can effect removal of the sulfonyl group from the exomethylene and the
isolated double bonds of the sugar moieties of nucleosides. Treatment of
17 (or 5) with the more reactive tris(trimethylsilyl)germane [(TMS)3GeH]
provided the corresponding vinyl (TMS)3Ge-uridine derivatives but in less
than 15% yields (1H NMR). Therefore, no further efforts were made to
optimize germyldesulfonylation reactions utilizing (TMS)3GeH reagent,
although the vinyl tris(trimethylsilyl)germanes could serve as precursors
for the further modifications via Pd-catalyzed couplings with aryl/alkenyl
halides.[18,34]
SCHEME 2 Reagents and conditions: (a) PhSO2CH2PO(OEt)2/LHMDS/THF; (b) Ph3GeH/
AIBN/PhCH3/heat; (c) TBAF/THF.

542
S. F. Wnuk et al.
In summary, we have developed a radical-mediated germyldesul-
fonylation procedure as a key step for the synthesis of 5ꢁ-deoxy-5ꢁ-
(halomethylene) nucleosides. The method utilizes less toxic germane hy-
drides rather than the previously employed tin hydride reagents. The
novel 5ꢁ-(tributylgermyl)methylene-5ꢁ-deoxyadenosine and uridine deriva-
tives underwent efficient halo- and protiodegermylation reactions while
the triphenyl counterparts were stable under acidic conditions and upon
treatment with NBS or NIS.
EXPERIMENTAL
1H NMR spectra at 400 MHz and 13C NMR at 100.6 MHz were deter-
mined with solutions in CDCl3, and mass spectra (MS) were obtained by
atmospheric pressure chemical ionization (APCI) technique unless noted
otherwise. Reagent grade chemicals were used and solvents were dried by
reflux over and distillation from CaH2 under an argon atmosphere. TLC
was performed on Merck kieselgel 60-F254 and products were detected with
254 nm light. Merck kieselgel 60 (230–400 mesh) was used for column chro-
matography. Germane hydrides were purchased from Aldrich (Milwaukee,
WI, USA) or Gelest (Morrisville, PA, USA) chemical corporations.
1-[6-(Tributylgermyl)-5,6-dideoxy-2,3-O-isopropylidene-β-D-ribo-
hex-5(E)-enofuranosyl]uracil (7a)
A suspension of 5[13] (48 mg, 0.11 mmol) in toluene (2 mL) was
deoxygenated (N2, 1 hour), and then Bu3GeH (49 mg, 0.052 mL, 0.20
mmol) was added. Deoxygenation was continued for 30 minutes, and AIBN
(8.2 mg, 0.05 mmol) was added. The resulting solution was refluxed for 14
hours [additional AIBN (16.4 mg, 0.1 mmol) in degassed toluene (1 mL)
was added to the reaction mixture periodically]. Volatiles were evaporated
(TLC analysis showed a formation of the less polar product) and the residue
was partitioned (CHCl3//H2O/NaHCO3). The organic layer was washed
with brine, dried (MgSO4) and was evaporated. The residue was column
chromatographed [EtOAc/hexane (7:3)] to give 7a (33 mg, 57%) as a
syrup: 1H NMR δ 0.72–0.78 (m, 6H, Bu), 0.84–0.88 (m, 9H, Bu), 1.24–1.33
(m, 12H, Bu), 1.39 (s, 3, CH3), 1.56 (s, 3, CH3), 4.52 (“dd”, J = 4.0, 6.0
Hz, 1, H4ꢁ), 4.69 (dd, J = 4.3, 6.4 Hz, 1, H3ꢁ), 4.92 (dd, J = 2.0, 6.4 Hz,
1, H2ꢁ), 5.70 (dd, J = 1.5, 8.2 Hz, 1, H5), 5.72 (d, J = 2.1 Hz, 1, H1ꢁ),
5.95 (dd, J = 6.3, 18.5 Hz, 1, H5ꢁ), 6.14 (dd, J = 1.1, 18.5 Hz, 1, H6ꢁ), 7.20
(d, J = 8.1 Hz, 1, H6), 8.75 (br s, 1, NH); 13C NMR δ 12.71 (Bu), 13.77
(Bu), 25.37 (CMe2), 26.42 (Bu), 27.15 (CMe2), 27.29 (Bu), 83.99 (C3ꢁ),
84.83 (C2ꢁ), 89.79 (C4ꢁ), 93.47 (C1ꢁ), 102.41 (C5), 114.65 (CMe2), 134.02
(C6ꢁ), 140.60 (C5ꢁ), 141.64 (C6), 149.77 (C2), 162.96 (C4); MS m/z 525

Germane-Containing Nucleosides
543
(100, MH+, 74Ge), 523 (70, MH+, 72Ge), 521 (50, MH+, 70Ge); HRMS calcd
for C25H4374GeN2O5 [M+H]+ 525.2384, found 525.2385.
1-[5,6-Dideoxy-2,3-O-isopropylidene-6-(triphenylgermyl)-β-D-
ribo-hex-5(E)-enofuranosyl]uracil (7b)
Treatment of 5[13](48 mg, 0.11 mmol) with Ph3GeH (60 mg, 0.20 mmol;
as described for 7a) gave 7b (46 mg, 72%) as a foam: 1H NMR δ 1.26 (s, 3,
CH3), 1.50 (s, 3, CH3), 4.61 (ddd, J = 1.2, 4.2, 5.6 Hz, 1, H4ꢁ), 4.71 (dd,
J = 4.1, 6.3 Hz, 1, H3ꢁ), 4.90 (dd, J = 1.9, 6.4 Hz, 1, H2ꢁ), 5.55 (d, J =
8.1 Hz, 1, H5), 5.64 (d, J = 1.9 Hz, 1, H1ꢁ), 6.12 (dd, J = 5.7, 18.3 Hz,
1, H5ꢁ), 6.52 (dd, J = 1.3, 18.3 Hz, 1, H6ꢁ), 7.10 (d, J = 8.1 Hz, 1, H6),
7.26–7.33 (m, 9H, Ph), 7.36–7.42 (m, 6H, Ph), 8.65 (br s, 1, NH); 13C NMR
δ 25.34 & 27.11 (CMe2), 84.14 (C3ꢁ), 84.69 (C2ꢁ), 89.48 (C4ꢁ), 93.92 (C1ꢁ),
102.61 (C5), 114.63 (CMe2), 128.35, 128.53, 129.26, 135.03 (Ph), 135.64
(C6ꢁ), 141.80 (C5ꢁ), 145.00 (C6), 149.75 (C2), 162.99 (C4); MS m/z 585
(100, MH+, 74Ge), 583 (70, MH+, 72Ge), 581 (50, MH+, 70Ge); HRMS calcd
for C31H3174GeN2O5 [M+H]+ 585.1485, found 585.1447.
9-[6-(Tributylgermyl)-5,6-dideoxy-2,3-O-isopropylidene-β-D-
ribo-hex-5(E)-enofuranosyl]adenine (8a)
Treatment of 6[12](50 mg, 0.11 mmol) with Bu3GeH (47 mg, 0.050 mL,
0.19 mmol; as described for 7a) gave 8a (27 mg, 46%) as a syrup: 1H NMR δ
0.66–0.71 (m, 6H, Bu), 0.85–0.89 (m, 9H, Bu), 1.26–1.34 (m, 12H, Bu) 1.42
(s, 3, CH3), 1.62 (s, 3, CH3), 4.71 (dd, J = 3.1, 5.0 Hz, 1, H4ꢁ), 5.02 (dd, J
= 3.1, 6.2 Hz, 1, H3ꢁ), 5.57 (dd, J = 1.8, 6.3 Hz, 1, H2ꢁ), 5.64 (br s, 2, NH2),
5.95 (dd, J = 5.1, 18.6 Hz, 1, H5ꢁ), 6.01 (d, J = 18.5 Hz, 1, H6ꢁ), 6.12 (d,
J = 1.8 Hz, 1, H1ꢁ), 7.88 (s, 1, H2), 8.35 (s, 1, H8); 13C NMR δ 12.69 (Bu),
13.85 (Bu), 26.54 (Bu), 26.63 & 27.26 (CMe2), 27.38 (Bu), 84.70 (C3ꢁ), 85.39
(C2ꢁ), 90.63 (C4ꢁ), 91.27 (C1ꢁ), 114.97 (CMe2), 120.99 (C5), 133.70 (C6ꢁ),
140.89 (C5ꢁ), 142.02 (C8), 150.44 (C4), 154.05 (C2), 156.36 (C6); MS m/z
548 (100, MH+, 74Ge), 546 (70, MH+, 72Ge), 544 (50, MH+, 70Ge); HRMS
calcd for C26H4474GeN5O3 [M+H]+ 548.2656, found 548.2650.
9-[5,6-Dideoxy-2,3-O-isopropylidene-6-(triphenylgermyl)-β-D-
ribo-hex-5(E)-enofuranosyl]adenine (8b)
Treatment of 612(50 mg, 0.11 mmol) with Ph3GeH (57 mg, 0.19 mmol;
as described for 7a) gave 8b (28 mg, 42%) as a foam: 1H NMR δ 1.39 (s, 3,
CH3), 1.62 (s, 3, CH3), 4.83 (ddd, J = 1.3, 3.2, 5.8 Hz, 1, H4ꢁ), 5.09 (dd, J =
3.2, 6.3 Hz, 1, H3ꢁ), 5.55 (dd, J = 1.9, 6.3 Hz, 1, H2ꢁ), 5.61 (br s, 2, NH2),
6.11 (d, J = 1.9 Hz, 1, H1ꢁ), 6.20 (dd, J = 5.9, 18.3 Hz, 1, H5ꢁ), 6.46 (dd, J =
1.4, 18.3 Hz, 1, H6ꢁ), 7.31–7.40 (m, 15H, Ph), 7.85 (s, 1, H2), 8.11 (s, 1, H8);

544
S. F. Wnuk et al.
13C NMR δ 25.44 & 27.11 (CMe2), 84.13 (C3ꢁ), 84.81 (C2ꢁ), 89.75 (C4ꢁ),
90.74 (C1ꢁ), 114.38 (CMe2), 120.13 (C5), 127.96, 128.26, 129.13, 134.95
(Ph), 135.67 (C6ꢁ), 140.03 (C5ꢁ), 145.44 (C8), 149.44 (C4), 153.04 (C2),
155.31 (C6) MS m/z 608 (100, MH+, 74Ge), 606 (68, MH+, 72Ge), 604 (50,
MH+, 70Ge); HRMS calcd for C32H3274GeN5O3 [M+H]+ 608.1717, found
608.1722.
1-[2,3-Di-O-acetyl-5,6-dideoxy-6-(p-toluenesulfonyl)-β-D-
ribo-hex-5(E)-enofuranosyl]uracil (9b)
DMAP (5 mg, 0.04 mmol) was added to a stirred solution of 9a[13]
(80 mg, 0.18 mmol) in Ac2O (4 mL) at ambient temperature. After 14
hours, MeOH (10 mL) was added and stirring was continued for 1 hour.
Volatiles were evaporated and the residue was co-evaporated with MeOH (2
× 5 mL). The crude product was partitioned (CHCl3//H2O/HCl) and the
organic layer was washed with NaHCO3/H2O, brine, dried (MgSO4) and
was evaporated to give 9b (83 mg, 96%) of sufficient purity to be used in
next step: 1H NMR δ 2.05 (s, 3H, Ac), 2.08 (s, 3H, Ac), 2.38 (s, 3, CH3), 4.64
(ddd, J = 1.6, 4.6, 6.0 Hz, 1, H4ꢁ), 5.24 (t, J = 6.1 Hz, 1, H3ꢁ), 5.36 (t, J = 5.5
Hz, 1, H2ꢁ), 5.70 (d, J = 8.1 Hz, 1, H5), 5.86 (d, J = 4.8 Hz, 1, H1ꢁ), 6.62 (dd,
J = 1.6, 15.1 Hz, 1, H6ꢁ), 6.98 (dd, J = 4.4, 15.1 Hz, 1, H5ꢁ), 7.18 (d, J = 8.1
Hz, 1, H6), 7.28 (d, J = 8.2 Hz, 2H, Ar), 7.71 (d, J = 8.3 Hz, 2H, Ar), 9.45
(br s, 1, NH); 13C NMR δ 20.39 (2×) & 21.65 (CH3 & 2 × Ac), 72.16 (C3ꢁ),
72.39 (C2ꢁ), 79.17 (C4ꢁ), 89.35 (C1ꢁ), 103.68 (C5), 127.94 (Ar), 129.78 (Ar),
133.33 (C6ꢁ), 136.47 (Ar), 138.66 (C5ꢁ), 140.21 (C6), 145.01 (Ar), 149.98
(C2), 162.67 (C4), 169.44 & 169.58 (2 × Ac); MS m/z 479 (100, MH+).
1-[2,3-Di-O-acetyl-5,6-dideoxy-6-(triphenylgermyl)-β-D-
ribo-hex-5(E)-enofuranosyl]uracil (10a)
Treatment of 9b (90 mg, 0.19 mmol) with Ph3GeH (104 mg, 0.34 mmol;
as described for 7a) gave 10a (81 mg, 68%) as an amorphous solid: 1H NMR
δ 2.09 (s, 3H, Ac), 2.11 (s, 3H, Ac), 4.66 (ddd, J = 1.5, 5.2, 5.4 Hz, 1, H4ꢁ),
5.27 (t, J = 5.2 Hz, 1, H3ꢁ), 5.32 (t, J = 5.4 Hz, 1, H2ꢁ), 5.65 (d, J = 8.1 Hz, 1,
H5), 6.10 (d, J = 5.1 Hz, 1, H1ꢁ), 6.17 (dd, J = 5.4, 18.3 Hz, 1, H5ꢁ), 6.73 (dd,
J = 1.4, 18.3 Hz, 1, H6ꢁ), 7.18 (d, J = 8.2 Hz, 1, H6), 7.37–7.43 (m, 9H, Ph),
7.45–7.50 (m, 6H, Ph), 8.98 (br s, 1, NH); 13C NMR δ 20.43 & 20.54 (2 ×
Ac), 72.55 (C2ꢁ), 72.96 (C3ꢁ), 83.18 (C4ꢁ), 87.43 (C1ꢁ), 103.47 (C5), 128.48,
129.44, 134.96, 135.21 (Ph), 131.02 (C6ꢁ), 139.34 (C6), 142.87 (C5ꢁ), 150.22
(C2), 162.63 (C4), 169.61 (2 × Ac); MS m/z 629 (100, MH+, 74Ge), 627
(70, MH+, 72Ge), 625 (50, MH+, 70Ge); HRMS calcd for C32H3174GeN2O7
[M+H]+ 629.1343, found 629.1335.

Germane-Containing Nucleosides
545
1-[5,6-Dideoxy-6-(triphenylgermyl)-β-D-ribo-hex-5(E)-
enofuranosyl]uracil (10b)
Method A. A solution of 10a (32 mg, 0.05 mmol) in NH3/MeOH (2
mL) was stirred at ∼0◦C for 2 hours, and was evaporated and co-evaporated
(MeOH). The residue was column chromatographed (EtOAc/hexane, 4:1)
to give 10b (26 mg, 96%) as a white powder: 1H NMR δ 4.01 (t, J = 5.5 Hz, 1,
H3ꢁ), 4.19 (dd, J = 3.5, 5.0 Hz, 1, H2ꢁ), 4.62 (“t”, J = 5.5 Hz, 1, H4ꢁ), 5.20 (br
s, 2, 2 × OH), 5.58 (d, J = 8.1 Hz, 1, H5), 5.82 (d, J = 3.2 Hz, 1, H1ꢁ), 6.20
(dd, J = 5.3, 18.4 Hz, 1, H5ꢁ), 6.71 (dd, J = 1.4, 18.3 Hz, 1, H6ꢁ), 7.32–7.46
(m, 16H, Ph & H6), 8.92 (br s, 1, NH); 13C NMR δ 73.82 (C3ꢁ), 75.10 (C2ꢁ),
85.81 (C4ꢁ), 91.11 (C1ꢁ), 102.52 (C5), 128.43, 128.87, 130.98, 134.85 (Ph),
136.36 (C6ꢁ), 139.54 (C6), 144.29 (C5ꢁ), 151.21 (C2), 163.69 (C4); MS m/z
545 (100, MH+, 74Ge), 543 (75, MH+, 72Ge), 541 (45, MH+, 70Ge); HRMS
calcd for C28H2774GeN2O5 [M+H]+ 545.1132, found 545.1132.
Method B. A solution of 7b (29 mg, 0.05 mmol) in TFA/H2O (9:1,
1.5 mL) was stirred at ∼0◦C for 1 hour. The volatiles were evaporated,
co-evaporated (3×) with toluene and the residue was column chro-
matographed (EtOAc) to give 10b (18 mg, 66%) with data identical as
above.
1-[2,3-Di-O-acetyl-6-(tributylgermyl)-5,6-dideoxy-β-D-ribo
-hex-5-(E)-enofuranosyl]uracil (11a)
Method A. Treatment of 9b (39 mg, 0.08 mmol) with Bu3GeH (39 mg,
0.041 mL, 0.16 mmol; as described for 7a) gave 11a (22 mg, 49%) as a foam:
1H NMR δ 0.78–0.92 (m, 15H, Bu), 1.26–1.38 (m, 12H, Bu), 2.08 (s, 3H, Ac),
2.10 (s, 3H, Ac), 4.52 (“t”, J = 5.5 Hz, 1, H4ꢁ), 5.22 (t, J = 5.3 Hz, 1, H3ꢁ),
5.30 (t, J = 5.4 Hz, 1, H2ꢁ), 5.75 (d, J = 8.1 Hz, 1, H5), 5.95 (dd, J = 5.7, 18.5
Hz, 1, H5ꢁ), 6.02 (d, J = 5.2 Hz, 1, H1ꢁ), 6.26 (dd, J = 1.2, 18.5 Hz, 1, H6ꢁ),
7.26 (d, J = 8.1 Hz, 1, H6), 8.27 (s, 1, NH); 13C NMR δ 12.71 (Bu), 13.73
(Bu), 26.35 (Bu), 27.32 (Bu), 20.42 & 20.49 (2 × Ac), 72.78 (C3ꢁ), 72.91
(C2ꢁ), 83.57 (C4ꢁ), 87.73 (C1ꢁ), 103.24 (C5), 135.65 (C6ꢁ), 138.84 (C5ꢁ),
139.50 (C6), 149.89 (C2), 162.27 (C4); 169.56 & 169.57 (2 × Ac); MS m/z
569 (100, MH+, 74Ge), 567 (72, MH+, 72Ge), 565 (51, MH+, 70Ge); HRMS
calcd for C26H4374GeN2O7 [M+H]+ 569.2282, found 569.2289.
Method B. A suspension of 9b (29 mg, 0.06 mmol) in toluene (4 mL)
was degassed (N2, 1 hour), and then Bu3GeH (29 mg, 0.031 mL, 0.12 mmol)
was added and deoxygenation was continued for an additional 1 hour. The
2-mercaptoethanol (2 mg, 2 µL, 0.02 mmol) and ACCN (14.5 mg, 0.06
mmol) were added and the resulting solution was refluxed for 20 hours.
The aqueous work-up and column chromatography (as described for 7a)
gave 11a (20 mg, 58%) with data as reported above.

546
S. F. Wnuk et al.
1-[6-(Tributylgermyl)-5,6-dideoxy-β-D-ribo-hex-5-(E)-
enofuranosyl]uracil (11b)
Treatment of 11a (23 mg, 0.04 mmol) with NH3/MeOH (2 mL; as
1
described for 10a) gave 11b (14 mg, 72%) as a white powder: H NMR
(MeOH-d4) δ 0.83–0.97 (m, 15H, Bu), 1.30–1.46 (m, 12H, Bu), 3.96 (“t”,
J = 5.7 Hz, 1, H3ꢁ), 4.18 (dd, J = 3.8, 5.3 Hz, 1, H2ꢁ), 4.35 (t, J = 5.8 Hz,
1, H4ꢁ), 5.69 (d, J = 8.1 Hz, 1, H5), 5.83 (d, J = 3.8 Hz, 1, H1ꢁ), 6.11 (dd,
J = 5.3, 18.5 Hz, 1, H5ꢁ), 6.20 (d, J = 18.6 Hz, 1, H6ꢁ), 7.55 (d, J = 8.1 Hz,
1, H6); 13C NMR (MeOH-d4) δ 13.71 (Bu), 14.09 (Bu), 27.46 (Bu), 28.56
(Bu), 75.12 & 75.13 (C2ꢁ/3ꢁ), 87.08 (C4ꢁ), 92.09 (C1ꢁ), 102.78 (C5), 133.15
(C6ꢁ), 142.39 (C5ꢁ), 143.20 (C6), 152.22 (C2), 166.08 (C4); MS m/z 485
(100, MH+, 74Ge), 483 (77, MH+, 72Ge), 481 (52, MH+, 70Ge); HRMS calcd
for C22H3974GeN2O5 [M+H]+ 485.2071, found 485. 2065.
1-[5,6-Dideoxy-6-iodo-2,3-O-isopropylidene-β-D-ribo-hex- 5(E)-
enofuranosyl]uracil (12)
A solution of NIS (22 mg, 0.10 mmol) in CHCl3/CH2Cl2 (1:1, 5 mL)
was added dropwise to a stirred solution of 7a (48 mg, 0.09 mmol) in
CHCl3/CH2Cl2 (1:1, 5 mL) at 0◦C. After 1 hour (TLC showed exclusive
formation of a more polar product), the pink reaction mixture was treated
with NaHSO3/H2O and the separated organic layer was washed with brine,
dried (MgSO4) and was evaporated. Purification on a short silica gel column
(CHCl3/MeOH, 30:1) gave 12 (34 mg, 92%) with data as reported.6
9-[6-Bromo-5,6-dideoxy-2,3-O-isopropylidene-β-D-ribo-hex-
5(E)-enofuranosyl]adenine (13)
A solution of NBS (18 mg, 0.10 mmol) in CHCl3/CH2Cl2 (1:1, 5 mL)
was added dropwise to a stirred solution of 8a (50 mg, 0.09 mmol) in
CHCl3/CH2Cl2 (1:1, 5 mL) at 0◦C. After 6 hours, the reaction mixture
was washed with NaHCO3/H2O and brine and the separated organic layer
was dried (Na2SO4) and was evaporated. Purification on a short silica gel
column (CHCl3/MeOH, 20:1) gave 13 (28 mg, 81%) with data as reported.3
9-(5,6-Dideoxy-β-D-ribo-hex-5-enofuranosyl)adenine
[5ꢁ-deoxy-5ꢁ-methyleneadenosine] (14)
A solution of 8a (22 mg, 0.04 mmol) in CF3CO2H/H2O (9:1, 1 mL)
was stirred at 0◦C for 1 hour. The volatiles were evaporated and the
residue was co-evaporated (2×) with toluene. The residue was column
chromatographed (1 → 5% MeOH/EtOAc) to give 14[3,12] (8 mg, 76%):
1H NMR (MeOH-d4) δ 4.25 (t, J = 5.1 Hz, 1, H3ꢁ), 4.48 (dd, J = 5.3, 6.5 Hz,
1, H4ꢁ), 4.74 (t, J = 4.9 Hz, 1, H2ꢁ), 5.26 (“dt”, J = 1.4, 10.5 Hz, 1, H6”), 5.41

Germane-Containing Nucleosides
547
(“dt”, J = 1.5, 17.1 Hz, 1, H6ꢁ), 6.04 (d, J = 5.0 Hz, 1, H1ꢁ), 6.11 (“ddd”, J =
6.6, 10.5, 17.1 Hz, 1, H5ꢁ), 8.23 (s, 1, H2), 8.26 (s, 1, H8).
2ꢁ-Deoxy-3ꢁ,5ꢁ-O-(1,1,3,3-tetraisopropyl-1,3-disiloxanyl)-2ꢁ
-[(phenylsulfonyl)methylene]uridine [16(Z)]
Lithium bis(trimethylsilyl)amide (1 M/THF; 0.18 mL, 0.18
mmol) was added dropwise to
a
stirred solution of diethyl
(phenylsulfonyl)methylphosphonate[18] (53 mg, 0.18 mmol) in THF
(2 mL) at -78◦C under nitrogen. After 30 minutes, ketone 15[33] (78 mg,
0.16 mmol) was added and the resulting solution was allowed to warm up
to -30◦C over 2 hours and then to ∼0◦C over 15 minutes. NH4Cl/H2O
(0.5 mL) was added and the volatiles were evaporated. The residue was
partitioned (CHCl3//H2O/NaHCO3) and the organic layer was washed
with brine, dried (MgSO4) and was evaporated. Column chromatography
(30 → 40% EtOAc/hexane) gave 16 (62 mg, 62%) as a pale-yellow powder:
1H NMR δ 0.97–1.05 (m, 28H, 4 × i-Pr), 3.62 (ddd, J = 3.0, 4.2, 8.7 Hz,
1, H4ꢁ), 3.99 (dd, J = 3.0, 12.8 Hz, 1, H5ꢁ), 4.06 (dd, J = 4.2, 12.8 Hz, 1,
H5ꢁꢁ), 5.35 (dt, J = 2.1, 8.5 Hz, 1, H3ꢁ), 5.70 (d, J = 8.0 Hz, 1, H5), 6.43
(“t”, J = 1.8 Hz, 1, H1ꢁ), 6.48 (“t”, J = 2.3 Hz, 1, H2”), 7.27 (d, J = 8.1 Hz,
1, H6), 7.51 (“t”, J = 7.4 Hz, 2H, Ph), 7.60 (“tt”, J = 1.3, 7.4 Hz, 1H, Ph),
7.68 (“dd”, J = 1.4, 7.1 Hz, 2H, Ph), 8.30 (s, 1, NH); 13C NMR δ 12.58 (CH),
16.86, 16.94, 17.05, 17.13, 17.20, 17.21, 17.23, 17.35 (CH3), 61.21 (C5ꢁ),
73.02 (C3ꢁ), 81.38 (C4ꢁ), 85.83 (C1ꢁ), 102.06 (C5), 124.17 (C2”), 126.57,
129.56, 134.02, 140.57 (Ph), 145.08 (C6), 148.65 (C2), 156.65 (C2ꢁ), 162.91
(C4); MS m/z 623 (100, MH+).
2ꢁ-Deoxy-3ꢁ,5ꢁ-O-(1,1,3,3-tetraisopropyl-1,3-disiloxanyl)-2ꢁ-
[(triphenylgermyl)methylene]uridine [17(Z)]
Treatment of 16 (43 mg, 0.07 mmol) with Ph3GeH (40 mg, 0.13 mmol;
1
as described for 7a) gave 17 (28 mg, 51%) as a white powder: H NMR δ
0.91–0.97 (m, 24H, 8 × CH3), 1.03 (s, 4H, 4 × CH), 3.50 (dt, J = 3.2, 8.7
Hz, 1, H4ꢁ), 3.86 (dd, J = 3.2, 12.1 Hz, 1, H5ꢁ), 3.91 (dd, J = 3.6, 12.1
Hz, 1, H5ꢁꢁ), 4.88 (“dt”, J = 2.2, 8.4 Hz, 1, H3ꢁ), 5.15 (d, J = 8.1 Hz, 1,
H5), 5.83 (t, J = 1.7 Hz, 1, H1ꢁ), 6.29 (d, J = 8.1 Hz, 1, H6), 6.77 (t, J =
2.1 Hz, 1, H2”), 7.20–7.26 (m, 9H, Ph), 7.30–7.36 (m, 6H, Ph), 8.28 (s, 1,
NH); 13C NMR δ 12.60, 12.66, 13.05, 13.65 (CH), 16.92, 17.02, 17.22, 17.24,
17.27, 17.31, 17.36 (CH3), 61.31 (C5ꢁ), 73.50 (C3ꢁ), 82.12 (C4ꢁ), 85.37 (C1ꢁ),
102.24 (C5), 122.63 (C2”), 128.62, 129.53, 134.63, 135.29 (Ph), 141.17 (C6),
149.03 (C2), 155.27 (C2ꢁ), 162.21 (C4); MS m/z 787 (50, MH+, 74Ge), 785
(35, MH+, 72Ge), 783 (25, MH+, 70Ge); HRMS calcd for C40H5374GeN2O6Si2
[M+H]+ 787.2654, found 787.2663.

548
S. F. Wnuk et al.
2ꢁ-Deoxy-2ꢁ-[(triphenylgermyl)methylene]uridine [18(Z)]
Bu4NF (1 M/THF, 0.12 mL, 0.12 mmol) was added to a solution of 17
(31 mg, 0.04 mmol) in THF (2 mL) and the resulting mixture was stirred at
∼0◦C for 3 hours. Volatiles were evaporated and the residue was partitioned
between diethyl ether and water. The aqueous layer was evaporated and the
oily residue was column chromatographed (EtOAc) to give 18 (16 mg, 73%)
1
as an amorphous solid: H NMR (MeOH-d4) δ 3.66–3.73 (m, 2, H4ꢁ,5ꢁ),
3.83–3.89 (m, 1, H5”), 4.77 (dt, J = 2.2, 8.0 Hz, 1, H3ꢁ), 5.32 (d, J = 8.0
Hz, H5), 6.14 (t, J = 1.7 Hz, 1, H1ꢁ), 6.86 (t, J = 2.2 Hz, 1, H2”), 7.04 (d, J
= 8.0 Hz, 1, H6), 7.37–7.43 (m, 9H, Ph), 7.49–7.52 (m, 6H, Ph); 13C NMR
(MeOH-d4) δ 62.33 (C5ꢁ), 73.43 (C3ꢁ), 85.44 (C4ꢁ), 86.93 (C1ꢁ), 102.93 (C5),
124.67 (C2”), 129.65, 130.54, 135.76, 136.76 (Ph), 143.85 (C6), 151.61 (C2),
159.02 (C2ꢁ), 166.01 (C4); MS m/z 545 (50, MH+, 74Ge), 543 (35, MH+,
72Ge), 541 (25, MH+, 70Ge); HRMS (ESI) calcd for C28H2674GeN2NaO5
[M+Na]+ 567.0951, found 567.0960.
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